Ras inhibitor and 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

RAS inhibitors and their uses

[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. 202510022392.X, filed with the China National Intellectual Property Administration on January 7, 2025;

[0004] Chinese Patent Application No. 202511228087.2, filed with the China National Intellectual Property Administration on August 29, 2025;

[0005] Chinese Patent Application No. 202511674807.8, filed with the China National Intellectual Property Administration on November 14, 2025; and

[0006] Chinese Patent Application No. 202511918454.1 was filed with the China National Intellectual Property Administration on December 18, 2025. Technical Field

[0007] This disclosure pertains to the field of pharmaceutical technology, specifically relating 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

[0008] 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 a reasonable amount of time, effort, and resources could be devoted to discovering small molecule regulators for most (if not all) proteins. 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 difficult to treat or manage with the aforementioned small molecule drugs. These targets are often referred to as “undruggable.” A large portion of these undruggable targets, or medically important human proteins, 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

[0009] This disclosure relates to compounds of formula (I) or their stereoisomers or pharmaceutically acceptable salts.

[0010] in,

[0011] X 1 and X 2 Each is independently selected from N and C;

[0012] L is selected from

[0013] Alternatively, L is connected to ring A to form

[0014] A is selected from C3-C 12 subcycloalkyl, 4- to 10-membered hetero-subcycloalkyl, C6-C 10 subaryl, and 5- to 12-membered hetero-subaryl, and the C3-C 12 subcycloalkyl, 4- to 10-membered hetero-subcycloalkyl, C6-C 10 subaryl, and 5- to 12-membered hetero-subaryl are optionally substituted with one or more R a substituents;

[0015] R 1 、R 11 and R 15 are independently selected from hydrogen, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C 10 aryl, and 5- to 12-membered heteroaryl, and the C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C 10 aryl, and 5- to 12-membered heteroaryl are optionally substituted with one or more R 1a substituents;

[0016] Alternatively, R 1 and R 11 and the carbon atom to which they are attached together form a carbonyl group;

[0017] R 2 、R 3 、R 7 、R 8 and R 9 are independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C 10 alkyl, C1-C 10 alkoxy, C1-C 10 haloalkyl, and C3-C7 cycloalkyl;

[0018] Alternatively, R 2 and R 3 and the atoms to which they are attached together form a C3-C6 cycloalkyl and a 4- to 6-membered heterocycloalkyl, and the C3-C6 cycloalkyl and the 4- to 6-membered heterocycloalkyl are optionally substituted with one or more R b substituents;

[0019] R 4 selected from absent, hydrogen, halogen, hydroxyl, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclic group, -C1-C3 alkylene-(C3-C6 cycloalkyl) and -C1-C3 alkylene-(4- to 6-membered heterocyclic group), and the hydroxyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclic group, -C1-C3 alkylene-(C3-C6 cycloalkyl) and -C1-C3 alkylene-(4- to 6-membered heterocyclic group) are optionally substituted by one or more R 4a substituents;

[0020] Alternatively, R 4 and R 7 and the atoms to which they are attached together form a 4- to 10-membered heterocyclic ring, and the 4- to 10-membered heterocyclic ring is optionally substituted by one or more R d substituents;

[0021] R 5 is selected from -O-5- to 10-membered heteroaryl, -S-5- to 10-membered heteroaryl, -NH-5- to 10-membered heteroaryl, 8- to 15-membered heterocyclic group and 8- to 15-membered heteroaryl, and the 8- to 15-membered heterocyclic group and 8- to 15-membered heteroaryl are bicyclic or tricyclic structures, and the -O-5- to 10-membered heteroaryl, -S-5- to 10-membered heteroaryl, 8- to 15-membered heterocyclic group and 8- to 15-membered heteroaryl are optionally substituted by one or more R 5a substituents;

[0022] R 6 is selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy;

[0023] R 10 is selected from halogen, hydroxyl, C1-C 10 alkyl, C1-C 10 haloalkyl, C1-C 10 hydroxyalkyl and C1-C 10 alkoxy;

[0024] L 1 is selected from a bond and -N(R 13 )C(O)-;

[0025] B is selected from a bond and 4- to 14-membered heterocyclic group, and the 4- to 14-membered heterocyclic group is optionally substituted by one or more R f substituents;

[0026] L2 Selected from carbonyl and -C1-C 10 Alkylene-N(R) 14 )C(O)-;

[0027] Q is selected from C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne group, C3-C6 cycloalkyl group and 3-6 membered heterocyclic group, wherein C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 The alkynyl group or C3-C6 cycloalkyl group is optionally surrounded by one or more R groups. q replace;

[0028] R 13 R 14 and R 16 Independently selected from hydrogen, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl groups and C1-C 10 Hydroxyalkyl;

[0029] X is selected from O and methylene;

[0030] Z is selected from a 3-10 nucleotide heterocyclic group, a C1-C6 alkylene group, or a 5-10 nucleotide heteroaryl group, wherein the 3-10 nucleotide heterocyclic group, the C1-C6 alkylene group, or the 5-10 nucleotide heteroaryl group is optionally replaced by R. z replace;

[0031] Each R z Independently selected from -L 2 -Q;

[0032] Each R q Independently selected from halogens, amino groups, hydroxyl groups, mercapto groups, cyano groups, oxo groups, C1-C4 alkyl groups, C3-C6 cycloalkyl groups, phenyl groups, 5-6 heteroaryl groups, and -C(O)-C groups. 2-4 alkenyl, said amino, hydroxyl, mercapto, C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, 5-6 heteroaryl and -C(O)-C 2-4 Alkenyl groups are optionally surrounded by one or more R groups. g replace;

[0033] Each R a R b and R g Independently selected from halogens, amino groups, hydroxyl groups, mercapto groups, cyano groups, oxo groups, and C1-C4 alkyl groups;

[0034] Each R 1a Independently selected from halogen, amino, hydroxyl, mercapto, cyano, C1-C 10Alkyl, 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;

[0035] Each R 4a and R d The radical is independently selected from halogen, amino, hydroxyl, mercapto, cyano, C1-C7 alkyl, C1-C7 haloalkyl, and C1-C7 alkoxy, wherein the amino, hydroxyl, mercapto, C1-C7 alkyl, C1-C7 haloalkyl, and C1-C7 alkoxy are optionally surrounded by one or more R... h replace;

[0036] Each R 5a Independently selected from halogen, hydroxyl, cyano, amino, oxo, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-14 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups, wherein the hydroxyl, amino, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-14 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one or more R groups. c replace;

[0037] Each R c Independently selected from halogen, amino, hydroxyl, mercapto, cyano, oxo, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the amino, hydroxy, mercapto, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl groups or 3-12-membered heterocyclic groups are optionally surrounded by one or more R groups. e replace;

[0038] Each R e and R fIndependently 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;

[0039] Each R h Independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups;

[0040] Each R 1aa Independently selected from halogen, amino, hydroxyl, mercapto, and cyano groups;

[0041] n is a natural number selected from 0 to 6;

[0042] One or more hydrogen atoms in the compound of formula (I) may be selected as deuterium atoms.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] In some embodiments, A is selected from 5-6-membered heterocyclic groups and 5-6-membered heteroaryl groups, each of which independently contains one or two heteroatoms independently selected from N, O, and S, and is optionally surrounded by one or more R atoms. a replace.

[0047] 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.

[0048] In some embodiments, A is selected from imidazolyl, imidazolinyl, and imidazolyl, wherein the imidazolyl, imidazolinyl, and imidazolyl are optionally surrounded by one or more R groups. a replace.

[0049] In some implementation schemes, A is selected from The Optional R a Replacement. In some implementations, A is selected from... The Optional R a Replacement. In some implementations, A is selected from... The Optional by one or more R a Substitution, where * represents the end connected to the benzene ring.

[0050] In some implementation schemes, A is selected from The Optional by one or more R a replace.

[0051] 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.

[0052] In some implementation schemes, each R a It is independently selected from halogen, amino, hydroxyl, mercapto and cyano groups.

[0053] In some implementation schemes, A is selected from In some implementation schemes, A is The asterisk (*) represents the end connected to the benzene ring.

[0054] In some implementation schemes, A is

[0055] In some implementation schemes, A is The asterisk (*) indicates the end connected to the benzene ring.

[0056] In some implementation schemes, L is selected from

[0057] In some implementation schemes, L is selected from

[0058] In some implementation schemes, L is selected from

[0059] In some implementation schemes, R 1and R 15 Independently selected from C1-C 10 Alkyl, C3-C 10 cycloalkyl, the C1-C 10 Alkyl, C3-C 10 The cycloalkyl group is optionally surrounded by one or more R 1a replace.

[0060] In some implementation schemes, R 1 and R 15 Independently selected from isopropyl and cyclopentyl, wherein the isopropyl and cyclopentyl groups are optionally separated by one or more R groups. 1a replace.

[0061] In some implementation schemes, R 1 and R 15 It can be cyclopentyl or isopropyl.

[0062] In some implementation schemes, R 1 Selected from C1-C 10 Alkyl, C3-C 10 cycloalkyl, the C1-C 10 Alkyl, C3-C 10 The cycloalkyl group is optionally surrounded by one or more R 1a replace.

[0063] In some implementation schemes, R 1 Selected from C1-C6 alkyl and C3-C6 cycloalkyl groups, wherein the C1-C6 alkyl and C3-C6 cycloalkyl groups are optionally surrounded by one or more R groups. 1a replace.

[0064] In some implementation schemes, R 1 Selected from isopropyl and cyclopentyl, wherein the isopropyl and cyclopentyl groups are optionally converted by one or more R groups. 1a replace.

[0065] In some implementation schemes, R 1 Selected from isopropyl and cyclopentyl.

[0066] In some implementation schemes, R 15 It is cyclopentyl.

[0067] In some implementation schemes, R 11 It is hydrogen.

[0068] In some implementation schemes, R 1 It is cyclopentyl and isopropyl, R 11 It is hydrogen; or R 1 and R 11 Together with the carbon atoms they are attached to, they form a carbonyl group.

[0069] In some implementation schemes, R1 and R 11 Together with the carbon atoms they are attached to, they form a carbonyl group.

[0070] In some implementations, L 1 Selected from the bond and -N(CH3)C(O)-. In some implementations, L 1 For key.

[0071] In some implementations, L 1 Selected from the bond and -N(CH3)C(O)-*, where * is the end connected to B.

[0072] In some embodiments, B is selected from a bond and a 6-13 membered subheterocyclic group, wherein the 6-13 membered subheterocyclic group is optionally surrounded by one or more R groups. f replace.

[0073] In some implementations, B is selected from bonds, piperidinyl groups, The piperinyl group, and Optional by one or more R f Replacement. In some implementations, each R f It is independently selected from halogens and C1-C4 alkyl groups.

[0074] In some implementation schemes, each R f It is independently selected from fluorine and methyl.

[0075] In some implementations, B is the key.

[0076] In some implementation schemes, B is

[0077] In some implementations, L 2 Selected from carbonyl and -C1-C4 alkylene-N(CH3)C(O)-.

[0078] In some implementations, L 2 Selected from carbonyl and methylene-N(CH3)C(O)-.

[0079] In some implementations, L 2 Selected from carbonyl and methylene-N(CH3)C(O)-*, where * is the end connected to Q.

[0080] In some implementations, L 2 It is a carbonyl group.

[0081] In some implementations, L 1 As the key, and L 2 It is a carbonyl group.

[0082] In some implementations, Q is selected from C2-C 10 Alkyne group and 3-6 membered heterocyclic group, the C2-C 10 The alkynyl group and the 3-6 membered heterocyclic group are optionally coupled with one or more R groups. q replace.

[0083] In some embodiments, Q is selected from C2-C5 ynyl groups and 3-6-membered heterocyclic groups, wherein the C2-C5 ynyl group and the 3-6-membered heterocyclic group are optionally surrounded by one or more R groups. q replace.

[0084] In some embodiments, Q is selected from azircyclic propyl, oxetyl, and... The aziridine, oxadiazine and Optional by one or more R q replace.

[0085] In some implementation schemes, each R q Independently selected from amino, oxo, C1-C4 alkyl, and C3-C6 cycloalkyl groups, wherein the amino, C1-C4 alkyl, and C3-C6 cycloalkyl groups are optionally surrounded by one or more R... g replace.

[0086] In some implementation schemes, each R q The amino, oxo, methyl, and cyclopropyl groups are independently selected from amino, methyl, and cyclopropyl groups, wherein the amino, methyl, and cyclopropyl groups are optionally surrounded by one or more R groups. g replace.

[0087] In some implementation schemes, each R g It is independently selected from halogens and C1-C4 alkyl groups.

[0088] In some implementation schemes, R g It is a methyl group.

[0089] In some implementation schemes, each R q It is independently selected from -N(CH3)2, oxo, methyl and cyclopropyl.

[0090] In some implementations, Q is selected from...

[0091] In some implementations, -L 2 -Q is selected from

[0092] In some implementations, -L 2 -Q is selected from

[0093] In some implementations, -L 2 -Q is selected from

[0094] In some implementations, -L 2 -Q is selected from

[0095] In some implementation schemes, L is selected from

[0096] In some implementation schemes, L is selected from

[0097] In some embodiments, Z is selected from 3-10 cyclic subheterocyclic groups, wherein the 3-10 cyclic subheterocyclic group is optionally replaced by R. z replace.

[0098] In some embodiments, Z is selected from piperidinyl groups, which are optionally converted by R. z replace.

[0099] In some implementation schemes, Z is selected from

[0100] In some implementation schemes, Z is

[0101] In some implementation schemes, Z is

[0102] In some implementations, X is oxygen.

[0103] In some implementation schemes, R 16 Selected from C1-C4 alkyl groups.

[0104] In some implementation schemes, R 16 It is a methyl group.

[0105] In some implementation schemes, for

[0106] In some implementation schemes, R 2 R 3 Independently selected from hydrogen, halogen, hydroxyl, cyano and C1-C 10 alkyl.

[0107] In some implementation schemes, R 2 R 3 It is independently selected from C1-C4 alkyl groups, such as methyl.

[0108] In some implementation schemes, R 2 R 3 All are methyl groups.

[0109] 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.

[0110] 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; 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] In some implementation schemes, R 4 Selected from -C1-C2 alkyl-(C3-C6 cycloalkyl) and -C1-C2 alkyl-(4-6 membered heterocyclic group), wherein the -C1-C2 alkyl-(C3-C6 cycloalkyl) and -C1-C2 alkyl-(4-6 membered heterocyclic group) are optionally surrounded by one or more R 4a replace.

[0116] In some implementation schemes, R 4 Selected from -CH2-(C3-C6 cycloalkyl) and -CH2-(4-6 membered heterocyclic group), wherein the -CH2-(C3-C6 cycloalkyl) and -CH2-(4-6 membered heterocyclic group) are optionally surrounded by one or more R 4a Replacement. In some implementations, R 4 The group selected from -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-azacyclobutyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -CH2-oxacyclobutyl, -CH2-thiocyclobutyl, and -CH2-tetrahydropyranyl, wherein the -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-azacyclobutyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -CH2-oxacyclobutyl, -CH2-thiocyclobutyl, and -CH2-tetrahydropyranyl groups are optionally marked with one or more R... 4a replace.

[0117] In some implementation schemes, R 4 Selected from one or more R 4a Substituted -CH2-oxocyclic butyl.

[0118] In some implementation schemes, each R 4a It is independently selected from halogen, amino, hydroxyl, mercapto and cyano groups.

[0119] In some implementation schemes, each R 4a The group is independently selected from fluorine, hydroxyl, and cyano groups, wherein the hydroxyl group is optionally R h replace.

[0120] In some implementation schemes, each R 4a It is independently selected from fluorine and cyano groups.

[0121] In some implementation schemes, R h It is selected from 4-6 membered heterocyclic groups, preferably tetrahydropyranyl.

[0122] In some implementation schemes, R 4Selected from ethyl, trifluoroethyl,

[0123] In some implementation schemes, R 4 Selected from C2H5-, CF3CH2-,

[0124] In some implementation schemes, R 4 Selected from ethyl, trifluoroethyl,

[0125] In some implementation schemes, R 4 Selected from ethyl, trifluoroethyl,

[0126] In some implementation schemes, R 4 Selected from ethyl, trifluoroethyl and

[0127] In some implementation schemes, R 4 Selected from

[0128] In some implementation schemes, R 4 It is ethyl. In some embodiments, R 4 It is CF3CH2-.

[0129] In some implementation schemes, R 5 The compounds are selected from -O-5-10-membered heteroaryl, -NH-5-10-membered heteroaryl, 9-15-membered heterocyclic, and 9-10-membered heteroaryl, wherein the 9-15-membered heterocyclic and 9-10-membered heteroaryl are bicyclic or tricyclic structures, and the -O-5-10-membered heteroaryl, -NH-5-10-membered heteroaryl, 9-15-membered heterocyclic, and 9-10-membered heteroaryl are optionally separated by one or more R... 5a replace.

[0130] In some implementation schemes, R 5 Selected from -O-pyridyl, -NH-pyridyl, The pyridyl group, Optionally by one or more R 5a replace.

[0131] In some implementation schemes, R 5 Selected from -O-pyridyl -NH-pyridyl The pyridyl group, Optionally by one or more R 5a replace.

[0132] In some implementation schemes, R 5 Selected from -O-pyridyl, -NH-pyridyl, The -O-pyridyl, -NH-pyridyl, Optionally by one or more R 5a replace.

[0133] In some implementation schemes, R 5 Selected from -O-pyridyl -NH-pyridyl The -O-pyridyl -NH-pyridyl Optionally by one or more R 5a replace.

[0134] In some implementation schemes, R 5 Selected from The Optionally by one or more R 5a replace.

[0135] In some implementation schemes, R 5 Selected from The Optionally by one or more R 5a replace.

[0136] In some implementation schemes, each R 5a Independently selected from halogen, cyano, amino, hydroxyl, oxo, C1-C 10 Alkyl, C2-C 10 alkynyl group, C1-C 10 alkoxy groups and 3-14 membered heterocyclic groups, wherein the amino, hydroxyl, C1-C 10 Alkyl, C2-C 10 alkynyl group, C1-C 10 The alkoxy group and the 3-14 membered heterocyclic group are optionally surrounded by one or more R groups. c replace.

[0137] In some implementation schemes, each R 5a Independently selected from halogen, cyano, amino, oxo, C1-C 10 Alkyl, C1-C10 alkoxy groups and 3-14 membered heterocyclic groups, wherein the amino group, C1-C 10 Alkyl, C1-C 10 The alkoxy group and the 3-14 membered heterocyclic group are optionally surrounded by one or more R groups. c replace.

[0138] In some implementation schemes, each R 5a Independently selected from halogen, cyano, oxo, C1-C 10 Alkyl groups and 3-14 membered heterocyclic groups, the C1-C 10 Alkyl groups and 3-14 membered heterocyclic groups are optionally surrounded by one or more R groups. c replace.

[0139] In some implementation schemes, each R 5a The radical is independently selected from halogen, cyano, amino, hydroxyl, oxo, C1-C4 alkyl, C2-C4 alkynyl, C1-C4 alkoxy, and 3-7 membered heterocyclic groups, wherein the amino, hydroxyl, C1-C4 alkyl, C2-C4 alkynyl, C1-C4 alkoxy, and 3-7 membered heterocyclic groups are optionally surrounded by one or more R groups. c replace.

[0140] In some implementation schemes, each R 5a The radical is independently selected from halogen, cyano, amino, oxo, C1-C4 alkyl, C1-C4 alkoxy, and 3-7 membered heterocyclic groups, wherein the amino, C1-C4 alkyl, C1-C4 alkoxy, and 3-7 membered heterocyclic groups are optionally surrounded by one or more R groups. c replace.

[0141] In some implementation schemes, each R 5a The radical is independently selected from halogen, cyano, oxo, C1-C4 alkyl, and 3-6 membered heterocyclic groups, wherein the C1-C4 alkyl and 3-6 membered heterocyclic groups are optionally surrounded by one or more R radicals. c replace.

[0142] In some implementation schemes, each R 5a Independently selected from fluorine, cyano, hydroxyl, methyl, oxo, ethyl, propynyl, piperazine, methoxy, ethoxy, isopropyloxy, amino, and aziridine. Morpholinyl, piperidinyl, and oxetyl, wherein the hydroxyl, methyl, ethyl, propynyl, piperazine, methoxy, ethoxy, isopropyloxy, amino, or aziridine, are used. Morpholinyl, piperidinyl, and oxetyl are optionally separated by one or more R c replace.

[0143] In some implementation schemes, each R 5aIndependently selected from fluorine, cyano, methyl, oxo, ethyl, piperazine, methoxy, ethoxy, isopropyloxy, amino, and aziridine. Morpholinyl, piperidinyl, and oxetyl, wherein the methyl, ethyl, piperazine, methoxy, ethoxy, isopropyloxy, amino, or aziridine-butyl groups are used. Morpholinyl, piperidinyl, and oxetyl are optionally separated by one or more R c replace.

[0144] In some implementation schemes, each R 5a The radical is independently selected from fluorine, cyano, methyl, oxo, ethyl, piperazine, piperidinyl, and oxetane, wherein the methyl, ethyl, piperazine, piperidinyl, and oxetane are optionally separated by one or more R groups. c replace.

[0145] In some implementation schemes, each R c Independently selected from halogen, amino, hydroxyl, mercapto, cyano, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the amino, hydroxy, mercapto, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl groups or 3-12-membered heterocyclic groups are optionally surrounded by one or more R groups. e replace;

[0146] In some implementation schemes, each R c Independently selected from halogen, hydroxyl, oxo, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the hydroxyl, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl groups and 3-12-membered heterocyclic groups are optionally surrounded by one or more R groups. e replace.

[0147] In some implementation schemes, each R c Independently selected from halogen, oxo, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl groups and 3-12-membered heterocyclic groups are optionally surrounded by one or more R groups. e replace.

[0148] In some implementation schemes, each R c Independently selected from C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the C1-C7 alkyl, C1-C7 alkoxy, C3-C 10Cycloalkyl groups and 3-12-membered heterocyclic groups are optionally surrounded by one or more R groups. e replace.

[0149] In some implementation schemes, each R c Independently selected from halogen, oxo, C1-C4 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, and 4-7 membered heterocyclic groups, wherein the C1-C4 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, and 4-7 membered heterocyclic groups are optionally surrounded by one or more R... e replace.

[0150] In some implementation schemes, each R c Independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, and 4-7 membered heterocyclic groups, wherein the C1-C4 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, and 4-7 membered heterocyclic groups are optionally surrounded by one or more R... e replace.

[0151] In some implementation schemes, each R c Independently selected from hydroxyl, fluorine, oxo, methyl, ethyl, methoxy, cyclopropyl, 1,4-Dioxanecyclohexane and oxetanecyclobutyl, wherein the methyl, ethyl, methoxy, cyclopropyl, 1,4-Dioxanecyclohexane and oxohexacyclobutyl are optionally coupled with one or more R... e replace.

[0152] In some implementation schemes, each R c The radical is independently selected from fluorine, oxo, methyl, ethyl, methoxy, cyclopropyl, 1,4-dioxane, and oxetane, wherein the methyl, ethyl, methoxy, cyclopropyl, 1,4-dioxane, and oxetane are optionally separated by one or more R... e replace.

[0153] In some implementation schemes, each R c The groups are independently selected from methyl, methoxy, cyclopropyl, and oxetyl, wherein the methyl, methoxy, cyclopropyl, and oxetyl groups are optionally surrounded by one or more R... e replace.

[0154] In some implementation schemes, each R e It is independently selected from halogen, cyano, =O, 4-10 membered heterocyclic groups, C1-C4 alkoxy, C1-C4 alkyl and -N(C1-C4 alkyl)2.

[0155] In some implementation schemes, each R e It is independently selected from halogen, cyano, =O, C1-C4 alkoxy and C1-C4 alkyl.

[0156] In some implementation schemes, each R e It is independently selected from fluorine, cyano, methyl, =O and methoxy.

[0157] In some implementation schemes, each R e It is independently selected from halogen, cyano, =O, 4-10 membered heterocyclic groups, C1-C4 alkyl and -N(C1-C4 alkyl)2.

[0158] In some implementation schemes, each R e It is independently selected from halogen, cyano, =O, C1-C4 alkyl and -N(C1-C4 alkyl)2.

[0159] In some implementation schemes, each R e It is independently selected from cyano and =O.

[0160] In some implementation schemes, R 5 Selected from

[0161] In some implementation schemes, R 5 Selected from Where R 5a Selected from fluorine, cyano, hydroxyl, methyl, oxo, ethyl, propynyl, piperazine, methoxy, ethoxy, isopropyloxy, amino, and aziridine. Morpholinyl, piperidinyl, and oxetyl, wherein the hydroxyl, methyl, ethyl, propynyl, piperazine, methoxy, ethoxy, isopropyloxy, amino, or aziridine, are used. Morpholinyl, piperidinyl, and oxetyl are optionally separated by one or more R c Replace, each R c Independently selected from hydroxyl, fluorine, oxo, methyl, ethyl, methoxy, cyclopropyl, 1,4-Dioxanecyclohexane and oxetanecyclobutyl, wherein the methyl, ethyl, methoxy, cyclopropyl, 1,4-Dioxanecyclohexane and oxohexacyclobutyl are optionally coupled with one or more R... e Replace, each R e Independently selected from halogen, cyano, =O, 4-10 membered heterocyclic groups, C1-C4 alkoxy, C1-C4 alkyl, and -N(C1-C4 alkyl)2; R 5b Selected from hydrogen, F, CN or cyclopropyl.

[0162] In some implementation schemes, R 5 Selected from Where R 5aSelected from fluorine, cyano, hydroxyl, methyl, oxo, ethyl, propynyl, piperazine, methoxy, ethoxy, isopropyloxy, amino, and aziridine. Morpholinyl, piperidinyl, and oxetyl, wherein the hydroxyl, methyl, ethyl, propynyl, piperazine, methoxy, ethoxy, isopropyloxy, amino, or aziridine, are used. Morpholinyl, piperidinyl, and oxetyl are optionally separated by one or more R c Replace, each R c Independently selected from hydroxyl, fluorine, oxo, methyl, ethyl, methoxy, cyclopropyl, 1,4-Dioxanecyclohexane and oxetanecyclobutyl, wherein the methyl, ethyl, methoxy, cyclopropyl, 1,4-Dioxanecyclohexane and oxohexacyclobutyl are optionally coupled with one or more R... e Replace, each R e Independently selected from halogen, cyano, =O, 4-10 membered heterocyclic groups, C1-C4 alkoxy, C1-C4 alkyl, and -N(C1-C4 alkyl)2; R 5b Selected from hydrogen, F, CN or cyclopropyl.

[0163] In some implementation schemes, R 5b It can be hydrogen or CN.

[0164] In some implementation schemes, R 5 Selected from

[0165] In some implementation schemes, R 5 Selected from as well as

[0166] In some implementation schemes, R 5 Selected from

[0167] In some implementation schemes, R 6 Selected from hydrogen and C1-C4 alkoxy groups.

[0168] In some implementation schemes, R 6 It is hydrogen.

[0169] In some implementation schemes, R 7 It is selected from hydrogen, halogen, hydroxyl and cyano groups.

[0170] In some implementation schemes, R 7 It is hydrogen.

[0171] 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.

[0172] In some implementation schemes, each R d It is independently selected from halogen, amino, hydroxyl, mercapto and cyano groups.

[0173] In some implementation schemes, each R d It is independently selected from halogens, such as fluorine.

[0174] In some implementation schemes, Selected from The value of t is selected from 0, 1, 2, and 3.

[0175] In some implementation schemes, Selected from

[0176] In some implementation schemes, R 8 Selected from hydrogen, halogen, hydroxyl, cyano and C1-C 10 alkyl.

[0177] In some implementation schemes, R 8 It is hydrogen.

[0178] In some implementation schemes, R 9 It is selected from hydrogen, halogen, hydroxyl and cyano groups.

[0179] In some implementation schemes, R 9 It is hydrogen.

[0180] In some implementation schemes, R 10 Selected from halogens, such as fluorine.

[0181] In some implementations, n is 0, 1, or 2.

[0182] In some implementations, n is 0.

[0183] In some implementation schemes, R 7 R 8 and R 9 All are hydrogen atoms, and n is 0.

[0184] In some implementation schemes, R 2 and R 3 All are methyl; X 1 Let C and X be the values ​​of C and X respectively. 2 For N; R6 It is hydrogen; R 7 R 8 and R 9 All are hydrogen; and / or n is 0.

[0185] In some implementation schemes, R 2 and R 3 All are methyl; X 1 Let C and X be the values ​​of C and X respectively. 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 It is either ethyl or trifluoroethyl.

[0186] In some embodiments, the compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof is selected from compounds of formula (II), (III) or (IV) or their stereoisomers or pharmaceutically acceptable salts thereof.

[0187] Among them, A, Q, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 and R 11 As defined above, m is 1 or 2, p is 0 or 1, and X 3 Selected from CH2 and O.

[0188] In some implementation schemes, X 3 It is CH2.

[0189] In some implementations, both m and p are 1.

[0190] 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.

[0191] In some embodiments, the compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt is selected from the compounds prepared in Examples 1-32 or their pharmaceutically acceptable salts.

[0192] On the other hand, this disclosure provides pharmaceutical compositions comprising a compound of formula (I), (II), (III), or (IV) of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0193] 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) or formula (II) or formula (III) or formula (IV) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0194] On the other hand, this disclosure provides the use of compounds of formula (I), (II), (III), or (IV) or their stereoisomers or pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of RAS-mediated diseases.

[0195] On the other hand, this disclosure provides the use of compounds of formula (I), (II), (III), or (IV) or their stereoisomers or pharmaceutically acceptable salts or pharmaceutical compositions thereof in the prevention or treatment of RAS-mediated diseases.

[0196] On the other hand, this disclosure provides compounds of formula (I), (II), (III), or (IV) for the prevention or treatment of RAS-mediated diseases, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[0197] In some implementations, the RAS-mediated disease is a tumor, such as pancreatic cancer or non-small cell lung cancer.

[0198] The compounds of formula (I), (II), (III) or (IV) provided herein, or their stereoisomers or pharmaceutically acceptable salts thereof, can achieve at least one of the following advantages: (1) strong inhibitory activity against KRAS G12D mutations; (2) good killing effect on RAS protein signaling pathway-dependent tumors, and can treat RAS mutation-mediated tumors; (3) good biosafety; and (4) good bioavailability, and / or favorable in vivo exposure and / or half-life.

[0199] Terminology Definitions and Explanations

[0200] 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.

[0201] In this article Indicates the connection site.

[0202] In this article, in the ring This indicates that the corresponding ring is an aromatic ring.

[0203] Some compounds of this application can exist as trans-restricted isomers, which are conformational isomers that occur when rotation around a single bond in the molecule is prevented or significantly slowed down due to steric interactions with other parts of the molecule. The compounds disclosed herein include all trans-restricted isomers, which can be pure, single trans-restricted isomers, trans-restricted isomers enriched in one of them, or nonspecific mixtures of each. Separation of isomers is permitted if the rotational potential around the single bond is sufficiently high and the interconversion between conformations is sufficiently slow. For example, and It is a pair of transisomers, wherein the pyridyl group is an inhibitor of the transisomer. This indicates that the orientation of this three-dimensional object is outward. This indicates that the orientation of this three-dimensional object is inward.

[0204] 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).

[0205] 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 or One of the two, but the absolute configuration has not yet been confirmed; The representative is However, the exact absolute configuration has not yet been confirmed.

[0206] 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.

[0207] 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 Selected from "-N(R) 13 When )C(O)-”, L is at this time 1 C and B can be connected in a direction from left to right to form a structure. Alternatively, C and B can be connected from right to left to form...

[0208] 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.

[0209] 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.

[0210] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

[0211] 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, ethyl “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. Substitution with one or more substituents herein can mean substitution with one, two, three, four, or five substituents. In some embodiments, substitution with one or more substituents means substitution with one or two substituents.

[0212] When any variable (e.g., R) a R b When a group appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is surrounded by two R... b Replaced, then each R b Each has its own independent options.

[0213] 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.

[0214] 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.

[0215] 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".

[0216] 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 containing one or more double bonds and having 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.

[0217] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms and having at least one triple bond. The term "C2-C"... 10 "Alkyne" can be understood as representing a straight-chain or branched unsaturated hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. "C2-C" 10 Examples of "alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH3, -CH2C≡CH), buty-1-alkynyl, buty-2-alkynyl, or buty-3-alkynyl. "C2-C 10"Alynyl" can include "C2-C3 alkynyl", and examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), propynyl-1-alkynyl (-C≡CCH3), and propynyl-2-alkynyl (-CH2C≡CH).

[0218] 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.

[0219] 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 atoms 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 "3-10 membered heterocyclic group" refers to a heterocyclic group with 3, 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 "4-10 membered heterocyclic group" refers to a heterocyclic group with 4, 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 "4-6 membered heterocyclic group" refers to a heterocyclic group with 4, 5, or 6 ring atoms, and whose ring atoms contain 1-3 heteroatoms or heterogroups independently selected from those described above (e.g., N, O, S). 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 heteroatoms or heterogroups independently selected from those described above (e.g., N, O, S). 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 heteroatoms or heterogroups independently selected from those described above (e.g., N, O, S). 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" can 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 heterogroups (e.g., N, O, S) as described above. Specific examples of 4-membered heterocyclic groups include, but are not limited to, azirrocyclobutane or oxocyclobutane; specific examples of 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoyl, 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, piperazinyl, 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.The term "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 is non-aromatic. The term "hypo-heterocyclic group" refers to a residue derived by further removing a hydrogen atom from a heterocyclic group.

[0220] 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 a ring number of 4, 5, 6, 7, 8, 9, or 10, and containing 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 alkyl" refers to a heterocyclic alkyl group having a ring number of 5, 6, 7, 8, 9, or 10, and containing 1-5 (e.g., 1-3 or 1-2) 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.

[0221] 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.

[0222] 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 "5-12-membered heteroaryl" can be understood to include the aforementioned 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 "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-membered heteroaryl" can be understood to include the aforementioned monocyclic or polycyclic aromatic ring systems, having 9 or 10 reductants, and containing 1 to 5, for example 1 to 3, heteroatoms independently selected from N, O, and S. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzothiazolyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl or isindolyl; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl and their benzo[derivatives], such as quinolinyl, quinazolinyl or isoquinolinyl; or acrylinyl, inazinyl, purinyl and their benzo[derivatives]; or cyclolinyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphthidyl, pteridinyl, carbazolyl, acrylinyl, phenazinyl, phenothiazinyl or phenothiazinyl. The term "6-10-membered heteroaryl" can be understood as including monocyclic or bicyclic aromatic ring systems having 6, 7, 8, 9, or 10 ring atoms, for example, 6, 9, or 10 ring atoms, and containing 1-5, for example 1-3, heteroatoms independently selected from N, O, and S. The term "5-6-membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and containing 1-3, for example 1-2, heteroatoms independently selected from N, O, and S. The term "hybrid aryl" refers to a residue derived from a heteroaryl group by further removing a hydrogen atom.

[0223] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0224] The term "hydroxyl group" refers to the -OH group.

[0225] The term "cyano" refers to the -CN group.

[0226] The term "amino" refers to the -NH2 group.

[0227] The term "imino" refers to the -NH- group.

[0228] The term "nitro" refers to the -NO2 group.

[0229] The term "oxo" refers to the =O group.

[0230] 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:

[0231] (i) Suppress the disease or disease state, that is, curb its development;

[0232] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] 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.

[0240] 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”.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] 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.

[0246] 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.

[0247] 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.

[0248] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] Abbreviations:

[0254] EA represents ethyl acetate; TBDPS represents tert-butyldiphenylsilyl; TBDPSCl represents tert-butyldiphenylchlorosilane; DCM represents dichloromethane; DMF represents N,N-dimethylformamide; THF represents tetrahydrofuran; MeOH represents methanol; TsOH·H2O represents p-toluenesulfonic acid monohydrate; diludine represents dihydropyridine; AgOTf represents silver trifluoromethanesulfonate; DMAP represents 4-dimethylaminopyridine; TMSCHN2 represents trimethylsilylated... 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)dicyclopentadiene] [Iron] 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; ACN / MeCN represents acetonitrile; NIS represents N-iodosuccinimide; AcOH represents acetic acid; KOAc / AcOK represents potassium acetate; EtI represents iodoethane; Boc represents tert-butyloxy Carbonyl; dioxane represents 1,4-dioxane; TCFH represents N,N,N',N'-tetramethylchloromethamphicanine hexafluorophosphate; NMI represents N-methylimidazolium; TBAF represents tetrabutylammonium fluoride; DMSO represents dimethyl sulfoxide; 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); Tf2O represents trifluoromethanesulfonic anhydride; 2,6-Lutidine represents 2,6-dimethylpyridine; Ti(OEt)4 represents tetraisopropyl titanate; LHMDS represents bis(trimethylsilylamino)lithium; PE represents petroleum ether; mCPBA represents m-chloroperoxybenzoic acid; TMSCN represents trimethylcyanosilane; Ms represents methanesulfonyl; NBS represents N-bromosuccinimide; XantPhos represents 4,5-bis(diphenylphosphino-9,9-dimethyloxanthracene); Bn represents benzyl; RuPhos Pd G2 represents chloro(2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II);RuPhos represents 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl; B2Pin2 represents pinacol diboronate; [Ir(COD)OMe]2 represents methoxy(cyclooctadiene)iridium dimer; dtbbpy represents 4,4'-di-tert-butyl-2,2'-dipyridine; TMSI represents trimethyliodosilane; iPrOH represents isopropanol; HOPO represents 2-hydroxypyridine-N-oxide; EDCI represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HFIP represents hexafluoroisopropanol; TLC represents thin-layer chromatography; FA represents formic acid; (HCHO) n Ru-L(S,S) represents paraformaldehyde; Ru-L(S,S) represents (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride; Piperidine represents piperidine; EtOH represents ethanol; DMAc represents N,N-dimethylacetamide; MsOH represents methanesulfonic acid; HOBT represents 1-hydroxybenzotriazole; B2(neop)2 represents neopentyl glycol diboronate; 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; XPhos represents 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl; DMF·DMA represents N,N-dimethylformamide dimethyl acetal. Detailed Implementation

[0255] 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.

[0256] 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.

[0257] Unless otherwise stated, the proportions expressed for mixed solvents are volume-based.

[0258] Unless otherwise stated, % refers to weight percentage (wt%).

[0259] Compounds are processed manually or Software naming conventions are used; commercially available compounds use supplier catalog names.

[0260] 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).

[0261] The eluent or mobile phase may be a mixture of two or more solvents, with the ratio being the volume ratio of each solvent.

[0262] Preparation Example

[0263] Preparation Example 1: Synthesis of intermediate compound Int-1

[0264] Step 1: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropionic acid (compound A2)

[0265] 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.

[0266] Step 2: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropionyl chloride (compound A3)

[0267] 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.

[0268] Step 3: Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropane-1-one (compound A4)

[0269] 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%).

[0270] MS(ESI + m / z = 534.0 [M+H] + .

[0271] Step 4: Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropane-1-ol (compound A5)

[0272] 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.

[0273] Step 5: Synthesis of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1H-indole (compound A6)

[0274] 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%).

[0275] MS(ESI + m / z = 520.0 [M+H] + .

[0276] Step 6: Synthesis of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-iodo-1H-indole (compound Int-1)

[0277] 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%).

[0278] MS(ESI + m / z = 646.1 [M+H] + .

[0279] Preparation Example 2: Synthesis of intermediate compound Int-2

[0280] Step 1: Synthesis of 3-(2-diazoacetyl)cyclobutane-1-one (compound B2)

[0281] 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%).

[0282] MS(ESI + m / z = 139.0 [M+H] + .

[0283] Step 2: Synthesis of 2-(3-oxocyclobutyl)acetic acid (compound B3)

[0284] 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.

[0285] MS(ESI + m / z = 127.0 [MH] - .

[0286] Step 3: Synthesis of (S)-4-benzyl-3-(2-(3-oxocyclobutyl)acetyl)oxazolidin-2-one (compound B4)

[0287] 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%).

[0288] MS(ESI + m / z = 288.1 [M+H] + .

[0289] Step 4: Synthesis of (S)-4-benzyl-3-(2-(3-hydroxycyclobutyl)acetyl)oxazolidin-2-one (compound B5)

[0290] 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.

[0291] MS(ESI + m / z = 290.2[M+H] + .

[0292] Step 5: Synthesis of (S)-3-(2-(4-benzyl-2-oxooxazolidine-3-yl)-2-oxoethyl)cyclobutyl-4-methylbenzenesulfonate (compound B6)

[0293] 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%).

[0294] MS(ESI + m / z = 444.1 [M+H] + .

[0295] Step 6: Synthesis of (S)-4-benzyl-3-(2-(3-bromocyclobutyl)acetyl)oxazolidin-2-one (compound B7)

[0296] 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 completed, 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%).

[0297] MS(ESI + m / z = 352.2[M+H] + .

[0298] Step 7: Synthesis of (S)-2,3-bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid (compound B8)

[0299] 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%).

[0300] MS(ESI + m / z = 343.1 [M+H] + .

[0301] 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)

[0302] 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%).

[0303] MS(ESI + m / z = 357.2[M+H] + .

[0304] Step 9: Synthesis of (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid methyl ester (compound Int-2)

[0305] 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%).

[0306] MS(ESI + m / z = 157.0 [M+H] + .

[0307] Preparation Example 3: Synthesis of intermediate compound Int-3

[0308] Step 1: Synthesis of 3-(5-bromo-1H-indol-3-yl)-2,2-dimethyl-1-propanol (compound C2)

[0309] 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 a saturated aqueous sodium chloride 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%).

[0310] MS(ESI + m / z = 282.1[M+H] + .

[0311] Step 2: Synthesis of 3-(5-bromo-1H-indol-3-yl)-2,2-dimethylacetic acid propyl ester (compound C3)

[0312] 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%).

[0313] MS(ESI + m / z = 324.1 [M+H] + .

[0314] 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)

[0315] 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%).

[0316] MS(ESI + m / z = 372.1 [MH] + .

[0317] 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)

[0318] 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%).

[0319] MS(ESI + m / z = 530.1 [M+H] + .

[0320] 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)

[0321] 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%).

[0322] MS(ESI + m / z = 656.5 [MH] + .

[0323] 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)

[0324] 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%).

[0325] MS(ESI + m / z = 600.0 [M+H] + .

[0326] 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)

[0327] 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%).

[0328] MS(ESI + m / z = 738.1 [M+H] + .

[0329] 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)

[0330] 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%).

[0331] MS(ESI + m / z = 724.1 [M+H] + .

[0332] Step 9: Synthesis of compound Int-3

[0333] 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%).

[0334] MS(ESI + m / z = 706.2[M+H] + .

[0335] Preparation Example 4: Synthesis of intermediate compound Int-4

[0336] The first step is the synthesis of 6-bromo-3-nitro-1,2-dihydroquinoline-2-ol (compound D2).

[0337] 2-Amino-5-bromobenzaldehyde (5.0 g, 25.0 mmol) and ethyl nitrate (6.65 g, 49.99 mmol) were added to a mixed solution 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%).

[0338] MS(ESI+)m / z=269.0[MH] - .

[0339] Step 2: Synthesis of 4-(3-nitro-2-oxo-1,2-dihydroquinoline-6-yl)piperazine-1-carboxylic acid benzyl ester (compound D3)

[0340] 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 reaction (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound D3 (1.2 g, 2.94 mmol, yield: 39.5%).

[0341] MS(ESI+)m / z = 409.1[M+H] + .

[0342] Step 3: Synthesis of 4-(2-chloro-3-nitroquinoline-6-yl)piperazine-1-carboxylic acid benzyl ester (compound D4)

[0343] 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%).

[0344] MS(ESI+)m / z = 427.1[M+H] + .

[0345] Step 4: Synthesis of 4-(2-acetyl-3-nitroquinoline-6-yl)piperazine-1-carboxylic acid benzyl ester (compound D5)

[0346] 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%).

[0347] MS(ESI+)m / z = 435.1[M+H] + .

[0348] Step 5: Synthesis of 4-(2-acetyl-3-aminoquinoline-6-yl)piperazine-1-carboxylic acid benzyl ester (compound D6)

[0349] 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 complete, 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 (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound D6 (280.0 mg, 692.2 μmol, yield: 91.1%).

[0350] MS(ESI+)m / z = 405.1[M+H] + .

[0351] Step 6: Synthesis of (S)-4-(3-amino-2-(1-hydroxyethyl)quinoline-6-yl)piperazine-1-carboxylic acid benzyl ester (compound D7)

[0352] 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%).

[0353] MS(ESI+)m / z = 407.1[M+H] + .

[0354] Step 7: Synthesis of (S)-4-(2-(1-hydroxyethyl)-3-iodoquinoline-6-yl)piperazine-1-carboxylic acid benzyl ester (compound D8)

[0355] 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%).

[0356] MS(ESI+)m / z = 518.0[M+H] + .

[0357] Step 8: Synthesis of (S)-4-(3-iodo-2-(1-methoxyethyl)quinolin-6-yl)piperazine-1-carboxylic acid benzyl ester (compound Int-4)

[0358] 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%).

[0359] MS(ESI+)m / z = 532.0 [M+H] + .

[0360] Preparation Example 5: Synthesis of intermediate compound Int-5

[0361] The first step is the synthesis of (4-bromothiazol-2-yl)methanol (compound E2).

[0362] 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%).

[0363] MS(ESI + m / z = 194.3 [M+H] + .

[0364] Step 2: Synthesis of 4-bromo-2-(bromomethyl)thiazole (compound E3)

[0365] Carbon tetrabromide (23.07 g, 69.57 mmol), compound E2 (9 g, 46.38 mmol), and triphenylphosphine (18.25 g, 69.57 mmol) were added to 120 mL of dichloromethane at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS until complete. The mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 0-10%) to give compound E3 (9.0 g, 35.20 mmol, yield: 75.9%).

[0366] MS(ESI + m / z = 255.7 [M+H] + .

[0367] Step 3: Synthesis of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (compound E5)

[0368] (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 above mixture, and the mixture was stirred at -78 °C for 1 h. The reaction was monitored by LC-MS to ensure complete reaction. The reaction was quenched with saturated ammonium chloride aqueous solution (30 mL), extracted with ethyl acetate (100 mL × 2), and the organic layer was evaporated to dryness and purified by silica gel column chromatography (0-15% petroleum ether / ethyl acetate) to give compound E5 (10.5 g, 29.14 mmol, yield: 83%).

[0369] MS(ESI + m / z = 360.2[M+H] + .

[0370] Step 4: Synthesis of methyl (S)-2-amino-3-(4-bromothiazol-2-yl)propionate (compound E6)

[0371] 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%).

[0372] MS(ESI + m / z = 264.9 [M+H] + .

[0373] Step 5: Synthesis of (S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonyl)amino)propionate methyl ester (compound Int-5)

[0374] 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%).

[0375] MS(ESI + m / z = 364.9 [M+H] + .

[0376] Preparation Example 6: Synthesis of intermediate compound Int-6

[0377] The first step is the synthesis of compound F2.

[0378] Under an argon atmosphere and ice bath conditions, trifluoromethanesulfonic anhydride (323.1 μL, 1.92 mmol) was added dropwise to a solution of compound F1 (300.0 mg, 1.28 mmol) and 2,6-dimethylpyridine (205.8 mg, 1.92 mmol) in dichloromethane (4.8 mL), and the mixture was stirred at 0 °C for 2.0 h. After the starting material disappeared as monitored by LC-MS, the mixture was added dropwise to ice water to quench the reaction, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give compound F2 (450.0 mg, 1.23 mmol, yield: 95.9%).

[0379] MS(ESI+)m / z = 367.0 [M+H] + .

[0380] The second step involves the synthesis of compound F3.

[0381] Cesium carbonate (800.4 mg, 2.46 mmol) was added to a tetrahydrofuran (10.0 mL) solution of compound F2 (450.0 mg, 1.23 mmol) and (S)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester (278 mg, 1.23 mmol). The mixture was stirred at 25 °C for 0.5 hours. After the starting material disappeared as monitored by LC-MS, the mixture was added dropwise to ice water to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The crude product was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to give compound F3 (500.0 mg, 1.13 mmol, yield: 92%).

[0382] MS(ESI+)m / z = 443.2[M+H]+ .

[0383] The third step involves the synthesis of compound Int-6.

[0384] Compound F3 (100.0 mg, 225.9 μmol) was dissolved in methanol (5.0 mL). Pd / C (10%, 24.0 mg, 225.9 μmol) was added to the reaction solution. Hydrogen gas was then purged five times. The mixture was stirred at room temperature for 3.0 hours under one atmosphere of pressure. The reaction was monitored by LC-MS until it was complete. The residue was filtered off, and the filtrate was directly concentrated to obtain compound Int-6 (60.0 mg, 170.2 μmol, yield: 75.3%).

[0385] MS(ESI + m / z = 353.2[M+H] + .

[0386] Preparation Example 7: Synthesis of intermediate compound Int-7

[0387] Synthesis of compound G2 (Step 1)

[0388] Tetraisopropyl titanate (8.11 g, 28.5 mmol) was added to a solution of compound G1 (1.0 g, 14.27 mmol) and (R)-4-methylbenzenesulfinamide (2.21 g, 14.27 mmol) in tetrahydrofuran (20.0 mL), and stirred at 75 °C under nitrogen protection for 2.0 h. After the reaction was complete, the mixture was added dropwise to a mixture of ice water (50.0 mL) and saturated brine (50.0 mL), ethyl acetate was added and stirred for 10 min, the residue was filtered off, the filtrate was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration of the filtrate was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound G2 (2.7 g, 13 mmol, yield: 91.1%).

[0389] MS(ESI+)m / z = 208.0[M+H] + .

[0390] The second step involves the synthesis of compound G3.

[0391] Under an argon atmosphere, a tetrahydrofuran (60.0 mL) solution of compound G2 (2.7 g, 13.0 mmol) and benzyl 2-bromoacetate (3.88 g, 16.9 mmol) was cooled to -65 °C. Bistrimethylsilylaminolithium (16.9 mL, 16.9 mmol, 1.0 M, THF solvent) was slowly added dropwise to the reaction system. After the addition was complete, the reaction mixture was transferred to -40 °C and stirred for 1.5 hours. After the reaction was complete, the reaction solution was added to water to quench the reaction, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration of the filtrate was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound G3 (3.45 g, 9.69 mmol, yield: 74.5%).

[0392] MS(ESI+)m / z = 356.1[M+H] + .

[0393] The third step involves the synthesis of compound G4.

[0394] Under an argon atmosphere, a tetrahydrofuran (60.0 mL) solution of compound G3 (2.45 g, 6.9 mmol) was cooled to -65 °C, and methyl magnesium bromide (6.9 mL, 20.7 mmol, 3.0 M, THF solvent) was slowly added dropwise to the reaction system. The mixture was stirred at -65 °C for 1.0 h. After the reaction was complete, a saturated aqueous solution of ammonium chloride was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the crude product obtained after concentration was purified by reverse-phase chromatography (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound G4 (670.0 mg, 3.08 mmol, yield: 44.7%).

[0395] MS(ESI+)m / z = 218.0[M+H] + .

[0396] Step 4: Synthesis of compound G5

[0397] Under an argon atmosphere and in an ice bath, 215 μL (3.45 mmol) of iodomethane was added dropwise to a tetrahydrofuran (5.0 mL) solution of compound G4 (300.0 mg, 1.38 mmol) and silver carbonate (951.3 mg, 3.45 mmol). After the addition was complete, the reaction mixture was slowly heated to 25 °C and stirred for 32.0 hours. After the reaction was complete, the residue was filtered off, and the mixture was washed with dichloromethane. The crude product obtained by concentrating the filtrate was purified by reverse-phase reaction (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound G5 (177.0 mg, 762.6 μmol, yield: 55.3%).

[0398] MS(ESI+)m / z = 232.1[M+H] + .

[0399] Step 5: Synthesis of compound Int-7

[0400] Under ice bath conditions, a solution of lithium hydroxide (15.3 mg, 640 μmol) in water (0.5 mL) was slowly added dropwise to a tetrahydrofuran (2.0 mL) solution containing compound G5 (74.0 mg, 320.0 μmol). After the addition was complete, the mixture was slowly heated to room temperature and stirred for 3.0 hours. After the reaction was complete, the reaction solution was concentrated at low temperature, and then the remaining aqueous solution was lyophilized to obtain compound Int-7 (54.0 mg).

[0401] Preparation Example 8: Synthesis of intermediate compound Int-8

[0402] The first step is the synthesis of compound H2.

[0403] m-chloroperoxybenzoic acid (34.86 g, 202.00 mmol) was added in portions to a solution of compound H1 (20.00 g, 101.00 mmol) in 150 mL of anhydrous ethyl acetate. The mixture was stirred at room temperature for 30 minutes, then heated to 50 °C and reacted for another 5 hours. 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 H2 (21.00 g, yield: 97%).

[0404] MS(ESI+)m / z = 213.9[M+H] + .

[0405] The second step involves the synthesis of compound H3.

[0406] Compound H2 (26.00 g, 121.48 mmol) was dissolved in acetonitrile (100 mL), and then trimethylcyanosilane (24.10 g, 242.92 mmol) and triethylamine (36.88 g, 364.46 mmol, 50.80 mL) were added. The mixture was heated to 80 °C and reacted for 12 hours. The reaction solution was concentrated, and methyl tert-butyl ether (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 methyl tert-butyl ether. The filter cake was dried to give compound H3 (20.00 g, yield: 74%).

[0407] MS(ESI + m / z = 222.9[M+H] + .

[0408] The third step involves the synthesis of compound H4.

[0409] At 0°C, methyl magnesium bromide (3M, 89.67 mL) was slowly added dropwise to a tetrahydrofuran (20 mL) solution of compound H3 (20 g, 89.67 mmol). The mixture was heated to room temperature and stirred for 3 hours. LC-MS was used to monitor the complete conversion of the reaction. The reaction mixture was then poured into a mixture of dilute hydrochloric acid (6M, 120 mL) and ice water (300 mL), and stirred for 50 minutes. The pH was adjusted to neutral using an aqueous sodium hydroxide solution (10M). The aqueous phase was extracted with ethyl acetate (3 x 250 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound H4 (19.00 g, yield: 88%).

[0410] MS(ESI + m / z = 240.2[M+H] + .

[0411] The fourth step is the synthesis of compound H5.

[0412] Compound H4 (19.00 g, 79.15 mmol) was dissolved in N,N-dimethylformamide (50 mL), and then cesium carbonate (77.36 g, 237.43 mmol) and 4-((methanesulfonyl)oxy)piperidine-1-carboxylic acid benzyl ester (34.72 g, 110.80 mmol) were added. The mixture was reacted at 100 °C for 8 hours. The reaction solution was filtered, and the filtrate was poured into water (100 mL). The solution 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 H5 (8.00 g, yield: 22%).

[0413] MS(ESI + m / z = 457.0 [M+H] + .

[0414] Step 5: Synthesis of compound H6

[0415] Formic acid (2.52 g, 54.75 mmol, 3.25 mL) was added to triethylamine (21.24 g, 209.90 mmol, 29.26 mL) at 0 °C, purged three times with nitrogen, and then (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (111.5 mg, 176.66 μmol) was added. The mixture was stirred at 40 °C for 30 minutes, cooled to room temperature, and then compound H5 (8.00 g, 17.49 mmol) was added. The mixture was stirred at 40 °C for 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 H6 (6.00 g, yield: 75%).

[0416] MS(ESI + m / z = 458.8 [M+H] + .

[0417] Step 6: Synthesis of compound H7

[0418] At 0 °C, sodium hydride (627.0 mg, 15.68 mmol, 60% purity) was added in portions to a solution of compound H6 (6.00 g, 13.06 mmol) in N,N-dimethylformamide (20 mL). The mixture was stirred at 0 °C for 1 hour. Then, iodomethane (3.71 g, 26.14 mmol, 1.63 mL) was added, and the reaction was continued at 0 °C for 1 hour. The reaction solution was poured into a saturated ammonium chloride aqueous solution (30 mL), followed by the addition of water (30 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 = 80:20-60:40) to give compound H7 (5.00 g, yield: 81%).

[0419] MS(ESI + m / z = 472.9 [M+H] + .

[0420] Step 7: Synthesis of compound H8

[0421] At room temperature, trifluoroacetic acid (72.3 mg, 634.10 μmol, 48.8 μL) and N-iodosuccinimide (784.2 mg, 3.49 mmol) were added sequentially to a dichloromethane (5 mL) solution of compound H7 (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 H8 (1.40 g, yield: 74%).

[0422] MS(ESI + m / z = 599.0 [M+H] + .

[0423] Step 8: Synthesis of compound Int-8

[0424] At room temperature, cuprous cyanide (56.2 mg, 627.51 μmol) was added to a pyridine (2 mL) solution of compound H8 (300.0 mg, 500.62 μmol), and the mixture was heated to 100 °C and stirred for 8 hours. After the reaction was completed, 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 Int-8 (180.0 mg, yield: 72%).

[0425] MS(ESI + m / z = 498.0 [M+H] + .

[0426] Preparation Example 9: Synthesis of intermediate compound Int-9

[0427] Synthesis of compound I1 in the first step

[0428] 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 hour. 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%).

[0429] MS(ESI + m / z = 513.0 [M+H] + .

[0430] The second step involves the synthesis of compound I2.

[0431] 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, 11.68 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 hours. The reaction solution was filtered, and the filtrate was poured into water (100 mL). Extraction was performed 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%).

[0432] MS(ESI + m / z = 460.1 [M+H] + .

[0433] The third step involves the synthesis of compound I3.

[0434] Under nitrogen protection, a solution of formic acid (3.61 g, 78.43 mmol) in triethylamine (15.86 g, 156.73 mmol) was cooled to 0 °C, and then (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (103.0 mg, 163.19 μmol) was added. The reaction solution was heated to 40 °C and stirred for 15 minutes, then cooled to room temperature, and then compound I2 (750.0 mg) was added. A solution of N,N-dimethylformamide (1 mL, g, 1.63 mmol) was prepared and reacted at 40 °C for 12 hours. 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%).

[0435] MS(ESI + m / z = 432.1 [M+H] + .

[0436] The fourth step is the synthesis of compound I4.

[0437] At 0 °C, compound I3 (550.0 mg, 1.27 mmol) and p-toluenesulfonic acid (1.10 g, 6.39 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, 6.39 mmol) (3 mL) was added dropwise to the system. The mixture was stirred at 0 °C for 10 minutes, and then gradually heated to room temperature and the reaction was continued for 2 hours. 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%).

[0438] MS(ESI + m / z = 543.0 [M+H] + .

[0439] Step 5: Synthesis of compound Int-9

[0440] 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 minutes, then iodomethane (177.9 mg, 1.25 mmol) was added, and the reaction was continued at 0 °C for 1 hour. 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-9 (340.0 mg, 611.08 μmol, yield: 97%).

[0441] MS(ESI + m / z = 557.1 [M+H] + .

[0442] Preparation Example 10: Synthesis of intermediate compound Int-10

[0443] Synthesis of compound J1 in the first step

[0444] Compound F3 (440 mg, 0.99 mmol) was dissolved in dichloromethane (12 mL), cooled to 0 °C, and then trifluoroacetic acid (1.9 mL) was added dropwise. The reaction mixture was transferred to room temperature and stirred for 2 hours until the reaction was complete. The mixture was then cooled to 0 °C again, and the reaction was quenched by adding saturated sodium bicarbonate solution. The organic phase was extracted with dichloromethane (10 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound J1 (300 mg, crude product). The product was used directly in the next step without further purification.

[0445] MS(ESI + m / z = 343.3[M+H] + .

[0446] The second step involves the synthesis of compound J2.

[0447] Compound J1 (320 mg, crude) and compound Int-7 (137 mg, 0.93 mmol) were dissolved in N,N-dimethylformamide (10 mL). After cooling to 0 °C, N,N-diisopropylethylamine (1.63 mL, 9.3 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (710 mg, 1.87 mmol) were added sequentially. After the addition was complete, the mixture was stirred at 0 °C for 1 hour. 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 obtain compound J2 (400 mg).

[0448] MS(ESI+)m / z = 466.3[M+H] + .

[0449] The third step involves the synthesis of compound Int-10.

[0450] Compound J2 (152 mg, 0.33 mmol) was dissolved in methanol (6 mL), and triethylamine (136 μL, 0.98 mmol) and palladium chloride (5.8 mg, 32.71 μmol) were added sequentially. The mixture was cooled to 0 °C and stirred for 1 hour under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered and concentrated to obtain compound Int-10 (110 mg, crude product).

[0451] MS(ESI+)m / z = 376.2[M+H] + .

[0452] Preparation Example 11: Synthesis of intermediate compound Int-11

[0453] The first step is the synthesis of compound K2.

[0454] Compound K1 (3.2 g, 9.87 mmol) was dissolved in N,N-dimethylformamide (20 mL) at room temperature. Sodium hydride (434.24 mg, 10.86 mmol, 60% purity) was added under ice bath conditions, followed by benzyl chloroformate (1.77 g, 10.38 mmol). The reaction was stirred at 25 °C for 2 hours. LC-MS was used to confirm the completeness of the reaction. The reaction was quenched with saturated ammonium chloride under ice bath conditions, extracted with ethyl acetate, washed once with saturated brine, concentrated, and the residue was purified by normal-phase chromatography (ethyl acetate / petroleum ether = 15%) to give compound K2 (3.3 g, 7.20 mmol, yield: 73%).

[0455] MS(ESI+)m / z = 458.1[M+H] + .

[0456] The second step involves the synthesis of compound K4.

[0457] Compound K2 (500 mg, 1.09 mmol) was added to 1,4-dioxane (20.0 mL), followed by compound K3 (377.45 mg, 1.31 mmol), cesium carbonate (1.07 g, 3.28 mmol), (2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) chloride (84.65 mg, 108.98 μmol), palladium acetate (24.49 mg, 109.08 μmol), and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (152.51 mg, 326.83 μmol). The mixture was stirred for 3 hours under argon protection at 100 °C. After the reaction was completed, the reaction solution was filtered, concentrated under reduced pressure to remove the solvent, and the residue was purified by normal phase chromatography (ethyl acetate / petroleum ether = 30%) to give compound K4 (330.0 mg, 495.67 μmol, yield: 45.44%).

[0458] MS(ESI+)m / z = 666.3[M+H] + .

[0459] The third step involves the synthesis of compound K5.

[0460] Compound K4 (350.0 mg, 525.71 μmol) was dissolved in methanol (10.0 mL). Palladium hydroxide / carbon (100 mg, 20% palladium hydroxide content) was added to the reaction solution, and then hydrogen gas was purged five times. The mixture was stirred at 25 °C for 1 hour under one atmosphere. 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 give compound K5 (270.0 mg, 507.86 μmol, yield: 96.61%).

[0461] MS(ESI + m / z = 532.3 [M+H] +

[0462] The fourth step involves the synthesis of compound Int-11.

[0463] Compound K5 (330 mg, 0.62 mmol) was dissolved in tetrahydrofuran (3.0 mL), and then pinacol diboron ester (158 mg, 622.19 μmol), methoxy(cyclooctadiene)iridium dimer (40.6 mg, 0.062 mmol), and 4,4'-di-tert-butyl-2,2'-dipyridine (40.6 mg, 151.27 μmol) were added sequentially. The reaction mixture was stirred at 65 °C for 10 hours. After the reaction was complete, the reaction mixture was evaporated to dryness under reduced pressure and purified by normal column chromatography (petroleum ether / ethyl acetate = 1:4) to give compound Int-11 (161 mg, 0.25 mmol, yield: 39%).

[0464] MS(ESI + m / z = 658.4 [M+H] +

[0465] Preparation Example 12: Synthesis of intermediate compound Int-12

[0466] Synthesis of compound L2 in the first step

[0467] Compound L1 (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 L2 (29.0 g, 116.3 mmol, yield: 95.0%).

[0468] MS(ESI + m / z = 247.9 [M+H] + .

[0469] The second step involves the synthesis of compound L3.

[0470] Compound L2 (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 L3 (17.5 g, 80.3 mmol, yield: 79.6%).

[0471] MS(ESI + m / z = 217.9 [M+H]+ .

[0472] The third step involves the synthesis of compound L4.

[0473] Compound L3 (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 L4 (40.0 g, 139.4 mmol, yield: 35.3%).

[0474] MS(ESI + m / z = 286.9 [M+H] + .

[0475] The fourth step is the synthesis of compound L5.

[0476] Compound L4 (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 L5 (31.2 g, 74.4 mmol, yield: 86.9%).

[0477] MS(ESI + m / z = 418.9 [M+H] + .

[0478] Step 5: Synthesis of compound L6

[0479] Under argon protection, compound L5 (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 L6 (4.0 g, 12.8 mmol, yield: 53.6%).

[0480] MS(ESI + m / z = 313.0 [M+H] + .

[0481] Step 6: Synthesis of compound Int-12

[0482] Under argon protection, compound L6 (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-12 (1.4 g, 5.2 mmol, yield: 48.0%).

[0483] MS(ESI + m / z = 260.0 [M+H] + .

[0484] Preparation Example 13: Synthesis of intermediate compound Int-13

[0485] The first step is the synthesis of compound M2.

[0486] 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 M2 (45.00 g, 167.25 mmol, yield: 67%).

[0487] MS(ESI + m / z = 268.9[M+H] + .

[0488] The second step involves the synthesis of compound M3.

[0489] At 0 °C, trifluoromethanesulfonic anhydride (39.32 g, 139.38 mmol) was added dropwise to a solution of compound M2 (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 M3 (28.00 g, 69.81 mmol, yield: 75%).

[0490] MS(ESI + m / z = 400.8[M+H] + .

[0491] The third step involves the synthesis of compound M4.

[0492] 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 M3 (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 50 mL of 20% potassium fluoride aqueous solution 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 M4 (8.00 g, 24.76 mmol, yield: 35%).

[0493] MS(ESI + m / z = 323.0 [M+H] + .

[0494] The fourth step involves the synthesis of compound Int-13.

[0495] At room temperature, 10 mL of hydrochloric acid aqueous solution (2N) was added dropwise to a tetrahydrofuran (50 mL) solution of compound M4 (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-13 (3.00 g, 10.17 mmol, yield: 41%).

[0496] MS(ESI + m / z = 295.0 [M+H] + .

[0497] Preparation Example 14: Synthesis of intermediate compound Int-14

[0498] Synthesis of compound N1 (Step 1)

[0499] 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-13 (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 N1 (176.0 mg, 0.66 mmol, yield: 43.2%).

[0500] MS(ESI + m / z = 267.0 [M+H] + .

[0501] The second step involves the synthesis of compound N2.

[0502] In a dry reaction tube, compound N1 (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 N2 (150.00 mg, 408.46 μmol, yield: 75.3%).

[0503] MS(ESI + m / z = 368.2[M+H] + .

[0504] The third step involves the synthesis of compound N4.

[0505] In a dry reaction tube, compound N3 (198.12 mg, 1.14 mmol), compound N2 (140 mg, 381.23 μmol), N,N-diisopropylethylamine (115.73 mg, 895.43 μmol), palladium dichloride bis(triphenylphosphine) (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 N,N-dimethylformamide (5 mL) was added. The system was heated to 80 °C and reacted overnight. The mixture was filtered and concentrated to obtain crude compound N4 (175 mg, 380.80 μmol, yield: 99%), which was used directly in the next step.

[0506] MS(ESI + m / z = 460.2[M+H] + .

[0507] Step 4: Synthesis of compound N5

[0508] Compound N4 (160 mg, 348.16 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added to the system. The reaction was carried out for 1 hour, and the crude product N5 (125 mg, 346.4 μmol, yield: 99%) was concentrated and used directly in the next step.

[0509] MS(ESI + m / z = 360.2[M+H] + .

[0510] Step 5: Synthesis of compound N6

[0511] At room temperature, compound N5 (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 N6 (56 mg, 119.07 μmol, yield: 34.4%).

[0512] MS(ESI + m / z = 471.0 [M+H] + .

[0513] Step 6: Synthesis of compound Int-14

[0514] Under ice-water bath conditions, sodium hydride (8.50 mg, 212.62 μmol, 60% purity) was added to replace argon gas in a dry reaction tube. N,N-dimethylformamide (2 mL) and compound N6 (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 Int-14 (13 mg, 26.8 μmol, yield: 25.2%).

[0515] MS(ESI + m / z = 485.0 [M+H] + .

[0516] Preparation Example 15: Synthesis of intermediate compound Int-15

[0517] The first step is the synthesis of compound O-1.

[0518] Compound Int-4 (266.0 mg, 0.5 mmol) was dissolved in hexafluoroisopropanol (4.0 mL), and methanesulfonic acid (288.65 mg, 3.0 mmol) was added to the reaction solution. The mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the mixture was quenched with water, extracted once with ethyl acetate, and the aqueous phase was adjusted to pH 8 with saturated sodium bicarbonate solution. The solution was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, yielding crude product O1 (190 mg), which was used directly in the next step.

[0519] MS(ESI+)m / z = 398.1[M+H] + .

[0520] The second step involves the synthesis of compound Int-15.

[0521] The crude compound O1 (198 mg) was dissolved in isopropanol (2.0 mL). Compound O2 (868.82 mg, 5.0 mmol), acetic acid (299.31 mg, 5.0 mmol), and sodium cyanoborohydride (313.22 mg, 5.0 mmol) were added to the reaction solution under ice bath conditions, and the mixture was stirred at 50 °C for 1 hour. After the reaction was complete, the crude product was purified by reversed-phase column chromatography (water (containing 0.5% concentrated ammonia): acetonitrile = 95:5-5:95) to obtain compound Int-15 (160 mg).

[0522] MS(ESI + m / z = 438.1 [M+H] +

[0523] Preparation Example 16: Synthesis of intermediate compound Int-16

[0524] The first step is the synthesis of compound P2.

[0525] Cesium carbonate (114.01 g, 349.92 mmol) and tert-butyl 4-((methanesulfonyl)oxy)piperidine-1-carboxylic acid (63.54 g, 227.46 mmol) were added sequentially to a solution of compound P1 (42 g, 174.96 mmol) in N,N-dimethylformamide (600 mL) at room temperature. The mixture was stirred at 90 °C for 8 hours. After cooling, the mixture was diluted with water (1.5 L), extracted with ethyl acetate (800 mL × 2), washed with saturated brine (500 mL × 3), concentrated the organic phase, and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 50%) to obtain the more polar target compound P2 (15.2 g, 35.91 mmol).

[0526] MS(ESI + m / z = 367.0[(M-56)+H] + .

[0527] The second step involves the synthesis of compound P3.

[0528] Formic acid (30.44 g, 661.31 mmol) and triethylamine (133.87 g, 1.32 mol) were mixed in an ice bath, and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (1.05 g, 1.66 mmol) was added, purging with nitrogen. The mixture was stirred at 40 °C for 30 minutes. After cooling to room temperature, compound P2 (14 g, 33.07 mmol) was added to the mixture, and the mixture was stirred at 40 °C for 16 hours. After the reaction was complete, water (300 mL) was added to the reaction solution and the mixture was extracted with ethyl acetate (300 mL). The organic phase was concentrated, slurried with methanol (100 mL), filtered, and the solids were combined and dried to give compound P3 (10.1 g, 23.75 mmol).

[0529] MS(ESI + m / z = 424.9[M+H] + .

[0530] 1 H NMR(400MHz, DMSO-d6)δ8.50(d,J=6.0Hz,2H),4.80–4.69(m,1H),4.11(q,J=5.3H z,4H),2.99(d,J=5.3Hz,2H),2.15–2.05(m,2H),2.02–1.90(m,2H),1.43(s,12H).

[0531] The third step involves the synthesis of compound P4.

[0532] Sodium hydride (1.14 g, 28.50 mmol, 60% purity) and methyl iodide (6.74 g, 47.48 mmol) were added sequentially to a solution of compound P3 (10.1 g, 23.75 mmol) in N,N-dimethylformamide (100.00 mL) under ice bath conditions. The reaction was carried out for 1 hour under ice bath conditions. After the reaction was complete, the reaction solution was poured into ice water (500 mL), filtered, and the filter cake was washed with water and a small amount of methanol to obtain the target compound P4 (9 g, 20.48 mmol).

[0533] MS(ESI + m / z = 438.9 [M+H] + .

[0534] The fourth step is the synthesis of compound P5.

[0535] At room temperature, trifluoroacetic acid (456.77 mg, 4.01 mmol) and N-iodosuccinimide (5.41 g, 24.05 mmol) were added sequentially to a dichloromethane (120 mL) solution of compound P4 (8.8 g, 20.03 mmol). The mixture was stirred at 40 °C for 16 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium sulfite solution and extracted with dichloromethane (300 mL). The combined organic phases were concentrated and then subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 30%) to give compound P5 (6.9 g, 12.21 mmol).

[0536] MS(ESI + m / z = 564.7 [M+H] + .

[0537] Step 5: Synthesis of compound Int-16

[0538] Cuprous cyanide (1.71 g, 19.11 mmol) was added to a pyridine (100 mL) solution of compound P5 (9 g, 15.92 mmol) at room temperature, and the reaction was carried out at 90 °C for 8 hours. After the reaction was complete, the reaction solution was diluted with water (100 mL), and ammonia (50 mL) was added. Extraction was performed with ethyl acetate (300 mL), and the organic phase was washed with saturated citric acid aqueous solution (200 mL × 2). The organic phase was concentrated and then subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 40%) to give compound Int-16 (6.7 g, 14.43 mmol).

[0539] MS(ESI + m / z = 463.9 [M+H] + .

[0540] 1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),5.03(ddd,J=11.2,7.0,4.1Hz,1H),4.94(q,J=6.3Hz,1H),4.10( d,J=13.1Hz,2H),3.25(s,3H),3.07(s,2H),2.20–2.12(m,2H),2.07–1.95(m,2H),1.48–1.41(m,12H).

[0541] Preparation Example 17: Synthesis of intermediate compound Int-17

[0542] The first step is the synthesis of compound Q2.

[0543] Compound Q1 (3.3 g, 6.16 mmol) was dissolved in tetrahydrofuran (33 mL), and tetrabutylammonium fluoride (4.81 g, 18.40 mmol) was added. The reaction solution was heated and stirred under reflux in an oil bath at 60 °C for 5 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate, extracted with ethyl acetate and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated to obtain crude compound Q2 (1.8 g), which was directly used in the next step of the reaction.

[0544] MS(ESI + m / z = 298.2 [MH] - .

[0545] The second step involves the synthesis of compound Q3.

[0546] The crude compound Q2 (1.8 g) and 4-dimethylaminopyridine (37.44 mg, 306.46 μmol) were dissolved in dichloromethane (20 mL), and N,N-diisopropylethylamine (2.48 g, 19.19 mmol) were added. The reaction solution was placed in an ice bath and stirred. Acetic anhydride (938.70 mg, 9.19 mmol) was slowly added dropwise to the reaction solution. After the addition was complete, the mixture was naturally heated to room temperature and stirred for 2 hours. After the reaction was complete, the reaction solution was concentrated and purified by normal-phase silica gel column chromatography (ethyl acetate / petroleum ether: 0%-25%) to obtain compound Q3 (1.4 g).

[0547] MS(ESI + m / z = 340.3 [MH] - .

[0548] The third step involves the synthesis of compound Q4.

[0549] Compound Q3 (1.4 g, 4.09 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (299.35 mg, 409.12 μmol), pinacol diboronate (1.56 g, 6.14 mmol), and potassium acetate (1.20 g, 12.23 mmol) were dissolved in toluene (5 mL). The air in the solution was replaced three times with argon. The reaction solution was stirred in an oil bath at 110 °C for 8 hours. After the reaction was complete, the solution was filtered through a normal-phase silica gel short column. The filter cake was washed with dichloromethane, and the filtrate was concentrated to obtain crude compound Q4 (1.1 g), which was directly used in the next step of the reaction.

[0550] MS(ESI+)m / z = 388.4 [MH] - .

[0551] Step 4: Synthesis of compound Q5

[0552] The crude compound Q4 (1.1 g), compound Int-5 (1.79 g, 4.90 mmol), [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium(II) dichloride (266.21 mg, 412.28 μmol), and potassium phosphate (2.60 g, 12.25 mmol) were dissolved in toluene (6 mL), 1,4-dioxane (2 mL), and water (2 mL). The air in the solution was replaced three times with argon. The reaction solution was stirred in an oil bath at 75 °C for 5 hours. After the reaction was complete, the reaction solution was concentrated and extracted with ethyl acetate and water. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal-phase silica gel column chromatography (ethyl acetate / petroleum ether: 0%-60%) to obtain compound Q5 (0.96 g).

[0553] MS(ESI+)m / z=546.5[MH] - .

[0554] Step 5: Synthesis of compound Q6

[0555] Compound Q5 (1.05 g, 1.92 mmol) and N-iodosuccinimide (647.05 mg, 2.88 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was placed in an oil bath at 40 °C and stirred for 5 hours. After the reaction was complete, the reaction was quenched with a saturated sodium bisulfite solution. The mixture was extracted with ethyl acetate and water, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal-phase silica gel column chromatography (ethyl acetate / petroleum ether: 0%-60%) to obtain compound Q6 (700 mg, 1.04 mmol).

[0556] MS(ESI+)m / z=672.3[MH] - .

[0557] Step 6: Synthesis of compound Q7

[0558] Compound Q6 (700 mg, 1.04 mmol) and lithium hydroxide (124.54 mg, 5.20 mmol) were dissolved in tetrahydrofuran (3 mL) and water (3 mL). The reaction solution was placed in an oil bath at 35 °C and stirred for 5 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 5-6 with 1 N hydrochloric acid, and then extracted with ethyl acetate and water. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to obtain compound Q7 (635 mg, 1.03 mmol).

[0559] MS(ESI+)m / z = 618.4[M+H] + .

[0560] Step 7: Synthesis of compound Q8

[0561] Compound Q7 (630 mg, 1.02 mmol) and compound Int-2 (191.22 mg, 1.22 mmol) were dissolved in dichloromethane (6 mL) and stirred in an ice bath. 4-Methylmorpholine (516.00 mg, 5.10 mmol) was added, and the mixture was stirred in an ice bath for 10 minutes. A mixture of 1-hydroxybenzotriazole (27.57 mg, 204.04 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (391.18 mg, 2.04 mmol), and dichloromethane (3 mL) was added dropwise to the reaction mixture. After the addition was complete, the mixture was stirred at room temperature for 8 hours. After the reaction was complete, the reaction was quenched with water, concentrated, extracted with ethyl acetate and water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal-phase silica gel column chromatography (ethyl acetate / petroleum ether: 0%-60%) to obtain compound Q8 (650 mg, 860.20 μmol).

[0562] MS(ESI+)m / z = 756.5[M+H] + .

[0563] Step 8: Synthesis of compound Q9

[0564] Compound Q8 (650 mg, 860.20 μmol) and lithium hydroxide (61.80 mol, 2.58 mmol) were dissolved in tetrahydrofuran (3 mL) and water (3 mL). The reaction solution was placed in an oil bath at 35 °C and stirred for 1 hour. After the reaction was complete, the pH of the reaction solution was adjusted to 5-6 with 1 N hydrochloric acid, and then extracted with ethyl acetate and water. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound Q9 (620 mg).

[0565] MS(ESI+)m / z = 742.5[M+H] + .

[0566] Step 12: Synthesis of compound Int-17

[0567] N,N,N',N'-Tetramethylchloroformamidin hexafluorophosphate (1.86 g, 6.63 mmol) was dissolved in acetonitrile (45 mL) and stirred in an ice bath. N-methylimidazole (1.09 g, 13.28 mmol) was added and stirred in an ice bath for 10 minutes. A mixture of compound Q9 (615 mg, 829.27 μmol), acetonitrile (5 mL), and N,N-dimethylformamide (1 mL) was added dropwise to the reaction mixture. After the addition was complete, the reaction was continued in an ice bath for 30 minutes. After the reaction was complete, the reaction was quenched with water, concentrated, extracted with ethyl acetate and water, and the organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and purified by normal-phase silica gel column chromatography (ethyl acetate / petroleum ether: 0%-60%) to obtain compound Int-17 (485 mg).

[0568] MS(ESI+)m / z = 724.5[M+H] + .

[0569] Preparation Example 18: Synthesis of intermediate compound Int-18

[0570] Referring to steps 1-2 of the synthesis method for Int-6, replace F1 in the first step with (R)-2-hydroxy-3-methylbutyrate benzyl ester. Intermediate R1 was obtained through the same reaction. Following the synthesis method of Int-10, F3 in the first step was replaced with R1, and the same reaction was performed to obtain compound Int-18 (500 mg).

[0571] MS(ESI+)m / z = 350.5[M+H] + .

[0572] Preparation Example 19: Synthesis of intermediate compound Int-19

[0573] Synthesis of compound S2 in the first step

[0574] Compound S1 (1.9 g, 4.7 mmol) obtained in the previous step was dissolved in N,N-dimethylformamide (47 mL). After cooling to 0 °C, compound Int-2 (0.98 g, 6.3 mmol), N,N-diisopropylethylamine DIPEA (1.2 g, 9.3 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate HATU (2.1 g, 5.6 mmol) were added sequentially. The reaction solution was stirred at 0 °C for 10 minutes until the reaction was complete. The reaction was quenched with ice water, and the organic phase was extracted with dichloromethane (30 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (water / acetonitrile = 1 / 0 to 1 / 1) to obtain compound S2 (2.4 g).

[0575] MS(ESI + m / z = 547.5 [M+H] + .

[0576] The second step involves the synthesis of compound S3.

[0577] Compound S2 (2.4 g, 4.4 mmol) was dissolved in hexafluoroisopropanol (44 mL), followed by the addition of palladium on carbon (55 wt%, 200 mg). The reaction mixture was stirred under hydrogen balloon conditions for 24 hours until the reaction was complete. The reaction mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and the resulting residue was used directly in the next reaction step.

[0578] The residue obtained in the previous step was dissolved in tetrahydrofuran (44 mL), followed by the sequential addition of sodium bicarbonate (0.74 g, 8.8 mmol) and 9-fluorenylmethyl-N-succinimide carbonate (1.8 g, 5.3 mmol). The reaction solution was reacted at room temperature for 1 h. After the reaction was complete, the reaction was quenched with ice water, and the organic phase was extracted with dichloromethane (30 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 7 / 10) to give compound S3 (2.4 g).

[0579] MS(ESI + m / z = 635.5[M+H] + .

[0580] Step 3: Synthesis of Int-19

[0581] Compound S3 (634 mg, 1.0 mmol) was dissolved in 1,2-dichloroethane (10 mL), followed by the addition of trimethyltin hydroxide (904 mg, 5.0 mmol). The reaction mixture was stirred at 70 °C for 18 h until complete. The reaction mixture was quenched at 0 °C with 1.0 M, 5 mL of hydrochloric acid solution, and the organic phase was extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give Int-19 (600 mg). The product was used directly in the next reaction without further purification.

[0582] MS(ESI + m / z = 621.5[M+H] + .

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

[0584] Synthesis of compound T2 (Step 1)

[0585] Under argon protection, (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (5.00 g, 14.62 mmol) was dissolved in N,N-dimethylformamide (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 T2 (2.88 g).

[0586] MS(ESI +m / z = 241.1[M+H] + .

[0587] The second step involves the synthesis of compound T3.

[0588] Compound T2 (2.50 g, 10.37 mmol) was dissolved in 1,2-dichloroethane (20 mL) 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 T3 (1.40 g).

[0589] MS(ESI + m / z = 257.1 [M+H] + .

[0590] The third step involves the synthesis of compound T4.

[0591] Compound T3 (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 the mixture was extracted 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 T4 (620.0 mg).

[0592] The fourth step is the synthesis of compound T5.

[0593] Compound T4 (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 T5 (220.0 mg).

[0594] Step 5: Synthesis of compound T6

[0595] Compound T5 (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 was carried out at 50 °C for 5 hours. The reaction solution was concentrated to obtain crude compound T6 (490.0 mg), which was directly used in the next step of the reaction.

[0596] MS(ESI + m / z = 256.0 [M+H] + .

[0597] Step 6: Synthesis of compound T7

[0598] Compound T6 (490.0 mg, crude) 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 7 (500.0 mg, crude).

[0599] MS(ESI + m / z = 275.0 [M+H] + .

[0600] Step 7: Synthesis of compound T8

[0601] Compound T7 (500.0 mg, crude), 4-amino-1-tert-butoxycarbonylpiperidine (728.0 mg, 3.64 mmol), and 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 T8 (590.0 mg), which was directly used in the next reaction step.

[0602] MS(ESI + m / z = 457.1 [M+H] + .

[0603] Step 8: Synthesis of compound T9

[0604] Compound T8 (300.0 mg, crude) 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 T9 (200.0 mg).

[0605] MS(ESI + m / z = 467.1 [M+H] + .

[0606] Step 9: Synthesis of compound T10

[0607] Compound T9 (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 residue was extracted with dichloromethane (30 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound T10 (150.0 mg, crude product).

[0608] MS(ESI + m / z = 367.0 [M+H] + .

[0609] Step 10: Synthesis of compound Int-20

[0610] Compound T10 (150.0 mg, crude) was dissolved in methanol (3 mL), followed by the addition of formaldehyde aqueous 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-20 (55.0 mg).

[0611] MS(ESI + m / z = 381.0 [M+H] + .

[0612] Example 1: Synthesis of Compound 1

[0613] Synthesis of Compounds 1-2 in Step 1

[0614] 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%).

[0615] MS(ESI + m / z = 706.4 [M+H] + .

[0616] The second step involves the synthesis of compounds 1-3.

[0617] 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%).

[0618] MS(ESI+)m / z = 983.4[M+H] + .

[0619] Step 3: Synthesis of compounds 1-4

[0620] 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%).

[0621] MS(ESI+)m / z=1011.4[M+H] + .

[0622] Step 4: Synthesis of compounds 1-5

[0623] 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%).

[0624] MS(ESI + m / z = 891.4 [M+H] + .

[0625] Step 5: Synthesis of compounds 1-6

[0626] 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 mixture was concentrated by rotary evaporation. The crude product was subjected to reversed-phase column chromatography (water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compounds 1-6 (8.0 mg, 10.1 μmol, yield: 39.1%).

[0627] MS(ESI + m / z = 791.4 [M+H] + .

[0628] Step 6: Synthesis of compounds 1-7

[0629] Compounds 1-6 (5.33 mg, 6.74 μmol) and N,N-diisopropylethylamine (3.5 μL, 20.2 μmol) were added sequentially to a solution of compound Int-6 (7.1 mg, 20.2 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (7.7 mg, 20.2 μmol) in N,N-dimethylformamide (1 mL). The mixture was stirred at 33 °C for 2.0 h. After the reaction was complete, the crude product was purified by column chromatography (dichloromethane / methanol = 10:1) to give compounds 1-7 (6.5 mg, 5.78 mmol, yield: 85.7%).

[0630] MS(ESI+)m / z = 1125.6[M+H] + .

[0631] Step 7: Synthesis of compounds 1-8

[0632] Compounds 1-7 (6.5 mg, 5.78 μmol) were 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 complete. The solution was concentrated by rotary evaporation to obtain compounds 1-8 (5.92 mg, 5.77 μmol, yield: 100.0%).

[0633] MS(ESI + m / z = 1025.6 [M+H] + .

[0634] Step 8: Synthesis of Compound 1

[0635] Under ice bath conditions, a solution of compounds 1-8 (5.92 mg, 5.77 μmol) and N,N-diisopropylethylamine (3.0 μL, 17.3 μmol) in N,N-dimethylformamide (0.3 mL) was added to a solution of compound Int-7 (1.7 mg, 11.55 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (3.29 mg, 8.66 μmol) in N,N-dimethylformamide (1.0 mL). The mixture was slowly heated to room temperature and stirred for 0.5 hours. 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: H2O-(NH3H2O), NH3H2O ​​concentration was 0.05%; mobile phase B: MeCN; MeCN ratio 60%-90%, time: 10 min, flow rate: 15 mL / min) to obtain compound 1 (2.0 mg, 1.74 μmol, yield: 30.2%).

[0636] MS(ESI + m / z = 1148.6 [M+H] + .

[0637] 1H NMR(400MHz, Methanol-d4)δ8.49(s,1H),8.18(s,1H),8.05(d,J=9.4Hz,1H),7.74–7.68(m, 2H),7.61(s,1H),7.51(d,J=8.5Hz,1H),7.26(d,J=2.7Hz,1H),5.59(s,1H),5.34(dd,J=5.4 ,4.2Hz,2H),4.74(s,1H),4.69–4.64(m,1H),4.48(q,J=6.1Hz,1H),4.37–4.27(m,1H),4.24 –4.12(m,1H),3.77–3.63(m,4H),3.49–3.46(m,1H),3.42(d,J=4.4Hz,4H),3.38(s,3H),3.1 4–3.12(m,1H),3.04–2.93(m,2H),2.84–2.71(m,2H),2.70–2.66(m,5H),2.64–2.58(m,1H), 2.51–2.43(m,1H),2.38(s,3H),2.29(s,1H),2.22–2.16(m,3H),2.06–1.98(m,4H),1.91–1. 79(m,3H),1.74–1.62(m,4H),1.62–1.55(m,5H),1.54(d,J=6.2Hz,3H),1.49–1.39(m,1H),0 .94(t,J=7.0Hz,3H),0.92–0.86(m,9H),0.66–0.48(m,2H),0.43(s,3H),0.32–0.22(m,1H).

[0638] Example 2: Synthesis of Compound 2

[0639] Synthesis of compound 2-1 in step one

[0640] Compound Int-8 (25.0 mg, 0.050 mmol) was dissolved in acetonitrile (0.5 mL), cooled to 0 °C, and then trimethyliodosilane (20.0 mg, 0.10 mmol) was added dropwise. The reaction mixture was transferred to room temperature and stirred for 1 hour until the reaction was complete. The mixture was then cooled to 0 °C, and the reaction was quenched with triethylamine. After removing the solvent by vacuum distillation, the organic phase was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The product was used directly in the next step without purification.

[0641] The residue obtained in the previous step was dissolved in isopropanol (0.5 mL), cooled to 0 °C, and then 3-oxetane (14.4 mg, 0.20 mmol), acetic acid (0.1 mL), and sodium cyanoborohydride (15 mg, 0.24 mmol) were added sequentially. The reaction solution was stirred at 0 °C for 30 minutes until the reaction was complete, and the reaction was quenched with ice water. The organic phase was extracted with dichloromethane (3.0 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by normal column chromatography (dichloromethane / methanol = 96 / 4) to give compound 2-1 (17.0 mg, yield: 81%).

[0642] MS(ESI + m / z = 420.1 [M+H] + .

[0643] The second step involves the synthesis of compound 2-2.

[0644] Compounds 2-1 (17.0 mg, 0.040 mmol) and 1-2 (25.0 mg, 0.035 mmol) were dissolved in a mixed solution of 1,4-dioxane (0.4 mL) / water (0.1 mL), and then [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (2.9 mg, 0.004 mmol) and potassium carbonate (11.0 mg, 0.080 mmol) were added sequentially. The reaction solution was then transferred to 70 °C and reacted for 3 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and then purified by reverse-phase silica gel column chromatography (water / acetonitrile = 1 / 0 to 1 / 1) to obtain compound 2-2 (20.0 mg).

[0645] MS(ESI + m / z = 919.4 [M+H] + .

[0646] The third step involves the synthesis of compounds 2-3.

[0647] Compound 2-2 (20.0 mg, 0.022 mmol) was dissolved in N,N-dimethylformamide (0.50 mL). After cooling to 0 °C, cesium carbonate (71.7 mg, 0.22 mmol) and iodoethane (34.3 mg, 0.22 mmol) were added sequentially. The reaction mixture was transferred to room temperature and stirred for 2 hours until the reaction was complete. The mixture was then cooled to 0 °C again and quenched with ice water. The organic phase was extracted with dichloromethane (3.0 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 2-3 (20.0 mg, crude product). The product was used directly in the next step without further purification.

[0648] MS(ESI + m / z = 947.5 [M+H]+ .

[0649] Step 4: Synthesis of compounds 2-4

[0650] Compounds 2-3 (20.0 mg, crude) were dissolved in dichloromethane (0.4 mL), cooled to 0°C, and then trifluoroacetic acid (0.1 mL) was added dropwise. The reaction mixture was transferred to room temperature and stirred for 1 hour until the reaction was complete. The mixture was then cooled again to 0°C, and the reaction was quenched by adding saturated sodium bicarbonate solution. The organic phase was extracted with dichloromethane (3.0 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compounds 2-4 (17.9 mg, crude). The product was used directly in the next step without further purification.

[0651] MS(ESI + m / z = 847.4 [M+H] + .

[0652] Step 5: Synthesis of Compound 2 and Compound 2'

[0653] Compound 2-4 (15.0 mg, crude) obtained in the previous step was dissolved in ethyl acetate (0.4 mL), and then compound Int-10 (13.3 mg, 0.035 mmol), N,N-diisopropylethylamine (11.4 mg, 0.088 mmol), 2-hydroxypyridine-N-oxide (1.8 mg, 0.016 mmol), 4-dimethylaminopyridine (10.8 mg, 0.088 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17.3 mg, 0.090 mmol) were added sequentially. The reaction mixture was then stirred at room temperature for 2 hours, cooled to 0 °C, and the reaction was quenched with ice water. The organic phase was extracted with dichloromethane (3.0 mL x 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative chromatography (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) to obtain compound 2 (3.0 mg, retention time: 9.23 min) and compound 2' (3.0 mg, retention time: 8.37 min).

[0654] Compound 2MS (ESI) + m / z = 1204.9 [M+H] + Compound 2' MS (ESI) + m / z = 1204.9 [M+H] +

[0655] Compound 2' 1 H NMR (400MHz, DMSO-d6) δ8.64 (s, 1H), 8.48–8.35 (m, 2H), 7.90 (d, J = 3.2Hz, 1H), 7.76(dd,J=8.6,1.2Hz,1H),7.57(d,J=8.7Hz,1H),5.93(dd,J=19.7,11.1Hz,1 H),5.34–5.28(m,1H),4.89–4.74(m,2H),4.59(t,J=6.5Hz,2H),4.53–4.48(m, 3H),4.07–3.98(m,1H),3.94–3.88(m,1H),3.78–3.66(m,1H),3.64–3.49(m,4H) ,3.05(s,3H),2.98–2.84(m,5H),2.70–2.61(m,3H),2.34–2.32(m,3H),2.25–2 .18(m,6H),2.16–2.09(m,4H),2.02–1.94(m,2H),1.89–1.79(m,2H),1.77–1.66 (m,4H),1.58–1.45(m,5H),1.40–1.31(m,3H),1.28–1.21(m,9H),1.13(t,J=6. 9Hz,3H),0.96–0.89(m,5H),0.58(s,3H),0.37–0.30(m,2H),0.20–0.12(m,1H).

[0656] Example 3: Synthesis of Compound 3

[0657] Synthesis of compound 3-1 in step one

[0658] Compounds Int-9 (40 mg, 72 μmol) and 1-2 (51 mg, 72 μmol) were dissolved in a mixed solution of 1,4-dioxane (1.6 mL) and water (0.4 mL), and then [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (5.3 mg, 7.2 μmol) and potassium phosphate (38 mg, 179.0 μmol) were added sequentially. The reaction solution was then transferred to 70 °C and reacted for 3 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and then purified by reversed-phase column chromatography (water / acetonitrile = 95 / 5-5 / 95) to give compound 3-1 (66 mg, yield: 90%).

[0659] MS(ESI + m / z = 1008.4 [M+H] + .

[0660] The second step involves the synthesis of compound 3-2.

[0661] Compound 3-1 (60 mg, 59.5 μmol) was dissolved in N,N-dimethylformamide (1.50 mL), cooled to 0 °C, and then cesium carbonate (194 mg, 595.4 μmol) and iodoethane (92.8 mg, 595.0 μmol) were added sequentially. The reaction mixture was transferred to room temperature and stirred for 2 hours until the reaction was complete. The reaction mixture was purified by reversed-phase column chromatography (water / acetonitrile = 95 / 5-5 / 95) to give compound 3-2 (61 mg, yield: 99%).

[0662] MS(ESI + m / z = 1036.5 [M+H] + .

[0663] The third step involves the synthesis of compound 3-3.

[0664] Compound 3-2 (60 mg, 57.9 μmol) was dissolved in methanol (3 mL), and palladium hydroxide / carbon (70 mg, 20% palladium hydroxide content) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. After the reaction was complete, the reaction solution was filtered and concentrated to obtain compound 3-3 (45 mg crude product). The product was used directly in the next step without purification.

[0665] MS(ESI+)m / z = 902.4[M+H] + .

[0666] Step 4: Synthesis of compounds 3-4

[0667] Compound 3-3 (30 mg, crude) was dissolved in methanol (2 mL), and paraformaldehyde (10 mg, 333.0 μmol), sodium cyanoborohydride (20.9 mg, 332.6 μmol), and glacial acetic acid (2 mg, 33.3 μmol) were added sequentially at room temperature. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was purified by reversed-phase column chromatography (water / acetonitrile = 95 / 5-5 / 95) to give compound 3-4 (25 mg).

[0668] MS(ESI+)m / z = 916.5[M+H] + .

[0669] Step 5: Synthesis of compounds 3-5

[0670] Compounds 3-4 (37 mg, 40.4 μmol) were dissolved in dichloromethane (1.4 mL), cooled to 0 °C, and then trifluoroacetic acid (0.12 mL) was added dropwise. The reaction mixture was transferred to room temperature and stirred for 1 hour until the reaction was complete. The mixture was then cooled again to 0 °C, and the reaction was quenched by adding saturated sodium bicarbonate solution. The organic phase was extracted with dichloromethane (5 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compounds 3-5 (30 mg, crude product). The product was used directly in the next step without further purification.

[0671] MS(ESI + m / z = 816.4 [M+H] + .

[0672] Step 6: Synthesis of Compound 3 and Compound 3'

[0673] Compound 3-5 (20 mg, crude) obtained in the previous step was dissolved in ethyl acetate (2 mL), and then compound Int-10 (18.4 mg, 49.0 μmol), N,N-diisopropylethylamine (63.3 mg, 489.8 μmol), 2-hydroxypyridine-N-oxide (2.4 mg, 21.6 μmol), 4-dimethylaminopyridine (15.0 mg, 122.8 μmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44.3 mg, 231.1 μmol) were added sequentially. The reaction mixture was then stirred overnight at room temperature, cooled to 0 °C, and the reaction was quenched with ice water. The organic phase was extracted with ethyl acetate (5 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative chromatography (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) to obtain compound 3 (5.66 mg, retention time: 8.25 min) and compound 3' (6.85 mg, retention time: 8.97 min).

[0674] Compound 3MS (ESI) + m / z = 1173.6 [M+H] + Compound 3' MS (ESI) + m / z = 1173.6 [M+H] + .

[0675] Compound 3 1H NMR (400MHz, CDCl3) δ8.48–8.46(m,1H),8.32(s,1H),8.30-8.28(m,1H),7.65-7.63(m,1H),7.50-7.34(m,4H),3.99(s,1 H),5.73–5.62(m,1H),5.38–5.32(m,3H),5.12–5.07(m,1H),4.91–4.89(m,1H),4.73–4.72(m,1H),4.50–4.45(m,1H),4. 25–4.19(m,2H),4.08–4.05(m,1H),3.75–3.60(m,8H),3.53–3.50(m,2H),3.43(s,3H)3.29–3.10(m,2H),3.00–2.84(m,3 H),2.76–2.64(m,7H),2.61–2.48(m,4H),2.42–2.39(m,7H),2.30–2.20(m,3H),2.14–1.99(m,12H),1.91–1.68(m,13H).

[0676] Example 4: Synthesis of Compound 4

[0677] Synthesis of compound 4-1 in step one

[0678] Compounds Int-9 (67 mg, 120 μmol) and Int-11 (66 mg, 100 μmol) were dissolved in a mixed solution of 1,4-dioxane (2.0 mL) / water (0.5 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (14.7 mg, 20.1 μmol) and potassium phosphate (42.6 mg, 200.7 μmol) were added sequentially. The reaction solution was then transferred to 70 °C and reacted for 2 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and then purified by reverse-phase column chromatography (water / acetonitrile = 95 / 5-5 / 95) to give compound 4-1 (70 mg, yield: 72%).

[0679] MS(ESI + m / z = 960.5[M+H] + .

[0680] The second step involves the synthesis of compound 4-2.

[0681] Compound 4-1 (200 mg, 208 μmol) was dissolved in methanol (12 mL), cooled to 0 °C, and potassium carbonate (288 mg, 2.08 mmol) was added. The mixture was then brought back to room temperature and stirred for 3 hours. After the reaction was complete, the solution was evaporated to dryness, and the crude product was used directly in the next step.

[0682] The crude product was dissolved in a mixture of tetrahydrofuran (5 mL) and water (5 mL), cooled to 0 °C, and lithium hydroxide monohydrate (43.4 mg, 1.03 mmol) was added. The mixture was then brought back to room temperature and stirred for 1 hour. After the reaction was complete, the mixture was cooled to 0 °C, acidified with 1 M dilute hydrochloric acid, and the organic phase was extracted with ethyl acetate (15 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 4-2 (180 mg crude product), which was used directly in the next step.

[0683] MS(ESI + m / z = 904.4 [M+H] + .

[0684] The third step involves the synthesis of compound 4-3.

[0685] Compound 4-2 (180 mg crude) and compound Int-2 (93 mg, 0.60 mol) were dissolved in N,N-dimethylformamide (5 mL). After cooling to 0 °C, N,N-diisopropylethylamine (258.48 mg, 2.0 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (227 mg, 0.60 mmol) were added sequentially. After the addition was complete, the mixture was stirred at 0 °C for 1 hour. After the reaction was completed, the mixture was quenched with water, and the crude product was purified by reversed-phase column chromatography (ammonia water (NH4OH content 0.5%):MeCN = 95:5 to 5:95) to give compound 4-3 (180 mg, yield: 86%).

[0686] MS(ESI+)m / z = 1042.5[M+H] + .

[0687] Step 4: Synthesis of compound 4-4

[0688] Compound 4-3 (170 mg, 0.16 mmol) was dissolved in a mixture of tetrahydrofuran (6 mL) and water (6 mL), cooled to 0 °C, and lithium hydroxide monohydrate (34.2 mg, 0.82 mmol) was added. The mixture was stirred for 1 hour. After the reaction was complete, the mixture was acidified with 1 M dilute hydrochloric acid, and the organic phase was extracted with ethyl acetate (15 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 4-4 (150 mg, crude product), which was used directly in the next step.

[0689] MS(ESI + m / z = 1028.2[M+H] + .

[0690] Step 5: Synthesis of compounds 4-5

[0691] N,N,N',N'-Tetramethylchloromethanesulfonyl hexafluorophosphate (464 mg, 1.65 mmol) was dissolved in acetonitrile (130 mL), cooled to 0 °C, and N-methylimidazole (271 mg, 3.30 mmol) was added. Then, compound 4-4 (170 mg, crude product dissolved in acetonitrile / dichloromethane (20 mL)) was slowly added dropwise. The reaction was stirred for 2 hours. After the reaction was complete, the mixture was quenched with ice water. The crude product was concentrated, and purified by reversed-phase column chromatography (ammonia water (NH4OH content 0.5%): MeCN = 95:5 to 5:95) to give compound 4-5 (118 mg).

[0692] MS(ESI + m / z = 1010.2[M+H] + .

[0693] Step 6: Synthesis of compounds 4-6

[0694] Compounds 4-5 (36 mg, 35.6 μmol) were dissolved in N,N-dimethylformamide (0.50 mL), cooled to 0 °C, and then cesium carbonate (116 mg, 356.0 μmol) and iodoethane (5.6 mg, 35.9 μmol) were added sequentially. The reaction mixture was transferred to room temperature and stirred for 2 hours until the reaction was complete. The reaction mixture was purified by reversed-phase column chromatography (water / acetonitrile = 95 / 5-5 / 95) to give compound 4-6 (25 mg, yield: 67%). (The compound is available in the QUITY series.) BEH C18, 1.7 μm column, elution time: 3 min, mobile phase water (NH4OH content 0.5%): MeCN = 40%-95%, retention time: 1.32 min.

[0695] MS(ESI + m / z = 1038.5 [M+H] + .

[0696] Step 7: Synthesis of compounds 4-7

[0697] Compounds 4-6 (25 mg, 24.1 μmol) were dissolved in methanol (3 mL), and palladium hydroxide / carbon (29.7 mg, 20% palladium hydroxide content) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. After the reaction was complete, the reaction solution was filtered and concentrated to obtain compound 4-7 (21 mg, crude product). The product was used directly in the next step without purification.

[0698] MS(ESI+)m / z = 904.1[M+H] + .

[0699] Step 8: Synthesis of compounds 4-8

[0700] Compound 4-7 (21 mg, crude) was dissolved in methanol (2 mL), and paraformaldehyde (8.3 mg, 276.4 μmol), sodium cyanoborohydride (15.3 mg, 243.5 μmol), and glacial acetic acid (2 mg, 33.3 μmol) were added sequentially at room temperature. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was purified by reversed-phase column chromatography (water / acetonitrile = 95 / 5-5 / 95) to give compound 4-8 (20 mg).

[0701] MS(ESI+)m / z = 918.1[M+H] + .

[0702] Step 9: Synthesis of compounds 4-9

[0703] Compounds 4-8 (25 mg, 27.2 μmol) were dissolved in dichloromethane (2.0 mL), cooled to 0 °C, and then trifluoroacetic acid (0.2 mL) was added dropwise. The reaction mixture was transferred to room temperature and stirred for 2 hours until the reaction was complete. The mixture was then cooled again to 0 °C, and the reaction was quenched by adding saturated sodium bicarbonate solution. The organic phase was extracted with dichloromethane (5 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compounds 4-9 (22 mg, crude product). The product was used directly in the next step without further purification.

[0704] MS(ESI + m / z = 818.1 [M+H] + .

[0705] Step 10: Synthesis of Compound 4

[0706] Compound 4-9 (22 mg, crude) obtained in the previous step was dissolved in ethyl acetate (2 mL), and then compound Int-10 (30.3 mg, 80.7 μmol), N,N-diisopropylethylamine (69.5 mg, 537.8 μmol), 2-hydroxypyridine-N-oxide (4.5 mg, 40.5 μmol), 4-dimethylaminopyridine (16.4 mg, 134.2 μmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (49 mg, 255.6 μmol) were added sequentially. The reaction mixture was then stirred overnight at room temperature, cooled to 0 °C, and the reaction was quenched with ice water. The organic phase was extracted with ethyl acetate (5 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative chromatography (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) to obtain compound 4 (9.56 mg).

[0707] MS(ESI + m / z = 1175.5 [M+H] + .

[0708] 1 H NMR (400MHz, CDCl3) δ8.30–8.27(m,2H),7.49–7.47(m,1H),7.37–7.31(m,2H),7.13–7.11(m,1H),6.99(s,1H),6.94–6.89 (m,1H),5.57–5.49(m,2H),5.39–5.30(m,3H),5.15–5.07(m,3H),4.83–4.81(m,1H),4.55–4.50(m,1H),4.45–4.43(m,1H), 4.21–4.05(m,5H),3.99–3.96(m,1H),3.84–3.81(m,1H),3.68–3.45(m,12H),3.34(s,2H),3.17–3.10(m,1H),3.03–2.93(m ,2H),2.88–2.67(m,13H),2.61–2.48(m,6H),2.40–2.28(m,9H),2.24–2.20(m,2H),2.13–2.04(m,14H),1.83–1.79(m,3H).

[0709] Example 5: Synthesis of Compound 5

[0710] Synthesis of compound 5-1 in step one

[0711] Compounds Int-8 (50.0 mg, 0.10 mmol) and Int-11 (79.0 mg, 0.12 mmol) were dissolved in a mixed solution of 1,4-dioxane (0.9 mL) / water (0.3 mL), and then [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (7.3 mg, 0.010 mmol) and potassium carbonate (27.6 mg, 0.20 mmol) were added sequentially. The reaction mixture was then heated to 70 °C for 4 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by reversed-phase silica gel column chromatography (water / acetonitrile = 1 / 0 to 1 / 1) to give compound 5-1 (40.0 mg, 0.042 mmol, yield: 42.0%).

[0712] MS(ESI + m / z = 949.7 [M+H] + .

[0713] The second step involves the synthesis of compound 5-2.

[0714] Compound 5-1 (20.0 mg, 0.021 mmol) was dissolved in N,N-dimethylformamide (0.20 mL). The reaction mixture was then moved to 0 °C and cesium carbonate (32.6 mg, 0.10 mmol) and iodoethane (15.6 mg, 0.10 mmol) were added sequentially. The reaction was allowed to complete at room temperature with stirring for 2 hours, then moved to 0 °C and quenched with ice water. The organic phase was extracted with dichloromethane (3.0 mL x 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 5-2 (20.0 mg, crude product). This product was used directly in the next step without further purification.

[0715] MS(ESI + m / z = 977.6 [M+H] + .

[0716] The third step involves the synthesis of compound 5-3.

[0717] Compound 5-2 (20.0 mg, crude) was dissolved in methanol (0.5 mL), the solution was transferred to 0 °C, and potassium carbonate (27.6 mg, 0.20 mmol) was added. The reaction was allowed to proceed with stirring at room temperature for 2 hours until complete, then the solution was transferred to 0 °C and quenched with ice water. The organic phase was extracted with dichloromethane (3.0 mL x 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used directly in the next step.

[0718] The residue obtained in the previous step was dissolved in a mixed solution of tetrahydrofuran (0.4 mL) and water (0.1 mL), transferred to 0 °C, and lithium hydroxide monohydrate (8.0 mg, 0.19 mmol) was added. After the reaction was completed by stirring at room temperature for 1 hour, the mixture was transferred to 0 °C and dilute hydrochloric acid (1.0 M) was added to neutralize the reaction solution. The organic phase was extracted with dichloromethane (3.0 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give compound 5-3 (18.0 mg, crude product). The product was used directly in the next step without further purification.

[0719] MS(ESI + m / z = 921.6 [M+H] + .

[0720] Step 4: Synthesis of compound 5-4

[0721] Compound 5-3 (18.0 mg, crude) was dissolved in N,N-dimethylformamide (0.20 mL), and the solution was heated to 0 °C. Compound Int-2 (5.9 mg, 0.038 mmol) and N,N-diisopropylethylamine (7.9 mg, 0.061 mmol) were added sequentially. The reaction mixture was stirred at this temperature for 10 minutes, followed by the addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (8.5 mg, 0.022 mmol). The reaction mixture was then cooled to room temperature and stirred for 30 minutes. After the reaction was complete, the solution was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by reversed-phase silica gel column chromatography (water / acetonitrile = 1 / 0 to 1 / 1) to give compound 5-4 (12.0 mg, 0.011 mmol, yield: 55.7%).

[0722] MS(ESI + m / z = 1059.8 [M+H] + .

[0723] Step 5: Synthesis of compound 5-5

[0724] Compound 5-4 (12.0 mg, 0.011 mmol) was dissolved in a mixed solution of tetrahydrofuran (0.4 mL) and water (0.1 mL), and the solution was heated to 0 °C and lithium hydroxide monohydrate (8.0 mg, 0.20 mmol) was added. The reaction was allowed to proceed until complete by stirring at 0 °C for 1 hour. The reaction solution was then neutralized with dilute hydrochloric acid (1.0 M). The organic phase was extracted with dichloromethane (3.0 mL x 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 5-5 (11.8 mg, crude product). This product was used directly in the next step without further purification.

[0725] MS(ESI + m / z = 1045.7 [M+H]+ .

[0726] Step 6: Synthesis of compounds 5-6

[0727] N,N,N',N'-Tetramethylchloromethanesulfonamide hexafluorophosphate (30.9 mg, 0.11 mmol) and N-methylimidazole (18.0 mg, 0.22 mmol) were dissolved in anhydrous acetonitrile (1.00 mL) and stirred at 0 °C for 10 min. Then, compound 5-5 (11.8 mg, 0.011 mmol) was dissolved in anhydrous acetonitrile (0.5 mL) and added dropwise to the above reaction solution at 0 °C. After the addition was complete, the reaction mixture was stirred at 0 °C for another 10 min. After the reaction was complete, the reaction solution was purified by normal column chromatography (dichloromethane:methanol = 96:4) to give compound 5-6 (8.0 mg, 0.008 mmol, yield: 71%).

[0728] MS(ESI + m / z = 1027.7 [M+H] + .

[0729] Step 7: Synthesis of Compounds 5-7

[0730] Compounds 5-6 (8.0 mg, 0.008 mmol) were dissolved in hexafluoroisopropanol (2.00 mL), and palladium hydroxide / carbon (3.00 mg, 20% palladium hydroxide content) was added. The reaction was stirred under a hydrogen atmosphere for 2 hours. After the reaction was completed, the reaction solution was filtered and concentrated to dryness under reduced pressure to obtain compound 5-7 (6 mg, crude product), which was used directly in the next step.

[0731] MS(ESI + m / z = 893.6 [M+H] + .

[0732] Step 8: Synthesis of compounds 5-8

[0733] Compound 5-7 (6 mg, crude) obtained in the previous step was dissolved in isopropanol (0.2 mL), and the solution was heated to 0 °C. Then, 3-oxetane (1.7 mg, 0.024 mmol), acetic acid (40 μL), and sodium cyanoborohydride (1.5 mg, 0.024 mmol) were added sequentially. The reaction mixture was stirred at the temperature for 30 minutes until complete, and then quenched with ice water. The organic phase was extracted with dichloromethane (3.0 mL x 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by normal column chromatography (dichloromethane:methanol = 96:04) to give compound 5-8 (5.0 mg).

[0734] MS(ESI + m / z = 949.5 [M+H] +.

[0735] Step 9: Synthesis of Compound 5

[0736] Compounds 5-8 (5 mg, 0.005 mmol) were dissolved in dichloromethane (0.4 mL), cooled to 0 °C, and then trifluoroacetic acid (0.1 mL) was added. The reaction mixture was then transferred to room temperature and stirred for 30 minutes until the reaction was complete. The mixture was cooled again to 0 °C, and the reaction was quenched with saturated sodium bicarbonate solution. The organic phase was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and then dissolved in ethyl acetate (0.4 mL). After cooling to 0 °C, Int-10 (3.8 mg, 0.010 mmol), N,N-diisopropylethylamine (3.88 mg, 0.030 mmol), 2-hydroxypyridine-N-oxide (0.7 mg, 0.006 mmol), 4-dimethylaminopyridine (2.4 mg, 0.020 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.9 mg, 0.010 mmol) were added sequentially. Subsequently, the reaction solution was kept at room temperature and stirred for 2 hours, then moved to 0°C, and the reaction was quenched with ice water. The organic phase was extracted with dichloromethane (3.0 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by preparative chromatography (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%-95%, time: 10 min, flow rate: 15 mL / min) to give compound 5 (0.9 mg, yield: 19%, retention time: 9.78 min).

[0737] MS(ESI + m / z = 1207.1 [M+H] + .

[0738] Example 6: Synthesis of Compound 6

[0739] Step 1: Synthesis of Compound 6-2

[0740] At room temperature, compound Int-12 (400 mg, 1.54 mmol) was dissolved in 5 mL of N-methylpyrrolidone solution. Then, compound 6-1 (161.34 mg, 1.85 mmol) and N,N-diisopropylethylamine (299.18 mg, 2.31 mmol) were added, and the reaction mixture was stirred at 90 °C for 1 hour. After the reaction was complete, the solution was cooled to room temperature, dissolved in 50 mL of water, and filtered to obtain crude compound 6-2 (450 mg). This crude compound was used directly in the next reaction.

[0741] MS(ESI+)m / z = 327.1[M+H] + .

[0742] Step 2: Synthesis of Compound 6-3

[0743] Under an argon atmosphere, (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (97.49 mg, 154.5 μmol) was added to triethylamine (900 mg, 8.89 mmol) and formic acid (180 mg, 3.91 mmol). The reaction mixture was stirred at 40 °C for 10 minutes. Then, under ice bath conditions, a solution (2 ml) of N,N-dimethylformamide containing 500 mg of crude compound 6-2 was added. The reaction mixture was stirred at 45 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, concentrated under reduced pressure, and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 6-3 (360 mg).

[0744] MS(ESI + m / z = 299.1 [M+H] + .

[0745] The third step involves the synthesis of compound 6-4.

[0746] Under an argon atmosphere, compound 6-3 (200 mg, 670.4 μmol) and p-toluenesulfonic acid monohydrate (636.86 mg, 3.35 mmol) were dissolved in acetonitrile (2.5 mL). Then, aqueous solutions of sodium nitrite (231.28 mg, 3.35 mmol) (0.25 mL) and potassium iodide (556.42 mg, 3.35 mmol) (0.25 mL) were added, respectively. The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the solution was quenched with saturated sodium sulfite solution, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to give crude compound 6-4 (274 mg). This was used directly in the next step.

[0747] MS(ESI + m / z = 410.0 [M+H] + .

[0748] Step 4: Synthesis of Compounds 6-5

[0749] Under an argon atmosphere, crude compound 6-4 (493 mg) was dissolved in 2 mL of N,N-dimethylformamide solution. Sodium hydride (192.74 mg, 4.82 mmol, 60% purity) and methyl iodide (683.99 mg, 4.82 mmol) were then added, and the reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the mixture was quenched with saturated ammonium chloride and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 6-5 (300 mg).

[0750] MS(ESI + m / z = 424.0 [M+H] + .

[0751] Step 5: Synthesis of compound 6-6

[0752] Under an argon atmosphere, compound 6-5 (35 mg, 82.7 μmol) was dissolved in dioxane (2 mL) and water (0.2 mL) solutions. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (6.05 mg, 8.3 μmol), potassium carbonate (34.24 mg, 247.7 μmol), and compound 1-2 (70.03 mg, 99.2 μmol) were added, respectively. The reaction mixture was stirred at 70 °C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was collected, concentrated under reduced pressure, and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:2) to obtain compound 6-6 (50 mg).

[0753] MS(ESI + m / z = 875.4 [M+H] + .

[0754] Step 6: Synthesis of compounds 6-7

[0755] Under an argon atmosphere, compound 6-6 (50 mg, 57.1 μmol) was dissolved in N,N-dimethylformamide (1 mL) solution, followed by the addition of cesium carbonate (93.09 mg, 285.7 μmol) and iodoethane (44.56 mg, 285.7 μmol), respectively. The reaction solution was stirred at 30 °C for 1 hour. After the reaction was completed, the solution was purified by reversed-phase column chromatography (Sepax BR-C18 21.22*250 mm*5 μm column; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%, mobile phase B: MeCN; MeCN ratio 70%-80%, time: 20 min, flow rate: 20 mL / min) to obtain compound 6-7 (20 mg, retention time: 16.18 min) and compound 6-7' (20 mg, retention time: 14.72 min).

[0756] MS(ESI+ m / z = 903.4 [M+H] + .

[0757] Step 7: Synthesis of compounds 6-8

[0758] Compound 6-7 (19 mg, 21.0 μmol) was dissolved in dichloromethane (2 mL) under an argon atmosphere, followed by the addition of trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at 30 °C for 1 hour. After the reaction was completed, the solution was quenched with saturated sodium bicarbonate, extracted with ethyl acetate, and the organic phase was concentrated to dryness under reduced pressure to obtain crude compound 6-8 (16.8 mg), which was directly used in the next reaction.

[0759] MS(ESI + m / z = 803.4 [M+H] + .

[0760] Step 8: Synthesis of Compound 6

[0761] Under an argon atmosphere, compound Int-10 (14.96 mg, 39.8 μmol) was dissolved in a solution of N,N-dimethylformamide (0.5 mL). Then, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (11.36 mg, 29.9 μmol) was added in an ice bath. Crude compound 6-8 (16.0 mg, crude product) and N,N-diisopropylethylamine (12.88 mg, 99.7 μmol) in a solution of N,N-dimethylformamide (0.5 mL) were added. The reaction solution was stirred at 0 °C for 0.5 hours. After the reaction was completed, the product was purified by reversed-phase column chromatography (Waters Xbridge OBD 150*19 mm*5 μm column; 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 6 (3.60 mg, retention time: 8.28 min).

[0762] MS(ESI+)m / z = 1160.6[M+H] + .

[0763] 1H NMR(400MHz, DMSO-d6)δ8.46(s,1H),8.46–8.32(m,1H),8.30–8.23(m,1H),8.12(s,1H),7.94–7.88(m,1H),7.84–7.72(m,2H),7.67–7.60(m, 1H),6.00–5.88(m,1H),5.38–5.28(m,1H),4.82–4.71(m,1H),4.54–4. 47(m,1H),4.48–4.31(m,1H),4.18–4.05(m,1H),3.86–3.77(m,4H),3.6 4–3.45(m,7H),3.32–3.19(m,7H),3.00–2.91(m,2H),2.91–2.81(m,2H ),2.74–2.58(m,3H),2.29–2.07(m,7H),2.04–1.92(m,2H),1.89–1.77 (m,1H),1.78–1.61(m,5H),1.63–1.43(m,10H),1.41–1.28(m,3H),0.9 2–0.79(m,7H),0.68–0.49(m,2H),0.41–0.28(m,3H),0.21–0.11(m,2H)

[0764] Example 7 Synthesis of Compound 7

[0765] Following the synthetic steps of compound 6, replace compound 6-1 in the first step with cyclopropanol. Following the same steps 1-6, the product was purified using a preparative column (Waters Xbridge OBD 150*19 mm*5 μm column; 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 7-1 (14 mg, retention time: 1.42 min) and compound 7-1' (14 mg, retention time: 1.32 min). Then, following the last two steps of Example 6, compound 7-1 was used to replace compound 6-7 to obtain compound 7 (5 mg).

[0766] MS(ESI + m / z = 1131.2[M+H] + .

[0767] 1H NMR (400MHz, DMSO-d6) δ8.50(d,J=8.0Hz,1H),8.46(s,1H),8.18-8.15(m,2H),7.91(m,1H),7.80(d,J=8.0Hz,1H),7.63(d,J=8.0Hz,1H),5. 97–5.90(m,1H),5.35–5.30(m,1H),4.76(d,J=12.0Hz,1H),4.52–4.46 (m,2H),4.42–4.33(m,2H),4.10–4.07(m,1H),3.60–3.47(m,3H),3.31 –3.16(m,18H),2.97-2.93(m,1H),2.88-2.82(m,1H),2.72-2.63(m,3H ),2.33–2.32(m,2H),2.26–2.24(m,2H),2.19–2.16(m,2H),2.16–2.13 (m,3H),2.13-2.07(m,2H),2.02-1.95(m,1H).1.48-1.47(m,4H),1.25 -1.21(m,5H),0.98-0.96(m,2H),0.86-0.83(m,9H)0.38-0.14(m,5H).

[0768] Example 8: Synthesis of Compound 8

[0769] Based on the synthesis steps of compound 3, replace compound Int-10 in the last step with compound Int-18. After the reaction, the mixture was purified by reversed-phase column chromatography (Waters Xbridge OBD 150*19 mm*5 μm column; 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 8 (2.06 mg).

[0770] MS(ESI + m / z = 1147.4 [M+H] + .

[0771] Example 9: Synthesis of Compound 9

[0772] Step 1: Synthesis of Compound 9-1

[0773] Compound Int-9 (500 mg, 898.6 μmol) was added to acetonitrile (5 mL), and nitrogen was introduced to replace the atmosphere. Trimethyliodosilane (269.72 mg, 1.35 mmol) was added dropwise under ice bath conditions, and the resulting mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was quenched with dilute hydrochloric acid (1 M) under ice bath conditions. The aqueous phase was washed with ethyl acetate, separated, and then adjusted to alkalinity with saturated sodium bicarbonate solution. The solution was extracted with dichloromethane, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product compound 9-1 (379 mg), which was used directly in the next reaction.

[0774] MS(ESI+)m / z = 423.1[M+H] + .

[0775] Step 2: Synthesis of Compound 9-2

[0776] Compound 9-1 (379 mg, crude product), (1-ethoxycyclopropoxy)trimethylsilane (782.27 mg, 4.49 mmol), and acetic acid (269.49 mg, 4.49 mmol) were added to isopropanol (8 mL), followed by sodium cyanoborohydride (282.01 mg, 4.49 mmol). The resulting mixture was stirred at 50 °C for 3 hours. After the reaction was complete, water was added to quench the reaction. The crude product was purified by reversed-phase chromatography (water (containing 0.5% concentrated ammonia): acetonitrile = 95:5 - 5:95) to obtain compound 9-2 (175 mg).

[0777] MS(ESI+)m / z = 463.1[M+H] + .

[0778] Step 3: Synthesis of Compound 9-3

[0779] Compound 9-2 (40 mg, 86.5 μmol) was added to 1,4-dioxane (1.0 mL) and water (0.2 mL), followed by compound 1-2 (79.37 mg, 112.5 μmol), potassium phosphate (45.86 mg, 216.1 μmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (6.33 mg, 8.7 μmol). The mixture was stirred for 5 hours at 70 °C under argon protection. 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, concentrated under reduced pressure to remove the solvent, and the residue was purified by reversed-phase chromatography (water (containing 0.5% concentrated ammonia): acetonitrile = 95:5-5:95) to give compound 9-3 (55 mg).

[0780] MS(ESI+)m / z = 914.4[M+H] + .

[0781] Step 4: Synthesis of compound 9-4-P2

[0782] Compound 9-3 (55 mg, 60.2 μmol) and cesium carbonate (97.77 mg, 300.1 μmol) were added to N,N-dimethylformamide (1 mL). Iodethane (46.92 mg, 300.8 μmol) was added to the reaction solution, and the resulting mixture was stirred at 35 °C for 3.0 h. After the reaction was completed, the mixture was purified by reversed-phase column chromatography (Waters Xbridge OBD 150*19 mm*5 μm column; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%, mobile phase B: MeCN; MeCN ratio 85%-88%, time: 10 min, flow rate: 15 mL / min) to obtain compound 9-4-P1 (20 mg, retention time: 5.90 min) and compound 9-4-P2 (20 mg, retention time: 6.45 min).

[0783] Compound 9-4-P2 MS (ESI+) m / z = 942.5 [M+H] + .

[0784] Step 5: Synthesis of Compound 9-5

[0785] Compound 9-4-P2 (20 mg, 21.2 μmol) was dissolved in dichloromethane (1 mL), followed by the addition of trifluoroacetic acid (0.2 mL). The reaction was stirred at room temperature for 1.0 h. After the reaction was complete, the mixture was quenched in a saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent, yielding crude compound 9-5 (18 mg). The crude product was used directly in the next reaction without purification.

[0786] MS(ESI + m / z = 842.4 [M+H] + .

[0787] Step 7: Synthesis of Compound 9

[0788] Compounds 9-5 (18 mg, 21.4 μmol), Int-10 (24.08 mg, 64.1 μmol), 2-hydroxypyridine-N-oxide (3.56 mg, 32.0 μmol), N,N-diisopropylethylamine (55.25 mg, 427.5 μmol), and 4-dimethylaminopyridine (13.06 mg, 106.9 μmol) were added to ethyl acetate (1 mL), and nitrogen gas was introduced. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.37 mg, 299.3 μmol) was added under ice bath conditions. The resulting mixture was stirred at room temperature for 15 hours. After the reaction was complete, water was added to quench the reaction, followed by extraction with dichloromethane. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by preparative 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% in 18 minutes) to obtain compound 9 (9.5 mg).

[0789] MS(ESI+)m / z = 1199.7 [M+H] + .

[0790] 1H NMR(400MHz, DMSO-d6)δ8.46(s,1H),8.39(dd,J=26.4,8.6Hz,1H),8.22(d,J=9.5Hz,1H),8.10 (s,1H),7.91(s,1H),7.80(d,J=8.7Hz,1H),7.75(d,J=9.5Hz,1H),7.63(d,J=8.7Hz,1H),5.94 (dd,J=15.8,11.4Hz,1H),5.35–5.31(m,1H),4.77(d,J=10.9Hz,1H),4.51(d,J=4.0Hz,1H),4. 46-4.35(m,2H),4.14-4.05(m,1H),3.60-3.51(m,7H),3.29(s,3H),3.27–3.19(m,3H),3.03(d, J=14.0Hz,1H),2.98-2.94(m,1H),2.90-2.84(m,2H),2.77-2.70(m,4H),2.69–2.63(m,2H),2. 34-2.32(m,1H),2.24(s,2H),2.19(s,2H),2.17–2.09(m,2H),2.03-1.96(m,2H),1.86-1.80(m, 1H),1.75–1.69(m,3H),1.68–1.61(m,2H),1.59–1.49(m,5H),1.49–1.43(m,5H),1.40-1.31(m ,3H),1.26-1.22(m,6H),0.90-0.84(m,6H),0.50-0.45(m,2H),0.40-0.31(m,4H),0.27(s,2H).

[0791] Example 10: Synthesis of Compound 10

[0792] Following the synthetic steps of compound 9, using intermediate 9-4-P2, the same last two steps were performed, except that in the last step, compound Int-10 was replaced with compound Int-18. After the reaction was completed, the mixture was purified by reversed-phase column chromatography (Waters Xbridge OBD 150*19 mm*5 μm column; 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 10 (11.4 mg).

[0793] MS(ESI + m / z = 1173.2[M+H]+ .

[0794] 1 H NMR (400MHz, DMSO-d6) δ8.46(s,1H),8.22(d,J=9.5Hz,1H),8.10(s,1H),7.89(d,J=2.0Hz ,1H),7.79(d,J=8.7Hz,1H),7.74(d,J=9.5Hz,1H),7.63(d,J=8.7Hz,1H),5.93(dd,J=18.3 ,11.1Hz,1H),5.40–5.32(m,1H),4.76(d,J=11.1Hz,1H),4.54–4.49(m,1H),4.47–4.35(m, 2H),4.15–4.05(m,1H),3.55(t,J=5.1Hz,7H),3.00(d,J=7.3Hz,1H),2.81(d,J=8.5Hz,2H) ,2.76(d,J=4.9Hz,4H),2.65(s,2H),2.35–2.31(m,3H),2.24(s,2H),2.19(s,2H),2.01–1 .94(m,2H),1.89–1.81(m,2H),1.81–1.60(m,9H),1.46(d,J=6.1Hz,3H),1.36(dt,J=19.4, 6.6Hz,2H),1.24(s,3H),0.98(dd,J=6.7,2.4Hz,4H),0.95–0.90(m,3H),0.89–0.84(m,10H ),0.47(dt,J=6.8,3.6Hz,2H),0.38(q,J=3.2,2.6Hz,2H),0.35–0.30(m,2H),0.28(s,3H).

[0795] Example 11 Synthesis of Compound 11

[0796] According to step 1 of the synthesis of compound 2, the intermediate is... Replace with After the mixture was heated to 55°C and reacted for 24 hours, intermediate 11-1 was prepared. Then, through the same reaction process, a mixture of compound 11 and compound 11' was obtained. After preparative chromatography purification (XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration of 0.05%; mobile phase B: MeCN; MeCN ratio of 65%-85%, time: 13 min, flow rate: 15 mL / min), compounds 11 (13.0 mg, retention time: 9.57 min) and 11' (13.0 mg, retention time: 8.05 min) were obtained.

[0797] Compound 11MS (ESI) + m / z = 1188.9 [M+H] + .

[0798] 1 H NMR(400MHz,DMSO-d6)δ8.47–8.44(m,2H),8.42–8.27(m,1H),7.90–7.87(m,1H) ,7.77(d,J=8.6Hz,1H),7.60(d,J=8.7Hz,1H),5.93(dd,J=16.5,11.1Hz,1H),5. 38–5.31(m,1H),4.88–4.79(m,1H),4.75(d,J=10.9Hz,1H),4.54–4.49(m,1H),4 .40–4.28(m,2H),4.07–3.96(m,1H),3.72–3.50(m,4H),3.42–3.35(m,3H),3.25 (s,3H),3.18–3.10(m,2H),3.00–2.92(m,2H),2.88–2.83(m,1H),2.73–2.57(m, 3H),2.38–2.07(m,15H),1.88–1.80(m,1H),1.79–1.48(m,12H),1.43(d,J=6.0H z,3H),1.39–1.30(m,3H),1.27–1.18(m,2H),0.90–0.81(m,7H),0.67–0.54(m,1 H),0.50–0.45(m,2H),0.40–0.32(m,4H),0.31–0.27(m,2H),0.20–0.11(m,1H).

[0799] Example 12 Synthesis of Compound 12

[0800] Following the synthetic steps of compound 2, the intermediate was... Replace with After heating the mixture to 55°C and reacting for another 24 hours, intermediate 11-1 was prepared. The final compound, Int-10, was replaced with compound Int-18. After the reaction, the product was purified by preparative chromatography (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 60%-80%, time: 10 min, flow rate: 15 mL / min) to obtain compounds 12 (3.4 mg, yield: 15%, retention time: 8.53 min) and 12' (3.4 mg, yield: 15%, retention time: 7.27 min).

[0801] Compound 12MS (ESI) + m / z = 1162.7 [M+H] + .

[0802] Example 13 Synthesis of Compound 13

[0803] Following the synthetic steps of compound 2, the intermediate was... Replace with After heating the mixture to 55°C and reacting for another 24 hours, intermediate 11-1 was prepared. This intermediate involved replacing iodoethane (EtI) from the third step with 4-(2-iodoethoxy)tetrahydro-2H-pyran. Following the same reaction process, a mixture of compounds 13 and 13' was obtained. After preparative chromatography purification (XBridge Prep C18 column; 150*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), compound 13 (1.4 mg, yield: 10%, retention time: 10.53 min) and compound 13' (2.5 mg, yield: 17%, retention time: 9.00 min) were obtained.

[0804] Compound 13MS (ESI) + m / z = 1288.89 [M+H] + .

[0805] Example 14 Synthesis of Compound 14

[0806] Synthesis of compound 14-1 (Step 1)

[0807] Compound Int-16 (231.0 mg, 0.50 mmol) was dissolved in dichloromethane (5.0 mL), cooled to 0 °C, and then trifluoroacetic acid (1.0 mL) was added dropwise. The reaction mixture was transferred to room temperature and stirred for 1 hour until the reaction was complete. The mixture was then cooled to 0 °C, and the reaction was quenched by adding saturated sodium bicarbonate solution. Dichloromethane was added to extract the organic phase. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The product was used directly in the next reaction without purification.

[0808] The residue obtained in the previous step (36.4 mg, crude product) was dissolved in acetonitrile (1.0 mL), and 2-bromoethyl methyl ether (20.8 mg, 0.15 mmol), potassium iodide (33.2 mg, 0.20 mmol), and potassium carbonate (27.6 mg, 0.20 mmol) were added sequentially. The reaction solution was stirred at 60 °C for 15 hours until the reaction was complete. The reaction was quenched with ice water, and the organic phase was extracted with dichloromethane (3.0 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by normal column chromatography (dichloromethane / methanol = 96 / 04) to give compound 14-1 (22.0 mg).

[0809] MS(ESI + m / z = 422.2[M+H] + .

[0810] The second step involves the synthesis of compound 14-2.

[0811] Compound 14-1 (22.0 mg, 0.052 mmol) and compound 1-2 (40.4 mg, 0.057 mmol) were dissolved in a mixed solution of 1,4-dioxane (0.5 mL) / water (0.1 mL), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (3.8 mg, 0.0052 mmol) and potassium phosphate (22.0 mg, 0.104 mmol) were added sequentially. The reaction solution was then transferred to 70 °C and reacted for 3 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and then purified by reverse-phase silica gel column chromatography (water / acetonitrile = 1 / 0 to 1 / 1) to obtain compound 14-2 (42.4 mg, 0.046 mmol).

[0812] MS(ESI + m / z = 921.6 [M+H] + .

[0813] The third step involves the synthesis of compound 14-3.

[0814] Compound 14-2 (42.4 mg, 0.046 mmol) was dissolved in N,N-dimethylformamide (0.50 mL). After cooling to 0 °C, cesium carbonate (163 mg, 0.50 mmol) and iodoethane (78.0 mg, 0.50 mmol) were added sequentially. The reaction mixture was transferred to room temperature and stirred for 2 hours until the reaction was complete. The mixture was then cooled to 0 °C again and the reaction was quenched with ice water. The organic phase was extracted with dichloromethane (3.0 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 14-3 (43.7 mg, crude product). The product was used directly in the next reaction without further purification.

[0815] MS(ESI + m / z = 949.6 [M+H] + .

[0816] Step 4: Synthesis of compound 14-4

[0817] Compound 14-3 (43.7 mg, crude) was dissolved in dichloromethane (0.5 mL), cooled to 0°C, and then trifluoroacetic acid (0.1 mL) was added dropwise. The reaction mixture was transferred to room temperature and stirred for 1 hour until the reaction was complete. The mixture was then cooled again to 0°C, and the reaction was quenched by adding saturated sodium bicarbonate solution. The organic phase was extracted with dichloromethane (3.0 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 14-4 (39.1 mg, crude). The product was used directly in the next reaction without purification.

[0818] MS(ESI + m / z = 849.4 [M+H] + .

[0819] Step 5: Synthesis of Compound 14

[0820] Compound 14-4 (39.1 mg, crude) obtained in the previous step was dissolved in ethyl acetate (0.5 mL), and then compound Int-10 (34.5 mg, 0.092 mmol), N,N-diisopropylethylamine (22.8 mg, 0.18 mmol), 2-hydroxypyridine-N-oxide (6.1 mg, 0.055 mmol), 4-dimethylaminopyridine (28.1 mg, 0.23 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17.5 mg, 0.091 mmol) were added sequentially. The reaction mixture was then stirred at room temperature for 16 hours, cooled to 0 °C, and the reaction was quenched with ice water. The organic phase was extracted with dichloromethane (3.0 mL * 3). The organic phase was washed with saturated brine, dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative chromatography (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%-75%, time: 10 min, flow rate: 15 mL / min) to obtain compound 14 (14.0 mg, retention time: 8.33 min) and compound 14' (14.0 mg, retention time: 7.07 min).

[0821] Compound 14MS (ESI) + m / z = 1206.68 [M+H] + .

[0822] Example 15 Synthesis of Compound 15

[0823] Synthesis of Compound 15-1 (Step 1)

[0824] Compounds Int-15 (30 mg, 68.6 μmol) and 1-2 (58.1 mg, 82.3 μmol) were dissolved in a mixed solution of 1,4-dioxane (2.0 mL) / water (0.5 mL), and then [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (5.0 mg, 6.8 μmol) and potassium carbonate (28.4 mg, 205.5 μmol) were added sequentially. The reaction solution was then transferred to 70 °C and reacted for 3 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and then purified by reversed-phase column chromatography (water / acetonitrile = 95 / 5-5 / 95) to give compound 15-1 (49 mg, yield: 80%).

[0825] MS(ESI + m / z = 890.1 [M+H] + .

[0826] The second step involves the synthesis of compound 15-2.

[0827] Compound 15-1 (49 mg, 55.1 μmol) was dissolved in N,N-dimethylformamide (0.50 mL), cooled to 0 °C, and then cesium carbonate (90.0 mg, 276.2 μmol) and iodoethane (43.0 mg, 275.7 μmol) were added sequentially. The reaction mixture was transferred to room temperature and stirred for 2 hours until the reaction was complete. The reaction mixture was purified by reversed-phase column chromatography (water / acetonitrile = 95 / 5-5 / 95) to give compound 15-2 (13 mg, yield: 26%). BEH C18, 1.7 μm column, elution time: 3 min, mobile phase water (NH4OH content 0.5%): MeCN = 40%-95%, retention time: 1.42 min) and 15-2' (13 mg, yield: 26%, compound in QUITY) BEH C18, 1.7 μm column, elution time: 3 min, mobile phase water (NH4OH content 0.5%): MeCN = 40%-95%, retention time: 1.38 min.

[0828] Compound 15-3MS (ESI) + m / z = 918.2[M+H] + .

[0829] The third step involves the synthesis of compound 15-3.

[0830] Compound 15-2 (13 mg, 14.2 μmol) was dissolved in dichloromethane (1.0 mL), cooled to 0 °C, and then trifluoroacetic acid (0.2 mL) was added dropwise. The reaction mixture was transferred to room temperature and stirred for 1 hour until the reaction was complete. The mixture was then cooled again to 0 °C, and the reaction was quenched by adding saturated sodium bicarbonate solution. The organic phase was extracted with dichloromethane (5 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 15-3 (15 mg, crude product). The product was used directly in the next step without further purification.

[0831] MS(ESI + m / z = 818.2[M+H] + .

[0832] Step 4: Synthesis of Compound 15

[0833] The crude compound 15-3 obtained in the previous step was dissolved in ethyl acetate (2 mL), and then compound Int-10 (10.6 mg, 28.2 μmol), N,N-diisopropylethylamine (36.7 mg, 284.0 μmol), 2-hydroxypyridine-N-oxide (1.4 mg, 12.6 μmol), 4-dimethylaminopyridine (8.7 mg, 71.2 μmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38.1 mg, 198.7 μmol) were added sequentially. The reaction mixture was then stirred overnight at room temperature, cooled to 0 °C, and the reaction was quenched with ice water. The organic phase was extracted with ethyl acetate (5 mL * 3). The organic phase was washed with saturated brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative chromatography (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) to obtain compound 15 (4.3 mg).

[0834] MS(ESI + m / z = 1174.3 [M+H] + .

[0835] Example 16 Synthesis of Compound 16

[0836] Synthesis of compound 16-2 (Step 1)

[0837] Following the synthesis steps of Int-15, the intermediate... Replace with Compound 16-1 was prepared.

[0838] Compound 16-1 (40 mg, 88.2 μmol) was added to 1,4-dioxane (1.0 mL) and water (0.2 mL), followed by compound 1-2 (80.95 mg, 114.7 μmol), potassium phosphate (46.77 mg, 220.3 μmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (6.46 mg, 8.8 μmol). The mixture was stirred for 5 hours at 70 °C under argon protection. 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, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by reversed-phase chromatography (water (containing 0.5% ammonia): acetonitrile = 95:5-5:95) to obtain compound 16-2 (60 mg).

[0839] MS(ESI+)m / z = 905.4[M+H] + .

[0840] Step 4: Synthesis of compound 16-3-P2

[0841] Compound 16-2 (60 mg, 66.3 μmol) and cesium carbonate (107.72 mg, 330.6 μmol) were added to N,N-dimethylformamide (1 mL). Iodethane (51.69 mg, 331.4 μmol) was added to the reaction solution, and the resulting mixture was stirred at 35 °C for 3.0 h. After the reaction was completed, the mixture was purified by preparative column chromatography (Waters Xbridge OBD 150*19 mm*5 μm column; 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 16-3-P1 (20 mg, retention time: 7.03 min) and compound 16-3-P2 (20 mg, retention time: 7.93 min).

[0842] MS(ESI+)m / z = 933.5[M+H] + .

[0843] Step 5: Synthesis of compound 16-4

[0844] Compound 16-3-P2 (20 mg, 21.4 μmol) was dissolved in dichloromethane (1 mL), followed by the addition of trifluoroacetic acid (0.2 mL). The reaction was stirred at room temperature for 1.0 h. After the reaction was complete, the mixture was quenched in a saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, yielding compound 16-4 (17.85 mg, crude product). The crude product was used directly in the next reaction without purification.

[0845] MS(ESI + m / z = 833.4 [M+H] + .

[0846] Step 7: Synthesis of Compound 16

[0847] Compound 16-4 (18 mg, 21.6 μmol), compound Int-10 (24.3 mg, 64.8 μmol), 2-hydroxypyridine-N-oxide (3.60 mg, 32.4 μmol), N,N-diisopropylethylamine (55.85 mg, 432.1 μmol), and 4-dimethylaminopyridine (13.20 mg, 108.0 μmol) were added to ethyl acetate (1 mL), and nitrogen gas was introduced. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.99 mg, 302.5 μmol) was added under ice bath conditions. The resulting mixture was stirred at room temperature for 15 hours. After the reaction was complete, water was added for quenching, followed by extraction with dichloromethane. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by preparative high-performance liquid chromatography (HPLC) using a Welch Xtimate C18 column (150 mm length, 30 mm inner diameter, 5 μm particle size; mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 minutes) to obtain compound 16 (10.0 mg).

[0848] MS(ESI+)m / z = 1190.7[M+H] + .

[0849] 1H NMR (400MHz, DMSO-d6) δ8.44(s,1H),8.42–8.32(m,1H),8.14(s,1H),7.93(d,J=9.4Hz,1H),7.89(d ,J=2.1Hz,1H),7.79–7.70(m,2H),7.60(d,J=8.7Hz,1H),7.31–7.27(m,1H),5.95(dd,J=16.3,11.2 Hz,1H),5.35–5.30(m,1H),4.76(d,J=11.0Hz,1H),4.59(t,J=6.5Hz,2H),4.52-4.48(m,3H),4.39- 4.31(m,2H),4.12(dd,J=14.9,7.2Hz,1H),3.61–3.45(m,4H),3.40-3.36(m,3H),3.27(s,3H),3.25- 3.22(m,1H),3.02–2.93(m,2H),2.91–2.82(m,2H),2.74–2.62(m,3H),2.48–2.44(m,4H),2.32(s,1 H),2.25(s,2H),2.19(s,2H),2.11(d,J=6.7Hz,2H),2.03-1.94(m,2H),1.85–1.80(m,1H),1.77–1. 59(m,5H),1.59–1.47(m,6H),1.45(d,J=6.0Hz,3H),1.37-1.33(m,2H),1.26-1.23(m,5H),0.88–0. 82(m,6H),0.65–0.55(m,1H),0.50-0.43(m,1H),0.39-0.32(m,2H),0.27(s,2H),0.19–0.13(m,2H).

[0850] Example 17 Synthesis of Compound 17

[0851] Following the same synthesis steps as compound 15, compound Int-15 in the first step was replaced with compound Int-14, and then compound 17 was obtained through the same reaction process.

[0852] MS(ESI+)m / z = 1236.6[M+H] + .

[0853] 1H NMR (400MHz, DMSO-d6) δ8.63–8.43(m,2H),8.25(d,J=7.9Hz,1H),8.12(d,J=8.3Hz,1 H),7.90–7.76(m,3H),7.65-7.55(m,1H),5.33(s,2H),4.78(s,1H),4.60-4.25(m,3H) ,4.17–4.00(m,3H),3.85–3.56(m,15H),3.15-3.05(m,10H),2.97(s,2H),2.95-2.8(m ,4H),2.27–1.92(m,11H),1.9–1.5(m,15H),1.16(d,J=7.6Hz,5H),0.65–0.23(m,8H).

[0854] Example 18 Synthesis of Compound 18

[0855] Synthesis of compound 18-1 (Step 1)

[0856] At room temperature, compound 6-5 (100 mg, 236.27 μmol), neopentyl glycol diboronate (162.5 mg, 719.38 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (17.29 mg, 23.63 μmol), and potassium acetate (53.09 mg, 541.76 μmol) were dissolved in anhydrous 1,4-dioxane (2.5 mL). The air in the solution was purged three times with nitrogen, and the reaction was stirred at 80 °C for 6 hours. After the reaction was complete, the insoluble matter was removed by filtration, the filtrate was concentrated, and the residue was purified by reversed-phase chromatography (water (containing 0.5% NH3):acetonitrile = 95:5-5:95) to give compound 18-1 (70 mg, 205.18 μmol).

[0857] MS(ESI+)m / z = 342.2[M+H] + .

[0858] The second step involves the synthesis of compound 18-2.

[0859] Compound Int-17 (85 mg, 117.47 μmol), compound 18-1 (52.10 mg, 152.71 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (8.60 mg, 11.75 μmol), and potassium phosphate (74.80 mg, 352.40 μmol) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL). The air in the mixture was replaced three times with argon. The reaction solution was placed in an oil bath at 70 °C and stirred for 5 hours. After the reaction was complete, the reaction solution was concentrated and extracted with ethyl acetate and water. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal-phase silica gel column chromatography (ethyl acetate / petroleum ether: 0%-100%) to obtain compound 18-2 (62 mg, 69.43 μmol).

[0860] MS(ESI+)m / z = 893.5[M+H] + .

[0861] The third step involves the synthesis of compound 18-3.

[0862] Compound 18-2 (62 mg, 69.43 μmol) and cesium carbonate (67.86 mg, 208.27 μmol) were dissolved in N,N-dimethylformamide (1.5 mL). The reaction solution was stirred at room temperature, and iodoethane (108.28 mg, 694.24 μmol) was added dropwise to the reaction solution. After the addition was complete, the reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was added dropwise to dilute hydrochloric acid to quench the reaction. The mixture was extracted with ethyl acetate and water, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal-phase silica gel column chromatography (ethyl acetate / petroleum ether: 0%-100%) to obtain compound 18-3 (58 mg, 62.97 μmol).

[0863] MS(ESI+)m / z = 921.7[M+H] + .

[0864] Step 4: Synthesis of compound 18-4

[0865] Compound 18-3 (58 mg, 62.97 μmol) was dissolved in dichloromethane (2.0 mL). The reaction solution was stirred at room temperature. Trifluoroacetic acid (0.5 mL) was added dropwise to the reaction solution. After the addition was complete, the reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated and extracted with saturated sodium bicarbonate solution and ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 18-4 (50 mg, crude product).

[0866] MS(ESI+)m / z = 821.7[M+H] + .

[0867] Step 4: Synthesis of Compound 18

[0868] Compound 18-4 (50 mg, crude), compound Int-10 (36.49 mg, 97.17 μmol), 2-hydroxypyridine-N-oxide (8.04 mg, 72.37 μmol), 4-dimethylaminopyridine (37.20 mg, 304.49 μmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (175.13 mg, 913.56 μmol) were dissolved in ethyl acetate (4 mL). The air in the solution was replaced three times with argon. N,N-diisopropylethylamine (157.43 mg, 1.22 mmol) was added to the reaction mixture. The reaction solution was reacted at room temperature for 8 hours. After the reaction was complete, the reaction was quenched with water. The crude product obtained by concentrating the reaction solution was purified by reverse-phase column chromatography (XBridge Prep column). C18; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration is 0.05%; mobile phase B: MeCN; MeCN ratio 60%-90%; time: 10 min, flow rate: 15 mL / min) to obtain compound 18 (24 mg).

[0869] MS(ESI+)m / z = 1178.2[M+H] + .

[0870] 1H NMR (400MHz, DMSO-d6) δ8.54(t,J=6.8Hz,1H),8.47–8.33(m,1H),8.33–8.11(m,2H),7.82–7.74(m,2H),7.62(dd,J=23.9,13.0Hz,1H),6.08–5. 95(m,1H),5.36–5.31(m,1H),4.76–4.64(m,1H),4.50(d,J=5.0Hz,1H), 4.45–4.26(m,1H),4.14–3.97(m,2H),3.86–3.72(m,5H),3.65–3.53(m,7 H),3.29–3.26(m,5H),3.07–2.95(m,4H),2.90–2.83(m,2H),2.76–2.59 (m,3H),2.38–2.32(m,1H),2.28–2.15(m,5H),2.10–1.95(m,3H),1.88–1 .42(m,12H),1.41–1.29(m,3H),1.23(s,3H),1.11(t,J=6.9Hz,2H),0.9 1–0.80(m,4H),0.65–0.50(m,2H),0.49–0.24(m,4H),0.20–0.11(m,1H).

[0871] Example 19 Synthesis of Compound 19

[0872] Following steps 1-4 of the synthesis of compound 18, compound 6-5 in the first step was replaced with compound 9-2. The same reaction process was then performed, followed by reversed-phase column purification (XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%; mobile phase B: MeCN; MeCN ratio 65%-75%, time: 15 min, flow rate: 15 mL / min) to obtain compounds 19-1 (14 mg, 17.05 μmol, retention time: 8.98 min) and 19-1' (14 mg, 17.05 μmol, retention time: 8.00 min). Then, following the final step of Example 18, compound 19-1 was used to replace compound 18-4 to obtain compound 19 (2 mg).

[0873] MS(ESI-)m / z = 1219.6 [M+H] + .

[0874] 1H NMR (400MHz, DMSO-d6) δ8.55(d,J=7.5Hz,1H),8.39(dd,J=26.4,8.6Hz,1H),8.22(d,J =9.5Hz,1H),8.11(s,1H),7.78(d,J=2.6Hz,1H),7.75(d,J=9.5Hz,1H),7.65(d,J=13. 0Hz,1H),6.06–5.96(m,1H),5.33(dd,J=11.2,6.6Hz,1H),4.68(d,J=11.0Hz,1H),4.5 0(d,J=5.0Hz,1H),4.44–4.28(m,2H),4.12–4.02(m,1H),3.73–3.52(m,6H),3.40–3.3 8(m,1H),3.31–3.24(m,6H),3.03–2.92(m,2H),2.90–2.83(m,2H),2.78–2.74(m,3H), 2.71–2.55(m,3H),2.33(s,2H),2.27–2.14(m,5H),2.10(d,J=6.2Hz,1H),2.05–1.91( m,2H),1.88–1.63(m,6H),1.61–1.45(m,8H),1.41–1.28(m,3H),1.23(s,5H),0.90–0. 80(m,5H),0.67–0.52(m,2H),0.50–0.43(m,2H),0.40–0.27(m,6H),0.20–0.10(m,1H).

[0875] Example 20 Synthesis of Compound 20

[0876] Referring to steps one through four of the synthesis of compound 9, the intermediate was... Replace with Intermediates 20-1 (60 mg) and 20-1' (65 mg) were obtained. The intermediates are manufactured under the product name QUITY. A BEH C18 1.7 μm column was used. Elution time: 3 min, flow rate: 0.7 mL / min, mobile phase: water (NH4OH content 0.5%): MeCN = 40%-95%. The retention time of intermediate 20-1 was 1.22 min, and the retention time of intermediate 20-1' was 1.20 min. Intermediate 20-1 was then subjected to the same subsequent reaction mechanism to obtain compound 20 (3.6 mg).

[0877] MS(ESI + m / z = 1215.6 [M+H] + .

[0878] 1 H NMR(400MHz,DMSO-d6)δ8.30(d,J=1.4Hz,1H),8.22(dd,J=26.4,8.7Hz,1H),8.08 (d,J=9.5Hz,1H),7.95(s,1H),7.75(d,J=2.3Hz,1H),7.64(d,J=8.8Hz,1H),7.61 (d,J=9.6Hz,1H),7.48(d,J=8.6Hz,1H),5.78(dd,J=15.6,11.7Hz,1H),5.18(t,J =6.4Hz,1H),4.61(d,J=11.0Hz,1H),4.39(dt,J=32.7,6.3Hz,6H),4.27(dq,J=11 .8,5.4Hz,2H),3.99–3.90(m,1H),3.49–3.44(m,5H),3.43–3.29(m,4H),3.17–3. 05(m,21H),2.87(d,J=13.8Hz,1H),2.83–2.77(m,1H),2.75–2.63(m,2H),2.58–2 .49(m,2H),2.22–2.15(m,1H),2.12–1.79(m,7H),1.67–1.48(m,1H),1.45–1.16( m,6H),1.08(s,1H),0.77–0.64(m,7H),0.45(d,J=27.1Hz,1H),0.30–0.09(m,6H).

[0879] Example 21 Synthesis of Compound 21

[0880] Following the synthetic steps of compound 9, compound 9-4-P2 was replaced with intermediate 20-1, and the final compound Int-10 was replaced with compound Int-18, to synthesize compound 21 (3.6 mg).

[0881] MS(ESI + m / z = 1189.6 [M+H] + .

[0882] 1H NMR (400MHz, DMSO-d6) δ8.30 (s, 1H), 8.07 (d, J = 9.6Hz, 2H), 7.94 (s, 1H), 7.7 4(d,J=2.4Hz,1H),7.62(dd,J=14.0,9.2Hz,2H),7.47(d,J=8.7Hz,1H),5.79 (dd,J=17.9,11.1Hz,1H),5.18(s,1H),4.61(d,J=10.9Hz,1H),4.42(t,J=6. 6Hz,2H),4.34(t,J=5.9Hz,3H),4.28(d,J=6.2Hz,1H),4.00–3.88(m,1H),3. 46(s,6H),3.36(d,J=7.2Hz,4H),3.13(s,6H),2.87(d,J=16.7Hz,1H),2.69– 2.60(m,3H),2.48(d,J=18.1Hz,4H),2.13–1.90(m,7H),1.89–1.58(m,6H),1 .57–1.42(m,2H),1.30(d,J=6.0Hz,3H),1.20(dt,J=19.4,6.5Hz,1H),1.08( s,4H),0.86–0.64(m,16H),0.44(dd,J=14.2,8.1Hz,1H),0.20–0.14(m,2H).

[0883] Example 22 Synthesis of Compound 22

[0884] Referring to steps one through six of the synthesis of compound 6, replace the intermediate morpholine from step one with... Following the same reaction and purification using a preparative column (Waters Xbridge OBD 150*19 mm*5 μm column; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%, mobile phase B: MeCN; MeCN ratio 75%-80%, time: 10 min, flow rate: 15 mL / min), compound 22-1 (20 mg, retention time: 8.38 min) and compound 22-1' (18 mg, retention time: 9.38 min) were obtained. Compound 22-1' was then subjected to the same subsequent reaction mechanism to obtain compound 22 (5.8 mg). MS (ESI+) m / z = 1194.6 [M+H] + .

[0885] 1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.40–8.30(m,1H),8.28–8.23(m,1H),8.13(s,1H),7.91–7.88(m,1H),7.83–7.78(m,2H),7.66–7.60(m,1H) ,5.97–5.88(m,1H),5.39–5.30(m,1H),4.81–4.71(m,1H),4.55–4.48(m, 1H),4.48–4.41(m,1H),4.41–4.33(m,1H),4.17–4.03(m,2H),3.74–3.66 (m,5H),3.64–3.49(m,4H),3.43–3.36(m,1H),3.09–3.00(m,2H),3.00–2 .91(m,2H),2.91–2.80(m,3H),2.75–2.61(m,4H),2.30–2.13(m,10H),1. 87–1.77(m,2H),1.77–1.69(m,3H),1.66–1.44(m,12H),1.40–1.32(m,2H ),1.24(s,3H),0.95–0.77(m,7H),0.40–0.29(m,4H),0.19–0.13(m,1H).

[0886] Example 23 Synthesis of Compound 23

[0887] Referring to steps one through six of the synthesis of compound 6, replace the intermediate morpholine from step one with... Following the same reaction, the compound was purified using a preparative column (Waters Xbridge OBD 150*19 mm*5 μm column; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%; mobile phase B: MeCN; MeCN ratio 65%-80%; time: 10 min; flow rate: 15 mL / min) to obtain compound 23-1 (25 mg, retention time: 7.72 min) and compound 23-1' (18 mg, retention time: 9.38 min). Compound 23-1' was then subjected to the same subsequent reaction to obtain compound 23 (5.5 mg).

[0888] MS(ESI+)m / z = 1189.0 [M+H] + .

[0889] 1H NMR (400MHz, DMSO-d6) δ8.46(s,1H),8.17(d,J=9.5Hz,1H),8.07(s,1H),7.91(d,J=2.3Hz,1H ),7.80(d,J=8.6Hz,1H),7.75(d,J=9.6Hz,1H),7.63(d,J=8.6Hz,1H),5.94(dd,J=16.3,10.9 Hz,2H),5.38–5.30(m,1H),4.77(d,J=11.2Hz,1H),4.55–4.46(m,2H),4.47–4.34(m,3H),4.1 6–4.05(m,2H),3.76–3.64(m,3H),3.60–3.50(m,5H);3.29–3.19(m,2H),3.07–2.93(m,4H),2. 91–2.80(m,3H),2.74–2.63(m,5H),2.59(d,J=8.7Hz,1H);2.34–2.31(m,3H),2.24(s,1H),2. 19(s,1H),2.16(d,J=5.6Hz,1H),2.10(d,J=6.7Hz,1H),2.03–1.91(m,2H),1.89–1.78(m,2H) ,1.78–1.62(m,7H),1.61–1.44(m,7H),1.36(dt,J=17.1,6.6Hz,3H),1.22(d,J=7.9Hz,5H); 0 .90–0.83(m,4H),0.67–0.53(m,1H),0.52–0.42(m,1H),0.41–0.26(m,4H),0.20–0.12(m,1H).

[0890] Example 24 Synthesis of Compound 24

[0891] According to the synthesis steps of compound 2, the intermediate from the first step... Replacing with paraformaldehyde yields intermediates 24-1 (20 mg) and 24-1' (20 mg), which are produced under the product name QUITY. A BEH C18 1.7 μm column was used. Elution time: 3 min, flow rate: 0.7 mL / min, mobile phase: water (NH4OH content 0.5%): MeCN = 40%-95%. Intermediate 24-1 had a retention time of 1.32 min, and intermediate 24-1' had a retention time of 1.30 min. Intermediate 24-1 was then subjected to the same subsequent reaction mechanism to obtain compound 24 (3.6 mg).

[0892] MS(ESI+ m / z = 1162.6 [M+H] + .

[0893] 1 H NMR (400MHz, DMSO-d6) δ8.48(s,1H),8.44(s,1H),7.90(d,J=2.7Hz,1H),7.7 8(d,J=8.6Hz,1H),7.61(d,J=8.7Hz,1H),5.95(dd,J=16.4,11.1Hz,1H),5.3 2(d,J=8.2Hz,1H),4.76(d,J=11.9Hz,2H),4.51(d,J=5.1Hz,1H),4.40–4.29 (m,2H),4.02(dd,J=15.1,7.9Hz,1H),3.65–3.49(m,3H),2.98(t,J=11.4Hz, 4H),2.84(t,J=12.3Hz,2H),2.68(d,J=20.3Hz,3H),2.35–2.31(m,4H),2.26 (d,J=10.6Hz,7H),2.18(d,J=7.6Hz,9H),1.83(t,J=12.8Hz,2H),1.77–1.62 (m,6H),1.60–1.46(m,8H),1.44(d,J=6.1Hz,4H),1.39–1.32(m,3H),1.23(s ,3H),0.91–0.85(m,6H),0.66–0.52(m,1H),0.39–0.32(m,2H),0.29(s,3H).

[0894] Example 25 Synthesis of Compound 25

[0895] Synthesis of compound 25-1 in step one

[0896] In a dry reaction tube, compound Int-9 (1.3 g, 2.34 mmol) was weighed to replace the argon gas. Tetrahydrofuran (10 mL) was added to dissolve the compound. The mixture was cooled in an ice-water bath, and isopropyl magnesium chloride and lithium chloride (3.51 mmol, 2.7 mL) were slowly added dropwise. The reaction was carried out for 1 hour. At -15°C, a tetrahydrofuran solution (5 mL) of 2,2-dimethylglutaric anhydride (398.56 mg, 2.80 mmol) was added dropwise, and the reaction was carried out for 2 hours. The reaction was quenched with a saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse-phase column chromatography (column: [column name missing]). Rapid silica gel column chromatography; mobile phase: acetonitrile / water (0.5% ammonia) = 5%-95% lyophilized to obtain compound 25-1 (1g).

[0897] MS(ESI+)m / z = 573.3[M+H] + .

[0898] The second step involves the synthesis of compound 25-2.

[0899] In a dry reaction tube, 6-bromo-3,4-dihydro-2H-quinoline-1-amine (475.89 mg, 2.10 mmol), compound 25-1 (800 mg, 1.40 mmol), and p-toluenesulfonic acid hydrate (531.47 mg, 2.79 mmol) were weighed to replace the argon gas. Anhydrous toluene (10 mL) was added, and the mixture was heated to 105 °C and reacted overnight. The crude product 25-2 (1.05 g) was concentrated and used directly in the next step of the reaction.

[0900] MS(ESI+)m / z=764.2 / 766.2[M+H] + .

[0901] The third step involves the synthesis of compound 25-3.

[0902] In a dry reaction tube, compound 25-2 (1.05 g, 1.40 mmol) was dissolved in N,N-dimethylformamide (5 mL), cesium carbonate (1.37 g, 4.20 mmol), and iodoethane (656.22 mg, 4.21 mmol). The reaction was allowed to proceed at room temperature for 1 hour. The mixture was then filtered, concentrated, and purified by reverse-phase column chromatography (column: [column number missing]). Rapid silica column chromatography; mobile phase: acetonitrile / water (0.5% ammonia) = 5%-95% yielded compound 25-3 (350 mg) and compound 25-3' (350 mg). The compounds were analyzed using the QUITY series of chromatography. BEH C18, 1.7 μm column, elution time: 3 min, flow rate: 0.7 mL / min, mobile phase water (NH4OH content 0.5%): MeCN = 70%-95%, elution conditions, compound 25-3 retention time was 1.63 min, compound 25-3' retention time was 1.49 min.

[0903] Compound 25-3MS(ESI+) m / z = 792.3 / 794.3 [M+H]+.

[0904] Step 4: Synthesis of compound 25-4

[0905] In a dry reaction tube, compound 25-3 (300 mg, 378.41 μmol) was dissolved in ethanol (3 mL). Calcium chloride (214.33 mg, 1.93 mmol) and sodium borohydride (73.06 mg, 1.93 mmol) were added sequentially at room temperature, and the reaction was allowed to proceed overnight. Calcium chloride (214.33 mg, 1.93 mmol) and sodium borohydride (73.06 mg, 1.93 mmol) were then added again, and the reaction was allowed to proceed overnight once more. The reaction was quenched with dilute hydrochloric acid, and the mixture was purified by reversed-phase column chromatography (column: [column number missing]). Rapid silica column chromatography; mobile phase: acetonitrile / water (0.5% ammonia) = 5%-95% yielded compound 25-4 (210 mg).

[0906] MS(ESI+)m / z=750.3 / 752.3[M+H] + .

[0907] Step 5: Synthesis of compound 25-5

[0908] In a dry reaction tube, compound 25-4 (210 mg, 279.72 μmol), pinacol diboronate (181.46 mg, 714.58 μmol), potassium acetate (82.36 mg, 839.21 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (20.91 mg, 28.58 μmol), and 1,4-dioxane (10 mL) were weighed in sequence, and the system was purged with argon gas. The reaction was heated to 90 °C for 1 hour. The crude product was then purified by reverse-phase column chromatography (column: [column name missing]). Rapid silica column chromatography; mobile phase: acetonitrile / water (0.5% ammonia) = 5%-95% to obtain compound 25-5 (120 mg).

[0909] MS(ESI+)m / z=798.4[M+H]+.

[0910] Step 6: Synthesis of compound 25-7

[0911] In a dry reaction tube, weigh out compound 25-6 (112.68 mg, 222.94 μmol), compound 25-5 (120 mg, 150.41 μmol), potassium carbonate (63.64 mg, 460.46 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (11.23 mg, 15.35 μmol), 1,4-dioxane (6 mL), and water (2 mL). Replace the gas with argon, heat to 70°C, react for [number] hours, cool to room temperature, extract with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify the crude product using a reverse-phase column chromatography (column: [column name missing]). Rapid silica column chromatography; mobile phase: acetonitrile / water (0.5% ammonia) = 5%-95% yielded compound 25-7 (135 mg).

[0912] MS(ESI+)m / z = 1080.5[M+H] + .

[0913] Step 7: Synthesis of compound 25-8

[0914] Compound 25-7 (135 mg, 124.96 μmol) was dissolved in tetrahydrofuran (5 mL), and water (3 mL) and lithium hydroxide (14.96 mg, 624.63 μmol) were added sequentially at room temperature. The reaction mixture was incubated at room temperature for 3 hours. The pH was adjusted to 3 with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The combined organic phases were dried, filtered, and concentrated to obtain the crude product. The crude product was then purified by reverse-phase column chromatography (column: [column number missing]). Rapid silica column chromatography; mobile phase: acetonitrile / water = 5%-95%) yielded compound 25-8 (120 mg).

[0915] MS(ESI+)m / z = 1066.5[M+H] + .

[0916] Step 8: Synthesis of Compounds 25-9

[0917] In a dry reaction tube, N-methylimidazole (172.83 mg, 2.11 mmol) was dissolved in acetonitrile (10 mL), purging the tube with argon gas. N,N,N',N'-tetramethylchloromethanemid hexafluorophosphate (592.02 mg, 2.11 mmol) was added. At room temperature, compound 25-8 (101.69 mg, 95.37 μmol) was dissolved in N,N-dimethylformamide (2 mL) and slowly added dropwise to the reaction system. The reaction was allowed to proceed for 1 hour. The reaction solution was purified by reverse-phase column chromatography (column: [column information missing]). Rapid silica column; mobile phase: acetonitrile / water (0.5% ammonia) = 5%-95% to obtain 25-9 (55mg).

[0918] MS(ESI+)m / z = 1048.5[M+H] + .

[0919] Step 9: Synthesis of compound 25-10

[0920] In a single-necked flask, compound 25-9 (55.85 mg, 53.28 μmol), paraformaldehyde (18.15 mg, 604.40 μmol), and methanol (3 mL) were weighed in sequence. 5% wt wetted palladium on carbon (55.85 mg, 100% wt) was added, and the mixture was purged with hydrogen at room temperature overnight. The mixture was then filtered, concentrated, dried, and purified using a reverse-phase column (column: [column name missing]). Rapid silica column chromatography; mobile phase: acetonitrile / water (0.5% ammonia) = 5%-95%, 10 min) to give compound 25-10 (30 mg).

[0921] MS(ESI+)m / z=928.5[M+H]+.

[0922] Step 10: Synthesis of compound 25-11

[0923] Compound 25-10 (17 mg, 18.32 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.3 mL) was added under ice-water bath conditions. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was then added dropwise to a saturated sodium bicarbonate aqueous solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 25-11 (15.13 mg, crude product).

[0924] MS(ESI+)m / z=828.4[M+H]+.

[0925] Step 11: Synthesis of Compound 25

[0926] In a dry reaction tube, compound 25-11 (15.13 mg, crude) and compound Int-10 (10.5 mg, 27.96 μmol) were dissolved in 0.5 mL of dry ethyl acetate. Under an ice-water bath, N,N-diisopropylethylamine (24.08 mg, 186.32 μmol), 4-dimethylaminopyridine (11.38 mg, 93.15 μmol), 2-hydroxypyridine-N-oxide (2.07 mg, 18.63 μmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.14 mg, 37.25 μmol) were added sequentially. The reaction was carried out overnight at room temperature. After washing with water, the organic phase was dried and concentrated to obtain the crude product, which was then purified by reverse-phase column chromatography (column: [column name missing]). Rapid silica column chromatography; mobile phase: acetonitrile / water (0.5% ammonia) = 5%-95%, 10 min) yielded compound 25 (9 mg).

[0927] MS(ESI+)m / z=1185.6[M+H]+.

[0928] 1 H NMR (400MHz, DMSO-d6) δ8.40-8.10(m,3H),8.00(s,1H),7.76–7.65(m,2H),7.43(s,1H),5.84(d,J=13.2Hz,1H),5.27(s,1H),4.72(d,J=11.0H z,1H),4.49(d,J=27.9Hz,2H),4.15(s,1H),3.60-3.45(m,9H),2.97–2. 70(m,8H),2.24–1.88(m,18H),1.71–1.33(m,21H),0.77–0.05(m,15H).

[0929] Example 26 Synthesis of Compound 26

[0930] Synthesis of compound 26-2 (Step 1)

[0931] According to steps one through three of the synthesis of compound 2, the intermediate from step one... The intermediate 26-1 was obtained by replacing paraformaldehyde. Compound 26-1 (10.0 mg, 0.011 mmol) was dissolved in acetonitrile (0.3 mL), cooled to 0 °C, and cesium carbonate (35.8 mg, 0.11 mmol) and (R)-2-(iodomethyl)oxetane (11.3 mg, 0.055 mmol) were added sequentially. The reaction mixture was transferred to 50 °C and stirred for 48 hours until the reaction was complete. The mixture was then cooled to 0 °C again and the reaction was quenched with ice water. The organic phase was extracted with dichloromethane (3.0 mL * 3). The organic phase was washed with saturated brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue, which was then purified by preparative chromatography (XBridge Prep C18 column; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O ​​concentration 0.05%; mobile phase B: MeCN; MeCN ratio 55%-65%, time: 13 min, flow rate: 15 mL / min) to obtain compound 26-2 (2.5 mg, retention time: 9.45 min) and compound 26-2' (2.5 mg, retention time: 8.42 min).

[0932] Compound 26-2MS (ESI) + m / z = 947.6 [M+H] + .

[0933] The second step involves the synthesis of compound 26-3.

[0934] Compound 26-2 (2.5 mg, 0.0026 mmol) was dissolved in dichloromethane (0.5 mL), cooled to 0 °C, and then trifluoroacetic acid (0.1 mL) was added dropwise. The reaction mixture was transferred to room temperature and stirred for 1 hour until the reaction was complete. The mixture was then cooled again to 0 °C, and the reaction was quenched by adding saturated sodium bicarbonate solution. The organic phase was extracted with dichloromethane (3.0 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 26-3 (2.2 mg). The product was used directly in the next reaction without purification.

[0935] MS(ESI + m / z = 847.6 [M+H] + .

[0936] The third step involves the synthesis of compound 26.

[0937] Compound 26-3 (2.2 mg, crude) was dissolved in ethyl acetate (0.25 mL), and then compound Int-10 (2.0 mg, 0.0054 mmol), N,N-diisopropylethylamine (1.71 mg, 0.013 mmol), 2-hydroxypyridine-N-oxide (0.35 mg, 0.0032 mmol), 4-dimethylaminopyridine (1.62 mg, 0.013 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 mg, 0.0054 mmol) were added sequentially. The reaction mixture was then stirred at room temperature for 16 hours, cooled to 0 °C, and the reaction was quenched with ice water. The organic phase was extracted with dichloromethane (3.0 mL x 3). The organic phase was washed with saturated brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative chromatography (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: 13 min, flow rate: 15 mL / min) to obtain compound 26 (1.0 mg, retention time: 7.67 min).

[0938] MS(ESI + m / z = 1204.5[M+H] + .

[0939] Example 27 Synthesis of Compound 27

[0940] Synthesis of compound 27-1 (Step 1)

[0941] Compound Int-16 (464 mg, 1.0 mmol) and neopentyl glycol diboronate (451 mg, 2.0 mmol) were dissolved in 1,4-dioxane (5.0 mL) solution, followed by the addition of [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (64 mg, 0.10 mmol) and potassium acetate (216 mg, 2.2 mmol). The reaction solution was then heated to 90 °C for 1 hour. After the reaction was complete, the solution was filtered through diatomaceous earth, concentrated under reduced pressure, and then purified by reverse-phase silica gel column chromatography (water / acetonitrile = 1 / 0 to 1 / 1) to obtain compound 27-1 (200 mg).

[0942] MS(ESI + m / z = 430.3[M+H] + .

[0943] The second step involves the synthesis of compound 27-3.

[0944] Compound 27-1 (100 mg, 0.23 mmol) and compound 27-2 (105 mg, 0.23 mmol) were dissolved in a mixed solution of 1,4-dioxane (0.5 mL) / water (0.1 mL), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (16 mg, 0.023 mmol) and potassium phosphate (97 mg, 0.46 mmol) were added sequentially. The reaction solution was then transferred to 70 °C and reacted for 3 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and then purified by reverse-phase silica gel column chromatography (water / acetonitrile = 1 / 0 to 1 / 1) to obtain compound 27-3 (100 mg).

[0945] MS(ESI + m / z = 707.5[M+H] + .

[0946] The third step involves the synthesis of compound 27-4.

[0947] Compound 27-3 (100 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (2.0 mL), cooled to 0 °C, and then cesium carbonate (230 mg, 0.71 mmol) and iodoethane (110 mg, 0.71 mmol) were added sequentially. The reaction mixture was transferred to room temperature and stirred for 2 hours until the reaction was complete. The mixture was then cooled to 0 °C again and the reaction was quenched with ice water. The organic phase was extracted with dichloromethane (3.0 mL x 3). The organic phase was washed with saturated brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by normal-phase column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound 27-4 (71 mg, 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: 70%-95%, time: 3 min, flow rate: 0.7 mL / min, retention time: 1.55 min) and compound 27-4' (71 mg, 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 70%-95%, flow time: 3 min, flow rate: 0.7 mL / min, retention time: 1.44 min).

[0948] Compound 27-4 MS (ESI) + m / z = 735.5 [M+H] + .

[0949] Step 4: Synthesis of compound 27-5

[0950] Compound 27-4 (90.0 mg, 0.13 mmol) was dissolved in dichloromethane (1.5 mL), cooled to 0 °C, and then trifluoroacetic acid (0.1 mL) was added dropwise. The reaction mixture was transferred to room temperature and stirred for 1 hour until the reaction was complete. The mixture was then cooled again to 0 °C, and the reaction was quenched by adding saturated sodium bicarbonate solution. The organic phase was extracted with dichloromethane (3.0 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 27-5 (77.5 mg). The product was used directly in the next reaction without further purification.

[0951] MS(ESI + m / z = 635.5[M+H] + .

[0952] Step 5: Synthesis of compound 27-6

[0953] Compound 27-5 (62 mg, crude) was dissolved in isopropanol (1.0 mL), cooled to 0 °C, and then paraformaldehyde (308 mg, 1.0 mmol), acetic acid (60 mg, 1.0 mmol), and sodium cyanoborohydride (63 mg, 1.0 mmol) were added sequentially. The reaction mixture was stirred at 25 °C for 15 hours until complete. The reaction was quenched with ice water, and the organic phase was extracted with dichloromethane (3.0 mL x 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (water / acetonitrile = 1 / 0 to 1 / 1) to give compound 27-6 (49.0 mg). MS (ESI) + m / z = 649.5 [M+H] + .

[0954] Step 6: Synthesis of compound 27-7

[0955] Compound 27-6 (57.4 mg, 0.088 mmol) was dissolved in methanol (1.0 mL), cooled to 0 °C, and then potassium carbonate (27.6 mg, 0.20 mmol) was added. The reaction mixture was transferred to room temperature and stirred for 2 h until the reaction was complete. The mixture was then cooled again to 0 °C and quenched with ice water. The organic phase was extracted with dichloromethane (3.0 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used directly in the next reaction step.

[0956] The residue obtained in the previous step was dissolved in a mixed solution of tetrahydrofuran (0.8 mL) and water (0.2 mL). After cooling to 0 °C, lithium hydroxide monohydrate (8.0 mg, 0.2 mmol) was added. The reaction solution was transferred to room temperature and stirred for 2 hours until the reaction was complete. It was then cooled to 0 °C again and neutralized with dilute hydrochloric acid (1.0 M). The organic phase was extracted with dichloromethane (3.0 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 27-7 (54.0 mg). The product was used directly in the next reaction without purification.

[0957] MS(ESI + m / z = 607.4 [M+H] + .

[0958] Step 7: Synthesis of compound 27-8

[0959] Compound 27-7 (36.0 mg, 0.059 mmol) and compound Int-19 (110 mg, 0.18 mmol) were dissolved in acetonitrile (0.6 mL). After cooling to 0 °C, N-methylimidazole (98 mg, 1.2 mmol) and N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (168 mg, 0.6 mmol) were added sequentially. The reaction mixture was stirred at 0 °C for 30 minutes until the reaction was complete. The reaction was quenched with ice water, and the organic phase was extracted with dichloromethane (3.0 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used directly in the next reaction step.

[0960] The residue obtained in the previous step was dissolved in N,N-dimethylformamide (1.0 mL), cooled to 0 °C, and then piperidine (0.1 mL) was added. The reaction mixture was transferred to room temperature and stirred for 2 hours until the reaction was complete. Then, reversed-phase column chromatography (water / acetonitrile = 1 / 0 to 1 / 1) was performed to give compound 27-8 (40.0 mg).

[0961] MS(ESI + m / z = 987.6 [M+H] + .

[0962] Step 8: Synthesis of compounds 27-9

[0963] Compound 27-8 (10 mg, 0.010 mmol) was dissolved in deoxygenated anisole (0.25 mL), and bis(tri-tert-butylphosphine)palladium (0.5 mg, 0.001 mmol) and cesium carbonate (16 mg, 0.050 mmol) were added sequentially. The reaction solution was then transferred to 90 °C and reacted for 18 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and then purified by reverse-phase silica gel column chromatography (water / acetonitrile = 1 / 0 to 1 / 1) to obtain compound 27-9 (4.5 mg).

[0964] MS(ESI + m / z = 907.6 [M+H] + .

[0965] Step 9: Synthesis of compound 27-10

[0966] Compound 27-9 (7.0 mg, 0.0077 mmol) was dissolved in dichloromethane (0.2 mL), cooled to 0 °C, and then trifluoroacetic acid (0.05 mL) was added dropwise. The reaction mixture was transferred to room temperature and stirred for 1 hour until the reaction was complete. The mixture was then cooled again to 0 °C, and the reaction was quenched by adding saturated sodium bicarbonate solution. The organic phase was extracted with dichloromethane (3.0 mL * 3). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 27-10 (6.2 mg). The product was used directly in the next reaction without further purification.

[0967] MS(ESI + m / z = 807.5[M+H] + .

[0968] Step 10: Synthesis of Compound 27

[0969] Compound 27-10 (6.2 mg, 0.0077 mmol) was dissolved in ethyl acetate (0.20 mL), and then compound Int-10 (5.8 mg, 0.015 mmol), N,N-diisopropylethylamine (10.1 mg, 0.077 mmol), 2-hydroxypyridine-N-oxide (0.99 mg, 0.0089 mmol), 4-dimethylaminopyridine (4.8 mg, 0.039 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.9 mg, 0.015 mmol) were added sequentially. The reaction mixture was then stirred at room temperature for 16 hours, cooled to 0 °C, and the reaction was quenched with ice water. The organic phase was extracted with dichloromethane (3.0 mL x 3). The organic phase was washed with saturated brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative chromatography (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) to obtain compound 27 (2.0 mg, retention time: 7.52 min).

[0970] MS(ESI + m / z = 1165.1 [M+H] + .

[0971] Example 28 Synthesis of Compound 28

[0972] Following the same synthesis steps as compound 16, the final step of compound Int-10 was replaced with compound Int-18 to synthesize compound 28 (5.3 mg).

[0973] MS(ESI+)m / z = 1165.78 [M+H] + .

[0974] 1H NMR (400MHz, DMSO) δ8.43(s,1H),8.38–8.19(m,1H),8.14(s,1H),7.93(d,J=9.3Hz,1H),7.8 8(d,J=2.4Hz,1H),7.80–7.68(m,2H),7.60(d,J=8.6Hz,1H),7.28(d,J=2.6Hz,1H),6.01–5.8 8(m,1H),5.39–5.26(m,1H),4.76(d,J=11.0Hz,1H),4.61–4.55(m,2H),4.53–4.45(m,3H),4 .40–4.28(m,2H),4.20–4.06(m,1H),3.63–3.43(m,4H),3.43–3.39(m,1H),3.27(s,6H),2.99 (d,J=14.3Hz,1H),2.85–2.72(m,3H),2.69–2.60(m,3H),2.58(s,1H),2.38–2.27(m,3H),2. 24(s,2H),2.20–2.17(m,2H),2.17–2.02(m,3H),2.02–1.82(m,4H),1.82–1.55(m,5H),1.45( d,J=6.0Hz,3H),1.41–1.28(m,2H),0.98(d,J=6.4Hz,3H),0.95–0.88(m,3H),0.88–0.80(m,7 H),0.64–0.55(m,1H),0.49–0.39(m,1H),0.38–0.29(m,3H),0.27(s,3H),0.19–0.13(m,1H).

[0975] Example 29 Synthesis of Compound 29

[0976] Synthesis of compound 29-2 (Step 1)

[0977] Compound 29-1 (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 (petroleum ether:dichloromethane:tetrahydrofuran = 11:84:5) to obtain compound 29-2 (6.2 g).

[0978] MS(ESI+)m / z = 409.1[M+H] + .

[0979] 1 H NMR (400MHz, DMSO) δ9.61(d,J=2.7Hz,1H),9.10(d,J=2.7Hz,1H),8.14(d,J=7.8Hz,1H),7.43–7.37(m,4H),7.37–7.31(m, 1H),6.87(d,J=7.7Hz,1H),5.11(s,2H),5.05–4.92(m,1H),4.21(d,J=13.3Hz,2H),3.10–2.93(m,2H),1.97–1.80(m,4H).

[0980] The second step involves the synthesis of compound 29-3.

[0981] Under an argon atmosphere, compound 29-2 (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) (12.9 mL, 12.9 mmol, 1.0 M in THF) 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 (petroleum ether: dichloromethane: tetrahydrofuran = 11:84:5) to obtain compound 29-3 (0.96 g).

[0982] MS(ESI+)m / z = 451.2[M+H] + .

[0983] 1 H NMR (400MHz, DMSO) δ9.09(d,J=0.8Hz,1H),8.19(d,J=7.8Hz,1H),7.42–7.38(m,4H),7.37–7.31(m,1H),6.87(dd,J=7.7 ,0.8Hz,1H),5.11(s,2H),5.03–4.93(m,1H),4.21(d,J=13.2Hz,2H),3.14–2.92(m,2H),2.66(s,3H),1.95–1.80(m,4H).

[0984] The third step involves the synthesis of compound 29-4.

[0985] Compound 29-3 (1.0 g, 2.2 mmol), ammonium chloride (356.2 mg, 6.7 mmol), and iron powder (867.9 mg, 15.5 mmol) were added to ethanol (30.0 mL) and water (10.0 mL). The mixture was stirred in an oil bath at 90 °C for 1.0 h. After the reaction was complete, the residue was filtered off, the mixture was washed with ethyl acetate and extracted, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give crude compound 29-4 (0.9 g).

[0986] MS(ESI+)m / z = 421.2[M+H] + .

[0987] Step 4: Synthesis of compound 29-5

[0988] Under an argon atmosphere and ice bath conditions, triethylamine (21.4 mL, 154.1 mmol) was slowly added dropwise to formic acid (2.9 mL, 77.1 mmol), followed by the addition of (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (136.1 mg, 214.1 μmol). The mixture was heated to 45 °C and stirred for 20.0 min. The reaction solution was cooled to room temperature and added to a solution of compound 29-4 (0.9 g, 2.1 mmol) in N,N-dimethylformamide (5.0 mL). The mixture was then heated to 45 °C and stirred for 1.0 h. After the reaction was complete, the crude product was purified by reverse-phase chromatography (water (containing 0.5% NH4OH):acetonitrile = 5:95-95:5) to obtain compound 29-5 (630.0 mg).

[0989] MS(ESI+)m / z = 423.2[M+H] + .

[0990] Step 5: Synthesis of compound 29-6

[0991] Under ice bath conditions, p-toluenesulfonic acid monohydrate (850.0 mg, 4.47 mmol) and compound 29-5 (630.0 mg, 1.49 mmol) were added to acetonitrile (30.0 mL), followed by the addition of an aqueous solution of sodium nitrite (205.8 mg, 3.0 mmol) and potassium iodide (618.9 mg, 3.7 mmol) (3.0 mL). The mixture was stirred for 10 minutes under ice bath conditions, then transferred to room temperature and stirred for another 1 hour. After the reaction was complete, the reaction was quenched with an aqueous solution of sodium sulfite, and the mixture was extracted with ethyl acetate. The crude product obtained after concentration of the organic phase was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound 29-6 (595.0 mg).

[0992] MS(ESI+)m / z = 534.1 [M+H] + .

[0993] Step 6: Synthesis of compound 29-7

[0994] Compound 29-6 (145.0 mg, 271.9 μmol) was added to N,N-dimethylformamide (4.0 mL) containing sodium hydride (20.8 mg, 543.7 μmol, 60% dispersion in Paraffin Liquid) under an argon atmosphere and ice bath conditions. After stirring for 10 minutes, iodomethane (57.9 mg, 407.8 μmol) was added, and the mixture was then transferred to room temperature and stirred for another 0.5 hours. After the reaction was complete, the reaction solution was added dropwise to dilute hydrochloric acid (2.0 mL, 1.0 mol / L), and then extracted with ethyl acetate. The crude product obtained after concentration of the organic phase was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give compound 29-7 (138.0 mg).

[0995] MS(ESI+)m / z = 548.1 [M+H] + .

[0996] Step 7: Synthesis of compound 29-8

[0997] Compound 29-7 (36.0 mg, 65.8 μmol) was added to 1,4-dioxane (2.0 mL), followed by 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (4.8 mg, 6.6 μmol), intermediate 1-2 (55.7 mg, 78.9 μmol), potassium phosphate (27.9 mg, 131.5 μmol), and water (0.5 mL). The mixture was stirred at 75 °C under nitrogen protection for 2.5 hours. After the reaction was complete, the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:4) to obtain compound 29-8 (56.0 mg).

[0998] MS(ESI+)m / z = 999.5[M+H] + .

[0999] Step 8: Synthesis of compound 29-9

[1000] Compound 29-8 (56.0 mg, 56.1 μmol) and cesium carbonate (182.6 mg, 560.5 μmol) were added to N,N-dimethylformamide (2.0 mL), and argon gas was purged. Iodoethane (87.4 mg, 560.5 μmol) was added dropwise to the reaction mixture under an argon atmosphere, and the resulting mixture was stirred at 35 °C for 1.0 h. After the reaction was complete, the crude product was purified by reverse-phase reaction (water (containing 0.5% NH4OH):acetonitrile = 5:95-95:5) to obtain compound 29-9 (52.0 mg).

[1001] MS(ESI+)m / z = 1027.8[M+H] + .

[1002] Step 9: Synthesis of compounds 29-10

[1003] Compound 29-9 (52.0 mg, 50.6 μmol) and paraformaldehyde (30.4 mg, 1.01 mmol) were added to methanol (2.5 mL), followed by the addition of palladium hydroxide / carbon (35.5 mg, 253.11 μmol). The mixture was then purged with hydrogen five times. The mixture was stirred at 33 °C for 16.0 hours under one atmosphere of pressure until the reaction was complete. After the crude product was filtered to remove the residue, the filtrate was purified by reverse-phase chromatography (water (containing 0.5% NH4OH): acetonitrile = 5:95-95:5) to obtain compound 29-10 (39 mg).

[1004] MS(ESI + m / z = 907.6 [M+H] + .

[1005] Step 10: Synthesis of Compounds 29-11

[1006] Compound 29-10 (39.0 mg, 43.0 μmol) was dissolved in dichloromethane (3.0 mL), and then trifluoroacetic acid (1.0 mL) was added. The mixture was stirred at room temperature for 0.5 hours and concentrated to obtain crude compound 29-11 (34.7 mg).

[1007] MS(ESI + m / z = 806.5[M+H] + .

[1008] The third step involves the synthesis of compound 29.

[1009] Compound 29-11 (7.5 mg, 9.29 μmol) and intermediate Int-18 (6.5 mg, 18.59 μmol) were added to ethyl acetate (1.0 mL), followed by the sequential addition of 4-dimethylaminopyridine (5.7 mg, 46.5 μmol), 2-hydroxypyridine-N-oxide (1.6 mg, 13.9 μmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (35.6 mg, 185.9 μmol), and N,N-diisopropylethylamine (64.9 μL, 371.7 μmol). The mixture was stirred at room temperature for 16.0 hours. After the reaction was completed, the crude product was purified by preparative column (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 55%-75%, time: 10 min, flow rate: 15 mL / min) to obtain compound 29 (3.9 mg, retention time 6.88 min).

[1010] MS(ESI+)m / z = 1138.73[M+H] + .

[1011] 1H NMR (400MHz, DMSO) δ8.28(s,1H),8.23(s,1H),8.21–8.06(m,1H),7.78–7.71( m,2H),7.66–7.60(m,1H),7.48–7.42(m,1H),6.67(d,J=7.7Hz,1H),5.86–5.7 2(m,1H),5.20–5.14(m,1H),4.61(d,J=10.9Hz,2H),4.38–4.31(m,1H),4.30– 4.16(m,2H),3.98–3.86(m,1H),3.43–3.35(m,2H),3.14(s,3H),2.88–2.74(m, 4H),2.73–2.56(m,4H),2.54–2.47(m,3H),2.47–2.38(m,2H),2.24–2.14(m,5 H),2.13–2.05(m,5H),2.03(s,2H),2.01–1.90(m,4H),1.90–1.77(m,6H),1.7 0–1.57(m,5H),1.56–1.42(m,3H),1.26(d,J=6.1Hz,3H),0.84–0.79(m,3H),0 .78–0.71(m,6H),0.67(q,J=5.9Hz,4H),0.50–0.41(m,1H),0.16–0.14(m,2H).

[1012] Example 30 Synthesis of Compound 30

[1013] According to the synthesis steps of compound 2, compound 2-3 was replaced with compound 24-1, and compound Int-10 was replaced with compound Int-18. After the reaction was completed, the mixture was purified by preparative chromatography (WELCH Xtimate Prep C18 column; 150 mm * 21.2 mm * 5 μm; mobile phase A: H2O-(NH4HCO3), NH4HCO3 concentration was 7 mmol / L; mobile phase B: MeCN; MeCN ratio 55%-95%, time: 16 min, flow rate: 18 mL / min) to obtain compound 30 (12.3 mg, retention time: 13.67 min).

[1014] MS(ESI + m / z = 1136.6 [M+H] + .

[1015] 1H NMR (400MHz, DMSO-d6) δ8.47(s,1H),8.44(s,1H),8.36–8.20(m,1H),7.92–7.86(m,1H),7. 77(d,J=8.6Hz,1H),7.60(d,J=8.6Hz,1H),5.95(dd,J=18.7,11.0Hz,1H),5.40–5.29(m,1H ),4.85–4.72(m,2H),4.57–4.46(m,1H),4.41–4.28(m,2H),4.07–3.95(m,1H),3.72–3.48( m,4H),3.45–3.38(m,2H),3.29–3.27(m,2H),3.25(s,3H),3.05–2.93(m,3H),2.86–2.74(m ,3H),2.69–2.56(m,3H),2.37–2.30(m,2H),2.30–2.23(m,5H),2.23–2.12(m,7H),2.11–2. 06(m,1H),2.01–1.81(m,3H),1.79–1.60(m,3H),1.43(d,J=6.0Hz,3H),1.38(t,J=6.6Hz,1 H),1.33(t,J=6.5Hz,1H),1.24(d,J=6.0Hz,1H),1.01–0.95(m,3H),0.95–0.79(m,9H),0.6 5–0.55(m,1H),0.50–0.39(m,1H),0.39–0.31(m,2H),0.31–0.25(m,3H),0.19–0.09(m,1H).

[1016] Example 31 Synthesis of Compound 31

[1017] Synthesis of compound 31-1 (Step 1)

[1018] 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 H8 (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 31-1 (140.0 mg).

[1019] MS(ESI + m / z = 513.1 [M+H] + .

[1020] The second step involves the synthesis of compound 31-2.

[1021] Under argon protection, compound 31-1 (200.0 mg, 389.54 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (34.2 mg, 46.76 μmol), and potassium phosphate (198.5 mg, 935.28 μmol) were successively added to a mixed solution of compound 1-2 (330.0 mg, 467.64 μmol) in 2 mL of 1,4-dioxane and 0.4 mL of water. The mixture was heated to 70 °C and stirred for 3 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the residue was washed with ethyl acetate (10 mL). The filtrates were combined and concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 30:70) to obtain compound 31-2 (200.0 mg).

[1022] MS(ESI + m / z = 1012.4[M+H] + .

[1023] The third step involves the synthesis of compound 31-3.

[1024] At room temperature, cesium carbonate (193.1 mg, 592.76 μmol) and iodoethane (92.5 mg, 592.76 μmol, 47.65 μL) were added to a 1 mL solution of N,N-dimethylformamide containing compound 31-2 (200.0 mg, 197.59 μmol), and the mixture was heated to 65 °C and reacted for 4 hours. After the reaction was complete, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to column chromatography (dichloromethane:ethyl acetate = 75:25) to give compounds 31-3 (65.0 mg, eluted with a ZORBAX Eclipse Plus C18 2.1*50 mm, 3.5 μm column, elution time: 5 min, mobile phase water (formic acid content 0.05%):MeCN = 10%-90%, retention time: 3.655 min) and 31-3' (65.0 mg, eluted with a ZORBAX Eclipse Plus C18 2.1*50 mm, 3.5 μm column, elution time: 5 min, mobile phase water (formic acid content 0.05%):MeCN = 10%-90%, retention time: 3.606 min).

[1025] Compound 31-3MS (ESI)+ m / z = 492.6[(M-56) / 2+H] + .

[1026] Step 4: Synthesis of compound 31-4

[1027] At room temperature, a solution of compound 31-3 (85.0 mg, 81.71 μmol) in hexafluoroisopropanol (3 mL) was added with 10% palladium hydroxide / carbon (55% water) (91.8 mg, 65.37 μmol), and the mixture was stirred at room temperature for 3 hours after purging with hydrogen. The mixture was filtered and evaporated to dryness to obtain crude compound 31-4 (74.0 mg), which was used directly in the next step.

[1028] MS(ESI + m / z = 906.4 [M+H] + .

[1029] Step 5: Synthesis of compound 31-5

[1030] To a methanol (1 mL) solution of compound 31-4 (42.0 mg, crude), formaldehyde aqueous solution (19.3 mg, 231.75 μmol, 18.0 μL, 36% purity) and glacial acetic acid (8.4 mg, 139.05 μmol, 8.0 μL) were added. The mixture was stirred at room temperature for 10 minutes, followed by the addition of sodium cyanoborohydride (7.3 mg, 115.88 μmol), and stirring was continued for 1 hour. The reaction was quenched by slow dropwise addition of water (10 mL), and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 31-5 (42.0 mg), which was used directly in the next step.

[1031] MS(ESI + m / z = 920.4 [M+H] + .

[1032] Step 6: Synthesis of compound 31-6

[1033] At room temperature, trifluoroacetic acid (260.2 mg, 2.28 mmol, 175.8 μL) was added dropwise to a dichloromethane (0.8 mL) solution of compound 31-5 (42.0 mg, crude). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was added dropwise to a saturated sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (20 mL * 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 31-6 (37.0 mg), which was used directly in the next step.

[1034] MS(ESI + m / z = 820.4[M+H]+ .

[1035] Step 7: Synthesis of Compound 31

[1036] Compound 31-6 (24.0 mg, crude) was dissolved in ethyl acetate (0.5 mL) under ice bath conditions. Compound Int-18 (20.5 mg, 58.53 μmol), N,N-diisopropylethylamine (75.7 mg, 585.33 μmol, 102.2 μL), 2-hydroxypyridine-N-oxide (4.9 mg, 43.90 μmol), 4-dimethylaminopyridine (17.9 mg, 146.33 μmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (78.6 mg, 409.73 μmol) were added sequentially. The reaction mixture was then stirred at room temperature for 16 hours, cooled to 0°C, and the reaction was quenched with ice water. Extraction was performed with dichloromethane (5 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative chromatography (WELCH column). Xtimate Prep C18; 150 mm * 21.2 mm * 5 μm; mobile phase A: H2O-(NH4HCO3), NH4HCO3 concentration 7 mmol / L; mobile phase B: MeCN; MeCN ratio 60%-95%, time: 16 min, flow rate: 18 mL / min) yielded compound 31 (2.0 mg, 1.65 μmol, yield: 5.64%, retention time: 11.77 min).

[1037] MS(ESI + m / z = 1151.6 [M+H] + .

[1038] 1H NMR(400MHz, DMSO-d6)δ8.42(s,1H),8.37–8.19(m,1H),8.06(s,1H),7.91–7.85(m,1H),7.74(d,J= 8.3Hz,1H),7.57(d,J=8.6Hz,1H),5.96(dd,J=18.9,11.0Hz,1H),5.40–5.30(m,1H),4.85–4.68(m, 2H),4.55–4.47(m,1H),4.36–4.21(m,2H),4.11–3.99(m,1H),3.70–3.49(m,4H),3.41–3.39(m,2H) ,3.31–3.29(m,1H),3.28–3.24(m,2H),3.21(s,3H),3.03–2.92(m,3H),2.85–2.75(m,3H),2.69–2.5 9(m,4H),2.57–2.54(m,1H),2.48–2.40(m,2H),2.35–2.28(m,3H),2.28–2.26(m,3H),2.26–2.23(m ,2H),2.20–2.17(m,2H),2.17–2.07(m,3H),2.05–1.93(m,3H),1.88–1.79(m,1H),1.77–1.58(m,3H) ,1.41(d,J=6.1Hz,3H),1.36–1.30(m,1H),1.16–1.10(m,2H),1.00–0.96(m,3H),0.96–0.89(m,4H) ,0.86(t,J=6.3Hz,7H),0.65–0.53(m,1H),0.48–0.35(m,1H),0.35–0.28(m,4H),0.20–0.11(m,1H).

[1039] Example 32 Synthesis of Compound 32

[1040] According to the synthesis steps of compound 15, the starting material Int-15 was replaced with Int-20, and the compound Int-10 in the last reaction step was replaced with compound Int-18. The reaction solution was purified by preparative chromatography (the chromatographic column was WELCH Xtimate C18, 150 mm * 21.2 mm * 5 μm; mobile phase A: H2O-(NH4HCO3), NH4HCO3 concentration was 7 mmol / L; mobile phase B: MeCN; MeCN ratio 45%-80%, time: 16 min, flow rate: 18 mL / min) to obtain compound 32 (12.0 mg, retention time: 12.50 min).

[1041] MS(ESI + m / z = 1139.6 [M+H] + .

[1042] 1 H NMR (400MHz, DMSO-d6) δ8.77(s,1H),8.44(s,1H),8.39(s,1H),8.29(dd,J=40.2,8.7Hz,1H),7.93–7.87(m,1H),7.78( d,J=8.6Hz,1H),7.61(d,J=8.6Hz,1H),5.95(dd,J=18.4,11.1Hz,1H),5.38–5.28(m,1H),4.76(d,J=11.0Hz,1H),4.59 –4.47(m,2H),4.46–4.33(m,2H),4.12–4.02(m,1H),3.72–3.61(m,1H),3.59–3.55(m,1H),3.54–3.50(m,1H),3.31–3. 30(m,3H),3.04–2.97(m,1H),2.96–2.91(m,2H),2.84–2.75(m,3H),2.69–2.64(m,2H),2.62–2.57(m,1H),2.43–2.38( m,1H),2.37–2.30(m,2H),2.25–2.24(m,1H),2.23–2.21(m,3H),2.20–2.17(m,2H),2.17–2.12(m,3H),2.11–2.08(m,1 H),2.08–2.02(m,2H),2.02–1.97(m,1H),1.96–1.91(m,1H),1.88–1.81(m,3H),1.77–1.60(m,4H),1.41(d,J=6.1Hz,3 H),1.40–1.36(m,1H),1.33(t,J=6.6Hz,1H),1.27–1.19(m,2H),1.00–0.96(m,3H),0.94–0.90(m,2H),0.90–0.87(m,4 H),0.86–0.80(m,4H),0.66–0.56(m,1H),0.48–0.40(m,1H),0.38–0.32(m,2H),0.32–0.28(m,3H),0.20–0.12(m,1H).

[1043] Biological tests

[1044] Test Example 1: Effect of Compounds on Tumor Cell Proliferative Activity

[1045] Experimental materials and instruments:

[1046] The materials required for this experiment include: RPMI-1640 cell culture medium (BasalMedia #L240KJ); DMEM (BasalMedia #L110KJ); fetal bovine serum (FBS) (Proteintech #PM00011); PBS phosphate buffer (BasalMedia #B320KJ); 0.25% trypsin (Gibco #25200-072); 100% DMSO (Sigma #D2650); 96-well permeable sterile culture plate (Corning #3599); 96-well plate (Corning #3610); 2.0 Luminescent cell viability assay kit (Vazyme#DD1101); 25 mL pipettes (Corning); 5 mL pipettes (Corning); P1000 pipette tips, P200 pipette tips and P10 pipette tips (Axygen).

[1047] The instruments and equipment required for this experiment include: Eppendorf pipettes; Eppendorf pipettes; Eppendorf centrifuges; ThermoFisher carbon dioxide incubator; Vi-cell XR fully automated cell counter (Beckman Coulter); and Envision microplate reader (Perkin Elmer).

[1048] The cells required for this experiment include: KRAS G12D Mutant cell line AsPC-1 (ATCC#CRL-1682) TM The complete culture medium is RPMI-1640 medium containing 10% FBS.

[1049] Experimental methods:

[1050] AsPC-1 cells were digested from the culture flasks using 0.25% trypsin and resuspended in the corresponding fresh complete culture medium. After counting, the AsPC-1 cell density was adjusted to 2000 cells / 90 μL / well. 90 μL of the solution was added to each well of a 96-well plate and incubated overnight at 37°C with 5% CO2. A 10 mM stock solution of the compound was diluted 10-fold to 1 mM with DMSO, then further diluted 100-fold to 10 μM with complete culture medium. Using this as the starting concentration, a 3-fold serial dilution was performed with complete culture medium containing 1% DMSO, resulting in nine consecutive concentration gradients. 10 μL of each serially diluted compound was then added to each well to ensure a final DMSO concentration of 0.1% in each well. The positive control group consisted of wells without cell seeding; the negative control group consisted of wells with cells but without the compound treatment. The cell culture plates were incubated at 37°C with 5% CO2 for 5 days. Add an equal volume of CellCounting-Lite 2.0 assay reagent to each well of the cell plate, vortex for 2-5 min to allow for complete cell lysis, and incubate at room temperature for 10 min to stabilize the luminescence signal. Read the luminescence value using an Envision microplate reader. Calculate the inhibition rate using the following formula: Inhibition (%) = (Signal negative control – Signal sample The formula is: (Signalnegative control – Signalpositive control) * 100, then IDBS XLfit is used to perform a 4-parameter fitting to calculate the IC. 50 Numerical value. Measured IC 50 The values ​​are shown in Table 1.

[1051] Table 1

[1052] Test Example 2: Evaluation of the effect of the compounds of this disclosure on hERG potassium ion channel current using automated patch-clamp technique

[1053] Patch clamp system instruments and software

[1054] Record the liquid used

[1055] Experimental methods:

[1056] I. Cell Sample Preparation

[1057] HEK-293 cell line stably expressing hERG potassium channels (purchased from Creacell, catalog number: A-0320) was used.

[1058] 1) HEK-293 cell line stably expressing hERG potassium channels was cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL G418 at 37°C and 5% carbon dioxide.

[1059] 2) Cell passage: Remove the old culture medium and wash once with PBS, then add 1 mL TrypLE TM Incubate with Express solution at 37°C for approximately 0.5 min. Once cells detach from the bottom of the dish, add approximately 5 mL of preheated (37°C) complete culture medium. Gently pipette the cell suspension to separate any aggregated cells. Transfer the cell suspension to sterile centrifuge tubes and centrifuge at 1000 rpm for 5 min to collect the cells. For expansion or maintenance culture, seed cells into 6 cm cell culture dishes at a density of 2.5 × 10⁶ cells per dish. 5 Cells (final volume: 5 mL).

[1060] 3) To maintain the electrophysiological activity of cells, the cell density must not exceed 80%.

[1061] 4) Patch-clamp assay: Cells were subjected to TrypLE assay before the experiment. TM Express separation, 4×10 3 Cells were seeded onto coverslips and cultured in 24-well plates (final volume: 500 μL). After 18 hours, the cells were tested.

[1062] All operations follow the standard operating procedures for cell culture of Beijing Aisiyipu Biotechnology Co., Ltd.

[1063] II. Patch Clamp Testing

[1064] The voltage stimulation protocol for whole-cell patch-clamp recording of hERG potassium currents is as follows: After whole-cell sealing, the cell membrane voltage is clamped at -80 mV. The clamping voltage is depolarized from -80 mV to -50 mV and maintained for 0.5 s (as a leakage current detection), then stepped to 30 mV and maintained for 2.5 s, and then rapidly restored to -50 mV and maintained for 4 s to excite the tail current of the hERG channel. Data is collected every 10 s to observe the effect of the drug on the hERG tail current. A 0.5 s stimulation at -50 mV is used as a leakage current detection. Experimental data are acquired using an EPC 10 or IPA amplifier and stored in PatchMaster or Sutter Patch software.

[1065] Patch-clamp procedure: First, the capillary glass tube is drawn into a recording electrode using a microelectrode drawing device. Then, the electrode, filled with intracellular fluid, is placed into the microelectrode holder. Under an inverted microscope, the microelectrode manipulator is manipulated to immerse the electrode in the extracellular fluid, and the electrode resistance (Rpip) is recorded. Next, the electrode is slowly brought into contact with the cell surface, and negative pressure is applied to aspirate and form a GΩ high-resistance seal. Fast capacitance compensation is then performed, and negative pressure is continued to rupture the cell membrane, establishing a whole-cell recording mode. Finally, slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded. Leakage compensation is not applied.

[1066] Once the hERG current recorded in whole cells stabilized, drug administration began. Each drug concentration was administered for 5 minutes (or until the current stabilized) before moving to the next concentration. One or more concentrations were measured for each test compound. A coverslip containing cells was placed in the recording bath of an inverted microscope. The working solution of the test compound and the external solution without the compound were administered sequentially from low to high concentration through the recording bath using gravity perfusion, while a peristaltic pump was used for fluid replacement during recording. The current detected in the external solution without the compound for each cell served as its control group.

[1067] Data Analysis

[1068] First, the peak tail current compound and the peak tail current control of the blank solvent treatment group were normalized (Peak tail current compound / Peak tail current control). Then, the inhibition rate (1-(Peak tail current compound / Peak tail current control) corresponding to each drug concentration was calculated. The mean, standard deviation (SD), and standard error (SE) of the inhibition rate at each concentration were calculated. The data are expressed as Mean ± SE and saved in Excel. Y = 1 / (1+10^((LogIC)) 50 -X)*HillSlope))

[1069] Calculate the IC for each compound using the above equations. 50 The values ​​were calculated, and a nonlinear fit was performed on the concentration-effect curve, where IC50 was used. 50 This is the half-inhibitory concentration.

[1070] IC 50 The calculations and curve fitting were performed using GraphPad Prism software. The experimental results are shown in Table 2.

[1071] Table 2

[1072] Test Example 3: Pharmacokinetic Test in Mice (PK)

[1073] Experimental Objective: Using mice as test animals, the plasma drug concentrations of the test compound at different time points after injection or oral administration were determined using LC / MS / MS. The pharmacokinetic behavior of the compound in mice was investigated, and its pharmacokinetic characteristics were evaluated.

[1074] Experimental Methods: Six healthy female Balbc nude mice were randomly divided into two dosage groups (n=3 per group). One group received administration via tail vein, and the other received administration orally. The dosages were 2-5 mg / kg and 10-150 mg / kg, respectively. The tail vein group used a fully dissolved solvent, while the oral administration group used either a fully dissolved solvent or a suspension. Individual dosages were calculated based on mouse body weight. In the tail vein group, blood samples were collected from the orbital cavity at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-administration. In the oral administration group, approximately 50 μL of whole blood was collected at each time point and placed in 1.5 mL centrifuge tubes anticoagulated with EDTA-2K. The tubes were then centrifuged at 8000 rpm for 5 min, and the plasma was stored at -80℃.

[1075] 20 μL of mouse plasma was taken, and 300 μL of acetonitrile solvent (containing an internal standard compound) was added to precipitate proteins. After vortexing for 0.5 min, the mixture was centrifuged (14000 rpm) for 5 min. The supernatant was diluted 2-fold with water containing 0.1% (v / v) FA and quantitatively detected using an LC-MS / MS system (AB Sciex Triple Quad 6500+). A mouse plasma standard curve and quality control samples were used concurrently with the sample concentration determination. For 10× diluted samples, 2 μL of the sample was added to 18 μL of blank plasma, vortexed for 0.5 min, and then 300 μL of acetonitrile solvent (containing an internal standard compound) was added to precipitate proteins. The remaining processing steps were the same as for the undiluted sample. The drug concentration in whole blood samples was determined using LC-MS / MS. The limit of detection for this method was 1.2 ng / mL. The main pharmacokinetic parameters were then calculated using the non-compartmental model method in WinNonlin software (Phoenix 8.3). The experimental results are shown in Table 3.

[1076] Table 3

Claims

Compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt, in, X 1 and X 2 Each is independently selected from N and C; L is selected from Alternatively, L can be connected to ring A to form 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 R 11 and R 15 Independently selected from hydrogen, 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; Or R 1 and R 11 Together with the carbon atoms they are attached to, they form a carbonyl group; R 2 R 3 R 7 R 8 and R 9 Independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl groups and C3-C7 cycloalkyl groups; Or, R 2 and R 3 The atoms attached to the cycloalkyl group and the 4-6-membered heterocyclic group together form a C3-C6 cycloalkyl group and a 4-6-membered heterocyclic group, wherein the C3-C6 cycloalkyl group and the 4-6-membered heterocyclic group are optionally connected by one or more R groups. b replace; R 4 Selected from: non-existent, hydrogen, halogen, hydroxyl, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, -C1-C3 alkylene-(C3-C6 cycloalkyl) and -C1-C3 alkylene-(4-6 membered heterocyclic), wherein the hydroxyl group, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, -C1-C3 alkylene-(C3-C6 cycloalkyl) and -C1-C3 alkylene-(4-6 membered heterocyclic) are optionally surrounded by one or more R 4a replace; Or, R 4 and R 7 The atoms connected to it together form a 4-10 membered heterocycle, which is optionally bounded by one or more R atoms. d replace; R 5 The compounds are selected from -O-5-10-membered heteroaryl, -S-5-10-membered heteroaryl, -NH-5-10-membered heteroaryl, 8-15-membered heterocyclic group, and 8-15-membered heteroaryl, wherein the 8-15-membered heterocyclic group and 8-15-membered heteroaryl group have a bicyclic or tricyclic structure, and the -O-5-10-membered heteroaryl, -S-5-10-membered heteroaryl, 8-15-membered heterocyclic group, and 8-15-membered heteroaryl group are optionally separated by one or more R groups. 5a replace; R 6 Selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; R 10 Selected from halogens, hydroxyl groups, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Hydroxyalkyl and C1-C 10 Alkoxy; L 1 Selected from the bond and -N(R) 13 )C(O)-; B is selected from a bond and a 4-14 membered subheterocyclic group, wherein the 4-14 membered subheterocyclic group is optionally surrounded by one or more R f replace; L 2 Selected from carbonyl and -C1-C 10 Alkylene-N(R) 14 )C(O)-; Q is selected from C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne group, C3-C6 cycloalkyl group and 3-6 membered heterocyclic group, wherein C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 The alkynyl group or C3-C6 cycloalkyl group is optionally surrounded by one or more R groups. q replace; R 13 R 14 and R 16 Independently selected from hydrogen, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl groups and C1-C 10 Hydroxyalkyl; X is selected from O and methylene; Z is selected from a 3-10 nucleotide heterocyclic group, a C1-C6 alkylene group, or a 5-10 nucleotide heteroaryl group, wherein the 3-10 nucleotide heterocyclic group, the C1-C6 alkylene group, or the 5-10 nucleotide heteroaryl group is optionally replaced by R. z replace; Each R z Independently selected from -L 2 -Q; Each R q Independently selected from halogens, amino groups, hydroxyl groups, mercapto groups, cyano groups, oxo groups, C1-C4 alkyl groups, C3-C6 cycloalkyl groups, phenyl groups, 5-6 membered heteroaryl groups, and -C(O)-C groups. 2-4 Alkenyl, wherein the amino, hydroxyl, mercapto, C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, 5-6 heteroaryl and -C(O)-C 2-4 Alkenyl groups are optionally surrounded by one or more R groups. g replace; Each R a R b and R g 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, C1-C7 alkyl, C1-C7 haloalkyl, and C1-C7 alkoxy, wherein the amino, hydroxyl, mercapto, C1-C7 alkyl, C1-C7 haloalkyl, and C1-C7 alkoxy are optionally surrounded by one or more R... h replace; Each R 5a Independently selected from halogen, hydroxyl, cyano, amino, oxo, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-14 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups, wherein the hydroxyl, amino, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-14 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, oxo, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the amino, hydroxy, mercapto, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl groups or 2-12 membered heterocyclic groups are optionally surrounded by one or more R groups. e replace; Each R e and R f Independently 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; Each R h Independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups; Each R 1aa Independently selected from halogen, amino, hydroxyl, mercapto, and cyano groups; n is a natural number selected from 0 to 6; One or more hydrogen atoms in the compound of formula (I) may be selected as deuterium atoms. According to claim 1, the compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt, wherein, X 1 Let C be the integer, and X be the integrity. 2 Let N be the number of elements in the array. The compound of formula (I) according to claim 1 or 2, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, A is selected from 4-10 membered heterocyclic groups, C6-C 10 arylene and 5-12-membered heteroarylene, the 4-10-membered heterocyclic group, C6-C 10 arylene and 5-12 heteroarylene are optionally enclosed by one or more R a Substitution; or A is selected from 5-6-membered heterocyclic groups, phenylene, and 5-6-membered heterocyclic groups, wherein the 5-6-membered heterocyclic group, phenylene, and 5-6-membered heterocyclic group are optionally converted by one or more R a Substitution; or A is selected from 5-6-membered heterocyclic groups and 5-6-membered heteroaryl groups, each of which independently contains one or two heteroatoms independently selected from N, O, and S, and optionally is replaced by one or more R atoms. a Substitution; or A is selected from imidazolyl, phenylene, and morpholinoyl, wherein the imidazolyl, phenylene, and morpholinoyl are optionally replaced by one or more R a Substitution; or A is selected from imidazolyl, imomorpholino, and imidinyl, wherein the imidazolyl, imomorpholino, and imidinyl are optionally replaced by one or more R a Replace; or A is selected from The Optional R a Replace; or A is selected from The Optional R a Replace; or A is selected from Or A is selected from The Optional by one or more R a Substitution, where * represents the end attached to the benzene ring; or A is Or A is The asterisk (*) indicates the end connected to the benzene ring. The compound of formula (I) according to any one of claims 1-3, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, Each R a It is independently selected from halogen, amino, hydroxyl, mercapto and cyano groups. The compound of formula (I) according to any one of claims 1-4, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, L is selected from Or L is selected from Or L is selected from Or L is selected from The compound of formula (I) according to any one of claims 1-5, or its stereoisomer or its pharmaceutically acceptable salt, wherein, R 1 and R 15 Independently selected from C1-C 10 Alkyl, C3-C 10 cycloalkyl, the C1-C 10 Alkyl, C3-C 10 The cycloalkyl group is optionally surrounded by one or more R 1a Replace; or R 1 and R 15 Independently selected from isopropyl and cyclopentyl, wherein the isopropyl and cyclopentyl groups are optionally separated by one or more R groups. 1a Replace; or R 1 and R 15 Independently cyclopentyl or isopropyl; or R 15 It is cyclopentyl. The compound of formula (I) according to any one of claims 1-6, or its stereoisomer or its pharmaceutically acceptable salt, wherein, R 1 Selected from C1-C 10 Alkyl, C3-C 10 cycloalkyl, the C1-C 10 Alkyl, C3-C 10 The cycloalkyl group is optionally surrounded by one or more R 1a Replace; or R 1 Selected from isopropyl and cyclopentyl, wherein the isopropyl and cyclopentyl groups are optionally converted by one or more R groups. 1a Replace; or R 1 It consists of cyclopentyl and isopropyl; R 11 It is hydrogen; or R 1 and R 11 Together with the carbon atoms they are attached to, they form a carbonyl group. The compound of formula (I) according to any one of claims 1-7, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, L 1 Selected from the bond and -N(CH3)C(O)-; or L 1 Selected from the bond and -N(CH3)C(O)-*, where * is the terminal connected to B. The compound of formula (I) according to any one of claims 1-8, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, B is selected from a bond and a 6-13 membered subheterocyclic group, wherein the 6-13 membered subheterocyclic group is optionally separated by one or more R. f Substitution; or B is selected from the bond, piperidinyl group, The piperinyl group, Optional by one or more R f Replacement; or B as the bond, The compound of formula (I) according to any one of claims 1-9, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, Each R f Independently selected from halogens and C1-C4 alkyl groups; or each R f It is independently selected from fluorine and methyl. The compound of formula (I) according to any one of claims 1-10, or its stereoisomer or its pharmaceutically acceptable salt, wherein, L 2 Selected from carbonyl and -C1-C4 alkylene-N(CH3)C(O)-; or L 2 Selected from carbonyl and methylene-N(CH3)C(O)-. The compound of formula (I) according to any one of claims 1-11, or its stereoisomer or its pharmaceutically acceptable salt, wherein, Q is selected from C2-C 10 Alkyne group and 3-6 membered heterocyclic group, the C2-C 10 The alkynyl group and the 3-6 membered heterocyclic group are optionally coupled with one or more R groups. q Substitution; or Q is selected from C2-C5 ynyl groups and 3-6-membered heterocyclic groups, wherein the C2-C5 ynyl groups and 3-6-membered heterocyclic groups are optionally replaced by one or more R groups. q Substitution; or Q is selected from azirropropyl, oxoheterobutyl and The aziridine, oxadiazine and Optional by one or more R q Replace; or Q is selected from The compound of formula (I) according to any one of claims 1-12, or its stereoisomer or its pharmaceutically acceptable salt, wherein, Each R q Independently selected from amino, oxo, C1-C4 alkyl, and C3-C6 cycloalkyl groups, wherein the amino, C1-C4 alkyl, and C3-C6 cycloalkyl groups are optionally surrounded by one or more R... g Replace; or each R q The amino, oxo, methyl, and cyclopropyl groups are independently selected from amino, methyl, and cyclopropyl groups, wherein the amino, methyl, and cyclopropyl groups are optionally surrounded by one or more R groups. g Replace; or each R q It is independently selected from -N(CH3)2, oxo, methyl and cyclopropyl. The compound of formula (I) according to any one of claims 1-13, or its stereoisomer or its pharmaceutically acceptable salt, wherein, Each R g Independently selected from halogens and C1-C4 alkyl groups; or R g It is a methyl group. The compound of formula (I) according to any one of claims 1-14, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, -L 2 -Q is selected from Or -L 2 -Q is selected from Or -L 2 -Q is selected from Or -L 2 -Q is selected from The compound of formula (I) according to any one of claims 1-15, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, Z is selected from 3-10 nucleotide subheterocyclic groups, wherein the 3-10 nucleotide subheterocyclic group is optionally replaced by R. z Substitution; or Z is selected from piperidinyl groups, wherein the piperidinyl group is optionally replaced by R. z Replace; or Z is selected from Or Z is Or Z is The compound of formula (I) according to any one of claims 1-16, or its stereoisomer or its pharmaceutically acceptable salt, wherein, X stands for oxygen. The compound of formula (I) according to any one of claims 1-17, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, R 16 Selected from C1-C4 alkyl groups; or R 16 It is a methyl group. The compound of formula (I) according to any one of claims 1-18, or its stereoisomer or its pharmaceutically acceptable salt, wherein, R 2 R 3 Independently selected from hydrogen, halogen, hydroxyl, cyano and C1-C 10 Alkyl; or R 2 R 3 Independently selected from C1-C4 alkyl groups, such as methyl; or R 2 R 3 All are methyl groups. The compound of formula (I) according to any one of claims 1-19, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, 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 -CH2- (C3-C6 cycloalkyl) and -CH2- (4-6 membered heterocyclic group), optionally surrounded 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 Selected from ethyl, trifluoroethyl, Or R 4 Selected from ethyl, trifluoroethyl and Or R 4 Selected from ethyl, trifluoroethyl, Or R 4 Selected from ethyl, trifluoroethyl, Or R 4 Selected from -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-azacyclobutyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -CH2-oxacyclobutyl, -CH2-thiocyclobutyl, and -CH2-tetrahydropyranyl; or R 4 Selected from Or R 4 Selected from C2H5-, CF3CH2-, Or R 4 It is ethyl; or R 4 It is CF3CH2-. The compound of formula (I) according to any one of claims 1-20, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Each R 4a Independently selected from halogen, amino, hydroxyl, mercapto, and cyano groups; or each R 4a Independently selected from fluorine and cyano groups; or each R 4a The group is independently selected from fluorine, hydroxyl, and cyano groups, wherein the hydroxyl group is optionally R h Replace; and / or R h Selected from 4-6 membered heterocyclic groups, or R h It is a tetrahydropyranyl group. The compound of formula (I) according to any one of claims 1-21, or its stereoisomer or its pharmaceutically acceptable salt, wherein, R 5 The compounds are selected from -O-5-10-membered heteroaryl, -NH-5-10-membered heteroaryl, 9-15-membered heterocyclic, and 9-10-membered heteroaryl, wherein the 9-15-membered heterocyclic and 9-10-membered heteroaryl are bicyclic or tricyclic structures, and the -O-5-10-membered heteroaryl, -NH-5-10-membered heteroaryl, 9-15-membered heterocyclic, and 9-10-membered heteroaryl are optionally separated by one or more R... 5a Replace; or R 5 Selected from -O-pyridyl, -NH-pyridyl, The pyridyl group, Optionally by one or more R 5a Replace; or R 5 Selected from -O-pyridyl, -NH-pyridyl, The -O-pyridyl, -NH-pyridyl, Optionally by one or more R 5a Replace; or R 5 Selected from The Optionally by one or more R 5a Replace; or R 5 Selected from The Optionally by one or more R 5a Replace; or R 5 Selected from Or R 5 Selected from Or R 5 Selected from The compound of formula (I) according to any one of claims 1-22, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Each R 5a Independently selected from halogen, cyano, amino, hydroxyl, oxo, C1-C 10 Alkyl, C2-C 10 alkynyl group, C1-C 10 alkoxy groups and 3-14 membered heterocyclic groups, wherein the amino, hydroxyl, C1-C 10 Alkyl, C2-C 10 alkynyl group, C1-C 10 The alkoxy group and the 3-14 membered heterocyclic group are optionally surrounded by one or more R groups. c Replace; or each R 5a Independently selected from halogen, cyano, amino, oxo, C1-C 10 Alkyl, C1-C 10 alkoxy groups and 3-14 membered heterocyclic groups, wherein the amino group, C1-C 10 Alkyl, C1-C 10 The alkoxy group and the 3-14 membered heterocyclic group are optionally surrounded by one or more R groups. c Replace; or each R 5a Independently selected from halogen, cyano, oxo, C1-C 10 Alkyl groups and 3-14 membered heterocyclic groups, the 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, hydroxyl, oxo, C1-C4 alkyl, C2-C4 alkynyl, C1-C4 alkoxy, and 3-7 membered heterocyclic groups, wherein the amino, hydroxyl, C1-C4 alkyl, C2-C4 alkynyl, C1-C4 alkoxy, and 3-7 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, C1-C4 alkoxy, and 3-7 membered heterocyclic groups, wherein the amino, C1-C4 alkyl, C1-C4 alkoxy, and 3-7 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, oxo, C1-C4 alkyl, and 3-6 membered heterocyclic groups, wherein the C1-C4 alkyl and 3-6 membered heterocyclic groups are optionally surrounded by one or more R radicals. c Replace; or each R 5a Independently selected from fluorine, cyano, hydroxyl, methyl, oxo, ethyl, propynyl, piperazine, methoxy, ethoxy, isopropyloxy, amino, and aziridine. Morpholinyl, piperidinyl, and oxetyl, wherein the hydroxyl, methyl, ethyl, propynyl, piperazine, methoxy, ethoxy, isopropyloxy, amino, or aziridine, are used. Morpholinyl, piperidinyl, and oxetyl are optionally separated by one or more R c Replace; or each R 5a The radical is independently selected from fluorine, cyano, methyl, oxo, ethyl, piperazine, piperidinyl, and oxetane, wherein the methyl, ethyl, piperazine, piperidinyl, and oxetane are optionally separated by one or more R groups. c replace. The compound of formula (I) according to any one of claims 1-23, or its stereoisomer or its pharmaceutically acceptable salt, wherein, Each R c Independently selected from halogen, amino, hydroxyl, mercapto, cyano, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the amino, hydroxy, mercapto, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl groups or 3-12-membered heterocyclic groups are optionally surrounded by one or more R groups. e Replace; or each R c Independently selected from halogen, oxo, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl groups and 3-12-membered heterocyclic groups are optionally surrounded by one or more R groups. e Replace; or each R c Independently selected from C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl groups and 3-12-membered heterocyclic groups are optionally surrounded by one or more R groups. e Replace; or each R c Independently selected from halogen, oxo, C1-C4 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, and 4-7 membered heterocyclic groups, wherein the C1-C4 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, and 4-7 membered heterocyclic groups are optionally surrounded by one or more R... e Replace; or each R c Independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, and 4-7 membered heterocyclic groups, wherein the C1-C4 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, and 4-7 membered heterocyclic groups are optionally surrounded by one or more R... e Replace; each R c Independently selected from fluorine, oxo, methyl, ethyl, methoxy, cyclopropyl, 1,4-Dioxanecyclohexyl and oxetanecyclobutyl, wherein the methyl, ethyl, methoxy, cyclopropyl, 1,4-Dioxanecyclohexane and oxohexacyclobutyl are optionally coupled with one or more R... e replace. The compound of formula (I) according to any one of claims 1-24, or its stereoisomer or its pharmaceutically acceptable salt, wherein, Each R e Independently selected from halogen, cyano, =O, 4-10 membered heterocyclic groups, C1-C4 alkoxy, C1-C4 alkyl and -N(C1-C4 alkyl)2; or each R e Independently selected from halogen, cyano, =O, C1-C4 alkoxy, and C1-C4 alkyl; or each R e Independently selected from fluorine, cyano, methyl, =O, and methoxy; or each R e Independently selected from halogen, cyano, =O, 4-10 membered heterocyclic groups, C1-C4 alkyl and -N(C1-C4 alkyl)2; or each R e Independently selected from halogen, cyano, =O, C1-C4 alkyl and -N(C1-C4 alkyl)2; or each R e It is independently selected from cyano and =O. The compound of formula (I) according to any one of claims 1-25, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, R 6 Selected from hydrogen and C1-C4 alkoxy groups; or R 6 It is hydrogen. The compound of formula (I) according to any one of claims 1-26, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, R 7 Selected from hydrogen, halogen, hydroxyl, and cyano groups; or R 7 It is hydrogen. The compound of formula (I) according to any one of claims 1-27, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, 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. The compound of formula (I) according to any one of claims 1-28, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, Each R d Independently selected from halogen, amino, hydroxyl, mercapto, and cyano groups; or each R d It is independently selected from halogens, such as fluorine. The compound of formula (I) according to any one of claims 1-29, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, Selected from The t is selected from 0, 1, 2, and 3; or Selected from The compound of formula (I) according to any one of claims 1-30, or its stereoisomer or its pharmaceutically acceptable salt, wherein, R 8 Selected from hydrogen, halogen, hydroxyl, cyano and C1-C 10 Alkyl; or R 8 It is hydrogen. The compound of formula (I) according to any one of claims 1-31, or its stereoisomer or its pharmaceutically acceptable salt, wherein, R 9 Selected from hydrogen, halogen, hydroxyl, and cyano groups; or R 9 It is hydrogen. The compound of formula (I) according to any one of claims 1-32, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, R 10 Selected from halogens, such as fluorine. The compound of formula (I) according to any one of claims 1-33, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, n can be 0, 1, or 2; or n can be 0. The compound of formula (I) as claimed in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Compound (I) or its stereoisomer or pharmaceutically acceptable salt thereof is selected from compounds (II), (III) or (IV) or their stereoisomers or pharmaceutically acceptable salts thereof: Among them, A, Q, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 and R 11 As defined in any one of claims 1-34, m is 1 or 2, p is 0 or 1, X 3 Selected from CH2 and O. The compound of formula (I) as claimed in claim 1, or its stereoisomer or a pharmaceutically acceptable salt thereof, is selected from the following compounds or their pharmaceutically acceptable salts: A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1-36, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Use of the compound of formula (I) according to any one of claims 1-36, or its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 37, in the preparation of a medicament for the prevention or treatment of RAS-mediated diseases; optionally, the RAS-mediated disease is a tumor; optionally, the RAS-mediated disease is pancreatic cancer or non-small cell lung cancer.

Images