Preparation and application of macrocyclic compound

Abstract

The invention relates to a RAS inhibitor compound shown in a formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the RAS inhibitor compound or the stereoisomer or the pharmaceutically acceptable salt thereof, and application of the RAS inhibitor compound or the stereoisomer or the pharmaceutically acceptable salt in preparation of drugs for preventing or treating RAS-mediated diseases.

Description

[0001] Cross-references to related applications

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

[0003] Patent application No. 202411174590.X was filed with the State Intellectual Property Office on August 26, 2024. Technical Field

[0004] This disclosure pertains to the field of pharmaceutical technology, specifically relating to macrocyclic compounds or stereoisomers of RAS inhibitors or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and their use as RAS inhibitors in the prevention or treatment of related diseases. Background Technology

[0005] The KRAS gene (Kirsten Rat Sarcoma Viral Oncogene Homolog) belongs to the RAS gene family (RAS is the first human oncogene discovered, among the KRAS gene family, there are also NRAS (Neuroblastoma-RAS) and HRAS (Harvey-RAS)), located on chromosome 12, involved in intracellular signal transduction. The KRAS gene encodes a KRAS protein, which is a small GTPase belonging to the RAS superfamily of proteins, the KRAS protein has 188 amino acids and a molecular weight of 21.6KD. KRAS is in an activated state when bound to GTP, and in a closed state when bound to GDP. KRAS protein is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) to be in an activated and inactivated state. The activated KRAS protein mainly activates downstream signaling pathways such as the PI3K-AKT-mTOR signaling pathway that controls cell generation, and the RAS-RAF-MEK-ERK signaling pathway that controls cell proliferation. Most small molecule drugs work by binding to functionally important pockets on target proteins, thereby modulating the activity of the protein. For example, cholesterol-lowering drugs called statins bind to the enzyme active site of HMG-CoA reductase, thereby preventing the enzyme from binding to its substrate. In fact, the knowledge of many such drug / target pairs can mislead one into believing that small molecule modulators can be found for most, if not all, proteins, and thus provide a reasonable amount of time, effort, and resources. This is not the case, and currently, it is estimated that only about 10% of all human proteins can be targeted by small molecules, the remaining 90% are currently considered to be small molecule drug discovery difficult to cure or difficult to handle as mentioned above. Such targets are often referred to as “undruggable”. A large portion of these undruggable targets or medically important human proteins have not yet been studied with a compound library. Therefore, there is a great interest in finding novel molecules that can modulate the function of such undruggable targets. Given the importance of the RAS signaling pathway in tumor therapy, targeted therapy against the RAS signaling pathway has become a research hotspot in the field of tumor therapy in recent years. The present disclosure finds a class of heterocyclic compounds, which have good killing effect on different RAS mutations and RAS protein-dependent tumors, and can treat RAS mutation-mediated tumors. SUMMARY

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

[0007]

[0008] in,

[0009] X 1 and X 2 Each is independently selected from N and C;

[0010] L is selected from imino, 4-10 heterocyclic sub-heterocyclic groups, C6-C 10 arylene and 5-12-membered heteroarylene, wherein the imino, 4-10-membered heterocyclic group, C6-C 10 arylene and 5-12 heteroarylene are optionally enclosed by one or more R L replace;

[0011] A is selected from C3-C 12 Cycloalkylene, 4-10 membered heterocyclic alkylene, C6-C 10 arylene and 5-12-membered heteroarylene, the C3-C 12 Cycloalkylene, 4-10 membered heterocyclic alkylene, C6-C 10 arylene and 5-12 heteroarylene are optionally enclosed by one or more R a replace;

[0012] R 1 Selected from C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-12 heteroaryl, the C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-12 heteroaryl groups are optionally bounded by one or more R groups. 1a replace;

[0013] R 2 R 3 R 7 R 8 and R 9 Independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl groups and C3-C7 cycloalkyl groups;

[0014] Or, R 2 and R 3The atoms attached to the cycloalkyl group and the 4-6-membered heterocyclic group together form a C3-C6 cycloalkyl group and a 4-6-membered heterocyclic group, wherein the C3-C6 cycloalkyl group and the 4-6-membered heterocyclic group are optionally connected by one or more R groups. b replace;

[0015] R 4 Selected from: non-existent, hydrogen, halogen, hydroxyl, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 Alkyl, the C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 Alkyl groups are optionally surrounded by one or more R 4a replace;

[0016] Or, R 4 and R 7 The atoms connected to it together form a 4-10 membered heterocycle, which is optionally bounded by one or more R atoms. k replace;

[0017] R 5 Selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl, the C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one or more R groups. 5a Substitution, and when the heteroatom is N, N can be optionally oxidized ( + NO - );

[0018] R 6 Selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy;

[0019] R 10 Selected from halogens, C2-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Hydroxyl-substituted alkyl and C1-C 10 Alkoxy;

[0020] Each R a R b and R L Independently selected from halogens, amino groups, hydroxyl groups, mercapto groups, cyano groups, oxo groups, and C1-C4 alkyl groups;

[0021] Each R 1a Independently selected from halogen, amino, hydroxyl, mercapto, cyano, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-12 heteroaryl, the C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-12 heteroaryl groups are optionally substituted with one or more R groups. 1aa replace;

[0022] Each R 4a and R k Independently selected from halogen, amino, hydroxyl, mercapto, cyano, C1-C7 alkyl, C1-C7 haloalkyl and C1-C7 alkoxy;

[0023] Each R 5a Independently selected C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-14 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl, the C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 4-14 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one or more R groups. c replace;

[0024] Each R c Independently selected from halogen, amino, hydroxyl, mercapto, cyano, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl and 4-12 membered heterocyclic groups, wherein the amino, hydroxyl, mercapto, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl groups and 4-12 membered heterocyclic groups are optionally surrounded by one or more R groups. h replace;

[0025] R 5b and R 5b’ Independently selected from C1-C7 alkyl groups, C3-C 12 Cycloalkyl, 4-12 membered heterocyclic, C6-C10 aryl and 5-10 heteroaryl, wherein the C1-C7 alkyl, C3-C 12 Cycloalkyl, 4-12 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally coated with one or more R groups. d replace;

[0026] Or, R 5b and R 5b’ The atoms connected to it together form a 4-12 membered heterocyclic group, wherein the 4-12 membered heterocyclic group is optionally bounded by one or more R atoms. e replace;

[0027] Each R d and R e The radical is independently selected from halogen, hydroxyl, amino, C1-C7 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and 4-10 membered heterocyclic groups, wherein the amino, C1-C7 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and 4-10 membered heterocyclic groups are optionally surrounded by one or more R... f replace;

[0028] Each R f Independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and 4-10 membered heterocyclic groups, wherein the C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and 4-10 membered heterocyclic groups are optionally surrounded by one or more R... g replace;

[0029] Each R g and R h Independently selected from halogens, hydroxyl groups, mercapto groups, amino groups, =O, C1-C4 alkyl groups, C1-C4 hydroxyalkyl groups, C1-C4 haloalkyl groups, C3-C6 cycloalkyl groups, 4-10 membered heterocyclic groups, C1-C4 alkylene groups, C1-C4 alkyl groups, and C1-C4 alkoxy groups;

[0030] Each R 1aa Independently selected from halogen, amino, hydroxyl, mercapto, and cyano groups;

[0031] n is a natural number selected from 1 to 6;

[0032] One or more hydrogen atoms in the compound of formula (I) may be selected as deuterium atoms.

[0033] In some implementation schemes, X 1 The answer is C.

[0034] In some implementation schemes, X 1 Let N be the number of elements in the array.

[0035] In some implementation schemes, X 2 Let N be the number of elements in the array.

[0036] In some implementation schemes, X 1 Let C be the integer, and X be the inverse. 2 Let N be the number of elements in the array.

[0037] In some implementation schemes, X 1 Let N be the number of elements, and X be the number of elements. 2 The answer is C.

[0038] In some implementations, A is selected from 4-10 membered heterocyclic groups, C6-C 10 arylene and 5-12-membered heteroarylene, the 4-10-membered heterocyclic group, C6-C 10 arylene and 5-12 heteroarylene are optionally enclosed by one or more R a replace.

[0039] In some embodiments, A is selected from 5-6-membered heterocyclic groups, phenylene, and 5-6-membered heterocyclic groups, wherein the 5-6-membered heterocyclic group, phenylene, and 5-6-membered heterocyclic group are optionally surrounded by one or more R groups. a replace.

[0040] In some embodiments, A is selected from imidazolyl, phenylene, and morpholinoyl, wherein the imidazolyl, phenylene, and morpholinoyl groups are optionally surrounded by one or more R groups. a replace.

[0041] In some implementation schemes, A is selected from The Optional by one or more R a replace.

[0042] In some implementation schemes, each R a It is independently selected from halogen, amino, hydroxyl, mercapto and cyano groups.

[0043] In some implementation schemes, R a It is a hydroxyl group.

[0044] In some implementation schemes, A is selected from

[0045] In some implementations, A is selected from those arbitrarily assigned to R. a Replacement

[0046] In some implementation schemes, A is

[0047] In some implementation schemes, A is The asterisk (*) represents the end connected to the benzene ring.

[0048] In some implementations, L is selected from imino, and 4-10-membered heterocyclic groups, wherein the imino and 4-10-membered heterocyclic groups are optionally surrounded by one or more R L replace.

[0049] In some implementations, L is selected from imino, and a 5-6 membered heterocyclic group, wherein the imino and the 5-6 membered heterocyclic group are optionally surrounded by one or more R L replace.

[0050] In some implementations, L is selected from imino, and a 5-membered nitrogen-containing heterocyclic group, wherein the imino group and the 5-membered nitrogen-containing heterocyclic group are optionally surrounded by one or more R L replace.

[0051] In some implementation schemes, each R L It is independently selected from halogens, hydroxyl groups, oxo groups, and C1-C4 alkyl groups.

[0052] In some implementations, L is selected from imino,

[0053] In some implementations, L is

[0054] In some implementations, L is Where # represents R 1 Connecting end.

[0055] In some implementation schemes, R 1 Selected from C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups and 5-12 membered heteroaryl groups, wherein the C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-10-membered heterocyclic and 5-12-membered heteroaryl groups are optionally surrounded by one or more R groups. 1a replace.

[0056] In some implementation schemes, R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic and 5-10-membered heteroaryl groups, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic and 5-10-membered heteroaryl groups are optionally surrounded by one or more R groups. 1a replace.

[0057] In some implementation schemes, R 1 Selected from C3-C6 cycloalkyl groups, wherein the C3-C6 cycloalkyl group is optionally surrounded by one or more R groups. 1a replace.

[0058] In some implementation schemes, R 1Selected from methyl, cyclopropyl, cyclopentyl, tetrahydropyrrolyl, isopropyl, pentyl, oxadiazolyl and The methyl, cyclopropyl, cyclopentyl, tetrahydropyrrolyl, isopropyl, pentyl, oxadiazolyl and Optionally by one or more R 1a replace.

[0059] In some implementation schemes, R 1 Selected from one or more R 1a Substituted cyclopropyl group.

[0060] In some implementation schemes, R 1 Selected from methyl, cyclopropyl, cyclopentyl, Isopropyl, The methyl, cyclopropyl, cyclopentyl, Isopropyl, Optionally by one or more R 1a replace.

[0061] In some implementation schemes, each R 1a Independently selected from halogens, C1-C 10 Alkyl and C3-C 10 cycloalkyl, the C1-C 10 Alkyl and C3-C 10 cycloalkyl groups are optionally surrounded by one or more R 1aa replace.

[0062] In some implementation schemes, each R 1a Independently selected from halogens, C1-C4 alkyl groups and C3-C4 alkyl groups. 10 Cycloalkyl, the C1-C4 alkyl and C3-C 10 cycloalkyl groups are optionally surrounded by one or more R 1aa replace.

[0063] In some implementation schemes, each R 1a Independently selected from C1-C4 alkyl groups, wherein the C1-C4 alkyl group is optionally surrounded by one or more R... 1aa replace.

[0064] In some implementation schemes, each R 1a The groups are independently selected from fluorine, methyl, pentyl, cyclopropyl, and cyclopentyl, wherein the methyl, pentyl, cyclopropyl, and cyclopentyl groups are optionally surrounded by one or more R groups. 1aa replace.

[0065] In some implementation schemes, each R 1a Independent selection by one or more R 1aa Substituted methyl group.

[0066] In some implementation schemes, each R 1aa It is independently selected from halogens.

[0067] In some implementation schemes, each R 1a It is a methyl group.

[0068] In some implementation schemes, R 1 for

[0069] In some implementation schemes, R 1 for

[0070] In some implementation schemes, R 2 R 3 Independently selected from hydrogen, halogen, hydroxyl, cyano and C1-C 10 alkyl.

[0071] In some implementation schemes, R 2 R 3 It is independently selected from C1-C4 alkyl groups, such as methyl.

[0072] In some implementation schemes, R 2 R 3 All are methyl groups.

[0073] In some implementation schemes, R 2 and R 3 The atoms connected to it together form a C3-C6 cycloalkyl group, which is optionally bound by one or more R atoms. b replace.

[0074] In some implementation schemes, R 2 and R 3 The cyclobutyl group and its connected atoms together form a cyclobutyl group, which is optionally bound by one or more R atoms. b replace.

[0075] In some implementation schemes, each R b It is independently selected from halogens, hydroxyl groups, and C1-C4 alkyl groups.

[0076] In some implementation schemes, R 2 and R 3 Together with the atoms they are attached to, they form a cyclobutyl group.

[0077] In some implementation schemes, R 4 Selected from hydrogen, halogen, hydroxyl, cyano, C1-C 10 Alkyl and C1-C 10 Halogenated alkyl groups.

[0078] In some implementation schemes, R 4Selected from C1-C4 alkyl and C1-C4 haloalkyl.

[0079] In some implementation schemes, R 4 Selected from ethyl and halogen-substituted ethyl groups.

[0080] In some implementation schemes, R 4 Selected from ethyl and fluorinated ethyl groups, such as trifluoroethyl.

[0081] In some implementation schemes, R 4 It is an ethyl group.

[0082] In some implementation schemes, R 5 Selected from 4-10-membered heterocyclic groups and 5-10-membered heteroaryl groups, wherein the 4-10-membered heterocyclic group and the 5-10-membered heteroaryl group are optionally surrounded by one or more R groups. 5a replace.

[0083] In some implementation schemes, R 5 Selected from 4-10-membered heterocyclic groups and 5-6-membered heteroaryl groups, wherein the 4-10-membered heterocyclic group and the 5-6-membered heteroaryl group are optionally surrounded by one or more R groups. 5a replace.

[0084] In some implementation schemes, R 5 Selected from pyridyl, thiophenyl, pyrazolyl, and tetrahydroindoleazine, wherein the N in the pyridyl group is optionally oxidized ( + NO - The pyridyl, thiophene, pyrazolyl, and tetrahydroindoleazine groups are optionally surrounded by one or more R groups. 5a replace.

[0085] In some implementation schemes, R 5 The group is selected from pyridyl, thiophene, pyrazolyl, and tetrahydroindoleazine, wherein the pyridyl, thiophene, pyrazolyl, and tetrahydroindoleazine are optionally surrounded by one or more R groups. 5a replace.

[0086] In some implementation schemes, R 5 Selected from The Optionally by one or more R 5a replace.

[0087] In some implementation schemes, R 5 for N can be oxidized to form The Optionally by one or more R 5a replace.

[0088] In some implementation schemes, R 5To be optionally controlled by one or more R 5a Replacement

[0089] In some implementation schemes, each R 5a Independently selected from C1-C 10 Alkyl, C2-C 10 alkynyl group, C1-C 10 Alkoxy groups and 4-14 membered heterocyclic groups, C6-C 10 Aryl and 5-10 heteroaryl, the C1-C 10 Alkyl, C2-C 10 alkynyl group, C1-C 10 Alkoxy groups and 4-14 membered heterocyclic groups, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one or more R groups. c replace.

[0090] In some implementation schemes, each R 5a Independently selected from C1-C4 alkyl, C2-C4 alkynyl, C1-C4 alkoxy, C6-C 10 Aryl and 4-10 membered heterocyclic groups, wherein the C1-C4 alkyl, C2-C4 alkynyl, C1-C4 alkoxy, C6-C 10 The aryl group and the 4-10 heterocyclic group are optionally separated by one or more R groups. c replace.

[0091] In some implementation schemes, each R 5a Independently selected from piperazinyl, piperidinyl, pyrimidinyl, propynyl, methoxy, ethyl, ethoxy, isopropyl, phenyl, The piperazinyl, piperidinyl, pyrimidinyl, propynyl, methoxy, ethyl, ethoxy, isopropyl, phenyl, Optionally by one or more R c replace.

[0092] In some implementation schemes, each R 5a Independently selected from piperazinyl, piperidinyl, pyrimidinyl, propynyl, methoxy, ethyl, ethoxy, isopropyl, phenyl and The piperazinyl, piperidinyl, pyrimidinyl, propynyl, methoxy, ethyl, ethoxy, isopropyl, phenyl and Optionally by one or more R c replace.

[0093] In some implementation schemes, each R 5a Independently selected from piperazine and ethyl groups, wherein the piperazine and ethyl groups are optionally separated by one or more R groups. c replace.

[0094] In some implementation schemes, each R c Independently selected from amino, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl and 4-12 membered heterocyclic groups, wherein the amino, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl groups and 4-12 membered heterocyclic groups are optionally surrounded by one or more R groups. h replace.

[0095] In some implementation schemes, each R c Independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, and 4-8 membered heterocyclic groups, wherein the C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, and 4-8 membered heterocyclic groups are optionally surrounded by one or more R... h replace.

[0096] In some implementation schemes, each R c Independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and 4-6 membered heterocyclic groups, wherein the C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and 4-6 membered heterocyclic groups are optionally surrounded by one or more R... h replace.

[0097] In some implementation schemes, each R c Independently selected from amino, methyl, ethyl, methoxy, cyclopropyl, piperazine, morpholino, aziridine, oxacyclobutyl, And piperidinyl, wherein the amino, methyl, ethyl, methoxy, cyclopropyl, piperazine, morpholinyl, aziridine, oxadiazine, And piperidinyl is optionally coupled with one or more R h replace.

[0098] In some implementation schemes, each R c Independently selected from methyl, methoxy, cyclopropyl, piperazine, morpholino, aziridine, oxacyclobutyl, The methyl, methoxy, cyclopropyl, piperazine, morpholino, azacyclobutyl, and oxacyclobutyl groups are mentioned. Optional by one or more R h replace.

[0099] In some implementation schemes, each R h It is independently selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, C3-C6 cycloalkyl and 4-10 heterocyclic groups.

[0100] In some implementation schemes, each R h It is independently selected from hydroxyethyl, methyl, cyclopropyl and morpholino.

[0101] In some implementation schemes, each R c It is independently selected from methoxy or methyl.

[0102] In some implementation schemes, each R 5a Independently selected from methoxy, isopropyl,

[0103] In some implementation schemes, each R 5a Independently selected from isopropyl, methoxy,

[0104] In some implementation schemes, each R 5a Independently selected

[0105] In some implementation schemes, R 6 It is selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano and C1-C4 alkyl.

[0106] In some implementation schemes, R 6 It is hydrogen.

[0107] In some implementation schemes, R 7 It is selected from hydrogen, halogen, hydroxyl and cyano groups.

[0108] In some implementation schemes, R 7 It is hydrogen.

[0109] In some implementation schemes, R 4 and R 7 The atoms connected to it together form a 6-7 membered heterocycle, which is optionally bounded by one or more R atoms. k replace.

[0110] In some implementation schemes, R k It is independently selected from halogen, amino, hydroxyl, mercapto and cyano groups.

[0111] In some implementation schemes, R k It is independently selected from halogens, such as fluorine.

[0112] In some implementation schemes, Selected from The value of t is selected from 0, 1, 2, and 3.

[0113] In some implementation schemes, R 8 Selected from hydrogen, halogen, hydroxyl, cyano and C1-C 10 alkyl.

[0114] In some implementation schemes, R 8It is hydrogen.

[0115] In some implementation schemes, R 9 It is selected from hydrogen, halogen, hydroxyl and cyano groups.

[0116] In some implementation schemes, R 9 Selected from hydrogen and halogens.

[0117] In some implementation schemes, R 9 Selected from hydrogen and fluorine.

[0118] In some implementation schemes, R 9 It is hydrogen.

[0119] In some implementation schemes, R 10 Selected from halogens, such as fluorine.

[0120] In some implementation schemes, R 10 It is fluorine.

[0121] In some implementations, n is 1, 2, or 3.

[0122] In some implementations, n is 1 or 2.

[0123] In some implementation schemes, Selected from Where n is 1 or 2.

[0124] In some implementation schemes, Selected from

[0125] In some implementation schemes, Selected from In some implementation schemes, for

[0126] In some embodiments, the compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compound of formula (II) or its stereoisomer or a pharmaceutically acceptable salt thereof.

[0127]

[0128] Where n is 1 or 2, A, L, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 and R 10 As defined above.

[0129] In some implementation schemes, R 10 Selected from halogens, such as fluorine.

[0130] In some embodiments, the compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compound of formula (III) or its stereoisomer or a pharmaceutically acceptable salt thereof.

[0131]

[0132] Where n is 1 or 2; R 10 Selected from halogens, preferably fluorine; R 1 R 2 R 3 R 4 and R 5a As defined above.

[0133] In some embodiments, the compounds of formula (I) of this disclosure, or their stereoisomers or pharmaceutically acceptable salts thereof, are selected from the following compounds, or their stereoisomers or pharmaceutically acceptable salts thereof.

[0134]

[0135]

[0136] On the other hand, this disclosure provides pharmaceutical compositions comprising a compound of formula (I) of this disclosure or a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0137] On the other hand, this disclosure provides a method for treating RAS-mediated diseases in individuals (e.g., mammals), comprising administering to an individual (e.g., a mammal, preferably a human) a therapeutically effective amount of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0138] On the other hand, this disclosure provides the use of a compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for the prevention or treatment of RAS-mediated diseases.

[0139] On the other hand, this disclosure provides the use of a compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of RAS-mediated diseases.

[0140] On the other hand, this disclosure provides a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the prevention or treatment of RAS-mediated diseases, or a pharmaceutical composition thereof.

[0141] In some implementations, the RAS-mediated disease is a tumor, such as non-small cell lung cancer.

[0142] Definitions and explanations of terms

[0143] Unless otherwise stated, the terms used in this disclosure have the following meanings: the definitions of groups and terms recorded in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in the examples, etc., can be arbitrarily combined and combined with each other. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0144] In this article Indicates the connection site.

[0145] Some compounds of this application can exist as trans-isomers, which are conformational isomers that occur when rotation around a single bond in the molecule is prevented or significantly slowed due to steric interactions with other parts of the molecule. The compounds disclosed herein include all trans-isomers, which can be pure, single trans-isomers, trans-isomers enriched in one of them, or nonspecific mixtures of each. Separation of isomers is permitted if the rotational potential around the single bond is sufficiently high and the interconversion between conformations is sufficiently slow. For example, (or )and (or () is a pair of transisomers, wherein the pyridyl group is an inhibitor of transisomers. This indicates that the orientation of this three-dimensional object is outward. This indicates that the orientation of this three-dimensional object is inward.

[0146] The diagrammatic representation of racemic or enantiomerically pure compounds in this article is derived from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise specified, wedge-shaped real and wedge-shaped imaginary bonds are used. and ) represents the absolute configuration of a solid center, using direct real keys and direct virtual keys ( and ) indicates the relative configuration of a stereocenter (such as the cis-trans configuration of alicyclic compounds).

[0147] When one of the variables is selected as a chemical bond or does not exist, it means that the two groups it is connected to are directly connected. For example, when L in ALZ represents a bond, it means that the structure is actually AZ.

[0148] If the linking group mentioned in this article does not specify its linking direction, then its linking direction is arbitrary. For example, when the structural unit... L in 1 When selected from "C1-C3 alkylene-O", L 1 Both loops Q and R can be connected in a left-to-right direction. 1 Composed of "cyclo-Q-C1-C3 alkylene-OR" 1 Alternatively, rings Q and R can be connected from right to left. 1 Composed of "cyclo-QO-C1-C3 alkylene-R" 1 ".

[0149] When a substituent is cross-bonded to two atoms on a ring, it can bond to any atom on that ring. For example, structural units. R represents 10 Substitution can occur at any position on the ring.

[0150] The compounds disclosed herein may have asymmetric atoms such as carbon, sulfur, nitrogen, and phosphorus atoms, or asymmetric double bonds, and therefore may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E- and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof or other mixtures, such as mixtures enriched with enantiomers or diastereomers. All such isomers and mixtures thereof are within the scope of the definition of the compounds disclosed herein. Alkyl groups or other substituents may contain additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms. All such isomers involved in all substituents, and mixtures thereof, are also included within the scope of the definition of the compounds disclosed herein. The compounds containing asymmetric atoms disclosed herein can be isolated in optically active pure form or in racemic form. The optically active pure form can be separated from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0151] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

[0152] The terms “optional,” “optional,” “optionally,” or “optionally” mean that the event or condition described below may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, the phrase “optionally” substituted with one or more halogens means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0153] When any variable (e.g., R) a R b When a group 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 surrounded by two R... b Replaced, then each R b Each has its own independent options.

[0154] C in this article m -C n It refers to having an integer number of carbon atoms in the range mn. For example, "C1-C 10 "" means that the group can have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0155] The term "alkyl" refers to a compound with the general formula C1. n H 2n+1 The alkyl group can be straight-chain or branched. The term "C1-C" refers to the hydrocarbon group. 10"Alkyl" can be understood as representing a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Specific examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1 The term "C1-C7 alkyl" can be understood as referring to alkyl groups having 1 to 7 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C5 alkyl" can be understood as referring to straight-chain or branched saturated alkyl groups having 1 to 5 carbon atoms. The term "C1-C4 alkyl" can be understood as referring to straight-chain or branched saturated alkyl groups having 1 to 4 carbon atoms. The term "C1-C3 alkyl" can be understood as referring to straight-chain or branched saturated alkyl groups having 1 to 3 carbon atoms. The term "C5-C6 alkyl" can also be understood as referring to straight-chain or branched saturated alkyl groups having 1 to 3 carbon atoms. 10 "Alkyl" can be understood as referring to a straight-chain or branched saturated alkyl group having 5 to 10 carbon atoms. The "C1-C" 10 "alkyl" can include "C1-C6 alkyl", "C1-C4 alkyl", "C1-C3 alkyl" or "C5-C6 alkyl". 10 The term "alkyl" is used within the range of "C1-C6 alkyl," which may further include "C1-C4 alkyl" or "C1-C3 alkyl." The term "halogenated alkyl" is intended to include both monohalogenated and polyhalogenated alkyl groups. For example, the term "C1-C6 alkyl" may include "C1-C4 alkyl" or "C1-C3 alkyl." 10 "Haloalkyl" refers to a C1-C alkyl group as defined above that has been substituted with one or more halogens. 10 Alkyl groups include, but are not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. The term "hydroxyalkyl" is intended to include both monohydroxy-substituted and polyhydroxy-substituted alkyl groups. For example, the term "C1-C4 hydroxyalkyl" refers to a C1-C4 alkyl group as defined above that is substituted with one or more hydroxyl groups.

[0156] The term "alkoxy" refers to a group formed by the loss of a hydrogen atom from a hydroxyl group in straight-chain or branched alcohols; it 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"alkyl-O-"; the term "C1-C7 alkoxy" can be understood as "C1-C7 alkyloxy" or "C1-C7 alkyl-O-". The "C1-C" 10 "Alkoxy" can include the range of "C1-C7 alkoxy" and "C1-C3 alkoxy", and the "C1-C7 alkoxy" can further include "C1-C3 alkoxy".

[0157] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms and having at least one double bond. The term "C2-C"... 10 "Alkenyl" can be understood as referring to a straight-chain or branched unsaturated hydrocarbon group that contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The term "C6-C" is used to describe this type of unsaturated hydrocarbon group. 10 "Alkenyl" can be understood as representing a straight-chain or branched unsaturated hydrocarbon group that contains one or more double bonds and has 6, 7, 8, 9, or 10 carbon atoms, "C2-C". 10 "Alkenyl" can include "C2-C6 alkenyl", "C2-C4 alkenyl", "C6-C6 alkenyl", "C2-C4 ... 10 "Alkenyl", C2 or C3 alkenyl. It is understood that when the alkenyl group contains more than one double bond, the double bonds may be separable or conjugated with each other. Specific examples of alkenyl groups 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.

[0158] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms and having at least one triple bond. The term "C2-C"... 10 "Alkyne" can be understood as representing a straight-chain or branched unsaturated hydrocarbon group 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≡CCH3, -CH2C≡CH), buty-1-alkynyl, buty-2-alkynyl, or buty-3-alkynyl. "C2-C 10 "Alynyl" can include "C2-C3 alkynyl", and examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), propynyl-1-alkynyl (-C≡CCH3), and propynyl-2-alkynyl (-CH2C≡CH).

[0159] 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" is also used. 12 "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 atom.

[0160] The term "heterocyclic group" or "heterocycle" refers to a fully saturated or partially saturated (not aromatic as a whole) monocyclic, fused-ring, spirocyclic, or bridged-ring group containing 1-5 (e.g., 1-3 or 1-2) heteroatoms or heteroatom groups (i.e., groups containing heteroatoms). These "heteratoms or heteroatom groups" include, but are not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (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 heterocyclic group" refers to a heterocyclic group with 4, 5, 6, 7, 8, 9, or 10 ring atoms, containing 1-5 heteroatoms or heteroatom groups independently selected from those described above. "4-10 membered heterocyclic groups" can include "4-7 membered heterocyclic groups". The term "4-7 membered heterocyclic group" refers to a heterocyclic group with 4, 5, 6 or 7 ring atoms, and whose ring atoms contain 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups independently selected from those described above. Specific examples of 4 membered heterocyclic groups include, but are not limited to, azirrocyclobutane or oxacyclobutane; specific examples of 5 membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6 membered heterocyclic groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazine, trithiaalkyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7 membered heterocyclic groups include, but are not limited to, diazacycloheptane. The heterocyclic group can also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopentano[c]pyrrolo-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 can be a benzofused cyclic group of the above-mentioned 4-7-membered heterocyclic groups, specific examples of which include, but are not limited to, dihydroisoquinolinyl, etc. "4-10 membered heterocyclic group" can include the ranges of "5-10 membered heterocyclic group", "4-7 membered heterocyclic group", "5-6 membered heterocyclic group", "6-8 membered heterocyclic group", "4-10 membered heterocyclic alkyl group", "5-10 membered heterocyclic alkyl group", "4-7 membered heterocyclic alkyl group", "5-6 membered heterocyclic alkyl group", and "6-8 membered heterocyclic alkyl group". "4-7 membered heterocyclic group" can further include the ranges of "4-6 membered heterocyclic group", "5-6 membered heterocyclic group", "4-7 membered heterocyclic alkyl group", "4-6 membered heterocyclic alkyl group", and "5-6 membered heterocyclic alkyl group".Although some bicyclic heterocyclic groups in this disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclic group as a whole remains non-aromatic. The term "subheterocyclic group" refers to a residue derived by further removing a hydrogen atom from a heterocyclic group.

[0161] The term "heterocyclic alkyl" refers to a fully saturated cyclic group existing in the form of a monocyclic, fused, bridged, or spirocyclic ring, wherein the ring atoms contain 1-5 heteroatoms or heteroatom groups (i.e., groups containing heteroatoms). These "heteroatoms or heteroatom groups" include, but are not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=O)2-, -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-. The term "4-10 membered heterocyclic alkyl" refers to a heterocyclic alkyl group with 4, 5, 6, 7, 8, 9, or 10 ring atoms, and its ring atoms contain 1-5 independently selected heteroatoms or heteroatom groups as described above. The term "5-10 membered heterocyclic alkyl" refers to a heterocyclic alkyl group with 5, 6, 7, 8, 9 or 10 ring atoms, and whose ring atoms contain 1 to 5 independent heteroatoms or heterogroups selected from those described above. "4-10-membered heterocyclic alkyl" and "5-10-membered heterocyclic alkyl" include "4-7-membered heterocyclic alkyl", wherein specific examples of 4-membered heterocyclic alkyl include, but are not limited to, acridine, oxadiazolyl, or thiobutylcycloyl; specific examples of 5-membered heterocyclic alkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, or tetrahydropyrazolyl; specific examples of 6-membered heterocyclic alkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxalyl, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, or 1,4-dithiaalkyl; and specific examples of 7-membered heterocyclic alkyl include, but are not limited to, azirheptanyl, oxaheptanyl, or thioheptanyl.

[0162] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic aromatic cyclic group with a conjugated π-electron system. Aryl groups can have 6-20, 6-14, or 6-12 carbon atoms. The term "C6-C"... 10 "Aryl" can be understood as an aryl group having 6 to 10 carbon atoms. The term "C6-C7 aryl" can be understood as an aryl group having 6 to 7 carbon atoms. For example, a ring with 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring with 9 carbon atoms ("C9 aryl"), such as indenyl or indenyl; or a ring with 10 carbon atoms ("C9 aryl"). 10 Aryl), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl. The term "aryl" refers to a residue derived from an aryl group by further removing a hydrogen atom.

[0163] The term "heteroaryl" refers to an aromatic monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, or S, with the remaining ring atoms being C. The term "5-12-membered heteroaryl" can be understood as including monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, for example, 5, 6, 9, 10, 11, or 12 ring atoms, and containing 1 to 5, for example 1 to 3, heteroatoms independently selected from N, O, and S. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzothiazolyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl or isindolyl; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl and their benzo[derivatives], such as quinolinyl, quinazolinyl or isoquinolinyl; or acrylinyl, inazinyl, purinyl and their benzo[derivatives]; or cyclolinyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphthidyl, pteridinyl, carbazolyl, acrylinyl, phenazinyl, phenothiazinyl or phenothiazinyl. The term "6-10-membered heteroaryl" can be understood as including monocyclic or bicyclic aromatic ring systems having 6, 7, 8, 9, or 10 ring atoms, for example, 6, 9, or 10 ring atoms, and containing 1-5, for example 1-3, 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 1-3, for example 1-2, heteroatoms independently selected from N, O, and S. The term "hybrid aryl" refers to a residue derived from a heteroaryl group by further removing a hydrogen atom.

[0164] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0165] The term "hydroxyl group" refers to the -OH group.

[0166] The term "cyano" refers to the -CN group.

[0167] The term "amino" refers to the -NH2 group.

[0168] The term "nitro" refers to the -NO2 group.

[0169] The term "treatment" means administering the compound or preparation described in this application to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0170] (i) Suppress the disease or disease state, that is, curb its development;

[0171] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0172] The term "therapeutic effective amount" means (i) the amount of the disclosed compound used to treat a particular disease, condition, or disorder, and (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder. The amount of the disclosed compound constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by someone skilled in the art based on their own knowledge and the content of this disclosure.

[0173] The term “prevention” means administering the compound or formulation described in this application to prevent a disease or one or more symptoms associated with the disease, and includes preventing the occurrence of a disease or disease state in an individual (e.g., a mammal), particularly when such an individual (e.g., a mammal) is susceptible to the disease state but has not yet been diagnosed with the disease state.

[0174] The term "individual" includes both 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; domesticated 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 "individual" are used interchangeably.

[0175] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0176] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of an acid or base, including salts formed by a compound with an inorganic or organic acid, and salts formed by a compound with an inorganic or organic base.

[0177] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the disclosed compounds to an organism.

[0178] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0179] The word “comprise” or “include” and its English variants such as comprises or comprising can be understood as having an open, non-exclusive meaning, that is, “including but not limited to”.

[0180] This disclosure also includes compounds of this disclosure that are identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this 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, etc.

[0181] Certain isotope-labeled compounds of this disclosure (e.g., using...) 3 H and 14 C-labeling can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e., 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. The isotopically labeled compounds of this disclosure can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0182] The pharmaceutical compositions disclosed herein can be prepared by combining the compounds disclosed herein with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0183] Typical routes of administration of the disclosed compounds or their pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0184] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, emulsification, freeze drying, etc.

[0185] In some embodiments, the pharmaceutical composition is in an 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 this disclosure to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

[0186] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, flow aids, or flavoring agents.

[0187] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0188] The dosage is determined based on factors such as the specific compound, the disease condition and its severity, the identity of the subject or host requiring treatment (e.g., weight, sex), and the specific circumstances of the case, including, for example, the specific formulation administered, the route of administration, the condition being treated, and the subject or host being treated.

[0189] In all methods of administration of the compounds of general formula (I) described herein, in the case of oral administration, the daily dose is from 0.001 mg / kg to 5000 mg / kg body weight, preferably from 0.01 mg / kg to 100 mg / kg body weight, in the form of single or separate doses. The daily dose and unit dose may vary according to many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the route of administration, the individual subject's requirements, the severity of the disease or condition to be treated, and the practitioner's judgment.

[0190] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

[0191] The chemical reactions in the specific embodiments of this disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of this disclosure and the reagents and materials required therefor. In order to obtain the compounds of this disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0192] Abbreviations:

[0193] EA represents ethyl acetate; TBDPS represents tert-butyldiphenylsilyl; TBDPSCl represents tert-butyldiphenylchlorosilane; DCM represents dichloromethane; DMF represents N,N-dimethylformamide; THF represents tetrahydrofuran; MeOH represents methanol; TsOH .H2O represents p-toluenesulfonic acid monohydrate; TsCl represents p-toluenesulfonyl chloride; n-BuLi represents n-butyllithium; Boc2O represents di-tert-butyl dicarbonate; TFA: trifluoroacetic acid; DIEA or DIPEA represents N,N-diisopropylethylamine; Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride; Pd(dtbpf)Cl2 represents 1,1'-bis(di-tert-butylphosphine)ferrocene palladium dichloride; HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N' ,N'-Tetramethylurea hexafluorophosphate (2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate); Et3N or TEA represents triethylamine; PPh3: triphenylphosphine; Pd(PPh3)4 represents tetratetraphenylphosphine palladium; BINAP represents (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; Ru-L(S,S) represents (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride; [Ir(cod)Cl]2 represents 1,5- Cyclooctadiene iridium chloride dimer; B2Pin2 represents bis-pinacol boronic acid ester or 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxacyclopentaborane); COMU represents (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinourea hexafluorophosphate; ACN / MeCN represents acetonitrile; NIS represents N-iodosuccinimide; KOAc represents potassium acetate; DME represents ethylene glycol dimethyl ether; EtI represents iodoethane; EDCI represents 1-ethyl-(3-dimethylaminopropyl) Carbodiimide hydrochloride; HOBT represents 1-hydroxybenzotriazole; AcOH represents acetic acid; Boc represents tert-butyloxycarbonyl; Cbz represents benzyloxycarbonyl; toluene represents toluene; dioxane represents dioxane; MTBE represents tert-butyl methyl ether; DAST represents diethylaminosulfur trifluoride; TCFH represents N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate; NMI represents N-methylimidazolium; TBAF represents tetrabutylammonium fluoride; DMSO represents dimethyl sulfoxide; NMM represents N-methylmorpholine; (CH2O) n LC-MS represents paraformaldehyde; MS represents mass spectrometry. 1 1H NMR represents proton nuclear magnetic resonance spectroscopy; ESI represents electrospray ionization; DTT represents dithiothreitol; HEPES represents 4-hydroxyethylpiperazine ethanesulfonic acid; PBS represents phosphate buffer; BSA represents bovine serum albumin; IC50 represents... 50 The half-maximum inhibitory concentration (WMC) refers to the concentration at which half of the maximum inhibitory effect is achieved. Detailed Implementation

[0194] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed herein, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

[0195] The present disclosure is described in detail below with reference to embodiments, but this does not imply any adverse limitation thereof. 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 of the present disclosure without departing from the spirit and scope thereof. All reagents used in this disclosure are commercially available and can be used without further purification.

[0196] Unless otherwise stated, the proportions of mixed solvents are volume-based.

[0197] Unless otherwise stated, % refers to weight percentage (wt%).

[0198] Compounds are processed manually or Software naming conventions are used; commercially available compounds use supplier catalog names.

[0199] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are measured in units of 10⁻⁶. -6 (ppm). The solvents used for NMR determination were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard was tetramethylsilane (TMS).

[0200] The eluent or mobile phase may be a mixture of two or more solvents, with the ratio being the volume ratio of each solvent.

[0201] Preparation Example

[0202] Preparation Example 1: Synthesis of intermediate compound Int-1

[0203]

[0204] Step 1: Synthesis of 3-((tert-butyldiphenylsilyl)oxo)-2,2-dimethylpropionic acid (compound A2)

[0205] tert-butyldiphenylchlorosilane (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 the filtrate was evaporated to dryness to give compound A2 (88 g, 246.82 mmol, yield: 97.19%). The product was used directly in the next step without purification.

[0206] Step 2: Synthesis of 3-((tert-butyldiphenylsilyl)oxo)-2,2-dimethylpropionyl chloride (compound A3)

[0207] Compound A2 (88 g, 246.82 mmol) was dissolved in dichloromethane (1000 mL) at 0 °C. Under nitrogen protection, N,N-dimethylformamide (1.80 g, 24.68 mmol, 1.91 mL) was added to the solution, followed by dropwise addition of oxaloyl chloride (62.69 g, 493.65 mmol, 42.13 mL). The mixture was stirred at 0 °C for 2 hours. The reaction was monitored by LC-MS until complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give compound A3 (80 g, 213.35 mmol, yield: 86.44%). The product was used directly in the next step without purification.

[0208] Step 3: Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxo)-2,2-dimethylpropane-1-one (compound A4)

[0209] Compound A3 (80 g, 213.35 mmol) was dissolved in dichloromethane (1.5 L) at 0 °C. Under nitrogen protection, 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 reacted at 0 °C for 10 hours. LC-MS showed complete consumption of the starting material and detection of the product. The reaction mixture was diluted with ethyl acetate (600 mL), washed four times with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and purified by silica gel chromatography (ethyl acetate / tetrahydrofuran = 5 / 1 to 3 / 1) to give compound A4 (8 g, 14.97 mmol, yield: 7.01%). MS (ESI) + m / z = 534.0 [M+H] + .

[0210] Step 4: Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxo)-2,2-dimethylpropane-1-ol (compound A5)

[0211] Compound A4 (8 g, 14.97 mmol) was dissolved in tetrahydrofuran (71.30 mL) at 0 °C. Under nitrogen protection, a 2 M lithium borohydride tetrahydrofuran solution (2 M, 18.71 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was then heated to 60 °C and reacted 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 combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give compound A5 (8 g, 14.91 mmol, yield: 99.62%). No further purification was performed, and it was used directly in the next step.

[0212] Step 5: Synthesis of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxo)-2,2-dimethylpropyl)-1H-indole (compound A6)

[0213] 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 for 2 hours under nitrogen protection. LC-MS showed complete consumption of the reactants and detection of the desired compound. After the reaction was completed, water (50 mL) was added to quench the reaction, and the mixture was washed three times with dichloromethane (50 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound A6 (7 g, 13.45 mmol, yield: 90.19%).

[0214] MS(ESI + m / z = 520.0 [M+H] + .

[0215] Step 6: Synthesis of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxo)-2,2-dimethylpropyl)-2-iodo-1H-indole (compound Int-1)

[0216] 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 mixture was stirred at room temperature for 2 hours. LC-MS showed complete consumption of the reactants and detection of the desired compound. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated Na2S2O3 aqueous solution (50 mL), and the combined organic layers were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give compound Int-1 (973 mg, 1.51 mmol, yield: 26.12%). MS (ESI) + m / z = 646.1 [M+H] + .

[0217] Preparation Example 2: Synthesis of intermediate compound Int-2

[0218]

[0219] The first step is the synthesis of (4-bromothiazol-2-yl)methanol (compound B2).

[0220] Compound B1 (10 g, 52 mmol) was added to methanol (15 mL) with sodium borohydride (2.95 g, 78.11 mmol), and the mixture was stirred at 0 °C for 0.5 h. Thin-layer chromatography showed that compound B1 reacted completely. The reaction was quenched by adding 10 mL of dilute hydrochloric acid. The reaction mixture was concentrated under reduced pressure to remove the solvent, giving compound B2 (9 g, 46.38 mmol, yield 89.07%).

[0221] MS(ESI + m / z = 194.3 [M+H] + .

[0222] Step 2: Synthesis of 4-bromo-2-(bromoethyl)thiazole (compound B3)

[0223] 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 120 mL of dichloromethane at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS to ensure 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 give compound B3 (9.0 g, 35.20 mmol, yield: 75.9%). MS (ESI) + m / z = 255.7 [M+H] + .

[0224] Step 3: Synthesis of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (compound B5)

[0225] (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 h. Compound B3 (9.0 g, 35.20 mmol) was added to the mixture, and the mixture was stirred at -78 °C for 1 h. The reaction was monitored by LC-MS to ensure complete reaction. The reaction was quenched with saturated ammonium chloride aqueous solution (30 mL), extracted with ethyl acetate (100 mL × 2), and the organic layer was evaporated to dryness and purified by silica gel column chromatography (0-15% petroleum ether / ethyl acetate) to give compound B5 (10.5 g, 29.14 mmol, yield: 83%).

[0226] MS(ESI + m / z = 360.2[M+H] + .

[0227] Step 4: Synthesis of (S)-2-amino-3-(4-bromothiazol-2-yl)propionate (B6)

[0228] Hydrochloric acid (195 mL, 0.3 M) was added to an acetonitrile solution (60 mL) of compound B5 (10.5 g, 29.14 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LC-MS until complete. The mixture was alkalized to pH 8 with saturated sodium bicarbonate solution. It was then extracted with ethyl acetate (100 mL × 6), the organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under vacuum to give compound B6 (6.8 g, 25.65 mmol, yield: 88%).

[0229] MS(ESI + m / z = 264.9 [M+H] + .

[0230] Step 5: Synthesis of methyl (S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonyl)amino)propionate (compound Int-2)

[0231] 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). The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS until complete. The reaction was quenched with water (75 mL) and extracted with dichloromethane (75 mL × 2). The organic layer was evaporated to dryness and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-30%) to give compound Int-2 (6.5 g, yield: 68%).

[0232] MS(ESI + m / z = 364.9 [M+H] + .

[0233] Preparation Example 3: Synthesis of intermediate compound Int-3

[0234]

[0235] Step 1: Synthesis of (S)-1-(3-bromopyridin-2-yl)ethanol-1-ol (compound C2)

[0236] 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. Then, (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (379 mg, 599.90 μmol) was added. The reaction mixture was heated to 40 °C and stirred for 15 minutes, then cooled to room temperature. Compound C1 (12 g, 59.99 mmol) was added, and the reaction mixture was heated to 40 °C and stirred for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and purified by column chromatography to give compound C2 (12 g, 59.41 mmol, yield: 99%). MS (ESI) + m / z = 202.1[M+H] + .

[0237] Step 2: Synthesis of (S)-3-bromo-2-(1-methoxyethyl)pyridine (compound C3)

[0238] 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, then methyl iodoformane (16.86 g, 118.78 mmol) was added, and the mixture was allowed to warm to room temperature naturally and stirred for 2 hours. The reaction mixture was slowly added to ice water (750 mL), and extracted with ethyl acetate (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to give compound C3 (11 g, 50.9 mmol, yield: 86%). MS (ESI) + m / z = 216.1 [M+H] + .

[0239] Step 3: Synthesis of 5-bromo-6-[(1S)-1-methoxyethyl]pyridin-3-ylboronic acid (compound C4)

[0240] 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 under a nitrogen atmosphere to a tetrahydrofuran (50 mL) solution of compound C3 (5.0 g, 23.14 mmol) and bis(pinnatrol)boronic acid ester (8.81 g, 34.71 mmol). 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 pH was adjusted to 10 with a solution of sodium carbonate (40 g) and sodium hydroxide (10 g) (4:1 ratio) in water (600 mL). Extraction was performed with ethyl acetate (100 mL). The aqueous phase was acidified to pH 6 with hydrochloric acid (6M) to give compound C4 (4.5 g, 17.3 mmol, yield: 75%).

[0241] MS(ESI + m / z = 260.0 [M+H] + .

[0242] Step 4: Synthesis of (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (compound C5)

[0243] 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. The reaction was monitored by LC-MS until complete. The resulting mixture was dissolved in dichloromethane (80 mL), washed with saturated sodium thiosulfate aqueous solution (80 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate: 0-15%) to give compound C5 (4.3 g, 12.6 mmol, yield: 73%).

[0244] MS(ESI + m / z = 341.8[M+H] + .

[0245] Step 5: Synthesis of (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (compound C7)

[0246] Under N2 protection, compounds C5 (4.3 g, 12.6 mmol), 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 mixed in a sealed tube. The resulting solution was stirred at 100 °C under a nitrogen atmosphere for 16 hours. The reaction was monitored by LC-MS until completion. After the reaction was complete, the reaction mixture was cooled to 25 °C. The mixture was extracted with ethyl acetate (80 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate: 0-45%) to give compound C7 (3.6 g, 8.29 mmol, yield: 65.92%).

[0247] MS(ESI + m / z = 434.2[M+H] + .

[0248] Step 6: Synthesis of (S)-4-(6-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (compound Int-3)

[0249] 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). Under nitrogen protection, Pd(dppf)Cl2 (1.62 g, 2.21 mmol) was added to the reaction solution, and the nitrogen atmosphere was purged five times. The mixture was stirred at 100 °C for 16 hours, and the reaction was monitored for completeness. The mixture was then filtered and concentrated under reduced pressure. Ethyl acetate (100 mL) and 6N HCl (100 mL) were added, and the mixture was stirred for 16 hours. The mixture was then filtered, concentrated under reduced pressure, and purified by reverse-phase silica gel column chromatography (water / acetonitrile = 1 / 0 to 1 / 1) to give compound Int-3 (4.6 g, 9.52 mmol, yield: 43.06%). MS (ESI) was then performed. + m / z = 482.2[M+H] + .

[0250] Preparation Example 4: Synthesis of intermediate compound Int-4

[0251]

[0252] The first step was the synthesis of (S)-4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxo)-2,2-dimethylpropyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (compound D1).

[0253] Compounds Int-1 (4 g, 6.19 mmol), Int-3 (4.47 g, 9.28 mmol), and potassium carbonate (2.57 g, 18.56 mmol) were dissolved in a solution of ethylene glycol dimethyl ether (40 mL) and water (8 mL). Under nitrogen protection, Pd(dppf)Cl2 (452.74 mg, 618.74 μmol) was added to the reaction solution, and the nitrogen atmosphere was replaced five times. The mixture was stirred at 100 °C for 16 hours, and the reaction was monitored for completeness by LC-MS. The mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0–1 / 5) to give compound D1 (2.3 g, 2.63 mmol, yield: 42.49%).

[0254] MS(ESI + m / z = 873.3 [M+H] + .

[0255] The second step involves the synthesis of (S)-4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxo)-2,2-dimethylpropyl)-1-ethyl-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (compound D2).

[0256] Compound D1 (2.3 g, 2.63 mmol) was dissolved in DMF (30 mL), and cesium carbonate (2.57 g, 7.89 mmol) and iodoethane (820.88 mg, 5.26 mmol) were added in portions. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS to ensure completion. The solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound D2 (2.0 g, crude product). This was used directly in the next step. MS (ESI) + m / z = 901.3[M+H] + .

[0257] The third step is the 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).

[0258] Compound D2 (2.0 g, crude) 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. The reaction was monitored by LC-MS until complete. The mixture was concentrated under reduced pressure and purified by normal-phase silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give the less polar isomer, compound D3 (0.5 g, 753.42 μmol, yield: 33.4%).

[0259] MS(ESI + m / z = 663.3 [M+H] + .

[0260] Step 4: Synthesis of (S)-4-(5-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (compound D4)

[0261] Compound D3 (0.5 g, 753.42 μmol), bis(dppf)boronic acid ester (573.96 mg, 2.26 mmol), and potassium acetate (184.86 mg, 1.88 mmol) were dissolved in toluene (10 mL). Under nitrogen protection, Pd(dppf)Cl2 (55.13 mg, 75.34 μmol) was added to the reaction solution, and the nitrogen atmosphere was replaced five times. The mixture was stirred at 100 °C for 16 hours, and the reaction was monitored to be complete by LC-MS. The solution was concentrated under reduced pressure by filtration, diluted with water (50 mL), extracted with ethyl acetate (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by normal-phase silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 3) to give compound D4 (0.4 g, 562.82 μmol, yield: 74.7%).

[0262] MS(ESI + m / z = 711.4[M+H] + .

[0263] Step 5: Synthesis of 4-(5-(5-(2-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-carbonylpropyl)thiazolyl-4-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (compound D5)

[0264] Compound D4 (260 mg, 365.83 μmol), compound Int-2 (133.16 mg, 365.83 μmol), and potassium phosphate (232.96 mg, 1.10 mmol) were dissolved in a mixed solution of dioxane (1 mL), toluene (3 mL), and water (1 mL). Under nitrogen protection, Pd(dtbpf)Cl2 (23.84 mg, 36.58 μmol) was added to the reaction solution, and nitrogen was purged five times. The mixture was stirred at 100 °C for 12 hours, and the reaction was monitored by LC-MS to ensure complete reaction. The mixture was diluted with water (50 mL), extracted with ethyl acetate (10 mL × 3), washed with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 3) to give compound D5 (200 mg, 230 μmol, yield: 62.87%).

[0265] MS(ESI + m / z = 869.4 [M+H] + .

[0266] Step 6: Synthesis of (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)thiazolyl-2-yl)-2-((tert-butoxycarbonyl)amino)propionic acid (compound Int-4).

[0267] Compound D5 (200 mg, 230 μmol) was dissolved in a mixed solution of tetrahydrofuran (5 mL) and water (5 mL). Lithium hydroxide (32.95 mg, 1.38 mmol) was added to the reaction solution, and the mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS until complete. The solution was diluted with ethyl acetate (30 mL) and water (30 mL). The pH of the aqueous phase was adjusted to approximately 6 with 1 M HCl aqueous solution. The aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid compound Int-4 (173.6 mg, 203 μmol, yield: 88.26%).

[0268] MS(ESI + m / z = 855.4 [M+H] + .

[0269] Preparation Example 5: Synthesis of intermediate compound Int-5

[0270]

[0271] The first step was the synthesis of 3-allyl-1,2-di-tert-butyl-4-oxotetrahydropyridazine-1,2,3-tricarboxylic acid ester (compound E2).

[0272] Di-tert-butyl azodicarbonate (460.5 mg, 2.0 mmol) was dissolved in tert-butyl methyl ether (1.0 mL), and allyl 3-oxopent-4-enoate (compound E1, 925.0 mg, 6.0 mmol) was added. The reaction was carried out at 60 °C for 48 hours under an argon atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 3) to give compound E2 (200 mg, 520 μmol, yield: 26%). MS (ESI) + m / z = 385.3 [M+H] + .

[0273] Step 2: Synthesis of 3-allyl-1,2-di-tert-butyl-4,4-difluorotetrahydropyridazine-1,2,3-tricarboxylic acid ester (compound E3)

[0274] Compound E2 (720.0 mg, 1.87 mmol) was dissolved in anhydrous dichloromethane (18.0 mL), and diethylaminosulfur trifluoride (452 ​​mg, 2.8 mmol) was added at 25 °C. The reaction was carried out at 25 °C for 12 hours. After the reaction was completed, the reaction solution was purified by normal column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 10 / 3) to give compound E3 (160 mg, 393 μmol, yield 21%).

[0275] MS(ESI + m / z = 407.3 [M+H] + .

[0276] Step 3: Synthesis of 4,4-difluorohexahydropyridazine-3-carboxylic acid allyl ester (compound Int-5)

[0277] Compound E3 (160 mg, 0.39 mmol) was dissolved in dichloromethane (1.0 mL), and trifluoroacetic acid (422 mg, 3.7 mmol) was added. The reaction was carried out at 25 °C for 2 hours, after which the reaction was completed. The organic phase was concentrated under reduced pressure to give the title compound Int-5 (80.8 mg, 0.39 mmol, yield: 99%). MS (ESI) + m / z = 207.3[M+H] +

[0278] Preparation Example 6: Synthesis of intermediate compound Int-6

[0279]

[0280] Synthesis of compound F1 in the first step

[0281] Compound 3-allyl-1,2-di-tert-butyl-4-oxotetrahydropyridazine-1,2,3-tricarboxylic acid ester E2 (384 mg, 1.00 mmol) was dissolved in anhydrous methanol (10.0 mL), sodium borohydride (113 mg, 3.00 mmol) was added at 0 °C, and the reaction was carried out at 0 °C for 2 hours. The reaction was quenched with saturated ammonium chloride aqueous solution, and the organic phase was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride aqueous solution, dried over sodium sulfate, filtered, and evaporated to dryness to give the title compound F1 (367.6 mg, 0.95 mmol, yield: 95%).

[0282] MS(ESI + m / z = 387.3 [M+H] +

[0283] The second step involves the synthesis of compound F2.

[0284] Compound F1 (367.6 mg, 0.95 mmol) was dissolved in dichloromethane (10.0 mL), and diethylaminosulfur trifluoride (242 mg, 1.50 mmol) was added at 25 °C. The reaction was carried out at 0 °C for 0.5 h. The reaction was quenched by adding saturated ammonium chloride aqueous solution at 0 °C, and the organic phase was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride aqueous solution, dried over sodium sulfate, filtered, and evaporated to dryness to give the title compound F2 (334.8 mg, 0.86 mmol, yield: 90.5%). MS (ESI) + m / z = 389.3 [M+H] +

[0285] The third step involves the synthesis of compound Int-6.

[0286] Compound F2 (334.8 mg, 0.86 mmol) was dissolved in dichloromethane (10.0 mL), and trifluoroacetic acid (2 mL) was added. The reaction was carried out at 25 °C for 2 hours, and the reaction was completed. The organic phase was concentrated to dryness under reduced pressure to give the title compound Int-6 (138.2 mg, 0.73 mmol, yield: 85.2%).

[0287] MS(ESI + m / z = 189.3 [M+H] +

[0288] Example 1: Synthesis of Compounds 1-P1 and 1-P2

[0289]

[0290] Step 1: Synthesis of 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)thiazolyl-2-yl)-2-((tert-butoxycarbonyl)amino)propionyl)-4,4-difluorohexahydropyridazine-3-carboxylic acid allyl ester (compound 1A)

[0291] Compound Int-5 (80.8 mg, 390 μmol) was dissolved in dichloromethane (4.0 mL) at 0 °C. N-methylmorpholine (222 mg, 2.22 mmol) was added and the mixture was stirred for 5 minutes. Subsequently, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (106 mg, 0.56 mmol), 1-hydroxybenzotriazole (10.0 mg, 0.074 mmol), and Int-4 (316 mg, 0.37 mmol) were added sequentially, and the reaction was stirred at 25 °C for 4 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by reverse-phase silica gel column chromatography (water / acetonitrile = 10 / 1 to 10 / 7) to give compound 1A (54 mg, 51.8 μmol, yield: 14%). MS (ESI) + m / z = 1043.5 [M+H] + .

[0292] Step 2: Synthesis of 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)thiazolyl-2-yl)-2-((tert-butoxycarbonyl)amino)propionyl)-4,4-difluorohexahydropyridazine-3-carboxylic acid (compound 1B)

[0293] Compound 1A (20 mg, 19 μmol) was dissolved in anhydrous acetonitrile (0.5 mL), and the temperature was lowered to 0 °C. Tetraphenylphosphine palladium (2.2 mg, 1.9 μmol) and tetrahydropyrrole (4.0 mg, 0.057 mmol) were added sequentially, and the reaction was stirred at 0 °C for 5 minutes. After the reaction was complete, 1 M hydrochloric acid aqueous solution (10 mL) was added to quench the reaction. The organic phase was extracted with dichloromethane, and the solution was evaporated to dryness to give the title compound 1B (19 mg, 19 μmol, yield: 99%), which was used directly in the next step. MS (ESI) + m / z = 1003.5[M+H] + .

[0294] The third step involves the synthesis of compound 1C.

[0295] Compound N,N,N',N'-tetramethylchloromethanemid hexafluorophosphate (53 mg, 0.19 mmol) and N-methylimidazole (31 mg, 0.38 mmol) were dissolved in anhydrous acetonitrile (1.0 mL) and stirred at 0 °C for 10 min. Then, compound 1B (51.6 mg, 51.5 μmol) was dissolved in anhydrous acetonitrile (1.0 mL) and added dropwise to the above reaction solution at 0 °C. After the addition was complete, the reaction mixture was stirred at 0 °C for another 10 min. After the reaction was complete, the reaction solution was evaporated to dryness, and the residue was purified by normal column chromatography (dichloromethane / methanol = 20:1) to give the title compound 1C (11 mg, 11.21 μmol, yield 21.7%). MS (ESI) + m / z = 985.5[M+H] + .

[0296] Step 4: Synthesis of Compound 1D

[0297] Compound 1C (11.0 mg, 0.011 mmol) was dissolved in anhydrous methanol (2 mL), and palladium hydroxide / carbon (5 mg) and paraformaldehyde (10 mg) were added. The reaction was stirred under a hydrogen atmosphere for 7 hours. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure to give the title compound 1D (9.52 mg, 11 μmol, yield 98%).

[0298] MS(ESI + m / z = 865.4 [M+H] + .

[0299] Step 5: Synthesis of compound 1E

[0300] Compound 1D (9.52 mg, 11 μmol) was dissolved in anhydrous dichloromethane (0.5 mL), and trifluoroacetic acid (13 mg, 0.11 mmol) was added. The reaction was carried out at 25 °C for 4 hours, and the reaction was completed. The organic phase was concentrated to dryness under reduced pressure to give the title compound 1E (8 mg, 10.45 μmol, yield 95%).

[0301] MS(ESI + m / z = 765.4M + H + .

[0302] Step 6: Synthesis of Compound 1-P1 and Compound 1-P2

[0303] Compound 1E (8 mg, 10.45 μmol) was dissolved in N,N-dimethylformamide (0.5 mL), and the temperature was lowered to 0 °C. Compound 1F (2.5 mg, 0.022 mmol), (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinourea hexafluorophosphate (19 mg, 0.044 mmol), and N,N-diisopropylethylamine (11.3 mg, 0.088 mmol) were added sequentially, and the reaction was carried out at 0 °C for 2 hours. The reaction was monitored by LC-MS until completion. 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 reversed-phase column chromatography (Boston Prime C18 column; 150*30 mm*5 μm; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O ​​concentration 0.05%, NH4HCO3 concentration 2 mM; mobile phase B: MeCN; MeCN ratio 45%-70%) to obtain compound 1-P1 (3.5 mg, 4.0 μmol, yield: 38.3%, retention time: 8.95 min) and compound 1-P2 (1.5 mg, 1.7 μmol, yield: 16.3%, retention time: 8.18 min).

[0304] Compound 1-P1 MS (ESI) + m / z = 861.3[M+H] + .

[0305] 1H NMR (400MHz, DMSO-d6) δ=8.47–8.40(m,3H),7.82(s,1H),7.85–7.82(m,1H),7.74–7.72(m,1H),7.56(d,J=8.6Hz,1H),7.20(d,J =2.9Hz,1H),5.84(d,J=12.4Hz,1H),5.51(t,J=9.1Hz,1H),4.70(dd,J=27.4,12.5Hz,1H),4.42–4.39(m,1H),4.32–4.26(m,1H), 4.20–4.11(m,2H),3.71–3.62(m,2H),3.53(d,J=14.8Hz,1H),3.28–3.25(m,4H),3.21(s,3H),3.11–3.01(m,2H),2.93(d,J=14. 3Hz,1H),2.48–2.43(m,6H),2.22(s,3H),1.32(d,J=6.1Hz,3H),1.23(s,3H),1.09–1.02(m,6H),0.92–0.88(m,6H),0.35(s,3H).

[0306] Example 2: Synthesis of Compound 2

[0307]

[0308]

[0309] Referring to Example 1, Int-5 was replaced with intermediate Int-6, and the reversed-phase column in step 6 was replaced with a preparative column (XBridge Prep C18 column; 150 mm * 19 mm * 5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration was 0.05%; mobile phase B: MeCN; MeCN ratio 50%-75%, time: 13 min, flow rate: 15 mL / min, retention time: 7.58 min), to obtain compound 2, a mixture of four isomers.

[0310] MS(ESI + m / z = 843.4 [M+H] + .

[0311] Biological tests

[0312] Test Example 1: Effect of Compounds on Tumor Cell Proliferative Activity

[0313] Experimental materials and instruments:

[0314] The materials required for this experiment include: RPMI-1640 cell culture medium (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 permeable sterile culture plate (Corning #3599); 96-well plate (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).

[0315] The instruments and equipment required for this experiment include: Eppendorf pipettes; Eppendorf pipettes; Eppendorf centrifuges; ThermoFisher incubator; Vi-cell XR (Beckman Coulter) fully automated cell counter; and Envision microplate reader (Perkin Elmer).

[0316] The cells required for this experiment include: KRAS G12D Mutant cell line AsPC-1 (ATCC#CRL-1682) TM The complete culture medium is RPMI-1640 medium containing 10% FBS.

[0317] Experimental methods:

[0318] AsPC-1 cells were digested from the culture flasks using 0.25% trypsin and resuspended in the corresponding fresh complete culture medium. After counting, the AsPC-1 cell density was adjusted to 2000 cells / 90 μL / well. 90 μL of the solution was added to each well of a 96-well plate and incubated overnight at 37°C with 5% CO2. A 10 mM stock solution of the compound (DMSO as solvent) was diluted 10-fold to 1 mM with DMSO, then diluted 100-fold to 10 μM with complete culture medium. Using this as the starting concentration, a 3-fold serial dilution was performed with complete culture medium containing 1% DMSO, resulting in 9 consecutive concentration gradients. 10 μL / well of each serially diluted compound was then added to the cell culture wells to ensure a final DMSO concentration of 0.1% in each well. The positive control group consisted of wells without cell seeding; the negative control group consisted of wells with cells but without the compound treatment. The cell culture plates were incubated at 37°C with 5% CO2 for 5 days. Add an equal volume of CellCounting-Lite 2.0 assay reagent to each well of the cell plate, vortex for 2-5 min to allow for complete cell lysis, and incubate at room temperature for 10 min to stabilize the luminescence signal. Read the luminescence value using an Envision microplate reader. Calculate the inhibition rate using the following formula: Inhibition (%) = (Signal) / (Inhibition (%)) negative control –Signal sample ) / (Signal negative control –Signal positive control )*100, then use IDBS XLfit to perform 4-parameter fitting to calculate IC. 50 Numerical value. Measured IC 50 The values ​​are shown in Table 1.

[0319] Table 1

[0320]

Claims

1. A compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, ###0001### Formula (I) n is selected from a natural number from 1 to 6; and wherein one or more hydrogen atoms of the compound are optionally deuterium atoms. n is 1, 2 or 3; or n is 1 or 2. X 1 and X 2 are each independently selected from N and C; L is selected from the group consisting of imino, 4-10 membered heterocyclylenyl, C6-C 10 arylenyl and 5-12 membered heteroarylenyl, said imino, 4-10 membered heterocyclylenyl, C6-C 10 arylenyl and 5-12 membered heteroarylenyl is optionally substituted with 1 or more R L ; A is selected from C3-C 12 Cycloalkylene, 4-10 membered heterocyclic alkylene, C6-C 10 arylene and 5-12-membered heteroarylene, the C3-C 12 Cycloalkylene, 4-10 membered heterocyclic alkylene, C6-C 10 arylene and 5-12 heteroarylene are optionally enclosed by one or more R a replace; R 1 selected from the group consisting of Ci-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-12 membered heteroaryl, said Ci-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-12 membered heteroaryl are optionally substituted with 1 or more R 1a ; R 2 , R 3 , R 7 , R 8 and R 9 are independently selected from hydrogen, halogen, hydroxyl, cyano, Ci-C 10 alkyl, Ci-C 10 alkoxy, Ci-C 10 haloalkyl and C3-C7cycloalkyl; or R 2 and the atom to which they are attached together form a C3-C6cycloalkyl and 4-6 membered heterocyclyl, optionally substituted with 1 or more R 3 substituents; and the atom to which they are attached together form a C3-C6cycloalkyl and 4-6 membered heterocyclyl, optionally substituted with 1 or more R b substituents; R 4 selected from the group consisting of nothing, hydrogen, halogen, hydroxyl, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl, and C1-C 10 alkyl, said C2-C 10 alkenyl, C2-C 10 alkynyl, and C1-C 10 alkyl optionally substituted with 1 or more R 4a ; or R 4 and the atom to which they are attached together form a 4-10 membered heterocyclyl ring, which is optionally substituted with 1 or more R 7 and the atom to which they are attached together form a 4-10 membered heterocyclyl ring, which is optionally substituted with 1 or more R k substituents; R 5 selected from the group consisting of C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl, said C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl are optionally substituted with 1 or more R 5a substituents, and when the heteroatom is N, N can optionally be oxidized + N-O - ); R 6 selected from hydrogen, halogen, amino, hydroxyl, thiol, cyano, C1-C4alkyl, C1-C4haloalkyl, and C1-C4alkoxy; R 10 selected from the group consisting of halogen, C2-C 10 alkenyl, C1-C 10 haloalkyl, C1-C 10 hydroxy-substituted alkyl and C1-C 10 alkoxy; Each R a R b and R L Independently selected from halogens, amino groups, hydroxyl groups, mercapto groups, cyano groups, oxo groups, and C1-C4 alkyl groups; Each R 1a Independently selected from halogen, amino, hydroxyl, mercapto, cyano, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-12 heteroaryl, the C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-12 heteroaryl groups are optionally substituted with one or more R groups. 1aa replace; Each R 4a and R k Independently selected from halogen, amino, hydroxyl, mercapto, cyano, C1-C7 alkyl, C1-C7 haloalkyl and C1-C7 alkoxy; Each R 5a Independently selected C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-14 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl, the C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 4-14 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one or more R groups. c replace; Each R c Independently selected from halogen, amino, hydroxyl, mercapto, cyano, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl and 4-12 membered heterocyclic groups, wherein the amino, hydroxyl, mercapto, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl groups and 4-12 membered heterocyclic groups are optionally surrounded by one or more R groups. h replace; R 5b and R 5b’ are independently selected from the group consisting of C1-C7alkyl, C3-C 12 cycloalkyl, 4-12 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, said C1-C7alkyl, C3-C 12 cycloalkyl, 4-12 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl are optionally substituted with 1 or more R d ; or R 5b and R 5b’ and the atom to which they are attached together form a 4-12 membered heterocyclyl group, which is optionally substituted with 1 or more R e substituents; Each R d and R e The radical is independently selected from halogen, hydroxyl, amino, C1-C7 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and 4-10 membered heterocyclic groups, wherein the amino, C1-C7 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and 4-10 membered heterocyclic groups are optionally surrounded by one or more R... f replace; Each R f Independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and 4-10 membered heterocyclic groups, wherein the C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and 4-10 membered heterocyclic groups are optionally surrounded by one or more R... g replace; Each R g and R h Independently selected from halogens, hydroxyl groups, mercapto groups, amino groups, =O, C1-C4 alkyl groups, C1-C4 hydroxyalkyl groups, C1-C4 haloalkyl groups, C3-C6 cycloalkyl groups, 4-10 membered heterocyclic groups, C1-C4 alkylene groups, C1-C4 alkyl groups, and C1-C4 alkoxy groups; Each R 1aa Independently selected from halogen, amino, hydroxyl, mercapto, and cyano groups; A compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from a compound of Formula (II) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof: ###0002### Formula (II) A compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from a compound of Formula (III) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof: ###0003### Formula (III) 2. The compound of claim 1 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, X 1 is N; or X 1 is C; and / or X 2 is N; or X 1 is C, and X 2 is N.

3. The compound of any one of claims 1-2 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, A is selected from 4-10 membered heterocyclylene, C6-C 10 arylene and 5-12 membered heteroarylene, said 4-10 membered heterocyclylene, C6-C 10 arylene and 5-12 membered heteroarylene is optionally substituted with 1 or more R a substituents; or A is selected from 5-6 membered heterocyclylene, phenylene and 5-6 membered heteroarylene, said 5-6 membered heterocyclylene, phenylene and 5-6 membered heteroarylene is optionally substituted with 1 or more R a substituents; or A is selected from thiazolylene, phenylene and morpholinylene, said thiazolylene, phenylene and morpholinylene is optionally substituted with 1 or more R a substituents; or A is selected from said is optionally substituted with 1 or more R a substituents; or A is selected from or A is selected from optionally substituted a or A is selected from optionally substituted or A is or A is wherein * represents the linking end to the phenyl ring; and / or each R a is independently selected from halogen, amino, hydroxyl, thiol and cyano; or R a is hydroxyl.

4. The compound of any one of claims 1-3 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, L is selected from imino, and 4-10 membered heterocyclylidenyl, said imino and 4-10 membered heterocyclylidenyl being optionally substituted with 1 or more R L L is selected from imino, and 5-6 membered heterocyclylidenyl, said imino and 5-6 membered heterocyclylidenyl being optionally substituted with 1 or more R L L is selected from imino, and 5 membered nitrogen containing heterocyclylidenyl, said imino and 5 membered nitrogen containing heterocyclylidenyl being optionally substituted with 1 or more R L L is selected from imino, L is L is wherein # represents the point of attachment to R 1 and R L is independently selected from halogen, hydroxy, oxo, and C1-C4 alkyl.

5. The compound of any one of claims 1-4 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 1 Selected from C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups and 5-12 membered heteroaryl groups, wherein the C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-10-membered heterocyclic and 5-12-membered heteroaryl groups are optionally surrounded by one or more R groups. 1a Replace; or R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic and 5-10-membered heteroaryl groups, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic and 5-10-membered heteroaryl groups are optionally surrounded by one or more R groups. 1a Replace; or R 1 Selected from C3-C6 cycloalkyl groups, wherein the C3-C6 cycloalkyl group is optionally surrounded by one or more R groups. 1a Replace; or R 1 Selected from methyl, cyclopropyl, cyclopentyl, tetrahydropyrrolyl, isopropyl, pentyl, oxadiazolyl and The methyl, cyclopropyl, cyclopentyl, tetrahydropyrrolyl, isopropyl, pentyl, oxadiazolyl and Optionally by one or more R 1a Replace; or R 1 Selected from one or more R 1a Substituted cyclopropyl; or R 1 Selected from methyl, cyclopropyl, cyclopentyl, Isopropyl, The methyl, cyclopropyl, cyclopentyl, Isopropyl, Optionally by one or more R 1a Replace; or R 1 for Or R 1 for And / or each R 1a Independently selected from C1-C4 alkyl groups, wherein the C1-C4 alkyl group is optionally surrounded by one or more R... 1aa Replace; or each R 1a Independent selection by one or more R 1aa Substituted methyl groups; or each R 1a It is a methyl group.

6. The compound of any one of claims 1-5 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 2 R 3 Independently selected from hydrogen, halogen, hydroxyl, cyano and C1-C 10 Alkyl; or R 2 R 3 Independently selected from C1-C4 alkyl groups, such as methyl; or R 2 R 3 All are methyl; or R 2 and R 3 The atoms connected to it together form a C3-C6 cycloalkyl group, which is optionally bound by one or more R atoms. b Replace; or R 2 and R 3 The cyclobutyl group and its connected atoms together form a cyclobutyl group, which is optionally bound by one or more R atoms. b Replace; or R 2 and R 3 The atoms connected to it together form a cyclobutyl group; and / or each R b It is independently selected from halogens, hydroxyl groups, and C1-C4 alkyl groups.

7. The compound of any one of claims 1-6 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 4 selected from hydrogen, halogen, hydroxyl, cyano, Ci-C4alkyl, and Ci-C4haloalkyl; or R 10 selected from hydrogen, halogen, hydroxyl, cyano, Ci-C4alkyl, and Ci-C4haloalkyl; or R 10 selected from hydrogen, halogen, hydroxyl, cyano, Ci-C4alkyl, and Ci-C4haloalkyl; or R 4 selected from hydrogen, halogen, hydroxyl, cyano, Ci-C4alkyl, and Ci-C4haloalkyl; or R 4 selected from hydrogen, halogen, hydroxyl, cyano, Ci-C4alkyl, and Ci-C4haloalkyl; or R 4 selected from hydrogen, halogen, hydroxyl, cyano, Ci-C4alkyl, and Ci-C4haloalkyl; or R 4 is ethyl.

8. The compound of any one of claims 1-7 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 5 selected from 4-10 membered heterocyclyl and 5-10 membered heteroaryl, said 4-10 membered heterocyclyl and 5-10 membered heteroaryl optionally substituted with 1 or more R 5a ; or R 5 selected from 4-10 membered heterocyclyl and 5-6 membered heteroaryl, said 4-10 membered heterocyclyl and 5-6 membered heteroaryl optionally substituted with 1 or more R 5a ; or R 5 selected from pyridinyl, thienyl, pyrazolyl, and tetrahydroindolizine, N in said pyridinyl optionally oxidized + N-O - ), said pyridinyl, thienyl, pyrazolyl, and tetrahydroindolizine optionally substituted with 1 or more R 5a ; or R 5 selected from pyridinyl, thienyl, pyrazolyl, and tetrahydroindolizine, said pyridinyl, thienyl, pyrazolyl, and tetrahydroindolizine optionally substituted with 1 or more R 5a ; or R 5 selected from said optionally substituted with 1 or more R 5a ; or R 5 is wherein N can be oxidized to form said optionally substituted with 1 or more R 5a ; or R 5 is optionally substituted with 1 or more R 5a ; or R 9. The compound of any one of claims 1-8 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, each R 5a is independently selected from the group consisting of C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C10aryl, and 4-10 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C10aryl, and 4-10 membered heterocyclyl being optionally substituted with 1 or more R 10 is independently selected from the group consisting of C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C 10 aryl, and 4-10 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C 10 aryl, and 5-10 membered heteroaryl, said C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C 10 aryl, and 5-10 membered heteroaryl, said C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C 10 aryl, and 4-10 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C 10 aryl, and 4-10 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C 10 aryl, and 5-10 membered heteroaryl, said C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C 10 aryl, and 5-10 membered heteroaryl, said C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C c is independently selected from the group consisting of C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C 5a aryl, and 4-10 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C 10 aryl, and 4-10 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C 10 aryl, and 4-10 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C c is independently selected from the group consisting of C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C 5a is independently selected from the group consisting of C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C is independently selected from the group consisting of C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C is independently selected from the group consisting of C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C c is independently selected from the group consisting of C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C 5a is independently selected from the group consisting of C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C is independently selected from the group consisting of C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C is independently selected from the group consisting of C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C c is independently selected from the group consisting of C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C 5a is independently selected from the group consisting of C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C c is independently selected from the group consisting of C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C 5a is independently selected from the group consisting of C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C is independently selected from the group consisting of C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C 5a is independently selected from the group consisting of C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C is independently selected from the group consisting of C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C 5a is independently selected from the group consisting of C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C6-C 10. The compound of any one of claims 1-9 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, each R c is independently selected from the group consisting of amino, C1-C7alkyl, C1-C7alkoxy, C3-C8cycloalkyl, and 4-12 membered heterocyclyl, said amino, C1-C7alkyl, C1-C7alkoxy, C3-C8cycloalkyl, and 4-12 membered heterocyclyl being optionally substituted with one or more R 10 is independently selected from the group consisting of amino, C1-C7alkyl, C1-C7alkoxy, C3-C8cycloalkyl, and 4-12 membered heterocyclyl, said amino, C1-C7alkyl, C1-C7alkoxy, C3-C8cycloalkyl, and 4-12 membered heterocyclyl being optionally substituted with one or more R 10 is independently selected from the group consisting of amino, C1-C7alkyl, C1-C7alkoxy, C3-C8cycloalkyl, and 4-12 membered heterocyclyl, said amino, C1-C7alkyl, C1-C7alkoxy, C3-C8cycloalkyl, and 4-12 membered heterocyclyl being optionally substituted with one or more R h is independently selected from the group consisting of C1-C4alkyl, C1-C4alkoxy, C3-C6cycloalkyl, and 4-6 membered heterocyclyl, said C1-C4alkyl, C1-C4alkoxy, C3-C6cycloalkyl, and 4-6 membered heterocyclyl being optionally substituted with one or more R c is independently selected from the group consisting of C1-C4alkyl, C1-C4alkoxy, C3-C6cycloalkyl, and 4-6 membered heterocyclyl, said C1-C4alkyl, C1-C4alkoxy, C3-C6cycloalkyl, and 4-6 membered heterocyclyl being optionally substituted with one or more R h is independently selected from the group consisting of C1-C4alkyl, C1-C4alkoxy, C3-C6cycloalkyl, and 4-6 membered heterocyclyl, said C1-C4alkyl, C1-C4alkoxy, C3-C6cycloalkyl, and 4-6 membered heterocyclyl being optionally substituted with one or more R c is independently selected from the group consisting of C1-C4alkyl, C1-C4alkoxy, C3-C6cycloalkyl, and 4-6 membered heterocyclyl, said C1-C4alkyl, C1-C4alkoxy, C3-C6cycloalkyl, and 4-6 membered heterocyclyl being optionally substituted with one or more R h is independently selected from the group consisting of C1-C4alkyl, C1-C4alkoxy, C3-C6cycloalkyl, and 4-6 membered heterocyclyl, said C1-C4alkyl, C1-C4alkoxy, C3-C6cycloalkyl, and 4-6 membered heterocyclyl being optionally substituted with one or more R c is independently selected from the group consisting of amino, methyl, ethyl, methoxy, cyclopropyl, piperazinyl, morpholinyl, azetidinyl, oxetanyl, and piperidinyl, said amino, methyl, ethyl, methoxy, cyclopropyl, piperazinyl, morpholinyl, azetidinyl, oxetanyl, and piperidinyl being optionally substituted with one or more R h is independently selected from the group consisting of methyl, methoxy, cyclopropyl, piperazinyl, morpholinyl, azetidinyl, oxetanyl, c is independently selected from the group consisting of methyl, methoxy, cyclopropyl, piperazinyl, morpholinyl, azetidinyl, oxetanyl, said methyl, methoxy, cyclopropyl, piperazinyl, morpholinyl, azetidinyl, oxetanyl, being optionally substituted with one or more R h is independently selected from the group consisting of methyl, methoxy, cyclopropyl, piperazinyl, morpholinyl, azetidinyl, oxetanyl, each R c is independently selected from methoxy or methyl; and / or each R h is independently selected from C1-C4alkyl, C1-C4hydroxyalkyl, C3-C6cycloalkyl, and 4-10 membered heterocyclyl; or each R h is independently selected from hydroxyethyl, methyl, cyclopropyl, and morpholinyl.

11. The compound of any one of claims 1-10 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 6 selected from hydrogen, halogen, amino, hydroxyl, thiol, cyano, and C1-C4alkyl; or R 6 is hydrogen.

12. The compound of any one of claims 1-11 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 7 selected from hydrogen, halogen, hydroxyl, and cyano; or R 7 is hydrogen.

13. The compound of any one of claims 1-12 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 8 Selected from hydrogen, halogen, hydroxyl, cyano and C1-C 10 Alkyl; or R 8 It is hydrogen.

14. The compound of any one of claims 1-13 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 9 is selected from hydrogen, halogen, hydroxyl, and cyano; or R 9 is selected from hydrogen and halogen; or R 9 is selected from hydrogen and fluorine; or R 9 is hydrogen.

15. The compound of any one of claims 1-14 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 10 selected from halogen, such as fluorine; or R 10 is fluorine.

16. The compound of any one of claims 1-15 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, 20. A compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, selected from the following compounds or a pharmaceutically acceptable salt thereof, ###0004### Formula (I) 17. The compound of any one of claims 1-16 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, selected from wherein n is 1 or 2; or selected from or selected from or is 18. The compound of claim 1 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, 21. A pharmaceutical composition comprising a compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20 and a pharmaceutically acceptable excipient. wherein n is 1 or 2, A, L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined in claims 1-17.

19. The compound of claim 1 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, 22. Use of a compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, or a pharmaceutical composition according to claim 21, for the manufacture of a medicament for the prevention or treatment of a RAS-mediated disease. wherein n is 1 or 2; R 10 selected from halogen, halogen is preferably fluorine; R 1 , R 2 , R 3 , R 4 and R 5a as defined in claims 1-17. ​ ​ ​

Images