Preparation and use of indole derivative

Abstract

The present disclosure relates to a RAS inhibitor compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing same, and a use thereof in preparation of drugs for preventing or treating RAS-mediated diseases.

Description

Preparation and application of indole derivatives

[0001] Cross-reference to related applications

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

[0003] Patent application No. 202411222341.3, filed with the State Intellectual Property Office on September 2, 2024;

[0004] Patent application No. 202411460752.6 was filed with the State Intellectual Property Office on October 18, 2024. Technical Field

[0005] 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

[0006] The KRAS gene (Kirsten Rat Sarcoma Viral Oncogene Homolog, a homolog of the Kirsten rat sarcoma virus oncogene) belongs to the RAS gene family (RAS was the first human tumor gene discovered; the KRAS gene family also includes NRAS (Neuroblastoma-RAS) and HRAS (Harvey-RAS)). Located on chromosome 12, it participates in intracellular signal transduction. The KRAS protein encoded by the KRAS gene is a small GTPase, belonging to the RAS superprotein family. The KRAS protein has 188 amino acids and a molecular weight of 21.6 kDa. KRAS is activated by binding to GTP and deactivated by binding to GDP. The KRAS protein is regulated by guanine nucleotide exchange factors (GEFs) and GTPase activators (GAPs) to maintain its activation and inactivation states. Activated KRAS proteins primarily activate downstream pathways such as the PI3K-AKT-mTOR signaling pathway, which controls cell production, and the RAS-RAF-MEK-ERK signaling pathway, which controls cell proliferation. Most small molecule drugs work by binding to functionally important pockets on target proteins, thereby modulating their activity. For example, cholesterol-lowering drugs called statins bind to the active site of HMG-CoA reductase, thereby preventing the enzyme from binding to its substrate. Indeed, many such drug / target interactions are known, which may mislead one into believing that with a reasonable amount of time, effort, and resources, small molecule regulators targeting most (if not all) proteins can be discovered. This is not the case. Currently, it is estimated that only about 10% of all human proteins are suitable targets for small molecules. The remaining 90% are currently considered difficult to treat or manage with the aforementioned small molecule drugs. These targets are often referred to as “undruggable.” A large portion of these undruggable targets, or medically important human proteins, do not yet have a studied library of compounds. Therefore, there is great interest in discovering novel molecules that can modulate the function of such druggable targets. Given the importance of the RAS signaling pathway in cancer treatment, targeted therapy against the RAS signaling pathway has become a research hotspot in the field of cancer treatment in recent years. This disclosure identifies a class of heterocyclic compounds that exhibit good killing effects against tumors with different RAS mutations and RAS protein dependence, and can treat RAS mutation-mediated tumors. Summary of the Invention

[0007] This disclosure relates to compounds of formula (I) or their stereoisomers or pharmaceutically acceptable salts.

[0008] in, Selected from

[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 group, hydroxyl group, 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. d replace;

[0017] R 5 Selected from 10-20 fused heterocyclic groups, wherein the 10-20 fused heterocyclic group comprises 3-4 monocyclic structures, and wherein the 10-20 fused heterocyclic group is optionally bounded by one or more R... 5a replace;

[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, hydroxyl groups, C1-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 groups, wherein the amino, hydroxyl, mercapto, C1-C 10Alkyl, 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 d Independently selected from halogen, amino, hydroxyl, mercapto, cyano, C1-C7 alkyl, C1-C7 haloalkyl and C1-C7 alkoxy;

[0023] Each R 5a Independently selected from halogen, hydroxyl, cyano, amino, oxo, 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 groups, wherein the hydroxyl, amino, 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. e replace;

[0025] Each R e Independently selected from halogens, hydroxyl groups, mercapto groups, cyano groups, amino groups, =O groups, 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;

[0026] Each R 1aa Independently selected from halogen, amino, hydroxyl, mercapto, and cyano groups;

[0027] n is a natural number selected from 0 to 6;

[0028] One or more hydrogen atoms in the compound of formula (I) may be selected as deuterium atoms.

[0029] In some implementation schemes, X 1 The answer is C.

[0030] In some implementation schemes, X 1 Let N be the number of elements in the array.

[0031] In some implementation schemes, X 2 Let N be the number of elements in the array.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] In some embodiments, A is selected from 5-6-membered heteroaryl groups, wherein the 5-6-membered heteroaryl group is optionally surrounded by one or more R groups. a replace.

[0037] 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.

[0038] In some implementation schemes, A is selected from The Optional by one or more R a replace.

[0039] In some implementation schemes, A is selected from The Optional R a replace.

[0040] In some implementation schemes, each Ra It is independently selected from halogen, amino, hydroxyl, mercapto and cyano groups.

[0041] In some implementation schemes, R a It is a hydroxyl group.

[0042] In some implementation schemes, A is selected from

[0043] In some implementation schemes, A is

[0044] In some implementation schemes, A is The asterisk (*) represents the end connected to the benzene ring.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] In some implementation schemes, each R L It is independently selected from halogens, hydroxyl groups, oxo groups, and C1-C4 alkyl groups.

[0049] In some implementations, L is selected from imino, In some implementation schemes, L is selected from

[0050] In some implementations, L is

[0051] In some implementations, L is Where # represents R 1 Connecting end.

[0052] In some implementation schemes, R 1 Selected from C1-C 10 Alkyl, C3-C 10 Cycloalkyl and 4-10 membered heterocyclic groups, the C1-C 10 Alkyl, C3-C 10Cycloalkyl groups and 4-10-membered heterocyclic groups are optionally surrounded by one or more R groups. 1a replace.

[0053] In some implementation schemes, R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, and 4-7 membered heterocyclic groups, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, and 4-7 membered heterocyclic groups are optionally surrounded by one or more R groups. 1a replace.

[0054] In some implementation schemes, R 1 Selected from cyclopropyl, tetrahydropyrrole, and pentyl, wherein the cyclopropyl, tetrahydropyrrole, and pentyl are optionally converted by one or more R... 1a replace.

[0055] In some implementation schemes, R 1 Selected from cyclopropyl, The cyclopropyl, Optionally by one or more R 1a replace.

[0056] In some implementation schemes, R 1 Selected from cyclopropyl and The cyclopropyl and Optionally by one or more R 1a replace.

[0057] In some implementation schemes, each R 1a Independently selected from halogens, C1-C 10 Alkyl groups and 5-12 heteroaryl groups, the C1-C 10 Alkyl groups and 5-12 heteroaryl groups are optionally bounded by one or more R groups. 1aa replace.

[0058] In some implementation schemes, each R 1a Independently selected from halogens, C1-C4 alkyl groups, and 5-6 heteroaryl groups, wherein the C1-C4 alkyl groups and 5-6 heteroaryl groups are optionally surrounded by one or more R groups. 1aa replace.

[0059] In some implementation schemes, each R 1a The radicals are independently selected from fluorine, methyl, pyrimidinyl, and pyridinyl, wherein the methyl, pyrimidinyl, and pyridinyl groups are optionally surrounded by one or more R groups. 1aa replace.

[0060] In some implementation schemes, each R 1a Independently selected from fluorine and methyl, wherein the methyl group is optionally surrounded by one or more R... 1aa replace.

[0061] In some implementation schemes, each R1aa It is independently selected from halogens.

[0062] In some implementation schemes, R 1 Selected from

[0063] In some implementation schemes, R 1 Selected from

[0064] In some implementation schemes, R 1 Selected from

[0065] In some implementation schemes, R 1 Selected from

[0066] In some implementation schemes, R 2 R 3 Independently selected from hydrogen, halogen, hydroxyl, cyano and C1-C 10 alkyl.

[0067] In some implementation schemes, R 2 R 3 It is independently selected from C1-C4 alkyl groups, such as methyl.

[0068] In some implementation schemes, R 2 R 3 All are methyl groups.

[0069] 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.

[0070] 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.

[0071] In some implementation schemes, each R b It is independently selected from halogens, hydroxyl groups, and C1-C4 alkyl groups.

[0072] In some implementation schemes, R 2 and R 3 Together with the atoms they are attached to, they form a cyclobutyl group.

[0073] In some implementation schemes, R 4 Selected from hydrogen, halogen, hydroxyl, cyano, C1-C10 Alkyl and C1-C 10 Halogenated alkyl groups.

[0074] In some implementation schemes, R 4 Selected from C1-C4 alkyl and C1-C4 haloalkyl.

[0075] In some implementation schemes, R 4 Selected from ethyl groups that are optionally substituted with halogens.

[0076] In some implementation schemes, R 4 Selected from ethyl groups that are optionally fluorinated, such as ethyl and trifluoroethyl.

[0077] In some implementation schemes, R 4 Selected from ethyl and trifluoroethyl.

[0078] In some implementation schemes, R 4 It is an ethyl group.

[0079] In some implementation schemes, R 5 Selected from 14-18 fused heterocyclic groups, wherein the 14-18 fused heterocyclic group comprises 3-4 monocyclic structures, and wherein the 14-18 fused heterocyclic group is optionally separated by one or more R 5a replace.

[0080] In some implementation schemes, R 5 Selected from 14-18 member fused heterocyclic groups, wherein the 14-18 member fused heterocyclic group comprises 3-4 monocyclic structures, wherein the 14-18 member fused heterocyclic group comprises at least one pyridine ring, and wherein the 14-18 member fused heterocyclic group is optionally surrounded by one or more R 5a replace.

[0081] In some implementation schemes, R 5 Selected from 14-18 membered fused heterocyclic groups, wherein the 14-18 membered fused heterocyclic group comprises 3-4 monocyclic structures, the 14-18 membered fused heterocyclic group is connected to the rest of the molecule through a pyridine ring, and the 14-18 membered fused tricyclic or fused tetracyclic group is optionally separated by one or more R... 5a replace.

[0082] In some implementation schemes, R 5 Selected from 14-18 membered fused heterocyclic groups, wherein the 14-18 membered fused heterocyclic group comprises 3-4 monocyclic structures, one of which is a pyridine ring, and the 14-18 membered fused heterocyclic group is connected to the rest of the molecule through the pyridine ring, and the 14-18 membered fused tricyclic or fused tetracyclic group is optionally separated by one or more R... 5a replace.

[0083] In some implementation schemes, R 5Selected from 14-membered fused heterocyclic groups, the 14-membered fused heterocyclic group comprises three monocyclic structures, one of which is a pyridine ring, the 14-membered fused heterocyclic group is connected to the rest of the molecule through the pyridine ring, and the 14-membered fused heterocyclic group is optionally bounded by one or more R 5a replace.

[0084] In some implementation schemes, R 5 Selected from R 5a Replacement Where m is 1 or 2, p is 0 or 1, Y is CH2, O or S, Z is C, CH or N, T is selected from C, CH and N, and ring C is selected from 6-10 membered heterocyclic rings or 5-6 membered heteroaromatic rings.

[0085] In some implementation schemes, R 5 Selected from R 5a Replacement Where m is 1 or 2, p is 0 or 1, Y is O or S, Z is C, CH or N, and ring C is selected from 6-10 membered heterocyclic rings or 5-6 membered heteroaromatic rings.

[0086] In some implementation schemes, R 5 Selected from R 5a Replacement Where Y is CH2, O or S, and Z is CH or N.

[0087] In some implementation schemes, R 5 Selected from R 5a Replacement Where Y is CH2 or O.

[0088] In some implementation schemes, R 5 Selected from The Optionally by one or more R 5a replace.

[0089] In some implementation schemes, R 5 Selected from The Optionally by one or more R 5a replace.

[0090] In some implementation schemes, each R 5a Independently selected from halogen, hydroxyl, cyano, amino, oxo, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkoxy, C3-C 12Cycloalkyl, 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.

[0091] In some implementation schemes, each R 5a Independently selected from halogen, amino, oxo, C1-C 10 Alkyl, C3-C 12 Cycloalkyl and 3-14 membered heterocyclic groups, wherein the amino group, C1-C 10 Alkyl, C3-C 12 Cycloalkyl groups and 3-14-membered heterocyclic groups are optionally surrounded by one or more R groups. c replace.

[0092] In some implementation schemes, each R 5a Independently selected from oxo, C1-C 10 Alkyl, C3-C 12 Cycloalkyl and 3-14 membered heterocyclic groups, the C1-C 10 Alkyl, C3-C 12 Cycloalkyl groups and 3-14-membered heterocyclic groups are optionally surrounded by one or more R groups. c replace.

[0093] In some implementation schemes, each R 5a Independently selected from oxo, C1-C4 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclic groups, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclic groups are optionally surrounded by one or more R groups. c replace.

[0094] In some implementation schemes, each R 5a The amino group is independently selected from fluorine, amino, oxo, methyl, ethyl, cyclopropyl, oxetyl, isopropyl, piperidinyl, and aziridine, wherein the amino, methyl, ethyl, cyclopropyl, oxetyl, isopropyl, piperidinyl, and aziridine groups are optionally separated by one or more R groups. c replace.

[0095] In some implementation schemes, each R 5aThe radical is independently selected from oxo, methyl, ethyl, cyclopropyl, oxetyl, isopropyl, piperidinyl, and aziridine, wherein the methyl, ethyl, cyclopropyl, oxetyl, isopropyl, piperidinyl, and aziridine are optionally separated by one or more R radicals. c replace.

[0096] In some implementation schemes, each R 5a The groups are independently selected from methyl, ethyl, and oxetyl, wherein the methyl, ethyl, and oxetyl groups are optionally surrounded by one or more R groups. c replace.

[0097] In some implementation schemes, each R c Independently selected from C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl and 4-12 membered heterocyclic groups, wherein the 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. e replace.

[0098] In some implementation schemes, each R c Independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, and 4-7 membered heterocyclic groups, wherein the C1-C4 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, and 4-7 membered heterocyclic groups are optionally surrounded by one or more R... e replace.

[0099] In some implementation schemes, each R c Independently selected from methyl, methoxy, cyclopropyl and The methyl, methoxy, cyclopropyl and Optional by one or more R e replace.

[0100] In some implementation schemes, each R e The groups can be independently selected from halogen, hydroxyl, cyano, amino, =O, C1-C4 alkyl, C1-C4 hydroxyalkyl, C3-C6 cycloalkyl and 4-10 heterocyclic groups.

[0101] In some implementation schemes, each R c Independently selected from methyl, methoxy, cyclopropyl and

[0102] In some implementation schemes, R c It is a methoxy group.

[0103] In some implementation schemes, each R 5a Independently selected from methyl, Or oxoheterobutyl.

[0104] In some implementation schemes, R 5 Selected from

[0105] In some implementation schemes, R 5 Selected from

[0106] In some implementation schemes, R 6 It is selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano and C1-C4 alkyl.

[0107] In some implementation schemes, R 6 It is hydrogen.

[0108] In some implementation schemes, R 7 It is selected from hydrogen, halogen, hydroxyl and cyano groups.

[0109] In some implementation schemes, R 7 It is hydrogen.

[0110] In some implementation schemes, R 4 and R 7 The atoms connected to it together form a 6-7 membered heterocycle, which is optionally bounded by one or more R atoms. d replace.

[0111] In some implementation schemes, each R d It is independently selected from halogen, amino, hydroxyl, mercapto and cyano groups.

[0112] In some implementation schemes, each R d It is independently selected from halogens, such as fluorine.

[0113] In some implementation schemes, Selected from The value of t is selected from 0, 1, 2, and 3.

[0114] In some implementation schemes, Selected from The value of t is selected from 0, 1, 2, and 3.

[0115] In some implementation schemes, Selected from

[0116] In some implementation schemes, R 8 Selected from hydrogen, halogen, hydroxyl, cyano and C1-C 10 alkyl.

[0117] In some implementation schemes, R 8 It is hydrogen.

[0118] In some implementation schemes, R 9 It is selected from hydrogen, halogen, hydroxyl and cyano groups.

[0119] In some implementation schemes, R 9 Selected from hydrogen and halogens.

[0120] In some implementation schemes, R 9 Selected from hydrogen and fluorine.

[0121] In some implementation schemes, R 9 It is hydrogen.

[0122] In some implementation schemes, R 10 Selected from halogens, such as fluorine.

[0123] In some implementation schemes, R 10 It is fluorine.

[0124] In some implementations, n is 0, 1, or 2.

[0125] In some implementations, n is 0.

[0126] In some implementation schemes, Selected from

[0127] In some implementation schemes, Selected from

[0128] In some implementation schemes, yes

[0129] 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.

[0130] Among them, A, L, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 and R 9 As defined above.

[0131] 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.

[0132] Among them, Z, Y, 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] 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.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] In some implementations, the RAS-mediated disease is a tumor, such as non-small cell lung cancer or pancreatic cancer.

[0140] Terminology Definitions and Explanations

[0141] 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.

[0142] In this article Indicates the connection site.

[0143] 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, and It is a pair of transisomers, wherein the pyridyl group is an inhibitor of the transisomer. This indicates that the orientation of this three-dimensional object is outward. This indicates that the orientation of this three-dimensional object is inward.

[0144] 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. The absolute configuration of a solid center is represented by direct real keys and direct virtual keys. It indicates the relative configuration of a stereocenter (such as the cis-trans configuration of alicyclic compounds).

[0145] 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.

[0146] 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 ".

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] The term "alkyl" refers to a compound with the general formula C10. n H 2n+1 The alkyl group can be straight-chain or branched. The term "C1-C" refers to a 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. 10Alkyl 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.

[0154] 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".

[0155] 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.

[0156] 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) and propynyl (-C≡CCH). 3、 -CH2C≡CH), but-1-ynyl, but-2-ynyl, or but-3-ynyl. "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).

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group formed by two or more saturated or partially unsaturated monocyclic rings sharing a pair of adjacent ring atoms, wherein the ring atoms contain one or more (e.g., 1, 2, 3, 4, or 5) heteroatoms or heteroatom groups (i.e., atomic groups containing heteroatoms). The "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-, etc. The term "10-20 membered fused heterocyclic group" refers to a fused heterocyclic group having 10 to 20 ring atoms, wherein the monocyclic ring sharing the pair of adjacent ring atoms is a 3- to 8-membered monocyclic heterocyclic group. The term "14-18 membered fused heterocyclic group" refers to a fused heterocyclic group having 14 to 18 ring atoms. Specific examples of fused heterocyclic groups include, but are not limited to, those that can be connected to the rest of the molecule by any suitable ring atom.

[0163] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0164] The term "hydroxyl group" refers to the -OH group.

[0165] The term "cyano" refers to the -CN group.

[0166] The term "amino" refers to the -NH2 group.

[0167] The term "nitro" refers to the -NO2 group.

[0168] 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:

[0169] (i) Suppress the disease or disease state, that is, curb its development;

[0170] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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”.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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.

[0186] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] Abbreviations:

[0192] EA represents ethyl acetate; TBDPS represents tert-butyldiphenylsilyl; TBDPSCl represents tert-butyldiphenylchlorosilane; DCM represents dichloromethane; DMF represents N,N-dimethylformamide; THF represents tetrahydrofuran; Fmoc represents 9-fluorenylmethoxycarbonyl; Cbz represents benzyloxycarbonyl; MeOH represents methanol; TsOH .H2O represents p-toluenesulfonic acid monohydrate; diludine represents dihydropyridine; AgOTf represents silver trifluoromethanesulfonate; DMAP represents 4-dimethylaminopyridine; TMSCHN2 represents trimethylsilyl diazomethane; TsCl represents p-toluenesulfonyl chloride; NMP represents N-methylpyrrolidone; LDA represents lithium diisopropylaminodimethyl ... 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; HATU represents 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; Et3N or TEA represents triethylamine; PPh3: triphenylphosphine; ACN / MeCN represents acetonitrile; NIS represents... N-Iodosuccinimide; KOAc / AcOK represents potassium acetate; EtI represents iodoethane; Boc represents tert-butyloxycarbonyl; dioxane represents 1,4-dioxane; TCFH represents N,N,N',N'-tetramethylchloromethanemid hexafluorophosphate; NMI represents N-methylimidazolium; TBAF represents tetrabutylammonium fluoride; DMSO represents dimethyl sulfoxide; mCPBA represents m-chloroperoxybenzoic acid; TFAA represents trifluoroacetic anhydride; DIAD represents azodicarbonic acid. Diisopropyl ester; Pd2(dba)3 represents tris(dibenzylacetone)dipalladium; XantPhos represents 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene); Sphos represents 2-biscyclohexylphosphine-2′,6′-dimethoxy-biphenyl; XPhos represents 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl; BINAP represents 1,1'-binaphthyl-2,2'-bis(diphenylphosphine); LC-MS represents liquid chromatography-mass spectrometry; 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

[0193] 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.

[0194] 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.

[0195] Unless otherwise stated, the proportions of mixed solvents are volume-based.

[0196] Unless otherwise stated, % refers to weight percentage (wt%).

[0197] Compounds are processed manually or Software naming conventions are used; commercially available compounds use supplier catalog names.

[0198] 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).

[0199] The eluent or mobile phase may be a mixture of two or more solvents, with the ratio being the volume ratio of each solvent.

[0200] Preparation Example

[0201] Preparation Example 1: Synthesis of intermediate compound Int-1

[0202] Step 1: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropionic acid (compound A2)

[0203] 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.

[0204] Step 2: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropionyl chloride (compound A3)

[0205] 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.

[0206] Step 3: Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropane-1-one (compound A4)

[0207] 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] + .

[0208] Step 4: Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropane-1-ol (compound A5)

[0209] 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.

[0210] Step 5: Synthesis of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1H-indole (compound A6)

[0211] 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 complete, 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%). MS (ESI) + m / z = 520.0 [M+H] + .

[0212] Step 6: Synthesis of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-iodo-1H-indole (compound Int-1)

[0213] 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] + .

[0214] Preparation Example 2: Synthesis of intermediate compound Int-2

[0215] Step 1: Synthesis of 3-(2-diazoacetyl)cyclobutane-1-one (compound B2)

[0216] Under ice bath conditions, thionyl chloride (89.12 mL, 1.23 mol) was added dropwise to a 0.7 L solution of compound B1 (70.0 g, 613.5 mmol) in ethyl acetate. The mixture was heated to 60 °C and stirred for 4 hours. After the reaction was complete, the reaction solution was concentrated to dryness and azeotropically treated with toluene. The crude product was dissolved in a mixed solution of tetrahydrofuran (250.0 mL) and acetonitrile (250.0 mL). At 0 °C, a 2.0 M solution of trimethylsilyl diazomethane in hexane (460.1 mL, 920.2 mmol) was added dropwise to the crude product solution, and the mixture was slowly heated to room temperature and stirred for 12 hours. After the reaction was complete, the reaction solution was cooled to 0 °C, and the reaction was quenched with acetic acid (50.0 mL) and water (200.0 mL). The solution was then concentrated to obtain a residue, which was diluted with a saturated aqueous sodium bicarbonate solution (200.0 mL). The obtained mixture was extracted three times with ethyl acetate (300 mL). The combined organic layers were washed with saturated sodium chloride aqueous solution (300 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound B2 (45.0 g, 325.77 mmol, yield: 53.1%). MS (ESI) + m / z = 139.0 [M+H] + .

[0217] Step 2: Synthesis of 2-(3-oxocyclobutyl)acetic acid (compound B3)

[0218] Silver nitrate (59.0 g, 347.5 mmol) was added in portions to a mixture of compound B2 (40.0 g, 289.6 mmol) and water (360.0 mL) and tetrahydrofuran (720.0 mL). The mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction mixture was concentrated to obtain a residue. Water (1.0 L) was added to the residue, and the pH was adjusted to 1-2 with dilute hydrochloric acid (1.0 M). The resulting mixture was extracted five times with ethyl acetate (300 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound B3 (36.0 g, 280.91 mmol, yield: 97.0%), which was used directly in the next step without further purification. MS (ESI) + m / z = 127.0 [MH] - .

[0219] The third step is the synthesis of (S)-4-benzyl-3-(2-(3-oxocyclobutyl)acetyl)oxazolidin-2-one (compound B4).

[0220] Compound B3 (36 g, 280.91 mmol), (S)-4-benzyloxazolidin-2-one (49.8 g, 281.0 mmol), 4-dimethylaminopyridine (3.8 g, 31.2 mmol), and triethylamine (130.6 mL, 936.6 mmol) were sequentially added to dichloromethane (800.0 mL), followed by the addition of 2-chloro-1-methylpyridine iodide (87.7 g, 343.4 mmol) in portions. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction was quenched with water, and the organic phase was washed twice with water (1000.0 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give compound B4 (49.43 g, 171.64 mmol, yield: 61.1%). MS (ESI) + m / z = 288.1 [M+H] + .

[0221] Step 4: Synthesis of (S)-4-benzyl-3-(2-(3-hydroxycyclobutyl)acetyl)oxazolidin-2-one (compound B5)

[0222] Compound B4 (49.43 g, 171.64 mmol) and acetic acid (22.9 g, 381.4 mmol) were sequentially added to tetrahydrofuran (550.0 mL), the mixture was cooled to 0 °C, and sodium borohydride (5.77 g, 152.6 mmol) was added in portions. After the addition was complete, the mixture was stirred for 2 hours. After the reaction was complete, a saturated ammonium chloride aqueous solution (150.0 mL) was slowly added dropwise to quench the reaction. The mixture was concentrated under reduced pressure to the residue, which was extracted three times with ethyl acetate (300.0 mL). The organic phase was washed with a saturated sodium bicarbonate aqueous solution, the pH was adjusted to 8, the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound B5 (48.68 g, 167.86 mmol, yield: 97.8%), which was used directly in the next step without further purification. MS (ESI) + m / z = 290.2[M+H] + .

[0223] Step 5: Synthesis of (S)-3-(2-(4-benzyl-2-oxooxazolidine-3-yl)-2-oxoethyl)cyclobutyl-4-methylbenzenesulfonate (compound B6)

[0224] Compound B5 (48.68 g, 167.86 mmol), 4-dimethylaminopyridine (18.2 g, 149.3 mmol), and N,N-diisopropylethylamine (48.8 mL, 280.0 mmol) were added to anhydrous dichloromethane (500.0 mL), and the mixture was cooled to 0 °C. p-Toluenesulfonyl chloride (39.1 g, 205.3 mmol) was added in portions. After the addition was complete, the reaction mixture was slowly heated to room temperature and stirred overnight. After the reaction was complete, the mixture was washed with water (500.0 mL) and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give compound B6 (49.8 g, 112.14 mmol, yield: 66.8%). MS (ESI) + m / z = 444.1 [M+H] + .

[0225] Step 6: Synthesis of (S)-4-benzyl-3-(2-(3-bromocyclobutyl)acetyl)oxazolidin-2-one (compound B7)

[0226] Compound B6 (49.8 g, 112.14 mmol) and lithium bromide (19.0 g, 219.2 mmol) were added to N-methylpyrrolidone (500.0 mL), and the reaction mixture was heated to 90 °C and stirred for 12 hours. After the reaction was complete, the mixture was diluted with saturated sodium chloride aqueous solution (1.0 L), extracted three times with ethyl acetate (300.0 mL), and the organic phase was washed once with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound B7 (34.74 g, 98.68 mmol, yield: 88.0%). MS (ESI) + m / z = 352.2[M+H] + .

[0227] Step 7: Synthesis of (S)-2,3-bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid (compound B8)

[0228] Under an argon atmosphere, compound B7 (10.0 g, 28.4 mmol) was dissolved in tetrahydrofuran (100.0 mL), cooled to -78 °C, and then a mixture of lithium diisopropylaminocarbonate in tetrahydrofuran and n-heptane (18.5 mL, 2.0 M) was slowly added dropwise, with stirring for 0.5 h. Then, a solution of di-tert-butyl azodicarbonate (7.84 g, 34.0 mmol) in anhydrous dichloromethane (20.0 mL) was added to the above solution, and stirring continued for 0.5 h. Next, N,N-dimethylpropenylurea (109.2 g, 851.7 mmol) was slowly added to the above reaction solution, the temperature was slowly raised to room temperature, and stirring continued for 13 h. After the reaction was complete, water (100.0 mL) was added to quench the reaction, followed by the addition of lithium hydroxide monohydrate (3.58 g, 85.1 mmol), and stirring was continued at room temperature for 1 h. After the reaction was complete, the reaction solution was concentrated and diluted with saturated sodium chloride aqueous solution (200.0 mL). The solution was extracted three times with ethyl acetate (200.0 mL), and the organic phase was discarded. The aqueous phase was adjusted to pH 5 with dilute hydrochloric acid (1.0 M) and extracted three more times with ethyl acetate (200.0 mL). The organic phase was washed once with saturated sodium chloride aqueous solution, and the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give compound B8 (1.0 g, 2.91 mmol, yield: 10.2%). MS (ESI) + m / z = 343.1 [M+H] + .

[0229] Step 8: Synthesis of 2,3-di-tert-butyl-4-methyl(S)-2,3-diazabicyclo[3.1.1]heptane-2,3,4-tricarboxylic acid ester (compound B9)

[0230] At room temperature, a solution of trimethylsilyldiazomethane in n-hexane (7.3 mL, 2.0 M) was slowly added dropwise to a methanol (10.0 mL) solution of compound B8 (1.0 g, 2.91 mmol), and the mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction was quenched dropwise with acetic acid (0.5 mL) under ice bath conditions. The reaction solution was concentrated to give the title compound B9 (1.0 g, 2.8 mmol, yield: 96.2%). MS (ESI) + m / z = 357.2[M+H] + .

[0231] Step 9: Synthesis of (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid methyl ester (compound Int-2)

[0232] Trifluoroacetic acid (2.0 mL) was slowly added dropwise to a solution of compound B9 (706.0 mg, 1.98 mmol) in dichloromethane (6.0 mL) at room temperature, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated to give the title compound Int-2 (312 mg, 1.98 mmol, yield: 100.0%). MS (ESI) + m / z = 157.0 [M+H] + .

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

[0234] Step 1: Synthesis of 3-(5-bromo-1H-indol-3-yl)-2,2-dimethyl-1-propanol (compound C2)

[0235] Compound A6 (10.4 g, 20.0 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature and added to a tetrahydrofuran solution of tetrabutylammonium fluoride (1.0 M, 50.0 mL). The mixture was stirred at 60 °C for 16 hours. After the reaction was complete, the reaction solution was quenched dropwise in water and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:3) to give the title compound C2 (4.67 g, 16.6 mmol, yield: 83.0%). MS (ESI) + m / z = 282.1[M+H] + .

[0236] Step 2: Synthesis of 3-(5-bromo-1H-indol-3-yl)-2,2-dimethylacetic acid propyl ester (compound C3)

[0237] Acetic anhydride (1.28 mL, 13.11 mmol) was slowly added dropwise to a solution of compound C2 (3.7 g, 13.11 mmol), 4-dimethylaminopyridine (80.1 mg, 655.6 μmol), and triethylamine (3.98 g, 39.34 mmol) in dichloromethane (40.0 mL) under ice bath conditions. The mixture was slowly heated to room temperature and stirred for 6 hours. After the reaction was complete, the reaction solution was quenched dropwise in ice water and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give the title compound C3 (4.0 g, 12.34 mmol, yield: 94.0%). MS (ESI) + m / z = 324.1 [M+H] + .

[0238] Step 3: Synthesis of propyl 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indol-3-yl)acetate (compound C4)

[0239] Compound C3 (4.6 g, 14.19 mmol), potassium acetate (3.48 g, 35.47 mmol), and bis-pinacolborate (9.0 g, 35.47 mmol) were added to 1,4-dioxane (46.0 mL), followed by the addition of [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (1.04 g, 1.42 mmol), purging with argon three times. The resulting mixture was heated to 90 °C under argon protection and stirred for 3 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give the title compound C4 (4.5 g, 12.12 mmol, yield: 85.4%). MS (ESI) + m / z = 372.1 [MH] + .

[0240] Step 4: Synthesis of methyl (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazolyl)-2-((tert-butoxycarbonyl)amino)propionate (compound C5)

[0241] Compound C4 (2.6 g, 7.0 mmol), Int-5 (2.81 g, 7.7 mmol), and potassium phosphate (3.71 g, 17.5 mmol) were dissolved in a mixed solution of dioxane (30.0 mL) and water (3.0 mL). Under nitrogen protection, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (452.2 mg, 618 μmol) was added to the reaction solution, and argon gas was purged five times. The mixture was stirred at 90 °C for 12 hours, and the reaction was monitored for completeness by LC-MS. The solution was diluted with water (50 mL), extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase silica gel column chromatography (water:acetonitrile, gradient: 95 / 5 to 5 / 95) to give compound C5 (3.0 g, 5.66 mmol, yield: 80.9%). MS (ESI) + m / z = 530.1 [M+H] + .

[0242] Step 5: Synthesis of methyl (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)-2-((tert-butoxycarbonyl)amino)propionate (compound C6)

[0243] Compound C5 (3.7 g, 6.98 mmol) and N-iodosuccinimide (1.57 g, 6.99 mmol) were added to N,N-dimethylformamide (40.0 mL), and the mixture was heated to 50 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was poured into water (400.0 mL), extracted three times with ethyl acetate (50.0 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by reversed-phase column chromatography (water:acetonitrile, gradient: 95 / 5 to 5 / 95) to give the title compound C6 (2.6 g, 3.97 mmol, yield: 56.77%). MS (ESI) + m / z = 656.5 [MH] + .

[0244] Step 6: Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl-2-yl)propionic acid (compound C7)

[0245] Compound C6 (2.6 g, 3.97 mmol) was dissolved in a mixed solution of tetrahydrofuran (30 mL) and water (5 mL). Lithium hydroxide (474.9 mg, 19.8 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. The reaction was monitored by LC-MS until complete. The organic solvent was removed by vacuum distillation, and the mixture was diluted with ethyl acetate and water. The pH of the aqueous phase was adjusted to approximately 6 with 1 M HCl aqueous solution, and the phase was extracted with ethyl acetate (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound C7 (2.3 g, 3.84 mmol, yield: 96.7%). MS (ESI) + m / z = 600.0 [M+H] + .

[0246] Step 7: Synthesis of (S)-2-((S)-2-(tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)propionyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid methyl ester (compound C8)

[0247] Compound C7 (393.0 mg, 655.2 μmol), compound Int-2 (265.0 mg, 1.7 mmol), N,N-diisopropylethylamine (1.69 g, 13.11 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (370.8 mg, 975.3 μmol) were added to an 8.0 mL solution of N,N-dimethylformamide and stirred at room temperature for 2 hours. After the reaction was complete, the crude product was purified by reversed-phase column chromatography (water:acetonitrile, gradient: 95 / 5 to 5 / 95) to give the title compound C8 (290.0 mg, 393.1 μmol, yield: 60.0%). MS (ESI) + m / z = 738.1 [M+H] + .

[0248] Step 8: Synthesis of (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)propionyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid (compound C9)

[0249] Compound C8 (290 mg, 393.1 μmol) was dissolved in a mixed solution of tetrahydrofuran (2.0 mL) and water (2.0 mL). Lithium hydroxide (94.1 mg, 3.93 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS until complete. The solution was diluted with ethyl acetate and water, and 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, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound C9 (200.0 mg, 276.4 μmol, yield: 70.3%). MS (ESI) + m / z = 724.1 [M+H] + .

[0250] Step 9: Synthesis of compound Int-3

[0251] Compound C9 (140.0 mg, 193.4 μmol), N-methylimidazole (794.2 mg, 9.67 mmol), and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (298.5 mg, 1.06 mmol) were added to a mixed solution of N,N-dimethylformamide (1.2 mL) and acetonitrile (12.0 mL), and stirred at room temperature for 2 hours. After the reaction was complete, the crude product was purified by reversed-phase column chromatography (water:acetonitrile, gradient: 95 / 5 to 5 / 95) to give the title compound Int-3 (44.0 mg, 62.3 μmol, yield: 32.2%). MS (ESI) + m / z = 706.2[M+H] + .

[0252] Preparation Example 4: Synthesis of intermediate compound Int-4

[0253] The first step was the synthesis of (S)-3-bromo-2-(1-methoxyethyl)pyridine-1-oxide (compound D2).

[0254] Under ice bath conditions, m-chloroperoxybenzoic acid (1.9 g, 11 mmol) was slowly added in three portions to a solution of compound D1 (1.2 g, 5.5 mmol) in dichloromethane (40 mL), and the reaction was carried out at room temperature for 12 hours. The reaction solution was quenched in 1 M sodium thiosulfate aqueous solution (20 mL), and extracted three times with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by normal silica gel column chromatography (methanol / dichloromethane: 0–9%) to give compound D2 (1.2 g, 5.2 mmol, yield: 94%). MS (ESI) + m / z = 232.1[M+H] + .

[0255] The second step involves the synthesis of (S)-5-bromo-6-(1-methoxyethyl)pyridine-2-phenol (compound D3).

[0256] Compound D2 (1.2 g, 5.2 mmol) was dissolved in tetrahydrofuran (50 mL), and trifluoroacetic anhydride (4.3 g, 20 mmol) was slowly added dropwise under ice bath conditions, followed by the slow addition of triethylamine (2.6 g, 26 mmol). The reaction mixture was continued under ice bath conditions for 3 hours. The reaction solution was poured into saturated brine (40 mL), and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were concentrated and dried to obtain crude compound D3, which was directly used in the next step. MS (ESI) + m / z = 232.1[M+H] + .

[0257] The third step is the synthesis of (S)-5-bromo-3-iodo-6-(1-methoxyethyl)pyridine-2-phenol (compound D4).

[0258] The crude compound D3 obtained in the previous step was dissolved in methanol (50 mL), and N-iodosuccinimide (2.3 g, 10 mmol) was added. The reaction was carried out at 50 °C for 2 hours. After the reaction solution cooled to room temperature, it was quenched in a saturated sodium thiosulfate aqueous solution (50 mL). The solution was extracted three times with ethyl acetate (30 mL), and the organic phases were combined, concentrated, and dried. The solution was then subjected to high performance liquid chromatography (HPLC) (column: Welch Xtimate C18, 150 mm long, 30 mm inner diameter, 5 μm particle size; mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95%, elution for 10 column volumes) to obtain compound D4 (0.55 g, 1.5 mmol, yield: 29%). MS (ESI) + m / z = 358.0 [M+H] + .

[0259] Step 4: Synthesis of (S)-3-(((5-bromo-3-iodo-6-((S)-1-methoxyethyl)pyridin-2-yl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester (compound D5)

[0260] Compound D4 (0.29 g, 0.83 mmol), 1-((9H-fluorene-9-yl)methyl)4-(tert-butyl)(S)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid ester (0.72 g, 1.7 mmol), and triphenylphosphine (0.65 g, 2.5 mmol) were dissolved in tetrahydrofuran (20 mL). The air was purged three times with argon. The reaction mixture was stirred in an ice bath for 10 minutes, and diisopropyl azodicarbonate (0.33 g, 1.7 mmol) was slowly added dropwise. The reaction mixture was stirred in an ice bath for 4 hours. After LC-MS monitoring confirmed the complete consumption of compound D4, the reaction solution was concentrated to dryness under reduced pressure and then subjected to high-performance liquid chromatography (HPLC) with a Welch Xtimate C18 column (150 mm long, 30 mm inner diameter, 5 μm particle size; mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95%, elution for 10 column volumes) to obtain compound D5 (0.18 g, 0.32 mmol, yield: 39%). + m / z = 556.2[M+H] + .

[0261] Step 5: Synthesis of (S)-9-bromo-8-((S)-1-methoxyethyl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyridino[2,3-b][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester (Int-4)

[0262] Compound D5 (45 mg, 80 μmol), cesium carbonate (80 mg, 0.24 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (9.1 mg, 16 μmol), and tris(dibenzylacetone)dipalladium (18 mg, 19.6 μmol) were dissolved in dioxane (4 mL), and the mixture was purged with argon three times. The reaction was carried out at 100 °C for 4 hours. After the reaction solution cooled to room temperature, the insoluble matter was removed by filtration, and the solution was concentrated and subjected to high performance liquid chromatography (HPLC) (column: Welch Xtimate C18, 150 mm long, 30 mm inner diameter, 5 μm particle size; mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95%, elution for 10 column volumes) to give compound Int-4 (33 mg, 77 μmol, yield: 95%). MS (ESI) + m / z = 428.3[M+H] + .

[0263] Preparation Example 5: Synthesis of intermediate compound Int-5

[0264] The first step is the synthesis of (4-bromothiazol-2-yl)methanol (compound E2).

[0265] Compound E1 (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. The reaction was monitored for completeness. 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 E2 (9 g, 46.38 mmol, yield 89.07%). MS (ESI) + m / z = 194.3 [M+H] + .

[0266] Step 2: Synthesis of 4-bromo-2-(bromoethyl)thiazole (compound E3)

[0267] Carbon tetrabromide (23.07 g, 69.57 mmol), compound E2 (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 until complete. 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 E3 (9.0 g, 35.20 mmol, yield: 75.9%).

[0268] MS(ESI + m / z = 255.7 [M+H] + .

[0269] Step 3: Synthesis of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (compound E5)

[0270] (R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (compound E4, 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 E3 (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 E5 (10.5 g, 29.14 mmol, yield: 83%). MS (ESI) + m / z = 360.2[M+H] + .

[0271] Step 4: Synthesis of methyl (S)-2-amino-3-(4-bromothiazol-2-yl)propionate (compound E6)

[0272] A solution of compound E5 (10.5 g, 29.14 mmol) in acetonitrile (60 mL) was added to hydrochloric acid (195 mL, 0.3 M). The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LC-MS until completion. The mixture was alkalized to pH 8 with saturated sodium bicarbonate solution. Extraction was then performed 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 E6 (6.8 g, 25.65 mmol, yield: 88%). MS (ESI) + m / z = 264.9 [M+H] + .

[0273] Step 5: Synthesis of (S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonyl)amino)propionate methyl ester (compound Int-5)

[0274] 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 E6 (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-5 (6.5 g, yield: 68%). MS (ESI) + m / z = 364.9 [M+H] + .

[0275] Preparation Example 6: Synthesis of intermediate compound Int-6

[0276] Using the same synthetic route as Int-4, the reactant in the fourth step of that route was replaced with 1-((9H-fluoren-9-yl)methyl)4-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid ester. The compound Int-6 was synthesized.

[0277] Preparation Example 7: Synthesis of intermediate compound Int-7

[0278] The first step is the synthesis of compound F2.

[0279] Compound F1 (8.00 g, 28.75 mmol) was dissolved in dichloromethane (80 mL), followed by the addition of di-tert-butyl dicarbonate (7.50 g, 34.49 mmol) and N,N-diisopropylethylamine (7.40 g, 57.49 mmol). The mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:0-10:1) to give compound F2 (10.00 g, 26.43 mmol, yield: 92%). MS (ESI) + m / z = 379.1 [M+H] + .

[0280] The second step involves the synthesis of compound F3.

[0281] At room temperature, lithium borohydride (1.00 g, 46.0 mmol) was slowly added in portions to a tetrahydrofuran (80 mL) solution of compound F2 (8.00 g, 21.14 mmol), and the mixture was reacted at room temperature for 4 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (100 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-75:25) to give compound F3 (7.00 g, 19.98 mmol, yield: 94%). MS (ESI) + m / z = 351.1[M+H] + .

[0282] The third step involves the synthesis of compound F4.

[0283] Oxaloyl chloride (9.40 g, 74.20 mmol, 6.5 mL) was dissolved in dichloromethane (100 mL), and then dimethyl sulfoxide (8.70 g, 111.30 mmol, 7.90 mL) was added dropwise. The mixture was reacted at -70 °C for 30 minutes. Then, a dichloromethane (100 mL) solution of compound F3 (6.50 g, 18.55 mmol) was added dropwise to the above reaction solution. The mixture was reacted at -70 °C for 1 hour. Then, triethylamine (15.00 g, 148.40 mmol, 20.7 mL) was added dropwise to the reaction solution. The mixture was reacted at -70 °C for 1 hour, and then the temperature was raised to 0 °C and reacted for 1 hour. The reaction mixture was washed with 100 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:0-75:25) to give compound F4 (3.00 g, 8.61 mmol, yield: 46%). MS (ESI) + m / z = 349.1 [M+H] + .

[0284] The fourth step involves the synthesis of compound Int-7.

[0285] At 0 °C, a potassium tert-butoxide solution (1 M, 11.5 mL) was added to a tetrahydrofuran solution of methyltriphenylphosphine bromide (4.10 g, 11.48 mmol) (20 mL). The mixture was stirred at 0 °C for 1 hour. A tetrahydrofuran solution of compound F4 (2.00 g, 5.74 mmol) (20 mL) was added dropwise to the reaction mixture. The mixture was reacted at 0 °C for 2 hours. A saturated ammonium chloride solution (20 mL) was slowly added to the reaction mixture at 0 °C. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-89:11) to give compound Int-7 (1.20 g, 3.46 mmol, yield: 60%). MS (ESI) + m / z = 347.2[M+H] + .

[0286] Preparation Example 8: Synthesis of intermediate compound Int-8

[0287] Synthesis of compound G2 (Step 1)

[0288] At 0 °C, hydrogen peroxide (13.10 g, 115.43 mmol, 30% purity) was added dropwise to a tetrahydrofuran (150 mL) solution of compound G1 (10.00 g, 38.48 mmol), and the mixture was reacted at room temperature for 12 hours. A saturated sodium sulfite aqueous solution (200 mL) was added to the reaction solution, followed by extraction with dichloromethane (100 mL x 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-50:50) to give compound G2 (5.00 g, 21.54 mmol, yield: 56%). MS (ESI) + m / z = 232.0 [M+H] + .

[0289] The second step involves the synthesis of compound G3.

[0290] Compound G2 (4.00 g, 17.24 mmol) and sodium carbonate (5.50 g, 51.71 mmol) were dissolved in water (50 mL), followed by the addition of elemental iodine (4.40 g, 17.24 mmol), and the reaction was carried out at room temperature for 3 hours. The pH was adjusted to 5 with hydrochloric acid (6 M), and then water (50 mL) and dichloromethane (50 mL x 3) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain crude compound G3 (5.00 g), which was used directly in the next step. MS (ESI) + m / z = 357.8 [M+H]+ .

[0291] The third step involves the synthesis of compound G4.

[0292] Under nitrogen protection, potassium carbonate (3.70 g, 26.82 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (1.70 g, 3.58 mmol), and palladium acetate (401.4 mg, 1.79 mmol) were successively added to a solution of compound G3 (3.20 g, 8.94 mmol) and compound Int-7 (3.60 g, 10.28 mmol) in N,N-dimethylformamide (70 mL). The mixture was reacted at 80 °C for 3 hours. The reaction solution was poured into water (200 mL), extracted with ethyl acetate (100 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:0-50:50) to give compound G4 (1.50 g, 2.60 mmol, yield: 29.1%). MS (ESI) + m / z = 576.2 [M+H] + .

[0293] Step 4: Synthesis of compound G5

[0294] Platinum dioxide (393.9 mg, 1.73 mmol) was added to a 25 mL solution of compound G4 (1.00 g, 1.73 mmol) in ethyl acetate at room temperature. The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction solution was filtered, the filter cake was washed with ethyl acetate, the combined organic phases were concentrated to dryness, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:0-1:1) to give compound G5 (560.0 mg, 968.03 μmol, yield: 56%). MS (ESI+) m / z = 578.2 [M+H] + .

[0295] Step 5: Synthesis of compound G6

[0296] Compound G5 (460.0 mg, 795.17 μmol) was dissolved in N,N-dimethylformamide (8 mL), followed by the addition of N-phenylbis(trifluoromethanesulfonyl)imide (397.7 mg, 1.11 mmol) and potassium carbonate (175.8 mg, 1.27 mmol). The mixture was stirred at 40 °C for 1 hour. The reaction solution was poured into water (20 mL), and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:0-67:33) to give compound G6 (450.0 mg, 633.3 μmol, yield: 80%). MS (ESI+) m / z = 710.1 [M+H] + .

[0297] Step 6: Synthesis of compound G7

[0298] At room temperature, 0.4 mL of trifluoroacetic acid was added dropwise to a 1.6 mL solution of compound G6 (550.0 mg, 774.04 μmol) in dichloromethane. The mixture was stirred at room temperature for 1 hour. The reaction mixture was then slowly added dropwise to a saturated aqueous sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound G7 (380.0 mg), which was used directly in the next step. MS (ESI+) m / z = 610.1 [M+H] + .

[0299] Step 7: Synthesis of compound Int-8

[0300] Under nitrogen protection, palladium acetate (10.3 mg, 45.87 μmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (14.3 mg, 22.93 μmol), and cesium carbonate (373.6 mg, 1.15 mmol) were sequentially added to a toluene (15 mL) solution of compound G7 (280.0 mg, 458.69 μmol). The mixture was reacted at 90 °C for 3 hours. The reaction solution was directly concentrated to dryness, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0.75:25) to give compound Int-8 (60.0 mg, 130.33 μmol, yield: 28%). MS (ESI+) m / z = 460.1 [M+H] + .

[0301] Example 1: Synthesis of compounds 1-P1 and 1-P2

[0302] Synthesis of Compounds 1-2 in Step 1

[0303] Compound Int-3 (0.10 g, 0.14 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS until complete. The reaction solution was evaporated to dryness, and then dichloromethane (5 mL) was added again. The pH was adjusted to 7 with saturated sodium bicarbonate aqueous solution (10 mL). The mixture was extracted three times with dichloromethane (5 mL), and the combined organic phases were evaporated to dryness for the next step. MS (ESI) + m / z = 606.5[M+H] + .

[0304] The second step involves the synthesis of compounds 1-3.

[0305] The crude compounds 1-2 and 4-fluoro-2-(2-fluoroethyl)butyric acid (22 mg, 0.14 mmol) obtained in the previous step were dissolved in acetonitrile (5 mL). N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (60 mg, 0.21 mmol) and 1-methylimidazole (30 mg, 0.36 mmol) were added to the solution under ice bath conditions, and the mixture was reacted under ice bath conditions for 1 hour. The reaction solution was diluted with 15 mL of dichloromethane and poured into 20 mL of water. The mixture was extracted three times with 20 mL of dichloromethane. The combined organic phases were concentrated and purified by high-performance liquid chromatography (HPLC) using a Welch Xtimate C18 column (150 mm length, 30 mm inner diameter, 5 μm particle size; mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95%, elution for 10 column volumes) to obtain compounds 1-3 (50 mg, 68 μmol, yield: 47%). MS (ESI) + m / z = 740.6 [M+H] + .

[0306] Step 3: Synthesis of compounds 1-4

[0307] Compounds 1-3 (50 mg, 68 μmol), 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl (5.1 mg, 13 μmol), tris(dibenzylacetone)dipalladium (12 mg, 13 μmol), and potassium acetate (23 mg, 0.24 mmol) were dissolved in tetrahydrofuran (4 mL), and the mixture was purged three times with argon gas and stirred for 5 minutes in an ice bath. Pinaral borane (70 mg, 0.54 mmol) was added dropwise to the reaction mixture, and the mixture was then moved to 50 °C and reacted for 3 hours. After the reaction was complete as monitored by LC-MS, the reaction mixture was filtered and purified by normal-reverse silica gel column chromatography (ethyl acetate / petroleum ether: 0%-80%) to give compounds 1-4 (22 mg, 30 μmol, yield: 44%). MS (ESI) + m / z = 740.7 [M+H] + .

[0308] Step 4: Synthesis of compounds 1-5

[0309] Compounds 1-4 (22 mg, 30 μmol), compound Int-4 (19 mg, 44 μmol), potassium phosphate (16 mg, 74 μmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (2.1 mg, 3.0 μmol) were dissolved in dioxane / water (3 mL / 1 mL), with the air purged three times by argon, and reacted at 70 °C for 12 hours. The reaction solution was filtered, evaporated to dryness, and purified by high performance liquid chromatography (HPLC) using a Welch Xtimate C18 column (150 mm length, 30 mm inner diameter, 5 μm particle size; mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95%, elution for 10 column volumes) to obtain compound 1-5 (15 mg, 16 μmol, yield: 52%). MS (ESI) + m / z = 961.1 [M+H] + .

[0310] Step 5: Synthesis of compounds 1-6

[0311] Compounds 1-5 (15 mg, 16 μmol) were dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (10 mg, 31 μmol) and iodoethane (3.6 mg, 23 μmol) were added. The reaction mixture was reacted at room temperature for 12 hours. The reaction solution was directly purified by high performance liquid chromatography (HPLC) using a Welch Xtimate C18 column (150 mm length, 30 mm inner diameter, 5 μm particle size); mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95%, elution for 10 column volumes) to give compounds 1-6 (14 mg, 14 μmol, yield: 91%). MS (ESI) was then used. + m / z = 989.2[M+H] + .

[0312] Step 6: Synthesis of compounds 1-7

[0313] Compounds 1-6 (14 mg, 14 μmol) were dissolved in 3 mL of 4 M dioxane hydrochloride solution and reacted at room temperature for 1 hour. The reaction solution was then evaporated to dryness and used directly in the next step. MS (ESI) + m / z = 889.2[M+H] + .

[0314] Step 7: Synthesis of Compound 1-P1 and Compound 1-P2

[0315] The crude compounds 1-7 obtained in the previous step were dissolved in methanol (5 mL), and formaldehyde (36% aqueous solution, 0.2 mL) and sodium cyanoborohydride (4.9 mg, 78 μmol) were added. The mixture was reacted at room temperature for two hours. The reaction solution was evaporated to dryness and purified by reverse-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 50%-70%) to obtain compounds 1-P1 (0.50 mg, 0.55 μmol, yield: 3.5%, retention time: 7.71 min) and 1-P2 (1.5 mg, 1.6 μmol, yield: 10.4%, retention time: 6.80 min).

[0316] Compound 1-P1MS (ESI) + m / z = 903.4 [M+H] + .

[0317] 1 H NMR (400MHz, Methanol-d4) δ8.50–8.36(m,1H),7.73–7.63(m,1H),7.59–7.53(m,1 H),7.48–7.40(m,1H),7.28–7.23(m,1H),5.41–5.37(m,1H),5.36–5.32(m,1H),4. 70–4.64(m,2H),4.59–4.56(m,3H),4.55–4.42(m,3H),4.25–4.18(m,1H),4.11–3. 99(m,1H),3.94–3.87(m,1H),3.85–3.72(m,2H),3.71–3.64(m,2H),3.50–3.36(m, 1H),3.22–3.18(m,3H),3.18–3.11(m,1H),3.04–2.94(m,2H),2.90–2.81(m,1H),2 .81–2.69(m,2H),2.68–2.59(m,1H),2.52–2.40(m,2H),2.40–2.36(m,3H),2.34–2 .24(m,1H),2.23–2.16(m,2H),2.14–1.86(m,4H),1.74–1.65(m,1H),1.65–1.55(m ,2H),1.22–1.17(m,3H),1.04–0.99(m,3H),0.94–0.83(m,2H),0.68–0.63(m,3H).

[0318] Compound 1-P2MS (ESI) + m / z = 903.3[M+H] + .

[0319] Example 2: Synthesis of compounds 2-P1 and 2-P2

[0320] Synthesis of compound 2-2 in step one

[0321] Compounds 1-2 (121 mg, 0.20 mmol) and (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid 2-1 (22.8 mg, 0.20 mmol) were dissolved in acetonitrile (5 mL). N,N,N',N'-tetramethylchloromethacin hexafluorophosphate (60 mg, 0.21 mmol) and N-methylimidazole (30 mg, 0.36 mmol) were added to the solution under ice bath conditions, and the mixture was reacted under ice bath conditions for 1 hour. The reaction solution was diluted with 15 mL of dichloromethane and poured into 20 mL of water. The mixture was extracted three times with 20 mL of dichloromethane. The combined organic phases were concentrated and purified by high-performance liquid chromatography (HPLC) using a Welch Xtimate C18 column (150 mm length, 30 mm inner diameter, 5 μm particle size; mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95%, elution for 10 column volumes) to obtain compound 2-2 (90 mg, 0.13 mmol, yield: 64%). MS (ESI) was then used. + m / z = 702.3[M+H] + .

[0322] The second step involves the synthesis of compounds 2-3.

[0323] Compound 2-2 (90 mg, 0.13 mmol), 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl (5.1 mg, 13 μmol), tris(dibenzylacetone)dipalladium (12 mg, 13 μmol), and potassium acetate (23 mg, 0.24 mmol) were dissolved in tetrahydrofuran (4 mL), and the mixture was purged three times with argon gas and stirred for 5 minutes in an ice bath. Pinarane (70 mg, 0.54 mmol) was added dropwise to the reaction mixture, and the mixture was then moved to 50 °C and reacted for 3 hours. After the reaction was complete as monitored by LC-MS, the reaction mixture was filtered and purified by normal silica gel column chromatography (ethyl acetate / petroleum ether: 0%-90%) to give compound 2-3 (48.4 mg, 69 μmol, yield: 53%). MS (ESI) + m / z = 702.2[M+H] + .

[0324] The third step involves the synthesis of compounds 2-4.

[0325] Compounds 2-3 (48.4 mg, 69 μmol), Int-4 (60.0 mg, 140 μmol), potassium phosphate (60 mg, 280 μmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (5.1 mg, 7.0 μmol) were dissolved in dioxane / water (3 mL / 1 mL), with the air purged three times by argon, and reacted at 70 °C for 12 hours. The reaction solution was filtered, evaporated to dryness, and purified by high performance liquid chromatography (HPLC) using a Welch Xtimate C18 column (150 mm length, 30 mm inner diameter, 5 μm particle size; mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 10% to 95%, elution for 8 column volumes) to obtain compound 2-4 (45.2 mg, 49 μmol, yield: 71%). MS (ESI) was then used. + m / z = 923.4 [M+H] + .

[0326] Step 4: Synthesis of compounds 2-5

[0327] Compound 2-4 (45.2 mg, 49 μmol) was dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (32.5 mg, 100 μmol) and iodoethane (15.7 mg, 100 μmol) were added. The reaction mixture was reacted at room temperature for 12 hours. The reaction solution was directly purified by high performance liquid chromatography (HPLC) using a Welch Xtimate C18 column (150 mm length, 30 mm inner diameter, 5 μm particle size); mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95%, elution for 10 column volumes) to give compound 2-5 (40 mg, 42.1 μmol, yield: 86%). MS (ESI) was then used. + m / z = 951.3 [M+H] + .

[0328] Step 5: Synthesis of compounds 2-6

[0329] Compound 2-5 (40 mg, 42.1 μmol) was dissolved in 3 mL of 4 M dioxane hydrochloride solution and reacted at room temperature for 1 hour. The reaction solution was then evaporated to dryness and used directly in the next step. MS (ESI) + m / z = 851.3[M+H] + .

[0330] Step 6: Synthesis of compounds 2-P1 and 2-P2

[0331] Compounds 2-6 obtained in the previous step were dissolved in methanol (5 mL), and formaldehyde (36% aqueous solution, 0.2 mL) and sodium cyanoborohydride (4.9 mg, 78 μmol) were added. The reaction mixture was reacted at room temperature for two hours. The reaction solution was evaporated to dryness and purified by reverse-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 50%-70%) to obtain compounds 2-P1 (5 mg, 5.8 μmol, yield: 13.8%, retention time: 7.25 min) and 2-P2 (11 mg, 12.7 μmol, yield: 30.1%, retention time: 7.9 min).

[0332] Compound 2-P1MS (ESI) + m / z = 865.5[M+H] + .

[0333] 1 H NMR(400MHz, Methanol-d4)δ8.45–8.31(m,1H),7.73–7.56(m,1H),7.57–7.50(m,1H),7.50–7.35(m,1H),7.17–7.00(m,1H),5. 66–5.50(m,1H),5.41–5.23(m,1H),4.70–4.45(m,4H),4.30–4.07(m,5H),3.79–3.57(m,4H),3.49–3.35(m,2H),3.15–2.85(m, 6H),2.84–2.51(m,5H),2.49–2.41(m,1H),2.41–2.35(m,3H),2.34–2.26(m,1H),2.25–2.14(m,1H),2.11–1.97(m,1H),1.98–1 .84(m,1H),1.66–1.48(m,2H),1.41–1.37(m,2H),1.19–1.06(m,7H),1.05–0.97(m,1H),0.94–0.91(m,3H),0.60–0.44(m,3H).

[0334] Compound 2-P2MS (ESI) + m / z = 865.5[M+H] + .

[0335] 1H NMR(400MHz, Methanol-d4)δ8.43–8.39(m,1H),7.70–7.64(m,1H),7.57–7.53(m ,1H),7.47–7.42(m,1H),7.28–7.24(m,1H),5.93–5.86(m,1H),5.45–5.40(m,1H ),4.78–4.72(m,1H),4.69–4.63(m,1H),4.61–4.55(m,1H),4.54–4.47(m,1H),4 .26–4.18(m,1H),4.10–4.00(m,1H),3.95–3.88(m,1H),3.86–3.79(m,1H),3.43– 3.36(m,1H),3.29–3.22(m,3H),3.20(s,3H),3.18–3.12(m,2H),3.03–2.93(m,2 H),2.81–2.69(m,2H),2.67–2.59(m,1H),2.51–2.41(m,2H),2.37(s,3H),2.33–2 .24(m,1H),2.23–2.15(m,1H),1.96–1.87(m,1H),1.74–1.64(m,1H),1.51–1.34 (m,3H),1.26(q,J=7.2,6.5Hz,3H),1.22–1.12(m,9H),1.01(s,3H),0.65(s,3H).

[0336] Example 3: Synthesis of compounds 3-P1 and 3-P2

[0337] Synthesis of compound 3-1 in step one

[0338] Compounds 2-3 (48.4 mg, 69 μmol), Int-6 (60.0 mg, 140 μmol), potassium phosphate (60 mg, 280 μmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (5.1 mg, 7.0 μmol) were dissolved in dioxane / water (3 mL / 1 mL), with the air purged three times by argon, and reacted at 70 °C for 10 hours. The reaction solution was filtered, evaporated to dryness, and purified by high-performance liquid chromatography (HPLC) using a Welch Xtimate C18 column (150 mm length, 30 mm inner diameter, 5 μm particle size; mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95%, elution for 10 column volumes) to obtain compound 3-1 (47.8 mg, 51.8 μmol, yield: 75%). MS (ESI) was then used. + m / z = 923.4 [M+H] + .

[0339] Step 4: Synthesis of compound 3-2

[0340] Compound 3-1 (47.8 mg, 51.8 μmol) was dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (32.5 mg, 100 μmol) and iodoethane (15.7 mg, 100 μmol) were added. The reaction mixture was reacted at room temperature for 8 hours. The reaction solution was directly purified by high performance liquid chromatography (HPLC) using a Welch Xtimate C18 column (150 mm long, 30 mm inner diameter, 5 μm particle size; mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95%, elution for 10 column volumes) to obtain compound 3-2 (40.9 mg, 43 μmol, yield: 83%). MS (ESI) was then used. + m / z = 951.4 [M+H] + .

[0341] Step 5: Synthesis of compound 3-3

[0342] Compound 3-2 (40.9 mg, 43 μmol) was dissolved in 3 mL of 4 M dioxane hydrochloride solution and reacted at room temperature for 1 hour. The reaction solution was then evaporated to dryness and used directly in the next step. MS (ESI) + m / z = 851.4 [M+H] + .

[0343] Step 6: Synthesis of compounds 3-P1 and 3-P2

[0344] The compound 3-3 obtained in the previous step was dissolved in methanol (5 mL), and formaldehyde (36% aqueous solution, 0.2 mL) and sodium cyanoborohydride (6.3 mg, 100 μmol) were added. The reaction mixture was reacted at room temperature for two hours. The reaction solution was evaporated to dryness and purified by reverse-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 50%-70%) to obtain compounds 3-P1 (13 mg, 15 μmol, yield: 34.9%, retention time: 6.73 min) and 3-P2 (6 mg, 7 μmol, yield: 16.3%, retention time: 7.58 min).

[0345] Compound 3-P1MS (ESI) + m / z = 865.5[M+H] + .

[0346] 11H NMR (400 MHz, Methanol-d4) δ 8.48–8.38 (m, 1H), 7.69–7.63 (m, 1H), 7.57–7.51 (m, 1H), 7.49–7.41 (m, 1H), 7.29–7.18 (m, 1H), 5.93–5.84 (m, 1H), 5.47–5.39 (m, 1H), 4.77–4.72 (m, 1H), 4.69–4.63 (m, 1H), 4.53–4.48 (m, 1H), 4.26–4.19 (m, 1H), 4.12–4.02 (m, 1H), 3.98–3.91 (m, 1H), 3.87–3.77 (m, 1H), 3.75–3.60 (m, 3H), 3.42–3.35 (m, 1H), 3.29–3.24 (m, 2H), 3.24–3.21 (m, 3H), 3.19–3.12 (m, 1H), 3.02–2.93 (m, 2H), 2.90–2.80 (m, 1H), 2.79–2.73 (m, 1H), 2.67–2.57 (m, 1H), 2.51–2.43 (m, 2H), 2.40–2.33 (m, 3H), 2.31–2.22 (m, 1H), 2.22–2.14 (m, 1H), 1.96–1.88 (m, 1H), 1.72–1.64 (m, 1H), 1.49–1.33 (m, 2H), 1.31–1.23 (m, 4H), 1.21–1.10 (m, 9H), 1.03–0.96 (m, 3H), 0.63–0.56 (m, 3H).

[0347] Compound 3-P2MS (ESI + ) m / z = 865.5 [M+H] + .

[0348] 1H NMR(400MHz, Methanol-d4)δ8.44–8.40(m,1H),7.69–7.63(m,1H),7.56–7.53(m,1H),7.49–7.44(m,1H),7.17–7.13(m,1H),5.64–5.54(m,2H) ,4.68–4.62(m,2H),4.59(s,2H),4.53–4.47(m,1H),4.30–4.11(m,4H) ,3.80–3.60(m,3H),3.45–3.38(m,2H),3.29–3.28(m,3H),3.08–3.01(m ,1H),3.01–2.94(m,2H),2.88–2.78(m,1H),2.73–2.64(m,2H),2.61–2 .54(m,1H),2.49–2.41(m,1H),2.40–2.35(m,3H),2.31–2.17(m,2H),1. 95–1.86(m,1H),1.60–1.50(m,1H),1.47–1.38(m,2H),1.38–1.34(m,3 H),1.20–1.10(m,6H),1.00(t,J=7.0Hz,3H),0.93(s,3H),0.53(s,3H).

[0349] Example 4: Synthesis of compounds 4-P1, 4-P2, 4-P3, and 4-P4

[0350] Referring to Example 2, intermediate Int-4 was replaced with compound Int-8, and formaldehyde (36% aqueous solution) was replaced with intermediate. Compounds 4-P1 (retention time: 8.03 min), 4-P2 (retention time: 8.48 min), 4-P3 (retention time: 8.93 min), and 4-P4 (retention time: 9.58 min) can be prepared using an XBridge Prep C18 column (150 mm * 19 mm * 5 μm); mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 50%-65%; time: 13 min; flow rate: 15 mL / min).

[0351] Compound 4-P1MS (ESI) + m / z = 905.4 [M+H] +

[0352] 11H NMR (400 MHz, Methanol-d4) δ 8.41 (d, J = 1.6 Hz, 1H), 7.69–7.64 (m, 1H), 7.55 (s, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.24 (s, 1H), 5.89 (d, J = 11.0 Hz, 1H), 5.45–5.40 (m, 1H), 4.78–4.69 (m, 3H), 4.68–4.59 (m, 3H), 4.14–4.05 (m, 1H), 4.04–3.98 (m, 1H), 3.84–3.75 (m, 2H), 3.71–3.62 (m, 2H), 3.57–3.51 (m, 1H), 3.39–3.36 (m, 1H), 3.29–3.26 (m, 1H), 3.24 (s, 3H), 3.20–3.16 (m, 1H), 3.15–3.11 (m, 1H), 3.10–3.04 (m, 2H), 2.92–2.88 (m, 2H), 2.79–2.73 (m, 1H), 2.66–2.58 (m, 1H), 2.50–2.40 (m, 2H), 2.22–2.12 (m, 2H), 2.13–2.04 (m, 2H), 1.92–1.83 (m, 2H), 1.72–1.65 (m, 1H), 1.47–1.40 (m, 1H), 1.40–1.33 (m, 1H), 1.31–1.27 (m, 3H), 1.21–1.16 (m, 6H), 1.16–1.11 (m, 3H), 0.99 (s, 3H), 0.58 (s, 3H).

[0353] Compound 4-P2MS (ESI + ) m / z = 905.4 [M+H] +

[0354] 11H NMR (400 MHz, Methanol-d4) δ 8.42 (d, J = 1.5 Hz, 1H), 7.69–7.64 (m, 1H), 7.54 (s, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.10 (s, 1H), 5.60–5.53 (m, 1H), 4.76–4.69 (m, 2H), 4.68–4.57 (m, 4H), 4.27–4.17 (m, 3H), 3.81–3.76 (m, 1H), 3.72–3.58 (m, 3H), 3.56–3.50 (m, 1H), 3.41–3.37 (m, 1H), 3.25–3.22 (m, 1H), 3.20–3.12 (m, 2H), 3.11–3.01 (m, 3H), 2.95–2.86 (m, 3H), 2.84–2.78 (m, 1H), 2.72–2.66 (m, 1H), 2.64–2.60 (m, 1H), 2.58–2.53 (m, 1H), 2.46–2.41 (m, 1H), 2.22–2.15 (m, 2H), 2.14–2.06 (m, 2H), 1.92–1.82 (m, 2H), 1.58–1.52 (m, 1H), 1.43–1.40 (m, 3H), 1.38 (s, 1H), 1.37–1.34 (m, 1H), 1.18–1.15 (m, 3H), 1.15–1.10 (m, 3H), 1.02–0.98 (m, 3H), 0.92 (s, 3H), 0.51 (s, 3H).

[0355] Compound 4-P3MS (ESI + ) m / z = 905.4 [M+H] +

[0356] 1¹H NMR (400 MHz, Methanol-d4) δ 8.42 (d, J = 1.7 Hz, 1H), 7.68–7.64 (m, 1H), 7.54 (s, 1H), 7.48–7.44 (m, 1H), 7.14 (s, 1H), 5.61–5.52 (m, 1H), 4.75–4.67 (m, 3H), 4.67–4.60 (m, 4H), 4.25–4.20 (m, 2H), 3.87–3.78 (m, 2H), 3.70–3.63 (m, 2H), 3.54–3.51 (m, 1H), 3.41–3.37 (m, 1H), 3.28–3.22 (m, 2H), 3.20–3.16 (m, 1H), 3.15–3.11 (m, 1H), 3.10–2.99 (m, 4H), 2.92–2.89 (m, 2H), 2.71–2.68 (m, 1H), 2.60–2.55 (m, 1H), 2.48–2.39 (m, 2H), 2.22–2.17 (m, 1H), 2.15–2.06 (m, 3H), 1.91–1.81 (m, 3H), 1.47–1.40 (m, 2H), 1.40–1.37 (m, 3H), 1.17–1.15 (m, 3H), 1.13 (d, J = 6.1 Hz, 3H), 1.01–0.96 (m, 3H), 0.93 (s, 3H), 0.50 (s, 3H).

[0357] Compound 4-P4MS (ESI + ) m / z = 905.4 [M+H] +

[0358] 1H NMR(400MHz,Methanol-d4)δ8.41(d,J=1.6Hz,1H),7.69–7.64(m,1H),7.55(s,1H),7 .44(d,J=8.6Hz,1H),7.25(s,1H),5.89(d,J=11.0Hz,1H),5.45–5.41(m,1H),4.78–4 .69(m,3H),4.69–4.59(m,3H),4.10–4.01(m,1H),3.99–3.92(m,1H),3.85–3.74(m,2 H),3.73–3.64(m,2H),3.58–3.51(m,1H),3.39–3.36(m,1H),3.29–3.24(m,1H),3.21 (s,3H),3.17–3.12(m,2H),3.11–3.00(m,2H),2.95–2.85(m,2H),2.82–2.72(m,2H), 2.67–2.59(m,1H),2.51–2.44(m,1H),2.44–2.37(m,1H),2.23–2.17(m,1H),2.17–2. 07(m,2H),1.91–1.80(m,2H),1.72–1.64(m,1H),1.48–1.40(m,1H),1.40–1.33(m,1H ),1.29–1.20(m,6H),1.19–1.16(m,3H),1.15–1.10(m,3H),1.00(s,3H),0.65(s,3H).

[0359] Biological tests

[0360] Test Example 1: Effect of Compounds on Tumor Cell Proliferative Activity

[0361] Experimental materials and instruments:

[0362] 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).

[0363] The instruments and equipment required for this experiment include: Eppendorf pipettes; Eppendorf pipettes; Eppendorf centrifuges; ThermoFisher carbon dioxide incubator; Vi-cell XR fully automated cell counter (Beckman Coulter); and Envision microplate reader (Perkin Elmer).

[0364] The cells required for this experiment include: KRAS G12D The mutant cell line AsPC-1 (ATCC#CRL-1682TM) was cultured in RPMI-1640 medium containing 10% FBS.

[0365] Experimental methods:

[0366] 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 was diluted 10-fold to 1 mM with DMSO, then further 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 nine consecutive concentration gradients. 10 μL of each serially diluted compound was then added to each well 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.

[0367] Table 1

Claims

1. A compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, Selected from X 1 and X 2 Each is independently selected from N and C; 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; 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 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; R 2 R 3 R 7 R 8 and R 9 Independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl groups and C3-C7 cycloalkyl groups; Or, R 2 and R 3 The 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; R 4 Selected from: non-existent, hydrogen, halogen, hydroxyl, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 Alkyl group, hydroxyl group, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 Alkyl groups are optionally surrounded by one or more R 4a replace; 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. d replace; R 5 Selected from 10-20 fused heterocyclic groups, wherein the 10-20 fused heterocyclic group comprises 3-4 monocyclic structures, and wherein the 10-20 fused heterocyclic group is optionally bounded by one or more R... 5a replace; R 6 Selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; R 10 Selected from halogens, hydroxyl groups, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Hydroxyl-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 groups, wherein the amino, hydroxyl, mercapto, 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 d Independently selected from halogen, amino, hydroxyl, mercapto, cyano, C1-C7 alkyl, C1-C7 haloalkyl and C1-C7 alkoxy; Each R 5a Independently selected from halogen, hydroxyl, cyano, amino, oxo, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-14 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups, wherein the hydroxyl, amino, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne 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. e replace; Each R e Independently selected from halogens, hydroxyl groups, mercapto groups, cyano groups, amino groups, =O groups, 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; n is a natural number selected from 0 to 6; One or more hydrogen atoms in the compound of formula (I) may be selected as deuterium atoms.

2. The compound of formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, X 1 For C; or X 1 Let N be the number of people in the group. and / or X 2 For N; or X 1 Let C be the integer, and X be the inverse. 2 For N; or X 1 Let N be the number of elements, and X be the number of elements. 2 The answer is C.

3. The compound of formula (I) according to any one of claims 1 or 2, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, 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 Substitution; or 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 converted by one or more R a Substitution; or A is selected from 5-6-membered heteroaryl groups, wherein the 5-6-membered heteroaryl group is optionally replaced by one or more R groups. a Substitution; or A is selected from imidazolyl, phenylene, and morpholinoyl, wherein the imidazolyl, phenylene, and morpholinoyl are optionally replaced by one or more R a Replace; or A is selected from The Optional by one or more R a Replace; or A is selected from The Optional R a Replace; or A is selected from Or A is Or A is Where * represents the end connected to the benzene ring; and / or each R a Independently selected from halogen, amino, hydroxyl, mercapto, and cyano groups; or R a It is a hydroxyl group.

4. The compound of formula (I) according to any one of claims 1-3, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, 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 Substitution; or 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 Substitution; or 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 Substitution; or L is selected from imino, Or L is selected from Or L is Or L is Where # represents R 1 Connected terminals; and / or each R L It is independently selected from halogens, hydroxyl groups, oxo groups, and C1-C4 alkyl groups.

5. The compound of formula (I) according to any one of claims 1-4, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 1 Selected from C1-C 10 Alkyl, C3-C 10 Cycloalkyl and 4-10 membered heterocyclic groups, the C1-C 10 Alkyl, C3-C 10 Cycloalkyl groups and 4-10-membered heterocyclic groups are optionally surrounded by one or more R groups. 1a Replace; or R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, and 4-7 membered heterocyclic groups, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, and 4-7 membered heterocyclic groups are optionally surrounded by one or more R groups. 1a Replace; or R 1 Selected from cyclopropyl, tetrahydropyrrole, and pentyl, wherein the cyclopropyl, tetrahydropyrrole, and pentyl are optionally converted by one or more R... 1a Replace; or R 1 Selected from cyclopropyl, The cyclopropyl, Optionally by one or more R 1a Replace; or R 1 Selected from cyclopropyl and The cyclopropyl and Optionally by one or more R 1a Replace; or R 1 Selected from Or R 1 Selected from Or R 1 Selected from Or R 1 Selected from 6. The compound of formula (I) according to any one of claims 1-5, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Each R 1a Independently selected from halogens, C1-C 10 Alkyl groups and 5-12 heteroaryl groups, the C1-C 10 Alkyl groups and 5-12 heteroaryl groups are optionally bounded by one or more R groups. 1aa Replace; or each R 1a Independently selected from halogens, C1-C4 alkyl groups, and 5-6 heteroaryl groups, wherein the C1-C4 alkyl groups and 5-6 heteroaryl groups are optionally surrounded by one or more R groups. 1aa Replace; or each R 1a The radicals are independently selected from fluorine, methyl, pyrimidinyl, and pyridinyl, wherein the methyl, pyrimidinyl, and pyridinyl groups are optionally surrounded by one or more R groups. 1aa Replace; or each R 1a Independently selected from fluorine and methyl, wherein the methyl group is optionally surrounded by one or more R... 1aa Replace; and / or each R 1aa It is independently selected from halogens.

7. The compound of formula (I) according to any one of claims 1-6, 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.

8. The compound of formula (I) according to any one of claims 1-7, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 4 Selected from hydrogen, halogen, hydroxyl, cyano, C1-C 10 Alkyl and C1-C 10 Halogenated alkyl; or R 4 Selected from C1-C4 alkyl and C1-C4 haloalkyl; or R 4 Selected from ethyl groups that are optionally halogenated; or R 4 Selected from ethyl groups optionally substituted with fluorine; or R 4 Selected from ethyl and trifluoroethyl; or R 4 It is an ethyl group.

9. The compound of formula (I) according to any one of claims 1-8, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 5 Selected from 14-18 fused heterocyclic groups, wherein the 14-18 fused heterocyclic group comprises 3-4 monocyclic structures, and wherein the 14-18 fused heterocyclic group is optionally separated by one or more R 5a Replace; or R 5 Selected from 14-18 member fused heterocyclic groups, wherein the 14-18 member fused heterocyclic group comprises 3-4 monocyclic structures, wherein the 14-18 member fused heterocyclic group comprises at least one pyridine ring, and wherein the 14-18 member fused heterocyclic group is optionally surrounded by one or more R 5a Replace; or R 5 Selected from 14-18 membered fused heterocyclic groups, wherein the 14-18 membered fused heterocyclic group comprises 3-4 monocyclic structures, the 14-18 membered fused heterocyclic group is connected to the rest of the molecule through a pyridine ring, and the 14-18 membered fused tricyclic or fused tetracyclic group is optionally separated by one or more R... 5a Replace; or R 5 Selected from 14-18 membered fused heterocyclic groups, wherein the 14-18 membered fused heterocyclic group comprises 3-4 monocyclic structures, one of which is a pyridine ring, and the 14-18 membered fused heterocyclic group is connected to the rest of the molecule through the pyridine ring, and the 14-18 membered fused tricyclic or fused tetracyclic group is optionally separated by one or more R... 5a Replace; or R 5 Selected from 14-membered fused heterocyclic groups, the 14-membered fused heterocyclic group comprises three monocyclic structures, one of which is a pyridine ring, the 14-membered fused heterocyclic group is connected to the rest of the molecule through the pyridine ring, and the 14-membered fused heterocyclic group is optionally bounded by one or more R 5a Replace; or R 5 Selected from R 5a Replacement Where m is 1 or 2, p is 0 or 1, Y is CH2, O or S, Z is C, CH or N, T is selected from C, CH and N, and ring C is selected from 6-10 membered heterocyclic rings or 5-6 membered heteroaromatic rings; or R 5 Selected from R 5a Replacement Where m is 1 or 2, p is 0 or 1, Y is O or S, Z is C, CH or N, and ring C is selected from 6-10 membered heterocyclic rings or 5-6 membered heteroaromatic rings; or R 5 Selected from R 5a Replacement Where Y is CH2, O, or S, and Z is CH or N; or R 5 Selected from R 5a Replacement Where Y is CH2 or O; or R 5 Selected from The Optionally by one or more R 5a Replace; or R 5 Selected from The Optionally by one or more R 5a Replace; or R 5 Selected from Or R 5 Selected from 10. The compound of formula (I) according to any one of claims 1-9, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Each R 5a Independently selected from halogen, hydroxyl, cyano, amino, oxo, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne 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 Alkyne 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; or each R 5a Independently selected from halogen, amino, oxo, C1-C 10 Alkyl, C3-C 12 Cycloalkyl and 3-14 membered heterocyclic groups, wherein the amino group, C1-C 10 Alkyl, C3-C 12 Cycloalkyl groups and 3-14-membered heterocyclic groups are optionally surrounded by one or more R groups. c Replace; or each R 5a Independently selected from oxo, C1-C 10 Alkyl, C3-C 12 Cycloalkyl and 3-14 membered heterocyclic groups, the C1-C 10 Alkyl, C3-C 12 Cycloalkyl groups and 3-14-membered heterocyclic groups are optionally surrounded by one or more R groups. c Replace; or each R 5a Independently selected from oxo, C1-C4 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclic groups, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclic groups are optionally surrounded by one or more R groups. c Replace; or each R 5a The amino group is independently selected from fluorine, amino, oxo, methyl, ethyl, cyclopropyl, oxetyl, isopropyl, piperidinyl, and aziridine, wherein the amino, methyl, ethyl, cyclopropyl, oxetyl, isopropyl, piperidinyl, and aziridine groups are optionally separated by one or more R groups. c Replace; or each R 5a The radical is independently selected from oxo, methyl, ethyl, cyclopropyl, oxetyl, isopropyl, piperidinyl, and aziridine, wherein the methyl, ethyl, cyclopropyl, oxetyl, isopropyl, piperidinyl, and aziridine are optionally separated by one or more R radicals. c Replace; or each R 5a Independently selected from methyl, ethyl, and oxetyl groups, wherein the methyl, ethyl, and oxetyl groups are optionally surrounded by one or more R groups. c Replace; or each R 5a Independently selected from methyl, Or oxoheterobutyl.

11. The compound of formula (I) according to any one of claims 1-10, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Each R c Independently selected from C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl and 4-12 membered heterocyclic groups, wherein the 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. e Replace; or each R c Independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, and 4-7 membered heterocyclic groups, wherein the C1-C4 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, and 4-7 membered heterocyclic groups are optionally surrounded by one or more R... e Replace; or each R c Independently selected from methyl, methoxy, cyclopropyl and The methyl, methoxy, cyclopropyl and Optional by one or more R e Replace; or each R c Independently selected from methyl, methoxy, cyclopropyl and Or R c For methoxy; and / or each R e The groups can be independently selected from halogen, hydroxyl, cyano, amino, =O, C1-C4 alkyl, C1-C4 hydroxyalkyl, C3-C6 cycloalkyl and 4-10 heterocyclic groups.

12. The compound of formula (I) according to any one of claims 1-11, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 6 Selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, and C1-C4 alkyl; or R 6 It is hydrogen.

13. The compound of formula (I) according to any one of claims 1-12, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 7 Selected from hydrogen, halogen, hydroxyl, and cyano groups; or R 7 It is hydrogen.

14. The compound of formula (I) according to any one of claims 1-13, 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.

15. The compound of formula (I) according to any one of claims 1-14, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 9 Selected from hydrogen, halogen, hydroxyl, and cyano groups; or R 9 Selected from hydrogen and halogens; or R 9 Selected from hydrogen and fluorine; or R 9 It is hydrogen.

16. The compound of formula (I) according to any one of claims 1-15, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 10 Selected from halogens, such as fluorine; or R 10 It is fluorine; and / or n is 0, 1 or 2; or n is 0.

17. The compound of formula (I) according to any one of claims 1-16, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Selected from or Selected from or yes 18. The compound of formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Compound (I) or its stereoisomer or pharmaceutically acceptable salt thereof is selected from compound (II) or its stereoisomer or pharmaceutically acceptable salt thereof: Among them, A, L, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 and R 9 As defined in any one of claims 1-17.

19. The compound of formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Compound (I) or its stereoisomer or pharmaceutically acceptable salt thereof is selected from compound (III) or its stereoisomer or pharmaceutically acceptable salt thereof: Among them, Z, Y, R 1 R 2 R 3 R 4 and R 5a As defined in any one of claims 1-17.

20. The compound of formula (I) as claimed in claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds or pharmaceutically acceptable salts thereof.

21. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

22. Use of the compound of formula (I) according to any one of claims 1-20, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 21, in the preparation of a medicament for the prevention or treatment of RAS-mediated diseases.

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