Amide compound, pharmaceutical composition comprising same, and use thereof

Abstract

The present invention relates to a compound as represented by formula (I), a pharmaceutical composition comprising same, and a use thereof for prevention or treatment of a disease.

Description

Amide compounds, pharmaceutical compositions comprising the same and uses thereof TECHNICAL FIELD

[0001] The present application relates to amide compounds, pharmaceutical compositions comprising the same, and uses thereof for preventing or treating diseases.

[0002] BACKGROUND

[0003] DHX9 (also known as RNA helicase A (RHA) or nuclear DNA helicase II (NDH II)) is a DExH-box RNA helicase. DHX9 is capable of utilizing four nucleoside triphosphates (NTPs) to drive its directional movement from 3’ to 5’ direction. Functionally, DHX9 is capable of binding and unwinding or separating double-stranded DNA / RNA, single-stranded DNA / RNA, DNA:RNA hybrids (e.g. R-loops), circular RNA, and DNA / RNA G-quadruplexes, etc. Due to its regulatory role in various RNA and DNA related cellular processes, DHX9 is involved in important biological processes such as transcription, translation, RNA splicing, editing, RNA transport and processing, microRNA generation, and genomic stability maintenance (Pan et al., 2021, Current Protein & Peptide Science (22), 29-40).

[0004] Studies have shown that DHX9 is involved in the regulation of genes associated with cancer characteristics such as persistent proliferation signals, evasion of growth inhibition, evasion of apoptosis, angiogenesis, and metastasis. In particular, microsatellite instability cancers (such as microsatellite instability (MSI) colorectal cancer) and tumors with mismatch repair (MMR) defects exhibit strong dependence on DHX9. In addition, studies have shown that BRAC1 / 2 mutant tumors also depend on DHX9 (Jennifer B. Castro et al., Cancer Res (2024) 84(6_Supplement):3908). Targeted inhibition of DHX9 can also be used for the treatment of such tumors.

[0005] In addition, DHX9 is also related to other diseases involving gene replication, translation or regulation. These diseases include viral infections and autoimmune diseases, etc. Therefore, the development of DHX9 inhibitors as potential therapeutic drugs is of great significance for the treatment of diseases or disease states that respond to DHX9 inhibition.

[0006] SUMMARY

[0007] The present application provides amide compounds, which are useful for preventing or treating DHX9-mediated diseases or disorders. In addition, the compounds of the present application also have more excellent properties such as better physicochemical properties (e.g., solubility, physical and / or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (e.g., reduced cardiotoxicity) and / or fewer side effects), less likely to develop resistance, etc.

[0008] One aspect of the present application provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically-labeled compound, or prodrug thereof, wherein the compound has the structure of Formula (I):

[0009] wherein:

[0010] Ring A is selected from C 3-6 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic ring, and 5-14 membered heteroaromatic ring;

[0011] X is N or CR 1c ;

[0012] Y is N or CR 1d ;

[0013] R 1a , R 1b , R 1c , and R 1d are each independently selected at each occurrence from H, D, halogen, -OH, -NH2, -CN, -NO2, -SF5, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR a R b , -S(=O)(=NR a )R b, -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b , -NR a -S(=O)2-NR a R b , -N=S(=O)R a R b , -NR a -S(=O)(=NR a )R b , -P(=O)R a R b , -C 1-6 alkylene-R a , -C 1-6 alkylene-OR a , -C 1-6 alkylene-NR a R b , -O-C 1-6 alkylene-NR a R b , (-C 3-6 cycloalkylene)-CN, (-C 3-6 cycloalkylene)-C 1-6 alkyl and (-C 3-6 cycloalkylene)-C 2-6 alkynyl;

[0014] R 2 is at each occurrence independently selected from the group consisting of D, halogen, -OH, -NH2, -CN, -NO2, -SF5, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -ORa -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b -S(=O)(=NR) a )R b -NR a R b -C(=O)NR a R b -NR a -C(=O)R b -NR a -C(=O)OR b -NR a -S(=O)2-R b -NR a -C(=O)-NR a R b -NR a -S(=O)2-NR a R b -N = S(=O)R a R b -NR a -S(=O)(=NR a )R b -P(=O)R a R b -C 1-6 Alkylene-R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR a R b -OC 1-6 Alkylene-NR a R b 、(-C 3-6 (-CN and (-C) 3-6 (Hydrocyclic hydrocarbon group)-C 1-6 alkyl;

[0015] Or two Rs 2 Together they form = O or = CR a R b Or two Rs 2 Together with the groups it is attached to, they constitute C 3-6 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings;

[0016] Z independently represents a direct bond, -CH2-, -O-, or -OC each time it appears. 1-4 Alkylene-*, -C 1-4 Alkylenes -O-*, -C(=O)-, -C(=O)O-*, -OC(=O)-*, -S(=O)2-, -S(=O)2N(Z) a )-*、-N(Z a )S(=O)2-*、-N(Z a )-、-N(Z a )-C 1-4 Alkylene-*, -C 1-4 Alkylene-N(Z) a )-*、-C(=O)N(Z a )-*、-N(Z a )C(=O)-* or -C(=O)N(Z a )-C 1-4 Alkylene-*, where * indicates resemblance to R 3 The connection point;

[0017] Z a Is it H or C? 1-4 alkyl;

[0018] R 3 Each time it appears, it is independently selected from C. 3-10 Cyclic hydrocarbon groups, 3-20 membered heterocyclic groups (e.g., 3-10 membered heterocyclic groups), C 6-10 Aryl and 5-14 membered heteroaryl groups; each of the cyclic hydrocarbon group, heterocyclic group, aryl group, and heteroaryl group is optionally substituted by one or more substituents; preferably, the substituents are independently selected from: D, halogen, -OH, =O, -NH2, -CN, -NO2, -SF5, =CH2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R a -OC(=O)R a -C(=O)OR a -OR a -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b -S(=O)(=NR)a )R b -NR a R b -C(=O)NR a R b -NR a -C(=O)R b -NR a -C(=O)OR b -NR a -S(=O)2-R b -NR a -C(=O)-NR a R b -NR a -S(=O)2-NR a R b -N = S(=O)R a R b -NR a -S(=O)(=NR a )R b -P(=O)R a R b -C 1-6 Alkylene-R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR a R b -OC 1-6 Alkylene-NR a R b 、(-C 3-6 (-CN and (-C) 3-6 (Hydrocyclic hydrocarbon group)-C 1-6 alkyl;

[0019] When Z is a direct bond, R 3 The substituents on R are optionally with R 2 Connection constitutes C 3-10 Hydrocarbon rings or 3-10 membered heterocyclic rings;

[0020] R a and R b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl; or R a and R bTogether with the groups it is attached to, they constitute C 3-6 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings;

[0021] The aforementioned alkylene, alkyl, alkenyl, alkynyl, cyclic alkylene, cyclic alkylene, alkyl ring, heterocyclic, heterocyclic, aryl, aromatic ring, heteroaryl, heteroaromatic ring, and aralkyl groups are each optionally substituted by one or more substituents independently selected from the following: deuterium atom, halogen, -OH, =O, -NH2, -CN, -NO2, =CR c R d (e.g., =CH2 or =CF2), -CH=CR c R d C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R c -OC(=O)R c -C(=O)OR c -OR c -SR c -S(=O)R c -S(=O)2R c -S(=O)2NR c R d -NR c R d -C(=O)NR c R d -NR c -C(=O)R d -NR c -C(=O)OR d -NR c -S(=O)2-R d -NR c -C(=O)-NR c R d -NR c -S(=O)2-NR c R d -N = S(=O)R c R d -NR c -S(=O)(=NR c )R d -P(=O)R c Rd -C 1-6 Alkylene-R c -C 1-6 Alkylene-OR c -C 1-6 Alkylene-OC(=O)R c -C 1-6 Alkylene-NR c R d and -OC 1-6 Alkylene-NR c R d The alkylene, alkyl, alkenyl, =CH2, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are each optionally further substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH2, -NH(C 1-6 Alkyl groups, -CN, -NO2, =CH2, =CF2, -P(=O)(C 1-6 Alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -N=S(=O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl group, -C 1-6 Alkylene-C 3-6 Cyclic hydrocarbon groups, -OC 1-6 Alkyl, -O-(halogenated C) 1-6 alkyl), -OC 3-6 Cyclic hydrocarbon groups and -C 1-6 Alkylene-OC 1-6 alkyl;

[0022] R c and R d Each time it appears, it is independently selected from H, halogen, C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl group, or R c and R d Together with the groups it is attached to, they constitute C 3-6Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic ring or 5-14 membered heteroaromatic ring, wherein the alkyl, cycloalkyl, hydrocarbon ring, heterocyclic group, heterocyclic group, aryl, aromatic ring, heteroaryl, heteroaromatic ring and aralkyl group are further optionally substituted by one or more substituents; preferably, the substituents are independently selected from: halogen, -OH, =O, -C(=O)OH, -C(=O)O-tert-butyl, -NH2, -CN, -NO2, =CF2, -P(=O)(C 1-6 Alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -N=S(=O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl groups, -OC 1-6 Alkyl, -OC 3-6 cycloalkyl and -C 1-6 Alkylene-OC 1-6 alkyl;

[0023] m is an integer selected from 0, 1, 2, or 3; and

[0024] n is an integer selected from 0, 1, or 2.

[0025] Another aspect of the invention provides a pharmaceutical composition comprising the compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug, and one or more pharmaceutically acceptable carriers.

[0026] Another aspect of the invention provides the use of the compounds of the invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs, or pharmaceutical compositions of the invention, in the preparation of medicaments for the prevention or treatment of DHX9-mediated diseases or conditions.

[0027] Another aspect of the present invention provides compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs of the present invention, or pharmaceutical compositions of the present invention, for the prevention or treatment of DHX9-mediated diseases or conditions.

[0028] Another aspect of the present invention provides a method for preventing or treating DHX9-mediated diseases or conditions, the method comprising administering to an individual in need an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug or pharmaceutical composition of the present invention. Detailed Implementation

[0029] definition

[0030] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0031] The terms “including,” “comprising,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0032] As used herein, the term "alkylene" means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0033] As used herein, the term "alkyl" is defined as a straight-chain or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example, 1 to 6 carbon atoms. For example, as used herein, the term "C" is used to refer to... 1-6 "Alkyl" refers to a linear or branched group with 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl), optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogens (in which case the group is called "haloalkyl") (e.g., CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C 1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain with 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0034] As used herein, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing one or more double bonds and having 2–6 carbon atoms ("C"). 2-6The alkenyl group is, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the present invention contain an alkenyl group, the compounds may exist in pure E (iso-side) form, pure Z (iso-side) form, or any mixture thereof. This indicates whether the alkenyl group is in the cis or trans configuration. The term "alkenyl" refers to the corresponding divalent group, including, for example, "C". 2-6 "Ideinyl", "C" 2-4 "Alkenyl", etc., specific examples of which include, but are not limited to: -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, buteneyl, pentenyl, hexeneyl, etc.

[0035] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group comprising one or more triple bonds, preferably having 2, 3, 4, 5, or 6 carbon atoms, such as ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. The alkynyl group is optionally substituted by one or more (such as 1 to 3) identical or different substituents. The term "ynynyl" refers to a corresponding divalent group, including, for example, "C..." 2-8 "Immyne", "C" 2-6 "Immyne", "C" 2-4 Examples include, but are not limited to, "ethynyl groups". The alkyne group is optionally substituted by one or more (such as 1 to 3) identical or different substituents.

[0036] As used herein, the term “fused ring” or “dense ring” refers to a ring system formed by two or more ring structures sharing two adjacent atoms.

[0037] As used herein, the term "spiroring" refers to a ring system consisting of two or more ring structures that share a single ring atom.

[0038] As used in this article, the term "bridged ring" refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.

[0039] As used herein, the terms “cycloalkylene group,” “cycloalkylene group,” and “hydrocarbon ring” refer to a saturated (i.e., “cycloalkylene group” and “cycloalkylene group”) or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon ring (including spirocyclic, fused (fused) ring, or bridged ring systems) having, for example, 3 to 10 (suitably 3 to 8, more preferably 3 to 6) cyclic carbon atoms, including but not limited to (cycloalkylene group) propyl(ring), (cycloalkylene group) butyl(ring), (cycloalkylene group) pentyl(ring), (cycloalkylene group) hexyl(ring), (cycloalkylene group) heptyl(ring), (cycloalkylene group) octyl(ring), (cycloalkylene group) nonyl(ring), (cycloalkylene group) hexenyl(ring), etc.

[0040] As used herein, the terms “subcyclic hydrocarbon group,” “cyclic hydrocarbon group,” and “hydrocarbon ring” cover spirocyclic and fused ring structures comprising at least one saturated or partially unsaturated hydrocarbon ring, and the other ring may be a hydrocarbon ring, heterocyclic ring, aromatic ring, or heteroaromatic ring, provided that the spirocyclic and fused ring structure is connected to other groups at a point on the saturated or partially unsaturated hydrocarbon ring.

[0041] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused, or bridged systems (such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.), optionally substituted with one or more (such as one to three) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-6 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) with 3 to 6 cyclic carbon atoms, which is optionally substituted by one or more (e.g., 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0042] As used herein, the term "heterocyclic group" (or "heterocycle") refers to a saturated or partially unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms in a ring and one or more (e.g., one, two, three, or four) heteroatoms selected from O, S (including S=O and S(=O)2), N, and P, and the "heterocyclic group" (or "heterocycle") may contain -C(=O)- as a ring member. The heterocyclic group may be attached to the remainder of the molecule via the carbon atoms and / or heteroatoms (if present). Specifically, 3-10 membered heterocyclic groups are groups having 3-10 carbon atoms and heteroatoms in the ring, such as, but not limited to, ethylene oxide, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolyl, pyrrolidone, imidazoalkyl, pyrazolyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

[0043] As used herein, the term "heterocyclic group" (or "heterocycle") encompasses fused ring structures, wherein the connection point between the fused ring structure and other groups is located on the heterocycle. Therefore, the heterocyclic groups of the present invention also include, but are not limited to, heterocyclic fused heterocyclic groups, heterocyclic fused cycloalkyl groups, monoheterocyclic fused monoheterocyclic groups, monoheterocyclic fused monocycloalkyl groups, aryl fused heterocyclic groups, and heteroaryl fused heterocyclic groups, such as 3-7 membered (mono)heterocyclic fused 3-7 membered (mono)heterocyclic groups, 3-7 membered (mono)heterocyclic fused (mono)cycloalkyl groups, and 3-7 membered (mono)heterocyclic fused C 4-6 (Mono)cycloalkyl, C 6-10 Aryl 3-7 membered heterocyclic groups and 5-6 membered heteroaryl 3-7 membered heterocyclic groups, examples of which include, but are not limited to, pyrrolidinyl cyclopropyl, cyclopentyl aziridine propyl, pyrrolidinyl cyclobutyl, pyrrolidinyl pyrrolidinyl, pyrrolidinyl piperidinyl, pyrrolidinyl piperazine, and piperidinyl morpholinyl.

[0044] As used herein, the term "heterocyclic group" (or "heterocycle") encompasses both bridged heterocyclic groups (bridged heterocycles) and spirocyclic groups (spirocyclic heterocycles).

[0045] As used herein, the term "bridged heterocycle" refers to a ring structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, and / or sulfur atoms) formed by two rings sharing two non-directly connected ring atoms. This includes, but is not limited to, 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7-10 membered oxygen-containing bridged heterocycles, 7-10 membered sulfur-containing bridged heterocycles, etc., for example... The "nitrogen-bridged heterocycle", "oxygen-bridged heterocycle", and "sulfur-bridged heterocycle" may optionally also contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur.

[0046] As used herein, the term "spiroheterocycle" refers to a cyclic structure consisting of two or more rings sharing a single ring atom and containing one or more heteroatoms (e.g., oxygen, nitrogen, or sulfur). The connection points between the spiroheterocycle structure and other groups are located on the heterocycle. Spiroheterocycles include, but are not limited to, 5-10 membered spiroheterocycles, 6-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, and 6-10 membered sulfur-containing spiroheterocycles, etc., for example... The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle", and "sulfur-containing spiroheterocycle" may optionally also contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur. The term "6-10-membered nitrogen-containing spiroheterocycle group" refers to a spiroheterocycle group containing a total of 6-10 ring atoms, of which at least one ring atom is a nitrogen atom.

[0047] As used herein, the terms “(aryl)aryl” and “aromatic ring” refer to all-carbon monocyclic or fused-ring polycyclic aromatic groups having a conjugated π-electron system. For example, as used herein, the term “C…” 6-10 (Asyl) aryl" and "C 6-10 "Aromatic ring" refers to an aromatic group containing 6 to 10 carbon atoms, such as ()phenylene (benzene ring) or ()naphthyl (naphthalene ring). The ()aryl and aromatic rings are optionally substituented with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C). 1-6 Alkyl groups, etc., are substituted. As used herein, the terms “(aryl)aryl” and “aromatic ring” cover fused ring structures, where the connection point between the fused ring structure and other groups is located on the aromatic ring.

[0048] The term "aralkyl" means an aryl-substituted alkyl group, wherein the aryl group and the alkyl group are as defined herein. Typically, the aryl group may have 6-14 carbon atoms, and the alkyl group may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0049] As used herein, the terms “(sub)heteroaryl” and “heteroary ring” refer to monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms, and containing at least one heteroatom that may be the same or different (the heteroatom being, for example, oxygen, nitrogen, or sulfur). Specifically, "(hybrid)aryl" or "heteroary ring" is selected from (thienyl)-(ring), (furanyl)-(ring), (pyrroleyl)-(ring), (oxazolyl)-(ring), (thiazolyl)-(ring), (imidazolyl)-(ring), (pyrazolyl)-(ring), (isooxazolyl)-(ring), (isothiazolyl)-(ring), (oxadiazolyl)-(ring), (triazolyl)-(ring), (thiadiazolyl)-(ring), etc., and their benzo[a] derivatives; or (pyridyl)-(ring), (pyridazinyl)-(ring), (pyrimidinyl)-(ring), (pyrazinyl)-(ring), (triazinyl)-(ring), etc. As used herein, the terms "(hybrid)aryl" and "heteroary ring" encompass fused ring structures, wherein the connection point of the fused ring structure with other groups is located on the heteroary ring.

[0050] As used herein, the term “halogenated” or “halogenated” is defined as including F, Cl, Br or I.

[0051] As used herein, the term "alkylthio" refers to an alkyl group as defined above, which is attached to a portion of the parent molecule via a sulfur atom. C 1-6 Representative examples of alkyl thio groups include, but are not limited to, methyl thio, ethyl thio, tert-butyl thio, and hexyl thio.

[0052] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or partially unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and at least one nitrogen atom in the ring, and optionally may also contain one or more (e.g., one, two, three, or four) ring members selected from N, O, S, S=O, and S(=O)2; the nitrogen-containing heterocycle is connected to the remainder of the molecule through any one of the ring members. The nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocyclic ring. Specifically, 3- to 14-membered nitrogen-containing heterocycles are groups having 3 to 14 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including but not limited to ternary nitrogen-containing heterocycles (such as aziridinyl), quaternary nitrogen-containing heterocycles (such as aziridine), pentazolidinyl, pyrrolinyl, pyrrolidone, imidazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolin ...

[0053] The term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0054] If a substituent is described as “optionally substituted,” then the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together with independently selected optional substituents. If the nitrogen of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted with independently selected optional substituents.

[0055] If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0056] As used herein, the term "one or more" means one or more under reasonable conditions, such as two, three, four, five, or ten.

[0057] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0058] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0059] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium (D, ...). 2 H), tritium (T), 3 H); nitrogen isotopes (e.g., H); 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes ... 32 P); and isotopes of sulfur (e.g. 35S). The isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0060] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0061] Solid lines may be used in this article. solid wedge Or virtual wedge The carbon-carbon bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom. Solid or imaginary wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and imaginary wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0062] Rotation-restricted isomers are compounds that can be isolated into rotation-restricted isomers.

[0063] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to encompass the various derivative forms of the compounds described above.

[0064] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts.

[0065] For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts for the compounds of the present invention are known to those skilled in the art.

[0066] As used herein, the term "ester" means an ester derived from the various general formula compounds of this application, including physiologically hydrolyzable esters (the compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the present invention may themselves also be esters.

[0067] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0068] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0069] This invention further includes, within its scope, prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention that may themselves have little or no pharmacological activity, which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that readily convert in vivo into the compounds with the desired therapeutic activity. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and “Bioreversible Carriers in Drug Design,” Pergamon Press, 1987 (EB Roche, editor, American Pharmaceutical Association). The prodrugs of the invention can be prepared, for example, by replacing suitable functional groups present in the compounds of the invention with certain portions known to those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0070] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in *Protective Groups in Organic Chemistry*, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P. ​​G.W. Uts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0071] As used herein, the term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0072] compound

[0073] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein said compound has the structure of formula (I):

[0074] in:

[0075] Ring A is selected from C 3-6 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings and 5-14 heterocyclic aromatic rings;

[0076] X is N or CR 1c ;

[0077] Y is N or CR 1d ;

[0078] R 1a R 1b R 1c and R 1d Each occurrence is independently selected from H, D, halogen, -OH, -NH2, -CN, -NO2, -SF5, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R a -OC(=O)R a -C(=O)OR a -OR a -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b -S(=O)(=NR) a )R b -NR a R b -C(=O)NR a R b -NR a -C(=O)R b -NR a -C(=O)OR b -NR a -S(=O)2-R b -NRa -C(=O)-NR a R b -NR a -S(=O)2-NR a R b -N = S(=O)R a R b -NR a -S(=O)(=NR a )R b -P(=O)R a R b -C 1-6 Alkylene-R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR a R b -OC 1-6 Alkylene-NR a R b 、(-C 3-6 (-CN, (-C) 3-6 (Hydrocyclic hydrocarbon group)-C 1-6 Alkyl and (-C) 3-6 (Hydrocyclic hydrocarbon group)-C 2-6 alkynyl group;

[0079] R 2 Each occurrence is independently selected from D, halogen, -OH, -NH2, -CN, -NO2, -SF5, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R a -OC(=O)R a -C(=O)OR a -OR a -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b -S(=O)(=NR) a )R b -NR a R b -C(=O)NRa R b -NR a -C(=O)R b -NR a -C(=O)OR b -NR a -S(=O)2-R b -NR a -C(=O)-NR a R b -NR a -S(=O)2-NR a R b -N = S(=O)R a R b -NR a -S(=O)(=NR a )R b -P(=O)R a R b -C 1-6 Alkylene-R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR a R b -OC 1-6 Alkylene-NR a R b 、(-C 3-6 (-CN and (-C) 3-6 (Hydrocyclic hydrocarbon group)-C 1-6 alkyl;

[0080] Or two Rs 2 Together they form = O or = CR a R b Or two Rs 2 Together with the groups it is attached to, they constitute C 3-6 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings;

[0081] Z independently represents a direct bond, -CH2-, -O-, or -OC each time it appears. 1-4 Alkylene-*, -C 1-4 Alkylenes -O-*, -C(=O)-, -C(=O)O-*, -OC(=O)-*, -S(=O)2-, -S(=O)2N(Z) a )-*、-N(Z a )S(=O)2-*、-N(Z a )-、-N(Z a )-C1-4 Alkylene-*, -C 1-4 Alkylene-N(Z) a )-*、-C(=O)N(Z a )-*、-N(Z a )C(=O)-* or -C(=O)N(Z a )-C 1-4 Alkylene-*, where * indicates resemblance to R 3 The connection point;

[0082] Z a Is it H or C? 1-4 alkyl;

[0083] R 3 Each time it appears, it is independently selected from C. 3-10 Cyclic hydrocarbon groups, 3-20 membered heterocyclic groups (e.g., 3-10 membered heterocyclic groups), C 6-10 Aryl and 5-14 membered heteroaryl groups; each of the cyclic hydrocarbon group, heterocyclic group, aryl group, and heteroaryl group is optionally substituted by one or more substituents; preferably, the substituents are independently selected from: D, halogen, -OH, =O, -NH2, -CN, -NO2, -SF5, =CH2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R a -OC(=O)R a -C(=O)OR a -OR a -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b -S(=O)(=NR) a )R b -NR a R b -C(=O)NR a R b -NR a -C(=O)R b -NR a -C(=O)OR b -NR a -S(=O)2-R b -NRa -C(=O)-NR a R b -NR a -S(=O)2-NR a R b -N = S(=O)R a R b -NR a -S(=O)(=NR a )R b -P(=O)R a R b -C 1-6 Alkylene-R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR a R b -OC 1-6 Alkylene-NR a R b 、(-C 3-6 (-CN and (-C) 3-6 (Hydrocyclic hydrocarbon group)-C 1-6 alkyl;

[0084] When Z is a direct bond, R 3 The substituents on R are optionally with R 2 Connection constitutes C 3-10 Hydrocarbon rings or 3-10 membered heterocyclic rings;

[0085] R a and R b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl; or R a and R b Together with the groups it is attached to, they constitute C 3-6 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings;

[0086] The aforementioned alkylene, alkyl, alkenyl, alkynyl, cyclic alkylene, cyclic alkylene, alkyl ring, heterocyclic, heterocyclic, aryl, aromatic ring, heteroaryl, heteroaromatic ring, and aralkyl groups are each optionally substituted by one or more substituents independently selected from the following: deuterium atom, halogen, -OH, =O, -NH2, -CN, -NO2, =CR cR d (e.g., =CH2 or =CF2), -CH=CR c R d C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R c -OC(=O)R c -C(=O)OR c -OR c -SR c -S(=O)R c -S(=O)2R c -S(=O)2NR c R d -NR c R d -C(=O)NR c R d -NR c -C(=O)R d -NR c -C(=O)OR d -NR c -S(=O)2-R d -NR c -C(=O)-NR c R d -NR c -S(=O)2-NR c R d -N = S(=O)R c R d -NR c -S(=O)(=NR c )R d -P(=O)R c R d -C 1-6 Alkylene-R c -C 1-6 Alkylene-OR c -C 1-6 Alkylene-OC(=O)R c -C 1-6 Alkylene-NR c R d and -OC 1-6 Alkylene-NR c Rd The alkylene, alkyl, alkenyl, =CH2, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are each optionally further substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH2, -NH(C 1-6 Alkyl groups, -CN, -NO2, =CH2, =CF2, -P(=O)(C 1-6 Alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -N=S(=O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl group, -C 1-6 Alkylene-C 3-6 Cyclic hydrocarbon groups, -OC 1-6 Alkyl, -O-(halogenated C) 1-6 alkyl), -OC 3-6 Cyclic hydrocarbon groups and -C 1-6 Alkylene-OC 1-6 alkyl;

[0087] R c and R d Each time it appears, it is independently selected from H, halogen, C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl group, or R c and R d Together with the groups it is attached to, they constitute C 3-6 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic ring or 5-14 membered heteroaromatic ring, wherein the alkyl, cycloalkyl, hydrocarbon ring, heterocyclic group, heterocyclic group, aryl, aromatic ring, heteroaryl, heteroaromatic ring and aralkyl group are further optionally substituted by one or more substituents; preferably, the substituents are independently selected from: halogen, -OH, =O, -C(=O)OH, -C(=O)O-tert-butyl, -NH2, -CN, -NO2, =CF2, -P(=O)(C 1-6 Alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -N=S(=O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl groups, -OC 1-6 Alkyl, -OC 3-6 cycloalkyl and -C 1-6 Alkylene-OC 1-6 alkyl;

[0088] m is an integer selected from 0, 1, 2, or 3; and

[0089] n is an integer selected from 0, 1, or 2;

[0090] The condition is: when R 1b C that is not cyano-substituted 2-6 When alkenyl (preferably R) 1b C is not arbitrarily replaced. 2-6 When alkenyl), at least two of the following conditions must be satisfied, preferably all of the following conditions:

[0091] 1).R 1a Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 Cyclic hydrocarbon group; preferably, R 1a The derivatives are Cl, Br, methyl, ethyl, isopropyl, CF3, CHF2, CH2F, vinyl, ethynyl, or cyclopropyl; more preferably, R 1a For Cl;

[0092] 2). R 1c Selected from H, -OH, -NH2, C 1-6 Alkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, -O(C) 1-6 Alkyl), -S(=O)2(C 1- 6-alkyl), -S(=O)2NH2, -NH(C 1-6 Alkyl), -C(=O)NH2, -NH-S(=O)2-(C 1-6 Alkyl groups), -NH-S(=O)2-NH2 and -NH-S(=O)(=NH)(C 1-6 Alkyl); and / or

[0093] 3) At least one of m and n is not 0, preferably both m and n are not 0.

[0094] In some implementations, when Y is CR 1d And R 1c For -NR a -S(=O)2-R b or -NR a -S(=O)(=NR a )R b At that time, R 1b Not H.

[0095] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein said compound has the structure of formula (I):

[0096] in:

[0097] Ring A is selected from C 3-6 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings and 5-14 heterocyclic aromatic rings;

[0098] X is N or CR 1c ;

[0099] Y is N or CR 1d ;

[0100] R 1a R 1b R 1c and R 1d Each occurrence is independently selected from H, D, halogen, -OH, -NH2, -CN, -NO2, -SF5, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R a -OC(=O)R a -C(=O)OR a -OR a -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b-S(=O)(=NR) a )R b -NR a R b -C(=O)NR a R b -NR a -C(=O)R b -NR a -C(=O)OR b -NR a -S(=O)2-R b -NR a -C(=O)-NR a R b -NR a -S(=O)2-NR a R b -N = S(=O)R a R b -NR a -S(=O)(=NR a )R b -P(=O)R a R b -C 1-6 Alkylene-R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR a R b -OC 1-6 Alkylene-NR a R b 、(-C 3-6 (-CN, (-C) 3-6 (Hydrocyclic hydrocarbon group)-C 1-6 Alkyl and (-C) 3-6 (Hydrocyclic hydrocarbon group)-C 2-6 alkynyl group;

[0101] R 2 Each occurrence is independently selected from D, halogen, -OH, -NH2, -CN, -NO2, -SF5, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R a -OC(=O)Ra -C(=O)OR a -OR a -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b -S(=O)(=NR) a )R b -NR a R b -C(=O)NR a R b -NR a -C(=O)R b -NR a -C(=O)OR b -NR a -S(=O)2-R b -NR a -C(=O)-NR a R b -NR a -S(=O)2-NR a R b -N = S(=O)R a R b -NR a -S(=O)(=NR a )R b -P(=O)R a R b -C 1-6 Alkylene-R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR a R b -OC 1-6 Alkylene-NR a R b 、(-C 3-6 (-CN and (-C) 3-6 (Hydrocyclic hydrocarbon group)-C 1-6 alkyl;

[0102] Or two Rs 2 Together they form = O or = CR a R b Or two Rs 2 Together with the groups it is attached to, they constitute C 3-6 Hydrocarbon rings or 3-10 membered heterocyclic rings;

[0103] Z independently represents a direct bond, -CH2-, -O-, or -OC each time it appears. 1-4 Alkylene-*, -C 1-4 Alkylenes -O-*, -C(=O)-, -C(=O)O-*, -OC(=O)-*, -S(=O)2-, -S(=O)2N(Z) a )-*、-N(Z a )S(=O)2-*、-N(Z a )-、-N(Z a )-C 1-4 Alkylene-*, -C 1-4 Alkylene-N(Z) a )-*、-C(=O)N(Z a )-*、-N(Z a )C(=O)-* or -C(=O)N(Z a )-C 1-4 Alkylene-*, where * indicates resemblance to R 3 The connection point;

[0104] Z a Is it H or C? 1-4 alkyl;

[0105] R 3 Each time it appears, it is independently selected from C. 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-14 membered heteroaryl groups; each of the cyclic hydrocarbon group, heterocyclic group, aryl group, and heteroaryl group is optionally substituted by one or more substituents independently selected from the following: D, halogen, -OH, =O, -NH2, -CN, -NO2, -SF5, =CH2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R a -OC(=O)R a -C(=O)OR a -OR a -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b -S(=O)(=NR) a )R b-NR a R b -C(=O)NR a R b -NR a -C(=O)R b -NR a -C(=O)OR b -NR a -S(=O)2-R b -NR a -C(=O)-NR a R b -NR a -S(=O)2-NR a R b -N = S(=O)R a R b -NR a -S(=O)(=NR a )R b -P(=O)R a R b -C 1-6 Alkylene-R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR a R b -OC 1-6 Alkylene-NR a R b 、(-C 3-6 (-CN and (-C) 3-6 (Hydrocyclic hydrocarbon group)-C 1-6 alkyl;

[0106] When Z is a direct bond, R 3 The substituents on R are optionally with R 2 Connection constitutes C 3-10 Hydrocarbon rings or 3-10 membered heterocyclic rings;

[0107] R a and R b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl; or R a and R b Together with the groups it is attached to, they constitute C 3-6 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10Aromatic rings or 5-14 heterocyclic aromatic rings;

[0108] The aforementioned alkylene, alkyl, alkenyl, alkynyl, cyclic alkylene, cyclic alkylene, alkyl ring, heterocyclic, heterocyclic, aryl, aromatic ring, heteroaryl, heteroaromatic ring, and aralkyl groups are each optionally substituted by one or more substituents independently selected from the following: deuterium atom, halogen, -OH, =O, -NH2, -CN, -NO2, =CH2, =CF2, -CH=CR c R d C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R c -OC(=O)R c -C(=O)OR c -OR c -SR c -S(=O)R c -S(=O)2R c -S(=O)2NR c R d -NR c R d -C(=O)NR c R d -NR c -C(=O)R d -NR c -C(=O)OR d -NR c -S(=O)2-R d -NR c -C(=O)-NR c R d -NR c -S(=O)2-NR c R d -N = S(=O)R c R d -NR c -S(=O)(=NR c )R d -C 1-6 Alkylene-R c -C 1-6 Alkylene-OR c -C 1-6 Alkylene-NR c Rd and -OC 1-6 Alkylene-NR c R d The alkylene, alkyl, alkenyl, =CH2, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are each optionally further substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH2, -NH(C 1-6 Alkyl groups, -CN, -NO2, =CH2, =CF2, -P(=O)(C 1-6 alkyl)2, -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -N=S(=O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl group, -C 1-6 Alkylene-C 3-6 Cyclic hydrocarbon groups, -OC 1-6 Alkyl, -O-(halogenated C) 1-6 alkyl), -OC 3-6 Cyclic hydrocarbon groups and -C 1-6 Alkylene-OC 1-6 alkyl;

[0109] R c and R d Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl group, or R c and R d Together with the groups it is attached to, they constitute C 3-6 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic ring or 5-14 membered heteroaromatic ring, wherein the alkyl, cycloalkyl, hydrocarbon ring, heterocyclic group, heterocyclic group, aryl, aromatic ring, heteroaryl, heteroaromatic ring and aralkyl group are further optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl groups and -C 1-6 Alkylene-OC 1-6 alkyl;

[0110] m is an integer selected from 0, 1, 2, or 3; and

[0111] n is an integer selected from 0, 1, or 2;

[0112] The condition is: when R 1b C that is not cyano-substituted 2-6 When alkenyl (preferably R) 1b C is not arbitrarily replaced. 2-6 When alkenyl), at least two of the following conditions must be satisfied, preferably all of the following conditions:

[0113] 1).R 1a Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 Cyclic hydrocarbon group; preferably, R 1a The derivatives are Cl, Br, methyl, ethyl, isopropyl, CF3, CHF2, CH2F, vinyl, ethynyl, or cyclopropyl; more preferably, R 1a For Cl;

[0114] 2). R 1c Selected from H, -OH, -NH2, C 1-6 Alkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, -O(C) 1-6 Alkyl), -S(=O)2(C 1- 6-alkyl), -S(=O)2NH2, -NH(C 1-6 Alkyl), -C(=O)NH2, -NH-S(=O)2-(C 1-6 Alkyl groups), -NH-S(=O)2-NH2 and -NH-S(=O)(=NH)(C 1-6 Alkyl); and / or

[0115] 3) At least one of m and n is not 0, preferably both m and n are not 0.

[0116] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein said compound has the structure of formula (I):

[0117] in:

[0118] Ring A is selected from C 3-6 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings and 5-14 heterocyclic aromatic rings;

[0119] X is N or CR 1c ;

[0120] Y is N or CR 1d ;

[0121] R 1a R 1b R 1c and R 1d Each occurrence is independently selected from H, D, halogen, -OH, -NH2, -CN, -NO2, -SF5, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R a -OC(=O)R a -C(=O)OR a -OR a -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b -S(=O)(=NR) a )R b -NR a R b -C(=O)NR a R b -NR a -C(=O)R b -NR a -C(=O)OR b -NR a -S(=O)2-R b -NR a -C(=O)-NR a R b -NR a -S(=O)2-NR a R b -N = S(=O)R aR b -NR a -S(=O)(=NR a )R b -P(=O)R a R b -C 1-6 Alkylene-R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR a R b -OC 1-6 Alkylene-NR a R b 、(-C 3-6 (-CN and (-C) 3-6 (Hydrocyclic hydrocarbon group)-C 1-6 alkyl;

[0122] R 2 Each occurrence is independently selected from D, halogen, -OH, -NH2, -CN, -NO2, -SF5, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R a -OC(=O)R a -C(=O)OR a -OR a -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b -S(=O)(=NR) a )R b -NR a R b -C(=O)NR a R b -NR a -C(=O)R b -NR a -C(=O)OR b -NR a -S(=O)2-R b -NR a-C(=O)-NR a R b -NR a -S(=O)2-NR a R b -N = S(=O)R a R b -NR a -S(=O)(=NR a )R b -P(=O)R a R b -C 1-6 Alkylene-R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR a R b -OC 1-6 Alkylene-NR a R b 、(-C 3-6 (-CN and (-C) 3-6 (Hydrocyclic hydrocarbon group)-C 1-6 alkyl;

[0123] Or two Rs 2 Together they form = O or = CR a R b Or two Rs 2 Together with the groups it is attached to, they constitute C 3-6 Hydrocarbon rings or 3-10 membered heterocyclic rings;

[0124] Z independently represents a direct bond, -CH2-, -O-, or -OC each time it appears. 1-4 Alkylene-*, -C 1-4 Alkylenes -O-*, -C(=O)-, -C(=O)O-*, -OC(=O)-*, -S(=O)2-, -S(=O)2N(Z) a )-*、-N(Z a )S(=O)2-*、-N(Z a )-、-N(Z a )-C 1-4 Alkylene-*, -C 1-4 Alkylene-N(Z) a )-*、-C(=O)N(Z a )-*、-N(Z a )C(=O)-* or -C(=O)N(Z a )-C 1-4 Alkylene-*, where * indicates resemblance to R 3 The connection point;

[0125] Z a Is it H or C? 1-4 alkyl;

[0126] R 3 Each time it appears, it is independently selected from C. 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-14 membered heteroaryl groups; each of the cyclic hydrocarbon group, heterocyclic group, aryl group, and heteroaryl group is optionally substituted by one or more substituents independently selected from the following: D, halogen, -OH, =O, -NH2, -CN, -NO2, -SF5, =CH2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R a -OC(=O)R a -C(=O)OR a -OR a -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b -S(=O)(=NR) a )R b -NR a R b -C(=O)NR a R b -NR a -C(=O)R b -NR a -C(=O)OR b -NR a -S(=O)2-R b -NR a -C(=O)-NR a R b -NR a -S(=O)2-NR a R b -N = S(=O)R a R b -NR a -S(=O)(=NR a )R b-P(=O)R a R b -C 1-6 Alkylene-R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR a R b -OC 1-6 Alkylene-NR a R b 、(-C 3-6 (-CN and (-C) 3-6 (Hydrocyclic hydrocarbon group)-C 1-6 alkyl;

[0127] When Z is a direct bond, R 3 The substituents on R are optionally with R 2 Connection constitutes C 3-10 Hydrocarbon rings or 3-10 membered heterocyclic rings;

[0128] R a and R b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl; or R a and R b Together with the groups it is attached to, they constitute C 3-6 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings;

[0129] The aforementioned alkylene, alkyl, alkenyl, alkynyl, cyclic alkylene, cyclic alkylene, alkyl ring, heterocyclic, heterocyclic, aryl, aromatic ring, heteroaryl, heteroaromatic ring, and aralkyl groups are each optionally substituted by one or more substituents independently selected from the following: deuterium atom, halogen, -OH, =O, -NH2, -CN, -NO2, =CH2, =CF2, -CH=CR c R d C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R c -OC(=O)R c -C(=O)ORc -OR c -SR c -S(=O)R c -S(=O)2R c -S(=O)2NR c R d -NR c R d -C(=O)NR c R d -NR c -C(=O)R d -NR c -C(=O)OR d -NR c -S(=O)2-R d -NR c -C(=O)-NR c R d -NR c -S(=O)2-NR c R d -N = S(=O)R c R d -NR c -S(=O)(=NR c )R d -C 1-6 Alkylene-OR c -C 1-6 Alkylene-NR c R d and -OC 1-6 Alkylene-NR c R d The alkylene, alkyl, alkenyl, =CH2, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are each optionally further substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH2, -CN, -NO2, =CH2, =CF2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl group, -C 1-6 Alkylene-C 3-6 Cyclic hydrocarbon groups, -OC 1-6 Alkyl, -OC 3-6 Cyclic hydrocarbon groups and -C 1-6 Alkylene-OC1-6 alkyl;

[0130] R c and R d Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl group, or R c and R d Together with the groups it is attached to, they constitute C 3-6 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic ring or 5-14 membered heteroaromatic ring, wherein the alkyl, cycloalkyl, hydrocarbon ring, heterocyclic group, heterocyclic group, aryl, aromatic ring, heteroaryl, heteroaromatic ring and aralkyl group are further optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl groups and -C 1-6 Alkylene-OC 1-6 alkyl;

[0131] m is an integer selected from 0, 1, 2, or 3; and

[0132] n is an integer selected from 0, 1, or 2.

[0133] In some implementations, when R 1b C that is not cyano-substituted 2-6 When alkenyl (preferably R) 1b C is not arbitrarily replaced. 2-6 When alkenyl), at least two of the following conditions must be satisfied, preferably all of the following conditions:

[0134] 1).R 1a Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 Cyclic hydrocarbon group; preferably, R 1a The derivatives are Cl, Br, methyl, ethyl, isopropyl, CF3, CHF2, CH2F, vinyl, ethynyl, or cyclopropyl; more preferably, R 1a For Cl;

[0135] 2). R 1cSelected from H, -OH, -NH2, C 1-6 Alkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, -O(C) 1-6 Alkyl), -S(=O)2(C 1- 6-alkyl), -S(=O)2NH2, -NH(C 1-6 Alkyl), -C(=O)NH2, -NH-S(=O)2-(C 1-6 Alkyl groups), -NH-S(=O)2-NH2 and -NH-S(=O)(=NH)(C 1-6 Alkyl); and / or

[0136] 3) At least one of m and n is not 0, preferably both m and n are not 0.

[0137] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein ring A is selected from:

[0138] Each of the above groups is marked with 0, 1, or 2 R groups. 2 and 0 or 1 ZR 3 replace.

[0139] In a preferred embodiment, ring A is selected from...

[0140] Each of the above groups is marked with 0, 1, or 2 R groups. 2 and 0 or 1 ZR 3 replace.

[0141] Preferably, ring A is selected from

[0142] Each of the above groups is marked with 0, 1, or 2 R groups. 2 and 0 or 1 ZR 3 replace.

[0143] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein

[0144] Selected from:

[0145] In a preferred embodiment, Selected from

[0146] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein

[0147] Selected from:

[0148] In a preferred embodiment, Selected from

[0149] In a preferred embodiment, Selected from

[0150] In a preferred embodiment, for

[0151] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein R 2 Each time it appears, it is independently a halogen or a carbon. 1-6 Alkyl, C 3-6 Cyclic hydrocarbon group or 3-10 membered heterocyclic group, preferably F, Cl, C 1-6 Alkyl or cyclopropyl, more preferably C 1-6 Alkyl group, most preferably methyl group; and

[0152] m is an integer that is either 0 or 1.

[0153] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein two R... 2 Together with the groups to which it is attached, it forms a benzene ring.

[0154] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein Z is a direct bond, -OC 1-4 Alkylene-*, -C 1-4 Alkylene-O-*, -N(Z) a )-C 1-4 Alkylene-*, -C 1-4 Alkylene-N(Z) a )-*、-C(=O)N(Z a )-*、-N(Z a )C(=O)-* or -C(=O)N(Z a )-C 1-4 Alkylene-*, where * indicates resemblance to R 3 Connection point; Z a Is it H or C? 1-3 Alkyl, preferably, Z a It is H; and

[0155] n is 1.

[0156] In the preferred embodiment, Z represents a direct bond and -OC. 1-4 Alkylenes -* (e.g., -O-CH2-*), -N(Z) a )-C 1-4 Alkylene -* (e.g., -NH-CH2-*), where * indicates resemblance to R 3 The connection point.

[0157] In a more preferred embodiment, Z is a direct bond.

[0158] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein R 3 Each time it appears, it is independently for

[0159] Each of the above groups may be optionally substituted by one or more substituents independently selected from the following: D, halogen, -OH, =O, -NH2, -CN, -NO2, -SF5, =CH2, =CF2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R a -OC(=O)R a -C(=O)OR a -OR a -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b -S(=O)(=NR) a )R b -NR a R b -C(=O)NR a R b -NR a -C(=O)R b -NR a -C(=O)OR b -NR a -S(=O)2-R b -NR a -C(=O)-NR a R b -N = S(=O)R a R b -P(=O)R a R b -C 1-6 Alkylene-R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR a R b -OC 1-6 Alkylene-NR a R b 、(-C 3-6 (-CN and (-C) 3-6 (Hydrocyclic hydrocarbon group)-C 1-6 alkyl;

[0160] R a and R b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl; or Ra and R b Together with the groups it is attached to, they constitute C 3-6 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings;

[0161] The aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are each optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, -OH, -NH2, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl groups, -OR c -C(=O)R c -C(=O)OR c -C 1-6 Alkylene-R c -C 1-6 Alkylene-OR c -C 1-6 Alkylene-OC(=O)R c -S(=O)R c -S(=O)2R c and -P(=O)R c R d The aforementioned alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are each optionally further selected independently by one or more elements selected from halogens, -OH, -C(=O)OH, -CN, -NH2, =CF2, -P(=O)(C 1-6 Alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -N=S(=O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-14 membered heteroaryl, -OC 1-6 Alkyl and -OC 3-6 Substitution of cycloalkyl groups.

[0162] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein R3 Each time it appears, it is independently for

[0163] Each of the above groups may be optionally substituted by one or more substituents independently selected from the following: D, halogen, -OH, =O, -NH2, -CN, -NO2, -SF5, =CH2, =CF2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R a -OC(=O)R a -C(=O)OR a -OR a -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b -S(=O)(=NR) a )R b -NR a R b -C(=O)NR a R b -NR a -C(=O)R b -NR a -C(=O)OR b -NR a -S(=O)2-R b -NR a -C(=O)-NR a R b -N = S(=O)R a R b -P(=O)R a R b -C 1-6 Alkylene-R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR a R b -OC 1-6 Alkylene-NR a R b、(-C 3-6 (-CN and (-C) 3-6 (Hydrocyclic hydrocarbon group)-C 1-6 alkyl;

[0164] R a and R b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl; or R a and R b Together with the groups it is attached to, they constitute C 3-6 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings;

[0165] The aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl groups, -OR c -C(=O)R c -C(=O)OR c and -C 1-6 Alkylene-R c The aforementioned alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are each optionally further selected independently by one or more elements selected from halogens, -OH, -CN, -NH2, -P(=O)(C 1-6 alkyl)2, -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -N=S(=O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -OC 1-6 Alkyl and -OC 3-6 Substituents of cycloalkyl groups;

[0166] Preferably, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, C.1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl groups, wherein the aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aryl groups are each optionally further selected independently by one or more elements selected from halogens, -OH, -CN, C. 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -OC 1-6 Alkyl and -OC 3-6 Substitution of cycloalkyl groups.

[0167] In some embodiments, this application provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein R 3 Each time it appears, it is independently for

[0168] Each of the above groups may be optionally substituted by one or more substituents independently selected from the following: halogen, -CN, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, -NR a R b -OR a -C(=O)NR a R b and -NR a -S(=O)2-R b ;

[0169] R a and R b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl groups;

[0170] The aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are each optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, -OH, -NH2, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, -OR c -C(=O)R c -C(=O)OR c -C 1-6 Alkylene-R c -C 1-6 Alkylene-OR c -C 1-6 Alkylene-OC(=O)R c -S(=O)R c -S(=O)2R c and -P(=O)R c R d The aforementioned alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally further selected independently by one or more elements selected from halogens, -OH, -C(=O)OH, -CN, -NH2, =CF2, -P(=O)(C 1-6 Alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -N=S(=O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-14 membered heteroaryl, -OC 1-6 Alkyl and -OC 3-6 Substitution of cycloalkyl groups.

[0171] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein R 3 Each time it appears, it is independently for

[0172] Each of the above groups may be optionally substituted by one or more substituents independently selected from the following: halogen, -CN, C. 1-6 Alkyl, deuterated C1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, -NR a R b -OR a and -NR a -S(=O)2-R b ;

[0173] R a and R b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl groups;

[0174] The aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, -OR c -C(=O)R c -C(=O)OR c and -C 1-6 Alkylene-R c The aforementioned alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally further selected independently by one or more elements selected from halogens, -OH, -CN, -NH2, -P(=O)(C 1-6 alkyl)2, -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -N=S(=O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -OC 1-6 Alkyl and -OC 3-6 Substitution of cycloalkyl groups.

[0175] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein R 3 Each time it appears, it is independently for In a preferred embodiment, R 3 for

[0176] Each of the above groups may be optionally substituted by one or more substituents independently selected from the following: halogen, -CN, C. 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic groups (preferably 3-8 membered heterocyclic groups) (preferably aza-butane, pyrrolidinyl, piperidinyl, piperazine, morpholinyl, 1,1-thiomorpholine, -NHR a -OR a -C(=O)NR a R b and -NR a -S(=O)2-R b ;

[0177] R a and R b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-14 membered heteroaryl; preferably, R a and R b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-6 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups;

[0178] The aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, -OH, -NH2, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, phenyl groups, 5-14 membered heteroaryl groups, -OC groups 1-6 Alkyl, -C(=O)-(C 1-6 Alkyl group, -C(=O)-(3-10 membered heterocyclic group), -C(=O)OC 1-6 Alkyl, -C 1-6 Alkylene-(C 3-8 cyclic hydrocarbon group), -C 1-6 alkylene-(3-10 membered heterocyclic group), -C 1-6 alkylene-O-(C 1-6 Alkyl), -C 1-6 Alkylene-OC(=O)-(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-S(=O)(C 1-6 Alkyl) and -S(=O)2(C 1-6 Alkyl), wherein the aforementioned alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, phenyl, and heteroaryl groups are each optionally further selected independently by one or more elements selected from halogen, -OH, -C(=O)OH, -CN, -NH2, =CF2, -P(=O)(C 1-6 Alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -N=S(=O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 3- 6-cycloalkyl, 3-6-membered heterocyclic, phenyl, 5-6-membered heteroaryl, -OC 1-6 Alkyl and -OC 3-6 Substituents of cycloalkyl groups;

[0179] Preferably, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, -OH, -NH2, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-6 membered heterocyclic groups, phenyl groups, 5-10 membered heteroaryl groups, -OC groups 1-6 Alkyl, -C(=O)-(C 1-6 Alkyl group), -C(=O)-(3-6 membered heterocyclic group), -C(=O)OC 1-6 Alkyl, -C 1-6 Alkylene-(C 3-6 cyclic hydrocarbon group), -C1-6 Alkylene-(3-6 membered heterocyclic group), -C 1-6 alkylene-O-(C 1-6 Alkyl), -C 1-6 Alkylene-OC(=O)-(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-S(=O)(C 1-6 Alkyl) and -S(=O)2(C 1-6 Alkyl), wherein the aforementioned alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, phenyl, and heteroaryl groups are each optionally further selected independently by one or more elements selected from halogen, -OH, -C(=O)OH, -CN, -NH2, =CF2, -P(=O)(C 1-6 Alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -N=S(=O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 3- 6-cycloalkyl, 3-6-membered heterocyclic, phenyl, 5-6-membered heteroaryl, -OC 1-6 Alkyl and -OC 3-6 Substitution of cycloalkyl groups.

[0180] In the preferred embodiment, R 3 Each time it appears, it is independently for

[0181] Each of the above groups may be optionally substituted by one or more substituents independently selected from the following: halogen, -CN, C. 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 3-8 membered heterocyclic groups (preferably azacyclic butyl, pyrrolidinyl, piperazine, morpholinyl, 1,1-thiomorpholine), -NHR a -OR a and -NR a -S(=O)2-R b ;

[0182] R a and R b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-14 heteroaryl groups;

[0183] The aforementioned alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, phenyl groups, 5-14 membered heteroaryl groups, -OC groups 1-6 Alkyl, -C(=O)-(C 1-6 Alkyl group, -C(=O)-(3-10 membered heterocyclic group), -C(=O)OC 1-6 Alkyl and -C 1-6 Alkylene-(C 3-6 Cycloalkyl group), wherein the aforementioned alkylene group, alkyl group, cycloalkyl group, heterocyclic group, phenyl group and heteroaryl group are each optionally further selected independently by one or more halogens, -OH, -CN, -NH2, -P (=O)(C 1-6 alkyl)2, -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -N=S(=O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -OC 1-6 Alkyl and -OC 3-6 Substitution of cycloalkyl groups.

[0184] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein R 3 Each time it appears, it is independently for

[0185] Each of the above groups may be optionally substituted by one or more substituents independently selected from the following: halogen, -CN, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 aryl, 5-14 heteroaryl and -OR a ;

[0186] R a Selected from H, C 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl groups;

[0187] The aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-14 membered heteroaryl groups, wherein the aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally further selected independently by one or more elements selected from halogen, -OH, -CN, C. 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -OC 1-6 Alkyl and -OC 3-6 Substitution of cycloalkyl groups.

[0188] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein R 3 Each time it appears, it is independently for

[0189] Each of the above groups may be optionally substituted by one or more substituents independently selected from the following: halogen, -CN, C. 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 3-8 membered heterocyclic groups (preferably azirrobutyl, pyrrolidinyl, piperazine, morpholinyl, 1,1-thiomorpholine or...) ) and -OR a ;

[0190] R a Selected from H, C 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-14 heteroaryl groups;

[0191] The aforementioned alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6Cycloalkyl group, 3-10 membered heterocyclic group, phenyl group and 5-14 membered heteroaryl group, wherein each of the above alkyl, cycloalkyl, heterocyclic, phenyl and heteroaryl groups is further optionally selected independently by one or more halogens, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -OC 1-6 Alkyl and -OC 3-6 Substitution of cycloalkyl groups.

[0192] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein when Z is a direct bond, R 3 The substituents on R are optionally with R 2 The links form a 6-8 membered heterocycle, preferably a 7-membered heterocycle, wherein the heterocycle contains one or two heteroatoms selected from O and N.

[0193] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein R 1a Selected from H, halogens, SF5, CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, -O-(C 1-6 Alkyl) and -C(=O)-(C 1-6 Alkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclic groups are optionally substituted with one or more halogens.

[0194] In the preferred embodiment, R 1a The group is selected from H, F, Cl, Br, SF5, CN, methyl, ethyl, isopropyl, CF3, CHF2, CH2F, vinyl, ethynyl, cyclopropyl, aziridine, oxetidine, pyrrolidine, -O-CHF2, -O-CF3 and acetyl, wherein the cyclopropyl, aziridine, oxetidine and pyrrolidine are optionally substituted with one or more halogens.

[0195] In a more preferred embodiment, R 1a Selected from H, F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, CHF2, CH2F, vinyl, ethynyl, cyclopropyl, -O-CHF2, and -O-CF3.

[0196] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein R 1a Selected from halogens, SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups and -C(=O)-(C 1-6 Alkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclic groups are optionally substituted with one or more halogens.

[0197] In the preferred embodiment, R 1a The hydroxyl group is selected from Cl, Br, SF5, methyl, ethyl, isopropyl, CF3, CHF2, CH2F, vinyl, ethynyl, cyclopropyl, aziridine, oxetidine, pyrrolidine, and acetyl, wherein the cyclopropyl, aziridine, oxetidine, and pyrrolidine are optionally substituted with one or more halogens.

[0198] In a more preferred embodiment, R 1a Selected from Cl, Br, methyl, ethyl, isopropyl, CF3, CHF2, CH2F, vinyl, ethynyl and cyclopropyl.

[0199] In a more preferred embodiment, R 1a It is Br or Cl.

[0200] In the most preferred embodiment, R 1a It is Cl.

[0201] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein R 1b Selected from C 2-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon group, 3-10 membered heterocyclic group, phenyl group, 5-14 membered heteroaryl group, -C 1-6 Alkylene-(C 3-6 cyclic hydrocarbon group), -C 1-6 Alkylene-(3-10 membered heterocyclic group), -C(=O)(C 1-6 Alkyl), -O(C) 1-6 alkyl), -O-(C 3-6 cyclic hydrocarbon group), -O(C 6-10 aryl), -S(C 1-6 alkyl), -NH(C)1-6 Alkyl), -CH2-O-(C 6-10 aryl) and (-C 3-6 (Hydrocyclic hydrocarbon group)-C 2-6 alkynyl group;

[0202] The alkylene, alkyl, alkenyl, alkynyl, cycloalkylene, cycloalkylene, heterocyclic, phenyl, aryl, and heteroaryl groups are each optionally substituted by one or more substituents independently selected from the following: halogen, -CN, -OH, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic, 5-14 membered heteroaryl, -O-(C 1-6 Alkyl groups and -C (=O) (C 1-6 Alkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclic, and heteroaryl groups are each optionally further substituted by one or more substituents independently selected from: halogen, -CN, -OH, -NH2, -NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, -OC 1-6 Alkyl and -O-(halogenated C) 1-6 alkyl).

[0203] In the preferred embodiment, R 1b Selected from C 2-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon group, 3-10 membered heterocyclic group, phenyl group, 5-14 membered heteroaryl group, -C(=O)(C 1-6 Alkyl), -O(C) 1-6 Alkyl), -O(C) 6-10 aryl), -S(C 1-6 alkyl) and -NH(C 1-6 alkyl) and (-C 3-6 (Hydrocyclic hydrocarbon group)-C 2-6 alkynyl group;

[0204] The alkyl, alkenyl, alkynyl, hemicyclic, cyclic, heterocyclic, phenyl, aryl, and heteroaryl groups are each optionally substituted by one or more substituents independently selected from the following: halogen, -CN, -OH, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, -O-(C 1-6 Alkyl groups and -C (=O) (C 1-6 Alkyl), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups is optionally further substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NH(C 1-6 Alkyl), C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, -OC 1-6 Alkyl and -O-(halogenated C) 1-6 alkyl).

[0205] In a more preferred embodiment, R 1b Selected from

[0206] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein R 1b Selected from C 2-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon group, 3-10 membered heterocyclic group, phenyl group, 5-14 membered heteroaryl group, -C 1-6 Alkylene-(C 3-6 cyclic hydrocarbon group), -C 1-6 Alkylene-(3-10 membered heterocyclic group), -C(=O)(C 1-6 Alkyl), -O(C) 1-6 alkyl), -O-(C 3-6 cyclic hydrocarbon group), -O(C 6-10 aryl), -S(C 1-6 alkyl), -NH(C) 1-6 alkyl) and -CH2-O-(C 6-10 (Aromatic);

[0207] The alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, phenyl, and heteroaryl groups are each optionally substituted by one or more substituents independently selected from the following: halogen, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic, 5-14 membered heteroaryl, -O-(C 1-6 Alkyl groups and -C (=O) (C 1-6Alkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclic, and heteroaryl groups are each optionally further substituted by one or more substituents independently selected from: halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group and C 3-6 Cyclic hydrocarbon group.

[0208] In the preferred embodiment, R 1b Selected from C 2-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon group, 3-10 membered heterocyclic group, phenyl group, 5-14 membered heteroaryl group, -C(=O)(C 1-6 Alkyl), -O(C) 1-6 Alkyl), -O(C) 6-10 aryl), -S(C 1-6 alkyl) and -NH(C 1-6 alkyl);

[0209] The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, phenyl, and heteroaryl groups are each optionally substituted by one or more substituents independently selected from the following: halogen, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, -O-(C 1-6 Alkyl groups and -C (=O) (C 1-6 Alkyl), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups is optionally further substituted by one or more substituents independently selected from: halogen and C 1-6 alkyl;

[0210] In the preferred embodiment, R 1b Selected from

[0211] In the most preferred embodiment, R 1b Selected from

[0212] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein R 1c Selected from H, halogens, -OH, -NH2, CN, C 1-6 Alkyl, C3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, 5-14 membered heteroaryl groups, -O(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl groups), -S(=O)2NH2, -NH(C 1-6 Alkyl), -C(=O)NH2, -NH-S(=O)2-(C 1-6 Alkyl groups), -NH-S(=O)2-NH2 and -NH-S(=O)(=NH)(C 1-6 Alkyl); the above alkyl, cycloalkyl, heterocyclic and heteroaryl groups are each optionally substituted by one or more substituents independently selected from the following: -OH, -NH2, halogen, C 1-6 Alkyl and -OC 1-6 alkyl.

[0213] In the preferred embodiment, R 1c Selected from H, F, CN, -CH3, -NH2, -NHCH3, -OH、 -C(=O)NH2, -NHS(=O)2CH3, -NHS(=O)2NH2, -NHS(=O)(=NH)CH3, -S(=O)2CH3 and -S(=O)2NH2.

[0214] In a more preferred embodiment, R 1c Selected from H, F, CN, -NH2, -OH, -C(=O)NH2 and -NHS(=O)2CH3.

[0215] In the most preferred embodiment, R 1c Selected from H, -NH2, and -OH.

[0216] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein R 1c Selected from H, -OH, -NH2, C 1-6 Alkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, -O(C) 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl groups), -S(=O)2NH2, -NH(C 1-6 Alkyl), -C(=O)NH2, -NH-S(=O)2-(C 1-6 Alkyl groups), -NH-S(=O)2-NH2 and -NH-S(=O)(=NH)(C 1-6Alkyl); the alkyl, cycloalkyl and heterocyclic groups mentioned above are each optionally substituted by one or more substituents independently selected from the following: -OH, -NH2, halogen and C. 1-6 alkyl.

[0217] In the preferred embodiment, R 1c Selected from H, -CH3, -NH2, -NHCH3, -OH、 -C(=O)NH2, -NHS(=O)2CH3, -NHS(=O)2NH2, -NHS(=O)(=NH)CH3, -S(=O)2CH3 and -S(=O)2NH2.

[0218] In a more preferred embodiment, R 1c Selected from H, -NH2, -OH, -C(=O)NH2 and -NHS(=O)2CH3.

[0219] In the most preferred embodiment, R 1c Selected from -NH2 and -OH.

[0220] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein R 1d Selected from H, halogens, and -CN.

[0221] In the preferred embodiment, R 1d Selected from H, F, and -CN.

[0222] In a more preferred embodiment, R 1d For H.

[0223] In some embodiments, this application provides a compound of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein

[0224] R 1b Selected from C 2-6 Alkenyl; preferably, R 1b C substituted with cyano 2-6 alkenyl; and / or

[0225] R 1c Selected from H, -NH2, -NH(C) 1-6 Alkyl groups and -OH.

[0226] In a preferred embodiment, the compound of formula (I) above has the structure of formula (II), (III), (IV), (V), (VI) or (VII):

[0227] in:

[0228] R 1b’ R 1b” R 1b”’ and R 1b”” Each time it appears, it is independently selected from H, halogen, -CN, -OH, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic, 5-14 membered heteroaryl, -O-(C 1-6 Alkyl groups and -C (=O) (C 1-6 Alkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclic, and heteroaryl groups are each optionally further substituted by one or more substituents independently selected from: halogen, -CN, -OH, -NH2, -NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, C optionally substituted with halogen or CN 3-6 Cycloalkyl group, phenyl group, 5-6 membered heterocyclic group, optionally covered by C 1-6 Alkyl-substituted 5-6-membered heteroaryl groups, -OC 1-6 Alkyl and -O-(halogenated C) 1-6 alkyl);

[0229] p is an integer selected from 0, 1 or 2, preferably 1;

[0230] q is an integer selected from 1, 2, 3, 4, or 5, preferably 1 or 2; and

[0231] The remaining groups are as defined in this document.

[0232] In a preferred embodiment, the compound of formula (I) above has the structure of formula (V) or (VI), wherein R 1b’ R 1b” and R 1b”’ Each occurrence is independently selected from H, halogen, -CN, C. 1-6 Alkyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, phenyl groups, 3-10 membered heterocyclic groups, 5-14 membered heteroaryl groups, and -O-(C 1-6Alkyl), wherein the alkyl, alkynyl, cycloalkyl, phenyl, heterocyclic, and heteroaryl groups are each optionally further substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NH(C 1-6 Alkyl), C 1-6 Alkyl, C 3-6 Cyclic hydrocarbon groups, -OC 1-6 Alkyl and -O-(halogenated C) 1-6 alkyl);

[0233] R 1b”” Each time it appears, it is independently selected from halogen, -CN, -OH, C. 1-6 Alkyl, C 2-6 alkynyl and -O-(C 1-6 Alkyl group), wherein the alkyl group and the alkynyl group are each optionally further substituted by one or more substituents independently selected from the following: -OH, -NH2, -NH(C 1-6 Alkyl), C 1-6 Alkyl groups, C groups optionally substituted with halogens or CN 3-6 Cycloalkyl group, phenyl group, 5-6 membered heterocyclic group, optionally covered by C 1-6 Alkyl-substituted 5-6-membered heteroaryl groups, -OC 1-6 Alkyl and -O-(halogenated C) 1-6 alkyl);

[0234] p is 1;

[0235] q is 1 or 2; and

[0236] The remaining groups are as defined in this document.

[0237] This invention covers technical solutions / compounds obtained by arbitrarily combining any two or more of the above embodiments.

[0238] In a preferred embodiment, this disclosure provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein the compound is selected from:

[0239] Pharmaceutical compositions and treatment methods

[0240] In some embodiments, the present invention provides pharmaceutical compositions comprising a preventive or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug, and one or more pharmaceutically acceptable carriers, wherein the pharmaceutical composition is preferably a solid dosage form, a liquid dosage form, or a transdermal dosage form.

[0241] In some embodiments, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs, or pharmaceutical compositions of the present invention, in the preparation of a medicament for the prevention or treatment of DHX9-mediated diseases or conditions.

[0242] In some embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs of the present invention, or pharmaceutical compositions of the present invention, for the prevention or treatment of DHX9-mediated diseases or conditions.

[0243] In some embodiments, the present invention provides a method for preventing or treating DHX9-mediated diseases or conditions, the method comprising administering to an individual in need an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug, or a pharmaceutical composition of the present invention.

[0244] In some implementations, the DHX9-mediated disease or condition is cancer, viral infection, or autoimmune disease.

[0245] In a preferred embodiment, the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, breast cancer, brain cancer, skin cancer, lung cancer, leukemia, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft tissue cancer, kidney cancer, and liver cancer.

[0246] In a preferred embodiment, the cancer is a microsatellite instability (MSI) cancer.

[0247] In a preferred embodiment, the cancer has a mutation or defect in DNA mismatch repair (MMR), and / or a mutation or defect in RNA splicing and kinetochore complex.

[0248] In a preferred embodiment, the cancer is a BRAC1 / 2 mutated cancer.

[0249] In this invention, "pharmaceutically acceptable carrier" refers to a diluent, excipient, vehicle, or medium that is administered co-administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0250] Unless otherwise stated, as used herein, the term “treatment” means to reverse, alleviate, or inhibit the progression of a disease or condition or one or more symptoms of such a disease or condition to which such term is applied, or to prevent such a disease or condition or one or more symptoms of such a disease or condition.

[0251] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0252] In another embodiment, the pharmaceutical composition of the present invention may also contain one or more additional therapeutic or preventative agents.

[0253] Example

[0254] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.

[0255] The abbreviations used in this invention have the following meanings:

[0256] Example 1. Synthesis of C10

[0257] 1) Step One

[0258] Under nitrogen protection, 2-chloro-5-hydroxypyrimidine (120 mg, 0.91 mmol), 1-methyl-3-hydroxyazacyclobutane (120 mg, 1.37 mmol), and triphenylphosphine (723 mg, 2.75 mmol) were dissolved in tetrahydrofuran (10 mL). DEAD (315 mg, 2.75 mmol) was slowly added dropwise to the reaction mixture at 0 °C. The reaction mixture was then stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (developing solvent: dichloromethane: methanol = 20:1) to give a yellow oily substance C10-1 (130 mg, 71%). LCMS m / z = 200.1 [M+H] + .

[0259] 2) Step Two

[0260] Under nitrogen protection, C10-1 (100 mg, 0.65 mmol), C10-2 (220 mg, 0.78 mmol, prepared according to the synthesis method in patent application No. WO2009 / 14620), Pd(dppf)Cl2 (48 mg, 0.06 mmol), and potassium carbonate (270 mg, 1.95 mmol) were dissolved in 1,4-dioxane (6 mL) and water (1.5 mL). The reaction solution was replaced with N2 three times and stirred at 105 °C for 3.5 hours. After the reaction was complete, the reaction solution was diluted with water (90 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 15:1) to obtain C10-3 (150 mg, 72%), which was a brown solid. LCMS m / z = 320.1 [M+H] + .

[0261] 3) Step Three

[0262] C10-3 (50 mg, 0.15 mmol) was dissolved in tetrahydrofuran / water (2 mL / 2 mL), and lithium hydroxide monohydrate (13 mg, 0.31 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the pH of the reaction mixture was adjusted to 3–4 with 1 N hydrochloric acid solution, and the solution was concentrated under reduced pressure to obtain C10-4. LCMS m / z = 306.1 [M+H] + .

[0263] 4) Step Four

[0264] Cuprous chloride (53.56 g, 541 mmol, 2.5 eq) was dissolved in acetonitrile (500 mL) and cooled to 0 °C. Tert-butyl nitrite (55.78 g, 541 mmol, 2.5 eq) was slowly added, and the reaction mixture was stirred at 0 °C for 10 minutes. Then, 2-methyl-3-nitro-5-bromoaniline (50 g, 216.4 mmol, 1.0 eq) was slowly added. The reaction mixture was slowly heated to room temperature and stirred for 3 hours. After the reaction was complete, the reaction mixture was quenched with water (500 mL), filtered through diatomaceous earth, concentrated under reduced pressure, diluted with water (3 L), and extracted with ethyl acetate (3 × 1 L). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give C10-5 (32 g, 59%), which was a white solid.

[0265] 5) Step Five

[0266] Under nitrogen protection, C10-5 (64 g, 255.51 mmol) was dissolved in acetonitrile (640 mL), and NBS (50.02 g, 281.1 mmol) and AIBN (4.2 g, 25.55 mmol) were added. The reaction mixture was stirred at 85 °C for 3 hours. After the reaction was complete, the reaction mixture was diluted with water (5 L) and extracted with ethyl acetate (3 × 1.5 L). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain C10-6 (98 g, crude product, purity 66%), which was a yellow solid and used directly in the next reaction.

[0267] 6) Step Six

[0268] C10-6 (95 g, 66% purity, 288.43 mmol) was dissolved in acetonitrile (1 L), and N-methylmorpholine N-oxide (67.6 g, 576.86 mmol) was added. The reaction mixture was stirred at room temperature for 6 h. After the reaction was complete, the reaction mixture was diluted with water (5 L) and extracted with ethyl acetate (3 × 1.5 L). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to obtain C10-7 (39.25 g, 75%), which was a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.23(s,1H),8.39(d,J=1.8Hz,1H),8.37(d,J=1.7Hz,1H).

[0269] 7) Step Seven

[0270] (Triphenylphosphine)acetonitrile (50 g, 165.83 mmol) was dissolved in toluene (1 L). The reaction solution was cooled to 0 °C, and NaHMDS (2 M in THF, 99.5 mL, 198.99 mmol) was slowly added. After stirring at room temperature for 1 hour, the reaction solution was cooled again to 0 °C, and iodomethane (28.06 g, 198.99 mmol) was slowly added. The reaction solution was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered, and the filter cake was washed with toluene (200 mL). The filter cake was then vacuum dried to obtain C10-8 (59 g), which was a yellow crude solid and used directly in the next step.

[0271] 8) Step Eight

[0272] C10-8 (23.82 g, 75.63 mmol) and C10-7 (10 g, 37.81 mmol) were dissolved in toluene (200 mL), and the reaction mixture was stirred at 60 °C for 3 hours. After the reaction was complete, the reaction mixture was diluted with water (1 L) and extracted with ethyl acetate (3 × 300 mL). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give a yellow solid C10-9 (6.29 g, 55.16%).

[0273] 9) Step Nine

[0274] C10-9 (6.29 g, 20.86 mmol) was dissolved in ethanol (90 mL), and zinc powder (5.0 g, 166.89 mmol) and acetic acid (10.0 g, 166.89 mmol) were added. The reaction mixture was stirred overnight at 85 °C. After the reaction was complete, the pH of the reaction mixture was adjusted to 8 with saturated sodium bicarbonate solution. The reaction mixture was diluted with water (500 mL) and then extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to give a yellow solid C10-10 (4.0 g, 71%). LCMS m / z = 271.0 [M+H] + .

[0275] 10) Step Ten

[0276] C10-10 (4.0 g, 17.06 mmol), DMAP (416.84 mg, 3.412 mmol), and triethylamine (5.17 g, 51.18 mmol) were dissolved in dichloromethane (80 mL), and di-tert-butyl dicarbonate (11.17 g, 51.18 mmol) was slowly added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to give a yellow solid C10-11 (6.35 g, 85.76%).

[0277] 11) Step Eleven

[0278] C10-11 (6.35 g, 13.46 mmol) and benzophenone imine (3.66 g, 20.19 mmol) were dissolved in dioxane (120 mL), and Pd2(dba)3 (1.23 g, 1.346 mmol), XantPhos (1.56 g, 2.692 mmol), and cesium carbonate (13.16 g, 40.38 mmol) were added. The reaction mixture was replaced three times with N2 and stirred at 95 °C for 4 hours. After the reaction was complete, the reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain C10-12 (12 g, crude product), which was used directly in the next step. LCMS m / z = 572.2 [M+H] + .

[0279] 12) Step Twelve

[0280] C10-12 (12 g crude, 25.42 mmol) was dissolved in methanol (120 mL). Potassium acetate (6.24 g, 63.55 mmol) and hydroxylamine hydrochloride (3.6 g, 50.85 mmol) were added to the reaction solution. The reaction solution was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to give a yellow solid C10-13 (3.5 g, 63.75%). LCMS m / z = 430.2 [M + Na] + ; 1 H NMR (400MHz, DMSO-d6) δ6.83(d,J=1.6Hz,1H),6.67(d,J=2.1Hz,1H),6.38(d,J=2.2Hz,1H),5.82(s,2H),1.73(d,J=1.5Hz,3H),1.41(s,18H).

[0281] 13) Step Thirteen

[0282] C10-4 (39 mg, 0.12 mmol, 1.3 eq), C10-13 (40 mg, 0.09 mmol, 1.0 eq), and N-methylimidazole (80 mg, 0.98 mmol, 10.0 eq) were dissolved in acetonitrile (2 mL). TCFH (83 mg, 0.27 mmol, 3.0 eq) was added to the reaction solution. The reaction solution was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative thin-layer chromatography (developing solvent: dichloromethane: methanol = 20:1) to obtain C10-14 (39 mg, 57%) as a yellow solid. LCMS m / z = 695.3 [M+H] + .

[0283] 14) Step Fourteen

[0284] C10-14 (39 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL), and hydrochloric acid-dioxane solution (4 M, 1 mL) was slowly added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the pH of the reaction mixture was adjusted to 9 with saturated sodium bicarbonate solution, and extracted with dichloromethane (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative thin-layer chromatography (developing solvent: dichloromethane: methanol = 10:1) to give compound C10 (7.7 mg, 28%). LCMS m / z = 495.2 [M + H] + ; 1H NMR (400MHz, DMSO-d6) δ10.30(s,1H),8.60(s,1H),8.55(s,2H),7.21(d,J=1.9Hz,1H),7.13(d,J=1.9Hz,1H),7.06(d,J=1.7H z,1H),5.49(s,2H),5.04–4.96(m,1H),3.80–3.74(m,2H),3.08–3.01(m,2H),2.81(s,3H),2.31(s,3H),1.78(d,J=1.5Hz,3H).

[0285] Example 2. Synthesis of C2

[0286] 1) Step One

[0287] 5-Bromo-2-chloro-3-fluoropyridine (300 mg, 1.43 mmol) and 3,3-difluoroazacyclobutane hydrochloride (221.6 mg, 1.71 mmol) were dissolved in dioxane (6 mL). Pd2(dba)3 (130.85 mg, 0.143 mmol), XantPhos (165.5 mg, 0.286 mmol), and cesium carbonate (1.4 g, 4.29 mmol) were added to the reaction solution. The reaction solution was purged three times with N2 and stirred overnight at 100 °C. After the reaction was complete, the reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1) to give a white solid C2-1 (100 mg, 31.5%). LCMS m / z = 223.1 [M+H] + .

[0288] 2) Step Two

[0289] C2-1 (100 mg, 0.45 mmol), C10-2 (152.1 mg, 0.54 mmol), Pd(dppf)Cl2 (32.93 mg, 0.040 mmol), and potassium carbonate (186.6 mg, 1.35 mmol) were dissolved in dioxane (4 mL) and water (1 mL). The reaction mixture was purged three times with nitrogen and stirred at 105 °C for 3 hours. After the reaction was complete, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1) to give a yellow solid C2-2 (134 mg, 87%). LCMS m / z = 343.1 [M+H]+ .

[0290] 3) Step Three

[0291] C2-2 (134 mg, 0.39 mmol) was dissolved in methanol / tetrahydrofuran / water (1 mL / 1 mL / 1 mL), and lithium hydroxide monohydrate (41.12 mg, 0.98 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the pH of the reaction mixture was adjusted to 3 with 1 N hydrochloric acid solution, diluted with water (30 mL), and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain C2-3 (110 mg, 86%). LCMS m / z = 329.1 [M+H] + .

[0292] 4) Step Four

[0293] Following the synthetic method for compound C10, compound C2 was synthesized by replacing C10-4 with C2-3. LCMS m / z = 518.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),8.14(d,J=1.5Hz,1H),7.95–7.91(m,1H),7.26(d,J=1.9Hz,1H),7.20(d,J=1.9Hz,1 H),7.14(dd,J=12.3,2.3Hz,1H),7.08(d,J=1.6Hz,1H),4.46(t,J=12.3Hz,4H),2.49–2.47(m,3H),1.77(d,J=1.5Hz,3H).

[0294] Example 3. Synthesis of C3

[0295] 1) Step One

[0296] 5-Bromopyrimidine (300 mg, 2.5 mmol), 3,3-difluoropyrrolidine hydrochloride (300 mg, 2.09 mmol), Pd2(dba)3 (191 mg, 0.20 mmol), BINAP (260 mg, 0.41 mmol), and sodium tert-butoxide (602 mg, 6.27 mmol) were dissolved in toluene (10 mL). The reaction solution was replaced three times with N2 and stirred overnight at 110 °C. After the reaction was complete, the reaction solution was concentrated. The crude product was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1) to give a yellow solid C3-1 (630 mg, 50% purity, 81%). LCMS: m / z = 186.1 [M+H] + .

[0297] 2) Step Two

[0298] C3-1 (630 mg, 50% purity, 1.70 mmol) was dissolved in acetonitrile (15 mL). NBS (302 mg, 1.70 mmol) was added in portions to the reaction solution at 0 °C. After stirring at room temperature for 1 hour, the reaction solution was cooled back to 0 °C, and NBS (302 mg, 1.70 mmol) was added to the reaction solution. The reaction solution was then stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was diluted with water (100 mL) and extracted with dichloromethane (3 × 40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:6) to give a yellow oily substance C3-2 (100 mg, 22%). LCMS m / z = 264.0 / 266.0 [M+H] + .

[0299] 3) Step Three

[0300] C3-2 (160 mg, 0.60 mmol), C10-2 (256 mg, 0.90 mmol), Pd(dppf)Cl2 (49 mg, 0.06 mmol), and potassium carbonate (248 mg, 1.80 mmol) were dissolved in 1,4-dioxane / water (10 mL, v / v 4 / 1). The reaction mixture was replaced three times with N2 and stirred at 90 °C for 1 hour. After the reaction was complete, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:4) to give a yellow solid C3-3 (100 mg, 49%). LCMS m / z = 340.1 [M+H] + .

[0301] 4) Step Four

[0302] C3-3 (40 mg, 0.12 mmol) was dissolved in tetrahydrofuran and methanol (1 mL / 1 mL), and lithium hydroxide monohydrate (9 mg, 0.24 mmol) was dissolved in water (1 mL) and added dropwise to the reaction solution. The reaction solution was stirred overnight at room temperature. After the reaction was complete, the pH of the reaction solution was adjusted to 2–3 with 1 N hydrochloric acid solution, and extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain C3-4 (40 mg, crude product), which was used directly in the next step. LCMS m / z = 326.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ8.30(s,2H),8.10(s,1H),3.84(t,J=13.2Hz,2H),3.62(t,J=7.3Hz,2H),2.78(s,3H),2.61–2.53(m,2H).

[0303] 5) Step Five

[0304] Following the synthetic method for compound C10, compound C3 was synthesized by replacing C10-4 with C3-4. LCMS m / z = 515.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),8.57(s,1H),8.31(s,2H),7.22(d,J=1.8Hz,1H),7.13(d,J=1.8Hz,1H),7.06–7.05( m,1H),5.48(s,2H),3.87(t,J=13.0Hz,2H),3.64(t,J=7.2Hz,2H),2.81(s,3H),2.63–2.56(m,2H),1.78(d,J=1.4Hz,3H).

[0305] Example 4. Synthesis of C5

[0306] Following the synthetic method for compound C10, compound C5 was synthesized by replacing C10-1 with 2-chloro-4-methoxypyrimidine. LCMS: m / z = 440.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),8.65(s,2H),8.61(s,1H),7.21(d,J=1.9Hz,1H),7.14(d,J =1.9Hz,1H),7.06(d,J=1.8Hz,1H),5.48(s,2H),3.97(s,3H),2.82(s,3H),1.78(d,J=1.6Hz,3H).

[0307] Example 5. Synthesis of C6

[0308] 1) Step One

[0309] Under nitrogen protection, 4-chloro-5-methoxypyrimidine (400 mg, 2.77 mmol), C10-2 (624.59 mg, 2.21 mmol), Pd(dppf)Cl2 (225.96 mg, 0.28 mmol), and potassium carbonate (1.15 g, 8.3 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL). The reaction mixture was purged three times with N2 and stirred at 105 °C for 3.5 hours. After the reaction was complete, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 40 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to give C6-1 (390 mg, 53%), which was a white solid. LCMS: m / z = 265.00 [M+H] + .

[0310] 2) Step Two

[0311] C6-1 (250 mg, 0.95 mmol) and sodium ethanethiol (651.76 mg, 7.557 mmol) were dissolved in DMF (10 mL), and the reaction mixture was heated to 100 °C and stirred overnight. After the reaction was complete, the reaction mixture was added dropwise to water (100 mL), and stirred for 30 minutes. The resulting solid was filtered and dried to give C6-2 (150 mg, 67%), a white solid. LCMS: m / z = 236.95 [M+H] + .

[0312] 3) Step Three

[0313] C6-2 (150 mg, 0.63 mmol) was dissolved in methanol (5 mL), and thionyl chloride (302.15 mg, 2.54 mmol) was slowly added. The reaction mixture was heated to 50 °C and stirred for 8 hours. After the reaction was complete, the reaction mixture was concentrated to give C6-3 (138 mg g, 87.52%) as a white solid. LCMS m / z = 250.95 [M+H] + .

[0314] 4) Step Four

[0315] Under nitrogen protection, C6-3 (118 mg, 0.47 mmol), triphenylphosphine (309.17 mg, 1.18 mmol), and C6-4 (120.34 mg, 0.71 mmol) were dissolved in tetrahydrofuran (10 mL). The reaction solution was cooled to 0 °C, and DEAD (205.28 mg, 1.18 mmol) was slowly added dropwise. The reaction solution was then stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (3 × 40 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to give C6-5 (96 mg, 50.76%), which was a white solid. LCMS: m / z = 403.20 [M+H] + .

[0316] 5) Step Five

[0317] C6-5 (96 mg, 0.24 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide monohydrate (20.04 mg, 0.48 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the pH of the reaction mixture was adjusted to approximately 4 with 1 N hydrochloric acid solution, and then extracted with ethyl acetate (3 × 30 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give C6-6 (90 mg, 97%), which was a yellow solid. LCMS m / z = 389.10 [M+H] + .

[0318] 6) Step Six

[0319] Following the synthetic method for compound C10, compound C6 was synthesized by replacing C10-4 with C6-6. LCMS: m / z = 578.10 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.09(s,1H),8.95(s,2H),8.14(s,1H),7.23–6.98(m,5H),6.10–5.99(m,1H),5 .48(s,2H),3.01–2.80(m,2H),2.72–2.62(m,1H),2.44(s,3H),2.23–2.13(m,1H),1.78(d,J=1.5Hz,3H).

[0320] Example 6. Synthesis of C7 and C8

[0321] 1) Step One

[0322] C7-1 (150 mg, 1.00 mmol), C10-2 (338 mg, 0.90 mmol), Pd(dppf)Cl2 (81 mg, 0.10 mmol), and potassium carbonate (414 mg, 3.00 mmol) were dissolved in 1,4-dioxane / water (10 mL, 4 / 1 v / v). The reaction solution was replaced with N2 three times and stirred at 105 °C for 3 hours. After the reaction was complete, the reaction solution was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:6) to give white solid C7-2 (180 mg, 66%). LCMS m / z = 269.0 [M+H] + .

[0323] 2) Step Two

[0324] C7-2 (137 mg, 0.51 mmol), C6-4 (95 mg, 0.56 mmol), palladium acetate (11 mg, 0.05 mmol), BINAP (63 mg, 0.10 mmol), and cesium carbonate (332 mg, 1.02 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction solution was replaced three times with N2 and stirred overnight at 90 °C. After the reaction was complete, the reaction solution was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10) to give a colorless oily substance C7-3 (170 mg, 82%). LCMS m / z = 403.1 [M+H] + .

[0325] 3) Step Three

[0326] C7-3 (155 mg, 0.38 mmol) was dissolved in tetrahydrofuran and methanol (5 mL / 5 mL), and lithium hydroxide monohydrate (32.3 mg, 0.77 mmol) was dissolved in water (5 mL). The resulting solution was then added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, the pH of the reaction mixture was adjusted to 2–3 with 1 N hydrochloric acid solution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid C7-4 (160 mg, 99%). LCMS m / z = 389.1 [M+H] + .

[0327] 4) Step Four

[0328] Following the synthetic method of compound C10, C7-4 was used instead of C10-4 to synthesize C7 and the deBoc reaction byproduct C8.

[0329] C7:LCMS m / z=578.2[M+H] +;H NMR (400MHz, DMSO-d6) δ10.09(s,1H),8.40(d,J=2.7Hz,1H),8.34(d,J=2.7Hz ,1H),8.15(s,1H),7.25(dd,J=8.3,2.2Hz,1H),7.20–7.14(m,2H),7.06(d,J= 1.8Hz,2H),6.57–6.53(m,1H),5.48(s,2H),3.04–2.97(m,1H),2.94–2.87(m, 1H), 2.75–2.69 (m, 1H), 2.42 (s, 3H), 2.22–2.14 (m, 1H), 1.78 (d, J = 1.5Hz, 3H).

[0330] C8:LCMS m / z=426.0[M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.21(s,1H),8.45(s,1H),7.45(s,2H),7.20(d,J=2.0Hz,1 H),7.12(d,J=1.8Hz,1H),7.06(d,J=1.6Hz,1H),2.57(s,3H),1.78(d,J=1.6Hz,3H).

[0331] Example 7. Synthesis of C9

[0332] 1) Step One

[0333] Triethylphosphonoacetate (1.32 g, 5.88 mmol) was dissolved in tetrahydrofuran (20 mL) under nitrogen protection and cooled to 0 °C. Sodium hydride (60% content, 235.29 mg, 5.88 mmol) was slowly added to the reaction solution, and the mixture was stirred for 20 minutes. 3-Bromo-5-fluoropyridine-4-carboxaldehyde (800 mg, 3.92 mmol) was slowly added at the same temperature, and the reaction solution was heated to room temperature and stirred for 2 hours. After the reaction was complete, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give a colorless oily liquid C9-1 (1.1 g, 100%). LCMS m / z = 273.85 [M+H] + .

[0334] 2) Step Two

[0335] Benzenesulfonyl hydrazine (4.08 g, 23.71 mmol) and sodium acetate trihydrate (6.45 g, 47.43 mmol) were dissolved in ethylene glycol dimethyl ether (20 mL) and water (20 mL). C9-1 (1.3 g, 4.74 mmol) was slowly added, and the reaction mixture was stirred at 90 °C for 0.5 hours. After the reaction was complete, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give a yellow oily liquid C9-2 (800 mg, 61%). LCMS m / z = 275.85 [M+H] + .

[0336] 3) Step Three

[0337] C9-2 (500 mg, 1.81 mmol) was dissolved in tetrahydrofuran (20 mL) under nitrogen protection. The reaction solution was cooled to below -70 °C, and n-butyllithium (2.5 M in hexane, 1.09 mL) was added dropwise. The reaction solution was stirred at -70 °C for 2 hours. After the reaction was complete, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3 × 40 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give white solid C9-3 (188 mg, 68%). LCMS m / z = 151.95 [M+H] + .

[0338] 4) Step Four

[0339] C9-3 (300 mg, 1.98 mmol) was dissolved in methanol (5 mL). The reaction solution was cooled to 0 °C, and sodium borohydride (75.09 mg, 1.98 mmol) was slowly added. The reaction solution was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction solution was diluted with water (50 mL) and then extracted with ethyl acetate (3 × 20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give a white solid C9-4 (303 mg, 99.9%). LCMS: m / z = 154.00 [M+H] + .

[0340] 5) Step Five

[0341] C9-4 (280 mg, 1.83 mmol), triphenylphosphine (1.2 g, 4.57 mmol), and 2-chloro-3-hydroxy-5-fluoropyridine (269.71 mg, 1.83 mmol) were dissolved in tetrahydrofuran (20 mL) under nitrogen protection. The reaction solution was cooled to 0 °C, and DEAD (795.93 mg, 4.57 mmol) was slowly added. The reaction solution was stirred at 0 °C for 10 minutes, then heated to room temperature and stirred for 3 hours. After the reaction was complete, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3 × 40 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give green solid C9-5 (485 mg, 94%). LCMS: m / z = 283.10 [M+H] + .

[0342] 6) Step Six

[0343] Following the synthetic method for compound C10, compound C9 was synthesized by replacing C10-1 with C9-5. LCMS: m / z = 578.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.00 (s, 1H), 8.43 (s, 1H), 8.40 (d, J = 2.1Hz, 1H), 8. 36(d,J=2.3Hz,1H),7.99(dd,J=10.7,2.4Hz,1H),7.93(s,1H),7.16(d,J=1. 9Hz,1H),7.10–7.02(m,2H),6.13–6.06(m,1H),5.48(s,2H),3.07–2.93(m,2 H),2.70–2.62(m,1H),2.28(s,3H),2.22–2.13(m,1H),1.78(d,J=1.5Hz,3H).

[0344] Example 8. Synthesis of C14

[0345] 1) Step One

[0346] Under N2 protection, 3-bromo-5-methoxypyridine (616 mg, 3.28 mmol), 3,3-difluoroazacyclobutane hydrochloride (510 mg, 3.93 mmol), Xantphos (376 mg, 0.65 mmol), cesium carbonate (3.2 g, 9.82 mmol), and Pd2(dba)3 (300 mg, 0.32 mmol) were dissolved in dioxane (25 mL), substituted with N2 three times, and stirred overnight at 110 °C. After the reaction was complete, the reaction solution was diluted with water (150 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give a brown oily compound C14-1 (350 mg, 53%).

[0347] 2) Step Two

[0348] C14-1 (300 mg, 1.49 mmol) was dissolved in MeCN (15 mL) and cooled to 0 °C. NBS solution (NBS (213 mg, 1.19 mmol) dissolved in MeCN (5 mL)) was added dropwise to the solution at 0 °C. The reaction mixture was stirred at 0 °C for 40 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to give a yellow oily compound C14-2 (100 mg, 23%). LCMS ESI m / z [M+H] + :279.0 / 281.0.

[0349] 3) Step Three

[0350] Under N2 protection, C14-2 (100 mg, 0.35 mmol), C10-2 (122 mg, 0.43 mmol), potassium carbonate (149 mg, 1.07 mmol), and Pd(dppf)Cl2 (30 mg, 0.03 mmol) were dissolved in dioxane (4 mL) and H2O (1 mL), and the mixture was substituted with N2 three times. The mixture was stirred at 105 °C for 3.5 h. After the reaction was complete, the reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give a brown solid compound C14-4 (80 mg, 63%). LCMS ESI m / z [M+H] + 355.1.

[0351] 4) Step Four

[0352] C14-4 (60 mg, 0.16 mmol) was dissolved in THF / MeOH / H2O (1 mL / 1 mL / 1 mL), and LiOH H2O (15 mg, 0.33 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the pH of the reaction mixture was adjusted to 3–4 with 1 N HCl solution, and extracted with DCM (3 × 20 mL). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a white solid compound C14-5 (50 mg, 87%). LCMS ESI m / z [M+H] + 341.0.

[0353] 5) Step Five

[0354] 2-Chloro-4-nitrotoluene (3.0 g, 17.4 mmol) was dissolved in sulfuric acid (30 mL), and NIS (4.7 g, 20.9 mmol) was slowly added in portions. The reaction mixture was stirred at 60 °C for 20 minutes. After the reaction was complete, the reaction mixture was slowly poured into ice water with stirring, then diluted with water (150 mL), and extracted with ethyl acetate (3 × 60 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give a yellow solid C14-6 (4.7 g, 90%).

[0355] 6) Step Six

[0356] Under nitrogen protection, C14-6 (1.0 g, 3.36 mmol), potassium hydroxide (566 mg, 10.0 mmol), t-Bu-Xphos (285 mg, 0.67 mmol), and Pd2(dba)3 (615 mg, 0.67 mmol) were dissolved in dioxane (10 mL) and water (2 mL). The reaction mixture was purged three times with N2 and stirred overnight at 80 °C. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 60 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give a yellow solid C14-7 (500 mg, 40%). 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),7.72(d,J=2.3Hz,1H),7.59(d,J=2.3Hz,1H),2.26(s,3H).

[0357] 7) Step Seven

[0358] Under nitrogen protection, C14-7 (250 mg, 1.33 mmol) and N,N-diisopropylethylamine (516 mg, 3.99 mmol) were dissolved in dichloromethane (6 mL) and cooled to 0 °C. Bromomethyl methyl ether (250 mg, 1.99 mmol) was added dropwise to the solution at 0 °C. The reaction mixture was stirred at room temperature for 2 hours, diluted with water (60 mL), and extracted with dichloromethane (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give a white solid C14-8 (260 mg, 84%).

[0359] 8) Step Eight

[0360] Under nitrogen protection, C14-8 (170 mg, 0.73 mmol) and AIBN (12 mg, 0.07 mmol) were dissolved in acetonitrile (5 mL), and NBS (261 mg, 1.46 mmol) was added to the solution. The reaction mixture was stirred at 85 °C for 3 hours. After the reaction was complete, the filtrate was diluted with water (60 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oily substance, C14-9 (270 mg, crude product), which was used directly in the next reaction.

[0361] 9) Step Nine

[0362] C14-9 (270 mg, 0.86 mmol) was dissolved in acetonitrile (6 mL), and then N-methylmorpholine N-oxide (407 mg, 3.47 mmol) was added. The reaction mixture was stirred at room temperature for 6 hours. After the reaction was complete, the filtrate was diluted with water (60 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to give a yellow oily substance C14-10 (100 mg, 55%). 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.02–7.98(m,2H),5.49(s,2H),3.45(s,3H).

[0363] 10) Step Ten

[0364] C14-10 (80 mg, 0.32 mmol) and C10-8 (205 mg, 0.65 mmol) were dissolved in toluene (3 mL), and the reaction mixture was stirred at 60 °C for 1.5 hours. After the reaction was complete, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give a yellow oily substance C14-11 (70 mg, 68%, double bond cis:trans ratio = 2:3).

[0365] 11) Step Eleven

[0366] C14-11 (70 mg, 0.27 mmol) was dissolved in ethanol (4 mL), and acetic acid (133 mg, 2.21 mmol) and zinc powder (65 mg, 2.21 mmol) were added. The reaction mixture was stirred at 70 °C for 3 hours. After the reaction was complete, the reaction mixture was filtered, and the pH of the filtrate was adjusted to approximately 9 with saturated sodium bicarbonate aqueous solution. The filtrate was then extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give a yellow oily substance C14-12 (50 mg, 80%). LCMS m / z = 253.1 [M+H] + .

[0367] 12) Step Twelve

[0368] C14-12 (25 mg, 0.09 mmol), C14-5 (40 mg, 0.11 mmol), methylimidazole (49 mg, 0.59 mmol), and TCFH (86 mg, 0.29 mmol) were dissolved in anhydrous acetonitrile (2 mL), and the reaction mixture was stirred at room temperature for 1 hour. The solution was diluted with water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine and concentrated by drying over anhydrous sodium sulfate. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 40:1) to give C14-13 (80 mg, 71%), which was a white solid. LCMS m / z = 575.1 [M+H] + .

[0369] 13) Step Thirteen

[0370] C14-13 (70 mg, 0.12 mmol) was dissolved in dioxane (3 mL) and cooled to 0 °C. A hydrochloric acid-dioxane solution (4 M, 1.5 mL) was added dropwise to the solution at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. The pH of the reaction mixture was adjusted to 9 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give compound C14 (21.1 mg, 33%, trans). LCMS m / z = 531.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.49(s,1H),10.27(s,1H),8.04(s,1H),7.62(s,1H),7.50(s,1H),7.43 (s,1H),7.11(s,1H),6.76(s,1H),4.43(t,J=12.1Hz,4H),3.84(s,3H),2.37(s,3H),1.79(s,3H).

[0371] Example 9. Synthesis of C20

[0372] 1) Step One

[0373] C20-1 (700 mg, 4.06 mmol) was dissolved in dioxane (15 mL), and selenium dioxide (585 mg, 5.27 mmol) was slowly added. The reaction mixture was stirred overnight at 110 °C under nitrogen protection. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, the filtrate was diluted with water (50 mL), and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 13:7) to give a yellow solid C20-2 (530 mg, 70%). LCMS m / z = 187.0 [M+H] + .

[0374] 2) Step Two

[0375] C20-2 (630 mg, 3.38 mmol), C10-8 (2.1 g, 6.75 mmol), and toluene (20 mL) were added to a single-necked flask. The reaction mixture was stirred at 60 °C for 3 hours. After the reaction was complete, the reaction mixture was diluted with water (120 mL) and extracted with ethyl acetate (3 × 60 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to give a yellow solid C20-3 (240 mg, 31.7%). LCMS m / z = 222.0 [MH] - .

[0376] 3) Step Three

[0377] C20-3 (240 mg, 1.07 mmol) was dissolved in ethanol (10 mL), and acetic acid (516 mg, 8.58 mmol) and zinc powder (561 mg, 8.58 mmol) were added. The reaction mixture was stirred at 70 °C for 3 hours. The pH of the reaction mixture was adjusted to approximately 7.5 with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 13:7) to give a white solid C20-4 (125 mg, 64.8%). LCMS m / z = 194.0 [M+H] + .

[0378] 4) Step Four

[0379] C20-4 (40 mg, 0.20 mmol) and C14-5 (91 mg, 0.27 mmol) were dissolved in acetonitrile (3 mL), and N-methylimidazole (102 mg, 1.24 mmol) and TCFH (174 mg, 0.62 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to give compound C20 (29.1 mg, 27.5%). LCMS m / z = 516.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.67(s,1H),8.94(d,J=2.2Hz,1H),8.44(d,J=2.2Hz,1H),8.07(s,1H),7.63(d,J=2.2Hz,1H ),7.44–7.41(m,1H),6.77(d,J=2.3Hz,1H),4.43(t,J=12.3Hz,4H),3.84(s,3H),2.39(s,3H),2.33(d,J=1.7Hz,3H).

[0380] Example 10. Synthesis of C46

[0381] 1) Step One

[0382] Under nitrogen protection, 4-bromo-2-iodopyrimidine (500 mg, 1.76 mmol), 3,3-difluoroazacyclobutane hydrochloride (454.7 mg, 3.51 mmol), L-proline (40 mg, 0.35 mmol), cuprous iodide (167.1 mg, 0.88 mmol), and potassium carbonate (485.2 mg, 3.51 mmol) were dissolved in dimethyl sulfoxide (15 mL). The reaction mixture was purged three times with N2 and stirred at 100 °C for 5 hours. The reaction mixture was cooled to room temperature and diluted with water (100 mL). The aqueous phase was extracted with ethyl acetate (40 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give a white solid C46-1 (350 mg, 79%). LCMS m / z = 250.0 [M+H] + .

[0383] 2) Step Two

[0384] Following the synthetic method for compound C10, compound C46 was synthesized by replacing C10-1 with C46-1. LCMS m / z = 501.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.07(s,1H),8.61(s,2H),8.03(s,1H),7.13(d,J=2.0Hz,1H),7.09(d,J= 2.0Hz,1H),7.06(d,J=1.6Hz,1H),5.51(s,2H),4.53(t,J=12.4Hz,4H),2.51(s,3H),1.78(s,3H).

[0385] Example 11. Synthesis of C11

[0386] 1) Step One

[0387] Under N2 protection, 4,6-dichloropyrimidine (100 mg, 0.67 mmol), 1-methylpiperazine (67.9 mg, 0.68 mmol), Xantphos (77.53 mg, 0.134 mmol), cesium carbonate (654.9 mg, 2.01 mmol), and Pd2(dba)3 (61.3 mg, 0.067 mmol) were dissolved in dioxane (2 mL). The reaction mixture was replaced with N2 three times and stirred at 120 °C for 3 hours. After the reaction was complete, the reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a yellow solid C11-1 (65 mg, 45.53%). LCMS m / z = 235.1 [M + Na] + .

[0388] 2) Step Two

[0389] Following the synthetic method for compound C10, compound C11 was synthesized by replacing C10-1 with C11-1. LCMS m / z = 508.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.57(s,1H),8.37(s,1H),7.19–7.09(m,2H),7.09–6.94(m ,2H),5.50(s,2H),3.74–3.64(m,4H),2.73(s,3H),2.44–2.36(m,4H),2.23(s,3H),1.78(s,3H).

[0390] Example 12. Synthesis of C12 and C13

[0391] 1) Step One

[0392] C12-1 (380 mg, 2.10 mmol) and C10-8 (1.98 g, 6.30 mmol) were dissolved in toluene (30 mL), and the reaction mixture was stirred at 60 °C for 3 hours. After the reaction was complete, the reaction mixture was diluted with water (120 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:10) to give a yellow solid C12-2 (300 mg, 64%, E:Z = 9:10). LCMS m / z = 223.1 [M+H]+ .

[0393] 2) Step Two

[0394] C12-2 (300 mg, 1.340 mmol) was dissolved in methanol (13 mL), and acetic acid (404 mg, 6.73 mmol) and zinc powder (440 mg, 6.73 mmol) were added. The reaction mixture was stirred at 70 °C for 3 hours. After the reaction was complete, the reaction mixture was diluted with saturated sodium bicarbonate aqueous solution (160 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:6) to give yellow solids C12-3E (100 mg, 38%) and C12-3Z (30 mg, 11%). LCMS m / z = 193.1 [M+H] + C12-3E: 1 H NMR (400MHz, DMSO-d6) δ7.27–7.19(m,2H),6.69(d,J=2.4Hz,1H),6.55(dd,J=8.6,2.4Hz,1H),5.95(s,2H),2.03(d,J=1.6Hz,3H).C12-3Z: 1 H NMR (400MHz, DMSO-d6) δ7.68(d,J=8.6Hz,1H),7.20(d,J=1.8Hz,1H),6.67(d, J=2.4Hz,1H),6.57(dd,J=8.6,2.4Hz,1H),5.95(s,2H),2.09(d,J=1.6Hz,3H).

[0395] 3) Step Three

[0396] C12-3E (28 mg, 0.12 mmol) and C14-5 (40 mg, 0.11 mmol) were dissolved in acetonitrile (3 mL), and N-methylimidazole (57 mg, 0.70 mmol) and TCFH (98 mg, 0.35 mmol) were added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to give C12 (27 mg, 45%). LCMS m / z = 515.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.43(s,1H),8.09–8.02(m,2H),7.77(dd,J=8.6,2.2Hz,1H),7.62(d,J=2.2Hz,1H),7.50(d,J= 8.6Hz,1H),7.36(s,1H),6.76(d,J=2.2Hz,1H),4.43(t,J=12.4Hz,4H),3.84(s,3H),2.38(s,3H),2.04(d,J=1.6Hz,3H).

[0397] Following the synthesis method of C12, C13 was synthesized by replacing C12-3E with C12-3Z. LCMS m / z = 515.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.08–8.03(m,2H),7.85–7.75(m,2H),7.63(d,J=2.2Hz,1H),7.36(d,J =1.8Hz,1H),6.76(d,J=2.4Hz,1H),4.43(t,J=12.4Hz,4H),3.84(s,3H),2.39(s,3H),2.17(d,J=1.6Hz,3H).

[0398] Example 13. Synthesis of C16

[0399] 1) Step One

[0400] C10-7 (465 mg, 2.26 mmol) was dissolved in tetrahydrofuran (8 mL) and cooled to 0 °C. Potassium tert-butoxide (1 M THF solution, 1.8 mL, 1.81 mmol) was added to the reaction solution, and the mixture was stirred at 0 °C for 10 minutes. C16-1 (400 mg, 1.51 mmol) was dissolved in tetrahydrofuran (2 mL) and added dropwise to the reaction solution. The reaction solution was stirred at 60 °C for 3 hours. After the reaction was complete, the reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (4 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10) to give a yellow solid C16-2 (380 mg, 79%). LCMS m / z = 315.0 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ8.40–8.35(m,2H),7.43–7.38(m,1H),2.02–1.97(m,2H),0.98(t,J=7.4Hz,3H).

[0401] 2) Step Two

[0402] Following the synthetic method for compound C10, compound C16 was synthesized by replacing C10-9 with C16-2 and C10-4 with C14-5. LCMS m / z = 544.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.14(s,1H),8.04(s,1H),7.70(d,J=2.2Hz,1H),7.16(d,J=1.9Hz,1H),7.12(d,J=1.9Hz,1H ),7.01–6.96(m,2H),4.48(t,J=12.3Hz,4H),3.89(s,3H),2.38(s,3H),2.09(q,J=7.5Hz,2H),1.04(t,J=7.5Hz,3H).

[0403] Example 14. Synthesis of C26

[0404] Following the synthetic method for compound C10, compound C26 was synthesized by replacing 1-methyl-3-hydroxyazacyclobutane with hydroxyethylmorpholine. LCMS m / z = 539.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ11.21(s,1H),10.33(s,1H),8.72(s,2H),8.63(s,1 H),7.24(d,J=1.9Hz,1H),7.15(d,J=1.8Hz,1H),7.07(d,J=1.7Hz,1H),4.6 7(t,J=4.9Hz,2H),4.01–3.96(m,2H),3.88–3.81(m,2H),3.64–3.60(m,2H) ,3.56–3.51(m,2H),3.26–3.17(m,2H),2.83(s,3H),1.78(d,J=1.5Hz,3H).

[0405] Intermediate C26-3: LCMS m / z = 350.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ11.74(s,1H),8.70(s,2H),8.18(s,1H),4.68(t,J=4.8Hz,2H),3 .96–3.89(m,4H),3.62–3.58(m,2H),3.54–3.48(m,2H),3.25–3.16(m,2H),2.82(s,3H).

[0406] Example 15. Synthesis of C27

[0407] Following the synthetic method for compound C10, compound C27 was synthesized by replacing 1-methyl-3-hydroxyazacyclobutane with 3-hydroxytetrahydrofuran. LCMS m / z = 496.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),8.65(s,2H),8.62(s,1H),7.24(d,J=2.0Hz,1H),7.16(d,J=1.9Hz,1H),7.11–7.03 (m,1H),5.31–5.26(m,1H),3.92–3.75(m,4H),2.83(s,3H),2.31–2.24(m,1H),2.09–1.99(m,1H),1.78(d,J=1.5Hz,3H).

[0408] Example 16. Synthesis of C30

[0409] Referring to the synthetic method of compound C10, using By substituting 1-methyl-3-hydroxyazacyclobutane, compound C30 was synthesized. LCMS m / z = 552.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.65(s,2H),8.61(s,1H),7.22(s,1H),7.13(s,1H),7.06(s,1H),5.49(s,2H),4 .35–4.26(m,2H),2.82(s,3H),2.73(t,J=5.6Hz,2H),2.49–2.43(m,4H),2.43–2.30(m,4H),2.19(s,3H),1.78(s,3H).

[0410] Example 17. Synthesis of C42

[0411] Following the synthetic method for compound C11, compound C42 was synthesized by replacing 4,6-dichloropyrimidine with 2-methyl-4,6-dichloropyrimidine. LCMS m / z = 522.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.30(s,1H),7.17(d,J=2.0Hz,1H),7.12(d,J=1.9Hz,1H),7.06(d,J=1.6Hz,1H),6.80(s ,1H),5.50(s,2H),3.67(t,J=4.8Hz,4H),2.71(s,3H),2.43(s,3H),2.39(t,J=5.0Hz,4H),2.23(s,3H),1.78(d,J=1.6Hz,3H).

[0412] Example 18. Synthesis of C43

[0413] Following the synthetic method for compound C11, compound C43 was synthesized by replacing 4,6-dichloropyrimidine with 2-methyl-4,6-dichloropyrimidine. LCMS m / z = 547.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ11.50(s,1H),10.34(s,1H),8.22(s,1H),7.23(d,J=1.9Hz,1H),7.18(d,J=1.8Hz,1H),7.07(d,J=1.8Hz,1H),4.74–4.67( m,2H),3.68(t,J=13.0Hz,2H),3.57(d,J=12.2Hz,2H),3.22–3.13(m,2H) ,2.80(d,J=4.1Hz,3H),2.59(s,3H),2.57(s,3H),1.77(d,J=1.4Hz,3H).

[0414] Example 19. Synthesis of C51

[0415] Following the synthetic method for compound C11, compound C51 was synthesized by replacing 4,6-dichloropyrimidine with 5-methyl-4,6-dichloropyrimidine. LCMS m / z = 522.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.60(s,1H),7.99(s,1H),7.15(s,1H),7.09(s,1H),7.06(s,1H), 5.50(s,2H),3.44–3.38(m,4H),2.51–2.45(m,4H),2.42(s,3H),2.24(s,3H),2.08(s,3H),1.77(s,3H).

[0416] Example 20. Synthesis of C52

[0417] Following the synthetic method for compound C12, compound C52 was synthesized by replacing C14-5 with C26-3. LCMS m / z = 524.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.64(s,1H),8.67–8.64(m,3H),8.09(d,J=2.1Hz,1H),7.81(dd,J=8.6,2.1Hz,1H),7.50(d,J=8.6Hz,1H),7.35 (d,J=1.7Hz,1H),4.31(t,J=5.6Hz,2H),3.60–3.56(m,4H),2.83(s,3H),2.73(t,J=5.6Hz,2H),2.49–2.46(m,4H),2.05(d,J=1.7Hz,3H).

[0418] Example 21. Synthesis of C57

[0419] 1) Step One

[0420] C12-1 (650 mg, 3.5 mmol) was dissolved in EtOH (6.5 mL) / H2O (6.5 mL), and propionaldehyde (305 mg, 5.25 mmol) was added. An aqueous solution of sodium hydroxide (42 mg, 1.05 mmol) (6.5 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, the solution was diluted with water (100 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a yellow oily substance, C57-1 (820 mg, crude product). 1H NMR (400MHz, CDCl3) δ9.72 (s, 1H), 8.36 (d, J = 2.3Hz, 1H), 8.20 (dd, J = 8.6, 2.3Hz, 1H), 7.61 (d, J = 8.5Hz, 1H), 7.47 (d, J = 1.7Hz, 1H), 1.98 (d, J = 1.4Hz, 3H).

[0421] 2) Step Two

[0422] C57-1 (420 mg crude, 1.86 mmol) was dissolved in methanol (4 mL), and potassium carbonate (514 mg, 3.72 mmol) and C57-2 (429.12 mg, 2.23 mmol) were added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a yellow solid C57-3 (100 mg, 24.23%). 1 H NMR (400MHz, CDCl3) δ8.30–8.26(m,1H),8.12(dd,J=8.4,2.3Hz,1H),7.45(d,J=8.5Hz,1H),6.97(s,1H),3.12(s,1H),2.00(s,3H).

[0423] 3) Step Three

[0424] C57-3 (50 mg, 0.226 mmol) was dissolved in methanol (3 mL), and zinc powder (73.76 mg, 1.13 mmol) and acetic acid (67.86 mg, 1.13 mmol) were added. The reaction mixture was stirred at 70 °C for 2 hours. After the reaction was complete, the reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give a yellow solid C57-4 (20 mg, 50% purity, 23.21%). LCMS m / z = 192.1 [M+H] + .

[0425] 4) Step Four

[0426] C57-4 (20 mg, 0.1 mmol), C26-3 (73 mg, 0.21 mmol), N-methylimidazole (50 mg, 0.6 mmol), and TCFH (84.17 mg, 0.3 mmol) were dissolved in acetonitrile (3 mL), and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain C57 (5.1 mg, 9.3%). LCMS m / z = 523.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),8.67(s,2H),8.64(s,1H),8.04(d,J=2.1Hz,1H),7.76(dd,J=8.5,2.1Hz,1H),7.42(d,J=8.5Hz,1H),6.84 (s,1H),4.32(t,J=5.6Hz,2H),4.09(s,1H),3.59(t,J=4.6Hz,4H),2.83 (s,3H),2.73(d,J=5.6Hz,2H),2.49–2.46(m,4H),1.93(d,J=1.5Hz,3H).

[0427] Example 22. Synthesis of C58

[0428] 1) Step One

[0429] C57-3 (40 mg, 0.18 mmol, 1.0 eq) was dissolved in THF (3 mL). Under nitrogen protection, LiHMDS (1 M in THF, 0.22 mL, 0.217 mmol, 1.2 eq) was added at -78 °C. After stirring for half an hour, iodomethane (30.74 mg, 0.217 mmol, 1.2 eq) was added at -78 °C. The reaction mixture was slowly brought to room temperature and stirred for 1.5 hours. After the reaction was complete, the reaction solution was quenched with water (60 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid C58-1 (37 mg, crude product), which was used directly in the next step. 1H NMR (400MHz, DMSO-d6) δ8.32(d,J=2.4Hz,1H),8.18(dd,J=8.6,2.4Hz,1H),7.68(d,J=8.6Hz,1H),6.75(s,1H),2.02(s,3H),1.92(d,J=1.5Hz,3H).

[0430] 2) Step Two

[0431] Following the synthetic method for C57, C58 was synthesized by replacing C57-3 with C58-1. LCMS m / z = 537.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.56(s,1H),8.66(s,2H),8.63(s,1H),8.02(s,1H),7.74(d,J=8.6Hz,1H),7.38(d,J=8.5Hz,1H),6.68(s, 1H),4.32(t,J=5.6Hz,2H),3.58(t,J=4.6Hz,4H),2.83(s,3H),2.74(t,J=5.5Hz,2H),2.49–2.46(m,4H),1.99(s,3H),1.90(s,3H).

[0432] Example 23. Synthesis of C63

[0433] 1) Step One

[0434] Isobutyronitrile (583 mg, 8.4 mmol) was dissolved in tetrahydrofuran (10 mL). Under nitrogen protection at 0 °C, LiHMDS solution (1 M tetrahydrofuran solution, 8.5 mL, 8.4 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 20 min. Then, 2 mL of tetrahydrofuran solution containing 2-chloro-4-bromobenzyl bromide (800 mg, 2.81 mmol) was added dropwise. After the addition was complete, the mixture was brought to room temperature and stirred for 3 h. After the reaction was complete, the reaction solution was cooled in an ice bath, quenched with saturated ammonium chloride solution (60 mL), and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried to obtain a colorless oily substance C63-1 (780 mg, 95%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.58 (d, J = 2.0Hz, 1H), 7.43–7.39 (m, 1H), 7.37–7.33 (m, 1H), 2.99 (s, 2H), 1.41 (s, 6H).

[0435] 2) Step Two

[0436] C63-1 (780 mg, 2.86 mmol) was dissolved in dioxane (20 mL), and benzophenone imine (1.3 g, 7.16 mmol), Pd2(dba)3 (262 mg, 0.29 mmol), Xantphos (330 mg, 0.57 mmol), and sodium tert-butoxide (825 mg, 8.59 mmol) were added. The reaction mixture was stirred at 95 °C for 4 h under nitrogen protection. After the reaction was complete, the reaction mixture was quenched with water (100 mL), extracted with ethyl acetate (3 × 60 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 92:8) to give a yellow solid C63-2 (350 mg, 33%). LCMS m / z = 373.2 [M+H] + .

[0437] 3) Step Three

[0438] C63-2 (350 mg, 0.94 mmol), hydroxylamine hydrochloride (130 mg, 1.88 mmol), and potassium acetate (230 mg, 2.35 mmol) were dissolved in methanol (8 mL), and the reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction mixture was directly concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 77:23) to give a white solid C63-3 (150 mg, 76.6%). LCMS m / z = 209.1 [M+H] + .

[0439] 4) Step Four

[0440] C63-3 (30 mg, 0.14 mmol) and C26-3 (75 mg, 0.22 mmol) were dissolved in acetonitrile (1.5 mL), and NMI (70 mg, 0.86 mmol) and TCFH (121 mg, 0.43 mmol) were added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (3 × 20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (dichloromethane:methanol = 20:1) to give C63 (40.2 mg, 51.8%). LCMS m / z = 540.3 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.67(s,2H),8.63(s,1H),8.00(d,J=2.2Hz,1H),7.72(dd,J=8.5,2.2Hz,1H),7.43(d,J=8.5 Hz,1H),4.32(t,J=5.6Hz,2H),3.60–3.56(m,4H),3.00(s,2H),2.83(s,3H),2.74(t,J=5.6Hz,2H),2.49–2.45(m,4H),1.37(s,6H).

[0441] Example 24. Synthesis of C29

[0442] 1) Step One

[0443] 5-Bromo-2-iodopyrimidine (431.18 mg, 3.19 mmol), C10-2 (300 mg, 1.06 mmol), Pd(dppf)Cl2 (77.56 mg, 0.106 mmol), and potassium acetate (439.51 mg, 3.18 mmol) were dissolved in dioxane (12 mL) and water (3 mL). The reaction mixture was purged three times with nitrogen and stirred at 70 °C for 1.5 hours. After the reaction was complete, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1) to give a white solid C29-1 (240 mg, 61.78%). 1 H NMR (400MHz, DMSO-d6) δ9.05(s,2H),8.25(s,1H),3.83(s,3H),2.83(s,3H).

[0444] 2) Step Two

[0445] C29-1 (50 mg, 0.159 mmol) was dissolved in MeOH / THF / H2O (1 mL / 1 mL / 1 mL), and lithium hydroxide monohydrate (16.75 mg, 0.4 mmol) was slowly added. The reaction mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the mixture was diluted with water, and the pH of the reaction mixture was adjusted to 3 with 1 N hydrochloric acid solution. The mixture was then extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a white solid C29-2 (40 mg, 83.75%). 1H NMR (400MHz, DMSO-d6) δ13.23(s,1H),9.05(s,2H),8.19(s,1H),2.82(s,3H).

[0446] 3) Step Three

[0447] C29-2 (40 mg, 0.134 mmol), compound C10-13 (45.45 mg, 0.11 mmol), N-methylimidazole (54.19 mg, 0.66 mmol), and TCFH (92.6 mg, 0.33 mmol) were dissolved in acetonitrile (4 mL), and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give a white solid C29-3 (60 mg, 78.15%). 1 H NMR (400MHz, DMSO-d6) δ10.71(s,1H),9.09(s,2H),8.69(s,1H),8.02(d,J=2.0Hz,1H),7.7 2(d,J=2.0Hz,1H),7.01(d,J=1.7Hz,1H),2.85(s,3H),1.77(d,J=1.5Hz,3H),1.44(s,18H).

[0448] 4) Step Four

[0449] Under N2 protection, C29-3 (40 mg, 0.05 mmol), thiomorpholine-1,1-dioxide (23.54 mg, 0.174 mmol), Xantphos (5.79 mg, 0.01 mmol), cesium carbonate (48.82 mg, 0.15 mmol), and Pd2(dba)3 (4.5 mg, 0.005 mmol) were dissolved in dioxane (4 mL). The reaction solution was replaced with N2 three times and stirred at 95 °C for 3 hours. After the reaction was complete, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by thin-layer chromatography (dichloromethane:methanol = 20:1) to give a yellow solid C29-4 (23 mg, 35.58%). LCMS m / z = 743.1 [M+H] + .

[0450] 5) Step Five

[0451] C29-4 (23 mg, 0.031 mmol) was dissolved in dichloromethane (2 mL). A dioxane solution of hydrochloric acid (4 M, 1 mL) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, a yellow solid precipitated. The reaction solution was directly filtered to obtain C29 (9.5 mg, 13.01%). LCMS m / z = 543.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),8.68(s,2H),8.59(s,1H),7.26(d,J=2.0Hz,1H),7.18(d,J=1.9H z,1H),7.07(d,J=1.8Hz,1H),3.98–3.92(m,4H),3.24–3.19(m,4H),2.82(s,3H),1.78(d,J=1.5Hz,3H).

[0452] Example 25. Synthesis of C54

[0453] 1) Step One

[0454] C29-1 (200 mg, 0.64 mmol), (R)-3-methylmorpholine (162 mg, 1.60 mmol), Pd2(dba)3 (59 mg, 0.064 mmol), Xantphos (74 mg, 0.13 mmol), and cesium carbonate (624 mg, 1.9 mmol) were dissolved in dioxane (10 mL). The reaction mixture was stirred at 110 °C for 3 hours under nitrogen protection. After the reaction was complete, the reaction mixture was quenched with water (60 mL), extracted with ethyl acetate (3 × 30 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 82:28) to give a yellow oily substance C54-1 (100 mg, 46.9%). LCMS m / z = 334.1 [M+H] + .

[0455] 2) Step Two

[0456] Following the synthetic method for compound C10, compound C54 was synthesized by replacing C10-3 with C54-1. LCMS m / z = 509.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.29(s,1H),8.58(s,1H),8.53(s,2H),7.22(d,J=1.9H z,1H),7.13(d,J=1.9Hz,1H),7.06(d,J=1.7Hz,1H),5.48(s,2H),4.12–4.05(m,1 H),3.99–3.93(m,1H),3.73(d,J=2.2Hz,2H),3.63–3.56(m,1H),3.49–3.43(m,1 H),3.15–3.07(m,1H),2.81(s,3H),1.78(d,J=1.5Hz,3H),1.10(d,J=6.6Hz,3H).

[0457] Example 26. Synthesis of C65

[0458] C26-3 (82.46 mg, 0.236 mmol), 3-chloro-4-trifluoromethoxyaniline (25 mg, 0.118 mmol), N-methylimidazole (58.13 mg, 0.708 mmol), and TCFH (99.33 mg, 0.354 mmol) were dissolved in acetonitrile (4 mL), and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by thin-layer chromatography (dichloromethane:methanol = 20:1) to give C65 (39 mg, 60.78%). LCMS m / z = 543.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),8.67(s,2H),8.64(s,1H),8.15(d,J=2.5Hz,1H),7.84(dd,J=9.1,2.5Hz,1H),7.5 7(d,J=9.0Hz,1H),4.32(t,J=5.6Hz,2H),3.58(t,J=4.7Hz,4H),2.83(s,3H),2.74(t,J=5.6Hz,2H),2.49–2.46(m,4H).

[0459] Example 27. Synthesis of C66

[0460] Following the synthetic method for compound C65, compound C66 was synthesized by replacing 3-chloro-4-trifluoromethoxyaniline with 3-chloro-4-phenoxyaniline. LCMS m / z = 551.25 [M+H] +; 1 H NMR(400MHz,DMSO-d6)δ10.55(s,1H),8.67(s,2H),8.63(s,1H),8.10(d,J =2.5Hz,1H),7.74(dd,J=8.9,2.5Hz,1H),7.41–7.33(m,2H),7.16(d,J=8.9 Hz,1H),7.11(t,J=7.4Hz,1H),6.96–6.90(m,2H),4.33(t,J=5.6Hz,2H),3. 58(t,J=4.7Hz,4H),2.84(s,3H),2.74(t,J=5.6Hz,2H),2.49–2.47(m,4H).

[0461] Example 28. Synthesis of C67

[0462] Following the synthetic method for compound C65, compound C67 was synthesized by replacing 3-chloro-4-trifluoromethoxyaniline with 3-chloro-4-phenylaniline. LCMS m / z = 535.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),8.67(s,2H),8.66(s,1H),8.07(d,J=2.1Hz,1H),7.82(dd,J=8.5,2.1Hz,1H), 7.49–7.39(m,6H),4.33(t,J=5.6Hz,2H),3.58(t,J=4.6Hz,4H),2.84(s,3H),2.76–2.72(m,2H),2.49–2.47(m,4H).

[0463] Example 29. Synthesis of C59 and C17

[0464] 1) Step One

[0465] 2-Bromo-5-nitrobenzoic acid (380 mg, 1.46 mmol) was dissolved in concentrated sulfuric acid (5 mL), and dichlorohydantoin (346 mg, 1.75 mmol) was added at 0 °C. The reaction mixture was heated to 50 °C and reacted for 5 hours. After the reaction was complete, the reaction mixture was slowly added dropwise to ice water (60 mL), and then stirred for 10 minutes. The precipitated solid was filtered and dried to obtain a white solid C59-1 (380 mg, 87%). LCMS m / z = 277.8 [MH] - .

[0466] 2) Step Two

[0467] Under nitrogen protection, C59-1 (394 mg, 1.4 mmol), pinacol ester of 2-methyl-1-propenylboronic acid (512 mg, 2.8 mmol), Pd(dppf)Cl2 (103 mg, 0.14 mmol), and potassium carbonate (583 mg, 4.21 mmol) were dissolved in 1,4-dioxane (6 mL) and water (2 mL). The reaction solution was purged with N2 three times and stirred at 90 °C for 3 h. After the reaction was complete, the reaction solution was diluted with water (60 mL), the pH of the reaction solution was adjusted to 3 with dilute hydrochloric acid, and then extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain C59-2 (1.2 g crude product, 100%), which was a brown oily substance. LCMS m / z = 254.0 [MH] - .

[0468] 3) Step Three

[0469] C59-2 (1.2 g crude, 1.4 mmol) was dissolved in methanol (20 mL), and thionyl chloride (333 mg, 2.80 mmol) was slowly added at 0 °C. The reaction mixture was stirred overnight at 70 °C. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated to give a white solid C59-3 (233 mg, 69%).

[0470] 4) Step Four

[0471] C59-3 (100 mg, 0.37 mmol) was dissolved in ethanol (2 mL), and iron powder (63 mg, 1.11 mmol) and ammonium chloride (60 mg, 1.11 mmol) were added. The reaction mixture was stirred at 70 °C for 2 h. After the reaction was complete, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a brown oily substance C59-4 (89 mg crude product, 100%). LCMS m / z = 240.0 [M+H] + .

[0472] 5) Step Five

[0473] C59-4 (29 mg, 0.12 mmol), C14-5 (46 mg, 0.13 mmol), and N-methylimidazole (40 mg, 0.48 mmol) were dissolved in acetonitrile (1 mL), and TCFH (68 mg, 0.24 mmol) was added to the reaction solution. The reaction solution was stirred overnight at room temperature. After the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative thin-layer chromatography (developing solvent: petroleum ether / ethyl acetate = 1:1) to give a white solid C59-5 (54 mg, 79%). LCMS m / z = 562.2 [M+H] + .

[0474] 6) Step Six

[0475] C59-5 (54 mg, 0.1 mmol) was dissolved in THF / H2O (1 mL / 1 mL), and LiOH·H2O (8 mg, 0.2 mmol) was slowly added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the pH of the reaction mixture was adjusted to 4–5 with 1 N HCl solution, diluted with water (10 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a white solid C59-6 (49 mg, 100%). LCMS m / z = 548.1 [M+H] + .

[0476] 7) Step Seven

[0477] C59-6 (10 mg, 0.018 mmol) was dissolved in DMF (0.2 mL), and triethylamine (4 mg, 0.036 mmol) and DPPA (8 mg, 0.027 mmol) were slowly added at 0 °C. The reaction mixture was stirred at room temperature for 2 h, then DMF (0.2 mL) and H2O (0.2 mL) were added, and the mixture was stirred overnight at 100 °C. After the reaction was complete, water (15 mL) was added and the mixture was stirred for 3 h, followed by extraction with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 1:1) to obtain C59 (7 mg, 89%). LCMS m / z = 519.1 [M+H] + ; 1H NMR(400MHz, DMSO-d6)δ9.95(s,1H),8.00(s,1H),7.62(d,J=2.0Hz,1H),7.09–7.01(m,2H),6.76(d,J=2.0Hz,1H) ,5.79(s,1H),5.01(s,2H),4.43(t,J=12.4Hz,4H),3.84(s,3H),2.37(s,3H),1.87(d,J=1.6Hz,3H),1.50(s,3H).

[0478] 8) Step Eight

[0479] C59 (30 mg, 0.058 mmol) was dissolved in methanol (2 mL), and then platinum dioxide (30 mg) was added. The reaction solution was replaced three times with H2 and stirred overnight at room temperature. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (developing solvent: petroleum ether / ethyl acetate = 1:1) to give C17 (8 mg, 27%). LCMS m / z = 521.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ9.91(s,1H),7.98(s,1H),7.62(d,J=2.4Hz,1H),7.09–7.02(m,2H),6.75(d,J=2.4Hz,1H),5.18 (s,2H),4.43(t,J=12.4Hz,4H),3.83(s,3H),2.48–2.43(m,2H),2.36(s,3H),1.96–1.90(m,1H),0.90(d,J=6.8Hz,6H).

[0480] Example 30. Synthesis of C25

[0481] Following the synthetic method for compound C29, compound C25 was synthesized by replacing thiomorpholine-1,1-dioxide with N-methylpiperazine. LCMS m / z = 508.2 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.58(s,3H),7.26–7.18(m,1H),7.17–7.10(m,1H),7.06(s ,1H),5.48(s,2H),3.32–3.29(m,4H),2.81(s,3H),2.49–2.45(m,4H),2.24(s,3H),1.78(s,3H).

[0482] Example 31. Synthesis of C28

[0483] Following the synthetic method for compound C29, compound C28 was synthesized by replacing thiomorpholine-1,1-dioxide with morpholine. LCMS m / z = 495.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),8.59(s,2H),8.57(s,1H),7.21(s,1H),7.13(d,J=1.8Hz,1 H),7.06(s,1H),5.46(s,2H),3.78(t,J=4.8Hz,4H),3.31–3.29(m,4H),2.81(s,3H),1.78(s,3H).

[0484] Example 32. Synthesis of C249

[0485] Following the synthetic method for compound C10, compound C249 was synthesized by replacing C10-3 with C249-1 (prepared according to the synthetic method described in patent application WO2014049133). LCMS m / z = 372.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ9.87(s,1H),8.47(s,1H),8.04(s,1H),7.25–7.15(m,2H),7.08(d,J=1.8Hz,1 H),5.15–5.01(m,1H),4.06–3.78(m,4H),2.47–2.37(m,1H),2.29–2.17(m,1H),1.77(d,J=1.5Hz,3H).

[0486] Example 33. Synthesis of C40

[0487] Following the synthetic method for compound C10, compound C40 was synthesized by replacing C10-4 with C40-1. LCMS m / z = 379.1 [M+H] + , 1 ¹H NMR (400 MHz, methanol-d⁴) δ 8.68–8.60 (m, 1H), 7.96–7.78 (m, 2H), 7.41–7.31 (m, 2H), 7.22 (s, 1H), 7.17 (s, 1H), 7.08 (d, J = 1.6 Hz, 1H), 1.87 (d, J = 1.5 Hz, 3H).

[0488] Example 34. Synthesis of C53

[0489] Following the synthetic method for compound C54, compound C53 was synthesized by replacing (R)-3-methylmorpholine with (S)-3-methylmorpholine. LCMS m / z = 509.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.58(s,1H),8.53(s,2H),7.22(s,1H),7.14(s,1H),7.06(s,1H) ,4.14–4.02(m,2H),3.98–3.94(m,1H),3.77–3.69(m,4H),2.81(s,3H),2.02–1.94(m,3H),1.78(s,3H).

[0490] Example 35. Synthesis of C55 and C56

[0491] 1) Step One

[0492] At 0 °C, C55-1 (681.3 mg, 1.86 mmol), C12-1 (230 mg, 1.24 mmol), and potassium tert-butoxide (208.6 mg, 1.86 mmol) were dissolved in tetrahydrofuran (5 mL). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) to give a colorless oily substance C55-2 (163 mg, 32%), which is a mixture of cis and trans isomers.

[0493] 2) Step Two

[0494] C55-2 (113 mg, 0.41 mmol) was dissolved in methanol (2 mL). Zinc powder (135 mg, 2.06 mmol) and acetic acid (124 mg, 2.06 mmol) were added sequentially to the reaction solution. The reaction solution was stirred at 70 °C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain colorless oily C55-3Z (Z configuration, 62 mg, 62%) and colorless oily C55-3E (E configuration, 22 mg, 22%). LCMS m / z = 244.1 [M+H] + ;

[0495] 3) Step Three

[0496] C55-3E (22 mg, 0.090 mmol), C26-3 (63.1 mg, 0.18 mmol), and TCFH (76 mg, 0.27 mmol) were dissolved in acetonitrile (0.5 mL). N-methylimidazole (44.5 mg, 0.54 mmol) was added dropwise to the reaction solution. The reaction solution was stirred overnight at room temperature. After the reaction was complete, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1), and then ground and filtered with dichloromethane (4 mL) to obtain C55 (16 mg, 30%). LCMS m / z = 575.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.57(s,1H),8.67(s,2H),8.65(s,1H),8.05(d,J=2.1Hz ,1H),7.78(dd,J=8.8,1.7Hz,1H),7.59(d,J=7.5Hz,2H),7.47(d,J=8.5Hz,1H),7 .45–7.38(m,2H),7.37–7.30(m,1H),6.84(s,1H),4.33(t,J=5.6Hz,2H),3.58(t, J=4.6Hz,4H),2.84(s,3H),2.74(t,J=5.6Hz,2H),2.49–2.46(m,4H),2.16(s,3H).

[0497] Compound C56 was synthesized by replacing C55-3E with C55-3Z. LCMS m / z = 575.2 [M+H]+ ; 1 H NMR(400MHz, chloroform-d)δ8.46(s,2H),8.11(s,1H),7.79(s,1H),7.63(s,1H),7.24–7.20(m,2H),7.16–7.12(m,2H),7.04–6.94(m,1H),6.7 1(d,J=8.5Hz,1H),6.58(s,1H),4.37–4.18(m,2H),3.86–3.71(m,4H),2.94–2.86(m,2H),2.86(s,3H),2.75–2.50(m,4H),2.26(s,3H).

[0498] Example 36. Synthesis of C68

[0499] 1) Step One

[0500] Under nitrogen protection, C68-1 (500 mg, 2.42 mmol), cyclopentenyl-1-boronic acid (271 mg, 2.42 mmol), Pd(dppf)Cl2 (177 mg, 0.24 mmol), and potassium carbonate (1.01 g, 7.26 mmol) were dissolved in 1,4-dioxane (9 mL) and water (3 mL). The reaction mixture was purged three times with N2 and stirred at 90 °C for 3 hours. After the reaction was complete, the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give C68-2 (420 mg, 89%) as a brown solid. LCMS m / z = 194.1 [M+H] + .

[0501] 2) Step Two

[0502] C68-2 (50 mg, 0.25 mmol, 1.0 eq) was dissolved in methanol (4 mL), and then platinum dioxide (50 mg) was added. The reaction solution was purged three times with H2 and stirred overnight at room temperature. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain C68-3 (40 mg, 80%), which was used directly in the next reaction. LCMS m / z = 196.1 [M+H] + .

[0503] 3) Step Three

[0504] C68-3 (40 mg, 0.20 mmol), compound C26-3 (93 mg, 0.26 mmol), and N-methylimidazole (101 mg, 1.23 mmol) were dissolved in acetonitrile (2 mL). TCFH (172 mg, 0.61 mmol, 3.0 eq) was added to the reaction solution. The reaction solution was stirred overnight at room temperature. After the reaction was complete, the reaction solution was diluted with water (45 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative chromatography to obtain C68 (10.2 mg, 10.1%). LCMS m / z = 527.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.65(s,2H),8.61(s,1H),7.91(d,J=2.1Hz,1 H),7.66(dd,J=8.6,2.2Hz,1H),7.36(d,J=8.6Hz,1H),4.31(t,J=5.6Hz,2H),3.58( t,J=4.6Hz,4H),3.31–3.22(m,1H),2.82(s,3H),2.73(t,J=5.6Hz,2H),2.49–2.46( m,4H),2.04–1.92(m,2H),1.84–1.73(m,2H),1.69–1.61(m,2H),1.56–1.46(m,2H).

[0505] Example 37. Synthesis of C243 and C69

[0506] 1) Step One

[0507] Following the synthetic method for compound C10, C243 was synthesized by replacing 1-methyl-3-hydroxyazacyclobutane with (S)-propionide glycerol and C12-3E with C10-13. LCMS m / z = 525.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.66(s,1H),8.68(s,2H),8.65(s,1H),8.09(d,J=2.1 Hz,1H),7.81(dd,J=8.6,2.1Hz,1H),7.51(d,J=8.6Hz,1H),7.36(s,1H),4.53–4 .40(m,1H),4.34–4.28(m,1H),4.26–4.20(m,1H),4.16–4.05(m,1H),3.79(dd,J =8.4,6.3Hz,1H),2.83(s,3H),2.05(d,J=1.6Hz,3H),1.36(s,3H),1.32(s,3H).

[0508] 2) Step Two

[0509] C243 (35 mg, 0.06 mmol) was dissolved in methanol (2 mL), and 3M hydrochloric acid solution (1 mL) was slowly added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the precipitated solid was directly filtered, washed, and dried to obtain C69 (22.3 mg, 69%). LCMS m / z = 485.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.67(s,1H),8.66(s,3H),8.10(d,J=2.0Hz,1H),7.82(dd,J=8.5,2.1Hz,1H),7.51(d,J=8.6Hz,1H),7.36( d,J=1.9Hz,1H),4.36–4.20(m,1H),4.19–4.04(m,1H),3.90–3.77(m,1H),3.47(d,J=5.9Hz,2H),2.84(s,3H),2.05(d,J=1.6Hz,3H).

[0510] Example 38. Synthesis of C244 and C70

[0511] Following the synthetic methods for compounds C243 and C69, C244 and C70 were synthesized by replacing (S)-propionide glycerol with (R)-propionide glycerol. C244: LCMS m / z = 525.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.66(s,1H),8.68(s,2H),8.65(s,1H),8.09(d,J=2.1Hz ,1H),7.81(dd,J=8.6,2.1Hz,1H),7.51(d,J=8.6Hz,1H),7.36(s,1H),4.53–4.40( m,1H),4.34–4.28(m,1H),4.26–4.20(m,1H),4.16–4.05(m,1H),3.79(dd,J=8.4,6 .3Hz,1H),2.83(s,3H),2.05(d,J=1.6Hz,3H),1.36(s,3H),1.32(s,3H).C70:LCMS m / z = 485.1 [M+H] + ; 1 H NMR (400MHz, CD3OD) δ8.61(s,2H),8.46(s,1H),8.02(d,J=2.0Hz,1H),7.72(dd,J=8.4,2.0Hz,1H),7.43(d,J=8.4Hz,1H),7.35(d,J=2.0Hz ,1H),4.29(dd,J=10.0,4.0Hz,1H),4.23–4.16(m,1H),4.07–3.98(m,1H),3.70(dd,J=5.6,1.6Hz,2H),2.86(s,3H),2.08(d,J=1.6Hz,3H).

[0512] Example 39. Synthesis of C71

[0513] Following the synthetic method for compound C54, C71 hydrochloride was synthesized by replacing (R)-3-methylmorpholine with piperazine (Boc) and C10-13 with C12-3E. LCMS m / z = 479.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.70(s,1H),9.33(s,2H),8.65(s,3H),8.10(d,J=2.0Hz,1H),7.85–7.80(m,1H),7.5 1(d,J=8.6Hz,1H),7.37(s,1H),3.60(t,J=5.2Hz,4H),3.30–3.21(m,4H),2.83(s,3H),2.05(d,J=1.6Hz,3H).

[0514] Example 40. Synthesis of C72

[0515] Following the synthetic method for compound C54, C72 was synthesized by replacing (R)-3-methylmorpholine with N-oxetane-butylpiperazine and C10-13 with C12-3E. LCMS m / z = 535.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),8.62(s,1H),8.59(s,2H),8.10(d,J=2.0Hz,1H),7.82(dd,J=8.8,2.0Hz,1H),7.51(d,J=8.8Hz,1H),7.3 6(s,1H),4.58(t,J=6.4Hz,2H),4.48(t,J=6.4Hz,2H),3.47(m,1H),3. 40–3.33(m,4H),2.83(s,3H),2.46–2.40(m,4H),2.05(d,J=1.7Hz,3H).

[0516] Example 41. Synthesis of C77

[0517] Referring to the synthetic method of compound C72, using By substituting N-oxetane butylpiperazine, C77 formate was synthesized. LCMS m / z = 505.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.64(s,1H),8.59(s,1H),8.20(s,HCOOH,1H),8.14(s,2H),8.09(d,J=2.0Hz,1H),7.81(dd,J =8.6,2.0Hz,1H),7.51(d,J=8.6Hz,1H),7.36(s,1H),4.07(s,4H),3.46(s,4H),2.80(s,3H),2.30(s,3H),2.05(s,3H).

[0518] Example 42. Synthesis of C22

[0519] Following the synthetic method for compound C10, compound C22 was synthesized by replacing C10-1 with 2-chloro-4-isopropoxypyrimidine. LCMS m / z = 468.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.33(s,1H),8.63(s,2H),8.61(s,1H),7.26(d,J=1.9Hz,1H),7.18(d,J=1.8Hz, 1H),7.07(d,J=1.7Hz,1H),4.91–4.84(m,1H),2.82(s,3H),1.78(d,J=1.4Hz,3H),1.34(d,J=5.9Hz,6H).

[0520] Example 43. Synthesis of C80

[0521] Referring to the synthesis method of compound C54, using By substituting (R)-3-methylmorpholine, C80 was synthesized. LCMS m / z = 507.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.27(s,1H),8.54(s,1H),8.14(s,2H),7.21(s,1H),7.13(s ,1H),7.06(s,1H),5.47(s,2H),4.74(s,4H),4.17(s,4H),2.78(s,3H),1.78(s,3H).

[0522] Example 44. Synthesis of C86

[0523] Following the synthetic method for compound C54, C86 was synthesized by replacing (R)-3-methylmorpholine with 3-morpholinone. LCMS m / z = 509.00 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),9.04(s,2H),8.69(s,1H),7.22(d,J=2.0Hz,1H),7.13(d,J=1.8Hz,1H),7.06( d,J=1.6Hz,1H),5.49(s,2H),4.30(s,2H),4.06–4.00(m,2H),3.95–3.89(m,2H),2.87(s,3H),1.78(d,J=1.4Hz,3H).

[0524] Example 45. Synthesis of C98

[0525] 1) Step One

[0526] C29-2 (500 mg, 1.67 mmol), C12-3E (322 mg, 1.67 mmol), and N-methylimidazole (823 mg, 10.1 mmol) were dissolved in acetonitrile (10 mL), and TCFH (1.4 g, 5.01 mmol) was added to the reaction solution. The reaction solution was stirred overnight at room temperature. After the reaction was complete, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (dichloromethane / methanol = 30:1) to obtain C98 (580 mg, 73%). LCMS m / z = 473.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.68(s,1H),9.08(s,2H),8.68(s,1H),8.08(d,J=2.1Hz,1H),7 .85–7.71(m,1H),7.51(d,J=8.6Hz,1H),7.36(s,1H),2.84(s,3H),2.05(d,J=1.6Hz,3H).

[0527] Example 46. Synthesis of C97

[0528] C98 (40 mg, 0.08 mmol) and (R)-3-pyrrolidone (9 mg, 0.10 mmol) were dissolved in dioxane (3 mL). Pd2(dba)3 (8 mg, 0.01 mmol), XantPhos (10 mg, 0.01 mmol), and cesium carbonate (83 mg, 0.25 mmol) were added to the reaction solution. The reaction solution was replaced with N2 three times and stirred at 95 °C for 3 hours. After the reaction was complete, the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by thin-layer chromatography (dichloromethane / methanol = 15:1) to obtain C97 (6.5 mg, 16%). LCMS m / z = 480.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.64(s,1H),8.60(s,1H),8.21(s,2H),8.10(d,J=2.1 Hz,1H),7.82(dd,J=8.6,2.2Hz,1H),7.51(d,J=8.6Hz,1H),7.37(d,J=1.8Hz,1 H),5.06(d,J=3.8Hz,1H),4.47–4.42(m,1H),3.54–3.48(m,1H),3.46–3.39(m, 2H),3.25–3.14(m,1H),2.81(s,3H),2.05(d,J=1.6Hz,3H),2.01–1.89(m,2H).

[0529] Example 47. Synthesis of C99

[0530] Following the synthetic method for compound C97, C99 was synthesized by replacing (R)-3-pyrrolanol with (S)-3-pyrrolanol. LCMS m / z = 480.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.60(s,1H),8.21(s,2H),8.10(d,J=2.1 Hz,1H),7.82(dd,J=8.6,2.1Hz,1H),7.51(d,J=8.6Hz,1H),7.36(d,J=2.0Hz,1 H),5.05(d,J=3.8Hz,1H),4.48–4.42(m,1H),3.51–3.47(m,1H),3.46–3.39(m, 2H),3.22(d,J=10.8Hz,1H),2.81(s,3H),2.09–2.02(m,4H),1.97–1.91(m,1H).

[0531] Example 48. Synthesis of C113

[0532] Following the synthetic method for compound C97, C113 was synthesized by replacing (R)-3-pyrrolidone with 1-amino-2-methyl-2-propanol. LCMS m / z = 482.05 / 484.05 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.61(s,1H),8.58(s,1H),8.32(s,2H),8.09(d,J=2.0Hz,1H),7.82(dd,J=8.6,2.2Hz,1H),7.51(d,J=8.6Hz, 1H),7.36(d,J=1.8Hz,1H),6.08(t,J=5.8Hz,1H),4.54(s,1H),3.07(d,J=6.0Hz,2H),2.79(s,3H),2.05(d,J=1.6Hz,3H),1.18(s,6H).

[0533] Example 49. Synthesis of C110

[0534] 1) Step One

[0535] Referring to the synthesis method of compound C97, using By substituting (R)-3-pyrrolidone, C110-1 was synthesized. LCMS m / z = 605.15 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.61(s,1H),8.51(s,2H),8.09(d,J=2.0Hz,1H),7.85–7.78(m,1H),7.51(d,J=8.6Hz,1H),7.38–7.34( m,1H),4.32–4.21(m,2H),3.69(d,J=11.2Hz,2H),2.94(d,J=11.2Hz,2H),2.82(s,3H),2.05(d,J=1.6Hz,3H),1.92–1.76(m,4H),1.43(s,9H).

[0536] 2) Step Two

[0537] C110-1 (126 mg, 0.21 mmol) was dissolved in dichloromethane (1.5 mL), and dioxane hydrochloride solution (4 M, 1.5 mL) was added. The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction mixture was filtered, and the resulting solid was dried to give C110 (100 mg, 94%). LCMS m / z = 505.70 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),9.31–9.25(m,1H),8.62(s,1H),8.57 (s,2H),8.08(d,J=2.0Hz,1H),7.82(dd,J=8.4,2.0Hz,1H),7.51(d,J=8.6H z,1H),7.36(d,J=1.8Hz,1H),4.22–4.15(m,2H),3.85(d,J=11.6Hz,2H),3. 23(d,J=12.2Hz,2H),2.82(s,3H),2.04(d,J=1.6Hz,3H),2.04–1.97(m,4H).

[0538] Example 50. Synthesis of C135

[0539] C110 (30 mg, 0.06 mmol) and sodium cyanoborohydride (11.2 mg, 0.18 mmol) were dissolved in methanol (0.5 mL), and then a methanol solution of 3-oxetane (12.84 mg, 0.18 mmol) in methanol (0.5 mL) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (dichloromethane:methanol = 25:1) to give C135 (7.1 mg, 21%). LCMS m / z = 561.55 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),8.60(s,1H),8.44(s,2H),8.09(d,J=2.0Hz,1H),7.81 (dd,J=8.4,2.2Hz,1H),7.51(d,J=8.6Hz,1H),7.36(d,J=1.9Hz,1H),4.60(t,J=6.2Hz,2H), 4.39(t,J=5.6Hz,2H),3.70–3.63(m,1H),3.58(dd,J=10.8,2.2Hz,2H),3.29–3.24(m,2H),3 .02–2.96(m,2H),2.82(s,3H),2.05(d,J=1.6Hz,3H),1.89–1.81(m,2H),1.72–1.62(m,2H).

[0540] Synthesis of Example 51.C1

[0541] 1) Step One

[0542] Under N2 protection, C1-1 (250 mg, 1.15 mmol), 3,3-difluoroazacyclobutane hydrochloride (178 mg, 1.38 mmol), Xantphos (133 mg, 0.23 mmol), cesium carbonate (750 mg, 2.3 mmol), and Pd2(dba)3 (110 mg, 0.12 mmol) were dissolved in dioxane (15 mL). The reaction solution was replaced with N2 three times, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the solid was removed by filtration, and the solid was washed with ethyl acetate (3 × 10 mL). The filtrates were combined and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain a pale yellow solid C1-2 (220 mg, 60%). LCMS m / z = 230.1 [M+H] + .

[0543] 2) Step Two

[0544] Following the synthetic method for compound C10, C10-1 was synthesized by replacing C10-1 with C1-2. LCMS m / z = 525.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.30(d,J=2.9Hz,1H),8.18(s,1H),7.64(d,J=2.9Hz,1H),7.33(d,J=2.0H z,1H),7.29(d,J=1.9Hz,1H),7.11(d,J=1.7Hz,1H),4.48(d,J=12.3Hz,4H),2.46(s,3H),1.77(d,J=1.5Hz,3H).

[0545] Example 52. Synthesis of C44

[0546] Following the synthesis method for C46, ​​C44 was synthesized by replacing 3,3-difluoroazacyclobutane with thiomorpholine-1,1-dioxide. LCMS m / z = 543.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.61(s,2H),8.14(s,1H),7.20(dd,J=17.8,2.0Hz,2H),7 .07(d,J=1.9Hz,1H),4.29–4.24(m,4H),3.22–3.18(m,4H),2.52(s,3H),1.77(d,J=1.5Hz,3H).

[0547] Example 53. Synthesis of C45

[0548] Following the synthetic method for C46, ​​C45 was synthesized by replacing 3,3-difluorozahexacyclic butane with morpholine. LCMS m / z = 495.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.04(s,1H),8.54(s,2H),8.05(s,1H),7.18(d,J=1.8Hz,1H),7.13(d,J=1.8Hz,1H ),7.06(s,1H),5.19(s,br,2H),3.81–3.74(m,4H),3.73–3.67(m,4H),2.51(s,3H),(1.79(d,J=1.5Hz,3H).

[0549] Example 54. Synthesis of C74

[0550] 1) Step One

[0551] C74-1 (1.0 g, 3.51 mmol) was dissolved in acetonitrile (10 mL). NBS (750 mg, 4.22 mmol) and azobisisobutyronitrile (58 mg, 0.35 mmol) were added to the reaction solution. The reaction solution was stirred overnight at 85 °C. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a brown oily substance C74-2 (1.45 g, crude product).

[0552] 2) Step Two

[0553] C74-2 (1.45 g crude, 3.51 mmol) was dissolved in acetonitrile (15 mL), and N-methylmorpholine oxide (822 mg, 7.02 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was poured into water (60 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give a brown oily substance C74-3 (470 mg, 50%).

[0554] 3) Step Three

[0555] C74-3 (100 mg, 0.38 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), and 4-pyrazoleboronic acid pinacol ester (147 mg, 0.76 mmol), Pd(dppf)Cl2 (28 mg, 0.04 mmol), and potassium carbonate (157 mg, 1.13 mmol) were added. The reaction solution was replaced with N2 three times and stirred at 85 °C for 3 hours. After the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1) to obtain a brown oily substance C74-4 (50 mg, 52%). LCMS m / z = 252.1 [M+H] + .

[0556] 4) Step Four

[0557] C74-4 (50 mg, 0.20 mmol) was dissolved in toluene (2 mL), and compound C10-8 (125 mg, 0.40 mmol) was added. The reaction mixture was stirred at 60 °C for 3 hours. After the reaction was complete, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give a brown oily substance C74-5 (35 mg, 61%). LCMS m / z = 289.1 [M+H] + .

[0558] 5) Step Five

[0559] Following the synthetic method for C57, C57-3 was replaced with 74-5 to synthesize compound C74. LCMS m / z = 590.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.92(s,1H),8.69(s,2H),8.63(s,1H),8.16(s,1H),7.35(d,J=1.6Hz,1H),6.75–6.69(m,2H),5.77(s, 1H), 4.32 (t, J = 5.6Hz, 2H), 3.58 (t, J = 4.6Hz, 4H), 2.90 (s, 3H), 2.74 (t, J = 5.6Hz, 2H), 2.53-2.48 (m, 4H), 1.55 (d, J = 1.4Hz, 3H).

[0560] Example 55. Synthesis of C92

[0561] 1) Step One

[0562] C29-1 (5.0 g, 6.39 mmol), (S)-1-Boc-3-methylpiperazine (9.5 g, 19.16 mmol), Pd2(dba)3 (733 mg, 0.32 mmol), Xantphos (925 mg, 0.64 mmol), and cesium carbonate (10.4 g, 12.77 mmol) were dissolved in dioxane (125 mL). The reaction mixture was stirred overnight at 110 °C under nitrogen protection. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 7:1) to give a yellow solid C92-1 (3.5 g, 51%). LCMS m / z = 433.2 [M+H] + .

[0563] 2) Step Two

[0564] C92-1 (3.5 g, 8.09 mmol) was dissolved in tetrahydrofuran (30 mL), and an aqueous solution of lithium hydroxide monohydrate (510 mg, 12.14 mmol) (30 mL) was slowly added. The reaction mixture was stirred at 60 °C for 2 h. After the reaction was complete, the reaction mixture was concentrated to remove the tetrahydrofuran, and then the pH of the reaction mixture was adjusted to about 4 with 3N HCl solution under ice bath conditions. A solid precipitated out, which was filtered, washed twice with pure water, collected, and dried to obtain a brown solid C92-2 (3.4 g, 98%). LCMS m / z = 419.2 [M+H] + .

[0565] 3) Step Three

[0566] C92-2 (48 mg, 0.11 mmol), C12-3E (20 mg, 0.10 mmol), and N-methylimidazole (51 mg, 0.62 mmol) were dissolved in anhydrous acetonitrile (2 mL), and then TCFH (87 mg, 0.31 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with water (45 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by thin-layer chromatography (petroleum ether / ethyl acetate = 1:1) to give a white oily substance C92-3 (40 mg, 65%). LCMS m / z = 593.2 [M+H] + .

[0567] 4) Step Four

[0568] C92-3 (35 mg, 0.05 mmol) was dissolved in dichloromethane (3 mL). A 4 M dioxane solution (1 mL) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the precipitated solid was filtered, and the filter cake was washed with dichloromethane and dried to obtain C92 hydrochloride (18.2 mg, 62%). LCMS m / z = 493.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.70 (s, 1H), 9.70 (d, J = 11.7Hz, 1H), 9.23 (s, 1H), 8.65 (s ,1H),8.60(s,2H),8.10(d,J=2.1Hz,1H),7.83(dd,J=8.6,2.2Hz,1H),7.51(d,J=8. 6Hz,1H),7.36(d,J=1.7Hz,1H),4.54–4.29(m,1H),3.82–3.66(m,1H),3.40–3.23(m ,4H),3.15–3.03(m,1H),2.83(s,3H),2.05(d,J=1.7Hz,3H),1.22(d,J=6.7Hz,2H).

[0569] Example 56. Synthesis of C89

[0570] Following the synthetic method for C92, (R)-1-Boc-3-methylpiperazine was used instead of (S)-1-Boc-3-methylpiperazine to synthesize compound C89 hydrochloride. LCMS m / z = 493.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.61(s,1H),8.50(s,2H),8.09(d,J=2.1Hz,1H),7.81(dd,J=8.6,2.2Hz,1H),7.51(d,J=8.6Hz,1H),7.36(d,J =1.8Hz,1H),4.13–4.04(m,1H),3.47–3.40(m,1H),3.02–2.89(m,3H),2.8 2(s,3H),2.81–2.64(m,3H),2.05(d,J=1.7Hz,3H),1.10(d,J=6.5Hz,3H).

[0571] Example 57. Synthesis of C81

[0572] Following the synthetic method for C135, C89 was used instead of C110 to synthesize compound C81. LCMS m / z = 549.15 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),8.27(s,1H),8.59(s,2H),8.09(d,J=2.1Hz,1H),7.82(dd,J=8.6,2.1Hz,1H),7.51(d, J=8.6Hz,1H),7.37(d,J=1.8Hz,1H),4.86–3.69(m,7H),3.39–3.00(m,4H),2.83(s,3H),2.05(d,J=1.6Hz,3H),1.20(s,3H).

[0573] Example 58. Synthesis of C82

[0574] Following the synthetic method for C135, C92 was used instead of C110 to synthesize compound C82. LCMS m / z = 549.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.61(s,1H),8.53(s,2H),8.09(d,J=2.1Hz,1H),7.81(dd,J=8.6,2 .1Hz,1H),7.51(d,J=8.6Hz,1H),7.36(d,J=1.8Hz,1H),4.61–4.56(m,2H),4.50(t,J=6.0Hz,1H),4.43(t, J=6.0Hz,1H),4.27–4.21(m,1H),3.59(d,J=12.1Hz,1H),3.45–3.42(m,1H),3.11–3.04(m,1H),2.82(s,3H ),2.81–2.78(m,1H),2.62(d,J=10.9Hz,1H),2.22–2.17(m,1H),2.07–2.02(m,4H),1.15(d,J=6.4Hz,3H).

[0575] Example 59. Synthesis of C91

[0576] C92 hydrochloride (40 mg, 0.08 mmol) was dissolved in dichloroethane (1 mL), followed by the addition of acrylonitrile (13 mg, 0.24 mmol) and triethylamine (17 mg, 0.16 mmol). The reaction mixture was stirred overnight at 85 °C. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (dichloromethanol / methanol = 30:1) to obtain C91 (21 mg, 41%). LCMS: m / z = 546.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.67(s,1H),8.64(s,1H),8.56(s,2H),8.12(d,J=2.0Hz,1H),7.84(dd,J =8.6,2.1Hz,1H),7.54(d,J=8.6Hz,1H),7.39(d,J=1.9Hz,1H),4.32–4.21(m,1H),3.68–3.55(m,1H ),3.16–3.04(m,1H),3.04–2.96(m,1H),2.92–2.86(m,1H),2.85(s,3H),2.77(t,J=6.6Hz,2H),2.6 8–2.57(m,2H),2.44–2.35(m,1H),2.31–2.17(m,1H),2.08(d,J=1.7Hz,3H),1.16(d,J=6.4Hz,3H).

[0577] Example 60. Synthesis of C93

[0578] C92 hydrochloride (30 mg, 0.061 mmol) and 1-ethoxy-1-trimethoxycyclopropane (32 mg, 0.18 mmol) were dissolved in methanol (1.5 mL). One drop of acetic acid was added, and the mixture was stirred at room temperature for 15 min. Sodium cyanoborohydride (12 mg, 0.18 mmol) was then added. After the addition was complete, the reaction mixture was stirred at 60 °C for 5 h. After the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) in an ice bath. The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) to obtain C93 (11.1 mg, 35%). LCMS m / z = 533.2 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ10.64(s,1H),8.61(s,1H),8.51(s,2H),8.09(d,J=2.1Hz,1H),7.81(dd,J=8.6, 2.1Hz,1H),7.51(d,J=8.6Hz,1H),7.39–7.33(m,1H),4.24–4.15(m,1H),3.59–3.52(m,1H),3.01–2.93(m ,2H),2.82(s,3H),2.81–2.75(m,1H),2.55(dd,J=11.1,3.6Hz,1H),2.42–2.34(m,1H),2.05(d,J=1.7Hz ,3H),1.67–1.60(m,1H),1.03(d,J=6.4Hz,3H),0.50–0.44(m,2H),0.43–0.38(m,1H),0.33–0.26(m,1H).

[0579] Example 61. Synthesis of C96

[0580] C92 hydrochloride (20 mg, 0.04 mmol), isobutane oxide (29.22 mg, 0.41 mmol), and potassium carbonate (28.0 mg, 0.2 mmol) were dissolved in ethanol (1.6 mL) and water (0.4 mL). The reaction mixture was stirred under microwave irradiation at 110 °C for 0.5 h. After the reaction was complete, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative chromatography to obtain C96 (7.4 mg, 33%). LCMS m / z = 565.2 [M+H] + ; 1H NMR (400MHz, CD3OD) δ8.44(s,2H),8.37(s,1H),8.00(d,J=2.0Hz,1H),7.71(dd,J=8.6,2.2Hz,1H) ,7.42(d,J=8.6Hz,1H),7.34(d,J=1.8Hz,1H),4.16–4.03(m,1H),3.49–3.41(m,1H),3.28–3.18(m ,1H),3.11–3.04(m,1H),2.97–2.91(m,1H),2.83(s,3H),2.66(dd,J=11.2,3.4Hz,1H),2.52–2.44 (m,1H),2.39–2.29(m,2H),2.08(d,J=1.6Hz,3H),1.27(d,J=6.4Hz,3H),1.26(s,3H),1.24(s,3H).

[0581] Example 62. Synthesis of C103 and C102

[0582] Following the synthetic method for C92, (S)-1-Boc-3-methylpiperazine was substituted for (2R,5S)-1-Boc-2,5-dimethylpiperazine to synthesize compounds C103 and C102. C103:LCMS:m / z=607.10[M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.60(s,1H),8.53(s,2H),8.09(d,J=2.0Hz,1H),7.81(d d,J=8.6,2.1Hz,1H),7.51(d,J=8.6Hz,1H),7.36(d,J=1.8Hz,1H),4.4–4.15(m,2H),3.70(d,J =13.5Hz, 1H), 3.48(dd, J = 12.8, 2.3Hz, 1H), 3.29–3.21(m, 2H), 2.82(s, 3H), 2.04(d, J = 1.6Hz, 3H), 1.43(s, 9H), 1.20(d, J = 6.7Hz, 3H), 1.03(d, J = 6.5Hz, 3H). C102 hydrochloride: LCMS: m / z = 507.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),9.56–9.44(m,1H),9.43–9.28(m,1H),8.68–8.65 (m,3H),8.10(d,J=2.1Hz,1H),7.82(dd,J=8.6,2.2Hz,1H),7.51(d,J=8.6Hz,1H),7.37 (d,J=1.9Hz,1H),3.93–3.86(m,1H),3.51–3.39(m,3H),3.33–3.27(m,1H),3.00–2.93( m,1H),2.85(s,3H),2.05(d,J=1.7Hz,3H),1.32(d,J=6.6Hz,3H),1.13(d,J=6.4Hz,3H).

[0583] Example 63. Synthesis of C104

[0584] C102 (35 mg, 0.069 mmol) and sodium cyanoborohydride (13 mg, 0.21 mmol) were dissolved in methanol (2 mL). Then, a solution of formaldehyde (18% in H2O, 35 mg, 0.21 mmol) dissolved in methanol (1 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (45 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain C104 (15.5 mg, 43%). LCMS: m / z = 521.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.64(s,1H),8.59(s,2H),8.09(d,J=2.1Hz,1H),7.81(d d,J=8.6,2.1Hz,1H),7.50(d,J=8.6Hz,1H),7.36(d,J=1.8Hz,1H),3.82–3.67(m,1H),3.22(dd ,J=11.8,3.4Hz,1H),3.07(dd,J=11.8,5.9Hz,1H),2.87–2.81(m,4H),2.66–2.59(m,1H),2.23 (s,3H),2.20–2.15(m,1H),2.05(d,J=1.6Hz,3H),1.04(d,J=6.2Hz,3H),0.98(d,J=6.4Hz,3H).

[0585] Example 64. Synthesis of C144

[0586] C92 hydrochloride (40 mg, 0.08 mmol) was dissolved in (EtOH / H2O = 2 mL / 0.5 mL). Ethylene oxide (71 mg, 1.62 mmol) and potassium carbonate (56 mg, 0.40 mmol) were then added to the reaction solution. The reaction mixture was stirred in a microwave at 100 °C for 0.5 h. After the reaction was complete, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to obtain C144 (6.8 mg, 14%). LCMS: m / z = 537.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.64(s,1H),8.61(s,1H),8.51(s,2H),8.09(d,J=2.1Hz,1H),7.8 1(dd,J=8.7,2.1Hz,1H),7.51(d,J=8.6Hz,1H),7.36(s,1H),4.42(t,J=5.3Hz,1H),4.19(s ,1H),3.57–3.52(m,3H),3.09–2.95(m,2H),2.82(s,3H),2.80–2.75(m,1H),2.43(t,J=6.2 Hz,2H),2.37–2.33(m,1H),2.21–2.15(m,1H),2.05(d,J=1.7Hz,3H),1.12(d,J=6.4Hz,3H).

[0587] Example 65. Synthesis of C136

[0588] Following the synthetic method for C135, C102 was used instead of C110 to synthesize compound C136. LCMS: m / z = 563.05 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.66(s,1H),8.62(s,1H),8.55(s,2H),8.10(d,J=2.0Hz,1H),7.82(dd,J=8.6,2. 0Hz,1H),7.51(d,J=8.6Hz,1H),7.37(s,1H),4.60–4.51(m,2H),4.46(t,J=6.1Hz,1H),4.12–4.05(m,1H),3 .84–3.77(m,1H),3.39–3.34(m,1H),3.29–3.21(m,1H),3.01–2.94(m,1H),2.83(s,3H),2.82–2.79(m,1H) ,2.37–2.27(m,1H),2.05(d,J=1.6Hz,3H),2.05–1.93(m,1H),1.14(d,J=6.3Hz,3H),0.91(d,J=6.5Hz,3H).

[0589] Example 66. Synthesis of C105

[0590] Following the synthetic method for compound C97, C105 was synthesized by replacing (R)-3-pyrrolanol with (R)-3-methoxypyrrolidine. LCMS m / z = 494.1 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.59(s,1H),8.22(s,2H),8.10(d,J=2 .0Hz,1H),7.82(dd,J=8.6,2.2Hz,1H),7.51(d,J=8.6Hz,1H),7.36(d,J=1.8 Hz,1H),4.16–4.10(m,1H),3.52–3.47(m,1H),3.45–3.42(m,1H),3.42–3.35 (m,2H),3.28(s,3H),2.81(s,3H),2.13–2.06(m,2H),2.05(d,J=1.6Hz,3H).

[0591] Example 67. Synthesis of C106

[0592] Following the synthetic method for compound C69, C106 was synthesized by replacing (S)-propionide glycerol with N-Boc-1-aminocyclopropanol. LCMS: m / z = 480.1 [M+H] + ; 1H NMR (400MHz, CD3OD) δ8.63(s,2H),8.50(s,1H),8.01(d,J=2.0Hz,1H),7.72(dd,J=8.8,2.0Hz,1H),7. 43(d,J=8.8Hz,1H),7.35(s,1H),4.34(s,2H),2.87(s,3H),2.08(d,J=1.6Hz,3H),1.20–1.11(m,4H).

[0593] Example 68. Synthesis of C107

[0594] Referring to the synthesis method of compound C97, using The hydrochloride salt was used to replace (R)-3-pyrrolidol to synthesize C107. LCMS m / z = 492.1 [M+H] + ; 1 ¹H NMR (400MHz, chloroform-d) δ 8.28 (s, 1H), 8.18 (s, 2H), 8.02–7.96 (m, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.57 (dd, J = 8.5, 2.2 Hz, 1H), 7.35–7.31 (m, 1H), 4.78–4.72 (m, 1H), 4.54–4.49 (m, 1H), 3.95–3.88 (m, 2H), 3.63 (d, J = 9.1 Hz, 1H), 3.27 (d, J = 9.2 Hz, 1H), 2.87 (s, 3H), 2.25–2.17 (m, 1H), 2.08 (d, J = 1.7 Hz, 3H), 2.03–1.94 (m, 1H).

[0595] Example 69. Synthesis of C108

[0596] Referring to the synthesis method of C92-3, using C108 was synthesized by substituting (S)-1-Boc-3-methylpiperazine with hydrochloride. LCMS: m / z = 506.00 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.62(s,1H),8.54(s,2H),8.09(d,J=2.0Hz,1H),7.82(dd,J=8.6,2.1Hz,1H),7.51(d,J=8.6Hz,1H),7. 36(d,J=1.9Hz,1H),4.42–4.37(m,2H),3.73(d,J=11.1Hz,2H),3.48(d,J=10.8Hz,2H),2.83(s,3H),2.05(d,J=1.6Hz,3H),2.02–1.94(m,4H).

[0597] Example 70. Synthesis of C111

[0598] Following the synthesis method of C104, C111 was synthesized by replacing C102 with C110. LCMS: m / z = 519.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.65(s,1H),8.60(s,1H),8.44(s,2H),8.09(d,J =2.0Hz,1H),7.82–7.80(m,1H),7.51(d,J=8.4Hz,1H),7.37(s,1H),3.54( d,J=10.8Hz,2H),3.29–3.23(m,2H),2.97(d,J=10.6Hz,2H),2.82(s,3H), 2.26(s,3H),2.05(d,J=1.8Hz,3H),2.01–1.95(m,2H),1.70–1.62(m,2H).

[0599] Example 71. Synthesis of C114

[0600] Referring to the synthetic method of compound C110, using replace C114 hydrochloride was synthesized. LCMS: m / z = 491.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),9.77(s,1H),9.23(s,1H),8.62(s,1H),8.38(s,2H), 8.10(d,J=2.0Hz,1H),7.83(dd,J=8.6,2.2Hz,1H),7.51(d,J=8.6Hz,1H),7.36(d,J=1.8Hz, 1H),4.87–4.83(m,1H),4.54–4.49(m,1H),3.66(d,J=10.4Hz,1H),3.57(d,J=10.6Hz,1H),3 .27–3.20(m,2H),2.82(s,3H),2.16–2.12(m,1H),2.05(d,J=1.6Hz,3H),2.03–1.99(m,1H).

[0601] Example 72. Synthesis of C100

[0602] Referring to the synthetic method of compound C110, using replace C100 hydrochloride was synthesized. LCMS m / z = 491.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.67(s,1H),9.49(s,1H),8.95(s,1H),8.62(s,1H), 8.38(s,2H),8.10(d,J=2.0Hz,1H),7.84–7.81(m,1H),7.51(d,J=8.8Hz,1H), 7.37(s,1H),4.86(s,1H),4.52(s,1H),3.67(d,J=10.4Hz,2H),3.26–3.21(m, 2H),2.82(s,3H),2.17–2.12(m,1H),2.05(d,J=1.6Hz,3H),2.03–1.94(m,1H).

[0603] Example 73. Synthesis of C101

[0604] Following the synthesis method of C104, C101 was synthesized by replacing C102 with C100. LCMS m / z = 505.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.64(s,1H),8.59(s,1H),8.29(s,2H),8.10(d,J=2.0Hz,1H) ,7.82(dd,J=8.6,2.1Hz,1H),7.51(d,J=8.6Hz,1H),7.37(s,1H),4.55(s,1H),3.57–3. 48(m,1H),3.42–3.39(m,1H),3.29–3.27(m,1H),2.85–2.82(m,1H),2.81(s,3H),2.36– 2.31(m,1H),2.30(s,3H),2.05(d,J=1.6Hz,3H),2.01–1.91(m,1H),1.82–1.76(m,1H).

[0605] Example 74. Synthesis of C119

[0606] Following the synthetic method for C135, C100 was used instead of C110 to synthesize compound C119. LCMS m / z = 547.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.64(s,1H),8.60(s,1H),8.29(s,2H),8.09(d,J=2.1Hz,1H),7.82(dd,J=8.5,2.2Hz, 1H),7.51(d,J=8.6Hz,1H),7.36(d,J=2.0Hz,1H),4.63–4.59(m,1H),4.57–4.52(m,2H),4.34(t,J=5.9Hz,1H),4 .24(t,J=5.8Hz,1H),3.94–3.81(m,1H),3.62–3.54(m,1H),3.41(d,J=9.0Hz,1H),3.11(d,J=9.4Hz,1H),2.81(s ,3H),2.80–2.76(m,1H),2.72–2.67(m,1H),2.05(d,J=1.7Hz,3H),1.89(d,J=9.5Hz,1H),1.79(d,J=8.8Hz,1H).

[0607] Example 75. Synthesis of C120

[0608] Following the synthetic method for C91, C100 was used instead of C92 to synthesize compound C120. LCMS m / z = 544.05 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.62(s,1H),8.32(s,2H),8.12(d,J=2.0Hz,1H), 7.84(dd,J=8.5,2.2Hz,1H),7.53(d,J=8.6Hz,1H),7.39(d,J=1.8Hz,1H),4.64–4.55(m ,1H),3.78–3.65(m,1H),3.49–3.40(m,1H),3.31–3.20(m,1H),2.97–2.88(m,1H),2.84 (s,3H),2.78–2.67(m,2H),2.64–2.57(m,2H),2.07(d,J=1.6Hz,3H),2.04–1.77(m,3H).

[0609] Example 76. Synthesis of C121

[0610] Following the synthetic method for C96, C92 was replaced with C100 to synthesize compound C121. LCMS: m / z = 563.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.64(s,1H),8.59(s,1H),8.28(s,2H),8.09(d,J=2.0Hz,1H),7.84–7.79( m,1H),7.51(d,J=8.6Hz,1H),7.41–7.30(m,1H),4.55–4.49(m,1H),4.02–3.94(m,1H),3.65–3.60(m ,1H),3.43–3.39(m,1H),3.30–3.26(m,1H),3.03(d,J=9.8Hz,1H),2.81(s,3H),2.61–2.55(m,1H), 2.43–2.32(m,2H),2.05(d,J=1.7Hz,3H),1.89(d,J=9.2Hz,1H),1.78(d,J=9.2Hz,1H),1.03(s,6H).

[0611] Example 77. Synthesis of C122

[0612] Under N2 protection, C98 (25 mg, 0.05 mmol), methanesulfonamide (12.5 mg, 0.13 mmol), Xantphos (6 mg, 0.01 mmol), cesium carbonate (51 mg, 0.15 mmol), and Pd2(dba)3 (5 mg, 0.01 mmol) were dissolved in dioxane (3 mL). The reaction solution was replaced with N2 three times, and the mixture was stirred at 110 °C for 3 hours. After the reaction was complete, the reaction solution was diluted with water (45 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give C122 (3 mg, 12%). LCMS: m / z = 487.95 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.68(s,1H),10.28(s,1H),8.72(s,2H),8.68(s,1H),8.09(d,J=2.1Hz,1H),7.81(dd,J =8.6,2.3Hz,1H),7.52(d,J=8.6Hz,1H),7.37(d,J=1.8Hz,1H),3.17(s,3H),2.86(s,3H),2.05(d,J=1.6Hz,3H).

[0613] Example 78. Synthesis of C124

[0614] 1) Step One

[0615] C92-2 (3.35 g, 8.00 mmol) was dissolved in dichloromethane (40 mL), and dioxane hydrochloride solution (4 M, 40 mL, 160.09 mmol) was added dropwise to the reaction solution. The reaction solution was stirred at room temperature for 2 hours. After the reaction was confirmed to be complete by LCMS, the reaction solution was concentrated under reduced pressure to give a yellow solid, C124-1 hydrochloride (3.7 g, 100%). LCMS m / z = 319.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.58(s,2H),8.16(s,1H),4.39–4.34(m,1H),3.33–3.21(m,5H),3.11–3.04(m,1H),2.81(s,3H),1.21(d,J=6.9Hz,3H).

[0616] 2) Step Two

[0617] C124-1 (500 mg, 1.41 mmol) and 3-oxetane (304.6 mg, 4.23 mmol) were dissolved in methanol (30 mL). Sodium cyanoborohydride (265.6 mg, 4.23 mmol) was slowly added to the reaction solution. The reaction solution was stirred overnight at room temperature. The solution was concentrated under reduced pressure, and the crude product was dissolved in dimethyl sulfoxide and purified by reversed-phase preparative chromatography (acetonitrile / 0.1% formic acid aqueous solution) to give a yellow solid C124-2 (257 mg, 49%). LCMS m / z = 375.2 [M+H] + .

[0618] 3) Step Three

[0619] Following the synthetic method for C10-9, C10-7 was synthesized by replacing C10-7 with 2-fluoro-6-chloro-4-bromobenzaldehyde; similarly, following the synthetic method for C10-14, C10-11 was synthesized by replacing C10-11 with C124-3, yielding compound C124. LCMS m / z = 567.2 [M+H] + ; 1 HNMR (400MHz, DMSO-d6) δ10.76(s,1H),8.61(s,1H),8.53(s,2H),7.90–7.88(m,1H),7.81(dd,J=12. 3,2.0Hz,1H),7.22(s,1H),4.63–4.54(m,2H),4.50(t,J=6.0Hz,1H),4.44(t,J=6.0Hz,1H),4.29–4. 21(m,1H),3.60(d,J=12.3Hz,1H),3.46–3.41(m,1H),3.15–3.01(m,1H),2.83(s,3H),2.63(d,J=11. 0Hz,1H),2.20(dd,J=11.0,3.5Hz,1H),2.08–1.93(m,2H),1.87–1.84(m,3H),1.15(d,J=6.4Hz,3H).

[0620] Example 79. Synthesis of C130

[0621] Following the synthetic method for C149, C130-1 was used instead of C149-2 to synthesize compound C130. LCMS m / z = 529.3 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.60(s,1H),8.55(s,2H),7.72–7.67(m,2H),7.44(s,1H),7.28(d,J=12Hz,1H),4.62 –4.26(m,5H),3.64–3.57(m,3H),3.16–3.09(m,3H),2.82(s,3H),2.67–2.61(m,1H),2.27(s,3H),2.01(s,3H),1.17(s,3H).

[0622] Example 80. Synthesis of C154

[0623] Following the synthetic method for C58, C124-2 was substituted for C26-3 to synthesize compound C154. LCMS m / z = 562.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),8.60(s,1H),8.53(s,2H),8.02(d,J=2.1Hz,1H),7.74(dd,J=8.5,2.1Hz,1 H),7.38(d,J=8.6Hz,1H),6.68(s,1H),4.61–4.56(m,2H),4.50(t,J=6.0Hz,1H),4.43(t,J=6.0Hz,1H),4.27–4.2 1(m,1H),3.62–3.57(m,1H),3.44–3.42(m,1H),3.11–3.05(m,1H),2.82(s,3H),2.81–2.78(m,1H),2.64–2.60(m ,1H),2.20(dd,J=11.1,3.5Hz,1H),2.07–2.02(m,1H),1.99(s,3H),1.90(d,J=1.4Hz,3H),1.15(d,J=6.4Hz,3H).

[0624] Example 81. Synthesis of C127

[0625] Following the synthetic method for C149, C127-1 was used instead of C149-2 to synthesize compound C127. LCMS m / z = 593.1 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.40(s,2H),8.21(s,1H),8.03(d,J=2.0Hz,1H),7.94(s,1H),7.64(dd,J=8.4 ,2.0Hz,1H),7.29–7.28(m,1H),7.27–7.24(m,1H),4.77–4.70(m,3H),4.69–4.62(m,1H),4.02(s,1 H),3.61(s,1H),3.45(d,J=11.6Hz,1H),3.25(t,J=10.4Hz,1H),2.89(s,3H),2.87–2.81(m,1H),2. 64–2.59(m,1H),2.53–2.44(m,1H),2.39–2.27(m,1H),2.06(d,J=1.6Hz,3H),1.25(d,J=6.2Hz,3H).

[0626] Example 82. Synthesis of C128

[0627] Following the synthetic method for C149, C128-1 was used instead of C149-2 to synthesize compound C128. LCMS: m / z = 515.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),8.61(s,1H),8.54(s,2H),7.91–7.85(m,2H),7.49(d,J=8.7Hz, 2H),7.33(d,J=1.7Hz,1H),4.64–4.55(m,2H),4.50(t,J=6.0Hz,1H),4.44(t,J=6.0Hz,1H),4.30–4.19 (m,1H),3.60(d,J=11.9Hz,1H),3.48–3.39(m,1H),3.14–3.02(m,1H),2.82(s,3H),2.81–2.77(m,1H), 2.70–2.59(m,1H),2.26–2.18(m,1H),2.15(d,J=1.5Hz,3H),2.03–1.94(m,1H),1.15(d,J=6.4Hz,3H).

[0628] Example 83. Synthesis of C133

[0629] Following the synthetic method for C149, C133-1 was used instead of C149-2 to synthesize compound C133. LCMS: m / z = 583.0 [M+H] + ;1 H NMR (400MHz, DMSO-d6) δ10.77(s,1H),8.64(s,1H),8.53(s,2H),8.32(d,J=2.1Hz,1H),8.16(dd,J=8.6,2.1Hz, 1H),7.54(d,J=8.5Hz,1H),7.45(s,1H),4.65–4.55(m,2H),4.50(t,J=6.0Hz,1H),4.44(t,J=6.0Hz,1H),4.31–4 .17(m,1H),3.60(d,J=12.1Hz,1H),3.46–3.39(m,1H),3.18–2.98(m,1H),2.83(s,3H),2.82–2.78(m,1H),2.63( d,J=11.0Hz,1H),2.20(dd,J=11.1,3.5Hz,1H),2.10–1.98(m,1H),1.98(d,J=1.6Hz,3H),1.16(d,J=6.4Hz,3H).

[0630] Example 84. Synthesis of C95 and C137

[0631] Referring to the synthesis method of C92, using By substituting (S)-1-Boc-3-methylpiperazine, compound C95 hydrochloride was synthesized. LCMS m / z = 505.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.68(s,1H),9.91–9.75(m,1H),9.35–9.22(m,1H),8.64(s,1H),8. 47(s,2H),8.10(d,J=2.1Hz,1H),7.82(dd,J=8.6,2.2Hz,1H),7.51(d,J=8.6Hz,1H),7.36(d ,J=1.9Hz,1H),4.06–4.00(m,1H),3.61–3.54(m,2H),3.40–3.34(m,2H),3.21–3.14(m,1H), 2.83(s,3H),2.64–2.58(m,1H),2.23–2.18(m,1H),2.13–2.06(m,2H),2.05(d,J=1.6Hz,3H).

[0632] Following the synthetic method for C135, C95 was used instead of C110 to synthesize compound C137. LCMS m / z = 561.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.61(s,1H),8.42(s,2H),8.09(d,J=2.0Hz,1H),7.81(dd, J=8.6,2.1Hz,1H),7.50(d,J=8.6Hz,1H),7.36(d,J=2.1Hz,1H),4.60–4.53(m,2H),4.48–4.43(m ,2H),3.88–3.83(m,1H),3.43–3.39(m,1H),2.92–2.85(m,3H),2.82(s,3H),2.46–2.41(m,1H),2 .23–2.13(m,2H),2.12–2.07(m,1H),2.04(d,J=1.6Hz,3H),1.98–1.93(m,1H),1.84–1.76(m,1H).

[0633] Example 85. Synthesis of C94 and C134

[0634] Referring to the synthesis method of C92, using By substituting (S)-1-Boc-3-methylpiperazine, compound C94 hydrochloride was synthesized. LCMS m / z = 505.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.69(s,1H),9.51–9.38(m,1H),9.10(s,1H),8.64(s,1H),8.61(s,2H),8.10(d,J=2.0Hz,1H),7.83–7.81(m,1H),7.51( d,J=8.6Hz,1H),7.37(d,J=1.8Hz,1H),4.63(s,2H),3.20–3.10(m,2H),3 .08–3.02(m,2H),2.84(s,3H),2.18–2.11(m,4H),2.05(d,J=1.6Hz,3H).

[0635] Following the synthetic method for C135, C94 was used instead of C110 to synthesize compound C134. LCMS: m / z = 561.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.60(s,1H),8.50(s,2H),8.09(d,J=2.0H z,1H),7.83–7.80(m,1H),7.51(d,J=8.6Hz,1H),7.36(d,J=1.9Hz,1H),4.52–4. 39(m,6H),3.41–3.36(m,1H),2.82(s,3H),2.47–2.45(m,1H),2.23–2.20(m,1H) ,2.19–2.17(m,1H),2.05(d,J=1.6Hz,3H),2.04–2.00(m,2H),1.94–1.87(m,2H).

[0636] Example 86. Synthesis of C88

[0637] Referring to the synthesis method of C97, using By substituting (R)-3-pyrrolidol, compound C88 hydrochloride was synthesized. LCMS m / z = 505.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.72(s,1H),9.91–9.83(m,2H),8.68–8.63(m,3H),8.12(d,J=2.0Hz,1H),7.85–7.83(m,1H),7.53(d,J=8.6Hz,1H),7.39 (d,J=1.8Hz,1H),3.67(t,J=5.2Hz,2H),3.54(s,2H),3.40–3.33(m,2H), 2.85(s,3H),2.07(d,J=1.6Hz,3H),1.20–1.14(m,2H),0.98–0.94(m,2H).

[0638] Example 87. Synthesis of C90

[0639] Following the synthesis method for C104, C90 was synthesized by replacing C102 with C92 hydrochloride. LCMS m / z = 507.2 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.62(s,1H),8.52(s,2H),8.10(d,J=2.1Hz,1H),7 .82(dd,J=8.6,2.2Hz,1H),7.51(d,J=8.6Hz,1H),7.37(d,J=1.8Hz,1H),4.26–4.16(m,1 H),3.56(d,J=11.8Hz,1H),3.10–3.02(m,1H),2.91–2.84(m,1H),2.83(s,3H),2.70(d,J =11.2Hz,1H),2.30–2.24(m,1H),2.22(s,3H),2.09–2.01(m,4H),1.12(d,J=6.4Hz,3H).

[0640] Example 88. Synthesis of C126

[0641] Following the synthetic method for C149, C126-1 was used instead of C149-2 to synthesize compound C126. LCMS m / z = 533.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.69(s,1H),8.62(s,1H),8.54(s,2H),7.84(d,J=13.1Hz,1H), 7.65(d,J=8.6Hz,1H),7.51(t,J=8.5Hz,1H),7.31(s,1H),4.67–4.57(m,2H),4.56–4.37 (m,2H),4.36–4.15(m,1H),3.69–3.54(m,1H),3.17–3.02(m,2H),2.87–2.78(m,4H),2.7 0–2.59(m,1H),2.30–2.16(m,1H),2.07(s,3H),2.05–1.92(m,1H),1.16(d,J=6.4Hz,3H).

[0642] Example 89. Synthesis of C132

[0643] 1) Step One

[0644] Under nitrogen protection, C127-2E (60 mg, 0.25 mmol), cyclopropylboronic acid (29 mg, 0.32 mmol), tricyclohexylphosphine (7 mg, 0.02 mmol), palladium acetate (3 mg, 0.01 mmol), and potassium phosphate (188 mg, 0.88 mmol) were dissolved in toluene (1.6 mL) and H2O (0.1 mL). The reaction solution was replaced with N2 three times, and the mixture was stirred overnight at 100 °C. After the reaction was complete, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give C132-1 (28 mg, 55%), which was a red oil. 1 H NMR (400MHz, DMSO-d6) δ7.52(d,J=1.6Hz,1H),7.05(d,J=8.4Hz,1H),6.41(dd,J=8.4,2.4Hz,1H),6.26(d, J=2.4Hz,1H),5.48(s,2H),2.02(d,J=1.6Hz,3H),1.90–1.74(m,1H),0.97–0.81(m,2H),0.61–0.43(m,2H).

[0645] 2) Step Two

[0646] Following the synthetic method for C133, C132-1 was used instead of C133-2E to synthesize compound C132. LCMS: m / z = 555.3 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.59(s,1H),8.53(s,2H),7.75(dd,J=8.5,2.1Hz,1H),7.63(d,J=1.7Hz,1H),7.45(d ,J=2.1Hz,1H),7.27(d,J=8.5Hz,1H),4.63–4.54(m,2H),4.50(t,J=6.1Hz,1H),4.43(t,J=6.0Hz,1H),4.27–4.20(m,1H),3 .59(d,J=12.0Hz,1H),3.46–3.38(m,1H),3.11–3.04(m,1H),2.82(s,3H),2.81–2.76(m,1H),2.62(d,J=10.9Hz,1H),2.20( dd,J=11.0,3.5Hz,1H),2.11–1.99(m,4H),1.98–1.90(m,1H),1.15(d,J=6.4Hz,3H),1.05–0.95(m,2H),0.69–0.60(m,2H).

[0647] Example 90. Synthesis of C147

[0648] 1) Step One

[0649] N-Boc-L-proline (24.5 mg, 0.11 mmol) was dissolved in DMF (1.5 mL), and DIPEA (48.5 mg, 0.38 mmol) and HATU (44 mg, 0.11 mmol) were added. The reaction mixture was stirred for 0.5 h, and then compound C92 (40 mg, 0.11 mmol) was added. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction mixture was quenched with water (30 mL), extracted with ethyl acetate (3 × 10 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (dichloromethane:methanol = 15:1) to give a white solid C147-1 (35 mg, 67.3%). LCMS m / z = 690.10 [M+H] + .

[0650] 2) Step Two

[0651] C147-1 (48 mg, 0.059 mmol) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride solution (4 M, 1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the precipitated solid was filtered, the filter cake was washed twice with dichloromethane, and the filter cake was collected and dried to obtain C147 (29 mg, 85%). LCMS m / z = 590.10 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.67(s,1H),8.62(s,1H),8.56(s,2H),8.10(d,J=2.1Hz,1H),7.82(dd,J=8.5,2.2Hz,1 H),7.51(d,J=8.6Hz,1H),7.36(d,J=1.9Hz,1H),4.36–4.22(m,2H),3.90–3.85(m,1H),3.67–3.61(m,1H),3.54–3 .46(m,1H),3.12–3.07(m,1H),3.03–2.98(m,1H),2.83(s,3H),2.67–2.62(m,1H),2.05(d,J=1.6Hz,3H),2.02–1. 94(m,1H),1.73–1.60(m,2H),1.58–1.52(m,1H),1.24–1.21(m,3H),1.06(d,J=6.4Hz,1H),0.95(d,J=6.4Hz,1H).

[0652] Example 91. Synthesis of C148

[0653] Following the synthetic method for C147, N-Boc-L-proline was substituted with N-Boc-glycine to synthesize compound C148 hydrochloride. LCMS m / z = 550.5 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.70(s,1H),8.64(s,1H),8.57(d,J=5.1Hz,2H),8.19(t,J=5.6Hz,3H) ,8.10(d,J=2.1Hz,1H),7.83(dd,J=8.6,2.2Hz,1H),7.51(d,J=8.6Hz,1H),7.36(d,J=1.9Hz,1H ),4.34–4.25(m,1H),4.24–4.07(m,1H),3.99–3.82(m,2H),3.71–3.63(m,2H),3.40–3.29(m,1H ),3.25–3.16(m,1H),3.14–3.03(m,1H),2.83(s,3H),2.05(d,J=1.7Hz,3H),1.08–0.99(m,3H).

[0654] Example 92. Synthesis of C84

[0655] Following the synthetic method for C10, C124-2 was used instead of C10-4 to synthesize compound C84. LCMS m / z = 564.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),8.57(s,1H),8.53(s,2H),7.22(d,J=2.0Hz,1H),7.13(d,J=2.0Hz, 1H),7.06(d,J=2.0Hz,1H),5.48(s,2H),4.61–4.57(m,2H),4.51(t,J=6.0Hz,1H),4.45(t,J=6.0Hz,1H), 4.24(s,1H),3.60(d,J=12.0Hz,1H),3.49–3.40(m,1H),3.12–3.05(m,1H),2.85–2.82(m,1H),2.81(s,3H ),2.68–2.61(m,1H),2.28–2.20(m,1H),2.11–2.02(m,1H),1.78(d,J=1.6Hz,3H),1.15(d,J=6.4Hz,3H).

[0656] Example 93. Synthesis of C83

[0657] Following the synthetic method for C92-2, (R)-1-Boc-3-methylpiperazine was used instead of (S)-1-Boc-3-methylpiperazine to synthesize C83-2; following the synthetic method for C124-2, C83-2 was used instead of C92-2 to synthesize C83-4; following the synthetic method for C10, C83-4 was used instead of C10-4 to synthesize compound C83. LCMS m / z = 564.2 [M+H] + ; 1 ¹H NMR (400 MHz, methanol-d⁴) δ 8.48 (s, 2H), 8.34 (s, 1H), 7.17–7.12 (m, 2H), 7.07 (s, 1H), 4.74–4.71 (m, 2H), 4.69–4.66 (m, 1H), 4.62–4.60 (m, 1H), 4.20–4.11 (m, 1H), 3.55–3.49 (m, 2H) H),3.27–3.19(m,1H),2.88–2.84(m,1H),2.83(s,3H),2.67(d,J=11.2Hz,1H),2.35(d d,J=11.2,3.6Hz,1H),2.19–2.15(m,1H),1.86(d,J=1.6Hz,3H),1.26(d,J=6.4Hz,3H).

[0658] Example 94. Synthesis of C23

[0659] 1) Step One

[0660] 2-Chloro-5-hydroxypyrimidine (1.0 g, 7.66 mmol) was dissolved in tetrahydrofuran (20 mL), and 2-tert-butyl-1,3-diisopropylisourea (9.3 mL, 45.97 mmol) was added dropwise under nitrogen protection at 60 °C. After the addition was complete, the reaction mixture was stirred at 60 °C for 2.5 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the crude product was directly purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 23:2) to give a colorless oily substance C23-1 (570 mg, 41%). LCMS m / z = 187.1 [M+H] + .

[0661] 2) Step Two

[0662] Following the synthetic method for compound C10, compound C23 was synthesized by replacing C10-1 with C23-1. LCMS m / z = 482.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.30(s,1H),8.64(s,1H),8.63(s,2H),7.21(d,J=1.9Hz,1H),7.13(d, J=1.9Hz,1H),7.08–7.04(m,1H),5.49(s,2H),2.84(s,3H),1.78(d,J=1.5Hz,3H),1.38(s,9H).

[0663] Example 95. Synthesis of C155

[0664] Following the synthetic method for C58, in step one, iodoethane was used instead of iodomethane, and C124-2 was used instead of C26-3 to synthesize compound C155. LCMS m / z = 576.3 [M+H] + ; 1 ¹H NMR (400 MHz, methanol-d⁴) δ 8.42 (s, 2H), 8.34 (s, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.60–7.56 (m, 1H), 7.27 (d, J = 8.5 Hz, 1H), 6.69 (s, 1H), 4.73–4.69 (m, 2H), 4.65 (t, J = 6.1 Hz, 1H), 4.61–4.58 (m, 1H), 4.14–4.08 (m, 1H),3.51–3.45(m,2H),3.22–3.15(m,1H),2.86–2.81(m,1H),2.81(s,3H),2.66–2.61(m,1H),2.41– 2.29(m,3H),2.18–2.11(m,1H),1.91(d,J=1.5Hz,3H),1.23(d,J=6.5Hz,3H),1.19(t,J=7.5Hz,3H).

[0665] Example 96. Synthesis of C257

[0666] 1) Step One

[0667] Following the synthesis method for C16-2, C257-1 was synthesized by replacing C16-1 with diethyl cyanomethyl phosphate. LCMS m / z = 287.0 [M+H] + .

[0668] 2) Step Two

[0669] Following the synthesis method of C16-7, C257-1 was used instead of C16-4 to synthesize C257-4. LCMS m / z = 546.1 [M+H] + .

[0670] 3) Step Three

[0671] 257-4 (39 mg, 0.17 mmol) was dissolved in THF (1.5 mL), and sodium dithionite (51 mg, 0.29 mmol) was dissolved in water (1.5 mL) and added dropwise to the reaction solution. The reaction solution was stirred at 40 °C for 1 hour. After the reaction was complete, the reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (ethyl acetate) to obtain C257 (1.7 mg, 11%, Z / E 1:1 mixture). LCMS m / z = 516.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.21–10.03(m,1H),8.12–7.95(m,1H),7.66–7.47(m,1H),7.31–7.08(m,2H),6.83–6. 62(m,2H),6.25–6.00(m,1H),5.97–5.49(m,2H),4.43(t,J=12.3Hz,4H),3.92–3.78(m,3H),2.42–2.34(m,3H).

[0672] Example 97. Synthesis of C19

[0673] 1) Step One

[0674] Under nitrogen protection, C10-7 (2.0 g, 7.56 mmol) was dissolved in tetrahydrofuran (40 mL). After cooling to -78 °C, methyl magnesium bromide (3 M, 3.8 mL, 11.34 mmol) was added dropwise to the reaction solution. The reaction solution was stirred at -78 °C for 10 minutes, then slowly raised to room temperature and stirred for 2 hours. After the reaction was confirmed to be complete by LCMS, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a yellow oily substance C19-1 (528 mg, 25%). LCMS m / z = 261.9 [M-H2O+H] + .

[0675] 2) Step Two

[0676] Under nitrogen protection, C19-1 (528 mg, 1.88 mmol) was dissolved in dichloromethane (15 mL). Desmartin reagent (1.2 g, 2.82 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was confirmed to be complete by LC-MS, the reaction mixture was quenched with saturated sodium sulfite solution (10 mL), and the pH was adjusted to neutral with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were 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 silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give a yellow solid C19-2 (446 mg, 85%). 1 H NMR (400MHz, CDCl3) δ8.26 (d, J = 1.8 Hz, 1H), 7.89 (d, J = 1.8 Hz, 1H), 2.64 (s, 3H).

[0677] 3) Step Three

[0678] Following the synthetic method for C257, C19 was synthesized by replacing C10-7 with C19-2. LCMS m / z = 530.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.81–7.64(m,2H),7.56(s,1H),7.22(s,1H),6.89(s,1H),6.41–6 .35(m,1H),5.38(s,1H),4.36(t,J=11.6Hz,4H),3.85(s,3H),2.47(s,3H),2.35(s,3H).

[0679] Example 98. Synthesis of C125

[0680] 1) Step One

[0681] Referring to the synthesis method of C12-2, C125-1 was synthesized by replacing C12-1 with C74-3. 1 HNMR (400MHz, DMSO-d6) δ8.52(d,J=2.0Hz,1H),8.45(d,J=2.0Hz,1H),7.44(d,J=1.6Hz,1H),1.78(d,J=1.6Hz,3H).

[0682] 2) Step Two

[0683] C125-1 (200 mg, 0.663 mmol) was dissolved in dioxane (4 mL) and water (1 mL). Trimethylcyclotriboroxane (50% THF solution, 500 mg, 1.99 mmol), Pd(dppf)Cl2 (48.29 mg, 0.066 mmol), and potassium carbonate (275 mg, 1.99 mmol) were added. The reaction mixture was purged with nitrogen three times and stirred at 90 °C for 4 hours. After the reaction was complete, the reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a yellow solid C125-2 (110 mg, 70%). 1 H NMR (400MHz, DMSO-d6) δ8.22(d,J=2.2Hz,1H),8.18(d,J=2.2Hz,1H),7.46(s,1H),2.34(s,3H),1.73(d,J=1.5Hz,3H).

[0684] 3) Step Three

[0685] C125-2 (50 mg, 0.21 mmol) was dissolved in ethanol (3 mL) and water (3 mL). Iron powder (59 mg, 1.05 mmol) and ammonium chloride (56.16 mg, 1.05 mmol) were added, and the reaction mixture was stirred at 65 °C for 2 hours. After the reaction was complete, the reaction mixture was filtered, the filtrate was diluted with water (60 mL), and then extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid C125-3 (47 mg crude product), which was used directly in the next step. LCMS m / z = 207.1 [M+H] + .

[0686] 4) Step Four

[0687] C125-3 (25 mg, 0.121 mmol), C124-2 (26.65 mg, 0.071 mmol), N-methylimidazole (34.97 mg, 0.426 mmol), and TCFH (59.9 mg, 0.213 mmol) were dissolved in acetonitrile (2 mL), and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain C125 (7.8 mg, 11%). LCMS m / z = 563.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.62(s,1H),8.54(s,2H),7.93–7.89(m,1H),7.71–7.67(m,1H) ,7.39–7.34(m,1H),4.62–4.58(m,2H),4.52(t,J=6.0Hz,1H),4.45(t,J=6.0Hz,1H),4.29–4.24(m,1H ),3.62(d,J=12.0Hz,1H),3.47–3.45(m,1H),3.12–3.07(m,1H),2.84(s,3H),2.83–2.79(m,1H),2.66 –2.62(m,1H),2.25–2.21(m,1H),2.22(s,3H),2.08–2.03(m,1H),1.76(s,3H),1.17(d,J=6.4Hz,3H).

[0688] Example 99. Synthesis of C149

[0689] 1) Step One

[0690] C149-1 (775 mg, 2.91 mmol, prepared according to the synthesis method of patent application WO2019200120) was dissolved in acetonitrile (14 mL), and N-methylmorpholine oxide (682 mg, 5.82 mmol) was added. The reaction mixture was stirred overnight at room temperature and diluted with water (80 mL). The aqueous phase was extracted with ethyl acetate (3 × 30 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give a yellow solid C149-2 (154 mg, 26%). 1 H NMR (400MHz, CDCl3) δ10.32(s,1H),8.69–8.62(m,1H),8.53(dd,J=8.4,2.1Hz,1H),8.17(d,J=8.3Hz,1H),7.42(t,J=54.4Hz,1H).

[0691] 2) Step Two

[0692] C149-2 (154 mg, 0.77 mmol) was dissolved in toluene (2 mL), and C10-8 (483 mg, 1.53 mmol) was added. The reaction mixture was stirred at 60 °C for 5 hours and diluted with water (50 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL), and the combined organic phases were 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 column chromatography (petroleum ether:ethyl acetate = 8:1) to give a yellow oily substance C149-3 (Z / E mixture, 134 mg, 74%). 1 H NMR(400MHz, CDCl3)δ8.51(d,J=2.3Hz,1H),8.40–8.37(m,1H),7.47(d,J=8.4 Hz, 1H), 7.41 (d, J = 2.1Hz, 1H), 6.72 (t, J = 54.4Hz, 1H), 2.00 (d, J = 1.6Hz, 3H).

[0693] 3) Step Three

[0694] C149-3 (134 mg, 0.56 mmol) and acetic acid (168.9 mg, 2.81 mmol) were dissolved in methanol (1 mL), and zinc powder (183.9 mg, 2.81 mmol) was added. The reaction mixture was stirred at 70 °C for 3 hours, filtered, and diluted with water (40 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL), and the combined organic phases were 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 column chromatography (petroleum ether: ethyl acetate = 8:1) to give a yellow oily substance C149-4 (Z / E mixture, 90 mg, 77%). 1 H NMR (400MHz, CDCl3) δ7.35(d,J=1.7Hz,1H),7.12(d,J=8.3Hz,1H),6.91(d,J=2.4Hz,1 H), 6.78 (d, J = 1.5Hz, 1H), 6.62 (t, J = 54.4Hz, 1H), 4.03 (s, 2H), 2.05 (d, J = 1.6Hz, 3H).

[0695] 4) Step Four

[0696] C149-4 (45 mg, 0.56 mmol) was dissolved in dioxane (1 mL). The reaction solution was stirred overnight at room temperature under UV irradiation, and then concentrated under reduced pressure to obtain a yellow oily substance C149-4E (E configuration, 45 mg, 100%), which was used directly in the next step of the reaction.

[0697] 5) Step Five

[0698] C149-4E (45 mg, 0.22 mmol), C124-2 (80.9 mg, 0.22 mmol), and N-methylimidazole (106.5 mg, 1.30 mmol) were dissolved in acetonitrile (0.5 mL), and TCFH (181.9 mg, 0.65 mmol) was added. The reaction mixture was stirred overnight at room temperature. The solution was diluted with water (30 mL), and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were 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 thin-layer chromatography (dichloromethane:methanol = 20:1) to give C149 (47 mg, 77%). LCMS m / z = 565.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.69(s,1H),8.63(s,1H),8.53(s,2H),8.17(s,1H),8.03(d,J=8.6Hz,1H),7.56(s,1H),7. 47(d,J=8.5Hz,1H),7.21(t,J=54.6Hz,1H),4.63–4.55(m,2H),4.50(t,J=6.0Hz,1H),4.44(t,J=6.0Hz,1H),4.29–4. 20(m,1H),3.60(d,J=12.1Hz,1H),3.47–3.39(m,1H),3.14–3.04(m,1H),2.83(s,3H),2.82–2.77(m,1H),2.62(d,J=1 1.0Hz, 1H), 2.21 (dd, J=11.0, 3.6Hz, 1H), 2.05 (dd, J=11.3, 3.5Hz, 1H), 2.01 (d, J=1.6Hz, 3H), 1.16 (d, J=6.5Hz, 3H).

[0699] Example 100. Synthesis of C112

[0700] 1) Step One

[0701] Under N2 protection, 2-chloro-5-hydroxypyrimidine (400 mg, 3.06 mmol), 1-bromo-2-methyl-2-propanol (468 mg, 3.06 mmol), and cesium carbonate (2.0 g, 6.12 mmol) were dissolved in DMF (10 mL) and reacted under microwave irradiation at 120 °C for 1 hour. The mixture was diluted with water (80 mL), the solid was filtered off, and the filtrate was extracted with ethyl acetate (3 × 40 mL). The combined organic phases were concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 24:1) to give a pale yellow solid C112-1 (120 mg, 19%). LCMS m / z = 203.1 [M+H] + .

[0702] 2) Step Two

[0703] Following the synthesis method of C243, C112-1 was used instead of C69-1 to synthesize C112. LCMS m / z = 483.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),8.66(s,2H),8.65(s,1H),8.09(d,J=2.1Hz,1H),7.82(dd,J=8.6,2.1Hz,1H),7. 51(d,J=8.6Hz,1H),7.36(d,J=1.9Hz,1H),4.74(s,1H),3.97(s,2H),2.83(s,3H),2.05(d,J=1.6Hz,3H),1.23(s,6H).

[0704] Example 101. Synthesis of C275

[0705] Referring to the synthesis method of C110, using replace C275 was synthesized. LCMS m / z = 493.50 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.67–10.60(m,1H),8.62–8.58(m,1H),8.51–8.25( m,1H),8.19(s,2H),8.10(d,J=2.0Hz,1H),7.86–7.78(m,1H),7.51(d,J=8.6H z,1H),7.37(d,J=1.8Hz,1H),3.59–3.51(m,1H),3.47–3.42(m,1H),3.34–3.2 7(m,2H),2.81(s,3H),2.05(d,J=1.6Hz,3H),2.01–1.91(m,2H),1.35(s,3H).

[0706] Example 102. Synthesis of C269

[0707] Referring to the synthesis method of C92-3, using replace C269 was synthesized. LCMS: m / z = 494.00 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.59(s,1H),8.21(s,2H),8.09(d,J=2.1Hz,1H ),7.82(dd,J=8.5,2.1Hz,1H),7.51(d,J=8.6Hz,1H),7.36(d,J=1.9Hz,1H),5.00(s, 1H),4.03(s,1H),3.76(q,J=6.5Hz,1H),3.51(t,J=9.0Hz,1H),2.81(s,3H),2.25–2. 12(m,1H),2.05(d,J=1.6Hz,3H),1.90(dd,J=13.0,6.6Hz,1H),1.11(d,J=6.5Hz,3H).

[0708] Example 103. Synthesis of C262

[0709] Following the synthesis method of C269, C262 was synthesized by replacing C12-3E with C127-2E. LCMS: m / z = 537.95, 539.95 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.62(s,1H),8.59(s,1H),8.27(d,J=2.1Hz,1H),8.21(s,2H ),7.87(dd,J=8.6,2.2Hz,1H),7.48(d,J=8.6Hz,1H),7.30(d,J=1.8Hz,1H),5.01(d,J =3.5Hz,1H),4.03(t,J=3.7Hz,1H),3.79–3.72(m,1H),3.55–3.46(m,1H),2.81(s,3H ),2.21–2.13(m,1H),2.03(d,J=1.7Hz,3H),1.95–1.85(m,1H),1.11(d,J=6.5Hz,3H).

[0710] Example 104. Synthesis of C151

[0711] Following the synthetic method for C124, compound C151 was synthesized by replacing 2-fluoro-6-chloro-4-bromobenzaldehyde with 4-bromo-2-trifluoromethoxybenzaldehyde. LCMS m / z = 599.05 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.74(s,1H),8.62(s,1H),8.53(s,2H),8.05(s,1H),7.89(dd,J=8.6,1.9Hz,1H),7.58( d,J=8.7Hz,1H),7.35–7.28(m,1H),4.59(td,J=6.4,2.6Hz,2H),4.50(t,J=6.0Hz,1H),4.44(t,J=6.0Hz,1H),4. 31–4.20(m,1H),3.64–3.55(m,1H),3.46–3.41(m,1H),3.13–3.03(m,1H),2.83(s,3H),2.81–2.78(m,1H),2.62( d,J=10.9Hz,1H),2.20(dd,J=11.0,3.3Hz,1H),2.06(d,J=1.5Hz,3H),2.04–1.98(m,1H),1.15(d,J=6.5Hz,3H).

[0712] Example 105. Synthesis of C293

[0713] Following the synthesis method for C97, C293 was synthesized by replacing (R)-3-pyrrolanol with D-prolyl. LCMS m / z = 494.15 [M+H] +; 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),8.58(s,1H),8.29(s,2H),8.09(d,J=2.0Hz,1H),7.81(dd,J=8.6,2.2Hz,1H),7.51(d,J=8.6Hz,1H),7.36(d,J =1.8Hz,1H),4.87(t,J=5.6Hz,1H),3.93–3.85(m,1H),3.54–3.45(m,3H), 3.20–3.11(m,1H),2.81(s,3H),2.04(d,J=1.6Hz,3H),1.99–1.90(m,4H).

[0714] Example 106. Synthesis of C291

[0715] Following the synthesis method of C97, C291 was synthesized by replacing (R)-3-pyrrolanol with cis-3,4-pyrrolidinediol. LCMS: m / z = 495.95 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.59(s,1H),8.18(s,2H),8.09(d,J=2.1Hz,1H),7.81(dd,J=8.6,2.2Hz,1H),7.51(d, J=8.5Hz,1H),7.36(s,1H),5.19–4.87(m,2H),4.19(s,2H),3.63–3.46(m,2H),3.30–3.12(m,2H),2.81(s,3H),2.05(s,3H).

[0716] Example 107. Synthesis of C279

[0717] C92 hydrochloride (100 mg, 0.19 mmol) and (S)-propionide glyceraldehyde (169.12 mg, 0.57 mmol) were dissolved in methanol (5 mL), and sodium cyanoborohydride (35.6 mg, 0.57 mmol) was added. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give C279 (52 mg, 48%). LCMS m / z = 567.15 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.62(s,1H),8.52(s,2H),8.10(d,J=2.0Hz,1H),7.82( dd,J=8.6,2.0Hz,1H),7.51(d,J=8.6Hz,1H),7.37(d,J=1.8Hz,1H),4.56–4.37(m,2H),4.25– 4.13(m,1H),3.71–3.63(m,1H),3.60–3.51(m,1H),3.43–3.35(m,2H),3.10–2.98(m,2H),2.8 3(s,3H),2.81–2.77(m,1H),2.44–2.17(m,4H),2.05(d,J=1.6Hz,3H),1.13(d,J=6.4Hz,3H).

[0718] Example 108. Synthesis of C272

[0719] Referring to the synthesis method of C92-3, using replace C272 was synthesized. LCMS m / z = 494.15 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.64(s,1H),8.59(s,1H),8.21(s,2H),8.09(d,J=2.0Hz,1 H),7.84–7.77(m,1H),7.51(d,J=8.6Hz,1H),7.36(d,J=2.0Hz,1H),5.16–5.08(m,1 H),4.48–4.40(m,1H),4.09–3.98(m,1H),3.75–3.59(m,2H),2.81(s,3H),2.30–2.1 9(m,1H),2.05(d,J=1.6Hz,3H),1.77–1.69(d,J=12.8Hz,1H),1.32(d,J=6.2Hz,3H).

[0720] Example 109. Synthesis of C153

[0721] 1) Step One

[0722] Following the synthesis method of C125-3, C153-1 was synthesized by replacing C125-2 with C125-1. LCMS m / z = 271.0 / 273.0 [M+H] + .

[0723] 2) Step Two

[0724] C153-1 (126 mg, 460 μmol), zinc cyanide (113 mg, 0.92 mmol), and tetraphenylphosphine palladium (55 mg, 46 μmol) were dissolved in DMF (7 mL), purged with nitrogen, and reacted overnight at 100 °C. Water (80 mL) was added to the reactants, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was then purified by preparative thin-layer chromatography to obtain C153-2 (75 mg, 74%). LCMS m / z = 216.0 [MH] - .

[0725] 3) Step Three

[0726] Following the synthesis method of C125, C153 was synthesized by replacing C125-3 with C153-2. LCMS m / z = 574.05 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.85(s,1H),8.62(s,1H),8.53(s,2H),8.32(d,J=2.0Hz,1H),8.28(d,J=2.2Hz,1H ),7.51–7.43(m,1H),4.58(td,J=6.5,2.6Hz,2H),4.50(t,J=6.0Hz,1H),4.43(t,J=6.0Hz,1H),4.28–4.20( m,1H),3.64–3.57(m,1H),3.45–3.42(m,1H),3.12–3.04(m,1H),2.83(s,3H),2.82–2.77(m,1H),2.62(d,J= 10.9Hz,1H),2.20(dd,J=10.9,3.4Hz,1H),2.07–2.00(m,1H),1.89(d,J=1.5Hz,3H),1.15(d,J=6.5Hz,3H).

[0727] Example 110. Synthesis of C292

[0728] Following the synthesis method of C97, C292 was synthesized by replacing (R)-3-pyrrolidone with L-prolyl. LCMS: m / z = 494.00 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.59(s,1H),8.29(s,2H),8.10(d,J=2.1Hz ,1H),7.82(dd,J=8.5,2.2Hz,1H),7.51(d,J=8.6Hz,1H),7.36(d,J=1.8Hz,1H),4. 85(t,J=5.8Hz,1H),3.90(q,J=6.5Hz,1H),3.56–3.43(m,2H),3.38–3.34(m,1H), 3.16(q,J=9.2,8.6Hz,1H),2.81(s,3H),2.05(d,J=1.6Hz,3H),2.01–1.91(m,4H).

[0729] Example 111. Synthesis of C290

[0730] Following the synthesis method of C97, C290 was synthesized by replacing (R)-3-pyrrolanol with (3S,4S)-3,4-pyrrolidinediol. LCMS m / z = 495.90, 497.90 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),8.60(s,1H),8.20(s,2H),8.10(d,J=2.0Hz,1H),7.85–7.75(m,1H),7.50(d,J=8.6Hz,1H),7.36(d,J =1.8Hz,1H),5.27(s,2H),4.10(d,J=3.6Hz,2H),3.56(dd,J=10.6,3.8Hz,2H),3.24(d,J=10.4Hz,2H),2.81(s,3H),2.05(d,J=1.6Hz,3H).

[0731] Example 112. Synthesis of C296

[0732] Following the synthetic method for C97, C296 (formate) was synthesized by replacing (R)-3-pyrrolidone with N-methylperpiperazine. LCMS m / z = 507.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.66(s,1H),8.60(s,1H),8.42(s,2H),8.14(s,1H),8.10(d,J=2.1Hz,1H), 7.82(dd,J=8.5,2.2Hz,1H),7.51(d,J=8.6Hz,1H),7.37(s,1H),3.77–3.75(m,1H),3.56–3.55(m,1H) ,3.12–3.11(m,1H),3.04–3.02(m,1H),2.93–2.91(m,1H),2.82(s,3H),2.76–2.74(m,1H),2.63–2.61 (m,1H),2.56–2.55(m,1H),2.34(s,3H),2.10–2.08(m,1H),2.05(d,J=1.6Hz,3H),1.88–1.85(m,1H).

[0733] Example 113. Synthesis of C287

[0734] Following the synthetic method for C97, C287 was synthesized by replacing (R)-3-pyrrolanol with (R)-3-methylpiperidin-3-ol. LCMS m / z = 508.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.68(s,1H),8.62(s,1H),8.55(s,2H),8.12(d,J=2.1Hz,1H ),7.84(dd,J=8.5,2.2Hz,1H),7.53(d,J=8.6Hz,1H),7.39–7.37(m,1H),4.49(s,1H) ,3.52–3.48(m,1H),3.19–3.11(m,2H),3.08(d,J=12.6Hz,1H),2.84(s,3H),2.07(d, J=1.7Hz,3H),2.03–1.99(m,1H),1.90–1.83(m,1H),1.60–1.55(m,2H),1.19(s,3H).

[0735] Example 114. Synthesis of C277

[0736] Following the synthesis method for C96, C277 was synthesized by replacing isobutane with (S)-propylene oxide. LCMS m / z = 551.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.65(s,1H),8.61(s,1H),8.51(s,2H),8.09(s,1H),7.81( d,J=8.3Hz,1H),7.50(d,J=8.6Hz,1H),7.36(s,1H),4.38–4.28(m,1H),4.24–4.15(m ,1H),3.85–3.76(m,1H),3.57–3.51(m,1H),3.08–2.94(m,2H),2.82(s,3H),2.40–2. 27(m,2H),2.24–2.15(m,2H),2.04(s,3H),1.16–1.11(m,3H),1.09(d,J=6.1Hz,3H).

[0737] Example 115. Synthesis of C152

[0738] 1) Step One

[0739] Following the synthesis method of C153-2, C152-1 was synthesized by replacing C153-1 with C127-2E. 1 H NMR (400MHz, DMSO-d6) δ7.39(d,J=8.7Hz,1H),7.22(d,J=1.6Hz,1H),6.95(d, J=2.4Hz,1H),6.88(dd,J=8.7,2.4Hz,1H),6.15(s,2H),2.07(d,J=1.6Hz,3H).

[0740] 2) Step Two

[0741] Following the synthetic method for C133, C152-1 was used instead of C133-2E to synthesize compound C152. LCMS m / z = 540.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.79(s,1H),8.62(s,1H),8.53(s,2H),8.34(d,J=2.2Hz,1H),8.12(d,J =8.7,2.2Hz,1H),7.67(d,J=8.7Hz,1H),7.45(s,1H),4.61–4.56(m,2H),4.50(t,J=6.0Hz,1H),4 .44(t,J=6.0Hz,1H),4.25(s,1H),3.60(d,J=12.3Hz,1H),3.44–3.41(m,1H),3.13–3.05(m,1H), 2.85–2.79(m,4H),2.63(d,J=11.0Hz,1H),2.21(s,1H),2.10–2.02(m,4H),1.15(d,J=6.4Hz,3H).

[0742] Example 116. Synthesis of C276

[0743] Following the synthesis method for C96, C276 was synthesized by replacing isobutane with (R)-propylene oxide. LCMS: m / z = 551.05 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.64(s,1H),8.61(s,1H),8.51(s,2H),8.09(d,J=2.1Hz,1H),7.81(dd,J=8.6,2 .1Hz,1H),7.51(d,J=8.6Hz,1H),7.36(d,J=2.0Hz,1H),4.35(d,J=4.0Hz,1H),4.22–4.15(m,1H),3.85–3. 77(m,1H),3.54(d,J=11.9Hz,1H),3.12–3.05(m,1H),2.96–2.91(m,1H),2.82(s,3H),2.81–2.77(m,1H), 2.37–2.31(m,1H),2.28–2.16(m,3H),2.05(d,J=1.7Hz,3H),1.13(d,J=6.4Hz,3H),1.09(d,J=6.1Hz,3H).

[0744] Example 117. Synthesis of C288

[0745] Following the synthetic method for C97, C288 was synthesized by replacing (R)-3-pyrrolanol with (S)-3-methylpiperidin-3-ol. LCMS m / z = 508.2 [M+H]+ ; 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.60(s,1H),8.53(s,2H),8.10(d,J=2.1Hz, 1H),7.83–7.80(m,1H),7.51(d,J=8.5Hz,1H),7.36(d,J=2.0Hz,1H),4.47(s,1H),3 .52–3.46(m,1H),3.38–3.33(m,1H),3.16–3.11(m,1H),3.05(d,J=12.5Hz,1H),2.8 2(s,3H),2.05(d,J=1.7Hz,3H),1.88–1.78(m,2H),1.57–1.53(m,2H),1.17(s,3H).

[0746] Example 118. Synthesis of C267

[0747] Following the synthesis method of C144, C267 was synthesized by replacing C92 with C102. LCMS m / z = 551.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.61(s,1H),8.54(s,2H),8.09(d,J=2.1Hz,1H),7.81(dd,J=8. 6,2.1Hz,1H),7.51(d,J=8.6Hz,1H),7.36(d,J=1.8Hz,1H),4.41–4.35(m,1H),4.02–3.93(m,1H),3.5 3–3.49(m,2H),3.28–3.26(m,2H),3.01–2.98(m,1H),2.91(dd,J=11.5,3.1Hz,1H),2.82(s,3H),2.43 –2.39(m,1H),2.05(d,J=1.3Hz,3H),1.99–1.96(m,2H),1.10(d,J=6.3Hz,3H),1.01(d,J=6.4Hz,3H).

[0748] Example 119. Synthesis of C115

[0749] Following the synthesis method of C104, C114 was used instead of C102 to synthesize C115. LCMS m / z = 505.3 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.64(s,1H),8.59(s,1H),8.29(s,2H),8.10(d,J=2.0Hz,1H ),7.82(dd,J=8.5,2.1Hz,1H),7.51(d,J=8.6Hz,1H),7.37(s,1H),4.55(s,1H),3.53( s,1H),3.41(d,J=9.3Hz,1H),3.30–3.27(m,1H),2.85–2.82(m,1H),2.81(s,3H),2.55 –2.51(m,1H),2.30(s,3H),2.05(s,3H),1.94(d,J=9.1Hz,1H),1.79(d,J=9.7Hz,1H).

[0750] Example 120. Synthesis of C129

[0751] 1) Step One

[0752] C153-1 (40 mg, 0.15 mmol), (BPin)2 (93.52 mg, 0.37 mmol), Pd(dppf)Cl2 (10.78 mg, 0.015 mmol), and potassium acetate (43.37 mg, 0.44 mmol) were dissolved in 1,4-dioxane (2 mL), purged with nitrogen, and heated to 90 °C with stirring for 4 h. The solution was diluted with water (40 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude brown solid C129-1 (56 mg, 117%). LCMS m / z = 319.10 [M+H] + .

[0753] 2) Step Two

[0754] C129-1 (30 mg, 0.08 mmol), C124-2 (38.29 mg, 0.12 mmol), and NMI (26.31 mg, 0.32 mmol) were dissolved in acetonitrile (2 mL), and then TCFH (44.96 mg, 0.16 mmol) was added. The mixture was stirred at room temperature for 1 h. The solution was diluted with water (40 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude yellow solid C129-2 (50 mg, 93%). LCMS m / z = 675.30 [M+H] + .

[0755] 3) Step Three

[0756] C129-2 (50 mg, 0.07 mmol), hydrogen peroxide (30%, 0.8 mL), and ammonium bicarbonate (5.86 mg, 0.07 mmol) were dissolved in water (1.0 mL) and stirred at room temperature for 1 h. The solution was diluted with water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative chromatography to obtain C129 (1.2 mg, 3%). LCMS m / z = 565.2 [M+H] + ; 1 H NMR (400MHz, CD3OD) δ8.48(s,2H),8.37(s,1H),7.45(d,J=2.0Hz,1H),7.32(d,J=2.0Hz,1H),7. 08(d,J=1.7Hz,1H),4.74–4.71(m,2H),4.67(t,J=6.1Hz,1H),4.61(t,J=6.1Hz,1H),4.56(s,2H ),3.53–3.49(m,1H),3.27–3.20(m,1H),2.83(s,3H),2.67(d,J=10.6Hz,1H),2.35(dd,J=11.1, 3.6Hz,1H),2.21–2.18(m,1H),2.06–2.01(m,1H),1.85(d,J=1.5Hz,3H),1.26(d,J=6.5Hz,3H).

[0757] Example 121. Synthesis of C142

[0758] Following the synthesis method of C149, C142-1 was used instead of C149-1 to synthesize C142. LCMS m / z = 567.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.51(s,1H),8.59(s,1H),8.53(s,2H),7.93(d,J=7.0Hz,1H),7.52(d,J=11.0H z,1H),7.36(d,J=1.9Hz,1H),4.61–4.56(m,2H),4.50(t,J=6.0Hz,1H),4.44(t,J=6.0Hz,1H),4.27–4.21 (m,1H),3.60(d,J=12.2Hz,1H),3.45–3.41(m,1H),3.11–3.05(m,1H),2.83(s,3H),2.82–2.78(m,1H),2. 62(d,J=10.9Hz,1H),2.22–2.18(m,1H),2.05(d,J=1.7Hz,3H),2.04–1.99(m,1H),1.15(d,J=6.4Hz,3H).

[0759] Example 122. Synthesis of C266

[0760] Following the synthesis method for C97, C266 was synthesized by replacing (R)-3-pyrrolanol with (S)-3-methylpyrrolan-3-ol. LCMS m / z = 494.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.60(s,1H),8.17(s,2H),8.10(d,J=2.0Hz,1H),7.82(dd,J=8.6,2.0Hz,1H),7.51(d,J=8.6Hz ,1H),7.36(s,1H),4.88(s,1H),3.51–3.43(m,2H),3.29(s,2H),2.81(s,3H),2.05(d,J=1.6Hz,3H),2.00–1.91(m,2H),1.38(s,3H).

[0761] Example 123. Synthesis of C273

[0762] Referring to the synthesis method of C92-3, using replace C273 was synthesized. LCMS m / z = 494.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.59(s,1H),8.21(s,2H),8.10(d,J=2.0Hz,1H),7 .82(dd,J=8.6,2.0Hz,1H),7.51(d,J=8.6Hz,1H),7.36(d,J=1.8Hz,1H),5.18(d,J=4.8Hz ,1H),4.32–4.25(m,1H),3.98–3.91(m,1H),3.50–3.43(m,1H),3.24–3.18(m,1H),2.81(s ,3H),2.16–2.10(m,1H),2.05(d,J=1.6Hz,3H),1.96–1.88(m,1H),1.07(d,J=6.4Hz,3H).

[0763] Example 124. Synthesis of C156

[0764] 1) Step One

[0765] C12-1 (2.0 g, 10.7 mmol) and carbon tetrabromide (7.1 g, 21.5 mmol) were dissolved in dichloromethane (30 mL), and the mixture was cooled to 0 °C. Triphenylphosphine (11.3 g, 1.91 mmol) was added to the reaction solution in portions, and the mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15:1) to obtain a white solid C156-1 (2.6 g, 72%). 1 H NMR (400MHz, DMSO-d6) δ8.37(d,J=2.4Hz,1H),8.25(dd,J=8.6,2.4Hz,1H),7.87(d,J=8.6Hz,1H),7.83(s,1H).

[0766] 2) Step Two

[0767] C156-1 (2.1 g, 6.15 mmol) was dissolved in toluene (35 mL), followed by the sequential addition of cuprous iodide (468 mg, 2.46 mmol), triethylamine (6.2 g, 61.5 mmol), Pd(dppf)Cl2 (431 mg, 0.61 mmol), and cyclopropanethylene (488 mg, 0.68 mmol). The mixture was purged with nitrogen and stirred overnight at room temperature. The solution was diluted with water (150 mL) and extracted with ethyl acetate (3 × 60 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (100% petroleum ether) to obtain a red oily substance C156-2 (400 mg, 50% purity), while C156-1 (1.2 g) was recovered.1 H NMR(400MHz,DMSO-d6)δ8.40(d,J=2.3Hz,1H),8.17(dd,J=8.6,2.3Hz,1H), 7.94–7.86(m,2H),1.49–1.40(m,1H),1.00–0.98(m,2H),0.89–0.87(m,2H).

[0768] 3) Step Three

[0769] Under nitrogen protection, C156-2 (400 mg, 50% purity), trimethylcyclotriboroxane (307 mg, 2.44 mmol), Pd(dppf)Cl2 (89 mg, 0.12 mmol), and potassium carbonate (505 mg, 3.66 mmol) were dissolved in 1,4-dioxane (6 mL) and water (1.5 mL), purged three times with N2, and stirred at 90 °C for 4 h. The solution was diluted with water (60 mL), extracted with ethyl acetate (3 × 30 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain yellow solids C156-3Z (30 mg, Z configuration) and C156-3E (28 mg, E configuration). C156-3E: 1 H NMR (400MHz, DMSO-d6) δ8.32(d,J=2.4Hz,1H),8.17(dd,J=8.6,2.4Hz,1H),7.67(d,J=8.6Hz,1H ),6.72(s,1H),1.90(d,J=1.5Hz,3H),1.60–1.46(m,1H),0.92–0.87(m,2H),0.76–0.68(m,2H).

[0770] 4) Step Four

[0771] Following the synthesis method of C58, C156 is synthesized by replacing C58-1 with C156-3E and C26-3 with C124-2. LCMS: m / z = 588.10 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.59(s,1H),8.53(s,2H),8.01(d,J=2.1Hz,1H),7.73(dd,J=8.5,2.1Hz,1H),7. 36(d,J=8.6Hz,1H),6.65(s,1H),4.62–4.56(m,2H),4.50(t,J=6.0Hz,1H),4.44(t,J=6.0Hz,1H),4.27–4.21(m,1H),3. 59(d,J=12.1Hz,1H),3.45–3.41(m,1H),3.12–3.06(m,1H),2.84–2.79(m,4H),2.65–2.60(m,1H),2.24–2.19(m,1H),2. 05–2.00(m,1H),1.88(d,J=1.5Hz,3H),1.51–1.45(m,1H),1.15(d,J=6.4Hz,3H),0.87–0.84(m,2H),0.72–0.66(m,2H).

[0772] Example 125. Synthesis of C192-2 and C192

[0773] Following the synthesis route of C92, C12-3E was replaced with C127-2E to obtain C192-2 (LCMS m / z = 537.1 [M+H]). + Referring to the synthesis method of C144, C192-2 was used instead of C92 to synthesize C192. LCMS m / z = 581.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),8.61(s,1H),8.51(s,2H),8.26(d,J=2.0Hz,1H),7.87(d d,J=8.6,2.0Hz,1H),7.48(d,J=8.6Hz,1H),7.30(d,J=1.8Hz,1H),4.42(t,J=5.4Hz,1H),4.19( s,1H),3.58–3.53(m,3H),3.09–3.02(m,1H),2.96(d,J=11.4Hz,1H),2.83–2.78(m,4H),2.45–2 .39(m,2H),2.38–2.33(m,1H),2.21–2.15(m,1H),2.03(d,J=1.6Hz,3H),1.12(d,J=6.4Hz,3H).

[0774] Example 126. Synthesis of C313

[0775] 1) Step One

[0776] Under nitrogen protection, C313-1 (1.0 g, 4.79 mmol), 1-bromo-2-methyl-2-propanol (1.83 g, 11.9 mmol), and cesium carbonate (4.6 g, 14.3 mmol) were dissolved in DMF (13 mL), purged with nitrogen, and reacted in a microwave environment at 120 °C for 1 hour. The solution was diluted with water (150 mL), the solid was filtered off, and the filtrate was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a white-yellow solid C313-2 (700 mg, 54%). LCMS m / z = 279.9 [M+H] + .

[0777] 2) Step Two

[0778] Under nitrogen protection, C313-2 (700 mg, 2.49 mmol), (S)-4-N-tert-butyloxycarbonyl-2-methylpiperazine (999 mg, 4.99 mmol), XantPhos (144 mg, 0.24 mmol), cesium carbonate (2.4 g, 7.47 mmol), and Pd2(dba)3 (114 mg, 0.12 mmol) were dissolved in 1,4-dioxane (8 mL), purged three times with nitrogen, and stirred overnight at 110 °C. The solution was diluted with water (90 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain a yellow oily substance C313-3 (320 mg, 32%). LCMS m / z = 400.05 [M+H] + .

[0779] 3) Step Three

[0780] C313-3 (320 mg, 0.803 mmol), C10-2 (338 mg, 1.20 mmol), and potassium carbonate (331 mg, 2.40 mmol) were dissolved in 1,4-dioxane (6 mL) and water (1.5 mL). Pd(dppf)Cl2 (59 mg, 0.08 mmol) was then added, and the mixture was purged with nitrogen three times. The reaction was carried out at 100 °C for 3 hours. The mixture was diluted with water (80 mL) and extracted with ethyl acetate (3 × 30 mL). The organic phases were combined and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain a yellow oily substance C313-4 (280 mg, 67%). LCMS m / z = 520.10 [M+H] + .

[0781] 4) Step Four

[0782] C313-4 (100 mg, 0.19 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was slowly added. The mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain crude C313-5. LCMS m / z = 420.05 [M+H] + .

[0783] 5) Step Five

[0784] C313-5 (80 mg, 0.19 mmol) and 3-oxetane (41 mg, 0.57 mmol) were dissolved in methanol (4 mL), and sodium cyanoborohydride (36 mg, 0.57 mmol) was added at 0 °C. The mixture was stirred at room temperature for 3 h. The solution was diluted with (50 mL) water and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a yellow solid C313-6 (35 mg, 38%). LCMS m / z = 476.05 [M+H] + .

[0785] 6) Step Six

[0786] C313-6 (35 mg, 0.07 mmol) was dissolved in tetrahydrofuran (1 mL) / water (1 mL), and then lithium hydroxide monohydrate (6 mg, 0.14 mmol) was added. The mixture was stirred at room temperature for 2 h. The pH of the reaction solution was adjusted to 3–4 with 1 N hydrochloric acid solution, and the solution was concentrated under reduced pressure to obtain crude C313-7. LCMS m / z = 462.20 [M+H] + ;

[0787] 7) Step Seven

[0788] C313-7 (30 mg, 0.06 mmol), C12-3E (14 mg, 0.078 mmol), and N-methylimidazole (32 mg, 0.38 mmol) were dissolved in acetonitrile (1 mL), and TCFH (54 mg, 0.19 mmol) was added. The mixture was stirred at room temperature for 2 h. The solution was diluted with water (30 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative chromatography to obtain C313 (13.5 mg, 32%). LCMS m / z = 636.05 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.32(s,1H),8.17(s,1H),8.06(d,J=2.0Hz,1H),7.91(d,J=2.2Hz,1H),7.76(dd,J=8.6,2.1H z,1H),7.57–7.48(m,1H),7.36(s,1H),7.13–6.85(m,1H),4.64(s,1H),4.62–4.56(m,2H),4.50(t,J=6.0Hz,1H),4.44( t,J=6.0Hz,1H),3.80(s,2H),3.64(s,1H),3.52(d,J=12.0Hz,1H),3.46–3.38(m,1H),3.13–3.01(m,1H),2.80(d,J=10. 8Hz,1H),2.47(s,3H),2.23–2.14(m,1H),2.04(d,J=1.6Hz,3H),2.02–1.93(m,1H),1.13(d,J=6.4Hz,3H),1.11(s,6H).

[0789] Example 127. Synthesis of C143

[0790] 1) Step One

[0791] 2-Bromo-5-chloro-4-methylaniline (1.0 g, 4.53 mmol), zinc cyanide (1.06 g, 9.07 mmol), and Pd(PPh3)4 (523 mg, 0.453 mmol) were dissolved in DMF (40 mL), purged with nitrogen, and reacted overnight at 120 °C. The mixture was diluted with water (400 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give a white solid C143-2 (1.0 g, 88%). LCMS m / z = 167.1 [M+H] + .

[0792] 2) Step Two

[0793] C143-2 (1.0 g, 6.0 mmol), di-tert-butyl dicarbonate (3.93 g, 18.01 mmol), triethylamine (1.82 g, 18.01 mmol), and DMAP (146 mg, 1.2 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 3 hours. The solution was diluted with water (200 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give a white solid C143-3 (1.7 g, 77%). LCMS m / z = 268.1 [M-Boc+H] + .

[0794] 3) Step Three

[0795] C143-3 (500 mg, 1.36 mmol), NBS (266 mg, 1.5 mmol), and benzoyl peroxide (66 mg, 0.27 mmol) were dissolved in carbon tetrachloride (12 mL) and stirred at 85 °C for 3 hours. The solution was diluted with water (100 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude C143-4, which was used directly in the next step. LCMS m / z = 345.0 [M-Boc+H] + .

[0796] 4) Step Four

[0797] C143-4 (300 mg, 0.673 mmol) was dissolved in acetonitrile (5 mL), and N-methylmorpholine oxide (157 mg, 1.35 mmol) was added. The mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give a white solid C143-5 (245 mg, 96%). LCMS m / z = 225.0 [M-Boc-tBu+H] + .

[0798] 5) Step Five

[0799] C143-5 (120 mg, 0.315 mmol) was dissolved in toluene (3 mL), and C10-8 (199 mg, 0.63 mmol) was added. The mixture was stirred at 60 °C for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give a yellow solid C143-6 (60 mg, 60%). LCMS m / z = 318.1 [M-Boc+H] + .

[0800] 6) Step Six

[0801] C143-6 (20 mg, 0.048 mmol) was dissolved in acetic acid (2 mL) and refluxed with stirring for 6 hours. The reaction solution was purified by reversed-phase column chromatography to obtain a white solid C143-7 (12 mg, 79%). LCMS m / z = 218.14 [M+H] + .

[0802] 7) Step Seven

[0803] Following the synthesis method of C274, C143 was synthesized by replacing C274-4 with C143-7. LCMS m / z = 574.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.60(s,1H),8.54(s,2H),8.03(s,1H), 7.89(s,1H),7.40–7.37(m,1H),4.58(td,J=6.4,2.6Hz,2H),4.50(t,J=6.0Hz, 1H),4.44(t,J=6.0Hz,1H),4.25(s,1H),3.61(d,J=12.3Hz,1H),3.12–3.04(m, 1H), 2.85 (s, 3H), 2.34–2.16 (m, 2H), 2.07–1.94 (m, 6H), 1.16 (d, J = 6.4Hz, 3H).

[0804] Example 128. Synthesis of C146

[0805] Following the synthetic method for C92-3, C146 was synthesized by replacing (S)-1-Boc-3-methylpiperazine with C149-1. LCMS m / z = 549.2 [M+H] + ; 1H NMR(400MHz,MeOD)δ8.65(s,2H),8.51(s,1H),8.01(d,J=2.0Hz,1H),7.73(dd,J=8.4,2.0Hz,1H),7.43 (d,J=8.8Hz,1H),7.35(d,J=2.0Hz,1H),3.92–3.83(m,1H),3.80–3.65(m,2H),3.38(m,1H),3.25(d,J=1 0.8Hz,1H),3.10(dd,J=11.2,2.8Hz,1H),2.94(dd,J=11.2,3.0Hz,1H),2.88(s,3H),2.76(d,J=11.6Hz ,1H),2.69(t,J=10.8Hz,1H),2.57–2.47(m,1H),2.41(m,1H),2.09–2.01(m,4H),1.03(d,J=6.0Hz,3H).

[0806] Example 129. Synthesis of C274

[0807] 1) Step One

[0808] C274-1 (500 mg, 2.27 mmol) was dissolved in toluene (5 mL). C10-8 (2.15 g, 6.80 mmol) was added to the reaction mixture, and the mixture was stirred overnight at 60 °C. The solution was diluted with water (50 mL), extracted with ethyl acetate (3 × 20 mL), and the combined organic phases were washed with saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give a yellow solid C274-2 (480 mg, 82%). LCMS m / z = 256.9 [M+H] + .

[0809] 2) Step Two

[0810] Under nitrogen protection, C274-2 (480 mg, 1.86 mmol), benzophenone imine (506.7 mg, 2.80 mmol), XantPhos (215.7 mg, 0.37 mmol), and cesium carbonate (1.82 g, 5.59 mmol) were dissolved in 1,4-dioxane (10 mL). Pd2(dba)3 (170.5 mg, 0.19 mmol) was added to the reaction mixture, and the mixture was stirred overnight at 95 °C. The mixture was diluted with water (50 mL), extracted with ethyl acetate (3 × 20 mL), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a black oily substance, C274-3 (600 mg, 90%). LCMS m / z = 358.2 [M+H] + .

[0811] 3) Step Three

[0812] C274-3 (264 mg, 0.74 mmol) was dissolved in methanol (2.5 mL), and hydroxylamine hydrochloride (104 mg, 1.48 mmol) and potassium acetate (181 mg, 1.84 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:7) to give a yellow solid C274-4 (49 mg, 34%). LCMS m / z = 194.1 [M+H] + .

[0813] 4) Step Four

[0814] C124-2 (40 mg, 0.11 mmol) and diisopropylethylamine (27.6 mg, 0.21 mmol) were dissolved in N,N-dimethylformamide (0.5 mL), and TSTU (35.4 mg, 0.12 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solution was diluted with water (50 mL), extracted with ethyl acetate (3 × 20 mL), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a yellow solid C274-5 (65 mg, 100%).

[0815] 5) Step Five

[0816] C274-5 (20.7 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (0.25 mL). Sodium hydride (60% concentration, 4.3 mg, 0.11 mmol) was added to the reaction solution at 0 °C, and the mixture was stirred at 0 °C for 5 minutes. Then, a solution of C274-4 (50.4 mg, 0.11 mmol) in N,N-dimethylformamide (0.25 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The solution was diluted with water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative HPLC to obtain C274 (4.3 mg, 7%). LCMS m / z = 550.2 [M+H] + ; 1 H NMR(400MHz, DMSO-d6)δ8.79(s,1H),8.53(s,2H),8.48(d,J=2.0Hz,1H),8.36–8.3 1(m,1H),7.35(s,1H),4.61–4.56(m,2H),4.50(t,J=6.1Hz,1H),4.43(t,J=6.1Hz,1 H),4.27–4.22(m,1H),3.61–3.58(m,2H),3.10–3.05(m,2H),2.81(s,3H),2.66–2.5 9(m,2H),2.20–2.18(m,1H),2.08(s,3H),2.04–2.00(m,1H),1.15(d,J=6.5Hz,3H).

[0817] Example 130. Synthesis of C304

[0818] C98 (100 mg, 0.21 mmol), C304-1 (232.3 mg, 1.06 mmol), ((2,4,6-triisopropyl)phenyl)di-cyclohexylphosphine (16.9 mg, 0.042 mmol), and cesium carbonate (206.3 mg, 0.63 mmol) were dissolved in tetrahydrofuran (2 mL) and water (0.5 mL). Palladium acetate (4.7 mg, 0.021 mmol) was added, the mixture was purged with nitrogen, and stirred overnight at 100 °C. The solution was diluted with water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative HPLC to obtain C304 formate (5.5 mg, 5%). LCMS m / z = 507.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.68(s,1H),8.81(s,2H),8.73(s,1H),8.16(s,1H),8.09(d,J=2.0Hz,1H),7.82(dd,J=8.6,2.1Hz ,1H),7.52(d,J=8.6Hz,1H),7.37(s,1H),3.55(s,2H),2.88(s,3H),2.48–2.25(m,8H),2.17(s,3H),2.05(d,J=1.6Hz,3H).

[0819] Example 131. Synthesis of C310 and C311

[0820] 1) Step One

[0821] C310-1 (300 mg, 1.26 mmol) was dissolved in dioxane (8 mL), followed by the addition of trimethylcyclotriboroxane (238 mg, 1.89 mmol), Pd(dppf)Cl2 (92.2 mg, 0.126 mmol), and potassium carbonate (522.43 mg, 3.78 mmol). The mixture was purged with nitrogen three times and stirred at 100 °C for 2 hours. The reaction solution was used directly for the next step of the reaction.

[0822] 2) Step Two

[0823] THF (3 mL), water (3 mL), and lithium hydroxide monohydrate (77.48 mg, 1.846 mmol) were added to the above reaction solution, and the mixture was stirred at 60 °C for 2 h. The solution was diluted with water (60 mL) and extracted with ethyl acetate (3 × 20 mL). The aqueous phase was adjusted to pH 3 with 1 N HCl solution and then extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow solid C310-3 (150 mg, 59%). LCMS m / z = 202.9 [M+H] + .

[0824] 3) Step Three

[0825] C310-3 (150 mg, 0.74 mmol) was dissolved in DMF (4 mL), and dimethylamine hydrochloride (90.56 mg, 1.11 mmol), HATU (422 mg, 1.11 mmol), and DIEA (478.2 mg, 3.7 mmol) were added. The mixture was stirred at room temperature for 2 hours. The solution was diluted with water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give a yellow solid C310-4 (110 mg, 65%). LCMS m / z = 230.0 [M+H] + .

[0826] 4) Step Four

[0827] Following the synthesis method of C243, C311 was synthesized by replacing C369-1 with C310-4. LCMS m / z = 509.9 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.71(s,1H),8.58(s,1H),8.08(d,J=2.1Hz,1H),7.83–7.78(m,1H),7.51(d,J=8.6Hz,1H ),7.37(d,J=1.8Hz,1H),3.82(s,3H),3.06(s,3H),2.89(s,3H),2.83(s,3H),2.56(s,3H),2.05(d,J=1.6Hz,3H).

[0828] 5) Step Five

[0829] C311 (45 mg, 0.088 mmol) was dissolved in anhydrous dichloromethane (6 mL). Boron tribromide (29 mg, 0.115 mmol) was slowly added dropwise at -78 °C under nitrogen protection, and the mixture was slowly brought to room temperature with stirring for 2 hours. The solution was quenched with water (50 mL) at -78 °C and then extracted with dichloromethane (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain C310 (4.2 mg, 10%). LCMS m / z = 495.9 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.68(s,1H),8.53(s,1H),8.08(d,J=2.0Hz,1H),7.81(dd,J=8.6,2.1Hz,1H),7.51(d, J=8.6Hz,1H),7.37(d,J=1.9Hz,1H),3.03(s,3H),2.93(s,3H),2.81(s,3H),2.51(s,3H),2.05(d,J=1.6Hz,3H).

[0830] Example 132. Synthesis of C322 and C323

[0831] 1) Step One

[0832] C322-1 (200 mg, 1.12 mmol) was dissolved in dioxane (8 mL) and water (2 mL). C10-2 (346.7 mg, 1.23 mmol), Pd(dppf)Cl2 (81.95 mg, 0.112 mmol), and potassium carbonate (464.38 mg, 3.36 mmol) were added, and the mixture was stirred at 105 °C for 3 hours under nitrogen protection. The mixture was diluted with water (60 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to give a yellow solid C322-2 (230 mg, 69%). LCMS m / z = 298.9 [M+H] + ;

[0833] 2) Step Two

[0834] C322-2 (230 mg, 1.28 mmol) was dissolved in dioxane (10 mL), and (S)-4-N-tert-butyloxycarbonyl-2-methylpiperazine (514.68 mg, 2.57 mmol), Pd2(dba)3 (117.12 mg, 0.128 mmol), RuPhos (120 mg, 0.256 mmol), and potassium phosphate (679.26 mg, 3.2 mmol) were added. The mixture was stirred at 110 °C for 4 hours under nitrogen protection. The solution was diluted with water (80 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to give a yellow solid C322-3 (100 mg, 18%). LCMS m / z = 463.0 [M+H] + .

[0835] 3) Step Three

[0836] Following the synthesis method for C92, C322-3 was used instead of C92-1 to synthesize C323 hydrochloride. LCMS m / z = 522.9 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.56(s,1H),9.45(s,1H),9.03(s,1H),8.15(s,1H),8. 08(d,J=2.0Hz,1H),7.80(dd,J=8.5,2.1Hz,1H),7.51(d,J=8.6Hz,1H),7.37(d, J=1.8Hz,1H),6.90(s,1H),4.98–4.92(m,1H),4.45(d,J=14.4Hz,1H),3.94(s,3 H),3.10–3.04(m,2H),2.43(s,3H),2.04(d,J=1.6Hz,3H),1.34(d,J=6.8Hz,3H).

[0837] 4) Step Four

[0838] Following the synthesis method of C277, C322 was synthesized by replacing C92 hydrochloride with C323 hydrochloride. LCMS m / z = 581.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.46(s,1H),8.10(s,1H),8.06(d,J=2.1Hz,1H),7.77(dd,J=8.6,2.2Hz,1H),7.51(d ,J=8.6Hz,1H),7.36(d,J=1.8Hz,1H),6.69(s,1H),4.68–4.58(m,1H),4.31(d,J=3.9Hz,1H),4.17(d,J=12.8Hz ,1H),3.89(s,3H),3.85–3.79(m,1H),3.18–3.11(m,1H),2.99(d,J=11.1Hz,1H),2.85(d,J=11.2Hz,1H),2.41 (s,3H),2.22–2.10(m,2H),2.04(d,J=1.6Hz,3H),2.02–1.95(m,1H),1.24–1.23(m,3H),1.10(d,J=6.1Hz,3H).

[0839] Example 133. Synthesis of C326

[0840] C92 hydrochloride (40 mg, 0.075 mmol), C326-1 (89 mg, 0.38 mmol), and potassium carbonate (52 mg, 0.38 mmol) were dissolved in ethanol / water (4 mL, v / v = 4 / 1), and the solution was sealed in a tube and stirred at 80 °C for 2 h. The solution was concentrated under reduced pressure, and the crude product was purified by thin-layer chromatography (dichloromethane:methanol = 10 / 1) to obtain C326 (19.8 mg, 37%). LCMS m / z = 581.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.60(s,1H),8.49(s,2H),8.08(d,J=2.0Hz,1H),7.80(dd ,J=8.6,2.0Hz,1H),7.50(d,J=8.6Hz,1H),7.36(s,1H),4.62(s,1H),4.19–4.13(m,1H),4.10(s ,1H),3.53–3.50(m,1H),3.29–3.25(m,2H),3.09–2.96(m,3H),2.82(s,3H),2.45–2.41(m,1H), 2.35–2.31(m,1H),2.30–2.20(m,2H),2.04(d,J=1.6Hz,3H),1.15(d,J=6.4Hz,3H),1.06(s,3H).

[0841] Example 134. Synthesis of C364

[0842] Following the synthesis method of C326, C364 was synthesized by replacing C92 hydrochloride with C88 hydrochloride. LCMS: m / z = 593.05 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),8.61(s,1H),8.54(s,2H),8.09(d,J=2.0Hz,1H),7.82(dd,J=8.6,2.1Hz,1H),7.51(d,J=8.6Hz,1H),7.3 6(s,1H),3.99–3.88(m,1H),3.25–3.13(m,6H),3.08(s,2H),2.82(s,3 H),2.65(s,2H),2.05(d,J=1.6Hz,3H),0.98(s,3H),0.74–0.53(m,4H).

[0843] Example 135. Synthesis of C365

[0844] Following the synthesis method for C326, C365 was synthesized by replacing C92 hydrochloride with C110 hydrochloride. LCMS m / z = 593.05 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.64(s,1H),8.61(s,1H),8.44(s,2H),8.09(d,J=2.1Hz,1H),7.81( dd,J=8.6,2.2Hz,1H),7.51(d,J=8.6Hz,1H),7.36(d,J=1.8Hz,1H),4.77–4.56(m,1H),4.03(s ,1H),3.57–3.51(m,2H),3.43–3.40(m,2H),3.30–3.25(m,2H),2.99(d,J=10.5Hz,2H),2.81( s,3H),2.32(s,2H),2.05(d,J=1.6Hz,3H),1.92–1.84(m,2H),1.69–1.62(m,2H),1.05(s,3H).

[0845] Example 136. Synthesis of C315

[0846] 1) Step One

[0847] C315-1 (2.0 g, 9.6 mmol), methyl iodide (1.5 g, 10.55 mmol), and potassium carbonate (2.65 g, 19.19 mmol) were dissolved in acetonitrile (50 mL) and stirred at 80 °C for 3 h. The solution was diluted with water (300 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give a yellow oily substance C315-2 (1.5 g, 70%). LCMS m / z = 223.80 [M+H] + .

[0848] 2) Step Two

[0849] C315-2 (1.3 g, 5.84 mmol), (S)-4-N-tert-butyloxycarbonyl-2-methylpiperazine (5.85 g, 29.22 mmol), Pd2(dba)3 (535.09 mg, 0.58 mmol), XantPhos (676.21 mg, 1.17 mmol), and cesium carbonate (5.71 g, 17.53 mmol) were dissolved in 1,4-dioxane (30 mL), purged with nitrogen, and stirred overnight at 110 °C. The solution was diluted with water (300 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give a yellow solid C315-3 (484 mg, 24%). LCMS m / z = 342.1 [M+H] + .

[0850] 3) Step Three

[0851] C315-3 (484 mg, 1.42 mmol), C10-2 (399.5 mg, 1.42 mmol), Pd(dppf)Cl2 (115.62 mg, 0.14 mmol), and potassium carbonate (578.06 mg, 4.25 mmol) were dissolved in 1,4-dioxane (15 mL) and water (3 mL), purged with nitrogen, and stirred at 105 °C for 3 h. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were 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 silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give a yellow solid C315-4 (650 mg, 99%). LCMS m / z = 462.2 [M+H] + .

[0852] 4) Step Four

[0853] C315-4 (600 mg, 1.3 mmol) was dissolved in dichloromethane (3 mL), and dioxane hydrochloride solution (4 M, 3 mL) was added. The mixture was stirred at room temperature for 1 h. The reaction solution was concentrated to give a red oily substance C315-5 (470 mg, 100%). LCMS m / z = 362.0 [M+H] + .

[0854] 5) Step Five

[0855] C315-5 (470 mg, 1.3 mmol), 3-oxetane (281.1 mg, 3.9 mmol), and sodium cyanoborocyanate (245.13 mg, 3.9 mmol) were dissolved in methanol (10 mL) and stirred at room temperature for 2 h. The solution was diluted with water (100 mL) and extracted with ethyl acetate (3 × 60 mL). The combined organic phases were 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 silica gel column chromatography (dichloromethane:methanol = 25:1) to obtain a yellow oily substance C315-6 (540 mg, 99%). LCMS m / z = 418.3 [M+H] + .

[0856] 6) Step Six

[0857] C315-6 (540 mg, 1.29 mmol) and lithium hydroxide monohydrate (217.28 mg, 5.17 mmol) were dissolved in tetrahydrofuran (3.0 mL), water (1.0 mL), and methanol (1.0 mL), and stirred at 60 °C for 2 h. The reaction solution was adjusted to pH 3–5 with hydrochloric acid solution (1 M), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were concentrated to give a white solid C315-7 (450 mg, 86%). LCMS m / z = 404.2 [M + H] + .

[0858] 7) Step Seven

[0859] C315-7 (100 mg, 0.25 mmol), C12-3E (47.74 mg, 0.25 mmol), and NMI (81.39 mg, 0.99 mmol) were dissolved in acetonitrile (3 mL), and TCFH (139.07 mg, 0.5 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was purified by preparative chromatography to obtain C315 (11.8 mg, 8%). LCMS m / z = 578.0 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.42(s,1H),8.06(d,J=2.2Hz,2H),7.91(d,J=2.2Hz,1H),7.77(dd,J=8.4,2.0Hz,1H),7.50( d,J=8.6Hz,1H),7.36(d,J=1.8Hz,1H),6.97(d,J=2.3Hz,1H),4.61–4.56(m,2H),4.50(t,J=6.0Hz,1H),4.44(t,J=6.0H z,1H),4.21(d,J=7.0Hz,1H),3.83(s,3H),3.53(d,J=12.2Hz,1H),3.47–3.39(m,1H),3.12–3.04(m,1H),2.81(d,J=10 .8Hz,1H),2.62(d,J=10.8Hz,1H),2.39(s,3H),2.20(dd,J=11.0,3.4Hz,1H),2.07–1.99(m,4H),1.14(d,J=6.4Hz,3H).

[0860] Example 137. Synthesis of C339

[0861] 1) Step One

[0862] C339-1 (2.0 g, 0.26 mmol), di-tert-butyl dicarbonate (3.21 g, 14.72 mmol), triethylamine (2.48 g, 24.52 mmol), and DMAP (75 mg, 0.61 mmol) were dissolved in dichloromethane (25 mL) and stirred overnight at room temperature. The solution was diluted with water (100 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic phases were 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 silica gel column chromatography (ethyl acetate: petroleum ether = 1%) to give a yellow solid C339-2 (1.7 g, 53%). LCMS m / z = 207.0 [M-tBu+H] + .

[0863] 2) Step Two

[0864] C339-2 (1.54 g, 5.85 mmol) was dissolved in tetrahydrofuran (20 mL), purged three times with nitrogen, and n-butyllithium (2.5 M, 2.3 mL, 14.63 mmol) was added dropwise at -78 °C, with stirring at -78 °C for 0.5 h. DMF (2.14 g, 29.25 mmol) was added dropwise at -78 °C, and stirring was continued for 0.5 h. The solution was quenched with hydrochloric acid aqueous solution (2 M), diluted with water (100 mL), and extracted with ethyl acetate (4 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a white solid C339-3 (1.8 g, crude product). 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),10.11(s,1H),7.62(s,1H),1.46(s,9H).

[0865] 3) Step Three

[0866] C339-3 (1.80 g, 6.18 mmol) and C10-8 (3.89 g, 12.36 mmol) were dissolved in toluene (30 mL) and stirred at 60 °C for 1 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 5%) to obtain a yellow solid C339-4 (1.25 g, 62%). LCMS m / z = 272.0 [M-tBu+H] + .

[0867] 4) Step Four

[0868] C124-2 (165 mg, 0.43 mmol) and ammonium chloride (28 mg, 0.52 mmol) were dissolved in DMF (4 mL), and DIPEA (167 mg, 1.29 mmol) and HATU (245 mg, 0.64 mmol) were added. The mixture was stirred at room temperature for 2 h. The solution was diluted with water (60 mL) and extracted with ethyl acetate (4 × 30 mL). The combined organic phases were 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 silica gel column chromatography (methanol:dichloromethane = 5%) to give a yellow solid C339-5 (160 mg, 99%). LCMS m / z = 374.2 [M+H] + .

[0869] 5) Step Five

[0870] C339-5 (50 mg, 0.13 mmol), C339-4 (53 mg, 0.16 mmol), Pd2(dba)3 (12 mg, 0.013 mmol), XantPhos (15 mg, 0.026 mmol), and cesium carbonate (127 g, 0.39 mmol) were dissolved in 1,4-dioxane (1.5 mL), purged with nitrogen three times, and stirred at 110 °C for 3 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by thin-layer chromatography (dichloromethane:methanol = 10 / 1) to obtain a yellow solid C339-6 (10 mg, 12%). LCMS m / z = 665.3 [M+H] + .

[0871] 6) Step Six

[0872] C339-6 (10 mg, 0.015 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 1 h. The solution was diluted with water (40 mL), and the pH was adjusted to 8-9 with sodium hydroxide aqueous solution (2 M). Extraction was performed with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (dichloromethane:methanol = 10 / 1) to obtain C339 (1.0 mg, 13%). LCMS m / z = 565.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.75(s,1H),8.69(s,1H),8.52(s,2H),7.48(s,1H),7.06(d,J=1.6Hz ,1H),6.16(s,2H),4.60–4.56(m,2H),4.50(t,J=6.0Hz,1H),4.44(t,J=6.0Hz,1H),4.27–4.21( m,1H),3.59(d,J=12.2Hz,1H),3.46–3.40(m,1H),3.10–3.05(m,1H),2.85–2.81(m,1H),2.80( s,3H),2.62(d,J=10.8Hz,1H),2.22–2.18(m,1H),1.80(d,J=1.5Hz,3H),1.15(d,J=6.4Hz,3H).

[0873] Example 138. Synthesis of C342

[0874] Following the synthesis method of C326, C342 was synthesized by replacing C92 hydrochloride with C71 hydrochloride. LCMS: m / z = 567.0 [M+H] + ;1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.62(s,1H),8.57(s,2H),8.10(d,J=2.0Hz,1H),7.84–7.80(m,1H),7.51(d,J=8.8Hz,1H), 7.37(s,1H),4.10(s,1H),3.31–3.16(m,5H),2.83(s,3H),2.77–2.63(m,4H),2.39–2.29(m,2H),2.19–2.03(m,3H),1.06(s,3H).

[0875] Example 139. Synthesis of C354

[0876] Following the synthesis method for C96, C92 hydrochloride was replaced with C88 hydrochloride, and isobutane was replaced with (R)-glycidyl ether, to synthesize C354. LCMS: m / z = 579.05 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.61(s,1H),8.54(s,2H),8.09(d,J=2.0Hz,1H),7.8 2(dd,J=8.6,2.2Hz,1H),7.50(d,J=8.6Hz,1H),7.36(d,J=1.8Hz,1H),4.44(s,1H),4.31(d, J=4.4Hz,1H),3.49–3.44(m,1H),3.30–3.27(m,2H),3.14–3.07(m,4H),2.82(s,3H),2.79–2 .73(m,1H),2.67–2.61(m,1H),2.05(d,J=1.6Hz,3H),0.67–0.62(m,2H),0.60–0.55(m,2H).

[0877] Example 140. Synthesis of C3O3

[0878] Following the synthesis method for C97, C303 was synthesized by replacing (R)-3-pyrrolidone with C303-1. LCMS m / z = 576.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.62(s,1H),8.58(s,2H),8.10(d,J=2. 1Hz,1H),7.82(dd,J=8.6,2.2Hz,1H),7.51(d,J=8.6Hz,1H),7.37(d,J=1.9Hz ,1H),3.96–3.89(m,2H),2.86–2.80(m,5H),2.55–2.51(m,5H),2.41–2.31(m, 4H), 2.18 (s, 3H), 2.05 (d, J = 1.7Hz, 3H), 1.89–1.83 (m, 2H), 1.56–1.47 (m, 2H).

[0879] Example 141. Synthesis of C352

[0880] Following the synthesis method for C96, C92 hydrochloride was synthesized by replacing it with C110 hydrochloride and isobutane with (R)-glycidyl ether. The LCMS m / z was 579.15 [M+H]. + ; 1 H NMR (400MHz, DMSO-d6) δ10.67(s,1H),8.61(s,1H),8.44(s,2H),8.10(d,J=2.0Hz,1H),7.82 (dd,J=8.4,2.4Hz,1H),7.51(d,J=8.6Hz,1H),7.36(d,J=1.8Hz,1H),4.66–4.46(m,2H),3.5 8–3.52(m,2H),3.48–3.45(m,1H),3.41–3.38(m,3H),3.26–3.22(m,1H),3.10–2.94(m,2H), 2.81(s,3H),2.73–2.53(m,1H),2.46–2.31(m,2H),2.05(d,J=1.6Hz,3H),1.93–1.88(m,1H).

[0881] Example 142. Synthesis of C345

[0882] 1) Step One

[0883] C92 hydrochloride (30 mg, 0.057 mmol), C345-1 (33.36 mg, 0.17 mmol), and sodium cyanoborohydride (10.62 mg, 0.17 mmol) were dissolved in methanol (1 mL) and stirred at room temperature for 2 h. The solution was diluted with water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a white solid, C345-2 (38 mg, 99.6%). LCMS m / z = 673.35 [M+H] + .

[0884] 2) Step Two

[0885] C345-2 (38 mg, 0.056 mmol) and lithium hydroxide monohydrate (9.48 mg, 0.23 mmol) were dissolved in tetrahydrofuran (1.0 mL), water (0.3 mL), and methanol (0.3 mL), and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative chromatography to obtain C345 (24.9 mg, 67%). LCMS m / z = 659.25 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.61(s,1H),8.51(s,2H),8.10(d,J=2.1Hz,1H),7.82(dd,J=8.6,2.2Hz,1H),7. 51(d,J=8.6Hz,1H),7.36(d,J=1.8Hz,1H),4.21(d,J=7.3Hz,1H),3.56(d,J=11.8Hz,1H),3.07–2.99(m,1H),2.98–2.92 (m,1H),2.82(s,3H),2.81–2.77(m,1H),2.38–2.27(m,2H),2.26–2.19(m,1H),2.11–2.06(m,1H),2.05(d,J=1.7Hz,3H) ,1.93–1.81(m,2H),1.74–1.61(m,2H),1.59–1.50(m,4H),1.48–1.43(m,2H),1.41–1.33(m,2H),1.11(d,J=6.4Hz,3H).

[0886] Example 143. Synthesis of C349-6 and C349

[0887] 1) Step One

[0888] C349-1 (500 mg, 2.60 mmol), C10-2 (740 mg, 2.60 mmol), Pd(dppf)Cl2 (190 mg, 0.26 mmol), and potassium carbonate (1.08 g, 7.80 mmol) were dissolved in 1,4-dioxane / water (7.5 mL, v / v 4 / 1). The mixture was purged with nitrogen three times and stirred at 105 °C for 3 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 50%) to obtain a yellow solid C349-2 (700 mg, 87%). LCMS m / z = 311.1 [M+H] + .

[0889] 2) Step Two

[0890] C349-2 (610 mg, 1.96 mmol), (S)-4-N-tert-butyloxycarbonyl-2-methylpiperazine (1.96 g, 9.81 mmol), Pd2(dba)3 (179 mg, 0.20 mmol), RuPhos (183 mg, 0.39 mmol), and potassium phosphate (1.25 g, 5.88 mmol) were dissolved in 1,4-dioxane (15 mL), purged three times with nitrogen, and stirred overnight at 130 °C. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 40%) to obtain a yellow solid C349-3 (570 mg, containing a large amount of ligand impurities, directly used in the next step). LCMS m / z = 475.2 [M+H] + .

[0891] 3) Step Three

[0892] C349-3 (570 mg, 1.20 mmol) was dissolved in tetrahydrofuran (3 mL), and an aqueous solution of lithium hydroxide monohydrate (25 mg, 0.60 mmol) (3 mL) was added dropwise. The mixture was stirred at 60 °C for 2 h. The solution was diluted with water (50 mL) and extracted with ethyl acetate (2 × 20 mL). The aqueous phase was adjusted to pH 3-4 with 3M hydrochloric acid solution and then extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a yellow solid C349-4 (90 mg, 50% purity). LCMS m / z = 461.2 [M+H] + .

[0893] 4) Step Four

[0894] Following the synthesis method of C92, C349-4 was used instead of C92-2 to synthesize C349-6. LCMS m / z = 535.2 [M+H] + .

[0895] 5) Step Five

[0896] Following the synthesis method of C135, C349 was synthesized by replacing C110 with C349-6. LCMS m / z = 591.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.49–10.40(m,1H),8.36(d,J=2.8Hz,1H),8.06(d,J=2.1Hz,1H),7.96(s,1H),7.76(d d,J=8.5,2.3Hz,1H),7.66(s,1H),7.50(d,J=8.6Hz,1H),7.42(s,1H),7.38–7.30(m,2H),4.61–4.56(m,2H),4. 51(t,J=6.1Hz,1H),4.44(t,J=6.0Hz,1H),4.25–4.17(m,1H),3.59–3.51(m,1H),3.48–3.39(m,2H),3.12–3.03 (m,1H),2.82(d,J=10.9Hz,1H),2.63(d,J=10.9Hz,1H),2.38(s,3H),2.06–1.97(m,4H),1.15(d,J=6.4Hz,3H).

[0897] Example 144. Synthesis of C340

[0898] Following the synthesis method of C326, C364 was synthesized by replacing C92 hydrochloride with C192-2 hydrochloride and C326-1 with C340-1. LCMS m / z = 624.65 / 626.65 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.73–8.54(m,3H),8.26(d,J=2.0Hz,1H),7.87(dd,J=8.6,2.2Hz,1H),7.49(d,J=8.6Hz,1H),7.31(d,J=1.8Hz ,1H),4.53(s,1H),4.07–3.80(m,3H),3.73–3.60(m,3H),3.38–3.18(m,4H ),2.84(s,3H),2.03(d,J=1.6Hz,3H),1.18(d,J=6.8Hz,3H),1.14(s,3H).

[0899] Example 145. Synthesis of C502-7 and C502

[0900] 1) Step One

[0901] Following the synthesis method of C315-4, C502-4 was synthesized by replacing iodomethane with C502-1. LCMS m / z = 511.9 [M+H] + .

[0902] 2) Step Two

[0903] Following the synthesis method of C92, C502-4 was used instead of C92-1 to synthesize C502-7. LCMS m / z = 571.9 [M+H] + .

[0904] 3) Step Three

[0905] Following the synthesis method of C341, C502 was synthesized by replacing C192-2 with C502-7. LCMS m / z = 659.9 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.06(s,2H),7.97–7.92(m,1H),7.77(dd,J=8.6,2.2Hz,1H),7.50( d,J=8.6Hz,1H),7.36(s,1H),7.02(d,J=2.2Hz,1H),6.54–6.20(m,1H),4.66–4.56(m,1H),4.45–4.35(m, 2H),4.19–4.12(m,1H),4.08(s,1H),3.53–3.44(m,1H),3.27–3.19(m,2H),3.12–2.94(m,3H),2.64–2.55 (m,1H),2.46–2.37(m,4H),2.33–2.20(m,2H),2.04(d,J=1.7Hz,3H),1.15(d,J=6.4Hz,3H),1.07(s,3H).

[0906] Example 146. Synthesis of C509

[0907] Following the synthesis method of C315, C509 was synthesized by replacing C12-3E with C127-2E. LCMS m / z = 622.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.42(s,1H),8.25(d,J=2.0Hz,1H),8.09(s,1H),7.93(d,J=2.2Hz,1H),7.85(dd,J=8.4,2.2H z,1H),7.50(d,J=8.6Hz,1H),7.32(d,J=1.8Hz,1H),7.00(d,J=2.2Hz,1H),4.64–4.58(m,2H),4.53(t,J=6.0Hz,1H),4 .46(t,J=6.0Hz,1H),4.27–4.18(m,1H),3.86(s,3H),3.56(d,J=12.0Hz,1H),3.48–3.41(m,1H),3.15–3.06(m,1H),2. 83(d,J=10.6Hz,1H),2.64(d,J=10.8Hz,1H),2.42(s,3H),2.25–2.18(m,1H),2.19–2.01(m,4H),1.17(d,J=6.4Hz,3H).

[0908] Example 147. Synthesis of C268

[0909] Following the synthesis method for C144, C268 was synthesized by replacing C92 hydrochloride with C95 hydrochloride. LCMS m / z = 549.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.61(s,1H),8.42(s,2H),8.09(d,J=2.1Hz,1H),7.81( dd,J=8.7,2.1Hz,1H),7.51(d,J=8.6Hz,1H),7.36(s,1H),4.46(s,1H),3.86–3.80(m,1H),3. 50–3.46(m,2H),3.08(d,J=11.5Hz,1H),2.92–2.82(m,2H),2.82(s,3H),2.44–2.30(m,4H),2 .22–2.16(m,1H),2.09–2.06(m,1H),2.05–2.03(m,3H),2.02–1.95(m,1H),1.79–1.70(m,1H).

[0910] Example 147. Synthesis of C341

[0911] C192-2 (570 mg, 1.1 mmol), C341-1 (280 mg, 5.3 mmol), and potassium carbonate (733 mg, 5.3 mmol) were dissolved in ethanol (12 mL) and water (3 mL) and stirred at 80 °C for 2 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain C341 (500 mg, 75%). LCMS m / z = 625.25, 627.25 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),8.59(s,1H),8.49(s,2H),8.26(d,J=2.0Hz,1H),7.9 1–7.81(m,1H),7.47(d,J=8.6Hz,1H),7.29(s,1H),4.51–4.43(m,1H),4.21–4.12(m,1H),3. 95(s,1H),3.54–3.47(m,1H),3.33–3.24(m,3H),3.15–3.02(m,2H),2.97(d,J=11.4Hz,1H) ,2.83(s,3H),2.39–2.24(m,3H),2.03(t,J=1.2Hz,3H),1.17(d,J=6.4Hz,3H),1.08(s,3H).

[0912] Example 148. Synthesis of C520

[0913] Following the synthesis method of C92, C92-1 was synthesized by replacing it with C313-4 and C12-3E with C127-2E. C520 was obtained. LCMS: m / z = 623.95, 625.95 [M+H] + ; 1 H NMR(400MHz, DMSO-d6)δ10.31(s,1H),8.22(d,J=2.1Hz,1H),8.19–8.16(m,2H),7 .91(d,J=2.2Hz,1H),7.81(dd,J=8.6,2.1Hz,1H),7.48(d,J=8.6Hz,1H),7.29(d, J=1.9Hz,1H),6.99(d,J=2.3Hz,1H),4.16–4.12(m,1H),3.80(s,2H),3.48–3.42( m,1H),3.09–2.82(m,6H),2.47(s,3H),2.02(d,J=1.6Hz,3H),1.11–1.09(m,9H).

[0914] Example 149. Synthesis of C507 and C378

[0915] 1) Step One

[0916] Following the synthesis method for C92, C507 hydrochloride was synthesized by replacing C92-2 with C520-1. LCMS m / z = 579.9 [M+H] + .

[0917] 2) Step Two

[0918] Following the synthesis method for C96, C378 was synthesized by replacing C92 hydrochloride with C507 hydrochloride. LCMS m / z = 651.9 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.18(s,1H),8.06(d,J=2.1Hz,1H),7.89(s,1H),7 .76(d,J=8.5Hz,1H),7.50(d,J=8.6Hz,1H),7.36(s,1H),6.96(s,1H),4.65(s,1H),4.16– 4.11(m,2H),3.80(s,2H),3.47–3.42(m,1H),3.09–3.00(m,2H),2.92(d,J=11.1Hz,1H),2 .47(s,3H),2.30–2.17(m,3H),2.07–2.02(m,3H),2.02–1.94(m,1H),1.16–1.09(m,15H).

[0919] Example 150. Synthesis of C503-8 and C503

[0920] 1) Step One

[0921] C315-1 (2.0 g, 9.59 mmol) was dissolved in DMF (15 mL), and 60 wt% sodium hydride (767 mg, 19.1 mmol) was added at 0 °C. The mixture was stirred for 30 minutes, and then chloromethyl methyl sulfide (1.38 g, 14.3 mmol) was added. The mixture was then heated to room temperature and stirred for 1 hour. The solution was diluted with water (150 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a yellow oily substance C503-2 (1.9 g, 66%). 1 H NMR (400MHz, CDCl3) δ8.13(d,J=2.1Hz,1H),7.43(d,J=2.0Hz,1H),5.26(s,2H),2.29(s,3H).

[0922] 2) Step Two

[0923] C503-2 (1.9 g, 7.07 mmol) was dissolved in dichloromethane (20 mL), and m-CPBA (3.6 g, 21.2 mmol) was added. The mixture was stirred overnight at room temperature. The solution was quenched with sodium bicarbonate solution, diluted with water (150 mL), and extracted with dichloromethane (3 × 60 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give a white solid C503-3 (1.1 g, 52%). LCMS m / z = 299.85, 301.85 [M+H] + .

[0924] 3) Step Three

[0925] Referring to the synthesis method of C502, C503-3 was used instead of C502-2 to synthesize C503-8 and C503.

[0926] C503-8: LCMS m / z=599.95[M+H] + .

[0927] C503: LCMS m / z = 688.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.08(s,1H),8.06(d,J=2.1Hz,1H),8.02(d,J=2.2Hz,1H),7.76(dd, J=8.6,2.1Hz,1H),7.50(d,J=8.6Hz,1H),7.36(d,J=1.9Hz,1H),7.23(d,J=2.3Hz,1H),5.38(d,J=2.4Hz,2H ),4.61(s,1H),4.17–4.12(m,1H),4.09(s,1H),3.51–3.47(m,1H),3.30–3.24(m,2H),3.10–2.98(m,3H),2. 84(s,3H),2.45–2.40(m,4H),2.38–2.23(m,3H),2.04(d,J=1.7Hz,3H),1.15(d,J=6.3Hz,3H),1.07(s,3H).

[0928] Example 151. Synthesis of C386

[0929] Following the synthesis method for C96, C386 was synthesized by replacing isobutane with C386-1. LCMS m / z = 607.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.61(s,1H),8.50(s,2H),8.10(d,J=2.1Hz,1H),7.8 2(dd,J=8.5,2.2Hz,1H),7.51(d,J=8.6Hz,1H),7.36(d,J=2.0Hz,1H),4.23(s,1H),4.20–4. 15(m,1H),3.67–3.49(m,6H),3.11–3.03(m,2H),2.93–2.87(m,1H),2.82(s,3H),2.34–2.28 (m,3H),2.05(d,J=1.6Hz,3H),1.65–1.58(m,2H),1.47–1.40(m,2H),1.15(d,J=6.4Hz,3H).

[0930] Example 152. Synthesis of C368-6 and C368

[0931] 1) Step One

[0932] C315-1 (7.0 g, 38.3 mmol), C386-1 (5.26 g, 46.1 mmol), and potassium carbonate (10.1 g, 76.7 mmol) were dissolved in DMF (80 mL) and stirred at 100 °C for 1 hour. The solution was diluted with 500 mL of water, the solid was filtered off, and the filtrate was extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a yellow oily substance, C368-1 (7.4 g, 60%). LCMS m / z = 321.95, 323.95 [M+H] + .

[0933] 2) Step Two

[0934] Referring to the synthesis method of C502, C368-1 was used instead of C502-2 to synthesize C368-6 and C368.

[0935] C368-6:LCMS m / z=622.05[M+H] + .

[0936] C368:LCMS m / z=710.1[M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.27(s,1H),8.21(s,1H),8.05(d,J=2.1Hz,1H),7.90(d,J=2.2Hz,1H),7.78(dd,J=8.6,2.2Hz,1H),7 .51(d,J=8.6Hz,1H),7.36(d,J=1.8Hz,1H),6.97(d,J=2.3Hz,1H),4.79(s,1H),4.62(s,1H),4.16–4.10(m,1H),4.08(s,1H),3. 88(s,2H),3.60–3.55(m,3H),3.47–3.42(m,1H),3.29–3.24(m,2H),3.07–2.96(m,3H),2.48(s,3H),2.45–2.41(m,1H),2.39–2 .35(m,1H),2.29–2.22(m,2H),2.04(d,J=1.6Hz,3H),1.67–1.60(m,2H),1.43–1.38(m,2H),1.14(d,J=6.4Hz,3H),1.07(s,3H).

[0937] Example 153. Synthesis of C370-2 and C370

[0938] Referring to the synthesis method of C368, C127-2E was used instead of C12-3E to synthesize C370-2 and C370.

[0939] C370-2:LCMS m / z=666.0[M+H] + .

[0940] C370:LCMS m / z=753.80[M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.33(s,1H),8.26(s,1H),8.24(d,J=2.0Hz,1H),7.90(d,J=2.2Hz,1H),7.86(dd,J=8.6,2.2Hz, 1H),7.49(d,J=8.6Hz,1H),7.30(s,1H),6.98(d,J=2.3Hz,1H),4.85(s,1H),4.66–4.57(m,1H),4.18–4.12(m,1H),4.10(s ,1H),3.88(s,2H),3.62–3.53(m,4H),3.48–3.41(m,1H),3.30–3.24(m,2H),3.09–2.96(m,3H),2.48(s,3H),2.45–2.35(m ,2H),2.29–2.21(m,2H),2.02(d,J=1.6Hz,3H),1.67–1.60(m,2H),1.44–1.38(m,2H),1.14(d,J=6.4Hz,3H),1.07(s,3H).

[0941] Example 154. Synthesis of C372-5 and C372

[0942] Following the synthesis method of C368, C372-5 and C372 were synthesized by replacing (S)-1-Boc-3-methylpiperazine with N-Boc piperazine.

[0943] C372-5: LCMS m / z=608.05[M+H] + .

[0944] C372: LCMS m / z = 696.05 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.27(s,1H),8.20(s,1H),8.05(d,J=2.1Hz,1H),7.95(d,J=2.2Hz,1H),7.78(d d,J=8.6,2.2Hz,1H),7.51(d,J=8.6Hz,1H),7.36(d,J=1.8Hz,1H),7.05(d,J=2.3Hz,1H),4.80(s,1H),4 .09(s,1H),3.89(s,2H),3.62–3.47(m,4H),3.29–3.20(m,6H),2.76–2.63(m,4H),2.48(s,3H),2.40–2. 28(m,2H),2.04(d,J=1.6Hz,3H),2.01–1.94(m,1H),1.71–1.58(m,2H),1.44–1.36(m,2H),1.06(s,3H).

[0945] Example 155. Synthesis of C385

[0946] Following the synthesis method of C368, C372 was synthesized by replacing...

Claims

1. A compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein the compound has the structure of formula (I): in: Ring A is selected from C 3-6 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings and 5-14 heterocyclic aromatic rings; X is N or CR 1c ; Y is N or CR 1d ; R 1a R 1b R 1c and R 1d Each occurrence is independently selected from H, D, halogen, -OH, -NH2, -CN, -NO2, -SF5, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R a -OC(=O)R a -C(=O)OR a -OR a -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b -S(=O)(=NR) a )R b -NR a R b -C(=O)NR a R b -NR a -C(=O)R b -NR a -C(=O)OR b -NR a -S(=O)2-R b -NR a -C(=O)-NR a R b -NR a -S(=O)2-NR a R b -N = S(=O)R a R b -NR a -S(=O)(=NR a )R b -P(=O)R a R b -C 1-6 Alkylene-R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR a R b -OC 1-6 Alkylene-NR a R b 、(-C 3-6 (-CN, (-C) 3-6 (Hydrocyclic hydrocarbon group)-C 1-6 Alkyl and (-C) 3-6 (Hydrocyclic hydrocarbon group)-C 2-6 alkynyl group; R 2 Each occurrence is independently selected from D, halogen, -OH, -NH2, -CN, -NO2, -SF5, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R a -OC(=O)R a -C(=O)OR a -OR a -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b -S(=O)(=NR) a )R b -NR a R b -C(=O)NR a R b -NR a -C(=O)R b -NR a -C(=O)OR b -NR a -S(=O)2-R b -NR a -C(=O)-NR a R b -NR a -S(=O)2-NR a R b -N = S(=O)R a R b -NR a -S(=O)(=NR a )R b -P(=O)R a R b -C 1-6 Alkylene-R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR a R b -OC 1-6 Alkylene-NR a R b 、(-C 3-6 (-CN and (-C) 3-6 (Hydrocyclic hydrocarbon group)-C 1-6 alkyl; Or two Rs 2 Together they form = O or = CR a R b Or two Rs 2 Together with the groups it is attached to, they constitute C 3-6 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; Z independently represents a direct bond, -CH2-, -O-, or -OC each time it appears. 1-4 Alkylene-*, -C 1-4 Alkylenes -O-*, -C(=O)-, -C(=O)O-*, -OC(=O)-*, -S(=O)2-, -S(=O)2N(Z) a )-*、-N(Z a )S(=O)2-*、-N(Z a )-、-N(Z a )-C 1-4 Alkylene-*, -C 1-4 Alkylene-N(Z) a )-*、-C(=O)N(Z a )-*、-N(Z a )C(=O)-* or -C(=O)N(Z a )-C 1-4 Alkylene-*, where * indicates resemblance to R 3 The connection point; Z a Is it H or C? 1-4 alkyl; R 3 Each time it appears, it is independently selected from C. 3-10 Cyclic hydrocarbon groups, 3-20 membered heterocyclic groups (e.g., 3-10 membered heterocyclic groups), C 6-10 Aryl and 5-14 membered heteroaryl groups; each of the cyclic hydrocarbon group, heterocyclic group, aryl group, and heteroaryl group is optionally substituted by one or more substituents; preferably, the substituents are independently selected from: D, halogen, -OH, =O, -NH2, -CN, -NO2, -SF5, =CH2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R a -OC(=O)R a -C(=O)OR a -OR a -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b -S(=O)(=NR) a )R b -NR a R b -C(=O)NR a R b -NR a -C(=O)R b -NR a -C(=O)OR b -NR a -S(=O)2-R b -NR a -C(=O)-NR a R b -NR a -S(=O)2-NR a R b -N = S(=O)R a R b -NR a -S(=O)(=NR a )R b -P(=O)R a R b -C 1-6 Alkylene-R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR a R b -OC 1-6 Alkylene-NR a R b 、(-C 3-6 (-CN and (-C) 3-6 (Hydrocyclic hydrocarbon group)-C 1-6 alkyl; When Z is a direct bond, R 3 The substituents on R are optionally with R 2 Connection constitutes C 3-10 Hydrocarbon rings or 3-10 membered heterocyclic rings; R a and R b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl; or R a and R b Together with the groups it is attached to, they constitute C 3-6 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; The aforementioned alkylene, alkyl, alkenyl, alkynyl, cyclic alkylene, cyclic alkylene, alkyl ring, heterocyclic, heterocyclic, aryl, aromatic ring, heteroaryl, heteroaromatic ring, and aralkyl groups are each optionally substituted by one or more substituents independently selected from the following: deuterium atom, halogen, -OH, =O, -NH2, -CN, -NO2, =CR c R d (e.g., =CH2 or =CF2), -CH=CR c R d C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R c -OC(=O)R c -C(=O)OR c -OR c -SR c -S(=O)R c -S(=O)2R c -S(=O)2NR c R d -NR c R d -C(=O)NR c R d -NR c -C(=O)R d -NR c -C(=O)OR d -NR c -S(=O)2-R d -NR c -C(=O)-NR c R d -NR c -S(=O)2-NR c R d -N = S(=O)R c R d -NR c -S(=O)(=NR c )R d -P(=O)R c R d -C 1-6 Alkylene-R c -C 1-6 Alkylene-OR c -C 1-6 Alkylene-OC(=O)R c -C 1-6 Alkylene-NR c R d and -OC 1-6 Alkylene-NR c R d The alkylene, alkyl, alkenyl, =CH2, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are each optionally further substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH2, -NH(C 1-6 Alkyl groups, -CN, -NO2, =CH2, =CF2, -P(=O)(C 1-6 Alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -N=S(=O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl group, -C 1-6 Alkylene-C 3-6 Cyclic hydrocarbon groups, -OC 1-6 Alkyl, -O-(halogenated C) 1-6 alkyl), -OC 3-6 Cyclic hydrocarbon groups and -C 1-6 Alkylene-OC 1-6 alkyl; R c and R d Each time it appears, it is independently selected from H, halogen, C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl group, or R c and R d Together with the groups it is attached to, they constitute C 3-6 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic ring or 5-14 membered heteroaromatic ring, wherein the alkyl, cycloalkyl, hydrocarbon ring, heterocyclic group, heterocyclic group, aryl, aromatic ring, heteroaryl, heteroaromatic ring and aralkyl group are further optionally substituted by one or more substituents; preferably, the substituents are independently selected from the following: halogen, -OH, =O, -C(=O)OH, -C(=O)O-tert-butyl, -NH2, -CN, -NO2, =CF2, -P(=O)(C 1-6 Alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -N=S(=O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl groups, -OC 1-6 Alkyl, -OC 3-6 cycloalkyl and -C 1-6 Alkylene-OC 1-6 alkyl; m is an integer selected from 0, 1, 2, or 3; and n is an integer selected from 0, 1, or 2; The condition is: when R 1b C that is not cyano-substituted 2-6 When alkenyl (preferably R) 1b C is not arbitrarily replaced. 2-6 When alkenyl), at least two of the following conditions must be satisfied, preferably all of the following conditions: 1).R 1a Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 Cyclic hydrocarbon group; preferably, R 1a The derivatives are Cl, Br, methyl, ethyl, isopropyl, CF3, CHF2, CH2F, vinyl, ethynyl, or cyclopropyl; more preferably, R 1a For Cl; 2). R 1c Selected from H, -OH, -NH2, C 1-6 Alkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, -O(C) 1-6 Alkyl), -S(=O)2(C 1- 6-alkyl), -S(=O)2NH2, -NH(C 1-6 Alkyl), -C(=O)NH2, -NH-S(=O)2-(C 1-6 Alkyl groups), -NH-S(=O)2-NH2 and -NH-S(=O)(=NH)(C 1-6 Alkyl); preferably, when Y is CR 1d And R 1c For -NR a -S(=O)2-R b or -NR a -S(=O)(=NR a )R b At that time, R 1b Not H; and / or 3) At least one of m and n is not 0, preferably both m and n are not 0.

2. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein the compound has a structure of formula (II), (III), (IV), (V), (VI) or (VII): in: R 1b’ R 1b” R 1b”’ and R 1b”” Each time it appears, it is independently selected from H, halogen, -CN, -OH, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic, 5-14 membered heteroaryl, -O-(C 1-6 Alkyl groups and -C (=O) (C 1-6 Alkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclic, and heteroaryl groups are each optionally further substituted by one or more substituents independently selected from: halogen, -CN, -OH, -NH2, -NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, C optionally substituted with halogen or CN 3-6 Cycloalkyl group, phenyl group, 5-6 membered heterocyclic group, optionally covered by C 1-6 Alkyl-substituted 5-6-membered heteroaryl groups, -OC 1-6 Alkyl and -O-(halogenated C) 1-6 alkyl); Preferably, R 1b’ R 1b” and R 1b”’ Each occurrence is independently selected from H, halogen, -CN, C. 1-6 Alkyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, phenyl groups, 3-10 membered heterocyclic groups, 5-14 membered heteroaryl groups, and -O-(C 1-6 Alkyl), wherein the alkyl, alkynyl, cycloalkyl, phenyl, heterocyclic, and heteroaryl groups are each optionally further substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NH(C 1-6 Alkyl), C 1-6 Alkyl, C 3-6 Cyclic hydrocarbon groups, -OC 1-6 Alkyl and -O-(halogenated C) 1-6 alkyl); R 1b”” Each time it appears, it is independently selected from halogen, -CN, -OH, C. 1-6 Alkyl, C 2-6 alkynyl and -O-(C 1-6 Alkyl group), wherein the alkyl group and the alkynyl group are each optionally further substituted by one or more substituents independently selected from the following: -OH, -NH2, -NH(C 1-6 Alkyl), C 1-6 Alkyl groups, C groups optionally substituted with halogens or CN 3-6 Cycloalkyl group, phenyl group, 5-6 membered heterocyclic group, optionally covered by C 1-6 Alkyl-substituted 5-6-membered heteroaryl groups, -OC 1-6 Alkyl and -O-(halogenated C) 1-6 alkyl); p is an integer selected from 0, 1 or 2, preferably 1; q is an integer selected from 1, 2, 3, 4, or 5, preferably 1 or 2; and The remaining groups are as defined in claim 1.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein ring A is selected from: Preferably, ring A is selected from Each of the above groups is marked with 0, 1, or 2 R groups. 2 and 0 or 1 ZR 3 replace.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein... Selected from: Preferably, Selected from 5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R 2 Each time it appears, it is independently a halogen or a carbon. 1-6 Alkyl, C 3-6 Cyclic hydrocarbon group or 3-10 membered heterocyclic group, preferably F, Cl, C 1-6 Alkyl or cyclopropyl, more preferably C 1-6 Alkyl group, most preferably methyl group; and m is an integer of 0 or 1; Or two Rs 2 Together with the groups to which it is attached, it forms a benzene ring.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein Z is a direct bond, -OC 1-4 Alkylene-*, -C 1-4 Alkylene-O-*, -N(Z) a )-C 1-4 Alkylene-*, -C 1-4 Alkylene-N(Z) a )-*、-C(=O)N(Z a )-*、-N(Z a )C(=O)-* or -C(=O)N(Z a )-C 1-4 Alkylene-*, where * indicates resemblance to R 3 Connection point; Z a Is it H or C? 1-3 Alkyl, preferably, Z a It is H; and n is 1; Preferably, Z is a direct bond, -OC 1-4 Alkylenes -* (e.g., -O-CH2-*), -N(Z) a )-C 1-4 Alkylene -* (e.g., -NH-CH2-*), where * indicates resemblance to R 3 The connection point; More preferably, Z is a direct bond.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R 3 Each time it appears, it is independently for Each of the above groups may be optionally substituted by one or more substituents independently selected from the following: D, halogen, -OH, =O, -NH2, -CN, -NO2, -SF5, =CH2, =CF2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R a -OC(=O)R a -C(=O)OR a -OR a -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b -S(=O)(=NR) a )R b -NR a R b -C(=O)NR a R b -NR a -C(=O)R b -NR a -C(=O)OR b -NR a -S(=O)2-R b -NR a -C(=O)-NR a R b -N = S(=O)R a R b -P(=O)R a R b -C 1-6 Alkylene-R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR a R b -OC 1-6 Alkylene-NR a R b 、(-C 3-6 (-CN and (-C) 3-6 (Hydrocyclic hydrocarbon group)-C 1-6 alkyl; R a and R b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl; or R a and R b Together with the groups it is attached to, they constitute C 3-6 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; The aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are each optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, -OH, -NH2, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl groups, -OR c -C(=O)R c -C(=O)OR c -C 1-6 Alkylene-R c -C 1-6 Alkylene-OR c -C 1-6 Alkylene-OC(=O)R c -S(=O)R c -S(=O)2R c and -P(=O)R c R d The aforementioned alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are each optionally further selected independently by one or more elements selected from halogens, -OH, -C(=O)OH, -CN, -NH2, =CF2, -P(=O)(C 1-6 Alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -N=S(=O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-14 membered heteroaryl, -OC 1-6 Alkyl and -OC 3-6 Substitution of cycloalkyl groups.

8. A compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R 3 Each time it appears, it is independently for Each of the above groups may be optionally substituted by one or more substituents independently selected from the following: halogen, -CN, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, -NR a R b -OR a -C(=O)NR a R b and -NR a -S(=O)2-R b ; R a and R b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl groups; The aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are each optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, -OH, -NH2, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, -OR c -C(=O)R c -C(=O)OR c -C 1-6 Alkylene-R c -C 1-6 Alkylene-OR c -C 1-6 Alkylene-OC(=O)R c -S(=O)R c -S(=O)2R c and -P(=O)R c R d The aforementioned alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally further selected independently by one or more elements selected from halogens, -OH, -C(=O)OH, -CN, -NH2, =CF2, -P(=O)(C 1-6 Alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -N=S(=O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-14 membered heteroaryl, -OC 1-6 Alkyl and -OC 3-6 Substituents of cycloalkyl groups; Preferably, R 3 Each time it appears, it is independently for Each of the above groups may be optionally substituted by one or more substituents independently selected from the following: halogen, -CN, C. 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic groups (preferably 3-8 membered heterocyclic groups) (preferably aza-butane, pyrrolidinyl, piperidinyl, piperazine, morpholinyl, 1,1-thiomorpholine, -NHR a -OR a -C(=O)NR a R b and -NR a -S(=O)2-R b ; R a and R b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-14 membered heteroaryl; preferably, R a and R b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-6 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; The aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, -OH, -NH2, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, phenyl groups, 5-14 membered heteroaryl groups, -OC groups 1-6 Alkyl, -C(=O)-(C 1-6 Alkyl group, -C(=O)-(3-10 membered heterocyclic group), -C(=O)OC 1-6 Alkyl, -C 1-6 Alkylene-(C 3-8 cyclic hydrocarbon group), -C 1-6 alkylene-(3-10 membered heterocyclic group), -C 1-6 alkylene-O-(C 1-6 Alkyl), -C 1-6 Alkylene-OC(=O)-(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-S(=O)(C 1-6 Alkyl) and -S(=O)2(C 1-6 Alkyl), wherein the aforementioned alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, phenyl, and heteroaryl groups are each optionally further selected independently by one or more elements selected from halogen, -OH, -C(=O)OH, -CN, -NH2, =CF2, -P(=O)(C 1-6 Alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -N=S(=O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 3- 6-cycloalkyl, 3-6-membered heterocyclic, phenyl, 5-6-membered heteroaryl, -OC 1-6 Alkyl and -OC 3-6 Substituents of cycloalkyl groups; Preferably, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, -OH, -NH2, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-6 membered heterocyclic groups, phenyl groups, 5-10 membered heteroaryl groups, -OC groups 1-6 Alkyl, -C(=O)-(C 1-6 Alkyl group), -C(=O)-(3-6 membered heterocyclic group), -C(=O)OC 1-6 Alkyl, -C 1-6 Alkylene-(C 3-6 cyclic hydrocarbon group), -C 1-6 Alkylene-(3-6 membered heterocyclic group), -C 1-6 alkylene-O-(C 1-6 Alkyl), -C 1-6 Alkylene-OC(=O)-(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-S(=O)(C 1-6 Alkyl) and -S(=O)2(C 1-6 Alkyl), wherein the aforementioned alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, phenyl, and heteroaryl groups are each optionally further selected independently by one or more elements selected from halogen, -OH, -C(=O)OH, -CN, -NH2, =CF2, -P(=O)(C 1-6 Alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -N=S(=O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 3- 6-cycloalkyl, 3-6-membered heterocyclic, phenyl, 5-6-membered heteroaryl, -OC 1-6 Alkyl and -OC 3-6 Substitution of cycloalkyl groups.

9. A compound of any one of claims 1-8 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein when Z is a direct bond, R 3 The substituents on R are optionally with R 2 The links form a 6-8 membered heterocycle, preferably a 7-membered heterocycle, wherein the heterocycle contains one or two heteroatoms selected from O and N.

10. A compound of any one of claims 1-9 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein R 1a Selected from H, halogens, SF5, CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, -O-(C 1-6 Alkyl) and -C(=O)-(C 1-6 Alkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclic groups are optionally substituted with one or more halogens; Preferably, R 1a The group is selected from H, F, Cl, Br, SF5, CN, methyl, ethyl, isopropyl, CF3, CHF2, CH2F, vinyl, ethynyl, cyclopropyl, aziridine, oxetidine, pyrrolidinyl, -O-CHF2, -O-CF3 and acetyl, wherein the cyclopropyl, aziridine, oxetidine and pyrrolidinyl are optionally substituted with one or more halogens; More preferably, R 1a Selected from H, F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, CHF2, CH2F, vinyl, ethynyl, cyclopropyl, -O-CHF2, and -O-CF3; More preferably, R 1a It is Br or Cl; Most preferably, R 1a It is Cl.

11. A compound of any one of claims 1-10, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R 1b Selected from C 2-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon group, 3-10 membered heterocyclic group, phenyl group, 5-14 membered heteroaryl group, -C 1-6 Alkylene-(C 3-6 cyclic hydrocarbon group), -C 1-6 Alkylene-(3-10 membered heterocyclic group), -C(=O)(C 1-6 Alkyl), -O(C) 1-6 alkyl), -O-(C 3-6 cyclic hydrocarbon group), -O(C 6-10 aryl), -S(C 1-6 alkyl), -NH(C) 1-6 Alkyl), -CH2-O-(C 6-10 aryl) and (-C 3-6 (Hydrocyclic hydrocarbon group)-C 2-6 alkynyl group; The alkylene, alkyl, alkenyl, alkynyl, cycloalkylene, cycloalkylene, heterocyclic, phenyl, aryl, and heteroaryl groups are each optionally substituted by one or more substituents independently selected from the following: halogen, -CN, -OH, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic, 5-14 membered heteroaryl, -O-(C 1-6 Alkyl groups and -C (=O) (C 1-6 Alkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclic, and heteroaryl groups are each optionally further substituted by one or more substituents independently selected from: halogen, -CN, -OH, -NH2, -NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, -OC 1-6 Alkyl and -O-(halogenated C) 1-6 alkyl); Preferably, R 1b Selected from C 2-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon group, 3-10 membered heterocyclic group, phenyl group, 5-14 membered heteroaryl group, -C(=O)(C 1-6 Alkyl), -O(C) 1-6 Alkyl), -O(C) 6-10 aryl), -S(C 1-6 alkyl) and -NH(C 1-6 alkyl) and (-C 3-6 (Hydrocyclic hydrocarbon group)-C 2-6 alkynyl group; The alkyl, alkenyl, alkynyl, hemicyclic, cyclic, heterocyclic, phenyl, aryl, and heteroaryl groups are each optionally substituted by one or more substituents independently selected from the following: halogen, -CN, -OH, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, -O-(C 1-6 Alkyl groups and -C (=O) (C 1-6 Alkyl), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups is optionally further substituted by one or more substituents independently selected from: halogen, -OH, -NH2, -NH(C 1-6 Alkyl), C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, -OC 1-6 Alkyl and -O-(halogenated C) 1-6 alkyl); Preferably, R 1b Selected from Most preferably, R 1b Selected from 12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R 1c Selected from H, halogens, -OH, -NH2, CN, C 1-6 Alkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, 5-14 membered heteroaryl groups, -O(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl groups), -S(=O)2NH2, -NH(C 1-6 Alkyl), -C(=O)NH2, -NH-S(=O)2-(C 1-6 Alkyl groups), -NH-S(=O)2-NH2 and -NH-S(=O)(=NH)(C 1-6 Alkyl); the above alkyl, cycloalkyl, heterocyclic and heteroaryl groups are each optionally substituted by one or more substituents independently selected from the following: -OH, -NH2, halogen, C 1-6 Alkyl and -OC 1-6 alkyl; Preferably, R 1c Selected from H, F, CN, -CH3, -NH2, -NHCH3, -OH、 -C(=O)NH2, -NHS(=O)2CH3, -NHS(=O)2NH2, -NHS(=O)(=NH)CH3, -S(=O)2CH3 and -S(=O)2NH2; More preferably, R 1c Selected from H, F, CN, -NH2, -OH, -C(=O)NH2 and -NHS(=O)2CH3; Most preferably, R 1c Selected from H, -NH2, and -OH.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R 1d Selected from H, halogens, and -CN; Preferably, R 1d Selected from H, F, and -CN; More preferably, R 1d For H.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein... R 1b Selected from C 2-6 Alkenyl; preferably, R 1b C substituted with cyano 2-6 alkenyl; and / or R 1c Selected from H, -NH2, -NH(C) 1-6 Alkyl groups and -OH.

15. A compound of any one of claims 1-14, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein the compound is selected from:

16. A pharmaceutical composition comprising a compound of any one of claims 1-15 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug, and one or more pharmaceutically acceptable carriers.

17. Use of any compound of claims 1-15 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug, or the pharmaceutical composition of claim 16, in the preparation of a medicament for the prevention or treatment of DHX9-mediated diseases or conditions.

18. The use of claim 17, wherein the DHX9-mediated disease or condition is cancer, viral infection, or autoimmune disease; Preferably, the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, breast cancer, brain cancer, skin cancer, lung cancer, leukemia, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft tissue cancer, kidney cancer, and liver cancer; Preferably, the cancer is a microsatellite instability (MSI) cancer; Preferably, the cancer has a mutation or defect in DNA mismatch repair (MMR), and / or a mutation or defect in RNA splicing and kinetochore complex; Preferably, the cancer is a BRAC1 / 2 mutated cancer.

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