Cyclic compound and preparation therefor and pharmaceutical use thereof

Abstract

Provided are an RAS inhibitor compound as represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing same, and the use thereof in the preparation of a drug for preventing or treating RAS-mediated diseases.

Description

Cyclic compounds, their preparation and pharmaceutical applications

[0001] Cross-references to related applications

[0002] This application claims priority and benefits from the following patent applications, the disclosure of which is incorporated herein by reference in its entirety:

[0003] Chinese Patent Application No. 202411627270.5, filed with the China National Intellectual Property Administration on November 14, 2024;

[0004] Chinese Patent Application No. 202510057462.5, filed with the China National Intellectual Property Administration on January 14, 2025;

[0005] Chinese Patent Application No. 202510334287.X, filed with the China National Intellectual Property Administration on March 20, 2025;

[0006] Chinese Patent Application No. 202510568722.5, filed with the China National Intellectual Property Administration on April 30, 2025;

[0007] Chinese Patent Application No. 202510953250.5, filed with the China National Intellectual Property Administration on July 10, 2025;

[0008] Chinese Patent Application No. 202511268600.0, filed with the China National Intellectual Property Administration on September 5, 2025; and

[0009] Chinese Patent Application No. 202511489039.9 was filed with the China National Intellectual Property Administration on October 17, 2025. Technical Field

[0010] This disclosure pertains to the field of pharmaceutical technology, and specifically relates to macrocyclic compounds or their stereoisomers or pharmaceutically acceptable salts as RAS inhibitors, pharmaceutical compositions containing them, and their use as RAS inhibitors in the prevention or treatment of RAS-mediated diseases. Background Technology

[0011] 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 RAS 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), resulting in its activation and inactivation states. Activated KRAS primarily activates 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 the activity of those proteins. 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 might 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. However, 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 intractable or difficult to treat 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, lacks a well-studied library of compounds. Therefore, there is great interest in discovering novel molecules that can modulate the function of such undruggable 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. Summary of the Invention

[0012] This disclosure relates to compounds of formula (I) or their stereoisomers or pharmaceutically acceptable salts.

[0013] in,

[0014] X 1 and X 2 Each is independently selected from N and C;

[0015] 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;

[0016] 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;

[0017] 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;

[0018] 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;

[0019] 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;

[0020] R 4Selected from: non-existent, hydrogen, halogen, hydroxyl, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkyl, C1-C 10 Hydroxyalkyl, C1-C 10 Halogenated alkyl groups, C3-C6 cycloalkyl groups, and 4-6 membered heterocyclic groups, wherein the hydroxyl group, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkyl, C1-C 10 Hydroxyalkyl, C1-C 10 The haloalkyl, C3-C6 cycloalkyl and 4-6 membered heterocyclic groups are optionally surrounded by one or more R groups. 4a replace;

[0021] 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;

[0022] R 5 The compounds are selected from 8-15 membered heterocyclic groups and 8-15 membered heteroaryl groups, wherein the 8-15 membered heterocyclic group and 8-15 membered heteroaryl group have a bicyclic structure, and the 8-15 membered heterocyclic group and 8-15 membered heteroaryl group are optionally separated by one or more R groups. 5a replace;

[0023] R 6 Selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups and C1-C4 alkoxy groups, wherein the hydroxyl, mercapto, amino, C1-C4 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups and C1-C4 alkoxy groups are optionally surrounded by one or more R groups. 6a replace;

[0024] 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;

[0025] 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;

[0026] 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;

[0027] Each R 4a and R d The radical is independently selected from halogen, amino, hydroxyl, mercapto, cyano, oxo, C1-C7 alkyl, C1-C7 haloalkyl, C3-C7 cycloalkyl, 4-6 membered heterocyclic, and C1-C7 alkoxy, wherein the amino, hydroxyl, mercapto, C1-C7 alkyl, C1-C7 haloalkyl, C3-C7 cycloalkyl, 4-6 membered heterocyclic, and C1-C7 alkoxy are optionally surrounded by one or more R... 2aa replace;

[0028] Each R 6a Independently selected from halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C3-C7 cycloalkyl and 4-6 membered heterocyclic groups;

[0029] Each R 5a Independently selected from halogen, hydroxyl, cyano, amino, oxo, P(O)R k R k SF5, 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;

[0030] Each R cIndependently selected from halogen, amino, hydroxyl, mercapto, cyano, =O, S(O)2R k 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;

[0031] Each R e Independently selected from halogen, hydroxyl, mercapto, cyano, amino, =O, =CR j R j C(O)R k S(O)2R k C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C4 alkylene O, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl)2, and -N(C1-C4 alkyl)2, wherein the hydroxyl, amino, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl, 5-10 heteroaryl, C1-C4 alkylene O, C1-C4 alkyl, C1-C4 alkoxy, -NH (C1-C4 alkyl) and -N (C1-C4 alkyl)2 optionally R n replace;

[0032] Each R 1aa R 2aa The amino, hydroxyl, mercapto, cyano, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 3-7 heterocyclic, phenyl and 5-6 heteroaryl groups are independently selected from halogens, amino, hydroxyl, mercapto, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 3-7 heterocyclic, phenyl and 5-6 heteroaryl groups, which may be optionally substituted by one or more halogens, amino, hydroxyl, mercapto, cyano and C1-C4 alkyl groups;

[0033] R j and R k Independently selected from H, halogen, hydroxyl, mercapto, cyano, amino, C1-C4 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 Alkoxy, hydroxyl, mercapto, amino, C1-C4 alkyl, C2-C 10 alkenyl, C2-C 10alkynyl and C1-C 10 The alkoxy group may be optionally substituted with halogen, hydroxyl, mercapto, amino, =O, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic alkyl, N(C1-C4 alkyl)2 and NH(C1-C4 alkyl);

[0034] R n Selected from CN, =O, halogen, C1-C4 alkyl, N(C1-C4 alkyl)2 and (C1-C4 alkyl)S(O)2-;

[0035] n is a natural number selected from 0 to 6;

[0036] One or more hydrogen atoms in the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt may optionally be deuterium atoms.

[0037] In some embodiments, the compounds of formula (I) described herein, or their stereoisomers or pharmaceutically acceptable salts thereof, do not include the following molecules:

[0038] In some implementation schemes, R 4 Selected from: non-existent, hydrogen, halogen, hydroxyl, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkyl, C3-C6 cycloalkyl and 4-6 membered heterocyclic groups, wherein the hydroxyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkyl, C3-C6 cycloalkyl and 4-6 membered heterocyclic groups are optionally surrounded by one or more R 4a replace.

[0039] In some implementation schemes, each R e Independently selected from halogen, hydroxyl, mercapto, cyano, amino, =O, =CR j R j C(O)R k S(O)2R k C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 4-10 heterocyclic, C1-C4 alkylene O, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl)2 and -N(C1-C4 alkyl)2.

[0040] In some implementation schemes, each R eIndependently selected from halogens, hydroxyl groups, mercapto groups, cyano groups, amino groups, =O, C1-C4 alkyl groups, C1-C4 hydroxyalkyl groups, C1-C4 haloalkyl groups, C3-C6 cycloalkyl groups, 4-10 membered heterocyclic groups, C1-C4 alkylene groups, C1-C4 alkyl groups, C1-C4 alkoxy groups, -NH(C1-C4 alkyl)2, and -N(C1-C4 alkyl)2.

[0041] In some implementation schemes, X 1 The answer is C.

[0042] In some implementation schemes, X 1 Let N be the number of elements in the array.

[0043] In some implementation schemes, X 2 Let N be the number of elements in the array.

[0044] In some implementation schemes, X 1 Let C be the integer, and X be the integrity. 2 Let N be the number of elements in the array.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] In some embodiments, A is selected from imidazolyl and imidazolinyl, wherein the imidazolyl and imidazolinyl are optionally surrounded by one or more R groups. a replace.

[0051] In some embodiments, A is selected from an imidazolyl group, wherein the imidazolyl group is optionally replaced by R. a replace.

[0052] In some implementation schemes, A is selected from The Optional by one or more R a replace.

[0053] In some implementation schemes, A is selected from The Optional by one or more R a The asterisk (*) represents the end connected to the benzene ring.

[0054] In some implementation schemes, A is selected from The Optional R a replace.

[0055] In some implementation schemes, each R a It is independently selected from halogen, amino, hydroxyl, mercapto and cyano groups.

[0056] In some implementation schemes, A is

[0057] In some implementation schemes, A is The asterisk (*) represents the end connected to the benzene ring.

[0058] In some implementation schemes, A is

[0059] In some implementation schemes, A is The asterisk (*) represents the end connected to the benzene ring.

[0060] 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 R L replace.

[0061] In some implementations, L is selected from imino, The imino, Optional R L replace.

[0062] In some implementations, L is selected from imino, The imino group is optionally coated with R L replace.

[0063] In some implementation schemes, each R L Independently selected from oxo and C1-C4 alkyl substitutions.

[0064] In some implementation schemes, each R L It is independently selected from oxo and isopropyl.

[0065] In some implementation schemes, R L It is oxygenated.

[0066] In some implementations, L is selected from imino,

[0067] In some implementations, L is selected from imino, Where # represents R 1 Connecting end.

[0068] In some implementations, L is selected from imino, Where # represents R 1 Connecting end.

[0069] In some implementations, L is selected from imino,

[0070] In some embodiments, L is selected from imino groups, which are optionally replaced by R. L replace.

[0071] In some implementations, L is selected from imino groups.

[0072] In some implementation schemes, L is selected from

[0073] In some implementation schemes, L is selected from Where # represents R 1 Connecting end.

[0074] In some implementations, L is

[0075] In some implementations, L is Where # represents R 1 Connecting end.

[0076] In some implementation schemes, Selected from

[0077] In some implementation schemes, R 1 Selected from C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups and 5-12 membered heteroaryl groups, wherein the C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-10-membered heterocyclic and 5-12-membered heteroaryl groups are optionally surrounded by one or more (e.g., two) R 1a replace.

[0078] In some implementation schemes, R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 heterocyclic, and 5-6 heteroaryl groups, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 heterocyclic, and 5-6 heteroaryl groups are optionally surrounded by one or more (e.g., two) R groups. 1a replace.

[0079] In some implementation schemes, R 1 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic and 5-6-membered heteroaryl groups, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic and 5-6-membered heteroaryl groups are optionally surrounded by one or more (e.g., two) R groups. 1a replace.

[0080] In some implementation schemes, R 1 Selected from cyclopropyl, aziridine, tetrahydropyrrolyl, oxadiazine, and other compounds. Oxadiazole, thiadiazole, thiazolyl, isoxazolyl, tetrazolyl, methyl, isopropyl, and pentyl, wherein cyclopropyl, aziridine, oxazolyl, tetrahydropyrrolyl, Oxadiazole, thiadiazole, thiazolyl, isoxazolyl, tetrazolyl, methyl, isopropyl, and pentyl are optionally surrounded by one or more (e.g., two) R 1a replace.

[0081] In some implementation schemes, R 1 Selected from cyclopropyl, aziridine, tetrahydropyrrole, Oxadiazole, thiadiazole, thiazolyl, isoxazolyl, tetrazolyl, methyl, isopropyl, and pentyl, wherein cyclopropyl, aziridine, tetrahydropyrrolyl, Oxadiazole, thiadiazole, thiazolyl, isoxazolyl, tetrazolyl, methyl, isopropyl, and pentyl are optionally surrounded by one or more (e.g., two) R 1a replace.

[0082] In some implementation schemes, R 1 Selected from cyclopropyl, tetrahydropyrrolidone, Oxadiazole, methyl and pentyl, said cyclopropyl, tetrahydropyrrolyl, Oxadiazolyl, methyl, and pentyl are optionally surrounded by one or more (e.g., two) R 1a replace.

[0083] In some implementation schemes, R 1 Selected from cyclopropyl, methyl, isopropyl and The cyclopropyl, methyl, isopropyl and Optionally by one or more (e.g., two) R 1a replace.

[0084] In some implementation schemes, R 1 Selected from cyclopropyl, azacyclobutyl, methyl, isopropyl and The cyclopropyl, aziridine, methyl, isopropyl and Optionally by one or more (e.g., two) R 1a replace.

[0085] In some implementation schemes, R 1 Selected from cyclopropyl, Methyl and The cyclopropyl, Methyl and Optionally by one or more (e.g., two) R 1a replace.

[0086] In some implementation schemes, R 1 Selected from cyclopropyl, Methyl and The cyclopropyl, Methyl and Optionally by one or more (e.g., two) R 1a replace.

[0087] In some implementation schemes, each R 1a Independently selected from halogens, C1-C 10 Alkyl, C3-C 10 cycloalkyl and 5-12-membered heteroaryl groups, the C1-C 10 Alkyl, C3-C 10 Cycloalkyl and 5-12 heteroaryl groups are optionally surrounded by one or more (e.g., two) R groups. 1aa replace.

[0088] In some implementation schemes, each R 1a Independently selected from halogens, C1-C5 alkyl groups, C3-C6 cycloalkyl groups, and 5-6 heteroaryl groups, wherein the C1-C5 alkyl groups, C3-C6 cycloalkyl groups, and 5-6 heteroaryl groups are optionally surrounded by one or more (e.g., two) R groups. 1aa replace.

[0089] In some implementation schemes, each R 1aThe radical is independently selected from fluorine, methyl, pyrimidinyl, pentyl, n-propyl, isopropyl, hydroxyl, and cyclopropyl, wherein the methyl, pyrimidinyl, pentyl, n-propyl, isopropyl, hydroxyl, and cyclopropyl groups are optionally represented by one or more (e.g., two) R groups. 1aa replace.

[0090] In some implementation schemes, each R 1a Independently selected from fluorine, methyl, pyrimidinyl, pentyl, and cyclopropyl, wherein the methyl, pyrimidinyl, pentyl, and cyclopropyl groups are optionally surrounded by one or more (e.g., two) R groups. 1aa replace.

[0091] In some implementation schemes, each R 1aa It is independently selected from halogen, amino, hydroxyl, mercapto and cyano groups.

[0092] In some implementation schemes, each R 1aa It is independently selected from halogens, C1-C4 alkyl groups, C3-C6 cycloalkyl groups, and phenyl groups.

[0093] In some implementation schemes, each R 1aa The halogen is independently selected from halogens, methyl, cyclopropyl and phenyl, with fluorine being the preferred halogen.

[0094] In some implementation schemes, each R 1aa It is independently selected from halogens, such as fluorine.

[0095] In some implementation schemes, R 1aa It is fluorine.

[0096] In some implementation schemes, each R 1a Independently selected from F, CH3, CH(CH3)2, CH(CH2CH3)2, CH2F, CH(CH2F)2, CH(CH2CH2F)2, OCH3, 5-Pyrimidinyl, CH(Ph)(CH2CH3) or cyclopropyl.

[0097] In some implementation schemes, each R 1a It is independently selected from F, CH3 and CH(CH2CH2F)2.

[0098] In some implementation schemes, R 1 Selected from isopropyl,

[0099] In some implementation schemes, R 1 Selected from isopropyl,

[0100] In some implementation schemes, R1 Selected from isopropyl,

[0101] In some implementation schemes, R 1 Selected from

[0102] In some implementation schemes, R 1 Selected from

[0103] In some implementation schemes, R 1 Selected from

[0104] In some implementation schemes, R 1 Selected from

[0105] In some implementation schemes, R 1 Selected from

[0106] In some implementation schemes, R 1 Selected from

[0107] In some implementation schemes, R 1 Selected from

[0108] In some implementation schemes, R 1 Selected from

[0109] In some implementation schemes, R 1 Selected from

[0110] In some implementation schemes, R 1 Selected from

[0111] In some implementation schemes, R 1 Selected from

[0112] In some implementation schemes, R 1 for

[0113] In some implementation schemes, R 1 for

[0114] In some implementation schemes, R 1 for

[0115] In some implementation schemes, R 1 for

[0116] In some implementation schemes, R 1 for

[0117] In some implementation schemes, R 1 for

[0118] In some implementation schemes, R 2 R 3 Independently selected from hydrogen, halogen, hydroxyl, cyano and C1-C 10 alkyl.

[0119] In some implementation schemes, R 2 R 3 It is independently selected from C1-C4 alkyl groups, such as methyl.

[0120] In some implementation schemes, R 2 R 3 All are methyl groups.

[0121] 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.

[0122] 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.

[0123] In some implementation schemes, each R b It is independently selected from halogens, hydroxyl groups, and C1-C4 alkyl groups.

[0124] In some implementation schemes, R 2 and R 3 Together with the atoms they are attached to, they form a cyclobutyl group.

[0125] In some implementation schemes, R 4 Selected from C1-C 10 Alkyl, C1-C 10 Hydroxyalkyl, C1-C 10 Halogenated alkyl groups and C3-C7 cycloalkyl groups, wherein the C1-C10 Alkyl, C1-C 10 Hydroxyalkyl, C1-C 10 The haloalkyl and C3-C7 cycloalkyl groups are optionally marked with one or more R... 4a Replacement. In some implementations, R 4 Selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, and C3-C6 cycloalkyl, wherein the C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, and C3-C6 cycloalkyl are optionally prefixed with one or more R... 4a replace.

[0126] In some implementation schemes, R 4 Selected from C1-C 10 Alkyl and C3-C6 cycloalkyl, wherein C1-C 10 Alkyl and C3-C6 cycloalkyl groups are optionally separated by one or more R 4a Replace; or 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.

[0127] In some implementation schemes, R 4 Selected from C1-C 10 Alkyl and C3-C6 cycloalkyl, wherein C1-C 10 Alkyl and C3-C6 cycloalkyl groups are optionally separated by one or more R 4a replace.

[0128] In some implementation schemes, R 4 Selected from C1-C4 alkyl and C3-C6 cycloalkyl, wherein the C1-C4 alkyl and C3-C6 cycloalkyl are optionally separated by one or more R 4a replace.

[0129] In some implementation schemes, R 4 Selected from ethyl, cyclopropyl, and cyclobutyl, wherein the ethyl, cyclopropyl, and cyclobutyl groups are optionally marked with one or more R... 4a replace.

[0130] In some implementation schemes, R 4 The group is selected from methyl, ethyl, trifluoroethyl, hydroxyethyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, trifluoroethyl, hydroxyethyl, cyclopropyl, and cyclobutyl groups are optionally marked with one or more R groups. 4a replace.

[0131] In some implementation schemes, R 4The group is selected from ethyl, trifluoroethyl, hydroxyethyl, cyclopropyl, and cyclobutyl, wherein the ethyl, trifluoroethyl, hydroxyethyl, cyclopropyl, and cyclobutyl groups are optionally marked with one or more R groups. 4a replace.

[0132] In some implementation schemes, each R 4a and R d It is independently selected from halogen, amino, hydroxyl, mercapto, cyano, C1-C7 alkyl, C1-C7 haloalkyl and C1-C7 alkoxy.

[0133] In some implementation schemes, each R 4a and R d The radical is independently selected from halogen, amino, hydroxy, mercapto, cyano, C1-C7 alkyl, C1-C7 haloalkyl, C3-C7 cycloalkyl, 4-6 membered heterocyclic, and C1-C7 alkoxy, wherein the amino, hydroxy, mercapto, C1-C7 alkyl, C1-C7 haloalkyl, C3-C7 cycloalkyl, 4-6 membered heterocyclic, and C1-C7 alkoxy are optionally surrounded by one or more R... 2aa replace.

[0134] In some implementation schemes, each R 4a Independently selected from halogen, amino, cyano, oxo, and 4-6 membered heterocyclic groups, wherein the amino and 4-6 membered heterocyclic groups are optionally surrounded by one or more R... 2aa replace.

[0135] In some implementation schemes, each R 4a Independently selected from cyano, C3-C7 cycloalkyl, and 4-6 membered heterocyclic groups, wherein the C3-C7 cycloalkyl and 4-6 membered heterocyclic groups are optionally surrounded by one or more R groups. 2aa replace.

[0136] In some implementation schemes, each R 4a Independently selected from fluorine, amino, cyano, oxo, tetrahydropyranyl, oxetyl and The amino group, tetrahydropyranyl group and Optional by one or more R 2aa replace.

[0137] In some implementation schemes, each R 4a Independently selected from cyano, cyclopropyl, tetrahydropyrano, and The cyclopropyl, tetrahydropyranyl and Optional by one or more R 2aa replace.

[0138] In some implementation schemes, each R 4a The groups are independently selected from cyano, cyclopropyl, and tetrahydropyrano, wherein the cyclopropyl and tetrahydropyrano groups are optionally surrounded by one or more R groups.2aa replace.

[0139] In some implementation schemes, each R 4a Independently selected from fluorine, oxo, -N(CH3)CH3, oxoheterobutyl, cyano,

[0140] In some implementation schemes, each R 4a Independently selected from halogen, amino, hydroxyl, mercapto, cyano, cyclopropyl,

[0141] In some implementation schemes, each R 4a It is independently selected from halogen, amino, hydroxyl, mercapto and cyano groups.

[0142] In some implementation schemes, each R 4a It is independently selected from halogens and cyano groups.

[0143] In some implementation schemes, each R 4a It is independently selected from fluorine and cyano groups.

[0144] In some implementation schemes, R 4a It is a cyano group.

[0145] In some implementation schemes, each R 2aa It is independently selected from C1-C4 alkyl groups, such as methyl.

[0146] In some implementation schemes, R 4 Selected from ethyl, trifluoroethyl,

[0147] In some implementation schemes, R 4 Selected from ethyl, trifluoroethyl, (For example ),

[0148] In some implementation schemes, R 4 Selected from ethyl, trifluoroethyl, (For example ),

[0149] In some implementation schemes, R 4 Selected from ethyl, trifluoroethyl, cyclopropylmethyl,

[0150] In some implementation schemes, R 4 Selected from ethyl, trifluoroethyl, cyclopropylmethyl,

[0151] In some implementation schemes, R 4 Selected from ethyl, trifluoroethyl,

[0152] In some implementation schemes, R 4 Selected from ethyl, trifluoroethyl,

[0153] In some embodiments, R4 is selected from ethyl, trifluoroethyl, (For example )and

[0154] In some implementation schemes, R 4 Selected from ethyl,

[0155] In some implementation schemes, R 4 for

[0156] In some implementation schemes, R 4 It is an ethyl group.

[0157] In some implementation schemes, R 4 Selected from C1-C 10 Alkyl and C1-C 10 Halogenated alkyl groups.

[0158] In some implementation schemes, R 4 Selected from C1-C4 alkyl and C1-C4 haloalkyl.

[0159] In some implementation schemes, R 4 Selected from ethyl groups that are optionally substituted with halogens.

[0160] In some implementation schemes, R 4 Selected from ethyl and trifluoroethyl.

[0161] In some implementation schemes, R 4 Selected from C1-C 10 Alkyl, C1-C 10 Hydroxyalkyl and C3-C7 cycloalkyl, wherein C1-C 10 Alkyl, C1-C 10 Hydroxyalkyl and C3-C7 cycloalkyl are optionally surrounded by one or more R 4a replace.

[0162] In some implementation schemes, R 4Selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, and C3-C6 cycloalkyl, wherein the C1-C4 alkyl, C1-C4 hydroxyalkyl, and C3-C6 cycloalkyl are optionally surrounded by one or more R... 4a replace.

[0163] In some implementation schemes, R 4 The group is selected from methyl, ethyl, hydroxyethyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, hydroxyethyl, cyclopropyl, and cyclobutyl groups are optionally marked with one or more R groups. 4a replace.

[0164] In some implementation schemes, each R 4a Independently selected from amino, cyano, oxo, and 4-6 membered heterocyclic groups, wherein the amino and 4-6 membered heterocyclic groups are optionally surrounded by one or more R... 2aa replace.

[0165] In some implementation schemes, each R 4a Independently selected from amino, cyano, oxo, tetrahydropyranyl, oxetyl and The amino group, tetrahydropyranyl group and Optional by one or more R 2aa replace.

[0166] In some implementation schemes, each R 4a Independently selected from oxo, -N(CH3)CH3, oxoheterobutyl, cyano,

[0167] In some implementation schemes, R 4 Selected from

[0168] In some implementation schemes, R 4 Selected from

[0169] In some implementation schemes, R 4 Selected from (For example )and

[0170] In some implementation schemes, R 5 The compounds are selected from 9-10-membered heterocyclic groups and 9-10-membered heteroaryl groups, wherein the 9-10-membered heterocyclic group and 9-10-membered heteroaryl group have a bicyclic structure, and the 9-10-membered heterocyclic group and 9-10-membered heteroaryl group are optionally separated by one or more R groups. 5a replace.

[0171] In some implementation schemes, R 5Selected from 9-10-membered heteroaryl groups, wherein the 9-10-membered heteroaryl group has a bicyclic structure, and wherein the 9-10-membered heteroaryl group is optionally surrounded by one or more R groups. 5a replace.

[0172] In some implementation schemes, R 5 Selected from one or more R 5a Replacement Where Y is CH or N, Z is C or N, Q is C or N, and the ring C is selected from 5-7 membered monocyclic heterocycles, benzene rings, and 5-6 membered heteroaromatic rings.

[0173] In some implementation schemes, R 5 Selected from one or more R 5a Replacement Where Y is CH or N, Z is C or N, Q is C or N, and the ring C is selected from benzene rings and 5-6 membered heteroaromatic rings.

[0174] In some implementation schemes, R 5 Selected from The Optionally by one or more R 5a replace.

[0175] In some implementation schemes, R 5 Selected from The Optionally by one or more R 5a replace.

[0176] In some implementation schemes, R 5 Selected from The Optionally by one or more R 5a replace.

[0177] In some implementation schemes, R 5 Selected from The Optionally by one or more R 5a replace.

[0178] In some implementation schemes, R 5 Selected from The Optionally by one or more R 5a replace.

[0179] 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 12 Cycloalkyl, 3-14 membered heterocyclic, C6-C 10 aryl and 5-10 heteroaryl groups, wherein the amino group, 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.

[0180] In some implementation schemes, each R 5a Independently selected from halogen, cyano, amino, oxo, P(O)R k R k SF5, C1-C 10 Alkyl, C1-C 10 Alkoxy, C2-C 10 alkynyl group, C3-C 12 Cycloalkyl, 3-14 membered heterocyclic, C6-C 10 aryl and 5-10 heteroaryl groups, wherein the amino group, C1-C 10 Alkyl, C2-C 10 alkynyl group, C3-C 12 Cycloalkyl, 3-14 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one or more R groups. c replace.

[0181] In some implementation schemes, each R 5a Independently selected from halogen, cyano, amino, hydroxyl, oxo, C1-C 10 Alkyl, C1-C 10 Alkoxy, C2-C 10 alkynyl group, C3-C 12 Cycloalkyl and 3-14 membered heterocyclic groups, wherein the amino, hydroxyl, C1-C 10 Alkyl, C2-C 10 alkynyl group, C3-C 12 Cycloalkyl groups and 3-14-membered heterocyclic groups are optionally surrounded by one or more R groups. c replace.

[0182] In some implementation schemes, each R 5a Independently selected from halogen, cyano, amino, oxo, C1-C 10 Alkyl, C2-C 10 alkynyl group, C3-C 12 Cycloalkyl and 3-14 membered heterocyclic groups, wherein the amino group, C1-C 10 Alkyl, C2-C 10 alkynyl group, C3-C 12 Cycloalkyl groups and 3-14-membered heterocyclic groups are optionally surrounded by one or more R groups. c replace.

[0183] In some implementation schemes, each R 5a Independently selected from halogen, cyano, amino, oxo, P(O)R k R k SF5, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkynyl, C3-C6 cycloalkyl, 3-12 heterocyclic, phenyl, and 5-10 heteroaryl, wherein the amino, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkynyl, C3-C6 cycloalkyl, 3-12 heterocyclic, phenyl, and 5-10 heteroaryl are optionally surrounded by one or more R c replace.

[0184] In some implementation schemes, each R 5a The radical is independently selected from halogen, cyano, amino, oxo, C1-C4 alkyl, C2-C4 ynyl, C3-C5 cycloalkyl, and 3-6 membered heterocyclic groups, wherein the amino, C1-C4 alkyl, C2-C4 ynyl, C3-C5 cycloalkyl, and 3-6 membered heterocyclic groups are optionally surrounded by one or more R groups. c replace.

[0185] In some implementation schemes, each R k The components are independently selected from C1-C4 alkyl groups, with C1-C4 alkyl groups preferably being methyl.

[0186] In some implementation schemes, each R 5a Independently selected from halogen, cyano, amino, C1-C 10 Alkyl groups and 3-14 membered heterocyclic groups, wherein the amino group, C1-C 10 Alkyl groups and 3-14 membered heterocyclic groups are optionally surrounded by one or more R groups. c replace.

[0187] In some implementation schemes, each R 5a The radical is independently selected from halogen, cyano, amino, C1-C4 alkyl, and 3-6 membered heterocyclic groups, wherein the amino, C1-C4 alkyl, and 3-6 membered heterocyclic groups are optionally surrounded by one or more R groups. creplace.

[0188] In some implementation schemes, each R 5a Independently selected from fluorine, iodine, amino, ethoxy, cyano, P(O)CH3CH3, SF5, methyl, ethyl, piperazine, piperidinyl, morpholinyl, Ethynyl, propynyl, oxo, cyclopropyl, cyclohexyl, tetrahydropyranyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, cyclobutyl, and tetrahydropyrroleyl, wherein the amino, ethoxy, methyl, ethyl, piperazinyl, piperidinyl, morpholinyl, The ethynyl, propynyl, cyclopropyl, cyclohexyl, tetrahydropyranyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, cyclobutyl, and tetrahydropyrroleyl groups are optionally separated by one or more R groups. c replace.

[0189] In some implementation schemes, each R 5a Independently selected from fluorine, iodine, amino, ethoxy, cyano, P(O)CH3CH3, SF5, methyl, ethyl, piperazine, piperidinyl, Ethynyl, propynyl, oxo, cyclopropyl, cyclohexyl, tetrahydropyranyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, cyclobutyl, and tetrahydropyrroleyl, wherein the amino, ethoxy, methyl, ethyl, piperazinyl, piperidinyl, The ethynyl, propynyl, cyclopropyl, cyclohexyl, tetrahydropyranyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, cyclobutyl, and tetrahydropyrroleyl groups are optionally separated by one or more R groups. c replace.

[0190] In some implementation schemes, each R 5a Independently selected from fluorine, iodine, amino, ethoxy, cyano, methyl, ethyl, piperazine, piperidinyl, Ethynyl, propynyl, oxo, cyclopropyl, and tetrahydropyrroleyl, wherein the amino, ethoxy, methyl, ethyl, piperazine, piperidinyl, The ethynyl, propynyl, cyclopropyl, and tetrahydropyrrolyl groups are optionally separated by one or more R groups. c replace.

[0191] In some implementation schemes, each R 5a Independently selected from fluorine, iodine, amino, cyano, methyl, ethyl, piperazine, piperidinyl, Propynyl, oxo, cyclopropyl and tetrahydropyrrole, wherein the amino, methyl, ethyl, piperazine, piperidinyl, The propynyl, cyclopropyl, and tetrahydropyrrole groups are optionally separated by one or more R groups. c replace.

[0192] In some implementation schemes, each R 5a Independently selected from fluorine, iodine, amino, cyano, methyl, ethyl, piperazine, piperidinyl, and tetrahydropyrrole, wherein the amino, methyl, ethyl, piperazine, piperidinyl, The tetrahydropyrrolidone is optionally surrounded by one or more R c replace.

[0193] 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;

[0194] In some implementation schemes, each R c Independently selected from halogens, amino groups, =O, and S(O)2R k C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl and 4-12 membered heterocyclic groups, wherein the amino, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl groups and 4-12 membered heterocyclic groups are optionally surrounded by one or more R groups. e replace.

[0195] In some implementation schemes, each R c Independently selected from amino, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl and 4-12 membered heterocyclic groups, wherein the amino, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl groups and 4-12 membered heterocyclic groups are optionally surrounded by one or more R groups. e replace.

[0196] In some implementation schemes, each R c Independently selected from halogens, amino groups, =O, and S(O)2R k C1-C5 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, and 4-8 membered heterocyclic groups, wherein the amino, C1-C5 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, and 4-8 membered heterocyclic groups are optionally surrounded by one or more R groups. e replace.

[0197] In some implementation schemes, each R c The amino group, C1-C4 alkyl group, C1-C4 alkoxy group, C3-C5 cycloalkyl group, and 4-7 membered heterocyclic group are independently selected from amino, C1-C4 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, and 4-7 membered heterocyclic groups, which are optionally surrounded by one or more R groups. e replace.

[0198] In some implementation schemes, each R c Independently selected from fluorine, amino, =O, S(O)2CH3, methyl, ethyl, methoxy, cyclopropyl, oxetyl, cyclobutyl, aziroxybutyl, morpholino, piperidinyl, isopropyl, piperazine, tetrahydropyrrolyl, The amino, methyl, ethyl, methoxy, cyclopropyl, oxetyl, cyclobutyl, aziridine, morpholino, piperidinyl, isopropyl, piperazine, and tetrahydropyrrolyl groups are mentioned. Optional by one or more R e replace.

[0199] In some implementation schemes, each R c Independently selected from amino, methyl, ethyl, methoxy, cyclopropyl, oxetyl, cyclobutyl, aziridine, morpholino, piperidinyl, isopropyl, piperazine, The amino, methyl, ethyl, methoxy, cyclopropyl, oxetyl, cyclobutyl, aziridine, morpholino, piperidinyl, isopropyl, piperazineyl, and other amino groups are mentioned. Optional by one or more R e replace.

[0200] In some implementation schemes, each R c Independently selected from amino, methyl, ethyl, methoxy, cyclopropyl, oxetyl, cyclobutyl, aziridine, morpholino, piperidinyl, isopropyl, piperazine, The amino, methyl, ethyl, methoxy, cyclopropyl, oxetyl, cyclobutyl, aziridine, morpholino, piperidinyl, isopropyl, piperazineyl, and other amino groups are mentioned. Optional by one or more R e replace.

[0201] In some implementation schemes, each R c Independently selected from amino, methyl, ethyl, methoxy, cyclopropyl, oxetyl, cyclobutyl, aziridine, morpholino, piperidinyl, isopropyl, The amino, methyl, ethyl, methoxy, cyclopropyl, oxetyl, cyclobutyl, aziridine, morpholino, piperidinyl, isopropyl, Optional by one or more Re replace.

[0202] In some implementation schemes, each R c Independently selected from amino, methyl, ethyl, methoxy, cyclopropyl, oxetyl, cyclobutyl, aziroxybutyl, morpholino, The amino, methyl, ethyl, methoxy, cyclopropyl, oxetyl, cyclobutyl, azirone, and morpholino groups are mentioned. Optional by one or more R e replace.

[0203] In some implementation schemes, each R e Independently selected from halogens, cyano groups, =O, =CR j R j S(O)2R k C1-C4 alkyl, C1-C4 hydroxyalkyl and -N(C1-C4 alkyl)2.

[0204] In some implementation schemes, each R j It is independently selected from H and halogens, preferably fluorine.

[0205] In some implementation schemes, each R k It is independently selected from C1-C4 alkyl groups, preferably methyl.

[0206] In some implementation schemes, each R e Independently selected from halogen, hydroxyl, mercapto, cyano, amino, =O, =CR j R j C(O)R k S(O)2R k C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclic, C1-C4 alkylene, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl)2, wherein the hydroxyl, amino, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclic, C1-C4 alkylene, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl)2, and -N(C1-C4 alkyl)2 are optionally R n replace;

[0207] In some implementation schemes, each R e Independently selected from halogen, cyano, C1-C4 alkoxy, =O, =CR j R j S(O)2R kC1-C4 alkyl, C1-C4 hydroxyalkyl, amino, C3-C6 cycloalkyl, 4-7 heterocyclic and 5-6 heteroaryl groups, wherein the C1-C4 alkoxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, amino, C3-C6 cycloalkyl, 4-7 heterocyclic and 5-6 heteroaryl groups are optionally R n replace.

[0208] In some implementation schemes, each R e Independently selected from halogen, cyano, C1-C4 alkoxy, =O, =CR j R j S(O)2R k C1-C4 alkyl, C1-C4 hydroxyalkyl, amino, C3-C6 cycloalkyl, and 4-7 membered heterocyclic groups, wherein the C1-C4 alkoxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, amino, C3-C6 cycloalkyl, and 4-7 membered heterocyclic groups are optionally R n replace.

[0209] In some implementation schemes, each R e Independently selected from fluorine, cyano, methyl, ethyl, OMe, =O, =CF2, S(O)2CH3, -CH2OH, amino, cyclopropyl, pyrazolyl, tetrahydropyrrole, and The methyl, ethyl, OMe, -CH2OH, amino, cyclopropyl, pyrazolyl, tetrahydropyrrolyl and Optional R n replace.

[0210] In some implementation schemes, each R e Independently selected from fluorine, cyano, methyl, ethyl, OMe, =O, =CF2, S(O)2CH3, -CH2OH, amino, cyclopropyl and The methyl, ethyl, OMe, -CH2OH, amino, cyclopropyl and Optional R n replace.

[0211] In some implementation schemes, R n Selected from CN, =O, halogen, C1-C4 alkyl and (C1-C4 alkyl)S(O)2-.

[0212] In some implementation schemes, R n Selected from halogen, cyano, (C1-C4 alkyl)S(O)2-, N(C1-C4 alkyl)2 and C1-C4 alkyl.

[0213] In some implementation schemes, R n Selected from halogen, cyano, (C1-C4 alkyl)S(O)2- and C1-C4 alkyl.

[0214] In some implementation schemes, R n Selected from F, cyano, S(O)2CH3 and methyl.

[0215] In some implementation schemes, R n Selected from F, cyano, S(O)2CH3, N(CH3)2 and methyl.

[0216] In some implementation schemes, each R e Independently selected from fluorine, cyano, hydroxyl, OMe, =O, =CF2, S(O)2CH3, methyl, -CH2OH, -N(CH3)CH3, tetrahydropyrrolyl, CH2CN,

[0217] In some implementation schemes, each R e Independently selected from fluorine, cyano, OMe, =O, =CF2, S(O)2CH3, methyl, -CH2OH, -N(CH3)CH3, CH2CN,

[0218] In some implementation schemes, each R e It is independently selected from fluorine, cyano, =O, =CF2, S(O)2CH3, methyl, -CH2OH and -N(CH3)CH3.

[0219] In some implementation schemes, each R e It is independently selected from halogen, cyano, =O, C1-C4 alkyl and -N(C1-C4 alkyl)2.

[0220] In some implementation schemes, each R e It is independently selected from =O, fluorine, methyl, cyano and -N(CH3)CH3.

[0221] In some implementation schemes, R 5 for Where Y is selected from CH or N; Z, Q, and X 4 Each is independently selected from C or N, X 5 Selected from CH, N or bond (i.e. X) 5 (Does not exist); X 3 Selected from CR 5a’ , N, O or S; X 6 Selected from CH, N, O or S, and the ring C and ring D contain one, two, three or four heteroatoms independently selected from N, O or S; Indicates a single or double bond; R 5a’ Selected from H, halogen, CN, C1-C4 alkyl, C1-C4 haloalkyl, oxo or C3-C6 cycloalkyl; R5a” Selected from C1-C6 alkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-12 heterocyclic, or 5-10 heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-12 heterocyclic, and 5-10 heteroaryl groups are optionally surrounded by one or more R groups. c replace.

[0222] In some implementation schemes, R 5 for

[0223] In some implementation schemes, R 5a’ It can be H, F, CN, CH3, oxo, CF3, or cyclopropyl.

[0224] In some implementation schemes, R 5a’ It can be H, F, CN or cyclopropyl.

[0225] In some implementation schemes, R 5a’ It is F, CN, or cyclopropyl.

[0226] In some implementation schemes, R 5a’ For H.

[0227] In some implementation schemes, R 5a’ For CN.

[0228] In some implementation schemes, R 5a’ It is cyclopropyl.

[0229] In some implementation schemes, R 5a” Selected from methyl, ethynyl, propynyl, piperazinyl, piperidinyl, morpholinyl, Cyclopropyl, cyclohexyl, tetrahydropyranyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, cyclobutyl, and tetrahydropyrroleyl, wherein the methyl, ethynyl, propynyl, piperazinyl, piperidinyl, morpholinyl, Cyclopropyl, cyclohexyl, tetrahydropyranyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, cyclobutyl, and tetrahydropyrroleyl are optionally separated by one or more R c replace.

[0230] In some implementation schemes, R 5a” Selected from methyl, ethynyl, propynyl, piperazinyl, piperidinyl, morpholinyl, And tetrahydropyranyl, wherein the methyl, ethynyl, propynyl, piperazine, piperidinyl, morpholinyl and tetrahydropyranyl groups are optionally surrounded by one or more R groups. c replace.

[0231] In some implementation schemes, R5a” Selected from methyl, ethynyl, propynyl, The methyl, ethynyl, propynyl, Optionally by one or more R c replace.

[0232] In some implementation schemes, each R c Independently selected from methyl, ethyl, isopropyl, cyclopropyl, cyanomethyl,

[0233] In some implementation schemes, R 5a Selected from piperazine and piperidinyl, wherein the piperazine and piperidinyl groups are optionally surrounded by one or more R groups. c replace.

[0234] In some implementation schemes, R 5a Selected from Where R c Selected from methyl, ethyl, isopropyl, cyclopropyl,

[0235] In some implementation schemes, R 5 Selected from

[0236] In some implementation schemes, R 5 Selected from

[0237] In some implementation schemes, R 5 Selected from

[0238] In some implementation schemes, R 5 Selected from

[0239] In some implementation schemes, R 5 for

[0240] In some implementation schemes, R5 for

[0241] In some implementation schemes, R 5 for

[0242] In some implementation schemes, R 5 for

[0243] In some implementation schemes, R 5 for

[0244] In some implementation schemes, R 5 Selected from

[0245] In some implementation schemes, R 6 It is selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy.

[0246] In some implementation schemes, R 6 Selected from hydrogen, halogen, hydroxyl, mercapto, C1-C4 alkyl, C1-C4 alkoxy, and 4-10 membered heterocyclic groups, wherein the hydroxyl, mercapto, C1-C4 alkyl, C1-C4 alkoxy, and 4-10 membered heterocyclic groups are optionally surrounded by one or more R... 6a replace.

[0247] In some implementation schemes, R 6 Selected from hydrogen, C1-C4 alkoxy groups and 4-10 membered heterocyclic groups, wherein the C1-C4 alkoxy groups and 4-10 membered heterocyclic groups are optionally surrounded by one or more R groups. 6a replace.

[0248] In some implementation schemes, R 6 Selected from hydrogen and C1-C4 alkoxy groups.

[0249] In some implementation schemes, R 6 It is hydrogen or ethoxy.

[0250] In some implementation schemes, R 6 Selected from hydrogen, ethoxy, Morpholinyl, aziridine, pyrrolidinyl and The ethoxy group, Morpholinyl, aziridine, pyrrolidinyl and Optional by one or more R 6a replace.

[0251] In some implementation schemes, each R6a It is independently selected from halogens, C1-C4 alkoxy groups, cyano groups, and C1-C4 alkyl groups.

[0252] In some implementation schemes, each R 6a It is independently selected from fluorine, cyano, methoxy and methyl.

[0253] In some implementation schemes, R 6 Selected from hydrogen, ethoxy, Morpholinyl pyrroleyl and

[0254] In some implementation schemes, R 6 Selected from hydrogen, ethoxy and

[0255] In some implementation schemes, R 6 for

[0256] In some implementation schemes, R 6 for

[0257] In some implementation schemes, R 6 It is hydrogen.

[0258] In some implementation schemes, R 6 for -LR 1 Selected from

[0259] In some implementation schemes, R 4 for R 6 for -LR 1 for

[0260] In some implementation schemes, R 4 for R 6 for -LR 1 for

[0261] In some implementation schemes, R 4 For ethyl, R 6 For hydrogen, -LR 1 Selected from

[0262] In some implementation schemes, R 4 For ethyl, R6 For hydrogen, -LR 1 Selected from (or -LR) 1 Selected from ), R 5 Selected from

[0263] In some implementation schemes, R 4 For ethyl, R 6 For hydrogen, -LR 1 Selected from (or -LR) 1 Selected from ), R 5 for

[0264] In some implementation schemes, R 4 For ethyl, R 6 For hydrogen, -LR 1 Selected from (-LR 1 Selected from ), R 5 for

[0265] In some implementation schemes, R 6 Selected from halogens, hydroxyl groups, mercapto groups, C1-C4 alkyl groups, C1-C4 alkoxy groups, and 4-10 membered heterocyclic groups, wherein the hydroxyl, mercapto, C1-C4 alkyl, C1-C4 alkoxy, and 4-10 membered heterocyclic groups are optionally surrounded by one or more R groups. 6a replace.

[0266] In some implementation schemes, R 6 Selected from C1-C4 alkoxy groups and 4-10 membered heterocyclic groups, wherein the C1-C4 alkoxy groups and 4-10 membered heterocyclic groups are optionally surrounded by one or more R groups. 6a replace.

[0267] In some implementation schemes, R 6 Selected from ethoxy, Morpholinyl, aziridine, pyrrolidinyl and The ethoxy group, Morpholinyl, aziridine, pyrrolidinyl and Optional by one or more R 6a replace.

[0268] In some implementation schemes, R 6Selected from ethoxy, Morpholinyl pyrroleyl and

[0269] In some implementation schemes, R 7 It is selected from hydrogen, halogen, hydroxyl and cyano groups.

[0270] In some implementation schemes, R 7 It is hydrogen.

[0271] 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.

[0272] In some implementation schemes, each R d It is independently selected from halogen, amino, hydroxyl, mercapto and cyano groups.

[0273] In some implementation schemes, each R d It is independently selected from halogens, such as fluorine.

[0274] In some implementation schemes, Selected from The value of t is selected from 0, 1, 2, and 3.

[0275] In some implementation schemes, Selected from

[0276] In some implementation schemes, R 8 Selected from hydrogen, halogen, hydroxyl, cyano and C1-C 10 alkyl.

[0277] In some implementation schemes, R 8 It is hydrogen.

[0278] In some implementation schemes, R 9 It is selected from hydrogen, halogen, hydroxyl and cyano groups.

[0279] In some implementation schemes, R 9 It is hydrogen.

[0280] In some implementation schemes, R 10 Selected from halogens, such as fluorine.

[0281] In some implementations, n is 0, 1, or 2.

[0282] In some implementations, n is 0.

[0283] In some implementation schemes, R 7 R8 and R 9 All are hydrogen atoms, and n is 0.

[0284] In some implementation schemes, R 2 and R 3 All are methyl; X 1 Let C, X 2 For N; R 6 It is hydrogen; R 7 R 8 and R 9 All are hydrogen; and / or n is 0.

[0285] In some implementation schemes, R 2 and R 3 All are methyl; X 1 Let C, X 2 For N; R 6 It is hydrogen; R 7 R 8 and R 9 All are hydrogen; n is 0; A is Where * represents the end connected to the benzene ring; and / or, R 4 Ethyl or

[0286] 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.

[0287] 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.

[0288] 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.

[0289] Among them, R 4 Selected from C1-C 10 Alkyl, C1-C 10 Hydroxyalkyl and C3-C7 cycloalkyl, wherein C1-C 10 Alkyl, C1-C 10 Hydroxyalkyl and C3-C7 cycloalkyl are optionally surrounded by one or more R 4a Replacement; More preferably R4 Selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, and C3-C6 cycloalkyl, wherein the C1-C4 alkyl, C1-C4 hydroxyalkyl, and C3-C6 cycloalkyl are optionally surrounded by one or more R... 4a Replacement; More preferably R 4 The group is selected from methyl, ethyl, hydroxyethyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, hydroxyethyl, cyclopropyl, and cyclobutyl groups are optionally marked with one or more R groups. 4a Replacement; More preferably R 4 Selected from

[0290] R 6 Selected from halogen, amino, hydroxyl, mercapto, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups and C1-C4 alkoxy groups, wherein the hydroxyl, mercapto, amino, C1-C4 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups and C1-C4 alkoxy groups are optionally surrounded by one or more R groups. 6a Replace; more preferably R 6 Selected from C1-C4 alkoxy groups and 4-10 membered heterocyclic groups, wherein the C1-C4 alkoxy groups and 4-10 membered heterocyclic groups are optionally surrounded by one or more R groups. 6a Replace; more preferably R 6 Selected from ethoxy, Morpholinyl pyrroleyl and

[0291] A, L, R 1 R 2 R 3 R 4a R 5 R 6a R 7 R 8 and R 9 As defined above.

[0292] In some implementations, R in equation (III) 4 Selected from (For example )and

[0293] In some implementations, R in equation (III) 6 for

[0294] In some implementations, R in equation (III) 6 for

[0295] In some implementations, L in formula (III) is selected from R 1 Selected from

[0296] In some implementations, L in formula (III) is selected from R 1 Selected from

[0297] In some implementations, L in formula (III) is selected from R 1 Selected from

[0298] In some implementations, R in equation (III) 5 Selected from

[0299] 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.

[0300] In some embodiments, the compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt is selected from the compounds prepared in Examples 1-88 or their pharmaceutically acceptable salts.

[0301] On the other hand, this disclosure provides pharmaceutical compositions comprising a compound of formula (I), (II), or (III) of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0302] On the other hand, this disclosure provides a method for treating an individual (e.g., a mammal) with a disease mediated by RAS, comprising administering to the individual (e.g., a mammal, preferably a human) a therapeutically effective amount of a compound of formula (I), formula (II), or formula (III) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0303] On the other hand, this disclosure provides the use of a compound of formula (I), formula (II), or formula (III) or its stereoisomer or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof, in the preparation of a medicament for the prevention or treatment of RAS-mediated diseases.

[0304] On the other hand, this disclosure provides the use of compounds of formula (I), (II), or (III) or their stereoisomers or pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in the prevention or treatment of RAS-mediated diseases.

[0305] On the other hand, this disclosure provides compounds of formula (I), formula (II), or formula (III) for the prevention or treatment of RAS-mediated diseases, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[0306] In some implementations, the RAS-mediated disease is a tumor, such as non-small cell lung cancer, pancreatic cancer, and colorectal cancer.

[0307] The compounds of formula (I), (II), or (III) of this disclosure, or their stereoisomers or pharmaceutically acceptable salts thereof, can achieve at least one of the following advantages compared with the prior art: (1) better killing effect on tumors with different RAS mutations and RAS protein dependence, and better treatment of RAS mutation-mediated tumors; (2) high selectivity for RAS protein with G12V mutation, and treatment of RAS G12V mutation-mediated tumors; (3) lower toxicity, such as lower hERG and CYP enzyme inhibitory activity, resulting in lower risk of cardiotoxicity and drug interaction; (4) higher bioavailability; (5) lower metabolic clearance and longer duration of drug action; (6) higher intratumoral drug distribution, resulting in better efficacy at lower doses and fewer side effects.

[0308] Terminology Definitions and Explanations

[0309] 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.

[0310] In this article Indicates the connection site.

[0311] Some compounds of this application can exist as trans-isomers, which are conformational isomers that occur when rotation around a single bond in the molecule is prevented or significantly slowed due to steric interactions with other parts of the molecule. The compounds disclosed herein include all trans-isomers, which can be pure, single trans-isomers, trans-isomers enriched in one of them, or nonspecific mixtures of each. Separation of isomers is permitted if the rotational potential around the single bond is sufficiently high and the interconversion between conformations is sufficiently slow. For example, (or )and (or ) is a pair of transisomers, wherein the pyridyl group is an inhibitor of transisomers. This indicates that the orientation of this three-dimensional object is outward. This indicates that the orientation of this three-dimensional object is inward.

[0312] 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).

[0313] In this article, in the ring This indicates that the corresponding ring is an aromatic ring.

[0314] When a compound's chiral center is labeled "or1," it indicates a single configuration isomer, but the absolute configuration at that chiral center has not yet been confirmed. For example, The representative is One of the two, but the absolute configuration has not yet been confirmed; The representative is One of four possible absolute configurations, but the specific absolute configuration has not yet been confirmed.

[0315] 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.

[0316] 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 For example, The L in the text is selected from At this time, L can connect the loop and R in a left-to-right direction. 1 Constitutes "cyclic -NH-C(O)R 1 Alternatively, the ring and R can be connected from right to left. 1 Composing "R" 1 -NH-C(O)- ring.

[0317] 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.

[0318] 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.

[0319] 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; oxoation does not occur on the aromatic group. For example, the substitution of "C1-C4 hydroxyalkyl" could mean that the hydrogen on the C of the C1-C4 hydroxyalkyl group is substituted, or it could mean that the hydrogen on the hydroxyl group is substituted.

[0320] 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.

[0321] 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 bEach has its own independent options.

[0322] 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.

[0323] 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 1,2-dimethylbutyl, etc.; the term "C1-C7 alkyl" is also used. The term "alkyl" can be understood as referring to an alkyl group having 1 to 7 carbon atoms, with specific examples including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C6 alkyl" can be understood as referring to a straight-chain or branched saturated alkyl group having 1 to 6 carbon atoms. The term "C1-C5 alkyl" can be understood as referring to a straight-chain or branched saturated alkyl group having 1 to 5 carbon atoms. The term "C1-C4 alkyl" can be understood as referring to a straight-chain or branched saturated alkyl group having 1 to 4 carbon atoms. The term "C1-C3 alkyl" can be understood as referring to a straight-chain or branched saturated alkyl group having 1 to 3 carbon atoms. The term "C5-C6 alkyl" can be understood as referring to a straight-chain or branched saturated alkyl group having 1 to 3 carbon atoms. 10 "Alkyl" can be understood as referring to a straight-chain or branched saturated alkyl group having 5 to 10 carbon atoms. The "C1-C" 10 "alkyl" can include "C1-C6 alkyl", "C1-C4 alkyl", "C1-C3 alkyl" or "C5-C6 alkyl". 10 The term "alkyl" is used within the range of "C1-C6 alkyl," which may further include "C1-C4 alkyl" or "C1-C3 alkyl." The term "halogenated alkyl" is intended to include both monohalogenated and polyhalogenated alkyl groups. For example, the term "C1-C6 alkyl" may include "C1-C4 alkyl" or "C1-C3 alkyl." 10"Haloalkyl" refers to a C1-C alkyl group as defined above that has been substituted with one or more halogens. 10 Alkyl groups include, but are not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. The term "hydroxyalkyl" is intended to include both monohydroxy-substituted and polyhydroxy-substituted alkyl groups. For example, the term "C1-C4 hydroxyalkyl" refers to a C1-C4 alkyl group as defined above that is substituted with one or more hydroxyl groups. The term "alkylene" is a residue derived from an alkyl group by further removing a hydrogen atom.

[0324] 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".

[0325] 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", and "C6-C6 alkenyl". 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.

[0326] 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).

[0327] 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-C" is also used. 10 "Cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, or 10 ring carbon atoms. The term "C3-C7 cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, 6, or 7 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.

[0328] 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 whose ring atoms contain heteroatoms or heteroatomic groups (i.e., groups containing heteroatoms). A "heterocyclic group" or "heterocycle" may contain 1-5 (e.g., 1-3 or 1-2) heteroatoms or heteroatomic groups, including but not limited to nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=O)2-, -S(=O)-, -P(=O)2-, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-, etc. In some embodiments, a "heterocyclic group" or "heterocycle" contains 1-2, 1-3, or 1-4 heteroatoms independently selected from N, O, and S. The term "3-14 membered heterocyclic group" refers to a heterocyclic group with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, and whose ring atoms contain 1-5 (e.g., 1-3 or 1-2) independently selected heteroatoms or heterogroups (e.g., N, O, S) as described above. The term "4-14 membered heterocyclic group" refers to a heterocyclic group with 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, and whose ring atoms contain 1-5 (e.g., 1-3 or 1-2) independently selected heteroatoms or heterogroups (e.g., N, O, S) as described above. The term "8-15 membered heterocyclic group" refers to a heterocyclic group with 8, 9, 10, 11, 12, 13, 14, or 15 ring atoms, and whose ring atoms contain 1-5 (e.g., 1-3 or 1-2) heteroatoms or heterogroups independently selected from those described above (e.g., N, O, S). The term "4-12 membered heterocyclic group" refers to a heterocyclic group with 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, and whose ring atoms contain 1-5 (e.g., 1-3 or 1-2) heteroatoms or heterogroups independently selected from those described above (e.g., N, O, S). The term "5-10 membered heterocyclic group" refers to a heterocyclic group with 5, 6, 7, 8, 9, or 10 ring atoms, and whose ring atoms contain 1-5 (e.g., 1-3 or 1-2) heteroatoms or heterogroups independently selected from those described above (e.g., N, O, S). The term "9-10 membered heterocyclic group" refers to a heterocyclic group with 9 or 10 ring atoms, wherein its ring atoms contain 1-5 (e.g., 1-3 or 1-2) heteroatoms or heterogroups independently selected from those described above (e.g., N, O, S). The term "4-10 membered heterocyclic group" refers to a heterocyclic group with 4, 5, 6, 7, 8, 9, or 10 ring atoms, wherein its ring atoms contain 1-5 (e.g., 1-3 or 1-2) heteroatoms or heterogroups independently selected from those described above (e.g., N, O, S).The term "4-6 membered heterocyclic group" refers to a heterocyclic group with 4, 5, or 6 ring atoms, and whose ring atoms contain 1-3 independently selected heteroatoms or heterogroups (e.g., N, O, S) as described above. The term "5-7 membered heterocyclic group" refers to a heterocyclic group with 5, 6, or 7 ring atoms, and whose ring atoms contain 1-4 independently selected heteroatoms or heterogroups (e.g., N, O, S) as described above. The term "6-7 membered heterocyclic group" refers to a heterocyclic group with 6 or 7 ring atoms, and whose ring atoms contain 1-4 independently selected heteroatoms or heterogroups (e.g., N, O, S) as described above. The term "3-6 membered heterocyclic group" refers to a heterocyclic group with 3, 4, 5, or 6 ring atoms, and whose ring atoms contain 1-3 independently selected heteroatoms or heterogroups (e.g., N, O, S) as described above. "4-10 membered heterocyclic group" may include "4-7 membered heterocyclic group". 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 independently selected heteroatoms or heteroatomic groups (e.g., N, O, S) as 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.

[0329] 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 heteroatoms or heteroatomic groups (i.e., atomic groups containing heteroatoms). A "heterocyclic alkyl" group may contain 1-5 heteroatoms or heteroatomic groups, including but 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-. In some embodiments, a "heterocyclic alkyl" group contains 1-2, 1-3, or 1-4 heteroatoms independently selected from N, O, and S. The term "4-10 membered heterocyclic alkyl" refers to a heterocyclic alkyl group having 4, 5, 6, 7, 8, 9, or 10 ring atoms, and containing 1 to 5 heteroatoms or heterogroups independently selected from those described above (e.g., N, O, S). The term "5-10 membered heterocyclic alkyl" refers to a heterocyclic alkyl group having 5, 6, 7, 8, 9, or 10 ring atoms, and containing 1 to 5 heteroatoms or heterogroups independently selected from those described above (e.g., N, O, S). "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.

[0330] The term "aryl" or "aromatic ring" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic aromatic ring 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.

[0331] The term "heteroaryl" or "heteroary ring" 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 to include monocyclic or polycyclic 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. The term "8-15-membered heteroaryl" can be understood to include the aforementioned monocyclic or polycyclic aromatic ring systems: having 8, 9, 10, 11, 12, 13, 14, or 15 ring atoms, for example, 8, 9, 10, 11, 12, 13, 14, or 15 ring atoms, and containing 1 to 5, for example, 1 to 3 heteroatoms independently selected from N, O, and S. The term "5-10-membered heteroaryl" can be understood to include the aforementioned monocyclic or polycyclic aromatic ring systems: having 5, 6, 7, 8, 9, or 10 ring atoms, for example, 5, 6, 9, or 10 ring atoms, and containing 1 to 5, for example, 1 to 3 heteroatoms independently selected from N, O, and S. The term "9-10 heteroaryl" can be understood to include the aforementioned monocyclic or polycyclic aromatic ring systems, having 9 or 10 reducing agents, and containing 1-5, for example 1-3, heteroatoms independently selected from N, O, and S. Specifically, the heteroaryl group is selected from thiophene, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-thiadiazolyl, or 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, or 1,2,5-thiadiazolyl, and their benzo[a] derivatives, such as benzofuranyl, etc. Benzothiophene, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, or isoindolyl, etc.; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazolinyl, or isoquinolinyl, etc.; or acridineyl, indazinyl, purinyl, etc., and their benzo derivatives; or terpineyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphridinyl, pteridineyl, carbazolyl, acridineyl, phenazinyl, phenothiazinyl, or phenothiazinyl, etc. 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.

[0332] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0333] The term "hydroxyl group" refers to the -OH group.

[0334] The term "cyano" refers to the -CN group.

[0335] The term "amino" refers to the -NH2 group. The term "imino" refers to the -NH- group.

[0336] The term "nitro" refers to the -NO2 group.

[0337] The term "oxo" refers to the =O group.

[0338] 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:

[0339] (i) Suppress the disease or disease state, that is, curb its development;

[0340] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0341] 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.

[0342] 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.

[0343] 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.

[0344] 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.

[0345] 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.

[0346] 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.

[0347] 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.

[0348] 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”.

[0349] 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.

[0350] 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.

[0351] 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.

[0352] 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.

[0353] 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.

[0354] 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.

[0355] 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.

[0356] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0357] 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.

[0358] 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.

[0359] 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.

[0360] 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.

[0361] Abbreviations:

[0362] EA represents ethyl acetate; TBDPS represents tert-butyldiphenylsilyl; TBDPSCl represents tert-butyldiphenylchlorosilane; DCM represents dichloromethane; DMF represents N,N-dimethylformamide; THF represents tetrahydrofuran; MeOH represents methanol; TsOH represents p-toluenesulfonic acid; TsOH.H2O represents p-toluenesulfonic acid monohydrate; diludine represents dihydropyridine; AgOTf represents silver trifluoromethanesulfonate; DMAP represents 4-dimethylaminopyridine; TMSCHN2 represents trimethylsilane. Diazomethane; TsCl represents p-toluenesulfonyl chloride; NMP represents N-methylpyrrolidone; LDA represents lithium diisopropylamino; DTBA represents di-tert-butyl azodicarbonate; DMPUN represents N,N-dimethylpropenylurea; n-BuLi represents n-butyllithium; Boc2O represents di-tert-butyl dicarbonate; TFA: trifluoroacetic acid; DIEA or DIPEA represents N,N-diisopropylethylamine; Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride; HATU represents 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; Et3N or TEA represents triethylamine; PPh3: triphenylphosphine; Pd(PPh3)2Cl2 represents bis(triphenylphosphine)palladium dichloride; Pd(PPh3)4 represents tetra(triphenylphosphine)palladium; ACN / MeCN represents acetonitrile; NIS represents N-iodosuccinimide; AcOH represents acetic acid; KOAc / AcOK represents potassium acetate; EtI represents iodoethane; Boc represents tert-butyloxycarbonyl. dioxane represents 1,4-dioxane; TCFH represents N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate; NMI represents N-methylimidazolium; TBAF represents tetrabutylammonium fluoride; DMSO represents dimethyl sulfoxide; mCPBA represents m-chloroperoxybenzoic acid; Pd2(dba)3 represents tris(dibenzylacetone)dipalladium; Sphos represents 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl; Cbz represents benzyloxycarbonyl; t-BuOH represents tert-butanol; tBuXPhos Pd G3 represents methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); PE represents petroleum ether; TLC represents thin-layer chromatography; FA represents formic acid; (HCHO)n represents paraformaldehyde; Ru-L(S,S) represents (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride; TMSCN represents trimethylcyanosilane; CDI represents 1,1-carbonyldiimidazole; i-PrOH or IPA represents isopropanol; MeNH2 represents methylamine; EtOH represents ethanol;CataCXium A Pd G3 represents [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II)methanesulfonic acid; piperidine represents piperidine; Tf2O represents trifluoromethanesulfonic anhydride; rt represents room temperature; NBS represents N-bromosuccinimide; XantPhos represents 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene; Acetone represents acetone; Pd(OAc)2 represents palladium acetate; B2Pin2 represents 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1,3,2-dioxoboropentane; P-ABSA represents 4-acetamidobenzenesulfonyl azide; Rhodium acetate represents rhodium acetate; toluene represents toluene; DMAc represents N,N-dimethylacetamide; Bn represents benzyl; XPhos represents 2-dicyclohexylphospho-2',4',6'-triisopropylbiphenyl; HFIP represents hexafluoroisopropanol; MsCl represents methanesulfonyl chloride; DMF-DMA represents N,N-dimethylformamide dimethyl acetal; 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. Attached Figure Description

[0363] Figure 1. Three-dimensional ellipsoidal diagram of Int-28 Detailed Implementation

[0364] 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.

[0365] 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.

[0366] Unless otherwise stated, the proportions expressed for mixed solvents are volume-based.

[0367] Unless otherwise stated, % refers to weight percentage (wt%).

[0368] Compounds are processed manually or Software naming conventions are used; commercially available compounds use supplier catalog names.

[0369] 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).

[0370] The eluent or mobile phase may be a mixture of two or more solvents, with the ratio being the volume ratio of each solvent.

[0371] Instrument source and parameters:

[0372] The polarization microscope (PLM) information used in this disclosure is as follows:

[0373] Table 1

[0374] The information regarding the single-crystal X-ray diffractometer (SXRD) used in this disclosure is as follows:

[0375] Table 2

[0376] Preparation Example

[0377] Preparation Example 1: Synthesis of intermediate compound Int-1

[0378] Step 1: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropionic acid (compound A2)

[0379] 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 2 M 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.

[0380] Step 2: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropionyl chloride (compound A3)

[0381] 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.

[0382] Step 3: Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropane-1-one (compound A4)

[0383] 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 h. The reaction was monitored by LC-MS until complete. 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 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%).

[0384] MS(ESI + m / z = 534.0 [M+H] + .

[0385] Step 4: Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropane-1-ol (compound A5)

[0386] Compound A4 (8 g, 14.97 mmol) was dissolved in tetrahydrofuran (71.30 mL) at 0 °C. Under nitrogen protection, a 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. The reaction was monitored for completeness by LC-MS. The reaction mixture was quenched with methanol (20 mL) and extracted three times with ethyl acetate (50 mL). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give compound A5 (8 g, 14.91 mmol, yield: 99.62%). The product was used directly in the next step without purification.

[0387] Step 5: Synthesis of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1H-indole (compound A6)

[0388] 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. The reaction was monitored by LC-MS until complete. After the reaction was completed, water (50 mL) was added to quench the reaction, and the mixture was washed three times with dichloromethane (50 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound A6 (7 g, 13.45 mmol, yield: 90.19%).

[0389] MS(ESI + m / z = 520.0 [M+H] + .

[0390] Step 6: Synthesis of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-iodo-1H-indole (compound Int-1)

[0391] 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. The reaction was monitored by LC-MS until complete. 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%).

[0392] MS(ESI + m / z = 646.1 [M+H] + .

[0393] Preparation Example 2: Synthesis of intermediate compound Int-2

[0394] Step 1: Synthesis of 3-(2-diazoacetyl)cyclobutane-1-one (compound B2)

[0395] 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%).

[0396] MS(ESI + m / z = 139.0 [M+H] + .

[0397] Step 2: Synthesis of 2-(3-oxocyclobutyl)acetic acid (compound B3)

[0398] 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.

[0399] MS(ESI + m / z = 127.0 [MH] - .

[0400] Step 3: Synthesis of (S)-4-benzyl-3-(2-(3-oxocyclobutyl)acetyl)oxazolidin-2-one (compound B4)

[0401] 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%).

[0402] MS(ESI + m / z = 288.1 [M+H] + .

[0403] Step 4: Synthesis of (S)-4-benzyl-3-(2-(3-hydroxycyclobutyl)acetyl)oxazolidin-2-one (compound B5)

[0404] 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 obtain 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, and 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.

[0405] MS(ESI + m / z = 290.2[M+H] + .

[0406] Step 5: Synthesis of (S)-3-(2-(4-benzyl-2-oxooxazolidine-3-yl)-2-oxoethyl)cyclobutyl-4-methylbenzenesulfonate (compound B6)

[0407] 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). The mixture was cooled to 0 °C, and 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%).

[0408] MS(ESI + m / z = 444.1 [M+H] + .

[0409] Step 6: Synthesis of (S)-4-benzyl-3-(2-(3-bromocyclobutyl)acetyl)oxazolidin-2-one (compound B7)

[0410] 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] + .

[0411] Step 7: Synthesis of (S)-2,3-bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid (compound B8)

[0412] 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 completed, the reaction solution was concentrated and then 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%).

[0413] MS(ESI + m / z = 343.1 [M+H] + .

[0414] 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)

[0415] 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) in an ice bath. The reaction solution was concentrated to give the title compound B9 (1.0 g, 2.8 mmol, yield: 96.2%).

[0416] MS(ESI + m / z = 357.2[M+H] + .

[0417] Step 9: Synthesis of (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid methyl ester (compound Int-2)

[0418] At room temperature, 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), and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated to give the title compound Int-2 (312 mg, 1.98 mmol, yield: 100.0%).

[0419] MS(ESI + m / z = 157.0 [M+H] + .

[0420] Preparation Example 3: Synthesis of intermediate compound Int-3

[0421] Step 1: Synthesis of 3-(5-bromo-1H-indol-3-yl)-2,2-dimethyl-1-propanol (compound C2)

[0422] 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] + .

[0423] Step 2: Synthesis of 3-(5-bromo-1H-indol-3-yl)-2,2-dimethylacetic acid propyl ester (compound C3)

[0424] 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 the 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%).

[0425] MS(ESI + m / z = 324.1 [M+H] + .

[0426] 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)

[0427] 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 the mixture three times with argon. 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%).

[0428] MS(ESI + m / z = 372.1 [MH] + .

[0429] 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)

[0430] Compound C4 (2.6 g, 7.0 mmol), compound 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 to be complete by LC-MS. The mixture 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%).

[0431] MS(ESI + m / z = 530.1 [M+H] + .

[0432] 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)

[0433] 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%).

[0434] MS(ESI + m / z = 656.5 [MH] + .

[0435] 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)

[0436] Compound C6 (2.6 g, 3.97 mmol) was dissolved in a mixture of tetrahydrofuran (30 mL) and water (5 mL). Lithium hydroxide (474.9 mg, 19.8 mmol) was added to the reaction solution. 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. 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. The mixture was extracted with ethyl acetate (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound C7 (2.3 g, 3.84 mmol, yield: 96.7%).

[0437] MS(ESI + m / z = 600.0 [M+H] + .

[0438] 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)

[0439] 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%).

[0440] MS(ESI + m / z = 738.1 [M+H] + .

[0441] 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)

[0442] 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. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS until complete. The mixture was diluted with ethyl acetate and water. The pH of the aqueous phase was adjusted to about 6 with 1 M HCl aqueous solution. The aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound C9 (200.0 mg, 276.4 μmol, yield: 70.3%).

[0443] MS(ESI + m / z = 724.1 [M+H] + .

[0444] Step 9: Synthesis of compound Int-3

[0445] 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%).

[0446] MS(ESI + m / z = 706.2[M+H] + .

[0447] Preparation Example 4: Synthesis of intermediate compound Int-4

[0448] The first step is the synthesis of 6-bromo-3-nitro-1,2-dihydroquinoline-2-ol (compound D2).

[0449] 2-Amino-5-bromobenzaldehyde (5.0 g, 25.0 mmol) and ethyl nitrate (6.65 g, 49.99 mmol) were added to a mixture of acetic acid (20.0 mL) and water (20.0 mL), followed by the addition of piperidine (1.23 mL, 12.5 mmol). The mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the mixture was added dropwise to ice water, and the precipitated solid was filtered off, washed with pure water, and dried to give compound D2 (6.0 g, 22.3 mmol, yield: 89.2%). MS (ESI+) m / z = 269.0 [MH] - .

[0450] Step 2: Synthesis of 4-(3-nitro-2-oxo-1,2-dihydroquinoline-6-yl)piperazine-1-carboxylic acid benzyl ester (compound D3)

[0451] Compound D2 (2.0 g, 7.43 mmol) and benzyl piperazine-1-carboxylate (2.46 g, 11.15 mmol) were added to tert-butanol (20.0 mL), followed by methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (590.2 mg, 743.3 μmol) and potassium tert-butoxide (2.5 g, 22.3 mmol). The mixture was stirred at 90 °C under argon protection for 16 hours, and the reaction was monitored for completeness by LC-MS. The mixture was filtered, and the filtrate was extracted with water (50 mL) and concentrated to obtain the crude product. The crude product was purified by reverse-phase (Water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound D3 (1.2 g, 2.94 mmol, yield: 39.5%).

[0452] MS(ESI+)m / z = 409.1[M+H] + .

[0453] Step 3: Synthesis of 4-(2-chloro-3-nitroquinoline-6-yl)piperazine-1-carboxylic acid benzyl ester (compound D4)

[0454] Compound D3 (1.2 g, 2.94 mmol) was added to phosphorus oxychloride (20.0 mL), and the mixture was stirred at 90 °C for 3 hours. After the reaction was complete, the mixture was added dropwise to ice water to quench the reaction, and then extracted with ethyl acetate. The organic phase was concentrated to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:1) to give compound D4 (500.0 mg, 1.17 mmol, yield: 39.8%).

[0455] MS(ESI+)m / z = 427.1[M+H] + .

[0456] Step 4: Synthesis of 4-(2-acetyl-3-nitroquinoline-6-yl)piperazine-1-carboxylic acid benzyl ester (compound D5)

[0457] Compound D4 (500.0 mg, 1.17 mmol) was added to N,N-dimethylformamide (10.0 mL), followed by palladium dichloride bis(triphenylphosphine) chloride (82.1 mg, 117.1 μmol) and (1-ethoxyethylene)trimethylstanane (846.0 mg, 3.58 mmol). The mixture was stirred at 110 °C under nitrogen protection for 1 hour. After the reaction was complete, 1,4-dioxane hydrochloride solution (10.0 mL, 4.0 M) was added to the reaction mixture, and the mixture was stirred for 30 minutes. After the reaction was completed by TLC monitoring, the pH was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution, followed by extraction with ethyl acetate. The crude product obtained after concentration of the organic phase was purified by column chromatography (PE:EA = 3:1) to give compound D5 (380.0 mg, 874.7 μmol, yield: 74.7%).

[0458] MS(ESI+)m / z = 435.1[M+H] + .

[0459] Step 5: Synthesis of 4-(2-acetyl-3-aminoquinoline-6-yl)piperazine-1-carboxylic acid benzyl ester (compound D6)

[0460] Compound D5 (330.0 mg, 759.5 μmol) and iron powder (849.4 mg, 15.19 mmol) were added to acetic acid (10.0 mL) and stirred in an oil bath at 60 °C for 1 hour. After the reaction was completed, the residue was filtered off, the filtrate was washed with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the crude product obtained by concentration of the organic phase was purified by reverse-phase reaction (Water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound D6 (280.0 mg, 692.2 μmol, yield: 91.1%).

[0461] MS(ESI+)m / z = 405.1[M+H] + .

[0462] Step 6: Synthesis of (S)-4-(3-amino-2-(1-hydroxyethyl)quinoline-6-yl)piperazine-1-carboxylic acid benzyl ester (compound D7)

[0463] Under an argon atmosphere and ice bath conditions, triethylamine (744.5 mg, 7.36 mmol) and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (39.0 mg, 61.3 μmol) were added to formic acid (67.7 mg, 1.47 mmol), and the mixture was heated to 40 °C and stirred for 15 minutes. The reaction solution was cooled to room temperature, and compound D6 (248.0 mg, 613.1 μmol) was added. The mixture was then heated to 40 °C and stirred for 2 hours. After the reaction was completed, the crude product obtained by concentration was purified by reverse-phase reaction (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound D7 (196.0 mg, 482.1 μmol, yield: 78.6%).

[0464] MS(ESI+)m / z = 407.1[M+H] + .

[0465] Step 7: Synthesis of (S)-4-(2-(1-hydroxyethyl)-3-iodoquinoline-6-yl)piperazine-1-carboxylic acid benzyl ester (compound D8)

[0466] Under ice bath conditions, p-toluenesulfonic acid (360.0 mg, 2.09 mmol) and compound D7 (170.0 mg, 418.23 μmol) were added to acetonitrile (10.0 mL), followed by the addition of an aqueous solution of sodium nitrite (144.3 mg, 2.09 mmol) and potassium iodide (347.1 mg, 2.09 mmol). The mixture was stirred for 10 minutes under ice bath conditions, then transferred to room temperature and stirred for another hour. After the reaction was complete, a saturated aqueous solution of sodium sulfite was added to quench the reaction, and the mixture was extracted with ethyl acetate. The crude product obtained after concentration of the organic phase was purified by column chromatography (PE:EA = 3:1) to give compound D8 (132.0 mg, 255.1 μmol, yield: 61.0%).

[0467] MS(ESI+)m / z = 518.0 [M+H] + .

[0468] Step 8: Synthesis of (S)-4-(3-iodo-2-(1-methoxyethyl)quinolin-6-yl)piperazine-1-carboxylic acid benzyl ester (compound Int-4)

[0469] Compound D8 (150.0 mg, 289.9 μmol) was added to N,N-dimethylformamide (5.0 mL) containing sodium hydride (23.2 mg, 579.9 μmol, dispersed at 60% concentration in liquid paraffin) under an argon atmosphere and ice bath conditions. After stirring for 10 minutes, iodomethane (82.3 mg, 579.9 μmol) was added, and the mixture was then transferred to room temperature and stirred for another hour. After the reaction was complete, the reaction solution was added dropwise to 0.5 M dilute hydrochloric acid and extracted with ethyl acetate. The crude product obtained after concentration of the organic phase was purified by column chromatography (PE:EA = 3:1) to give compound Int-4 (132.0 mg, 248.1 μmol, yield: 85.6%).

[0470] MS(ESI+)m / z = 532.0 [M+H] + .

[0471] Preparation Example 5: Synthesis of intermediate compound Int-5

[0472] The first step is the synthesis of (4-bromothiazol-2-yl)methanol (compound E2).

[0473] Compound E1 (10 g, 52 mmol) was dissolved in methanol (15 mL), and sodium borohydride (2.95 g, 78.11 mmol) was added. The mixture was stirred at 0 °C for 0.5 h. The reaction was monitored for completeness. 10 mL of dilute hydrochloric acid was added to quench the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, giving compound E2 (9 g, 46.38 mmol, yield 89.07%).

[0474] MS(ESI + m / z = 194.3 [M+H] + .

[0475] Step 2: Synthesis of 4-bromo-2-(bromomethyl)thiazole (compound E3)

[0476] 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 to ensure completion. The mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 0-10%) to give compound E3 (9.0 g, 35.20 mmol, yield: 75.9%). MS (ESI) + m / z = 255.7 [M+H] + .

[0477] Step 3: Synthesis of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (compound E5)

[0478] (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 until complete. The reaction was quenched with saturated ammonium chloride aqueous solution (30 mL), extracted with ethyl acetate (100 mL × 2), and the organic layer was purified by silica gel column chromatography (0-15% petroleum ether / ethyl acetate) to give compound E5 (10.5 g, 29.14 mmol, yield: 83%).

[0479] MS(ESI + m / z = 360.2[M+H] + .

[0480] Step 4: Synthesis of methyl (S)-2-amino-3-(4-bromothiazol-2-yl)propionate (compound E6)

[0481] 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 complete. The mixture was alkalized to pH 8 with saturated sodium bicarbonate solution. It was then extracted with ethyl acetate (100 mL × 6), and the organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated under vacuum to give compound E6 (6.8 g, 25.65 mmol, yield: 88%).

[0482] MS(ESI + m / z = 264.9 [M+H] + .

[0483] Step 5: Synthesis of (S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonyl)amino)propionate methyl ester (compound Int-5)

[0484] 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%).

[0485] MS(ESI + m / z = 364.9 [M+H] + .

[0486] Preparation Example 6: Synthesis of intermediate compound Int-6

[0487] Synthesis of compound F3 in the first step

[0488] Compound F1 (40 g, 184.95 mmol) was dissolved in N,N-dimethylformamide (800 mL) and cooled to 0 °C. Sodium hydroxide (18.49 g, 462.38 mmol, 60% purity) was slowly added under nitrogen protection and the mixture was stirred at 0 °C for 0.5 h. Then, compound F2 (58.70 g, 462.38 mmol) was added dropwise to the reaction mixture at 0 °C, and the mixture was stirred at 25 °C under nitrogen protection for 16 h. The reaction was monitored for completeness by LC-MS. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound F3 (45 g, 145.54 mmol, yield: 78.69%).

[0489] MS(ESI + m / z = 309.2[M+H] + .

[0490] The second step involves the synthesis of compound F4.

[0491] Compound F3 (45 g, 145.54 mmol) was dissolved in a solution of trifluoroacetic acid (120 mL) and dichloromethane (480 mL), and stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS to ensure completion. The mixture was filtered and concentrated under reduced pressure to give compound F4 (14.8 g, 75.09 mmol, yield: 51.59%). MS (ESI) + m / z = 197.1 [M+H] + .

[0492] The third step involves the synthesis of compound Int-6.

[0493] Compound F4 (14.8 g, 75.09 mmol) was dissolved in tetrahydrofuran (200 mL), and 1,1-carbonyldiimidazole (13.46 g, 83.00 mmol) was added in portions. The mixture was stirred at 25 °C for 16 hours. Then, sodium hydroxide (5 M, 45.27 mL) was added, and the mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS to ensure complete reaction. The mixture was adjusted to pH 1 with 6N hydrochloric acid, extracted first with ethyl acetate (100 mL * 2), then with dichloromethane (100 mL * 2), washed with brine (100 mL * 2), combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound Int-6 (10.6 g, 69.24 mmol, yield: 92.21%).

[0494] MS(ESI + m / z = 153.1 [M+H] + .

[0495] Preparation Example 7: Synthesis of intermediate compound Int-7

[0496] Synthesis of compound G2 (Step 1)

[0497] Compound G1 (5.0 g, 21.37 mmol) was added fractionally to a boranetetrahydrofuran complex (12.55 mL, 126.2 mmol, 1.0 M THF solution) under ice bath conditions. After the addition was complete, the mixture was transferred to room temperature and stirred for 16.0 hours. After the reaction was completed, methanol was added dropwise to quench the reaction. The mixture was washed with saturated sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give compound G2 (4.2 g, 19.09 mmol, yield: 89.3%).

[0498] MS(ESI + m / z = 220.0 [M+H] + .

[0499] The second step involves the synthesis of compound Int-7.

[0500] Under ice bath conditions, manganese dioxide (9.96 g, 114.53 mmol) was added in portions to a dichloromethane (180.0 mL) solution of compound G2 (4.2 g, 19.09 mmol). After the addition was complete, the mixture was transferred to room temperature and stirred for 16.0 hours. After the reaction was completed, the reaction solution was filtered through organodiatomaceous earth to remove the residue. The organic phase was concentrated to give compound Int-7 (4.0 g, 18.35 mmol, yield: 96.1%).

[0501] MS(ESI + m / z = 218.0 [M+H] + .

[0502] Preparation Example 8: Synthesis of intermediate compound Int-8

[0503] Using a synthetic route and steps similar to those in Preparation Example 4, compound Int-8 was synthesized by replacing starting material D1 with intermediate Int-7.

[0504] MS(ESI+)m / z=550.0[M+H]+.

[0505] Preparation Example 9: Synthesis of intermediate compound Int-9

[0506] At room temperature, compound Int-6 (121.6 mg, 800.0 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (349.7 mg, 919.91 μmol), and N,N-diisopropylethylamine (198.1 mg, 1.53 mmol) were added to N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 15 minutes, and then a solution of hydrazine hydrate (1.44 g, 24.53 mmol, 85% purity) in N,N-dimethylformamide (1 mL) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was poured into ethyl acetate (30 mL), washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound Int-9 (113 mg, 680.02 μmol, yield: 85.08%).

[0507] MS(ESI + m / z = 167.1 [M+H] + .

[0508] Preparation Example 10: Synthesis of intermediate compound Int-10

[0509] Synthesis of compound H1 in the first step

[0510] Compound 10⁻⁵ (178 mg, 200.01 μmol) and acetic acid (22.10 mg, 368.08 μmol) were dissolved in methanol (5 mL) and stirred at 25 °C for 1 hour. Then, paraformaldehyde (36.85 mg, 1.23 mmol) and NaBH₃CN (23.13 mg, 368.08 μmol) were added to the reaction solution, and the mixture was stirred at 25 °C for 14 hours. The reaction was monitored by LC-MS until complete. The mixture was filtered and concentrated under reduced pressure to give compound H₁ (138 mg, 152.35 μmol, yield: 76.2%).

[0511] MS(ESI + m / z = 905.4 [M+H] + .

[0512] The second step involves the synthesis of compound Int-10.

[0513] Compound H1 (138 mg, 152.35 μmol) was dissolved in methanol (10 mL). Under nitrogen protection, 4N hydrochloric acid 1,4-dioxane solution (5 mL) was added to the reaction solution. The mixture was stirred at 25 °C for 5 hours. The reaction was monitored by LC-MS until it was complete. The solution was concentrated by rotary evaporation to give a white solid compound Int-10 (114.1 mg, 141.68 μmol, yield: 93%).

[0514] MS(ESI + m / z = 805.4 [M+H] + .

[0515] Preparation Example 11: Synthesis of intermediate compound Int-11

[0516] Synthesis of compound I1 in the first step

[0517] At room temperature, N-bromosuccinimide (737.4 mg, 4.14 mmol) was added in portions to a 20 mL solution of compound D5 (1.50 g, 3.45 mmol) in dichloromethane. The mixture was reacted at room temperature for 1 h. A saturated sodium sulfite solution (2 mL) and water (10 mL) were added to the reaction mixture, followed by extraction with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 80:20-20:80) to give compound I1 (1.50 g, 2.92 mmol, yield: 84%).

[0518] MS(ESI + m / z = 513.0 [M+H] + .

[0519] The second step involves the synthesis of compound I2.

[0520] Under nitrogen protection, 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (1.69 g, 2.92 mmol), palladium dichloride (414.5 mg, 2.34 mmol), zinc cyanide (686.2 mg, 5.84 mmol), and N,N-diisopropylethylamine (1.51 g, 11.69 mmol) were added to a solution of compound I1 (1.50 g, 2.92 mmol) in N,N-dimethylformamide (15 mL). The mixture was reacted at 100 °C for 5 h. The reaction solution was filtered, and the filtrate was poured into water (100 mL). The solution was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 90:10-20:80) to give compound I2 (600.0 mg, 1.31 mmol, yield: 44%).

[0521] MS(ESI + m / z = 460.1 [M+H] + .

[0522] The third step involves the synthesis of compound I3.

[0523] Under nitrogen protection, a solution of formic acid (3.61 g, 78.35 mmol) in triethylamine (15.86 g, 156.71 mmol) was cooled to 0 °C, and then (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (103.0 mg, 163.24 μmol) was added. The reaction solution was heated to 40 °C and stirred for 15 min, then cooled to room temperature, and then compound I2 (750.0 mg) was added. A solution of N,N-dimethylformamide (1 mL) was prepared and reacted at 40 °C for 12 h. The reaction solution was concentrated, and the residue was poured into water (50 mL). The residue was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 50:50-20:80) to give compound I3 (550.0 mg, 1.27 mmol, yield: 78%).

[0524] MS(ESI + m / z = 432.1 [M+H] + .

[0525] The fourth step is the synthesis of compound I4.

[0526] At 0 °C, compound I3 (550.0 mg, 1.27 mmol) and p-toluenesulfonic acid (1.10 g, 6.37 mmol) were dissolved in acetonitrile (10 mL), and then an aqueous solution of sodium nitrite (439.7 mg, 6.37 mmol) and potassium iodide (1.06 g, 6.37 mmol) (3 mL) was added dropwise to the system. The mixture was stirred at 0 °C for 10 min, and then gradually heated to room temperature and reacted for 2 h. The reaction was quenched by adding saturated sodium sulfite solution (1 mL), and then extracted with water (10 mL) and ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 80:20-20:80) to give compound I4 (350.0 mg, 645.32 μmol, yield: 50%).

[0527] MS(ESI + m / z = 543.0 [M+H] + .

[0528] Step 5: Synthesis of compound Int-11

[0529] Sodium hydride (50.1 mg, 1.25 mmol, 60% purity) was added to a solution of compound I4 (340.0 mg, 626.88 μmol) in N,N-dimethylformamide (10 mL) at 0 °C. The mixture was stirred at 0 °C for 10 min, and then iodomethane (177.9 mg, 1.25 mmol) was added. The reaction was continued at 0 °C for 1 h. The reaction was quenched by adding saturated ammonium chloride (10 mL), followed by extraction with water (50 mL) and ethyl acetate (30 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 80:20-30:70) to give compound Int-11 (340.0 mg, 611.08 μmol, yield: 97%).

[0530] MS(ESI + m / z = 557.1 [M+H] + .

[0531] Preparation Example 12: Synthesis of intermediate compound Int-12

[0532] Synthesis of compound J2 (first step)

[0533] 2-Amino-5-bromobenzaldehyde (50.00 g, 249.96 mmol) and ethyl nitrate (66.54 g, 499.92 mmol) were dissolved in ethanol (300 mL), and then piperidine (10.77 g, 124.98 mmol) was added. The mixture was reacted at 85 °C for 18 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with ethanol (30 mL) to give compound J2 (45.00 g, 167.25 mmol, yield: 67%).

[0534] MS(ESI + m / z = 268.9[M+H] + .

[0535] The second step involves the synthesis of compound J3.

[0536] At 0 °C, trifluoromethanesulfonic anhydride (39.32 g, 139.38 mmol) was added dropwise to a solution of compound J2 (25.00 g, 92.92 mmol) in dichloromethane (500 mL), followed by N,N-diisopropylethylamine (36.03 g, 278.76 mmol). After the addition was complete, the mixture was allowed to react at room temperature for 1 hour. Water (300 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (150 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-50:50) to give compound J3 (28.00 g, 69.81 mmol, yield: 75%).

[0537] MS(ESI + m / z = 400.8[M+H] + .

[0538] The third step involves the synthesis of compound J4.

[0539] Under nitrogen protection, tributyl(1-ethoxyethylene)tin (22.69 g, 62.83 mmol) and bis(triphenylphosphine)palladium dichloride (4.90 g, 6.98 mmol) were added to a solution of compound J3 (28.00 g, 69.81 mmol) in N,N-dimethylformamide (200 mL). The mixture was reacted at 60 °C for 4 hours. The reaction solution was cooled to room temperature, and 20% potassium fluoride aqueous solution (50 mL) was added. The mixture was stirred at room temperature for 30 min, filtered, and the filtrate was extracted with water (300 mL) and ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-50:50) to give compound J4 (8.00 g, 24.76 mmol, yield: 35%).

[0540] MS(ESI + m / z = 323.0 [M+H] + .

[0541] The fourth step involves the synthesis of compound Int-12.

[0542] At room temperature, 10 mL of hydrochloric acid aqueous solution (2N) was added dropwise to a tetrahydrofuran (50 mL) solution of compound J4 (8.00 g, 24.76 mmol), and the mixture was stirred at room temperature for 1 hour. The pH of the reaction mixture was adjusted to 9 by adding saturated sodium bicarbonate solution, followed by extraction with water (50 mL) and ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-70:30) to give compound Int-12 (3.00 g, 10.17 mmol, yield: 41%).

[0543] MS(ESI + m / z = 295.0 [M+H] + .

[0544] Preparation Example 13: Synthesis of intermediate compound Int-13

[0545] The first step is the synthesis of compound K1.

[0546] Under ice-water bath conditions, formic acid (1.80 g, 39.11 mmol) and triethylamine (9.00 g, 88.94 mmol) were added sequentially to a dry reaction tube, followed by the catalyst (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (48.13 mg, 76.25 μmol). The system was heated to 40 °C and reacted for 10 minutes. After cooling to room temperature, a solution of compound Int-12 (450 mg, 1.52 mmol) in N,N-dimethylformamide (2 mL) was added, and the reaction was carried out at room temperature for 1 hour. The crude product was purified by reverse-phase reaction (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound K1 (176.0 mg, 0.66 mmol, yield: 43.2%).

[0547] MS(ESI + m / z = 267.0 / 269.0 [M+H] + .

[0548] The second step involves the synthesis of compound K2.

[0549] In a dry reaction tube, compound K1 (145 mg, 542.82 μmol) and 4-dimethylaminopyridine (6.63 mg, 54.28 μmol) were dissolved in tetrahydrofuran (5 mL), and di-tert-butyl dicarbonate (142.16 mg, 651.39 μmol) was added. The reaction was carried out for 1 hour. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give solid compound K2 (150.00 mg, 408.46 μmol, yield: 75.3%).

[0550] MS(ESI + m / z = 368.2[M+H] + .

[0551] The third step involves the synthesis of compound K4.

[0552] In a dry reaction tube, compound K3 (198.12 mg, 1.14 mmol), compound K2 (140 mg, 381.23 μmol), N,N-diisopropylethylamine (115.73 mg, 895.43 μmol), Pd(PPh3)2Cl2 (26.76 mg, 38.12 μmol), lithium chloride (48.48 mg, 1.14 mmol), and cuprous iodide (14.52 mg, 76.25 μmol) were added. Argon gas was purged, and DMF (5 mL) was added. The system was heated to 80 °C and reacted overnight. The mixture was filtered and concentrated to obtain crude compound K4 (175 mg, 380.80 μmol, yield: 99%), which was used directly in the next step.

[0553] MS(ESI + m / z = 460.2[M+H] + .

[0554] Step 4: Synthesis of compound K5

[0555] Compound K4 (160 mg, 348.16 μmol) was dissolved in DCM (1 mL), and TFA (0.5 mL) was added to the system. The reaction was carried out for 1 hour, and the crude product K5 (125 mg, 346.4 μmol, yield: 99%) was concentrated and used directly in the next step.

[0556] MS(ESI + m / z = 360.2[M+H] + .

[0557] Step 5: Synthesis of compound K6

[0558] At room temperature, compound K5 (125 mg, 346.4 μmol) and p-toluenesulfonic acid (101.44 mg, 0.59 mmol) were dissolved in acetonitrile (5 mL), followed by 1 mL of an aqueous solution of sodium nitrite (134.37 mg, 1.95 mmol), and then potassium iodide (323.28 mg, 1.95 mmol, 104.29 μL). The reaction was carried out for 1 hour. The crude product was purified by reverse-phase reaction (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound K6 (56 mg, 119.07 μmol, yield: 34.4%).

[0559] MS(ESI + m / z = 471.0 [M+H] + .

[0560] Step 6: Synthesis of compound Int-13

[0561] Under ice-water bath conditions, sodium hydride (8.50 mg, 212.62 μmol, 60% purity) was added to a dry reaction tube to replace the argon gas. N,N-dimethylformamide (2 mL) and compound K6 (50 mg, 106.31 μmol) were then added, and the reaction was allowed to proceed for 10 minutes. Iodomethane (22.63 mg, 159.46 μmol) was then added, and the reaction was allowed to continue at room temperature for 1 hour. The reaction was then quenched with water. The crude product was purified by reverse-phase reaction (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to obtain compound Int13 (13 mg, 26.8 μmol, yield: 25.2%).

[0562] MS(ESI + m / z = 485.0 [M+H] + .

[0563] Preparation Example 14: Synthesis of intermediate compound Int-14

[0564] Referring to Preparation Example 13, intermediate compound Int-14 was prepared by replacing intermediate K3 with compound L1. MS(ESI) + m / z = 458.1 [M+H] +

[0565] Preparation Example 15: Synthesis of intermediate compound Int-15

[0566] The first step is the synthesis of compound M2.

[0567] 1-Methanesulfonylethylene (1.5 g, 14.13 mmol, 1.24 mL) was slowly added dropwise to methylamine ethanol (27% by mass, 15 mL) under ice bath conditions. The resulting mixture was stirred at room temperature for 2.0 h. After the reaction was complete, the mixture was concentrated under reduced pressure to give compound M2 (1.94 g, 14.0 mmol, yield: 99%). No purification was required, and it was used directly in the next reaction.

[0568] MS(ESI+)m / z = 138.1[M+H] + .

[0569] The second step involves the synthesis of compound M3.

[0570] Compound M2 (1.8 g, 13.12 mmol), potassium bicarbonate (2.63 g, 26.24 mmol), potassium iodide (217.79 mg, 1.31 mmol), and potassium (bromomethyl)trifluoroborate (3.95 g, 19.68 mmol) were added to THF (30.00 mL) and nitrogen was purged. The resulting mixture was stirred at 80 °C for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, dissolved in acetonitrile, filtered, and the filtrate was concentrated to obtain compound M3 (2.6 g, 10.12 mmol, yield: 77.1%), which was directly used in the next reaction.

[0571] MS(ESI+)m / z = 200.1[M+H-KF] + .

[0572] The third step involves the synthesis of compound Int-15.

[0573] 1-(6-bromo-3-nitro-2-quinolinyl) acetone (compound Int-12, 300 mg, 1.02 mmol), compound M3 (607.02 mg, 2.36 mmol), cesium carbonate (662.48 mg, 2.03 mmol), and CataCXium A Pd G3 (74.04 mg, 101.66 μmol) were added to a mixture of water (1 mL) and 1,4-dioxane (5 mL), and nitrogen was purged. The resulting mixture was heated to 100 °C under nitrogen protection for 3.0 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase reaction (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to obtain compound Int-15 (160 mg, 0.44 mmol, yield: 43.1%).

[0574] MS(ESI+)m / z = 366.1[M+H] + .

[0575] Preparation Example 16: Synthesis of intermediate compound Int-16

[0576] Referring to Preparation Example 4, intermediate D5 was replaced with compound Int-15 to prepare intermediate compound Int-16. MS(ESI) + m / z = 463.1 [M+H] + .

[0577] Preparation Example 17: Synthesis of intermediate compound Int-17

[0578] Referring to Preparation Example 15, intermediate M2 was replaced with compound N1 to prepare intermediate compound Int-17. MS(ESI) + m / z = 364.1 [M+H] + .

[0579] Preparation Example 18: Synthesis of intermediate compound Int-18

[0580] Referring to Preparation Example 4, intermediate D5 was replaced with compound Int-17 to prepare intermediate compound Int-18. MS(ESI) + m / z = 461.1 [M+H] + .

[0581] Preparation Example 19: Synthesis of intermediate compound Int-19

[0582] Referring to Preparation Example 12, intermediate compound Int-19 was prepared by replacing intermediate J1 with compound O1. MS(ESI) + m / z = 295.0 [M+H] + .

[0583] Preparation Example 20: Synthesis of intermediate compound Int-20

[0584] Referring to Preparation Example 15, intermediate Int-12 was replaced with compound Int-19 to prepare intermediate compound Int-20. MS(ESI) + m / z = 366.1 [M+H] + .

[0585] Preparation Example 21: Synthesis of intermediate compound Int-21

[0586] Referring to Preparation Example 4, intermediate D5 was replaced with compound Int-20 to prepare intermediate compound Int-21. MS(ESI) +m / z = 463.1 [M+H] + .

[0587] Preparation Example 22: Synthesis of intermediate compound Int-22

[0588] Referring to Preparation Example 15, intermediate M2 was replaced with compound N1, and intermediate Int-12 was replaced with compound Int-19 to prepare intermediate compound Int-22. MS(ESI) + m / z = 364.1 [M+H] + .

[0589] Preparation Example 23: Synthesis of intermediate compound Int-23

[0590] Referring to Preparation Example 4, intermediate compound Int-23 was prepared by replacing intermediate D5 with compound Int-22. MS(ESI) + m / z = 461.1 [M+H] + .

[0591] Preparation Example 24: Synthesis of intermediate compound Int-24

[0592] Step 1: Synthesis of compound P2

[0593] Compound C4 (1.08 g, 2.90 mmol), compound P1 (synthetic method referred to patent application WO2025080946 intermediate 2, 1.0 g, 2.23 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (326.41 mg, 446.10 μmol), and potassium carbonate (924.80 mg, 6.69 mmol) were added to a mixture of water (3 mL) and 1,4-dioxane (15 mL), and nitrogen was purged. The resulting mixture was heated to 85 °C under nitrogen protection and stirred for 15.0 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase reaction (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to obtain compound P2 (0.6 g, 978.3 μmol, yield: 43.9%).

[0594] MS(ESI+)m / z = 613.3[M+H] + .

[0595] Step 2: Synthesis of compound P3

[0596] Compound P2 (200 mg, 326.41 μmol), sodium bicarbonate (30.16 mg, 359.05 μmol), and silver trifluoromethanesulfonate (92.25 mg, 359.05 μmol) were added to tetrahydrofuran (3 mL), and nitrogen was introduced to replace the atmosphere. Iodine (91.13 mg, 359.05 μmol) was then added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by reverse-phase chromatography (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound P3 (115 mg, 155.6 μmol, yield: 47.7%). MS (ESI+) m / z = 739.2 [M+H] + .

[0597] Step 3: Synthesis of compound P4

[0598] Compound P3 (115 mg, 155.69 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (88.80 mg, 233.54 μmol) were added to DMF (3 mL), and nitrogen was introduced. A DMF (3 mL) solution of compound Int-2 (36.43 mg, 233.54 μmol) and N,N-diisopropylethylamine (60.37 mg, 467.08 μmol) was added dropwise under ice bath conditions. The resulting mixture was stirred at room temperature for 1.0 h. After the reaction was complete, the crude product was purified by reverse-phase chromatography (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound P4 (70 mg, 79.8 μmol, yield: 51.3%). MS (ESI+) m / z = 877.2 [M+H] + .

[0599] Step 4: Synthesis of compound P5

[0600] Compound P4 (70 mg, 79.84 μmol) was added to THF (2 mL), and nitrogen gas was introduced. An aqueous solution of LiOH (1 M, 399.18 μmol, 399.18 μL) was added dropwise under ice bath conditions. The resulting mixture was stirred at room temperature for 3.0 hours. After the reaction was complete, the pH was adjusted to 6 with dilute hydrochloric acid (1 M), and the product was lyophilized. The crude product was purified by reverse-phase chromatography (water:MeCN = 95:5 to 5:95) to give compound P5 (55 mg, 66.98 μmol, yield: 83.9%).

[0601] MS(ESI+)m / z = 821.2[M+H] + .

[0602] Step 5: Synthesis of compound Int-24

[0603] N,N,N',N'-Tetramethylchloromethamidine hexafluorophosphate (188.03 mg, 670.13 μmol) was added to acetonitrile (6 mL), and nitrogen was introduced to replace the atmosphere. N-methylimidazole (110.04 mg, 1.34 mmol) was added under ice bath conditions, followed by the dropwise addition of a 2 mL solution of DMF containing compound P5 (55 mg, 69.98 μmol). The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was purified by reverse-phase reaction (water:MeCN = 95:5 to 5:95) to give compound Int-24 (40 mg, 49.8 μmol, yield: 71.2%).

[0604] MS(ESI+)m / z = 803.2[M+H] + .

[0605] Preparation Example 25: Synthesis of intermediate compound Int-25

[0606] Compound Q1 (synthetic method referred to patent application WO2025080946, intermediate 1, 10.0 g, 33.29 mmol) and sodium iodide (7.49 g, 49.94 mmol, 2.02 mL) were added to acetone (100 mL), and nitrogen was introduced. The resulting mixture was stirred at 65 °C for 2.0 h. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by normal silica gel column chromatography (ethyl acetate / petroleum ether: 0%-80%) to obtain compound Int-25 (7.7 g, 30.1 mmol, yield: 90.4%).

[0607] MS(ESI+)m / z = 257.1[M+H] + .

[0608] Preparation Example 26: Synthesis of intermediate compounds Int-26-P1 and Int-26-P2

[0609] Step 1: Synthesis of compound R1

[0610] At room temperature, compounds Int-4 (10 mg, 18.8 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1,3,2-dioxoboropentane (9.6 mg, 37.6 μmol), palladium acetate (0.8 mg, 3.76 μmol), tricyclohexylphosphine (1 mg, 3.6 μmol), and potassium acetate (5.5 mg, 56.5 μmol) were dissolved in anhydrous 1,4-dioxane (1 mL), the air in the solution was replaced three times with nitrogen, and the reaction was stirred at 80 °C for 16 hours. The reaction was confirmed to be complete by LC-MS. Insoluble matter was removed by filtration, the filtrate was concentrated, and the residue was purified by reversed-phase chromatography (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound R1 (5 mg, 9.39 μmol, yield: 50.0%).

[0611] MS(ESI+)m / z = 532.5[M+H] + .

[0612] Step 2: Synthesis of compound R2

[0613] Compound R1 (34.8 mg, 65.4 μmol) was added to 1,4-dioxane (2.0 mL), followed by intermediate Int-24 (35.0 mg, 43.6 μmol), potassium carbonate (18.1 mg, 130.8 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (6.5 mg, 8.9 μmol), and water (0.25 mL). The mixture was stirred at 75 °C under argon protection for 1.0 h. After the reaction was complete, the reaction solution was diluted with ethyl acetate and brine, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, yielding compound R2 (42.7 mg, 39.5 μmol, yield: 90.6%). The crude product was used directly in the next reaction without purification.

[0614] MS(ESI+)m / z = 1080.5[M+H] + .

[0615] Step 3: Synthesis of compound R3

[0616] Compound R2 (49.0 mg, 45.4 μmol) and cesium carbonate (147.8 mg, 454 μmol) were added to N,N-dimethylformamide (0.5 mL). Compound Int-25 (116.2 mg, 454 μmol) was added to the reaction mixture, and the resulting mixture was stirred at 40 °C for 4.0 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate and filtered. The filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to remove the solvent, and the crude product was purified by reverse-phase reaction (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound R3 (28.0 mg, 23.2 μmol, yield: 51.1%).

[0617] MS(ESI+)m / z=1208.5[M+H] + .

[0618] Step 4: Synthesis of compounds Int-26-P1 and Int-26-P2

[0619] Compound R3 (28.0 mg, 23.2 μmol) was dissolved in methanol (4.0 mL). Pd(OH)₂ / C (28 mg) and paraformaldehyde (28.0 mg, 933 μmol) were added to the reaction solution. The mixture was then purged with hydrogen five times, and stirred at 25 °C for 7 hours under one atmosphere of pressure. After the reaction was completed, the reaction solution was diluted with dichloromethane and methanol and filtered. The filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure to remove the solvent. The crude product was purified by reversed-phase column chromatography (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to obtain compound Int-26-P1 (10.0 mg, 9.19 μmol, yield: 39.7%, LC-MS (ACQUITY UPLC BEH C18 50*2.1 mm*1.7 μm column; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 40%-95%, time: 3 min, flow rate: 0.7 mL / min, retention time: 1.27 min) and compound Int-26-P2 (8.5 mg, 7.81 μmol, yield: 33.7%, LC-MS (ACQUITY UPLC BEH C18 column)). 50*2.1 mm*1.7 μm; Mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%; Mobile phase B: MeCN; MeCN ratio 40%-95%, flow time: 3 min, flow rate: 0.7 mL / min, retention time: 1.36 min).

[0620] Compound Int-26-P1: MS (ESI) +m / z = 1088.6 [M+H] + Compound Int-26-P2: MS (ESI) + m / z = 1088.6 [M+H] + .

[0621] Preparation Example 27: Synthesis of intermediate compounds Int-27-P1 and Int-27-P2

[0622] Step 1: Synthesis of compound S2

[0623] Compound S1 (24.5 g, 97.89 mmol) and 4-acetamidobenzenesulfonyl azide (23.5 g, 97.89 mmol) were dissolved in acetonitrile (600 mL). The system was cooled to 0 °C, and then triethylamine (29.72 g, 293.66 mmol) was added. The system was stirred overnight at room temperature under argon protection. After the reaction was complete, the mixture was filtered, and the filter cake was washed with ethyl acetate (2 × 80 mL). The filtrate was concentrated under reduced pressure to remove the solvent, and the crude product was purified by column chromatography (tetrahydrofuran / petroleum ether: 0%–8%) to give compound S2 (26 g, 94.10 mmol, yield: 96.1%).

[0624] MS(ESI+)m / z=294.3[M+NH4] + .

[0625] Step 2: Synthesis of compound S3

[0626] Rhodium acetate (304.07 mg, 1.09 mmol) was added to toluene (100 mL), and the system was cooled to 0 °C. Then, under argon protection, a toluene (5 mL) solution of (2R)-2-bromopropanol (5.03 g, 36.19 mmol) was added. Next, a toluene solution (10 mL) of compound S2 (10 g, 36.19 mmol) was added. The system was heated and stirred at 60 °C for 5 h under argon protection until fully reacted. The solvent was then removed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography (tetrahydrofuran / petroleum ether: 0%-15%) to give compound S3 (8.59 g, 22.18 mmol, yield: 61.3%).

[0627] MS(ESI+)m / z=404.4,406.4[M+NH4] + .

[0628] Step 3: Synthesis of compound S4

[0629] Compound S3 (8.6 g, 22.21 mmol) was dissolved in N,N-dimethylformamide (90 mL) and cooled to 0 °C. Sodium hydride (977.2 mg, 24.43 mmol, 60% purity) was then added, and the reaction mixture was gradually heated to room temperature and stirred at room temperature for 5 h. The reaction was then quenched with a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic layer was separated and washed with saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography (tetrahydrofuran / petroleum ether: 0%-15%) to give compound S4 (4.6 g, 15.02 mmol, yield: 67.6%).

[0630] MS(ESI+)m / z = 324.4[M+NH4] + .

[0631] Step 4: Synthesis of compound S5

[0632] Compound S4 (4.6 g, 15.02 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (4 mL) was added at 0 °C. The system was stirred overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation. The residue was diluted with ethyl acetate (50 mL), washed once with water (20 mL) and once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent, yielding compound S5 (3.5 g, 14.0 mmol, yield: 93.2%). The crude product was used directly in the next reaction without purification.

[0633] MS(ESI+)m / z = 268.3[M+NH4] + .

[0634] Step 5: Synthesis of compounds Int-27-P1 and Int-27-P2

[0635] 4-Dimethylaminopyridine (3.35 g, 27.45 mmol) was added to a 1,4-dioxane solution (50 mL) of compound S5 (5 g, 19.98 mmol). The system was stirred overnight at 100 °C. After the reaction was complete, the mixture was cooled to room temperature, the solid was removed by filtration, and the filter cake was washed with ethyl acetate. The crude product obtained by concentration of the filtrate under reduced pressure was purified by silica gel column chromatography (tetrahydrofuran / petroleum ether: 0%-8%) to give compounds Int-27-P1 (800 mg, 3.88 mmol, yield: 19.4%) and Int-27-P2 (940 mg, 4.56 mmol, yield: 22.8%).

[0636] Compound Int-27-P1: LC-MS (Column: ACQUITY UPLC BEH C18 50*2.1 mm*1.7 μm; Mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; Mobile phase B: MeCN; MeCN ratio: 40%-95%, Flow time: 3 min, Flow rate: 0.7 mL / min, Retention time: 0.98 min). MS (ESI) + m / z = 207.2[M+H] + .

[0637] Compound Int-27-P2: LC-MS (Column: ACQUITY UPLC BEH C18 50*2.1 mm*1.7 μm; Mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; Mobile phase B: MeCN; MeCN ratio: 40%-95%; Duration: 3 min; Flow rate: 0.7 mL / min; Retention time: 1.01 min). MS (ESI) + m / z = 207.2[M+H] + .

[0638] Preparation Example 28: Synthesis of intermediate compound Int-28

[0639] Compound Int-27-P1 (100 mg, 485.4 μmol) was dissolved in ethyl acetate (4 mL). Then, Pd(OH)₂ / C (25 mg) was added. Hydrogen gas was then introduced five times, and the reaction mixture was stirred at room temperature for 2 hours under one atmosphere of pressure. After the reaction was complete, the mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to remove the solvent, yielding compound Int-28 (40 mg, 344.2 μmol, yield: 70.9%).

[0640] MS(ESI + m / z = 115.2 [MH] - .

[0641] Compound Int-28 was identified as (2S,3S)-3-methyloxetane-2-carboxylic acid by single-crystal culture, as follows:

[0642] Single crystal cultivation method:

[0643] Weigh 100 mg of compound Int-28 into a 20 mL glass bottle, add 10 mL of ethyl acetate, and sonicate appropriately to promote solid dissolution. Filter the solution, and transfer 4 mL of the filtrate to a 10 mL single crystal growth flask. Seal the flask with a single crystal stopper and make a small hole in the stopper. Place the flask in a fume hood to allow the solvent to evaporate slowly. As the solvent decreases, the crystals grow slowly within the flask. Observe the crystals under a microscope, and select those of suitable size and with well-formed crystals for single crystal XRD analysis.

[0644] The obtained single crystal samples were subjected to X-ray analysis, and the test results are shown in Table 3 and Figure 1.

[0645] Table 3. Single crystal sample data of compound Int-28

[0646] The chemical structure and absolute configuration of compound Int-28 can be determined by the above X-ray crystal diffraction experiment, and it is identified as (2S,3S)-3-methyloxetane-2-carboxylic acid.

[0647] Preparation Example 29: Synthesis of intermediate compound Int-29

[0648] Compound Int-27-P2 (220 mg, 1.07 mmol / L) was dissolved in ethyl acetate (4 mL). Then, Pd(OH)2 / C (25 mg) was added. Hydrogen gas was then introduced five times, and the reaction was carried out at room temperature under amblycium for 4 hours with stirring. After the reaction was complete, the mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to remove the solvent, yielding compound Int-29 (120 mg, 1.03 mmol / L, yield: 96%).

[0649] MS(ESI + m / z = 115.2 [MH] - .

[0650] Preparation Example 30: Synthesis of intermediate compound Int-30

[0651] Referring to Preparation Example 26, intermediate Int-4 was replaced with compound Int-11 to prepare intermediate compound Int-30-P1 (LC-MS (ACQUITY UPLC BEH C18 50*2.1 mm*1.7 μm column; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%; mobile phase B: MeCN; MeCN ratio 60-90%, time: 3 min, flow rate: 0.7 mL / min, retention time: 1.25 min) and compound Int-26-P2 (LC-MS (ACQUITY UPLC BEH C18 column)). 50*2.1 mm*1.7 μm; Mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%; Mobile phase B: MeCN; MeCN ratio 60-90%, flow time: 3 min, flow rate: 0.7 mL / min, retention time: 1.33 min).

[0652] Compound Int-30-P1 MS (ESI) + m / z = 1113.6[M+H] + Compound Int-30-P2 MS (ESI) + m / z = 1113.6[M+H] + Preparation Example 31: Synthesis of intermediate compound Int-31

[0653] Following steps 1 to 3 of Preparation Example 26, intermediate Int-4 was replaced with compound 10-2 to prepare intermediate compound Int-31.

[0654] MS(ESI + m / z = 1222.5[M+H] + .

[0655] Preparation Example 32: Synthesis of intermediate compound Int-32

[0656] Synthesis of compound T2 (Step 1)

[0657] Compound T1 (25.0 g, 123.2 mmol) and concentrated sulfuric acid (100 mL) were added to a reaction flask. Potassium nitrate (24.9 g, 246.3 mmol) was added in portions under ice bath conditions, and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC until complete. The reaction solution was added dropwise into ice water, filtered, and the filter cake was washed with ice water and dried to give compound T2 (29.0 g, 116.3 mmol, yield: 95.0%).

[0658] MS(ESI +m / z = 247.9 [M+H] + .

[0659] The second step involves the synthesis of compound T3.

[0660] Compound T2 (25.0 g, 100.8 mmol), ethanol (300 mL), and water (30 mL) were added to a reaction flask. Reduced iron powder (33.8 g, 604.8 mmol) was added in portions at 80 °C, followed by concentrated hydrochloric acid (1.7 mL, 20.2 mmol). The mixture was stirred at 80 °C for 90 minutes. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature and diluted with ethyl acetate (300 mL). The mixture was filtered through diatomaceous earth, and the filtrate was washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound T3 (17.5 g, 80.3 mmol, yield: 79.6%). MS (ESI) was then used. + m / z = 217.9 [M+H] + .

[0661] The third step involves the synthesis of compound T4.

[0662] Compound T3 (86.0 g, 394.5 mmol), ethyl nitroacetate (105.0 g, 788.9 mmol), piperidine (16.8 g, 197.2 mmol), and ethanol (300 mL) were added to a reaction flask, and the mixture was stirred at 80 °C for 18 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with ice-cold ethanol and dried to give compound T4 (40.0 g, 139.4 mmol, yield: 35.3%).

[0663] MS(ESI + m / z = 286.9 [M+H] + .

[0664] The fourth step is the synthesis of compound T5.

[0665] Compound T4 (24.6 g, 85.7 mmol) and anhydrous dichloromethane (600 mL) were added to a reaction flask, followed by trifluoromethanesulfonic anhydride (36.3 g, 128.6 mmol). N,N-diisopropylethylamine (33.2 g, 257.1 mmol) was added dropwise to the system under ice bath conditions, and the mixture was stirred at room temperature for 1 hour. Water (500 mL) was added to the system, and after separation, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 92:8) to give compound T5 (31.2 g, 74.4 mmol, yield: 86.9%).

[0666] MS(ESI +m / z = 418.9 [M+H] + .

[0667] Step 5: Synthesis of compound T6

[0668] Under argon protection, compound T5 (10.0 g, 23.9 mmol), tributyl(1-ethoxyethylene)tin (8.6 g, 23.9 mmol), bis(triphenylphosphine)palladium dichloride (1.7 g, 2.4 mmol), and anhydrous tetrahydrofuran (100 mL) were added to a reaction flask, and the mixture was stirred at 60 °C for 6 hours. After the reaction solution cooled to room temperature, dilute hydrochloric acid (60 mL, 3 N) was added, and the mixture was stirred overnight at room temperature. The mixture was extracted with ethyl acetate (400 mL * 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 88:12) to give compound T6 (4.0 g, 12.8 mmol, yield: 53.6%).

[0669] MS(ESI + m / z = 313.0 [M+H] + .

[0670] Step 6: Synthesis of compound Int-32

[0671] Under argon protection, compound T6 (3.4 g, 10.9 mmol), zinc cyanide (765.1 mg, 6.5 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (628.4 mg, 1.1 mmol), palladium chloride (192.6 mg, 1.1 mmol), N,N-diisopropylethylamine (561.4 mg, 4.3 mmol), and anhydrous N,N-dimethylacetamide (34 mL) were added to a reaction flask, and the mixture was stirred at 85 °C for 15 hours. The reaction solution was poured into water (400 mL), extracted with ethyl acetate (400 mL * 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 82:18) to give compound Int-32 (1.4 g, 5.2 mmol, yield: 48.0%).

[0672] MS(ESI + m / z = 260.0 [M+H] + .

[0673] Preparation Example 33: Synthesis of intermediate compound Int-33

[0674] The first step is the synthesis of compound U2.

[0675] Piperidine (37.8 g, 438.5 mmol) was dissolved in dichloromethane (200 mL). Compound U1 (15.0 g, 87.7 mmol, 10.4 mL) was slowly added in portions at 0 °C. The mixture was reacted at 0 °C for 1 hour. After the reaction was complete, a solid precipitated from the reaction solution at low temperature. The solid was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated to obtain crude compound U2 (15.0 g), which was used directly in the next step.

[0676] MS(ESI + m / z = 177.1 [M+H] + .

[0677] The second step involves the synthesis of compound U3.

[0678] Compound U2 (10.0 g, 56.7 mmol) and 3-oxetane (4.1 g, 56.7 mmol, 3.7 mL) were dissolved in toluene (200 mL), and then 1,2,3-triazole (4.7 g, 68.1 mmol) was added. The mixture was reacted at 125 °C for 2 hours, and then the reaction solution was cooled to room temperature. Under a nitrogen atmosphere, the above-mentioned room-temperature reaction solution was added dropwise to a solution of methyl magnesium bromide (3 M, 147.5 mmol, 49.2 mL) at 10 °C. The mixture was reacted at 20 °C for 30 minutes. After the reaction was completed, the reaction solution was quenched with ice water, extracted with ethyl acetate (200 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-90:10) to give compound U3 (6.0 g, 24.4 mmol, yield: 43%).

[0679] MS(ESI + m / z = 247.1 [M+H] + .

[0680] The third step involves the synthesis of compound U4.

[0681] Under a hydrogen atmosphere, 10% palladium / carbon (2.5 g, 20.6 mmol) was added to an ethanol (100 mL) solution of compound U3 (5.0 g, 20.3 mmol), and the mixture was reacted at room temperature for 10 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the filter residue was washed with ethanol, the filtrates were combined and concentrated to obtain crude compound U4 (3.0 g), which was used directly in the next step.

[0682] MS(ESI + m / z = 157.1 [M+H] + .

[0683] The fourth step involves the synthesis of compound Int-33.

[0684] Compound U4 (180.8 mg, 1.2 mmol) and compound Int-32 (200.0 mg, 771.6 μmol) were dissolved in N-methylpyrrolidone (3 mL), followed by the addition of N,N-diisopropylethylamine (200.0 mg, 1.5 mmol). The mixture was reacted at 90 °C for 2 hours. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate (50 mL * 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-83:17) to give compound Int-33 (220.0 mg, 556.3 μmol, yield: 72%).

[0685] MS(ESI + m / z = 396.1 [M+H] + .

[0686] Preparation Example 34: Synthesis of intermediate compound Int-34

[0687] Referring to Preparation Example 11, intermediate I2 was replaced with compound Int-33 to prepare intermediate compound Int-34.

[0688] MS(ESI + m / z = 493.1 [M+H] + .

[0689] Preparation Example 35: Synthesis of intermediate compound Int-35

[0690] Following steps 1 to 3 of Preparation Example 26, intermediate Int-4 was replaced with compound Int-34 to prepare intermediate compound Int-35.

[0691] MS(ESI + m / z = 1169.6 [M+H] + .

[0692] Preparation Example 36: Synthesis of intermediate compound Int-36

[0693] Referring to steps 1 to 3 of Example 1, intermediate Int-4 was replaced with compound Int-11 to prepare intermediate compound Int-36.

[0694] MS(ESI + m / z = 1036.5 [M+H] + .

[0695] Preparation Example 37: Synthesis of intermediate compound Int-37

[0696] Under argon protection, cyclopropylboronic acid (424.3 mg, 4.94 mmol), palladium acetate (13.9 mg, 617.43 μmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (58.9 mg, 123.49 μmol), and cesium carbonate (603.5 mg, 1.85 mmol) were added to a mixed solution of compound 10-1 (370.0 mg, 617.43 μmol) and water (0.2 mL). The mixture was heated to 60 °C and reacted for 6 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 50:50) to give compound Int-37 (140.0 mg, 272.68 μmol, yield: 44.2%).

[0697] MS(ESI + m / z = 513.1 [M+H] + .

[0698] Preparation Example 38: Synthesis of intermediate compound Int-38

[0699] Compound Int-32 (400.0 mg, 1.5 mmol), benzyl 4-(piperidin-4-yl)piperazine-1-carboxylate (561.9 mg, 1.9 mmol), and N,N-diisopropylethylamine (299.2 mg, 2.3 mmol) were added to anhydrous N-methylpyrrolidone (8 mL). The mixture was heated to 90 °C and stirred for 2 hours. After the reaction was completed, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:0-0:100) to give compound Int-38 (757.0 mg, 1.4 mmol, yield: 90.4%).

[0700] MS(ESI + m / z = 543.2[M+H] + .

[0701] Preparation Example 39: Synthesis of intermediate compound Int-39

[0702] Referring to Preparation Example 11, intermediate I2 was replaced with compound Int-38 to prepare intermediate compound Int-39.

[0703] MS(ESI + m / z = 640.2[M+H] + .

[0704] Preparation Example 40: Synthesis of intermediate compound Int-40

[0705] Referring to Preparation Example 38, the intermediate was prepared... Replace with compound The intermediate compound Int-40 was prepared.

[0706] MS(ESI + m / z = 499.2[M+H] + .

[0707] Preparation Example 41: Synthesis of intermediate compound Int-41

[0708] Referring to Preparation Example 11, intermediate I2 was replaced with compound Int-40 to prepare intermediate compound Int-41.

[0709] MS(ESI + m / z = 596.1 [M+H] + .

[0710] Preparation Example 42: Synthesis of intermediate compound Int-42

[0711] Referring to the first step of Example 37, compound 9-2 was replaced with compound Int-36 to prepare intermediate compound Int-42. MS(ESI) + m / z = 902.4[M+H] + .

[0712] Synthesis of intermediate compound Int-43 in Preparation Example 43

[0713] Referring to steps 1 to 3 of Preparation Example 26, intermediate Int-4 was replaced with compound Int-11 to prepare intermediate compound Int-43.

[0714] MS(ESI + m / z = 1233.6 [M+H] + .

[0715] Preparation Example 44: Synthesis of intermediate compound Int-44

[0716] Referring to steps 1 to 3 of Preparation Example 26, intermediate Int-4 was replaced with compound Int-11, and intermediate Int-25 was replaced with... The intermediate compound Int-44 was prepared.

[0717] MS(ESI + m / z = 1175.5 [M+H] + .

[0718] Preparation Example 45: Synthesis of intermediate compound Int-45

[0719] Referring to steps 1 to 3 of Preparation Example 26, intermediate Int-4 was replaced with compound Int-11, and intermediate Int-25 was replaced with... The intermediate compound Int-45 was prepared.

[0720] MS(ESI + m / z = 1190.5[M+H] + .

[0721] Preparation Example 46: Synthesis of intermediate compound Int-46

[0722] Referring to steps 1 to 3 of Preparation Example 26, intermediate Int-4 was replaced with compound Int-11, and intermediate Int-25 was replaced with... The intermediate compound Int-46 was prepared.

[0723] MS(ESI + m / z = 1175.5 [M+H] + .

[0724] Preparation Example 47: Synthesis of intermediate compound Int-47

[0725] Referring to Preparation Example 38, the intermediate was prepared... Replace with compound The intermediate compound Int-47 was prepared.

[0726] MS(ESI + m / z = 327.1 [M+H] + .

[0727] Preparation Example 48: Synthesis of intermediate compound Int-48

[0728] Referring to Preparation Example 11, intermediate I2 was replaced with compound Int-47 to prepare intermediate compound Int-48.

[0729] MS(ESI + m / z = 424.1 [M+H] + .

[0730] Synthesis of intermediate compound Int-49 in Preparation Example 49

[0731] Following steps 1 to 3 of Preparation Example 26, intermediate Int-4 was replaced with compound Int-48 to prepare intermediate compound Int-49.

[0732] MS(ESI + m / z = 1100.5[M+H] + .

[0733] Preparation Example 50: Synthesis of intermediate compound Int-50

[0734] Compound V1 (1.9 g, 7.6 mmol) and triethylamine (2.7 g, 26.5 mmol) were added to anhydrous dichloromethane (20 mL), and methanesulfonyl chloride (1.3 g, 11.5 mmol) was added dropwise under ice bath conditions. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (50 mL * 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-0:100) to give compound Int-50 (2.16 g, 6.6 mmol).

[0735] MS(ESI + m / z = 328.1 [M+H] + .

[0736] Preparation Example 51: Synthesis of intermediate compound Int-51

[0737] Referring to steps 4 to 6 of Example 2, the intermediate is... The intermediate compound Int-51 was prepared by replacing it with compound Int-50.

[0738] MS(ESI + m / z = 487.2[M+H] + .

[0739] Preparation Example 52: Synthesis of intermediate compound Int-52

[0740] At 0 °C, methanesulfonyl chloride (616.3 mg, 5.38 mmol) was added dropwise to a solution of compound W1 (500.0 mg, 4.30 mmol) and N,N-diisopropylethylamine (834.4 mg, 6.46 mmol) in dichloromethane (10 mL). The mixture was heated to room temperature and reacted for 2 hours. The reaction solution was poured into water (25 mL), extracted with dichloromethane (20 mL * 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound Int-52 (900.0 mg, 4.62 mmol).

[0741] MS(ESI + m / z = 195.1 [M+H] + .

[0742] Synthesis of intermediate compound Int-53 in Preparation Example 53

[0743] Referring to steps 4 to 6 of Example 2, the intermediate is... The intermediate compound Int-53 was prepared by replacing it with compound Int-52.

[0744] MS(ESI + m / z = 354.1 [M+H] + .

[0745] Preparation Example 54: Synthesis of intermediate compound Int-54

[0746] Referring to Preparation Example 37, the intermediate compound Int-54 was prepared by replacing the intermediate cyclopropylboronic acid with methylboronic acid.

[0747] MS(ESI + m / z = 487.1 [M+H] + .

[0748] Preparation Example 55: Synthesis of intermediate compound Int-55

[0749] At 0 °C, methanesulfonyl chloride (616.3 mg, 5.38 mmol) was added dropwise to a solution of compound X1 (500.0 mg, 2.02 mmol) and N,N-diisopropylethylamine (834.4 mg, 6.46 mmol) in dichloromethane (10 mL). The mixture was heated to room temperature and reacted for 2 hours. The reaction solution was poured into water (25 mL), extracted with dichloromethane (20 mL * 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound Int-55 (428.0 mg, 1.31 mmol).

[0750] MS(ESI+ m / z = 326.1 [M+H] + .

[0751] Preparation Example 56: Synthesis of intermediate compound Int-56

[0752] Referring to steps 4 to 6 of Example 2, the intermediate is... The intermediate compound Int-56 was prepared by replacing compound Int-55 with compound Int-55. MS(ESI) + m / z = 485.1 [M+H] + .

[0753] Preparation Example 57: Synthesis of intermediate compound Int-57

[0754] Under argon protection, cuprous iodide (94.3 mg, 495.36 μmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (407.9 mg, 2.12 mmol, 268.4 μL), and hexamethylphosphoric triamine (380.4 mg, 2.12 mmol) were added sequentially to a solution of compound 10⁻¹ (200.0 mg, 333.72 μmol) in N,N-dimethylformamide (3 mL) at room temperature. The mixture was stirred at 85 °C for 6 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate (20 mL) and washed with saturated brine (10 mL * 2). After the organic phase was concentrated, the residue was purified by column chromatography (petroleum ether:ethyl acetate: = 85:15) to give compound Int-57 (120.0 mg, 221.77 μmol).

[0755] MS(ESI + m / z = 541.1 [M+H] + .

[0756] Preparation Example 58: Synthesis of intermediate compound Int-58

[0757] Referring to Preparation Examples 40 and 41, the intermediate was prepared... Replace with The intermediate compound Int-58 was prepared.

[0758] MS(ESI + m / z = 596.1 [M+H] + .

[0759] Synthesis of intermediate compound Int-59 (Preparation Example 59)

[0760] Referring to steps 4 to 6 of Example 2, the reaction temperature in step 4 was adjusted to 90°C to prepare the intermediate compound Int-59.

[0761] MS(ESI + m / z = 473.1 [M+H] + .

[0762] Preparation Example 60: Synthesis of intermediate compound Int-60

[0763] The first step is the synthesis of compound Y2.

[0764] Compound Y1 (4.0 g, 19.0 mmol) and N,N-dimethylformamide dimethyl acetal (2.72 g, 22.8 mmol) were added to N,N-dimethylformamide (40.0 mL). After the addition was complete, the mixture was heated and stirred in an oil bath at 100 °C for 0.5 h. After the starting material disappeared as monitored by LC-MS, the reaction solution was cooled to room temperature, and then 4-aminopiperidine-1-carboxylic acid benzyl ester (5.35 g, 22.8 mmol) and acetic acid (40.0 mL) were added. After the addition was complete, the mixture was heated and stirred in an oil bath at 80 °C for 16.0 h. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate, and the organic phase was washed once with saturated brine and dried with anhydrous sodium sulfate. The crude product was concentrated and purified by column chromatography (PE:DCM:THF = 11:84:5) to obtain compound Y2 (6.2 g, 15.16 mmol).

[0765] MS(ESI + m / z = 409.1 [M+H] + .

[0766] The second step involves the synthesis of compound Int-60.

[0767] Under an argon atmosphere, compound Y2 (5.8 g, 14.2 mmol) was dissolved in tetrahydrofuran (300.0 mL), and the solution was cooled to -70 °C. Then, lithium magnesium chloride (2,2,6,6-tetramethylpiperidine) salt (12.9 mL, 12.9 mmol, 1.0 M THF solution) was added dropwise to the reaction solution with stirring. After the addition was complete, stirring was continued at -70 °C for 10.0 min. Next, N,N-dimethylacetamide (13.2 mL, 142.0 mmol) was added dropwise to the reaction solution. After the addition was complete, the cryogenic bath was removed, and the reaction solution was slowly heated and stirred for 30.0 min. After the reaction was complete, dilute hydrochloric acid (200.0 mL, 2.0 mol / L) was added to the reaction solution to quench the reaction, and stirring was continued for 10.0 min. After stirring, the product was extracted with ethyl acetate, and the crude product was concentrated and dried. It was then purified by column chromatography (PE:DCM:THF = 11:84:5) to obtain compound Int-60 (0.96 g, 2.13 mmol).

[0768] MS(ESI + m / z = 451.2[M+H] + .

[0769] Preparation Example 61: Synthesis of intermediate compound Int-61

[0770] Referring to Preparation Example 11, intermediate I2 was replaced with compound Int-60 to prepare intermediate compound Int-61.

[0771] MS(ESI + m / z = 548.1 [M+H] + .

[0772] Preparation Example 62: Synthesis of intermediate compound Int-62

[0773] Referring to Preparation Example 50, intermediate V1 of Preparation Example 50 was replaced with compound Preparation of intermediate compounds Referring again to steps 4-6 of Example 2, the intermediate is... Replace with compound The intermediate compound Int-62 was prepared.

[0774] MS(ESI + m / z = 473.1 [M+H] + .

[0775] Preparation Example 63: Synthesis of intermediate compound Int-63

[0776] Synthesis of compound Z2 in the first step

[0777] Under argon protection, (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine Z1 (5.00 g, 14.62 mmol) was dissolved in DMF (50 mL), followed by the addition of zinc cyanide (944.3 mg, 8.04 mmol) and tetrakis(triphenylphosphine)palladium (1.69 g, 1.46 mmol). The mixture was reacted at 80 °C for 6 hours. After the reaction was complete, the reaction solution was poured into water (80 mL), extracted with ethyl acetate (80 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether: dichloromethane = 100:0-70:30) to give compound Z2 (2.88 g, 11.95 mmol).

[0778] MS(ESI + m / z = 241.1[M+H] + .

[0779] The second step involves the synthesis of compound Z3.

[0780] Compound Z2 (2.50 g, 10.37 mmol) was dissolved in 20 mL of 1,2-dichloroethane at room temperature, and m-chloroperoxybenzoic acid (3.16 g, 15.55 mmol, 85% purity) was added. The mixture was reacted at 50 °C for 12 hours. The reaction solution was diluted with dichloromethane, washed with saturated sodium thiosulfate solution, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-75:25) to give compound Z3 (1.40 g, 5.45 mmol).

[0781] MS(ESI + m / z = 257.0 [M+H] + .

[0782] The third step involves the synthesis of compound Z4.

[0783] Compound Z3 (0.80 g, 3.11 mmol) was dissolved in 1,2-dichloroethane (8 mL), followed by the addition of (chloromethylene)dimethylammonium chloride (796.6 mg, 6.22 mmol). The mixture was reacted at 70 °C for 0.5 h. Excess saturated sodium bicarbonate solution was added to the reaction mixture, and extraction was performed with ethyl acetate (80 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:0-70:30) to give compound Z4 (620.0 mg, 2.25 mmol).

[0784] MS(ESI + m / z = 275.0 [M+H]+ .

[0785] The fourth step is the synthesis of compound Z5.

[0786] Compound Z4 (0.30 g, 1.09 mmol) was dissolved in dimethyl sulfoxide (3 mL) at room temperature, and potassium fluoride (253.0 mg, 4.36 mmol) was added. The mixture was reacted at 80 °C for 5 hours. The reaction solution was poured into water (80 mL), extracted with ethyl acetate (80 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-70:30) to give compound Z5 (220.0 mg, 849.18 μmol).

[0787] MS(ESI + m / z = 259.0 [M+H] + .

[0788] Step 5: Synthesis of compound Z6

[0789] Compound Z5 (500.0 mg, 1.93 mmol) was dissolved in acetonitrile (3 mL), and then ammonia (3.38 g, 19.30 mmol, 20% purity) was added. The reaction mixture was reacted at 50 °C for 5 hours. The reaction solution was concentrated to obtain crude compound Z6 (490.0 mg, 1.91 mmol), which was used directly in the next step.

[0790] MS(ESI + m / z = 256.0 [M+H] + .

[0791] Step 6: Synthesis of compound Z7

[0792] Compound Z6 (490.0 mg, 1.91 mmol) was dissolved in concentrated hydrochloric acid (5 mL) and reacted at 100 °C for 6 hours. The reaction solution was then concentrated to obtain compound Z7 (500.0 mg, 1.82 mmol).

[0793] MS(ESI + m / z = 275.0 [M+H] + .

[0794] Step 7: Synthesis of compound Z8

[0795] Compound Z7 (500.0 mg, 1.82 mmol), 4-amino-1-tert-butoxycarbonylpiperidine (728.0 mg, 3.64 mmol), and N,N,N′,N′-tetramethyl-2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.04 g, 2.73 mmol) were dissolved in N,N-dimethylformamide (10 mL), followed by the addition of N,N-diisopropylethylamine (1.17 g, 9.09 mmol). The mixture was reacted at room temperature for 2 hours. The reaction solution was poured into water (100 mL), resulting in the precipitation of a large amount of solid. The reaction solution was filtered, washed with water, and the filter cake was collected and dried to obtain crude compound Z8 (590.0 mg, 1.29 mmol), which was used directly in the next step. MS (ESI) + m / z = 457.1 [M+H] + .

[0796] Step 8: Synthesis of compound Z9

[0797] Compound Z8 (300.0 mg, 655.94 μmol) was dissolved in N,N-dimethylformamide dimethyl acetal (5 mL), and the mixture was stirred at 120 °C for 36 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-50:50) to give compound Z9 (200.0 mg, 0.43 mmol).

[0798] MS(ESI + m / z = 467.1 [M+H] + .

[0799] Step 9: Synthesis of compound Z10

[0800] Compound Z9 (200.0 mg, 427.94 μmol) was dissolved in dichloromethane (4 mL), and then trifluoroacetic acid (2 mL) was added. The mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated, and excess saturated sodium bicarbonate aqueous solution was added to the residue. The mixture was extracted with dichloromethane (30 mL * 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound Z10 (150.0 mg, 408.45 μmol).

[0801] MS(ESI + m / z = 367.0 [M+H] + .

[0802] Step 10: Synthesis of compound Int-63

[0803] Compound Z10 (150.0 mg, 408.45 μmol) was dissolved in methanol (3 mL), followed by the addition of aqueous formaldehyde solution (102.1 mg, 1.23 mmol, 36% purity), acetic acid (122.6 mg, 2.04 mmol), and sodium cyanoborohydride (102.6 mg, 1.63 mmol). The mixture was stirred at room temperature for 1 hour. The reaction solution was poured into saturated sodium bicarbonate aqueous solution (20 mL), extracted with dichloromethane (30 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (dichloromethane:methanol = 100:0-90:10) to give compound Int-63 (55.0 mg, 144.26 μmol).

[0804] MS(ESI + m / z = 381.0 [M+H] + .

[0805] Example 1: Synthesis of compounds 1-P1 and 1-P2

[0806] Synthesis of Compounds 1-2 in Step 1

[0807] Compound Int-3 (48 mg, 68 μmol), 2-biscyclohexylphosphine-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). The air in the solution was replaced three times with argon, and the mixture was stirred in an ice bath for 5 minutes. Pinaranoborane (70 mg, 0.54 mmol) was added dropwise to the reaction solution. After the addition was complete, the mixture was moved to 50 °C and reacted for 3 hours. After the reaction was monitored by LC-MS to ensure complete reaction, the reaction solution was filtered and purified by normal silica gel column chromatography (ethyl acetate / petroleum ether: 0%-80%) to give compounds 1-2 (31.2 mg, 44.2 μmol, yield: 65%).

[0808] MS(ESI + m / z = 706.4 [M+H] + .

[0809] The second step involves the synthesis of compounds 1-3.

[0810] Compound Int-4 (37.6 mg, 70.8 μmol) was added to 1,4-dioxane (2.0 mL), followed by [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (5.2 mg, 7.1 μmol), compound 1-2 (50.0 mg, 70.8 μmol), potassium phosphate (16.6 mg, 78.1 μmol), and water (0.25 mL). The mixture was stirred at 65 °C under nitrogen protection for 2 hours. After the reaction was complete, the crude product was purified by reverse-phase reaction (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound 1-3 (36.0 mg, 36.6 μmol, yield: 51.6%).

[0811] MS(ESI+)m / z = 983.4[M+H] + .

[0812] Step 3: Synthesis of compounds 1-4

[0813] Compounds 1-3 (36.0 mg, 36.6 μmol) and cesium carbonate (35.8 mg, 109.8 μmol) were added to N,N-dimethylformamide (4.0 mL), and argon gas was purged. Iodoethane (8.57 mg, 54.9 μmol) was added dropwise to the reaction mixture under an argon atmosphere, and the resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was slowly poured into ice water and stirred. Extraction was performed with ethyl acetate, and the organic phase was concentrated to obtain a crude product. The crude product was purified by reverse-phase chromatography (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compounds 1-4 (27.0 mg, 26.7 μmol, yield: 72.9%).

[0814] MS(ESI+)m / z=1011.4[M+H] + .

[0815] Step 4: Synthesis of compounds 1-5

[0816] Compounds 1-4 (27.0 mg, 26.7 μmol) were dissolved in methanol (5.0 mL). Pd(OH)₂ / C (20%) (26.2 mg) and paraformaldehyde (24.0 mg, 801 μmol) were added to the reaction solution. The mixture was then purged with hydrogen five times. The mixture was stirred at 25 °C for 5 hours under one atmosphere of pressure. The reaction was monitored by LC-MS to ensure complete reaction. The crude product was purified by reversed-phase column chromatography (water / NH₄OH (0.5%):MeCN = 95:5 to 5:95) to give compounds 1-5 (23.0 mg, 25.8 μmol, yield: 96.6%).

[0817] MS(ESI +m / z = 891.4 [M+H] + .

[0818] Step 5: Synthesis of compounds 1-6

[0819] Compounds 1-5 (23.0 mg, 25.8 μmol) were dissolved in dichloromethane (1.0 mL). Under nitrogen protection, 4 M dioxane hydrochloride solution (3.0 mL) was added to the reaction solution. The mixture was stirred at 25 °C for 0.5 hours. The reaction was monitored by LC-MS until complete. The solution was concentrated by rotary evaporation to obtain compounds 1-6 (20.0 mg, 25.3 μmol, yield: 98.0%).

[0820] MS(ESI + m / z = 791.4 [M+H] + .

[0821] Step 6: Synthesis of compounds 1-P1 and 1-P2

[0822] Compounds 1-6 (20.0 mg, 25.3 μmol) and N,N-diisopropylethylamine (13.2 μL, 75.8 μmol) were added sequentially to a solution of (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (4.3 mg, 37.9 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (14.4 mg, 37.9 μmol) in N,N-dimethylformamide (2.0 mL), and stirred at room temperature for 1 hour. After the reaction was completed, the product was purified by reversed-phase column chromatography (Waters XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%; mobile phase B: MeCN; MeCN ratio 60%-80%, time: 10 min, flow rate: 15 mL / min) to obtain compound 1-P1 (5.5 mg, 6.2 μmol, yield: 24.5%, retention time: 6.78 min) and compound 1-P2 (4.26 mg, 4.8 μmol, yield: 19%, retention time: 7.52 min).

[0823] Compound 1-P1 MS (ESI) + m / z = 887.8 [M+H] + .

[0824] 11H NMR (400 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.30 (s, 1H), 8.11–8.06 (m, 1H), 7.75–7.69 (m, 2H), 7.58 (s, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.29 (d, J = 2.7 Hz, 1H), 5.43 (d, J = 5.3 Hz, 1H), 5.34 (t, J = 4.9 Hz, 2H), 4.81–4.74 (m, 1H), 4.68–4.63 (m, 1H), 4.60 (s, 3H), 4.25 (q, J = 6.3 Hz, 1H), 4.19–4.07 (m, 1H), 3.78–3.68 (m, 3H), 3.45 (s, 3H), 3.25–3.21 (m, 1H), 2.83–2.77 (m, 3H), 2.77–2.73 (m, 1H), 2.52–2.44 (m, 4H), 2.35 (d, J = 14.3 Hz, 1H), 2.19 (t, J = 7.7 Hz, 3H), 1.69 (t, J = 9.5 Hz, 1H), 1.64–1.55 (m, 3H), 1.46–1.42 (m, 1H), 1.18 (d, J = 5.9 Hz, 3H), 1.16–1.12 (m, 4H), 1.12–1.08 (m, 2H), 0.94 (s, 3H), 0.92–0.86 (m, 5H), 0.59 (s, 3H).

[0825] Compound 1-P2 MS (ESI + ) m / z = 887.8 [M+H] + .

[0826] 1H NMR (400MHz, Methanol-d4) δ8.45(d,J=1.4Hz,1H),8.40(d,J=2.9Hz,1H),7.72–7.68(m,1H),7.58(s,1H),7.49(d,J=8.6H z,1H),7.32(d,J=2.8Hz,1H),5.53–5.46(m,1H),4.71–4.65(m,2H),4.52–4.42(m,2H),4.33–4.16(m,3H),3.98–3.86(m,2 H),3.76–3.61(m,7H),3.32(s,3H),2.92–2.81(m,3H),2.75–2.68(m,1H),2.62–2.55(m,2H),2.51–2.41(m,2H),2.27–2.1 4(m,2H),2.08–1.88(m,8H),1.67–1.56(m,4H),1.42(d,J=6.2Hz,3H),0.99–0.93(m,6H),0.92–0.87(m,2H),0.46(s,3H).

[0827] Example 2: Synthesis of compounds 2-P1 and 2-P2

[0828] Synthesis of compound 2-2 in step one

[0829] Compound 2-1 (6.00 g, 30.30 mmol) was dissolved in anhydrous ethyl acetate (80 mL), and then m-chloroperoxybenzoic acid (10.46 g, 60.60 mmol) was added. The mixture was reacted at room temperature for 30 minutes, then heated to 50 °C and reacted for another 5 hours. The reaction mixture was filtered, and the filter cake was washed with a small amount of ethyl acetate. The filter cake was dried to give compound 2-2 (5.60 g, 26.17 mmol, yield: 86.4%).

[0830] MS(ESI + m / z = 213.9[M+H] + .

[0831] The second step involves the synthesis of compounds 2-3.

[0832] Compound 2-2 (5.40 g, 25.23 mmol) was dissolved in acetonitrile (100 mL), and then trimethylcyanosilane (5.01 g, 50.46 mmol) and triethylamine (7.66 g, 75.69 mmol, 10.55 mL) were added. The mixture was heated to 80 °C and reacted for 12 hours. The reaction solution was concentrated, and ethyl acetate (20 mL) was added to the residue and stirred. The reaction solution was filtered, and the filter cake was washed with a small amount of ethyl acetate. The filter cake was dried to give compound 2-3 (4.10 g, 18.39 mmol, yield: 73%).

[0833] MS(ESI + m / z = 222.9[M+H] + .

[0834] The third step involves the synthesis of compounds 2-4.

[0835] At 0 °C, methyl magnesium bromide (3 M, 18 mL) was added dropwise to a tetrahydrofuran (20 mL) solution of compound 2-3 (4.00 g, 17.93 mmol). The mixture was heated to room temperature and stirred for 3 hours. The reaction solution was poured into dilute hydrochloric acid (6 M, 20 mL), and the tetrahydrofuran was removed by concentration under reduced pressure. Water (60 mL) was added to the residue, and the mixture was extracted with dichloromethane (80 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (dichloromethane:methanol = 100:0-90:10) to give compound 2-4 (2.80 g, 11.66 mmol, yield: 65%).

[0836] MS(ESI + m / z = 240.2[M+H] + .

[0837] Step 4: Synthesis of compounds 2-5

[0838] Compound 2-4 (1.4 g, 5.83 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of potassium carbonate (2.4 g, 17.50 mmol) and 4-((methanesulfonyl)oxy)piperidine-1-carboxylic acid benzyl ester (2.92 g, 9.33 mmol). The mixture was reacted at 100 °C for 8 hours. The reaction solution was filtered, and water (100 mL) was added to the filtrate. The filtrate was extracted with ethyl acetate (80 mL * 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 = 100:0-50:50) to give compound 2-5 (640.0 mg, 1.40 mmol, yield: 24%).

[0839] MS(ESI + m / z = 457.0 [M+H] + .

[0840] Step 5: Synthesis of compounds 2-6

[0841] Formic acid (130.2 mg, 2.83 mmol) was added to triethylamine (1.43 g, 14.17 mmol, 1.97 mL) at 0 °C, and nitrogen was exchanged three times. Then (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (7.5 mg, 11.81 μmol) was added, and the mixture was reacted at 40 °C for 30 minutes. After cooling to room temperature, compound 2-5 (540.0 mg, 1.18 mmol) was added, and the mixture was reacted at 40 °C for another 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 80:20-50:50) to give compound 2-6 (480.0 mg, 1.04 mmol, yield: 89%).

[0842] MS(ESI + m / z = 458.3 [M+H] + .

[0843] Step 6: Synthesis of compounds 2-7

[0844] Sodium hydride (51.5 mg, 1.25 mmol, dispersed in paraffin liquid at 60% concentration) was added in portions to a solution of compound 2-6 (480.0 mg, 1.04 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred at 0 °C for 1 hour, followed by the addition of iodomethane (296.7 mg, 2.09 mmol), and the reaction was continued at 0 °C for another hour. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (10 mL), then water (10 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give compound 2-7 (480.0 mg, 1.01 mmol, yield: 97%). MS (ESI) + m / z = 473.0 [M+H] + .

[0845] Step 7: Synthesis of compounds 2-8

[0846] Compounds 1-2 (300.0 mg, 425.13 μmol), compounds 2-7 (201.2 mg, 425.13 μmol), potassium carbonate (117.3 mg, 850.26 μmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (31.1 mg, 42.51 μmol) were dissolved in dioxane / toluene / water (1 mL / 3 mL / 0.3 mL), and the air in the solution was replaced three times with argon. The reaction was carried out at 65 °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 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 2-8 (100 mg, 102.83 μmol, yield: 24%).

[0847] MS(ESI + m / z = 972.4 [M+H] + .

[0848] Step 8: Synthesis of compounds 2-9

[0849] Compound 2-8 (96.0 mg, 98.75 μmol) was dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (64.35 mg, 197.50 μmol) and iodoethane (30.8 mg, 197.50 μmol) were added. The reaction mixture was reacted at room temperature for 8 hours. The reaction solution was then purified directly 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 8 column volumes) to give compound 2-9 (98.0 mg, 97.96 μmol, yield: 99%).

[0850] MS(ESI + m / z = 1000.4[M+H] + .

[0851] Step 9: Synthesis of Compounds 2-10

[0852] Compound 2-9 (98.0 mg, 97.96 μmol) was dissolved in methanol (5.0 mL). Pd(OH)₂ / C (20%) (110.1 mg) and paraformaldehyde (88.26 mg, 2.94 mmol) were added to the reaction solution, and the mixture was purged with hydrogen five times. The mixture was stirred at 25 °C for 15 hours under one atmosphere of pressure, and the reaction was monitored to be complete by LC-MS. The crude product was purified by reversed-phase column chromatography (water / NH₄OH (0.5%):MeCN = 95:5 to 5:95) to give compound 2-10 (81.9 mg, 93.06 μmol, yield: 95%).

[0853] MS(ESI + m / z = 880.6 [M+H] + .

[0854] Step 10: Synthesis of compound 2-11

[0855] Compound 2-10 (90 mg, 102.26 μmol) was dissolved in dichloromethane (2.0 mL). Under nitrogen protection, 4 M dioxane hydrochloride solution (5.0 mL) was added to the reaction solution. The mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS until it was complete. The solution was concentrated by rotary evaporation to obtain compound 2-11 (78.2 mg, 100.21 μmol, yield: 98.0%).

[0856] MS(ESI + m / z = 780.4 [M+H] + .

[0857] Step 11: Synthesis of compounds 2-P1 and 2-P2

[0858] Compound 2-11 (20.0 mg, 25.62 μmol) and N,N-diisopropylethylamine (13.2 μL, 75.8 μmol) were added sequentially to a solution of (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (4.3 mg, 37.9 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (14.4 mg, 37.9 μmol) in N,N-dimethylformamide (2.0 mL), and stirred at room temperature for 1 hour. After the reaction was completed, the product was purified by reversed-phase column chromatography (Waters XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%; mobile phase B: MeCN; MeCN ratio 50%-60%, time: 10 min, flow rate: 15 mL / min) to obtain compound 2-P1 (6.5 mg, 7.42 μmol, yield: 28.9%, retention time: 6.68 min) and compound 2-P2 (3.8 mg, 4.3 μmol, yield: 16.8%, retention time: 7.25 min).

[0859] Compound 2-P1 MS (ESI) + m / z = 876.5 [M+H] + .

[0860] 11H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.50 (d, J = 1.6 Hz, 1H), 8.31 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.73 (dd, J = 8.6, 1.6 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 6.29 (d, J = 10.3 Hz, 1H), 5.77 (t, J = 8.5 Hz, 1H), 4.61–4.53 (m, 1H), 4.53–4.47 (m, 1H), 4.31 (d, J = 10.3 Hz, 1H), 4.11–4.02 (m, 1H), 4.02–3.95 (m, 1H), 3.95–3.85 (m, 2H), 3.66–3.58 (m, 1H), 3.58–3.51 (m, 1H), 3.23–3.15 (m, 1H), 3.11–3.05 (m, 1H), 3.04 (s, 2H), 2.99–2.91 (m, 2H), 2.62–2.55 (m, 3H), 2.43–2.35 (m, 1H), 2.32–2.28 (m, 2H), 2.26 (s, 3H), 2.23–2.18 (m, 1H), 2.18–2.08 (m, 4H), 1.64–1.56 (m, 1H), 1.30–1.25 (m, 3H), 1.16–1.07 (m, 5H), 1.06–1.00 (m, 4H), 1.00–0.93 (m, 3H), 0.75 (s, 3H), 0.66 (s, 3H).

[0861] Compound 2-P2 MS (ESI + ) m / z = 876.5 [M+H] + .

[0862] 1H NMR(400MHz, DMSO-d6)δ8.59(s,1H),8.39–8.32(m,1H),8.26(s,1H),7.90(d,J=7.0Hz,1H),7.74(s,1H),7.69–7.63(m,1H),7.57–7.48(m,1H ),6.51(d,J=8.4Hz,1H),5.50–5.42(m,1H),4.58–4.51(m,2H),4.30–4 .24(m,1H),4.18–4.06(m,4H),3.76–3.72(m,1H),3.63–3.60(m,1H),3. 04(s,1H),2.97–2.94(m,2H),2.91–2.88(m,1H),2.83(s,2H),2.41–2. 38(m,1H),2.30–2.25(m,4H),2.21–2.12(m,7H),2.09–2.00(m,2H),1. 93–1.86(m,1H),1.39(d,J=6.2Hz,3H),1.32–1.28(m,1H),1.27–1.21( m,4H),1.18–1.12(m,4H),1.08–1.05(m,3H),0.74(s,3H),0.61(s,3H).

[0863] Example 3: Synthesis of Compound 3

[0864] Synthesis of compound 3-2 in step one

[0865] Compounds 1-3 (181.0 mg, 184.1 μmol) and cesium carbonate (300.0 mg, 920.5 μmol) were added to N,N-dimethylformamide (10.0 mL), and argon gas was purged. Iodethane (287.1 mg, 1.84 mmol) was added dropwise to the reaction mixture under an argon atmosphere, and the resulting mixture was stirred at 30 °C for 3.0 h. After the reaction was completed, the product was purified by reversed-phase column chromatography (XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: water / NH4OH (0.05%); mobile phase B: MeCN; mobile phase B ratio: 78%; time: 10 min; flow rate: 15 mL / min) to obtain the less polar isomer 3-2 (72.0 mg, 71.2 μmol, yield: 38.7%, retention time: 11.05 min), and simultaneously obtained another more polar isomer (77.0 mg, 76.1 μmol, yield: 41.3%, retention time: 10.36 min).

[0866] MS(ESI +m / z = 1011.4[M+H] + .

[0867] The second step involves the synthesis of compound 3-3.

[0868] Compound 3-2 (70.0 mg, 69.22 μmol) was dissolved in methanol (20.0 mL). Pd(OH)₂ / C (20%) (48.6 mg, 346.1 μmol) and paraformaldehyde (41.57 mg, 1.38 mmol) were added to the reaction solution, followed by purging with hydrogen five times. The mixture was stirred at 25 °C for 8.0 h under one atmosphere of pressure, and the reaction was monitored for completeness by LC-MS. The crude product was purified by reversed-phase column chromatography (water / NH₄OH (0.5%):MeCN = 95:5 to 5:95) to give compound 3-3 (50.0 mg, 56.11 μmol, yield: 81.0%).

[0869] MS(ESI + m / z = 891.4 [M+H] + .

[0870] The third step involves the synthesis of compounds 3-4.

[0871] Compound 3-3 (5.6 mg, 6.28 μmol) was dissolved in dichloromethane (0.3 mL). Under nitrogen protection, 4 M dioxane hydrochloride solution (1.0 mL) was added to the reaction solution. The mixture was stirred at 25 °C for 0.5 h. The reaction was monitored by LC-MS until it was complete. The solution was concentrated by rotary evaporation to obtain compound 3-4 (4.97 mg, 6.28 μmol, yield: 100.0%).

[0872] MS(ESI + m / z = 791.4 [M+H] + .

[0873] Step 4: Synthesis of Compound 3

[0874] A solution of compounds 3-4 (4.97 mg, 6.28 μmol) and N,N-diisopropylethylamine (3.3 μL, 18.85 μmol) in N,N-dimethylformamide (0.3 mL) was added to a solution of compound 4-fluoro-2-(2-fluoroethyl)butyric acid (1.9 mg, 12.49 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (3.58 mg, 9.42 μmol) in N,N-dimethylformamide (1.0 mL). The mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the product was purified by reversed-phase column chromatography (waters XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: water / NH4OH (0.05%); mobile phase B: MeCN; MeCN ratio 50%-80%; time: 10 min; flow rate: 15 mL / min) to obtain compound 3 (2.5 mg, 2.70 μmol, yield: 43.0%).

[0875] MS(ESI + m / z = 925.4 [M+H] + .

[0876] 1 H NMR (400MHz, Methanol-d4) δ8.48(d,J=1.6Hz,1H),8.18(s,1H),8.05(d,J=9.4Hz,1H),7.75–7.68(m,2H),7.59(s,1H),7.51(d,J=8.6Hz,1H),7.27(d ,J=2.7Hz,1H),5.50(d,J=6.4Hz,1H),5.34(t,J=4.8Hz,1H),4.69–4.55(m, 2H),4.53–4.27(m,3H),4.23–4.12(m,1H),3.75–3.63(m,2H),3.50–3.47(m ,1H),3.43–3.40(m,3H),3.38(s,3H),3.17–3.12(m,1H),2.90–2.80(m,1H) ,2.74–2.69(m,5H),2.63–2.57(m,1H),2.51–2.43(m,1H),2.41(s,3H),2.2 2–2.16(m,2H),2.07–1.99(m,3H),1.97–1.89(m,2H),1.66–1.57(m,2H),1. 54(d,J=6.2Hz,3H),1.37(s,1H),0.98–0.92(m,3H),0.92–0.86(m,6H),0.4 2(s,3H).

[0877] Example 4: Synthesis of Compound 4

[0878] Synthesis of compound 4-2 (Step 1)

[0879] Compound 4-1 (1 g, 10.1 mmol) and triethylamine (1.42 g, 14.06 mmol, 1.96 mL) were dissolved in dichloromethane (20 mL) and stirred. Compound 4A (1.5 g, 11 mmol) was added dropwise to the reaction solution at 0 °C, and then stirred at 25 °C for 2 hours. The reaction was monitored by LC-MS until complete. The mixture was extracted with ethyl acetate (100 mL) and water (100 mL), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 4-2 (0.86 g, 4.3 mmol, yield: 42.57%).

[0880] MS(ESI + m / z = 200.2[M+H] + .

[0881] The second step involves the synthesis of compound 4-3.

[0882] Compound 4-2 (0.86 g, 4.3 mmol) was dissolved in tetrahydrofuran (5 mL), and LiOH·H₂O (629.51 mg, 15 mmol) was dissolved in water (5 mL) and added to the reaction solution. The mixture was stirred at 25 °C for 1 hour, and the reaction was monitored by LC-MS until complete. The mixture was extracted with ethyl acetate (30 mL) and water (30 mL). The pH of the aqueous phase was adjusted to approximately 2 with 6 M hydrochloric acid, and the mixture was extracted again with ethyl acetate (30 mL). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 4-3 (460 mg, 2.68 mmol, yield: 62.3%).

[0883] MS(ESI + m / z = 172.0 [M+H] + .

[0884] Step 3: Synthesis of Compound 4

[0885] A solution of compounds 3-4 (4.0 mg, 5.06 μmol) and N,N-diisopropylethylamine (2.64 μL, 15.17 μmol) in N,N-dimethylformamide (0.5 mL) was added to a solution of compounds 4-3 (1.73 mg, 10.11 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (3.85 mg, 10.11 μmol) in N,N-dimethylformamide (0.5 mL). The mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the product was purified by reversed-phase column chromatography (waters XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: water / NH4OH (0.05%); mobile phase B: MeCN; MeCN ratio 55%-80%; time: 10 min; flow rate: 15 mL / min) to obtain compound 4 (1.98 mg, 2.09 μmol, yield: 41.0%).

[0886] MS(ESI + m / z = 944.3 [M+H] + .

[0887] 1 H NMR (400MHz, Methanol-d4) δ8.48(d,J=1.6Hz,1H),8.21(s,1H),8.09(d,J=9.3Hz,1H),7.76–7.69(m,2H),7.59(s,1H),7.55–7.50(m,1H) ,7.34(d,J=2.7Hz,1H),5.66–5.58(m,1H),5.36–5.32(m,2H),4.75–4.64(m,3H),4.58(s,1H),4.48(q,J=6.1Hz,1H),4.43–4.10(m,3H),3 .77–3.57(m,2H),3.53–3.40(m,2H),3.37(s,3H),3.25–3.06(m,4H),2.82–2.71(m,4H),2.64–2.55(m,1H),2.50–2.42(m,1H),2.31–2.13 (m,5H),1.65–1.57(m,5H),1.54(d,J=6.2Hz,3H),1.24(d,J=6.4Hz,3H),1.16(d,J=6.7Hz,3H),0.96(t,J=7.0Hz,3H),0.91–0.86(m,7H).

[0888] Example 5: Synthesis of Compound 5

[0889] A solution of compounds 3-4 (2.66 mg, 3.36 μmol) and N,N-diisopropylethylamine (1.17 μL, 6.73 μmol) in N,N-dimethylformamide (0.5 mL) was added to a solution of compounds 5-1 (0.37 mg, 3.73 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.56 mg, 6.73 μmol) in N,N-dimethylformamide (0.5 mL). The mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the compound was purified by reversed-phase column chromatography (XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: water / NH4OH (0.05%); mobile phase B: MeCN; MeCN ratio 60%-85%; time: 10 min; flow rate: 15 mL / min) to obtain compound 5 (1.72 mg, 1.97 μmol, yield: 58.6%).

[0890] MS(ESI + m / z = 873.4 [M+H] + .

[0891] 1 H NMR (400MHz, Methanol-d4) δ8.62 (s, 1H), 8.49 (d, J = 1.5 Hz, 1H), 8.26 (d, J = 9.5 Hz,1H),7.98–7.90(m,1H),7.77–7.72(m,1H),7.59(s,1H),7.56–7.52(m,2H), 5.63(s,1H),5.34(t,J=4.8Hz,2H),4.66(q,J=4.9Hz,1H),4.61–4.54(m,2H),4 .43–4.33(m,1H),4.20(d,J=12.4Hz,2H),4.12–4.01(m,1H),3.78–3.74(m,1H) ,3.74–3.64(m,4H),3.52–3.46(m,1H),3.43(s,3H),3.02(s,3H),2.82–2.74(m ,1H),2.71–2.65(m,1H),2.61–2.53(m,1H),2.48–2.40(m,1H),2.19(dd,J=9.5 ,5.4Hz,4H),2.06–2.00(m,5H),1.62–1.58(m,2H),1.56(d,J=6.2Hz,3H),1.50 –1.48(m,1H),1.13(t,J=6.1Hz,5H),0.99(t,J=7.0Hz,3H),0.92–0.89(m,3H).

[0892] Example 6: Synthesis of compounds 6-P1 and 6-P2

[0893] Synthesis of compound 6-1 in step one

[0894] Compound 2-9 (360.0 mg, 359.92 μmol) was dissolved in isopropanol (20 mL), and then 10% palladium hydroxide / carbon (404.4 mg, 2.88 mmol) was added. The mixture was purged with hydrogen five times and stirred at 25 °C for 15 hours under a hydrogen atmosphere and at one atmosphere. The reaction was monitored by LC-MS until it was complete. The reaction solution was filtered, and the filtrate was concentrated to give compound 6-1 (260.0 mg, 300.20 μmol, yield: 83%).

[0895] MS(ESI + m / z = 866.4 [M+H] + .

[0896] The second step involves the synthesis of compound 6-2.

[0897] Compound 6-1 (250.0 mg, 288.66 μmol), 3-oxetane (62.4 mg, 865.97 μmol, 55.52 μL), and acetic acid (156.0 mg, 2.60 mmol) were dissolved in isopropanol (10 mL), and then sodium cyanoborohydride (108.8 mg, 1.73 mmol) was added. The mixture was stirred at 25 °C for 6 hours. The reaction solution was poured into a saturated sodium bicarbonate solution (20 mL), extracted with dichloromethane (20 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by reversed-phase column chromatography (H2O / NH4OH (0.5%):MeCN = 95:5 to 5:95) to obtain compound 6-2 (241.0 mg, 261.62 μmol, yield: 91%).

[0898] MS(ESI + m / z = 922.4 [M+H] + .

[0899] The third step involves the synthesis of compound 6-3.

[0900] Under nitrogen protection, trifluoroacetic acid (1 mL) was added dropwise to a dichloromethane (4 mL) solution of compound 6-2 (260.0 mg, 281.95 μmol). The mixture was stirred at 25 °C for 2 hours. The reaction solution was poured into a saturated sodium bicarbonate (50 mL) solution and extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 6-3 (200.0 mg, 243.59 μmol, yield: 86%).

[0901] MS(ESI + m / z = 822.4[M+H] + .

[0902] Step 4: Synthesis of compounds 6-P1 and 6-P2

[0903] (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (8.3 mg, 72.99 μmol) was dissolved in N,N-dimethylformamide (1 mL), and then 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (34.7 mg, 91.24 μmol) and triethylamine (18.5 mg, 182.48 μmol, 25.43 μL) were added. The mixture was stirred at room temperature for 20 minutes, and then compound 6-3 (50 mg, 60.83 μmol) was added. The mixture was stirred at room temperature for another hour. After the reaction was completed, water (10 mL) was added to the reaction solution, and ethyl acetate (10 mL × 3) was used for extraction. The organic phases were combined, concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (column: Waters XBridge Prep C18; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 40%-60%, time: 10 min, flow rate: 15 mL / min) to obtain compound 6-P1 (19.7 mg, 21.4 μmol, yield: 35.2%, retention time: 9.18 min) and compound 6-P2 (12.6 mg, 13.7 μmol, yield: 22.6%, retention time: 9.67 min).

[0904] Compound 6-P1 MS (ESI) + m / z = 918.4 [M+H] + .

[0905] 11H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 1.5 Hz, 1H), 8.10–8.03 (m, 2H), 7.60 (dd, J = 8.5, 1.5 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.30 (s, 1H), 6.79 (d, J = 8.1 Hz, 1H), 5.48–5.43 (m, 1H), 5.25 (d, J = 10.7 Hz, 1H), 4.90 (d, J = 10.7 Hz, 1H), 4.79–4.62 (m, 5H), 4.54 (s, 1H), 4.07–3.96 (m, 2H), 3.79–3.74 (m, 1H), 3.73–3.65 (m, 2H), 3.63–3.55 (m, 1H), 3.46 (d, J = 15.1 Hz, 1H), 3.25–3.11 (m, 5H), 3.04–2.92 (m, 2H), 2.81–2.75 (m, 1H), 2.62–2.56 (m, 1H), 2.41–2.34 (m, 3H), 2.19–2.05 (m, 3H), 1.74–1.68 (m, 1H), 1.51–1.48 (m, 1H), 1.40–1.34 (m, 3H), 1.27–1.24 (m, 3H), 1.24–1.20 (m, 3H), 1.15 (d, J = 6.2 Hz, 3H), 1.11 (d, J = 6.2 Hz, 3H), 0.96–0.86 (m, 5H), 0.62 (s, 3H). Compound 6 - P2 MS (ESI + ) m / z = 918.4 [M + H] + .

[0906] 1H NMR (400MHz, CDCl3) δ8.39(s,1H),8.04(s,1H),7.99(s,1H),7.59(d,J=8.4Hz,1H),7.3 6(d,J=8.5Hz,1H),7.30(s,1H),6.68(d,J=8.4Hz,1H),5.59–5.54(m,1H),5.27(d,J=10. 8Hz,1H),4.81(d,J=10.7Hz,1H),4.77–4.63(m,5H),4.58–4.50(m,1H),4.45–4.39(m,1 H),4.27–4.16(m,2H),3.77(d,J=10.9Hz,1H),3.61(d,J=10.8Hz,2H),3.44(dd,J=15.2, 3.2Hz,1H),3.34(s,3H),3.17(dd,J=15.2,5.4Hz,1H),3.10(d,J=14.4Hz,1H),3.02–2. 91(m,2H),2.75–2.69(m,1H),2.59–2.53(m,1H),2.48(d,J=14.4Hz,1H),2.44–2.27(m,5 H),2.12–2.09(m,1H),1.68–1.63(m,1H),1.49–1.45(m,1H),1.30–1.21(m,5H),1.15(d, J=6.2Hz,3H),1.10(d,J=6.2Hz,3H),0.98–0.92(m,3H),0.91–0.85(m,5H),0.40(s,3H).

[0907] Example 7 Synthesis of Compound 7

[0908] p-Nitrophenyl chloroformate (2.8 mg, 13.91 μmol) was added to a solution of compounds 3-4 (10.0 mg, 12.64 μmol) and pyridine (3.0 mg, 37.93 μmol) in dichloromethane (1.0 mL). The mixture was stirred at room temperature for 16.0 h. The reaction was monitored by TLC until complete. Then, 2S,5S-2,5-dimethylpyrrolidine hydrochloride (7.09 mg, 52.29 μmol) and N,N-diisopropylethylamine (6.76 mg, 52.29 μmol) were added sequentially to the reaction mixture, and the mixture was stirred at room temperature for 6.0 h. After the reaction was completed, the reaction was quenched with water, extracted with dichloromethane, and the crude product obtained by organic phase concentration was purified by reversed-phase column chromatography (column: Waters XBridge Prep C18; 150 mm * 19 mm * 5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 50%-60%, time: 10 min, flow rate: 15 mL / min) to obtain compound 7 (2.6 mg, 2.84 μmol, yield: 22.45%).

[0909] MS(ESI + m / z = 916.26 [M+H] + .

[0910] 1 H NMR (400MHz, Methanol-d4) δ8.50(d,J=1.5Hz,1H),8.18(s,1H),8.06(d,J=9.4Hz,1H),7.76–7.68(m,2H),7.57(s,1H),7.51(d,J=8.6Hz,1H),7. 28(d,J=2.8Hz,1H),6.35(d,J=9.2Hz,1H),5.44–5.35(m,1H),4.48(q,J= 6.1Hz,1H),4.41–4.27(m,1H),4.26–4.08(m,3H),3.77–3.61(m,2H),3.4 6(d,J=12.9Hz,4H),3.39(s,3H),3.36(d,J=4.8Hz,2H),3.13(d,J=3.2H z,1H),2.80(s,3H),2.76–2.57(m,3H),2.53–2.39(m,4H),2.28–2.13(m, 3H),2.03(d,J=6.2Hz,1H),1.69–1.57(m,3H),1.54(d,J=6.1Hz,3H),1.3 9–1.32(m,3H),1.26–1.18(m,6H),0.97–0.91(m,3H),0.91–0.80(m,6H).

[0911] Example 8: Synthesis of Compound 8

[0912] Synthesis of compound 8-1 in step one

[0913] Compound 3-2 (300.0 mg, 296.74 μmol) was dissolved in isopropanol (20 mL), and then 10% palladium hydroxide / carbon (404.4 mg, 2.88 mmol) was added. The mixture was purged with hydrogen five times and stirred at 25 °C for 15 hours under a hydrogen atmosphere and at one atmosphere. The reaction was monitored by LC-MS until it was complete. The reaction solution was filtered, and the filtrate was concentrated to give compound 8-1 (213.7 mg, 243.61 μmol, yield: 82%).

[0914] MS(ESI + m / z = 877.4 [M+H] + .

[0915] The second step involves the synthesis of compound 8-2.

[0916] Compound 8-1 (7.8 mg, 8.89 μmol) and 3-oxetane (6.41 mg, 88.93 μmol) were added to isopropanol (3.0 mL), followed by one drop of acetic acid. Then, sodium cyanoborohydride (5.59 mg, 88.93 μmol) was added. The mixture was stirred at room temperature for 5.0 h, and the reaction was monitored by LC-MS until complete. The reaction was quenched with saturated ammonium chloride aqueous solution. The reaction solution was filtered, the filtrate was concentrated, and purified by reverse-phase chromatography (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound 8-2 (8.0 mg, 8.57 μmol, yield: 96.4%).

[0917] MS(ESI + m / z = 933.4 [M+H] + .

[0918] The third step involves the synthesis of compound 8-3.

[0919] Compound 8-2 (4.0 mg, 4.29 μmol) was dissolved in dichloromethane (0.9 mL), and then trifluoroacetic acid (0.3 mL) was added to the reaction solution. The mixture was stirred at 25 °C for 0.5 h. The reaction was monitored by LC-MS until complete. The reaction solution was concentrated to give compound 8-3 (3.57 mg, 4.29 μmol, yield: 100.0%). MS (ESI) + m / z = 833.4 [M+H] + .

[0920] Step 4: Synthesis of Compound 8

[0921] Compound 8-3 (3.57 mg, 4.29 μmol) and N,N-diisopropylethylamine (7.46 μL, 42.85 μmol) were added sequentially to a solution of intermediate Int-6 (1.96 mg, 12.86 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.89 mg, 12.86 μmol) in N,N-dimethylformamide (1.0 mL), and stirred at room temperature for 1.0 h. After the reaction, the compound was purified by reversed-phase column chromatography (Waters 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%-70%, time: 10 min, flow rate: 15 mL / min) to obtain compound 8 (2.0 mg, 2.01 μmol, yield: 46.83%). MS (ESI) + m / z = 967.2[M+H] + .

[0922] 1H NMR (400MHz, Methanol-d4) δ8.48(d,J=1.6Hz,1H),8.17(s,1H),8.05(d,J=9.3Hz,1 H),7.75–7.68(m,2H),7.59(s,1H),7.51(d,J=8.6Hz,1H),7.26(d,J=2.8Hz,1H),5.5 0(d,J=6.4Hz,1H),4.92(s,5H),4.75–4.64(m,4H),4.61–4.56(m,2H),4.49–4.42(m ,2H),4.39–4.28(m,1H),4.23–4.12(m,1H),3.73(d,J=10.8Hz,1H),3.65(d,J=11.0H z,1H),3.61–3.55(m,1H),3.46–3.41(m,5H),3.38(s,3H),3.36–3.32(m,3H),3.16– 3.11(m,1H),2.89–2.80(m,1H),2.76–2.64(m,2H),2.63–2.56(m,5H),2.51–2.41(m, 1H),2.24–2.18(m,1H),2.00(d,J=15.2Hz,2H),1.97–1.88(m,2H),1.65–1.59(m,1H) ,1.54(d,J=6.1Hz,3H),1.39–1.34(m,1H),0.94(t,J=7.0Hz,3H),0.92–0.84(m,3H).

[0923] Example 9: Synthesis of Compound 9

[0924] Synthesis of compound 9-1 (Step 1)

[0925] Compound Int-8 (101.0 mg, 183.9 μmol) was added to 1,4-dioxane (10.0 mL), followed by [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (13.5 mg, 18.4 μmol), compound 1-2 (181.6 mg, 257.4 μmol), potassium phosphate (78.0 mg, 367.7 μmol), and water (2.0 mL). The mixture was stirred at 65 °C under nitrogen protection for 2.0 h. After the reaction was complete, the crude product was purified by reverse-phase reaction (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound 9-1 (174.0 mg, 173.8 μmol, yield: 94.5%).

[0926] MS(ESI+)m / z=1001.4[M+H] + .

[0927] The second step involves the synthesis of compound 9-2.

[0928] Compound 9-1 (170.0 mg, 169.8 μmol) and cesium carbonate (276.6 mg, 849.0 μmol) were added to N,N-dimethylformamide (10.0 mL), and argon gas was purged. Iodethane (264.8 mg, 1.7 mmol) was added dropwise to the reaction mixture under an argon atmosphere, and the resulting mixture was stirred at 25 °C for 3.0 h. After the reaction was complete, the reaction mixture was slowly poured into ice water and stirred. Extraction was performed with ethyl acetate, and the organic phase was concentrated to obtain a crude product. The crude product was purified by reverse-phase chromatography (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound 9-2 (158.0 mg, 153.5 μmol, yield: 90.4%). MS (ESI+) m / z = 1029.4 [M+H] + .

[0929] The third step involves the synthesis of compound 9-3.

[0930] Compound 9-2 (43.0 mg, 41.8 μmol) was dissolved in methanol (5.0 mL). Pd(OH)₂ / C (20% loading, 45.6 mg) and paraformaldehyde (24.0 mg, 801 μmol) were added to the reaction solution. The mixture was then purged with hydrogen five times. The mixture was stirred at 25 °C for 5 hours under one atmosphere of pressure. The reaction was monitored by LC-MS to ensure complete reaction. The crude product was purified by reversed-phase column chromatography (water / NH₄OH (0.5%):MeCN = 95:5 to 5:95) to give compound 9-3 (35.4 mg, 38.9 μmol, yield: 93.2%).

[0931] MS(ESI + m / z = 909.4 [M+H] + .

[0932] Step 4: Synthesis of compound 9-4

[0933] Compound 9-3 (12.0 mg, 13.2 μmol) was dissolved in dichloromethane (0.3 mL). Under nitrogen protection, 4 M dioxane hydrochloride solution (1.5 mL) was added to the reaction solution. The mixture was stirred at 25 °C for 0.5 hours. The reaction was monitored by LC-MS until it was complete. The solution was concentrated by rotary evaporation to obtain compound 9-4 (10.6 mg, 13.2 μmol, yield: 100.0%).

[0934] MS(ESI + m / z = 809.3 [M+H] + .

[0935] Step 5: Synthesis of compounds 9-P1 and 9-P2

[0936] Compound 9-4 (10.6 mg, 13.2 μmol) and N,N-diisopropylethylamine (13.8 μL, 79.2 μmol) were added sequentially to a solution of intermediate Int-6 (6.0 mg, 39.6 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (15.1 mg, 39.6 μmol) in N,N-dimethylformamide (1.0 mL), and stirred at room temperature for 1.0 h. After the reaction was completed, the product was purified by reversed-phase column chromatography (Waters 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 70%-90%, time: 13 min, flow rate: 20 mL / min) to obtain compound 9-P1 (3.5 mg, 3.71 μmol, yield: 28.1%, retention time: 6.48 min) and compound 9-P2 (3.3 mg, 3.5 μmol, yield: 26.5%, retention time: 8.33 min).

[0937] Compound 9-P1 MS (ESI) + m / z = 943.3 [M+H] + .

[0938] 11H NMR (400 MHz, Methanol-d4) δ 8.50 (d, J = 6.6 Hz, 2H), 8.03 (d, J = 9.0 Hz, 1H), 7.77–7.70 (m, 2H), 7.61 (s, 1H), 7.51 (d, J = 8.6 Hz, 1H), 5.40 (d, J = 4.9 Hz, 1H), 5.34 (t, J = 4.7 Hz, 1H), 4.70–4.63 (m, 1H), 4.62–4.55 (m, 2H), 4.54–4.39 (m, 2H), 4.27 (q, J = 6.4 Hz, 1H), 4.22–4.09 (m, 1H), 3.72 (d, J = 6.0 Hz, 3H), 3.48 (s, 4H), 3.07–2.96 (m, 4H), 2.91–2.69 (m, 3H), 2.63 (s, 4H), 2.52–2.44 (m, 1H), 2.35–2.28 (m, 1H), 2.21–2.16 (m, 2H), 2.10–1.90 (m, 8H), 1.83–1.66 (m, 2H), 1.65–1.52 (m, 2H), 1.48–1.41 (m, 1H), 1.38–1.36 (m, 3H), 0.95 (s, 3H), 0.92–0.86 (m, 4H).

[0939] Compound 9-P2 MS (ESI + ) m / z = 943.3 [M+H] + .

[0940] 1H NMR(400MHz, Methanol-d4)δ8.50(d,J=1.6Hz,1H),8.38(s,1H),8.02–7.96(m ,1H),7.76–7.69(m,2H),7.60(s,1H),7.56–7.51(m,1H),5.50(d,J=6.4Hz,1H) ,4.69–4.60(m,1H),4.59–4.56(m,2H),4.52–4.45(m,2H),4.44–4.28(m,1H),4 .20–4.09(m,1H),3.76–3.63(m,2H),3.49–3.44(m,1H),3.43–3.38(m,5H),3.3 7(s,3H),3.15–3.10(m,1H),2.89–2.83(m,1H),2.83–2.77(m,3H),2.73(q,J= 5.8Hz,1H),2.69–2.55(m,2H),2.47(s,3H),2.23–2.18(m,1H),2.13–1.94(m,4 H),1.93(s,1H),1.92–1.74(m,1H),1.65–1.60(m,1H),1.54(d,J=6.2Hz,3H),1 .39–1.35(m,3H),1.34–1.31(m,2H),0.95(t,J=7.1Hz,3H),0.91–0.84(m,5H).

[0941] Example 10 Synthesis of compounds 10-P1 and 10-P2

[0942] Synthesis of compound 10-1 in the first step

[0943] At room temperature, trifluoroacetic acid (72.3 mg, 633.76 μmol, 48.8 μL) and N-iodosuccinimide (784.2 mg, 3.49 mmol) were added sequentially to a dichloromethane (5 mL) solution of compound 2-7 (1.5 g, 3.17 mmol). The mixture was heated to 40 °C and stirred for 4 hours. After the reaction solution cooled to room temperature, it was added dropwise to a saturated sodium bicarbonate solution (20 mL), followed by the addition of water (20 mL) and extraction with ethyl acetate (100 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:00-70:30) to give compound 10-1 (1.40 g, 2.34 mmol, yield: 74%).

[0944] MS(ESI + m / z = 599.0 [M+H] + .

[0945] The second step involves the synthesis of compound 10-2.

[0946] At room temperature, cuprous cyanide (56.2 mg, 627.51 μmol) was added to a pyridine (2 mL) solution of compound 10⁻¹ (300.0 mg, 500.62 μmol), and the mixture was heated to 100 °C and stirred for 8 hours. After the reaction was complete, the reaction solution was directly evaporated to dryness, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 80:20-50:50) to give compound 10⁻² (180.0 mg, 361.18 μmol, yield: 72%).

[0947] MS(ESI + m / z = 498.0 [M+H] + .

[0948] The third step involves the synthesis of compound 10⁻³.

[0949] Under argon protection, compound 10⁻² (108.8 mg, 218.23 μmol), compound 1-2 (140.0 mg, 198.39 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (29.03 mg, 39.68 μmol), and potassium carbonate (82.26 mg, 595.18 μmol) were added sequentially to dioxane (4 mL) and water (1 mL). The mixture was heated to 70 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was poured into water (20 mL), extracted with ethyl acetate (30 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:00-40:60) to give compound 10⁻³ (110.0 mg, 110.31 μmol, yield: 55%).

[0950] MS(ESI + m / z = 997.4 [M+H] + .

[0951] Step 4: Synthesis of compound 10⁻⁴

[0952] At room temperature, cesium carbonate (98.0 mg, 300.85 μmol) and iodoethane (31.3 mg, 200.57 μmol, 16.0 μL) were added sequentially to a solution of compound 10⁻³ (110.0 mg, 110.31 μmol) in N,N-dimethylformamide (5 mL). The mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was poured into water (20 mL), extracted with ethyl acetate (20 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:00-50:50) to give compound 10⁻⁴ (100.0 mg, 97.54 μmol, yield: 88%).

[0953] MS(ESI + m / z = 1025.5 [M+H] + .

[0954] Step 5: Synthesis of compound 10⁻⁵

[0955] Under nitrogen protection, palladium hydroxide / carbon (137.0 mg, 975.40 μmol) was added to a solution of compound 10⁻⁴ (100.0 mg, 97.54 μmol) in isopropanol (5 mL). The mixture was then purged three times with hydrogen. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the residue was washed with isopropanol (10 mL x 5). The filtrate was concentrated to give compound 10⁻⁵ (80.0 mg, 89.78 μmol, yield: 92%).

[0956] MS(ESI + m / z = 891.4 [M+H] + .

[0957] Step 6: Synthesis of compound 10⁻⁶

[0958] At room temperature, 3-oxetane (12.9 mg, 179.56 μmol, 11.6 μL) and acetic acid (16.2 mg, 269.33 μmol) were added sequentially to a solution of compound 10⁻⁵ (80.0 mg, 89.78 μmol) in isopropanol (5 mL). The mixture was stirred at room temperature for 15 minutes, followed by the addition of sodium cyanoborohydride (11.3 mg, 179.56 μmol), and the mixture was stirred for another hour at room temperature. After the reaction was complete, the reaction solution was poured into a saturated sodium bicarbonate solution (20 mL), extracted with dichloromethane (20 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (dichloromethane:methanol = 100:00-95:5) to give compound 10⁻⁶ (60.0 mg, 63.35 μmol, yield: 71%).

[0959] MS(ESI + m / z = 947.5 [M+H] + .

[0960] Step 7: Synthesis of compound 10-7

[0961] Under nitrogen protection, trifluoroacetic acid (0.2 mL) was added dropwise to a solution of compound 10⁻⁶ (60 mg, 63.35 μmol) in dichloromethane (2 mL). The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was poured into a saturated sodium bicarbonate solution (50 mL), extracted with dichloromethane (20 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 10⁻⁷ (50.0 mg, 59.03 μmol, yield: 93%). MS (ESI) + m / z = 847.5 [M+H] + .

[0962] Step 8: Synthesis of compounds 10-P1 and 10-P2

[0963] At room temperature, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (67.3 mg, 177.09 μmol) and N,N-diisopropylethylamine (76.3 mg, 590.29 μmol, 102.82 μL) were added to a solution of (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (13.5 mg, 118.06 μmol) in N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 20 minutes, and then compound 10-7 (50 mg, 59.03 μmol) was added. The mixture was stirred at room temperature for another hour. After the reaction was completed, water (10 mL) was added to the reaction solution, and ethyl acetate (10 mL × 3) was used for extraction. The organic phases were combined, concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (column: Waters XBridge Prep C18; 150 mm × 19 mm × 5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 55%-70%, time: 10 min, flow rate: 15 mL / min) to obtain compound 10-P1 (6.0 mg, 6.04 μmol, yield: 10%, retention time: 6.43 min) and compound 10-P2 (4.0 mg, 4.03 μmol, yield: 7%, retention time: 7.23 min).

[0964] Compound 10-P1 MS (ESI) + m / z = 943.3 [M+H] + .

[0965] 1 1H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 1H), 8.47 (d, J = 1.6 Hz, 1H), 7.73 (dd, J = 8.7, 1.6 Hz, 1H), 7.59 (s, 1H), 7.51 (d, J = 8.7 Hz, 1H), 5.46–5.40 (m, 1H), 5.12–5.01 (m, 1H), 4.80 (t, J = 6.8 Hz, 2H), 4.77 (s, 1H), 4.72 (t, J = 6.5 Hz, 2H), 4.70–4.64 (m, 1H), 4.22–4.09 (m, 2H), 3.79–3.66 (m, 3H), 3.44–3.37 (m, 1H), 3.28–3.26 (m, 1H), 3.25 (s, 3H), 3.24–3.22 (m, 1H), 2.79–2.73 (m, 1H), 2.67–2.52 (m, 4H), 2.51–2.43 (m, 2H), 2.42–2.33 (m, 2H), 2.33–2.27 (m, 1H), 2.23–2.16 (m, 1H), 1.73–1.66 (m, 1H), 1.49–1.42 (m, 1H), 1.41–1.35 (m, 1H), 1.33–1.30 (m, 3H), 1.28–1.25 (m, 3H), 1.21–1.17 (m, 4H), 1.16–1.13 (m, 3H), 0.96 (s, 3H), 0.63 (s, 3H), 0.10–0.10 (m, 3H). Compound 10-P2 MS (ESI + ) m / z = 943.3 [M+H] + .

[0966] 1H NMR (400MHz, Methanol-d4) δ8.48(s,1H),8.41(s,1H),7.72(dd,J=8.6,1.7H z,1H),7.58(s,1H),7.53(d,J=8.7Hz,1H),5.61–5.50(m,1H),5.07–4.97(m,1 H),4.80–4.74(m,2H),4.73–4.68(m,2H),4.68–4.62(m,2H),4.49–4.42(m,1 H),4.37–4.30(m,1H),4.13–4.05(m,1H),3.74(d,J=10.9Hz,1H),3.66(d,J=1 0.7Hz,1H),3.46–3.39(m,1H),3.27–3.24(m,1H),2.73–2.68(m,1H),2.66–2 .51(m,4H),2.48–2.40(m,2H),2.40–2.30(m,3H),2.24–2.16(m,1H),1.62–1. 57(m,1H),1.54(d,J=6.2Hz,3H),1.49–1.32(m,4H),1.19–1.15(m,4H),1.15– 1.12(m,3H),1.00–0.95(m,3H),0.89(s,3H),0.44(s,3H),0.11–0.09(m,6H).

[0967] Example 11 Synthesis of compounds 11-P1, 11-P2, 11-P3, and 11-P4

[0968] Synthesis of compound 11-1 in step one

[0969] At -5°C, 1,1'-thiocarbonylbis(pyridin-2(1H)-one) (11.6 mg, 50.06 μmol) was slowly added to a solution of compound 1-6 (36.0 mg, 45.51 μmol) and N,N-diisopropylethylamine (11.7 mg, 91.02 μmol) in dichloromethane (2 mL). The mixture was reacted at -5°C for 5 minutes. The reaction solution was concentrated, and the residue was purified by column chromatography (dichloromethane:methanol = 100:0-90:10) to give compound 11-1 (36.0 mg, 43.2 μmol, yield:

[0970] 95%.

[0971] MS m / z (ESI): 833.3 [M+H] + .

[0972] The second step involves the synthesis of compound 11-2.

[0973] Under nitrogen protection, compound 11-1 (36.0 mg, 43.2 mmol) and compound Int-9 (15.9 mg, 96.03 μmol) were dissolved in acetonitrile (2 mL). The mixture was reacted at 90 °C for 15 min. The reaction solution was concentrated, and the residue was purified by column chromatography (dichloromethane:methanol = 100:0-90:10) to give compound 11-2 (20.0 mg, 20.02 μmol, yield: 42%).

[0974] MS(ESI + m / z = 999.4 [M+H] + .

[0975] The third step involves the synthesis of compounds 11-P1, 11-P2, 11-P3, and 11-P4.

[0976] Compound 11-2 (20.0 mg, 20.02 μmol) was dissolved in acetonitrile (2 mL), followed by the addition of triphenylphosphine (10.5 mg, 40.03 μmol), N,N-diisopropylethylamine (20.7 mg, 160.12 μmol), and hexachloroethane (9.48 mg, 40.03 μmol). The mixture was reacted at room temperature for 5 hours. After the reaction was complete, water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (10 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (Waters XBridge Prep column). C18; 150 mm * 19 mm * 5 μm; Mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%; Mobile phase B: MeCN; MeCN ratio 55%-75%, time: 13 min, flow rate: 15 mL / min) yielded compounds 11-P1 (2.0 mg, 2.07 μmol, yield: 10.2%, retention time: 6.92 min), 11-P2 (2.6 mg, 2.7 μmol, yield: 13.4%, retention time: 8.27 min), 11-P3 (1.6 mg, 1.6 μmol, yield: 7.9%, retention time: 7.57 min), and 11-P4 (3.0 mg, 3.05 μmol, yield: 15.1%, retention time: 8.97 min).

[0977] Compound 11-P1 MS (ESI) + m / z = 965.4 [M+H] + .

[0978] 11H NMR (400 MHz, Methanol-d4) δ 8.50 (d, J = 1.6 Hz, 1H), 8.32 (s, 1H), 8.14 (d, J = 9.3 Hz, 1H), 7.89 (s, 1H), 7.80–7.70 (m, 2H), 7.60 (s, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.38–7.34 (m, 1H), 5.21–5.17 (m, 1H), 4.83–4.79 (m, 1H), 4.72–4.67 (m, 1H), 4.65–4.57 (m, 2H), 4.55–4.45 (m, 2H), 4.43–4.37 (m, 1H), 4.30–4.23 (m, 1H), 4.21–4.08 (m, 2H), 3.79–3.67 (m, 3H), 3.60–3.54 (m, 2H), 3.53–3.49 (m, 1H), 3.26–3.24 (m, 2H), 2.88–2.74 (m, 4H), 2.71–2.61 (m, 2H), 2.52–2.46 (m, 1H), 2.38–2.33 (m, 1H), 2.26–2.08 (m, 5H), 2.05–2.00 (m, 1H), 1.74 (t, J = 9.5 Hz, 1H), 1.63–1.57 (m, 1H), 1.38–1.20 (m, 10H), 0.95 (s, 2H), 0.92–0.88 (m, 2H), 0.60 (s, 3H).

[0979] Compound 11-P2 MS (ESI + ) m / z = 965.4 [M+H] + .

[0980] 11H NMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 8.19 (s, 1H), 8.07 (d, J = 9.4 Hz, 1H), 7.77–7.69 (m, 3H), 7.59 (s, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.30 (d, J = 2.7 Hz, 1H), 5.36–5.32 (m, 1H), 5.31–5.28 (m, 1H), 4.73–4.66 (m, 1H), 4.59–4.51 (m, 1H), 4.51–4.43 (m, 2H), 4.42–4.31 (m, 1H), 4.23–4.13 (m, 1H), 3.78–3.72 (m, 1H), 3.71–3.63 (m, 1H), 3.53–3.51 (m, 1H), 3.38–3.38 (m, 3H), 2.97–2.88 (m, 4H), 2.75–2.72 (m, 1H), 2.66–2.61 (m, 1H), 2.59–2.53 (m, 3H), 2.50–2.46 (m, 1H), 2.26–2.22 (m, 1H), 2.21–2.16 (m, 2H), 2.15–2.07 (m, 3H), 2.05–2.00 (m, 2H), 1.69–1.63 (m, 1H), 1.62–1.57 (m, 1H), 1.5(4 d, J = 6.2 Hz, 3H), 0.99–0.92 (m, 4H), 0.92–0.83 (m, 8H), 0.43 (s, 3H).

[0981] Compound 11-P3 MS (ESI + ) m / z = 981.4 [M+H] + .

[0982] 11H NMR (400 MHz, Methanol-d4) δ 8.50 (d, J = 1.6 Hz, 1H), 8.32 (s, 1H), 8.11 (d, J = 9.4 Hz, 1H), 7.79–7.69 (m, 2H), 7.59 (s, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 2.7 Hz, 1H), 5.41–5.35 (m, 1H), 4.82 (s, 1H), 4.72–4.65 (m, 1H), 4.61 (s, 1H), 4.59–4.52 (m, 1H), 4.51–4.41 (m, 2H), 4.39–4.31 (m, 1H), 4.28–4.22 (m, 1H), 4.18–4.10 (m, 1H), 3.76–3.69 (m, 2H), 3.58–3.49 (m, 3H), 3.44–3.38 (m, 1H), 3.28–3.22 (m, 2H), 3.11–2.96 (m, 4H), 2.81–2.74 (m, 1H), 2.69–2.59 (m, 3H), 2.53–2.46 (m, 1H), 2.35 (d, J = 14.3 Hz, 1H), 2.27–1.99 (m, 6H), 1.73 (t, J = 9.5 Hz, 1H), 1.64–1.56 (m, 1H), 1.37–1.16 (m, 10H), 0.95 (s, 2H), 0.92–0.82 (m, 2H), 0.60 (s, 3H).

[0983] Compound 11-P4 MS (ESI + ) m / z = 981.4 [M+H] + .

[0984] 1H NMR (400MHz, Methanol-d4) δ8.50 (s, 1H), 8.20 (s, 1H), 8.08 (d, J = 9.4Hz, 1H), 7.77–7.68(m,3H),7.59(s,1H),7.52(d,J=8.7Hz,1H),7.31(d,J=2.6Hz,1H),5 .47(d,J=7.3Hz,1H),5.36–5.32(m,1H),4.71–4.66(m,1H),4.61(s,2H),4.56– 4.52(m,1H),4.50–4.47(m,1H),4.46–4.40(m,2H),4.36–4.28(m,3H),4.22–4. 14(m,2H),3.85–3.79(m,1H),3.70–3.66(m,1H),3.56–3.50(m,4H),3.39–3.3 8(m,2H),3.07–2.99(m,4H),2.76–2.72(m,1H),2.67–2.60(m,4H),2.52–2.45( m,2H),2.26–2.23(m,1H),2.21–2.17(m,2H),2.15–2.08(m,3H),2.05–2.01(m, 2H),1.69–1.64(m,1H),1.55(d,J=6.2Hz,2H),0.95–0.87(m,6H),0.43(s,3H).

[0985] Example 12 Synthesis of Compound 12

[0986] Referring to Example 11, compounds 1-6 were replaced with compound Int-10 to prepare (chromatographic column: Waters XBridge Prep C18; 150 mm * 19 mm * 5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 50%-75%, time: 13 min, flow rate: 15 mL / min, retention time: 7.11 min) to obtain compound 12, which has lower polarity.

[0987] MS(ESI + m / z = 979.4 [M+H] + .

[0988] 1H NMR (400MHz, DMSO-d6) δ8.52(s,1H),8.48(s,1H),8.13(d,J=9.6Hz,1H),7.87(s,1H),7.79(dd,J=8.8,1.7Hz,1H),7.61(d,J=8.7Hz,1H),6.0 5(d,J=11.0Hz,1H),5.10(t,J=8.8Hz,1H),4.73(d,J=10.9Hz,1H),4.61–4.54(m,1H),4.54–4.42(m,4H),4.42–4.26(m,4H),4.05–3.91(m,1H) ),3.67–3.61(m,1H),3.59–3.52(m,1H),3.26–3.21(m,4H),3.17–3.11 (m,1H),2.99–2.91(m,1H),2.83–2.72(m,1H),2.66–2.60(m,1H),2.44 –2.34(m,2H),2.22–2.14(m,1H),2.13–1.93(m,5H),1.69–1.62(m,1H) ,1.47–1.38(m,4H),1.32–1.13(m,6H),0.95–0.81(m,8H),0.31(s,3H).

[0989] Example 13 Synthesis of Compound 13

[0990] Referring to Example 11, compounds 1-6 were replaced with intermediates 10-7 to prepare (chromatographic column: Waters XBridge Prep C18; 150 mm * 19 mm * 5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 55%-75%, time: 13 min, flow rate: 15 mL / min, retention time: 7.35 min) to obtain compound 13, which has lower polarity.

[0991] MS(ESI + m / z = 1021.4 [M+H] + .

[0992] 1H NMR (400MHz, CD3OD) δ8.42(d,J=1.7Hz,1H),8.29(s,1H),7.64(dd,J=8.6,1.7Hz,1H),7.49(s,1H),7.43(d,J=8.5Hz,1H),5. 23–5.19(m,1H),4.66–4.54(m,6H),4.53–4.40(m,7H),4.39–4.33(m,2H),4.32–4.18(m,2H),4.07–3.96(m,1H),3.71–3.64(m ,1H),3.63–3.51(m,2H),3.43–3.39(m,1H),3.08–3.00(m,1H),2.99–2.90(m,2H),2.66–2.60(m,1H),2.58–2.48(m,2H),2.48 –2.33(m,3H),2.26–1.94(m,12H),1.60–1.52(m,1H),1.44(d,J=6.1Hz,3H),0.87(t,J=7.0Hz,3H),0.81(s,3H),0.35(s,3H).

[0993] Example 14 Synthesis of Compound 14

[0994] Referring to Example 11, compounds 1-6 were replaced with intermediates 9-4 to prepare (chromatographic column: Waters XBridge Prep C18; 150 mm * 19 mm * 5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 55%-75%, time: 13 min, flow rate: 15 mL / min, retention time: 7.25 min) to obtain compound 14, which has lower polarity.

[0995] MS(ESI + m / z = 983.4 [M+H] + .

[0996] 1H NMR (400MHz, CD3OD) δ8.52(s,1H),8.38(s,1H),7.98(d,J=9.2Hz,1H),7.77–7.71(m,2H),7.59(s,1H),7.53(d,J=8.6Hz,1H),4.74 –4.65(m,1H),4.57–4.55(m,1H),4.54–4.43(m,2H),4.43–4.31(m,1H),4.14(dd,J=16.1,8.2Hz,1H),3.80–3.64(m,4H),3.42–3.4 0(m,2H),3.37–3.36(m,3H),3.23–3.19(m,3H),2.76–2.73(m,3H),2.66–2.61(m,1H),2.51–2.45(m,1H),2.20–2.17(m,5H),2.04– 2.02(m,5H),1.62–1.58(m,4H),1.55(d,J=6.3Hz,3H),1.38–1.37(m,3H),1.36–1.36(m,3H),0.93–0.91(m,3H),0.91–0.89(m,5H).

[0997] Example 15 Synthesis of Compound 15

[0998] Referring to Example 11, compounds 1-6 were replaced with intermediates 9-4 to prepare (chromatographic column: Waters XBridge Prep C18; 150 mm * 19 mm * 5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 55%-75%, time: 13 min, flow rate: 15 mL / min, retention time: 7.62 min) to obtain compound 15, which has lower polarity.

[0999] MS(ESI + m / z = 999.4 [M+H] + .

[1000] 1H NMR (400MHz, CD3OD) δ8.53(d,J=1.5Hz,1H),8.37(s,1H),7.98(d,J=9.2Hz,1H),7.78–7.70(m,2H),7.59(s,1H),7.53(d,J=8. 6Hz,1H),5.55–5.46(m,1H),4.56–4.30(m,4H),4.21–4.06(m,1H),3.79–3.63(m,3H),3.51–3.46(m,2H),3.39–3.37(m,3H),3. 21–3.16(m,1H),2.72–2.68(m,4H),2.65–2.58(m,1H),2.52–2.44(m,1H),2.28–2.22(m,1H),2.21–2.16(m,5H),2.14–2.10(m, 1H),2.05–2.01(m,6H),1.62–1.58(m,3H),1.55(d,J=6.1Hz,3H),1.37–1.35(m,5H),0.96(t,J=7.0Hz,3H),0.90–0.88(m,6H).

[1001] Example 16 Synthesis of Compound 16

[1002] Referring to Example 9, the intermediate Int-6 is replaced with the intermediate... After preparation (using a Boston Prime C18 column; 150*30 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%; mobile phase B: MeCN; MeCN ratio 65%-90%, flow rate 20.0 mL / min, duration 15.0 min), compound 16-P1 (retention time 7.54 min) and compound 16 (retention time 8.11 min) were obtained. Compound 16 was analyzed by MS (ESI). + m / z = 906.5[M+H] + .

[1003] 1H NMR(400MHz,DMSO)δ8.46(d,J=1.6Hz,1H),8.40(d,J=8.8Hz,1H),8.28(s,1H), 7.92(d,J=9.2Hz,1H),7.83(s,1H),7.79–7.69(m,2H),7.60(d,J=8.7Hz,1H),5. 93(d,J=11.1Hz,1H),5.39(t,J=8.1Hz,1H),4.67(d,J=11.0Hz,1H),4.49(q,J=4 .9Hz,1H),4.44–4.30(m,2H),4.17–4.00(m,1H),3.68–3.39(m,5H),3.25(s,3H) ,3.20–3.10(m,1H),2.96(d,J=14.4Hz,1H),2.71–2.66(m,1H),2.66–2.58(m,3H ),2.57–2.53(m,1H),2.48–2.43(m,1H),2.33(d,J=5.8Hz,4H),2.15(t,J=9.8Hz ,1H),2.06–1.88(m,1H),1.57(t,J=9.3Hz,1H),1.46(d,J=6.1Hz,3H),1.34–1.2 2(m,5H),1.22–1.12(m,3H),1.11–1.04(m,6H),0.93–0.86(m,3H),0.83(s,3H).

[1004] Example 17 Synthesis of Compound 17

[1005] Referring to Example 10, the intermediate in step six... Compound 17-1 was prepared by replacing paraformaldehyde, and then prepared according to steps 7-8 of Example 10 (chromatographic column: Waters XBridge Prep C18; 150 mm * 19 mm * 5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 50%-75%, time: 13 min, flow rate: 15 mL / min, retention time: 9.02 min) to obtain compound 17, which has lower polarity.

[1006] MS(ESI + m / z = 901.4[M+H] + .

[1007] 1H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.45–8.40(m,2H),7.83(s,1H),7.79– 7.74(m,1H),7.60(d,J=8.7Hz,1H),5.95(d,J=11.0Hz,1H),5.41–5.31(m,1 H),4.84–4.74(m,1H),4.67(d,J=11.1Hz,1H),4.51–4.44(m,1H),4.39–4.2 6(m,2H),4.07–3.94(m,1H),3.61(d,J=10.8Hz,1H),3.53(d,J=10.9Hz,1H) ,3.29–3.24(m,1H),3.22(s,3H),3.18–3.10(m,1H),3.02–2.88(m,3H),2.6 6–2.59(m,1H),2.57–2.53(m,1H),2.34–2.29(m,2H),2.29–2.23(m,4H),2. 23–2.11(m,6H),2.03–1.94(m,1H),1.58(t,J=9.3Hz,1H),1.43(d,J=6.0Hz ,3H),1.19–1.14(m,2H),1.11–1.05(m,6H),0.91–0.84(m,6H),0.31(s,3H).

[1008] Example 18 Synthesis of Compound 18

[1009] Referring to Example 10, the intermediate in step six... 17-1 was prepared by replacing paraformaldehyde with it, while the intermediate was also prepared. The intermediate Int-6 was replaced to prepare (the column was a Waters XBridge Prep C18; 150 mm * 19 mm * 5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration was 0.05%; mobile phase B: MeCN; MeCN ratio 55%-75%, time: 13 min, flow rate: 15 mL / min, retention time: 7.31 min) to obtain compound 18, which has lower polarity.

[1010] MS(ESI + m / z = 939.4 [M+H] + .

[1011] 1H NMR (400MHz, DMSO-d6) δ8.62(d,J=8.4Hz,1H),8.50–8.42(m,2H),7.87(s,1H),7.81–7.73(m,1H),7.60(d,J=8.7Hz,1H),5.96(d, J=11.0Hz,1H),5.33–5.25(m,1H),4.83–4.70(m,2H),4.62–4.47(m,3H),4.45–4.31(m,3H),4.08–3.96(m,1H),3.67–3.48(m,2H), 3.29–3.27(m,2H),3.25(s,3H),3.24–3.19(m,2H),3.01–2.96(m,2H),2.66–2.59(m,3H),2.33–2.29(m,2H),2.29–2.24(m,4H),2 .24–2.10(m,6H),2.02–1.96(m,1H),1.94–1.77(m,3H),1.68–1.60(m,1H),1.44(d,J=6.1Hz,3H),0.90–0.85(m,6H),0.29(s,3H).

[1012] Example 19 Synthesis of Compound 19

[1013] Referring to step six of Example 10, the intermediate is... Replace with After the mixture was heated to 55°C and reacted for another 24 hours, intermediate 19-1 was prepared. Then, through similar steps in steps seven and eight, compound 19 with lower polarity was obtained. (Chromatographic column: Waters XBridge Prep C18; 150 mm * 19 mm * 5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 65%-85%; time: 13 min; flow rate: 15 mL / min; retention time: 7.80 min)

[1014] MS(ESI + m / z = 927.4 [M+H] + .

[1015] 1H NMR (400MHz, DMSO-d6) δ8.50(s,1H),8.47(d,J=1.5Hz,1H),8.44(d,J=8.8H z,1H),7.85(s,1H),7.78(dd,J=8.6,1.6Hz,1H),7.62(d,J=8.7Hz,1H),5.96 (d,J=11.1Hz,1H),5.40(t,J=8.2Hz,1H),4.92–4.80(m,1H),4.69(d,J=11.0 Hz,1H),4.54–4.47(m,1H),4.41–4.30(m,2H),4.08–3.97(m,1H),3.66–3.56 (m,2H),3.31–3.28(m,1H),3.24(s,3H),3.20–3.14(m,3H),2.99–2.92(m,1H ),2.68–2.62(m,1H),2.36–2.27(m,2H),2.27–2.15(m,5H),1.79–1.73(m,1H ),1.64–1.58(m,1H),1.45(d,J=6.1Hz,3H),1.13–1.07(m,6H),1.05–1.00(m ,3H),0.95–0.83(m,9H),0.52–0.47(m,2H),0.43–0.39(m,2H),0.34(s,3H).

[1016] Example 20 Synthesis of Compound 20

[1017] Referring to Example 1, intermediate Int-4 was replaced with intermediate Int-11 to prepare (chromatographic column: Waters XBridge Prep C18; 150 mm * 19 mm * 5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 55%-75%, time: 13 min, flow rate: 15 mL / min, retention time: 7.17 min) to obtain compound 20 with lower polarity.

[1018] MS(ESI + m / z = 912.4[M+H] + .

[1019] 1H NMR (400MHz, DMSO-d6) δ8.42–8.38(m,1H),8.35(d,J=9.0Hz,1H),8.16(d,J=9 .5Hz,1H),8.04(s,1H),7.77(s,1H),7.72(d,J=8.1Hz,1H),7.69(d,J=9.7Hz, 1H),7.55(d,J=8.7Hz,1H),5.86(d,J=10.9Hz,1H),5.35–5.28(m,1H),5.26(t ,J=4.9Hz,2H),4.61(d,J=11.0Hz,1H),4.44–4.39(m,1H),4.38–4.33(m,1H), 4.33–4.25(m,1H),4.03–3.98(m,1H),3.54–3.52(m,4H),3.49–3.44(m,2H),3 .19(s,4H),3.12–3.04(m,2H),2.95–2.88(m,1H),2.57–2.54(m,3H),2.22–2. 19(m,3H),2.12–2.04(m,1H),1.98–1.86(m,6H),1.40(d,3H),1.03(d,J=6.1H z,3H),1.01–0.98(m,3H),0.83–0.80(m,3H),0.80–0.78(m,3H),0.23(s,3H).

[1020] Example 21 Synthesis of Compound 21

[1021] Referring to Example 9, intermediate Int-8 was replaced with intermediate Int-11 to prepare (chromatographic column: Waters XBridge Prep C18; 150 mm * 19 mm * 5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 55%-75%; time: 13 min; flow rate: 15 mL / min; retention time: 7.32 min) to obtain compound 21 with lower polarity.

[1022] MS(ESI + m / z = 950.4 [M+H] + .

[1023] 1H NMR (400MHz, DMSO-d6) δ8.64(d,J=8.4Hz,1H),8.50–8.44(m,1H),8.25(d,J=9.8Hz,1H),8.11(s,1H),7.89(s,1H),7.83–7.74(m,2H),7.63(d,J= 8.7Hz,1H),5.96(d,J=11.1Hz,1H),5.37–5.22(m,1H),4.75(d,J=11.1H z,1H),4.64–4.46(m,4H),4.46–4.38(m,3H),4.17–4.03(m,1H),3.69–3. 56(m,4H),3.55–3.48(m,2H),3.31–3.29(m,4H),3.29–3.27(m,3H),3.2 6–3.21(m,2H),3.08–2.98(m,1H),2.66–2.62(m,2H),2.36–2.34(m,1H), 2.21–2.12(m,1H),2.04–1.92(m,2H),1.91–1.78(m,3H),1.68–1.58(m, 1H), 1.46 (d, J = 6.1Hz, 3H), 1.24 (s, 3H), 0.89–0.84 (m, 6H), 0.27 (s, 3H).

[1024] Example 22 Synthesis of Compound 22

[1025] Referring to Example 1, intermediate Int-4 was replaced with intermediate Int-13, and the final step was not split, to prepare compound 22 (a mixture of two isomers).

[1026] MS(ESI + m / z = 960.4 [M+H] + .

[1027] 1H NMR (400MHz, DMSO-d6) δ8.60 (s, 1H), 8.44 (d, J = 15.2Hz, 2H), 8.25 (dd, J = 4.3 ,1.8Hz,1H),8.10(dd,J=8.8,4.7Hz,1H),7.84(q,J=3.3,2.8Hz,2H),7.78–7. 74(m,1H),7.59(dd,J=15.4,8.6Hz,1H),5.92(t,J=11.4Hz,2H),5.35(d,J=2 5.4Hz, 2H), 4.70 (dd, J=27.0, 11.0Hz, 2H), 4.54–4.31 (m, 4H), 4.06 (dq, J=19. 9,6.5Hz,3H),3.79(s,4H),3.65–3.49(m,4H),3.26(s,2H),3.11(s,3H),2.9 7(t,J=6.8Hz,1H),2.16(d,J=9.6Hz,1H),2.02–1.96(m,1H),1.65–1.56(m,2H ),1.48(d,J=6.1Hz,2H),1.29(s,2H),1.17(d,J=3.8Hz,2H),1.13(s,1H),1.1 1–1.07(m,4H),0.95(d,J=6.5Hz,3H),0.87(s,3H),0.49(s,2H),0.29(s,2H).

[1028] Example 23 Synthesis of Compound 23

[1029] Referring to Example 1, intermediate Int-4 was replaced with intermediate Int-14, and the final step was not split, to prepare compound 23 (a mixture of two isomers).

[1030] MS(ESI + m / z = 933.4 [M+H] + .

[1031] 1H NMR (400MHz, DMSO-d6) δ8.61(s,1H),8.47(d,J=11.7Hz,2H),8.42(d,J=7.8Hz,1H),8.32(dd,J=5.9,1.9Hz,1H),8.12(dd,J=8.7,4.4Hz,1H),7 .89–7.83(m,2H),7.79–7.74(m,1H),7.62–7.55(m,1H),5.92(t,J=11.7 Hz,2H),5.42–5.30(m,2H),4.70(dd,J=29.7,11.1Hz,2H),4.54–4.34(m ,4H),4.07(dq,J=21.5,6.9,6.5Hz,3H),3.79–3.71(m,1H),3.67–3.52 (m,3H),3.26(s,2H),3.22(d,J=1.3Hz,3H),3.11(s,2H),2.14(d,J=10. 1Hz,1H),2.03–1.96(m,1H),1.64–1.56(m,2H),1.48(d,J=6.1Hz,2H),1 .30(s,2H),1.21–1.07(m,12H),0.81(s,2H),0.49(s,2H),0.28(s,2H).

[1032] Example 24 Synthesis of Compound 24

[1033] Referring to Example 1, intermediate Int-4 was replaced with intermediate Int-16, and the final step was not split, to prepare compound 24 (a mixture of two isomers).

[1034] MS(ESI + m / z = 938.4 [M+H] + .

[1035] 1H NMR(400MHz,DMSO-d6)δ8.43(d,J=16.9Hz,3H),8.08(dd,J=8.7,4.6Hz,1H), 7.96(s,1H),7.87–7.73(m,3H),7.59(dd,J=15.3,8.6Hz,1H),5.92(t,J=12.4 Hz,1H),5.40–5.30(m,1H),4.70(dd,J=27.8,11.1Hz,1H),4.49(t,J=4.7Hz, 1H),4.07(q,J=7.6,7.1Hz,1H),3.75(d,J=5.2Hz,3H),3.58(dt,J=24.0,11.0 Hz,3H),3.40(t,J=7.0Hz,3H),3.26(s,2H),3.11(s,2H),3.04(s,3H),2.87( t,J=7.1Hz,2H),2.32(s,2H),2.23(d,J=2.0Hz,3H),2.15(t,J=9.8Hz,1H),2. 00(q,J=7.1,6.6Hz,2H),1.29(d,J=6.1Hz,2H),1.24(d,J=3.7Hz,6H),1.19– 1.14(m,3H),1.13–1.01(m,8H),0.95(d,J=6.5Hz,1H),0.86(d,J=6.6Hz,3H).

[1036] Example 25 Synthesis of Compound 25

[1037] Referring to Example 1, intermediate Int-4 was replaced with intermediate Int-18, and the final step was not split, to prepare compound 25 (a mixture of two isomers).

[1038] MS(ESI + m / z = 936.4 [M+H] + .

[1039] 1H NMR(400MHz, DMSO-d6)δ8.54(s,1H),8.44(d,J=14.4Hz,2H),8.10(dd,J=8.7,5.2Hz,1H),8.00(s,1H),7.90–7.82(m,2H),7.76(d,J=8.3Hz,1H),7.62 –7.55(m,1H),5.93(t,J=12.1Hz,2H),5.39–5.28(m,2H),4.71(dd,J=26.3, 11.0Hz,2H),4.53–4.31(m,4H),4.12–4.00(m,3H),3.90(d,J=3.6Hz,3H),3 .80–3.71(m,2H),3.59(d,J=15.1Hz,3H),3.27(d,J=4.3Hz,2H),3.11(s,3 H),2.15(t,J=9.9Hz,2H),2.07–1.95(m,2H),1.63–1.56(m,1H),1.48(d,J= 6.1Hz,2H),1.29(d,J=6.3Hz,3H),1.16–1.06(m,7H),1.02(d,J=5.9Hz,1H) ,0.93(d,J=15.8Hz,2H),0.84(d,J=11.9Hz,2H),0.50(s,2H),0.29(s,2H).

[1040] Example 26 Synthesis of Compound 26

[1041] Referring to Example 1, intermediate Int-4 was replaced with intermediate Int-21, and the final step was not split, to prepare compound 26 (a mixture of two isomers).

[1042] MS(ESI + m / z = 938.4 [M+H] + .

[1043] 1H NMR(400MHz, DMSO-d6)δ8.80(s,1H),8.46(t,J=1.9Hz,1H),8.41(t,J=8.3Hz, 1H),8.05(t,J=7.4Hz,1H),7.83(d,J=2.4Hz,1H),7.78(ddt,J=14.5,8.6,2.0 Hz,2H),7.66–7.55(m,2H),5.97–5.85(m,1H),5.36–5.29(m,1H),4.70(dd,J= 33.3,11.0Hz,1H),4.49(t,J=4.9Hz,1H),4.46–4.30(m,1H),4.18–4.02(m,2H) ,4.01–3.82(m,2H),3.78–3.51(m,3H),3.28(d,J=2.8Hz,3H),3.19–3.13(m,1 H),3.11(s,2H),2.91(s,2H),2.85(d,J=7.9Hz,3H),2.68–2.62(m,1H),2.37–2 .32(m,1H),2.14(d,J=7.2Hz,3H),2.03–1.97(m,1H),1.30(d,J=6.3Hz,2H),1 .24(d,J=3.4Hz,6H),1.20–1.13(m,4H),1.12–0.99(m,8H),0.93–0.80(m,5H).

[1044] Example 27 Synthesis of Compound 27

[1045] Referring to Example 1, intermediate Int-4 was replaced with intermediate Int-23, and the final step was not split, to prepare compound 27 (a mixture of two isomers).

[1046] MS(ESI + m / z = 936.4 [M+H] + .

[1047] 1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),8.49–8.45(m,1H),8.44–8.38(m,1H),8.1 0–8.04(m,1H),7.85–7.82(m,1H),7.81–7.77(m,1H),7.77–7.73(m,1H),7.68–7 .55(m,2H),5.96–5.86(m,1H),5.41–5.29(m,1H),4.79–4.70(m,1H),4.71–4.6 4(m,1H),4.52–4.42(m,1H),4.42–4.27(m,2H),4.19–4.10(m,2H),4.09–4.00(m ,2H),3.96–3.87(m,1H),3.81–3.70(m,1H),3.66–3.59(m,2H),3.56–3.49(m,2 H),3.29–3.24(m,3H),3.13(s,3H),3.02–2.98(m,3H),2.96–2.90(m,2H),2.70– 2.59(m,2H),2.37–2.29(m,2H),2.16(s,1H),1.67–1.54(m,2H),1.50–1.45(m,1 H),1.32–1.22(m,4H),1.20–1.13(m,3H),1.13–1.03(m,6H),0.92–0.79(m,3H).

[1048] Example 28 Synthesis of Compound 28

[1049] Synthesis of compound 28-1 (Step 1)

[1050] Compound Int-26-P1 (5.0 mg, 4.6 μmol) was dissolved in dichloromethane (0.3 mL), followed by the addition of trifluoroacetic acid (0.1 mL). The reaction was stirred at room temperature for 1.0 h. After the reaction was complete, the solution was concentrated under reduced pressure to give compound 28-1 (3.9 mg, 3.9 μmol, yield: 84.8%). The crude product was used directly in the next reaction without purification.

[1051] MS(ESI + m / z = 988.5[M+H] + .

[1052] The second step involves the synthesis of compound 28.

[1053] N,N-diisopropylethylamine (3.51 mg, 27.22 μmol) was added to a solution of compound 28-1 (3.9 mg, 3.9 μmol) in N,N-dimethylformamide (0.3 mL). Then, a solution of compound Int-28 (3.16 mg, 27.22 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (3.1 mg, 8.16 μmol) in N,N-dimethylformamide (0.2 mL) was added. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the product was purified by reversed-phase column chromatography (Waters XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%, mobile phase B: MeCN; MeCN ratio 40%-65%, time: 10 min, flow rate: 15 mL / min) to obtain compound 28 (2.3 mg, 2.06 μmol, yield: 52.8%, retention time: 8.87 min).

[1054] MS(ESI+)m / z = 1087.47 [M+H] + .

[1055] 1H NMR(400MHz,DMSO-d6)δ8.48(d,J=1.7Hz,1H),8.30(s,1H),8.02–7.88(m,3H),7 .81-7.69(m,2H),7.61(d,J=8.7Hz,1H),7.22(d,J=2.7Hz,1H),6.04(d,J=11.1H z,1H),5.36(d,J=8.5Hz,1H),4.90–4.77(m,2H),4.65–4.52(m,5H),4.36(t,J=6 .2Hz,1H),4.24–4.14(m,1H),4.12(s,1H),3.90(q,J=6.2Hz,1H),3.73–3.53(m, 7H),3.47(d,J=7.7Hz,2H),3.35-3.33(m,3H),3.25(d,J=7.7Hz,3H),3.21–3.12 (m,3H),3.10–3.02(m,4H),2.97(p,J=6.7Hz,1H),2.72–2.65(s,2H),2.58–2.52 (m,5H),2.41–2.24(m,6H),2.19(t,J=9.8Hz,1H),1.86(t,J=9.3Hz,1H),1.73–1 .56(m,3H),1.36(d,J=6.8Hz,3H),1.31–1.14(m,3H),0.92(s,3H),0.60(s,3H).

[1056] Example 29 Synthesis of Compound 29

[1057] At room temperature, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.62 mg, 6.89 μmol) and N,N-diisopropylethylamine (5.94 mg, 45.94 μmol) were added to a solution of compound Int-29 (1.60 mg, 13.78 μmol) in N,N-dimethylformamide (0.2 mL). The mixture was stirred at room temperature for 5 minutes, and then compound 28-1 (4.54 mg, 4.59 μmol) was added. The mixture was stirred at room temperature for another hour. After the reaction was completed, water (10 mL) was added to the reaction solution, and ethyl acetate (10 mL × 3) was used for extraction. The organic phases were combined, concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (column: Waters XBridge Prep C18; 150 mm × 19 mm × 5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 55%-75%, time: 13 min, flow rate: 15 mL / min, retention time: 7.04 min) to obtain compound 29 (3.0 mg, 2.72 μmol, yield: 59.2%).

[1058] MS(ESI + m / z = 1086.5 [M+H] + .

[1059] 1 H NMR (400MHz, DMSO-d6) δ8.47(d,J=1.6Hz,1H),8.30(s,1H),8.07(d,J=8.0Hz,1H),7.94(d,J=10.2Hz,2H),7.81–7.69(m,2H),7.60(d,J=8 .7Hz,1H),7.21(d,J=2.7Hz,1H),6.00(d,J=11.0Hz,1H),5.29(d,J=8.0Hz,1H),5.06(d,J=8.8Hz,1H),4.89–4.81(m,2H),4.68–4.55(m,4 H),4.37–4.05(m,5H),3.91(t,J=6.2Hz,1H),3.77–3.41(m,9H),3.41–3.31(m,6H),3.28–3.11(m,6H),3.04(s,4H),2.70(s,1H),2.47–2. 37(m,3H),2.26(s,4H),1.88(t,J=9.4Hz,1H),1.64(t,J=14.0Hz,2H),1.35–1.17(m,6H),1.09(d,J=7.1Hz,2H),0.92(s,4H),0.60(s,3H).

[1060] Example 30 Synthesis of Compound 30

[1061] Synthesis of compound 30-1 in step one

[1062] Compound Int-26-P2 (4.0 mg, 3.7 μmol) was dissolved in dichloromethane (0.3 mL), and then trifluoroacetic acid (0.1 mL) was added. The reaction was stirred at room temperature for 1.0 h. After the reaction was completed, the solution was concentrated under reduced pressure to give compound 30-1 (3.6 mg, 3.6 μmol, yield: 78.3%). The crude product was used directly in the next reaction without purification.

[1063] MS(ESI + m / z = 988.5[M+H] + .

[1064] Step 2: Synthesis of Compound 30

[1065] N,N-diisopropylethylamine (2.93 mg, 22.68 μmol) was added to a solution of compound 30-1 (3.6 mg, 3.6 μmol) in N,N-dimethylformamide (0.3 mL). Then, a solution of compound Int-28 (2.6 mg, 22.68 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.6 mg, 6.81 μmol) in N,N-dimethylformamide (0.2 mL) was added. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the product was purified by reversed-phase column chromatography (waters XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%; mobile phase B: MeCN; MeCN ratio 50%-60%, time: 10 min, flow rate: 15 mL / min) to obtain compound 30 (1.1 mg, 0.99 μmol, yield: 27.5%, retention time: 8.22 min).

[1066] MS(ESI+)m / z = 1086.5[M+H] + .

[1067] 1H NMR (400MHz, DMSO-d6) δ8.47(s,1H),8.09(s,1H),8.01–7.89(m,3H),7.78(d,J=8.7Hz,1H),7.74–7.69(m,1H),7.65(d,J=8.7Hz,1H),7.33–7.18(m ,1H),6.09(d,J=11.3Hz,1H),5.36(d,J=8.6Hz,1H),4.90–4.76(m,2H),4. 69–4.44(m,6H),4.41–4.36(m,2H),4.30–4.19(m,1H),4.15(s,1H),3.69– 3.60(m,1H),3.57–3.42(m,6H),3.31–3.22(m,9H),3.11–2.89(m,5H),2. 72–2.64(m,2H),2.62–2.55(m,4H),2.40–2.25(m,5H),2.19(t,J=9.9Hz,1 H),2.04–1.95(m,1H),1.92-1.82(m,1H),1.50–1.40(m,4H),1.35(d,J=6. 9Hz,2H),1.31–1.20(m,3H),1.11–0.97(m,2H),0.88(s,3H),0.29(s,3H).

[1068] Example 31 Synthesis of Compound 31

[1069] N,N-diisopropylethylamine (2.93 mg, 22.68 μmol) was added to a solution of compound 30-1 (3.2 mg, 3.2 μmol) in N,N-dimethylformamide (0.3 mL). Then, a solution of compound Int-29 (2.6 mg, 22.68 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.6 mg, 6.81 μmol) in N,N-dimethylformamide (0.2 mL) was added. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the product was purified by reversed-phase column chromatography (Waters XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%; mobile phase B: MeCN; MeCN ratio 50%-60%, time: 10 min, flow rate: 15 mL / min) to obtain compound 31 (1.2 mg, 1.1 μmol, yield: 34.4%, retention time: 8.17 min).

[1070] MS(ESI+)m / z = 1086.5[M+H] +.

[1071] 1 H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.14–8.01(m,2H),8.00–7.91(m,2H),7.82–7.68(m,2H),7.67–7.60(m,1H),7.26(s,1H),6.1 1–5.98(m,1H),5.28(d,J=8.1Hz,1H),5.05(d,J=8.7Hz,1H),4.92–4.80(m,2H),4.70–4.44(m,6H),4.38–4.32(m,1H),4.29–4.12(m ,3H),3.68–3.58(m,2H),3.57–3.42(m,8H),3.29–3.25(m,5H),3.09–2.93(m,5H),2.81–2.63(m,5H),2.40–2.24(m,5H),2.23–2.14 (m,2H),2.05–1.95(m,1H),1.89(t,J=9.3Hz,1H),1.45(d,J=6.0Hz,5H),1.24(s,3H),1.11–1.02(m,3H),0.89(s,3H),0.28(s,3H).

[1072] Example 32 Synthesis of Compound 32

[1073] Synthesis of compound 32-1 (Step 1)

[1074] Compound Int-30-P2 (12 mg, 10.78 μmol) was dissolved in dichloromethane (0.5 mL), and then trifluoroacetic acid (0.2 mL) was added. The reaction was stirred at room temperature for 1.0 h. After the reaction was completed, the mixture was neutralized with aqueous sodium bicarbonate solution, extracted with dichloromethane (10 mL * 3), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give compound 32-1 (10.8 mg, 10.67 μmol, yield: 99%).

[1075] MS(ESI + m / z = 1013.5[M+H] + .

[1076] The second step involves the synthesis of compound 32.

[1077] N,N-diisopropylethylamine (13.93 mg, 107.78 μmol) was added to a solution of compound 32-1 (10.8 mg, 10.67 μmol) in N,N-dimethylformamide (0.3 mL). Then, a solution of compound Int-28 (2.5 mg, 21.56 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (6.15 mg, 16.17 μmol) in N,N-dimethylformamide (0.2 mL) was added. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the product was purified by reversed-phase column chromatography (waters XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration was 0.05%; mobile phase B: MeCN; MeCN ratio 45%-70%, time: 10 min, flow rate: 15 mL / min) to obtain compound 32 (3.9 mg, 3.48 μmol, yield: 32.2%, retention time: 8.15 min).

[1078] MS(ESI + m / z = 1111.5[M+H] + .

[1079] 1 H NMR (400MHz, DMSO-d6) δ8.54(s,1H),8.28(d,J=9.5Hz,1H),8.18(s,1H),8.05(s,1H),7.99(d,J=8.6Hz ,1H),7.83(dd,J=20.8,9.1Hz,2H),7.71(d,J=8.7Hz,1H),6.13(d,J=10.5Hz,1H),5.41(d,J=8.6Hz,1H) ,4.88(d,J=12.6Hz,2H),4.62(d,J=25.8Hz,6H),4.41(s,2H),4.22(s,2H),3.73–3.50(m,9H),3.07(s,7 H),2.72(s,3H),2.27(d,J=33.0Hz,7H),1.98(d,J=43.4Hz,4H),1.56–1.24(m,15H),1.15–0.88(m,7H).

[1080] Example 33 Synthesis of Compound 33

[1081] N,N-diisopropylethylamine (9.29 mg, 71.85 μmol) was added to a solution of compound 32-1 (8.1 mg, 7.99 μmol) in N,N-dimethylformamide (0.3 mL). Then, a solution of compound Int-29 (1.67 mg, 14.37 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.10 mg, 10.78 μmol) in N,N-dimethylformamide (0.2 mL) was added. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the product was purified by reversed-phase column chromatography (Waters XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%; mobile phase B: MeCN; MeCN ratio 45%-70%, time: 10 min, flow rate: 15 mL / min) to obtain compound 33 (2.7 mg, 2.47 μmol, yield: 30.39%, retention time: 8.2 min).

[1082] MS(ESI+)m / z=1111.5[M+H] + .

[1083] 1 H NMR(400MHz, DMSO-d6)δ8.48(s,1H),8.22(d,J=9.4Hz,1H),8.13–8.02(m,2H),7.98(s,1H),7.89–7.7 4(m,2H),7.66(d,J=8.7Hz,1H),6.04(d,J=11.2Hz,1H),5.35–5.25(m,2H),5.05(d,J=8.7Hz,1H),4.8 5(d,J=9.3Hz,2H),4.60(s,7H),4.40–4.10(m,6H),3.66–3.46(m,10H),3.01(d,J=9.8Hz,7H),2.26(s ,6H),1.95(dt,J=34.1,8.4Hz,5H),1.51–1.39(m,7H),1.07(d,J=7.2Hz,5H),0.88(d,J=19.5Hz,7H).

[1084] Example 34 Synthesis of compounds 34-P1 and 34-P2

[1085] Step 1: Synthesis of Compound 34-1

[1086] Compound R3 (12.0 mg, 9.93 μmol) was dissolved in hexafluoroisopropanol (4.0 mL). Pd(OH)₂ / C (10 mg) was added to the reaction solution, and the mixture was then purged with hydrogen five times. The mixture was stirred at 25 °C for 7 hours under one atmosphere of pressure. After the reaction was complete, the reaction solution was diluted with dichloromethane and methanol and filtered. The filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure to remove the solvent, yielding compound 34-1 (10 mg, 9.31 μmol, yield: 93.7%), which was used directly in the next step.

[1087] MS(ESI+)m / z = 1074.5[M+H] + .

[1088] Step 2: Synthesis of compound 34-3

[1089] Compound 34-1 (10 mg, 9.31 μmol) was dissolved in isopropanol (2.0 mL). Compound 34-2 (8.11 mg, 46.54 μmol), acetic acid (9.82 mg, 163.60 μmol), and sodium cyanoborohydride (10.28 mg, 163.60 μmol) were added to the reaction solution under ice bath conditions, and the mixture was stirred at 25 °C for 4 hours. After the reaction was completed, the crude product was purified by reversed-phase column chromatography (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound 34-3 (8 mg, 7.18 μmol, yield: 77.1%).

[1090] MS(ESI + m / z = 1114.6 [M+H] +

[1091] Step 3: Synthesis of compound 34-4

[1092] Compound 34-3 (8.0 mg, 7.18 μmol) was dissolved in dichloromethane (0.3 mL), and then trifluoroacetic acid (0.1 mL) was added. The reaction was stirred at room temperature for 1.0 h. After the reaction was completed, the solution was concentrated under reduced pressure to give compound 34-4 (7.0 mg, 6.90 μmol, yield: 96.1%). The crude product was used directly in the next reaction without purification.

[1093] MS(ESI + m / z = 1014.5[M+H] + .

[1094] Step 4: Synthesis of compounds 34-P1 and 34-P2

[1095] N,N-diisopropylethylamine (3.51 mg, 27.22 μmol) was added to a solution of compound 34-4 (7 mg, 6.90 μmol) in N,N-dimethylformamide (0.3 mL). Then, a solution of compound Int-28 (3.16 mg, 27.22 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (3.1 mg, 8.16 μmol) in N,N-dimethylformamide (0.2 mL) was added. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the product was purified by reversed-phase column chromatography (Waters XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%, mobile phase B: MeCN; MeCN ratio 40%-65%, time: 10 min, flow rate: 15 mL / min) to obtain compound 34-P1 (2.5 mg, 2.25 μmol, yield: 32.6%, retention time: 6.98 min) and compound 34-P2 (2.1 mg, 1.89 μmol, yield: 27.4%, retention time: 8.13 min).

[1096] Compound 34-P1 MS (ESI+) m / z = 1112.6 [M+H] + .

[1097] Compound 34-P2 MS (ESI+) m / z = 1112.6 [M+H] + .

[1098] Compound 34-P2: 1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.08(s,1H),7.98(s,1H),7.96–7.91(m,2H), 7.80–7.74(m,1H),7.73–7.68(m,1H),7.67–7.62(m,1H),7.25–7.21(m,1H),6.13– 6.04(m,1H),5.39–5.33(m,1H),4.87–4.78(m,2H),4.63–4.56(m,5H),4.56–4.44( m,2H),4.39–4.30(m,2H),4.29–4.20(m,1H),4.15(s,1H),3.67–3.58(m,1H),3.57– 3.43(m,6H),3.31–3.26(m,6H),3.08–2.90(m,5H),2.78–2.64(m,6H),2.39–2.32( m,1H),2.21–2.16(m,1H),2.05–1.94(m,1H),1.90–1.83(m,1H),1.72–1.64(m,1H), 1.48–1.40(m,3H),1.40–1.32(m,3H),1.27–1.15(m,4H),1.09–0.97(m,2H),0.96– 0.91(m,1H),0.91–0.81(m,4H),0.48–0.42(m,2H),0.40–0.33(m,2H),0.28(s,3H).

[1099] Example 35 Synthesis of compounds 35-P1 and 35-P2

[1100] Referring to Example 34, intermediate R3 is replaced with intermediate Int-31, and intermediate 34-2 is replaced with... Compounds 35-P1 and 35-P2 were prepared. (The chromatographic column was a Waters XBridge Prep C18; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration was 0.05%; mobile phase B: MeCN; MeCN ratio 40%-65%; time: 10 min; flow rate: 15 mL / min). Compound 35-P1 (retention time: 7.33 min) and compound 35-P2 (retention time: 7.63 min) were obtained.

[1101] Compound 35-P2 MS (ESI+) m / z = 1142.5 [M+H] + .

[1102] 1H NMR (400MHz, DMSO-d6) δ8.49(s,1H),8.31(s,1H),7.99(s,1H),7.94(d,J=8.6Hz,1H),7.79(d,J=8.6Hz,1H),7.64(d,J= 8.7Hz,1H),6.16–6.04(m,1H),5.39–5.28(m,1H),4.91–4.75(m,3H),4.67–4.55(m,6H),4.55–4.44(m,4H),4.40–4.27( m,2H),4.20–4.03(m,3H),3.74–3.65(m,2H),3.63–3.44(m,6H),3.14–2.88(m,6H),2.40–2.08(m,10H),2.05–1.94(m,1 H),1.92–1.83(m,1H),1.59–1.40(m,4H),1.34(d,3H),1.23(s,5H),1.11–0.97(m,3H),0.96–0.76(m,5H),0.32(s,3H).

[1103] Example 36 Synthesis of compounds 36-P1 and 36-P2

[1104] Synthesis of compound 36-1 (Step 1)

[1105] Compound Int-35 (20.0 mg, 17.10 μmol) was dissolved in dichloromethane (0.5 mL), and then trifluoroacetic acid (0.2 mL) was added. The reaction mixture was stirred at room temperature for 1.0 h. After the reaction was complete, the reaction solution was added dropwise to a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried, and concentrated to give compound 36-1 (18.1 mg, 16.93 μmol, yield: 99%). The crude product was used directly in the next reaction without purification.

[1106] MS(ESI+)m / z = 1069.5[M+H] + .

[1107] The second step involves the synthesis of compounds 36-P1 and 36-P2.

[1108] N,N-diisopropylethylamine (22.11 mg, 171.04 μmol) was added to a solution of compound 36-1 (18.1 mg, 16.93 μmol) in N,N-dimethylformamide (0.3 mL). Then, a solution of compound Int-28 (5.96 mg, 51.31 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (9.76 mg, 25.66 μmol) in N,N-dimethylformamide (0.2 mL) was added. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the compound 36-P2 (4.0 mg, 3.43 μmol, yield: 20.0%, retention time: 8.68 min) was obtained by reversed-phase column purification (waters XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 45%-70%, time: 10 min, flow rate: 15 mL / min).

[1109] Compound 36-P2 MS (ESI+) m / z = 1167.6 [M+H] + .

[1110] 1 H NMR (400MHz, DMSO-d6) δ8.49(s,1H),8.23(d,J=9.5Hz,1H),8.13(s,1H),8.00(s,1H),7.94(d,J=8.5Hz,1H),7.78(dd ,J=19.1,9.0Hz,2H),7.66(d,J=8.7Hz,1H),6.08(d,J=11.1Hz,1H),5.36(d,J=8.6Hz,1H),4.83(d,J=12.7Hz,2H),4.7 1–4.27(m,11H),4.17(d,J=5.4Hz,4H),3.73–3.37(m,17H),3.29(s,4H),3.11–2.73(m,6H),2.36(d,J=5.6Hz,1H),2. 18(t,J=9.8Hz,1H),1.99(t,J=7.2Hz,1H),1.88(t,J=9.2Hz,1H),1.64–1.17(m,13H),1.10–0.93(m,3H),0.89(s,4H).

[1111] Example 37 Synthesis of compounds 37-P1 and 37-P2

[1112] Synthesis of compound 37-1 (Step 1)

[1113] Compound 9-2 (20.0 mg, 19.43 μmol) was dissolved in isopropanol (3.0 mL), and Pd(OH)₂ / C (13.64 mg, 9.72 μmol, purity: 20%) was added. Hydrogen was then purged five times. The mixture was stirred at 35 °C for 16.0 h under one atmosphere of pressure, and the reaction was monitored for completeness by LC-MS. After filtering off the residue from the crude product, the filtrate was concentrated to give compound 37-1 (14.0 mg, 15.64 μmol, yield: 80.5%).

[1114] MS(ESI + m / z = 895.4 [M+H] + .

[1115] The second step involves the synthesis of compound 37-3.

[1116] Compound 37-1 (15.0 mg, 16.76 μmol) and compound 37-2 (18.96 mg, 167.58 μmol) were added to isopropanol (3.0 mL), followed by one drop of acetic acid. Sodium cyanoborohydride (11.77 mg, 18.72 μmol) was then added to the reaction mixture. The mixture was stirred at room temperature for 2.0 h, and the reaction was monitored for completeness by LC-MS. The reaction was quenched with an aqueous solution of saturated ammonium chloride. The crude product was purified by reverse-phase chromatography (water / NH4OH (0.05%):MeCN = 95:5 to 1:99) to give compound 37-3 (10.0 mg, 10.08 μmol, yield: 60.1%).

[1117] MS(ESI+)m / z = 992.5[M+H] +

[1118] The third step involves the synthesis of compound 37-4.

[1119] Compound 37-3 (10.0 mg, 10.08 μmol) was dissolved in dichloromethane (1.0 mL), and then trifluoroacetic acid (0.35 mL) was added to the reaction solution. The mixture was stirred at 25 °C for 1.0 h. The reaction was monitored by LC-MS until complete, and the solution was concentrated by rotary evaporation to give compound 37-4 (8.9 mg, 9.98 μmol, yield: 99.0%). MS (ESI) + m / z = 892.5[M+H] + .

[1120] The fourth step involved the synthesis of compounds 37-P1 and 37-P2.

[1121] Compound 37-4 (8.9 mg, 9.98 μmol) and N,N-diisopropylethylamine (7.0 μL, 39.9 μmol) were added sequentially to a solution of (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (3.42 mg, 29.93 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (5.69 mg, 14.96 μmol) in N,N-dimethylformamide (1.0 mL), and stirred at room temperature for 1.0 h. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography (column: Waters XBridge Prep C18; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 55%-70%, time: 10 min, flow rate: 15 mL / min) to obtain the less polar compound 37-P2 (3.0 mg, 3.03 μmol, yield: 30.4%, retention time: 7.62 min).

[1122] Compound 37-P2 MS (ESI+) m / z = 988.5 [M+H] +

[1123] 1H NMR (400MHz, DMSO-d6) δ8.48–8.41(m,2H),8.27(s,1H),7.91(d,J=9.2Hz,1H), 7.84(s,1H),7.82–7.75(m,1H),7.71(t,J=9.2Hz,1H),7.61(d,J=8.7Hz,1H),5. 95(d,J=11.1Hz,1H),5.42–5.35(m,1H),4.68(d,J=11.1Hz,1H),4.51–4.46(m, 1H),4.43–4.31(m,2H),4.13–4.01(m,1H),3.63–3.51(m,2H),3.29–3.22(m,9H) ,3.19–3.11(m,1H),3.00–2.93(m,1H),2.89(s,1H),2.70–2.66(m,4H),2.63(d ,J=5.9Hz,1H),2.35–2.30(m,2H),2.27–2.21(m,3H),2.19–2.10(m,2H),2.04–1 .95(m,3H),1.83–1.77(m,2H),1.61–1.49(m,2H),1.47–1.44(m,4H),1.31–1.2 7(m,2H),1.19–1.16(m,2H),1.11–1.06(m,6H),0.92–0.85(m,5H),0.83(s,3H).

[1124] Example 38 Synthesis of compounds 38-P1 and 38-P2

[1125] Synthesis of compound 38-1 (Step 1)

[1126] Compound 37-1 (20.0 mg, 22.34 μmol) and N,N-diisopropylethylamine (11.7 μL, 67.0 μmol) were added sequentially to a solution of cyanoacetic acid (5.7 mg, 67.0 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (12.74 mg, 33.5 μmol) in N,N-dimethylformamide (0.5 mL). The mixture was stirred at room temperature for 1.0 h. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography (dichloromethane:methanol = 10:1) to give compound 38-1 (12.0 mg, 12.47 μmol, yield: 55.8%).

[1127] MS(ESI+)m / z = 962.4[M+H] +

[1128] The second step involves the synthesis of compound 38-2.

[1129] Compound 38-1 (10.0 mg, 10.39 μmol) was dissolved in dichloromethane (0.9 mL), and then trifluoroacetic acid (0.3 mL) was added to the reaction solution. The mixture was stirred at 25 °C for 1.0 h. The reaction was monitored by LC-MS until complete. The solution was concentrated under reduced pressure to give compound 38-2 (8.9 mg, 10.32 μmol, yield: 99.3%). MS (ESI) + m / z = 862.4 [M+H] + .

[1130] The third step involves the synthesis of compounds 38-P1 and 38-P2.

[1131] Compound 38-2 (8.9 mg, 10.32 μmol) and N,N-diisopropylethylamine (5.4 μL, 30.97 μmol) were added sequentially to a solution of (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (3.54 mg, 30.97 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (5.89 mg, 15.49 μmol) in N,N-dimethylformamide (1.0 mL), and stirred at room temperature for 1.0 h. After the reaction was completed, the compound was purified by reversed-phase column chromatography (Waters XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%; mobile phase B: MeCN; MeCN ratio 60%-80%, time: 10 min, flow rate: 15 mL / min) to obtain the less polar compound 38-P2 (3.0 mg, 3.13 μmol, yield: 30.3%, retention time: 8.22 min).

[1132] Compound 38-P2 MS (ESI+) m / z = 958.5 [M+H] +

[1133] 1H NMR(400MHz,DMSO-d6)δ8.46(d,J=1.5Hz,1H),8.43–8.36(m,1H),8.30(s, 1H),7.99–7.91(m,1H),7.83(s,1H),7.79–7.69(m,2H),7.64–7.55(m,1H), 5.97–5.86(m,1H),5.42–5.31(m,1H),4.77–4.62(m,1H),4.53–4.46(m,1H ),4.46–4.33(m,1H),4.12(s,2H),4.09–3.98(m,1H),3.71–3.65(m,2H),3. 64–3.49(m,4H),3.29–3.20(m,6H),3.19–3.11(m,1H),3.08(s,1H),2.69– 2.60(m,1H),2.35–2.30(m,1H),2.15(t,J=9.8Hz,1H),2.07–1.95(m,1H),1 .65–1.53(m,1H),1.46(d,J=6.1Hz,2H),1.35–1.25(m,4H),1.22–1.12(m, 4H),1.12–1.06(m,6H),1.05–1.00(m,3H),0.96–0.85(m,4H),0.83(s,2H).

[1134] Example 39 Synthesis of compounds 39-P1 and 39-P2

[1135] Referring to Example 38, intermediate cyanoacetic acid was replaced with intermediate 39-1, and the following preparation was performed (chromatographic column: Waters XBridge Prep C18; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 55%-75%; time: 10 min; flow rate: 15 mL / min) to obtain compound 39-P2 with lower polarity (retention time: 8.57 min).

[1136] Compound 39-P2 MS (ESI+) m / z = 977.5 [M+H] +

[1137] 1H NMR(400MHz,DMSO-d6)δ8.50–8.40(m,2H),8.32(s,1H),7.94(d,J=9.2Hz,1H),7.84 (s,1H),7.79–7.72(m,2H),7.61(d,J=8.6Hz,1H),5.95(d,J=11.1Hz,1H),5.42–5.3 4(m,1H),4.68(d,J=11.0Hz,1H),4.52–4.45(m,1H),4.44–4.31(m,2H),4.08(dd,J= 14.8,7.4Hz,1H),3.80(s,3H),3.66–3.57(m,1H),3.56–3.49(m,1H),3.48–3.39(m, 1H),3.30–3.28(m,1H),3.26(s,3H),3.19–3.10(m,1H),3.02–2.91(m,1H),2.66–2. 60(m,1H),2.47(s,1H),2.34–2.31(m,1H),2.19–2.11(m,1H),2.02–1.94(m,1H),1. 64–1.52(m,1H),1.46(d,J=6.1Hz,3H),1.36–1.32(m,1H),1.32–1.26(m,3H),1.26– 1.22(m,6H),1.21–1.13(m,3H),1.11–1.05(m,6H),0.94–0.85(m,4H),0.84(s,3H).

[1138] Example 40 Synthesis of compounds 40-P1 and 40-P2

[1139] Referring to Example 37, intermediate 9-2 was replaced with intermediate Int-36, and intermediate 37-2 was replaced with 3-pentanone. The preparation (chromatographic column: Waters XBridge Prep C18; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 65%-85%; time: 10 min; flow rate: 15 mL / min) yielded the less polar compound 40-P2 (retention time: 8.32 min).

[1140] Compound 40-P2 MS (ESI+) m / z = 968.5 [M+H] +

[1141] 1H NMR(400MHz, DMSO-d6)δ8.46(s,1H),8.43(d,J=8.8Hz,1H),8.22(d,J=9.5Hz,1H),8 .10(s,1H),7.85(s,1H),7.81–7.77(m,1H),7.74(d,J=9.5Hz,1H),7.62(d,J=8.8Hz, 1H),5.94(d,J=11.1Hz,1H),5.41–5.35(m,1H),4.68(d,J=11.1Hz,1H),4.51–4.46( m,1H),4.45–4.40(m,1H),4.40–4.34(m,1H),4.13–4.03(m,1H),3.62–3.52(m,7H),3 .32–3.29(m,3H),3.26(s,3H),3.18–3.11(m,1H),3.03–2.94(m,1H),2.71–2.67(m, 4H),2.65–2.59(m,1H),2.33–2.28(m,1H),2.27–2.21(m,1H),2.15(t,J=9.8Hz,1H), 1.62–1.55(m,1H),1.55–1.48(m,2H),1.46(d,J=6.0Hz,3H),1.37–1.26(m,3H),1.19 –1.15(m,2H),1.13–1.04(m,6H),0.94–0.87(m,9H),0.86–0.84(m,2H),0.30(s,3H).

[1142] Example 41 Synthesis of compounds 41-P1 and 41-P2

[1143] Referring to Example 10, intermediate 10-2 was replaced with intermediate Int-37, and the following preparation was performed (chromatographic column: Waters XBridge Prep C18; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 50%-75%; time: 10 min; flow rate: 15 mL / min) to obtain the less polar compound 41-P2 (retention time: 7.45 min).

[1144] Compound 41-P2 MS (ESI+) m / z = 958.4 [M+H] +

[1145] 1H NMR(400MHz,DMSO-d6)δ8.45–8.39(m,2H),8.07(s,1H),7.81(s,1H),7.75 –7.70(m,1H),7.56(d,J=8.7Hz,1H),5.96(d,J=11.1Hz,1H),5.43–5.34(m ,1H),4.89–4.80(m,1H),4.65(d,J=11.0Hz,1H),4.61–4.56(m,2H),4.54– 4.46(m,3H),4.32–4.25(m,2H),4.09–3.99(m,1H),3.63(d,J=10.8Hz,1H) ,3.59–3.49(m,2H),3.28–3.23(m,2H),3.18(s,3H),3.15–3.10(m,1H),2. 96–2.85(m,3H),2.65–2.59(m,1H),2.33–2.20(m,5H),2.19–1.97(m,6H), 1.57(t,J=9.2Hz,1H),1.41(d,J=6.1Hz,3H),1.18–1.12(m,4H),1.10–1.0 4(m,6H),0.97–0.93(m,1H),0.91–0.87(m,4H),0.84(s,3H),0.36(s,3H).

[1146] Example 42 Synthesis of compounds 42-P1 and 42-P2

[1147] Referring to Example 10, intermediate 10-2 is replaced with intermediate Int-37. The compound 42-P2, with lower polarity, was obtained after replacing paraformaldehyde with a Waters XBridge Prep C18 column (150*19 mm*5 μm); mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%; mobile phase B: MeCN; MeCN ratio 50%-80%; time: 13 min; flow rate: 15 mL / min). The MS (ESI+) m / z of compound 42-P2 was 916.4 [M+H]. +

[1148] 1H NMR(400MHz,DMSO-d6)δ8.46–8.39(m,2H),8.11(s,1H),7.82(s,1H),7.74(dd ,J=8.7,1.6Hz,1H),7.57(d,J=8.7Hz,1H),5.97(d,J=11.0Hz,1H),5.39(t,J= 8.4Hz,1H),5.13–5.01(m,1H),4.65(d,J=11.1Hz,1H),4.51–4.46(m,1H),4.3 4–4.23(m,2H),4.02(dd,J=14.9,7.5Hz,1H),3.65–3.54(m,2H),3.52–3.38(m ,2H),3.30–3.24(m,2H),3.19–3.11(m,4H),2.94–2.88(m,1H),2.78–2.69(m, 2H),2.66–2.56(m,2H),2.46–2.39(m,3H),2.36–2.22(m,5H),2.21–2.12(m,2 H),1.57(t,J=9.2Hz,1H),1.41(d,J=6.0Hz,3H),1.19–1.13(m,4H),1.11–1.0 5(m,6H),0.99–0.93(m,2H),0.89(t,J=7.1Hz,4H),0.84(s,3H),0.35(s,3H).

[1149] Example 43 Synthesis of compounds 43-P1 and 43-P2

[1150] Referring to Example 1, intermediate Int-4 was replaced with intermediate Int-39, and the following preparation was performed (chromatographic column: Waters XBridge Prep C18; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 60%-70%; time: 10 min; flow rate: 15 mL / min) to obtain the less polar compound 43-P2 (retention time: 7.30 min).

[1151] Compound 43-P2 MS (ESI+) m / z = 995.4 [M+H] +

[1152] 1H NMR (400MHz, DMSO-d6) δ8.47–8.41(m,2H),8.19(d,J=9.6Hz,1H),8.09(s,1H),7.85(s,1H),7.78(dd,J=8.6,1.7Hz,1H),7.74(d,J=5.5Hz,1H),7.62( d,J=8.7Hz,1H),5.94(d,J=11.1Hz,1H),5.42–5.35(m,1H),4.68(d,J=11. 0Hz,1H),4.53–4.46(m,1H),4.45–4.32(m,2H),4.15–3.97(m,4H),3.63–3. 49(m,2H),3.26(s,3H),3.23–3.12(m,5H),3.09–3.04(m,1H),3.02–2.93( m,1H),2.66–2.60(m,1H),2.37–2.30(m,5H),2.16(s,5H),2.00–1.90(m,3H ),1.67–1.53(m,4H),1.46(d,J=6.1Hz,3H),1.20–1.15(m,3H),1.10(d,J=6 .2Hz,3H),1.08–1.06(m,3H),0.91–0.86(m,4H),0.84(s,3H),0.29(s,3H).

[1153] Example 44 Synthesis of compounds 44-P1 and 44-P2

[1154] Referring to Example 1, the intermediate Int-34 was replaced with Int-4 to prepare (chromatographic column: Waters XBridge Prep C18; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 55%-80%; time: 10 min; flow rate: 15 mL / min) to obtain the less polar compound 44-P2 (retention time: 8.87 min).

[1155] Compound 44-P2 MS (ESI) + m / z = 968.4 [M+H] + .

[1156] 1H NMR (400MHz, DMSO-d6) δ8.48–8.41(m,2H),8.23(d,J=9.5Hz,1H),8.10(s,1H ),7.84(s,1H),7.81–7.73(m,2H),7.62(d,J=8.7Hz,1H),5.94(d,J=11.0Hz,1 H),5.43–5.31(m,1H),4.68(d,J=11.0Hz,1H),4.48(d,J=5.6Hz,3H),4.45–4. 31(m,2H),4.17(d,J=5.6Hz,2H),4.12–4.01(m,1H),3.63–3.60(m,4H),3.59– 3.57(m,1H),3.55–3.51(m,2H),3.47–3.44(m,2H),3.29–3.23(m,4H),3.19–3 .10(m,1H),3.03–2.93(m,1H),2.68–2.59(m,3H),2.35–2.27(m,1H),2.19–2. 10(m,1H),1.63–1.53(m,1H),1.46(d,J=6.0Hz,3H),1.31(s,3H),1.28–1.20( m,2H),1.19–1.14(m,2H),1.11–1.04(m,6H),0.90–0.81(m,6H),0.29(s,3H).

[1157] Example 45 Synthesis of compounds 45-P1 and 45-P2

[1158] Referring to Example 1, Int-4 was replaced with intermediate Int-41, and paraformaldehyde was replaced with... After preparation (using a Waters XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%, mobile phase B: MeCN; MeCN ratio 50%-75%, time: 10 min, flow rate: 15 mL / min), the less polar compound 45-P2 was obtained (retention time: 8.98 min).

[1159] Compound 45-P2 MS (ESI) + m / z = 993.5[M+H] + .

[1160] 1H NMR (400MHz, DMSO-d6) δ8.46(s,1H),8.44(d,J=8.8Hz,1H),8.27(d,J=9.4Hz,1H ),8.13(s,1H),7.85(s,1H),7.81–7.75(m,2H),7.62(d,J=8.7Hz,1H),5.94(d,J =11.1Hz,1H),5.41–5.31(m,1H),4.68(d,J=11.1Hz,1H),4.64–4.51(m,5H),4.5 0–4.34(m,3H),4.11–4.04(m,1H),4.02–3.95(m,1H),3.70–3.63(m,2H),3.58–3. 52(m,4H),3.30–3.24(m,4H),3.18–3.12(m,1H),3.10–3.05(m,1H),3.02–2.96( m,1H),2.92–2.86(m,1H),2.82–2.74(m,2H),2.67–2.59(m,2H),2.34–2.29(m,1 H),2.14(t,J=9.8Hz,1H),1.58(t,J=9.3Hz,1H),1.46(d,J=6.1Hz,3H),1.24–1. 22(m,2H),1.19–1.15(m,2H),1.11–1.06(m,6H),0.90–0.83(m,6H),0.29(s,3H).

[1161] Example 46 Synthesis of compounds 46-P1 and 46-P2

[1162] Referring to Example 10, The chromatographic column was replaced with acetone, and the preparation (waters XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%, mobile phase B: MeCN; MeCN ratio 60%-85%, time: 13 min, flow rate: 15 mL / min) yielded the less polar compound 46-P2 (retention time: 8.63 min).

[1163] Compound 46-P2 MS (ESI+) m / z = 929.5 [M+H] +

[1164] 1H NMR (400MHz, DMSO-d6) δ8.48(s,1H),8.46–8.40(m,2H),7.84(s,1H),7.79–7.73(m,1H),7.60(d,J=8.6Hz,1H),5.95(d,J=11.0Hz,1H),5.43–5.31 (m,1H),4.85–4.73(m,1H),4.68(d,J=11.0Hz,1H),4.52–4.44(m,1H),4. 40–4.28(m,2H),4.06–3.95(m,1H),3.66–3.58(m,1H),3.57–3.51(m,1H), 3.26–3.20(m,4H),3.17–3.11(m,1H),3.06–2.98(m,2H),2.93(d,J=14.2 Hz,1H),2.88–2.79(m,1H),2.68–2.56(m,2H),2.36–2.28(m,2H),2.28–2. 10(m,5H),1.59(t,J=9.2Hz,1H),1.44(d,J=6.0Hz,3H),1.28–1.21(m,3H ),1.19–1.15(m,2H),1.11–1.03(m,12H),0.91–0.84(m,6H),0.31(s,3H).

[1165] Example 47 Synthesis of compounds 47-P1 and 47-P2

[1166] Referring to Example 10, The solution was replaced with acetaldehyde, and the chromatography was performed (column: Waters XBridge Prep C18; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 50%-80%; time: 13 min; flow rate: 15 mL / min) to obtain the less polar compound 47-P2 (retention time: 9.55 min).

[1167] Compound 47-P2 MS (ESI+) m / z = 915.5 [M+H] +

[1168] 1H NMR (400MHz, DMSO-d6) δ8.48(s,1H),8.46–8.42(m,2H),7.83(s,1H),7.76(d,J=8.5Hz,1H),7.60(d,J=8.6Hz,1H),5.95(d,J=11.1Hz,1H),5.36 (t,J=8.2Hz,1H),4.84–4.75(m,1H),4.67(d,J=11.0Hz,1H),4.51–4.44 (m,1H),4.38–4.29(m,2H),4.05–3.94(m,1H),3.61(d,J=10.6Hz,1H),3 .53(d,J=10.9Hz,1H),3.34–3.32(m,2H),3.22(s,3H),3.19–3.03(m,4H ),2.92(d,J=14.3Hz,1H),2.65–2.58(m,1H),2.44–2.40(m,2H),2.34–2 .29(m,2H),2.24–2.12(m,6H),1.62–1.54(m,1H),1.43(d,J=6.0Hz,3H) ,1.19–1.14(m,2H),1.11–1.03(m,10H),0.91–0.84(m,6H),0.31(s,3H).

[1169] Example 48 Synthesis of compounds 48-P1 and 48-P2

[1170] Referring to Example 38, intermediate 37-1 was replaced with intermediate Int-42, and intermediate cyanoacetic acid was replaced with intermediate 39-1. The preparation (chromatographic column: Waters XBridge Prep C18; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 60%-80%; time: 15 min; flow rate: 15 mL / min) yielded the less polar compound 48-P2 (retention time: 8.65 min).

[1171] Compound 48-P2 MS (ESI+) m / z = 984.5 [M+H] +

[1172] 1H NMR (400MHz, DMSO-d6) δ8.46(d,J=1.6Hz,1H),8.43(d,J=8.8Hz,1H),8.26(d,J=9.4H z,1H),8.14(s,1H),7.85(s,1H),7.81–7.76(m,2H),7.63(d,J=8.7Hz,1H),5.94(d,J =11.1Hz,1H),5.43–5.33(m,1H),4.68(d,J=11.2Hz,1H),4.51–4.45(m,1H),4.45–4. 34(m,2H),4.15–4.04(m,1H),3.97–3.75(m,3H),3.74–3.65(m,4H),3.64–3.49(m,2H ),3.39–3.35(m,2H),3.31–3.28(m,2H),3.27(s,3H),3.20–3.09(m,1H),3.06–2.93( m,1H),2.65–2.60(m,1H),2.32–2.27(m,1H),2.15(t,J=9.8Hz,1H),1.62–1.56(m,1H ),1.47(d,J=6.1Hz,3H),1.36–1.32(m,1H),1.32–1.25(m,3H),1.22–1.19(m,1H),1. 19–1.14(m,2H),1.11–1.05(m,6H),0.88(t,J=7.0Hz,3H),0.84(s,3H),0.29(s,3H).

[1173] Example 49 Synthesis of compounds 49-P1 and 49-P2

[1174] Referring to Example 10, the intermediate is... Replacing it with paraformaldehyde, compound 17-1 was prepared, and then the intermediate from the last step was... Replace with The preparation (using a Waters 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 60%-80%, time: 13 min, flow rate: 15 mL / min, retention time: 7.50 min) yielded a compound with low polarity, 49-P2.

[1175] MS(ESI + m / z = 887.4 [M+H] + .

[1176] 1 H NMR(400MHz,DMSO-d6)δ8.55(d,J=8.9Hz,1H),8.48(s,1H),8.46–8.43(m,1H), 7.83(s,1H),7.76(dd,J=8.6,1.6Hz,1H),7.60(d,J=8.7Hz,1H),5.96(d,J=11. 1Hz,1H),5.38(t,J=8.1Hz,1H),4.83–4.73(m,1H),4.68(d,J=11.0Hz,1H),4.5 3–4.44(m,1H),4.40–4.26(m,2H),4.07–3.92(m,1H),3.61(d,J=10.9Hz,1H),3. 53(d,J=10.7Hz,1H),3.31–3.26(m,2H),3.23(s,3H),3.17–3.10(m,1H),3.02– 2.88(m,3H),2.65–2.60(m,1H),2.57–2.55(m,1H),2.33–2.29(m,2H),2.29–2. 23(m,4H),2.23–2.11(m,6H),1.60(t,J=9.3Hz,1H),1.52–1.47(m,1H),1.43(d ,J=6.1Hz,3H),1.07(s,4H),0.90–0.84(m,6H),0.61–0.52(m,1H),0.31(s,3H).

[1177] Example 50 Synthesis of compounds 50-P1 and 50-P2

[1178] Referring to Example 34, intermediate Int-28 was replaced with Int-6, and the following preparation was performed (chromatographic column: Waters XBridge Prep C18; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration: 0.05%; mobile phase B: MeCN; MeCN ratio: 60%-80%; time: 13 min; flow rate: 15 mL / min) to obtain compound 50-P1 (retention time: 7.82 min) and compound 50-P2 (retention time: 8.93 min).

[1179] Compound 50-P2 MS (ESI) + m / z = 1148.6 [M+H] + .

[1180] 1H NMR (400MHz, DMSO-d6) δ8.39(s,1H),8.03(s,1H),7.92(s,1H),7.87(d,J=9.4Hz,1H),7.76–7.62(m ,2H),7.58(d,J=8.7Hz,1H),7.48(d,J=8.1Hz,1H),7.17(d,J=2.7Hz,1H),5.90(d,J=11.0Hz,1H),5. 32(d,J=8.0Hz,1H),4.76(d,J=11.0Hz,1H),4.59(d,J=9.0Hz,1H),4.54(s,3H),4.53–4.45(m,3H),4 .41–4.35(m,2H),4.29(q,J=5.3Hz,1H),4.18(dd,J=14.1,6.8Hz,1H),4.00(s,1H),3.58(d,J=10.8H z,1H),3.49(d,J=8.0Hz,2H),3.46–3.38(m,3H),3.23(d,J=8.6Hz,9H),3.15(d,J=7.7Hz,2H),2.92– 2.84(m,5H),2.67(t,J=4.8Hz,3H),2.61(d,J=6.7Hz,1H),2.30(dd,J=10.6,5.3Hz,1H),2.11(t,J=9 .8Hz,1H),1.98–1.90(m,1H),1.79–1.72(m,4H),1.66–1.59(m,1H),1.39(d,J=6.1Hz,5H),1.18(s,5 H),1.03–0.93(m,2H),0.81(d,J=9.9Hz,3H),0.45–0.36(m,2H),0.32(d,J=3.6Hz,2H),0.23(s,2H).

[1181] Example 51 Synthesis of compounds 51-P1 and 51-P2

[1182] Referring to Example 34, the intermediate is... The intermediate Int-28 was replaced with Int-6, and the preparation was carried out (using a Waters XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%, mobile phase B: MeCN; MeCN ratio 50%-70%, time: 13 min, flow rate: 15 mL / min) to obtain compound 51-P1 (retention time: 7.52 min) and compound 51-P2 (retention time: 8.52 min).

[1183] ...

Claims

1. A compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, X 1 and X 2 are each independently selected from N and C; L is selected from imino, -NH-, -N=, 4-10 membered heterocyclyl, C6-C 10 arylene and 5-12 membered heteroarylene, said imino, 4-10 membered heterocyclyl, C6-C 10 arylene and 5-12 membered heteroarylene is optionally substituted with 1 or more R L substituents; A is selected from C3-C 12 Cycloalkylene, 4-10 membered heterocyclic alkylene, C6-C 10 arylene and 5-12-membered heteroarylene, the C3-C 12 Cycloalkylene, 4-10 membered heterocyclic alkylene, C6-C 10 arylene and 5-12 heteroarylene are optionally enclosed by one or more R a replace; R 1 selected from the group consisting of Ci-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-12 membered heteroaryl, said Ci-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-12 membered heteroaryl are optionally substituted with 1 or more R 1a ; R 2 , R 3 , R 7 , R 8 and R 9 are independently selected from hydrogen, halogen, hydroxyl, cyano, Ci-C 10 alkyl, Ci-C 10 alkoxy, Ci-C 10 haloalkyl and C3-C7cycloalkyl; or R 2 and the atom to which they are attached together form a C3-C6cycloalkyl and 4-6 membered heterocyclyl, optionally substituted with 1 or more R 3 and the atom to which they are attached together form a C3-C6cycloalkyl and 4-6 membered heterocyclyl, optionally substituted with 1 or more R b substituents; R 4 selected from the group consisting of absent, hydrogen, halogen, hydroxyl, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C1-C 10 hydroxyalkyl, C1-C 10 haloalkyl, C3-C6cycloalkyl, and 4-6 membered heterocyclyl, said hydroxyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C1-C 10 hydroxyalkyl, C1-C 10 haloalkyl, C3-C6cycloalkyl, and 4-6 membered heterocyclyl optionally substituted with 1 or more R 4a substituents; or R 4 and the atom to which they are attached together form a 4-10 membered heterocyclyl ring, which is optionally substituted with 1 or more R 7 and the atom to which they are attached together form a 4-10 membered heterocyclyl ring, which is optionally substituted with 1 or more R d substituents; R 5 selected from 8-15 membered heterocyclyl and 8-15 membered heteroaryl, and said 8-15 membered heterocyclyl and 8-15 membered heteroaryl are bicyclic structures, said 8-15 membered heterocyclyl and 8-15 membered heteroaryl being optionally substituted with 1 or more R 5a substituents; R 6 Selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups and C1-C4 alkoxy groups, wherein the hydroxyl, mercapto, amino, C1-C4 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups and C1-C4 alkoxy groups are optionally surrounded by one or more R groups. 6a replace; R 10 selected from the group consisting of halogen, hydroxy, C1-C 10 alkyl, C1-C 10 haloalkyl, C1-C 10 hydroxy-substituted alkyl and C1-C 10 alkoxy; Each R a R b and R L Independently selected from halogens, amino groups, hydroxyl groups, mercapto groups, cyano groups, oxo groups, and C1-C4 alkyl groups; Each R 1a Independently selected from halogen, amino, hydroxyl, mercapto, cyano, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl and 5-12 heteroaryl 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 The radical is independently selected from halogen, amino, hydroxyl, mercapto, cyano, oxo, C1-C7 alkyl, C1-C7 haloalkyl, C3-C7 cycloalkyl, 4-6 membered heterocyclic, and C1-C7 alkoxy, wherein the amino, hydroxyl, mercapto, C1-C7 alkyl, C1-C7 haloalkyl, C3-C7 cycloalkyl, 4-6 membered heterocyclic, and C1-C7 alkoxy are optionally surrounded by one or more R... 2aa replace; Each R 6a Independently selected from halogen, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C3-C7 cycloalkyl and 4-6 membered heterocyclic groups; 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, P(O)R k R k SF5, 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, =O, S(O)2R k 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 halogen, hydroxyl, mercapto, cyano, amino, =O, =CR j R j C(O)R k S(O)2R k C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C4 alkylene O, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl)2, and -N(C1-C4 alkyl)2, wherein the hydroxyl, amino, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl, 5-10 heteroaryl, C1-C4 alkylene O, C1-C4 alkyl, C1-C4 alkoxy, -NH (C1-C4 alkyl) and -N (C1-C4 alkyl)2 optionally R n replace; Each R 1aa R 2aa The amino, hydroxyl, mercapto, cyano, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 3-7 heterocyclic, phenyl and 5-6 heteroaryl groups are independently selected from halogens, amino, hydroxyl, mercapto, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 3-7 heterocyclic, phenyl and 5-6 heteroaryl groups, which may be optionally substituted by one or more halogens, amino, hydroxyl, mercapto, cyano and C1-C4 alkyl groups; R j and R k Independently selected from H, halogen, hydroxyl, mercapto, cyano, amino, C1-C4 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 Alkoxy, hydroxyl, mercapto, amino, C1-C4 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 The alkoxy group may be optionally substituted with halogen, hydroxyl, mercapto, amino, =O, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic alkyl, N(C1-C4 alkyl)2 and NH(C1-C4 alkyl); R n selected from CN, =0, halogen, Ci-C4-alkyl, N(Ci-C4-alkyl)2and (Ci-C4-alkyl)S(0)2-; n is selected from a natural number from 0 to 6; one or more hydrogen atoms of the compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is optionally deuterium.

2. The compound of claim 1 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Excluded are molecules such as:

3. The compound of claim 1 or 2 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, X 1 is C; or X 1 is N; or X 2 is N; or X 1 is C, and X 2 is N; or X 1 is N, and X 2 is C.

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

5. The compound of any one of claims 1-4 of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, L is selected from imino, and 4-10 membered heterocyclylidene, said imino and 4-10 membered heterocyclylidene optionally substituted with R L ; or L is selected from imino, said imino, optionally substituted with R L ; or L is selected from imino, said imino optionally substituted with R L ; or L is selected from imino, or L is selected from imino, or L is selected from imino, said imino optionally substituted with R L ; or L is selected from imino; or, L is selected from or L is or L is wherein # represents the point of attachment to R 1 .

6. The compound of any one of claims 1-5 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 1 selected from C1-C 10 alkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, and 5-12 membered heteroaryl, said C1-C 10 alkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, and 5-12 membered heteroaryl are optionally substituted with 1 or more R 1a ; or R 1 is selected from cyclopropyl, azetidinyl, pyrrolidinyl, oxetanyl, oxetanyl, pyrazolidinyl, thiazolidinyl, isoxazolidinyl, tetrazolyl, methyl, isopropyl, and pentyl, said cyclopropyl, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolidinyl, thiazolidinyl, isoxazolidinyl, tetrazolyl, methyl, isopropyl, and pentyl are optionally substituted with 1 or more R 1a ; or R 1 is selected from cyclopropyl, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolidinyl, thiazolidinyl, isoxazolidinyl, tetrazolyl, methyl, isopropyl, and pentyl, said cyclopropyl, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolidinyl, thiazolidinyl, isoxazolidinyl, tetrazolyl, methyl, isopropyl, and pentyl are optionally substituted with 1 or more R 1a ; or R 1 is selected from cyclopropyl, pyrrolidinyl, oxetanyl, pyrazolidinyl, thiazolidinyl, isoxazolidinyl, tetrazolyl, methyl, isopropyl, and pentyl, said cyclopropyl, pyrrolidinyl, oxetanyl, pyrazolidinyl, thiazolidinyl, isoxazolidinyl, tetrazolyl, methyl, isopropyl, and pentyl are optionally substituted with 1 or more R 1a ; or R 1 is selected from cyclopropyl, methyl, isopropyl, and said cyclopropyl, methyl, isopropyl, and are optionally substituted with 1 or more R 1a ; or R 1 is selected from isopropyl, ; or R 1 is selected from ; or R 1 is selected from ; or R 1 is selected from or R 1 selected from or R 1 is or R 1 is and / or, Each R 1a Independently selected from halogens, C1-C 10 Alkyl, C3-C 10 cycloalkyl and 5-12-membered heteroaryl groups, the C1-C 10 Alkyl, C3-C 10 Cycloalkyl 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-C5 alkyl groups, C3-C6 cycloalkyl groups, and 5-6 heteroaryl groups, wherein the C1-C5 alkyl groups, C3-C6 cycloalkyl groups, and 5-6 heteroaryl groups are optionally surrounded by one or more R... 1aa Replace; or each R 1a The radical is independently selected from fluorine, methyl, pyrimidinyl, pentyl, n-propyl, isopropyl, hydroxyl, and cyclopropyl, wherein the methyl, pyrimidinyl, pentyl, n-propyl, isopropyl, hydroxyl, and cyclopropyl groups are optionally prefixed with one or more R groups. 1aa Replace; or each R 1a The groups are independently selected from fluorine, methyl, pyrimidinyl, pentyl, and cyclopropyl, wherein the methyl, pyrimidinyl, pentyl, and cyclopropyl groups are optionally prefixed with one or more R groups. 1aa replace; and / or, each R 1aa is independently selected from the group consisting of halogen, amino, hydroxy, thiol and cyano; or each R 1aa is independently selected from the group consisting of halogen, C1-C4 alkyl, C3-C6 cycloalkyl and phenyl; or each R 1aa is independently selected from the group consisting of halogen, methyl, cyclopropyl and phenyl, the halogen preferably being fluorine; or each R 1aa is independently selected from the group consisting of halogen; or R 1aa is fluorine.

7. The compound of any one of claims 1-6 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 2 , R 3 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano and Ci-C4alkyl; or R 10 and R 2 are both hydrogen; or R 3 and R 2 are both methyl. 3 and R 3 are both methyl.

8. The compound of any one of claims 1-7 of Formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 4 Selected from C1-C 10 Alkyl, C1-C 10 Hydroxyalkyl, C1-C 10 Halogenated alkyl groups and C3-C7 cycloalkyl groups, wherein the C1-C 10 Alkyl, C1-C 10 Hydroxyalkyl, C1-C 10 The haloalkyl and C3-C7 cycloalkyl groups are optionally surrounded by one or more R... 4a Replace; or R 4 Selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, and C3-C6 cycloalkyl, wherein the C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, and C3-C6 cycloalkyl are optionally prefixed with one or more R... 4a Replace; or R 4 Selected from C1-C 10 Alkyl and C3-C6 cycloalkyl, wherein C1-C 10 Alkyl and C3-C6 cycloalkyl groups are optionally separated by one or more R 4a Replace; or R 4 Selected from C1-C4 alkyl and C3-C6 cycloalkyl, wherein the C1-C4 alkyl and C3-C6 cycloalkyl are optionally separated by one or more R 4a Replace; or R 4 Selected from ethyl, cyclopropyl, and cyclobutyl, wherein the ethyl, cyclopropyl, and cyclobutyl groups are optionally marked with one or more R... 4a Replace; or R 4 The group is selected from methyl, ethyl, trifluoroethyl, hydroxyethyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, trifluoroethyl, hydroxyethyl, cyclopropyl, and cyclobutyl groups are optionally marked with one or more R groups. 4a Replace; or R 4 The group is selected from ethyl, trifluoroethyl, hydroxyethyl, cyclopropyl, and cyclobutyl, wherein the ethyl, trifluoroethyl, hydroxyethyl, cyclopropyl, and cyclobutyl groups are optionally marked with one or more R groups. 4a Replace; or R 4 Selected from ethyl, trifluoroethyl, Or R 4 Selected from ethyl, trifluoroethyl, cyclopropylmethyl, Or R 4 Selected from ethyl, trifluoroethyl, cyclopropylmethyl, Or R 4 Selected from ethyl, trifluoroethyl, Or R 4 Selected from ethyl, trifluoroethyl, Or R 4 Selected from ethyl, Or R 4 selected from ethyl, trifluoroethyl; or R 4 is selected from or R 4 is and / or, each R 4a and R d is independently selected from the group consisting of halogen, amino, hydroxyl, thiol, cyano, C1-C7alkyl, C1-C7haloalkyl, and C1-C7alkoxy; or each R 4a is independently selected from the group consisting of cyano, C3-C7cycloalkyl, and 4-6 membered heterocyclyl, said C3-C7cycloalkyl and 4-6 membered heterocyclyl optionally substituted with 1 or more R 2aa ; or each R 4a is independently selected from the group consisting of cyano, cyclopropyl, tetrahydropyranyl, and said cyclopropyl, tetrahydropyranyl and optionally substituted by 1 or more R 2aa ; or each R 4a is independently selected from the group consisting of cyano, cyclopropyl and tetrahydropyranyl, said cyclopropyl and tetrahydropyranyl being optionally substituted by 1 or more R 2aa ; or each R 4a is independently selected from the group consisting of halogen, amino, hydroxy, thiol, cyano, cyclopropyl, or each R is independently selected from the group consisting of halogen, amino, hydroxy, thiol, and cyano; or each R 4a is independently selected from the group consisting of halogen, amino, hydroxy, thiol, and cyano; or each R 4a is independently selected from the group consisting of halogen and cyano; or each R 4a is independently selected from the group consisting of fluorine and cyano; or R 4a is cyano.

9. The compound of any one of claims 1-8 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 5 selected from 9-10 membered heteroaryl, and said 9-10 membered heteroaryl is a bicyclic structure, said 9-10 membered heteroaryl is optionally substituted with 1 or more R 5a ; or R 5 selected from 9-10 membered heteroaryl, and said 9-10 membered heteroaryl is a bicyclic structure, said 9-10 membered heteroaryl is optionally substituted with 1 or more R 5a ; or R 5 selected from 9-10 membered heteroaryl, and said 9-10 membered heteroaryl is a bicyclic structure, said 9-10 membered heteroaryl is optionally substituted with 1 or more R 5a ; or R wherein Y is CH or N, Z is C or N, Q is C or N, ring C is selected from 5-7 membered monocyclic heterocyclic ring, phenyl ring and 5-6 membered heteroaromatic ring; or R 5 selected from 9-10 membered heteroaryl, and said 9-10 membered heteroaryl is a bicyclic structure, said 9-10 membered heteroaryl is optionally substituted with 1 or more R 5a ; or R wherein Y is CH or N, Z is C or N, Q is C or N, ring C is selected from phenyl ring and 5-6 membered heteroaromatic ring; or R 5 selected from said optionally substituted with 1 or more R 5a ; or R 5 selected from said optionally substituted with 1 or more R 5a ; or R 5 selected from said optionally substituted with 1 or more R 5a ; or R 5 selected from and / or, Each R 5a Independently selected from halogen, cyano, amino, oxo, C1-C 10 Alkyl, C2-C 10 alkynyl group, C3-C 12 Cycloalkyl and 3-14 membered heterocyclic groups, wherein the amino group, C1-C 10 Alkyl, C2-C 10 alkynyl group, 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 The radical is independently selected from halogen, cyano, amino, oxo, C1-C4 alkyl, C2-C4 ynyl, C3-C5 cycloalkyl, and 3-6 membered heterocyclic groups, wherein the amino, C1-C4 alkyl, C2-C4 ynyl, C3-C5 cycloalkyl, and 3-6 membered heterocyclic groups are optionally surrounded by one or more R groups. c Replace; or each R 5a Independently selected from halogen, cyano, amino, C1-C 10 Alkyl groups and 3-14 membered heterocyclic groups, wherein the amino group, C1-C 10 Alkyl groups and 3-14 membered heterocyclic groups are optionally surrounded by one or more R groups. c Replace; or each R 5a The radical is independently selected from halogen, cyano, amino, C1-C4 alkyl, and 3-6 membered heterocyclic groups, wherein the amino, C1-C4 alkyl, and 3-6 membered heterocyclic groups are optionally surrounded by one or more R groups. c Replace; or, each R 5a Independently selected from fluorine, iodine, amino, ethoxy, cyano, methyl, ethyl, piperazine, piperidinyl, morpholino, ethenyl, ethynyl, propynyl, oxo, cyclopropyl, and tetrahydropyrrolyl, said amino, ethoxy, methyl, ethyl, piperazinyl, piperidinyl, morpholinyl, ethynyl, propynyl, cyclopropyl, and tetrahydropyrrolyl are optionally substituted with 1 or more R c each R 5a is independently selected from the group consisting of fluoro, iodo, amino, cyano, methyl, ethyl, piperazinyl, piperidinyl, propynyl, oxo, cyclopropyl and tetrahydropyrrolyl, said amino, methyl, ethyl, piperazinyl, piperidinyl, propynyl, cyclopropyl, and tetrahydropyrrolyl are optionally substituted with 1 or more R c each R 5a is independently selected from the group consisting of fluoro, iodo, amino, cyano, methyl, ethyl, piperazinyl, piperidinyl, and tetrahydropyrrolyl, said amino, methyl, ethyl, piperazinyl, piperidinyl, and tetrahydropyrrolyl is optionally substituted with 1 or more R c each R is independently selected from the group consisting of fluoro, iodo, amino, ethoxy, cyano, P(O)CH3CH3, SF5, methyl, ethyl, piperazinyl, piperidinyl, 5a each R is independently selected from the group consisting of fluoro, iodo, amino, ethoxy, cyano, P(O)CH3CH3, SF5, methyl, ethyl, piperazinyl, piperidinyl, ethenyl, propenyl, oxo, cyclopropyl, cyclohexyl, tetrahydropyranyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, cyclobutyl, and tetrahydropyrrolyl, said amino, ethoxy, methyl, ethyl, piperazinyl, piperidinyl, ethynyl, propynyl, cyclopropyl, cyclohexyl, tetrahydropyranyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, cyclobutyl, and tetrahydropyrrolyl groups are optionally substituted with 1 or more R c substituents; and / or, Each R c Independently selected from halogens, amino groups, =O, and S(O)2R k C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl and 4-12 membered heterocyclic groups, wherein the amino, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl groups and 4-12 membered heterocyclic groups are optionally surrounded by one or more R groups. e Replace; or each R c Independently selected from amino, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl and 4-12 membered heterocyclic groups, wherein the amino, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl groups and 4-12 membered heterocyclic groups are optionally surrounded by one or more R groups. e Replace; or each R c The amino group, C1-C4 alkyl group, C1-C4 alkoxy group, C3-C5 cycloalkyl group, and 4-7 membered heterocyclic group are independently selected from amino, C1-C4 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, and 4-7 membered heterocyclic groups, which are optionally surrounded by one or more R groups. e Replace; or, each R c Independently selected from amino, methyl, ethyl, methoxy, cyclopropyl, oxetyl, cyclobutyl, aziridine, morpholino, piperidinyl, isopropyl, piperazine, said amino group, methyl group, ethyl group, methoxy group, cyclopropyl group, oxetanyl group, cyclobutyl group, azetidinyl group, morpholinyl group, piperidinyl group, isopropyl group, piperazinyl group, optionally substituted with 1 or more R e ; or each R c is independently selected from amino, methyl, ethyl, methoxy, cyclopropyl, oxetanyl, cyclobutyl, azetidinyl, morpholinyl, piperidinyl, isopropyl, piperazinyl, said amino group, methyl group, ethyl group, methoxy group, cyclopropyl group, oxetanyl group, cyclobutyl group, azetidinyl group, morpholinyl group, piperidinyl group, isopropyl group, piperazinyl group, optionally substituted with 1 or more R e ; or each R c is independently selected from amino, methyl, ethyl, methoxy, cyclopropyl, oxetanyl, cyclobutyl, azetidinyl, morpholinyl, piperidinyl, isopropyl, said amino group, methyl group, ethyl group, methoxy group, cyclopropyl group, oxetanyl group, cyclobutyl group, azetidinyl group, morpholinyl group, piperidinyl group, isopropyl group, optionally substituted with 1 or more R e ; or each R c is independently selected from amino, methyl, ethyl, methoxy, cyclopropyl, oxetanyl, cyclobutyl, azetidinyl, morpholinyl, said amino group, methyl group, ethyl group, methoxy group, cyclopropyl group, oxetanyl group, cyclobutyl group, azetidinyl group, morpholinyl group, optionally substituted by 1 or more R e ; or each R c is independently selected from fluoro, amino, =0, S(0)2CH3, methyl, ethyl, methoxy, cyclopropyl, oxetanyl, cyclobutyl, azetidinyl, morpholinyl, piperidinyl, isopropyl, piperazinyl, tetrahydropyrrolyl, said amino group, methyl group, ethyl group, methoxy group, cyclopropyl group, oxetanyl group, cyclobutyl group, azetidinyl group, morpholinyl group, piperidinyl group, isopropyl group, piperazinyl group, tetrahydropyrrolyl group, optionally substituted by 1 or more R e substituents; and / or, Each R e Independently selected from halogen, hydroxyl, mercapto, cyano, amino, =O, =CR j R j C(O)R k S(O)2R k C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclic, C1-C4 alkylene, C1-C4 alkyl, C1-C4 alkoxy, -NH (C1-C4 alkyl) and -N (C1-C4 alkyl)2; or, each R e Independently selected from halogen, cyano, C1-C4 alkoxy, =O, =CR j R j S(O)2R k C1-C4 alkyl, C1-C4 hydroxyalkyl, amino, C3-C6 cycloalkyl, and 4-7 membered heterocyclic groups, wherein the C1-C4 alkoxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, amino, C3-C6 cycloalkyl, and 4-7 membered heterocyclic groups are optionally R n Replace; or, each R e Independently selected from fluorine, cyano, methyl, ethyl, OMe, =O, =CF2, S(O)2CH3, -CH2OH, amino, cyclopropyl and said methyl, ethyl, OMe, -CH2OH, amino, cyclopropyl and optionally substituted with R n ; or each R e is independently selected from the group consisting of halogen, cyano, =0, =CR j R j , S(O)2R k , C1-C4 alkyl, C1-C4 hydroxyalkyl, and -N(C1-C4 alkyl)2; or each R e is independently selected from the group consisting of fluorine, cyano, OMe, =0, =CF2, S(O)2CH3, methyl, -CH2OH, -N(CH3)CH3, CH2CN, or each R is independently selected from the group consisting of fluoro, cyano, =0, =CF2, S(O)2CH3, methyl, -CH2OH, and -N(CH3)CH3; or each R e is independently selected from the group consisting of fluoro, cyano, =0, =CF2, S(O)2CH3, methyl, -CH2OH, and -N(CH3)CH3; or each R e is independently selected from the group consisting of halo, cyano, =0, C1-C4 alkyl, and -N(C1-C4 alkyl)2; or each R e is independently selected from the group consisting of =0, fluoro, methyl, cyano, and -N(CH3)CH3; or each R e is independently selected from the group consisting of fluoro, cyano, hydroxyl, OMe, =0, =CF2, S(O)2CH3, methyl, -CH2OH, -N(CH3)CH3, tetrahydropyrrolyl, CH2CN, and / or, R n selected from halogen, cyano, (Ci-C4alkyl)S(O)2- and Ci-C4alkyl; or, R n is selected from F, cyano, S(O)2CH3and methyl.

10. The compound of any one of claims 1-9 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 6 selected from hydrogen, halogen, amino, hydroxyl, thiol, cyano, C1-C4alkyl, C1-C4haloalkyl, and C1-C4alkoxy; or R 6 selected from hydrogen, halogen, hydroxyl, thiol, C1-C4alkyl, C1-C4alkoxy, and 4-10 membered heterocyclyl, which hydroxyl, thiol, C1-C4alkyl, C1-C4alkoxy, and 4-10 membered heterocyclyl are optionally substituted with one or more R 6a ; or R 6 selected from hydrogen, C1-C4alkoxy, and 4-10 membered heterocyclyl, which C1-C4alkoxy and 4-10 membered heterocyclyl are optionally substituted with one or more R 6a ; or R 6 selected from hydrogen and C1-C4alkoxy; or R 6 is hydrogen or ethoxy; or R 6 selected from hydrogen, ethoxy, morpholinyl, azetidinyl, pyrrolidinyl, and the ethoxy, morpholinyl, azetidinyl, pyrrolidinyl, and which is optionally substituted with one or more R 6a ; or R 6 selected from hydrogen, ethoxy, morpholinyl, pyrrolidinyl, and ; or R 6 selected from hydrogen, ethoxy, and ; or R 6 is ; or R 6 is hydrogen; and / or, R 7 selected from hydrogen, halogen, hydroxyl, and cyano; or R 7 is hydrogen; and / or, R 8 selected from hydrogen, halogen, hydroxyl, cyano and Ci-C 10 alkyl; or R 8 is hydrogen; and / or, R 9 selected from hydrogen, halogen, hydroxyl, and cyano; or R 9 is hydrogen; and / or, R 10 selected from halogen, such as fluorine; and / or, n is 0, 1 or 2; or n is 0.

11. The compound of claim 1 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (II) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof: wherein A, L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined in claim 1.

12. The compound of claim 1 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (III) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: wherein R 4 is selected from the group consisting of C1-C 10 alkyl, C1-C 10 hydroxyalkyl and C3-C7 cycloalkyl, said C1-C 10 alkyl, C1-C 10 hydroxyalkyl and C3-C7 cycloalkyl are optionally substituted with one or more R 4a ; more preferably R 4 is selected from the group consisting of C1-C4 alkyl, C1-C4 hydroxyalkyl and C3-C6 cycloalkyl, said C1-C4 alkyl, C1-C4 hydroxyalkyl and C3-C6 cycloalkyl are optionally substituted with one or more R 4a ; more preferably R 4 is selected from the group consisting of methyl, ethyl, hydroxyethyl, cyclopropyl and cyclobutyl, said methyl, ethyl, hydroxyethyl, cyclopropyl and cyclobutyl are optionally substituted with one or more R 4a ; more preferably R 4 is selected from the group consisting of R 6 Selected from halogen, amino, hydroxyl, mercapto, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups and C1-C4 alkoxy groups, wherein the hydroxyl, mercapto, amino, C1-C4 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups and C1-C4 alkoxy groups are optionally surrounded by one or more R groups. 6a Replace; more preferably R 6 Selected from C1-C4 alkoxy groups and 4-10 membered heterocyclic groups, wherein the C1-C4 alkoxy groups and 4-10 membered heterocyclic groups are optionally surrounded by one or more R... 6a Replace; more preferably R 6 Selected from ethoxy, morpholinyl, pyrrolidinyl and A, L, R 1 A, L, R 2 A, L, R 3 A, L, R 4a A, L, R 5 A, L, R 6a A, L, R 7 A, L, R 8 A, L, R 9 A, L, R 13. The compound of claim 1 of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from the following compounds or a pharmaceutically acceptable salt thereof, 14. A pharmaceutical composition comprising the compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1-13 and a pharmaceutically acceptable excipient.

15. Use of the compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1-13, or the pharmaceutical composition according to claim 14, for the manufacture of a medicament for the prevention or treatment of a RAS-mediated disease; optionally, the RAS-mediated disease is a tumor; optionally, the RAS-mediated disease is non-small cell lung cancer, pancreatic cancer and colorectal cancer.

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