Aromatic amide compounds as WRN helicase inhibitors, preparation method therefor and use thereof

Abstract

Disclosed in the present invention are compounds shown as formula (I) and pharmaceutically acceptable salts thereof. In particular, disclosed in the present invention are aromatic amide compounds serving as WRN helicase inhibitors as well as a preparation method therefor and the use thereof.

Description

Aromatic amide compounds as WRN helicase inhibitors, their preparation methods and applications

[0001] This invention claims the following priority:

[0002] Application number CN2024105197151, application date: April 26, 2024;

[0003] Application number CN2024111363657, application date: August 16, 2024;

[0004] Application number CN2024114229503, application date: October 11, 2024;

[0005] Application number CN2025104895428, application date: April 17, 2025. Technical Field

[0006] This invention relates to the compounds represented by formula (I) and their pharmacologically acceptable salts. Specifically, this invention relates to a class of aromatic amide compounds as WRN helicase inhibitors, their preparation methods, and applications. Background Technology

[0007] The human genome contains numerous short tandem repeat regions, known as microsatellites. These repetitive DNA regions are prone to slippage and errors during replication, making them highly dependent on the MMR (mismatch repair) system for repair. When the MMR system malfunctions, resulting in dMMR (mismatch repair deficiency), it cannot recognize and repair microsatellite replication errors, leading to MSI (microsatellite instability-high / deficient mismatch repair), which can cause frameshift mutations, thereby inducing abnormalities in tumor-related genes and ultimately inducing cancer development and progression. In 2017, immune checkpoint inhibitors (ICIs) were approved for the treatment of tumors with high microsatellite instability-high / deficient mismatch repair (MSI-H / dMMR), making MSI-H / dMMR the first pan-tumor marker. Microsatellite instability-high (MSI-H) cancer cells rely on WRN (Werner syndrome RecQ helicase) activity. Inhibition of WRN can induce DNA double-strand breaks, activate DNA damage responses, and induce apoptosis and cell cycle capture. Common treatments for dMMR (mismatch repair deficient) / MSI-H cancer patients include targeted therapy, chemotherapy, and immunotherapy. The clinical efficacy of targeted therapy and chemotherapy is limited by drug resistance and toxicity; furthermore, approximately half of immunotherapy patients do not respond positively to immune checkpoint inhibitors. 45-60% of MSI-H cancer patients do not respond to immunotherapy, highlighting the urgent need to address primary and secondary resistance to targeted therapy, chemotherapy, and immunotherapy. In 2019, the Broad Institute at Harvard and MIT analyzed the Achilles and Drive databases to assess the dependence of various cell lines on different targets. They found that the activity of the RecQ DNA helicase WRN is essential both in vivo and in vitro in dMMR / MSI-H cell lines, while MSS cells do not depend on WRN for survival. In the MSI-H model, WRN knockout induces double-strand DNA breaks and selectively promotes apoptosis and cell cycle arrest. This anti-cancer mechanism differs from that of targeted drugs (which inhibit specific oncogenic alterations in cancer cells) and immunotherapy (which suppresses immune evasion and tolerance). In 2021, Dr. Mathew J. Garnett's research group at the Wellcome Sanger Institute demonstrated using a PDX model that WRN inhibitors can serve as second- or third-line monotherapy for dMMR patients. In dMMR tumors, tumor mutational load is negatively correlated with immune checkpoint blockade response, while WRN sensitivity is independent of mutational burden. Due to these different modes of action, combining checkpoint inhibitors, chemotherapy, or targeted therapy with WRN inhibitors may suppress cross-resistance and promote tumor eradication.Furthermore, because the loss of DNA repair modulates the structure of neoantigens, increases the mutational burden, and leads to an enhanced immune response, WRN inhibition may also have a synergistic effect with immunotherapy. Therefore, WRN can serve as a key target for monotherapy or in combination with targeted drugs, chemotherapy, or immunotherapy in dMMR / MSI-H tumors.

[0008] MSI-H tumors can occur in multiple sites, with the highest incidence in endometrial cancer (31%), colon adenocarcinoma (20%), and gastric cancer (19%). Approximately 325,000 new MSI-H tumors are diagnosed annually in the United States and about 300,000 in China, indicating significant market potential for drug development. In tumors with normal mismatch repair (MSS), the loss (or reduction) of WRN expression does not affect tumor cell growth. However, in tumors with defective mismatch repair (MSI-H), the simultaneous loss (or reduction) of WRN expression can lead to an increased accumulation of DNA double-strand breaks, cell cycle arrest at the G1 or G2 / M phase, resulting in tumor cell death. This is known as the synthetic lethal effect. Developing WRN helicase inhibitors holds promise as an effective treatment for MSI-H cancers. Summary of the Invention

[0009] In one aspect of the invention, the invention provides a compound of formula (I), an optical isomer thereof, or a pharmacologically acceptable salt thereof.

[0010] in,

[0011] X is selected from CR7 or N;

[0012] Z is selected from CR8 or N;

[0013] L1 is selected from single bonds, C 1-20 Alkyl or C 1-20 Heteroalkyl, the C 1-20 Alkyl and C 1-20 The heteroalkyl group may be optionally substituted with 1, 2 or 3 Rs;

[0014] L2 is selected from single bond, -O-, -S-, -N(R) b1 )-、-C(R b2 -2-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2- or

[0015] L3 is selected from single bonds, C 1-20 Alkyl or C 1-20 Heteroalkyl, the C 1-20 Alkyl and C 1-20 The heteroalkyl group may be optionally substituted with 1, 2 or 3 Rs;

[0016] T is selected from O or N(R)b1 );

[0017] R1 is selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 heteroaryl, wherein C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6- 20 Aryl and 5-20 heteroaryl groups may be substituted by 1, 2 or 3 Rs;

[0018] R2 is selected from C 6-20 Aryl, 5-20 heteroaryl, C 3-20 Cycloalkyl or 3-20 membered heterocycloalkyl, wherein C 6-20 Aryl, 5-20 heteroaryl, C 3-20 Cycloalkyl and 3-20 membered heterocyclic alkyl groups may be optionally substituted with 1, 2 or 3 Rs;

[0019] R3 is selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -COOH, -C(=O)NH2, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 heteroaryl, wherein C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl and 5-20 heteroaryl groups may be substituted by 1, 2 or 3 Rs;

[0020] R4 is selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl or 3-20 membered heterocycloalkyl, wherein C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl and 3-20 membered heterocyclic alkyl groups may be optionally substituted with 1, 2 or 3 Rs;

[0021] R5 is selected from -F, -Cl, -Br, -I, -CN, or C. 1-20 Alkyl, the C 1-20 Alkyl groups may be optionally substituted with 1, 2, or 3 Rs;

[0022] R6 is selected from C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl or 3-20 membered heterocycloalkyl, wherein C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl and 3-20 membered heterocyclic alkyl groups may be optionally substituted with 1, 2 or 3 Rs;

[0023] R7 and R8 are independently selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, and C, respectively. 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl or 3-20 membered heterocycloalkyl, wherein C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl and 3-20 membered heterocyclic alkyl groups may be optionally substituted with 1, 2 or 3 Rs;

[0024] R b1 Each occurrence is independently selected from -H, C 1-12 Alkyl, C 1-12 Heteroalkyl, C 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl, wherein C 1- 12 Alkyl, C 1-12 Heteroalkyl, C 3-12 Cycloalkyl and 3-12 membered heterocycloalkyl groups may be optionally substituted with 1, 2 or 3 Rs;

[0025] R b2 Each occurrence is independently selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, C 1-12 Alkyl or C 1-12 Heteroalkyl, the C 1-12 Alkyl and C 1-12 The heteroalkyl group may be optionally substituted with 1, 2 or 3 Rs;

[0026] Each occurrence of R is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -CHO, -COOH, -C(=O)NH2, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 heteroaryl, wherein C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C6-20 Aryl and 5-20 heteroaryl groups may be optionally substituted by 1, 2 or 3 R's;

[0027] Each time R' appears, it is independently selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CH3, -CF3, -C2H5, -CN, -SF5, -CHO, -COOH or -C(=O)NH2;

[0028] The above C 1-12 Heteroalkyl, C 1-20 Heteroalkyl, 3-12-membered heterocyclic alkyl, 3-20-membered heterocyclic alkyl and 5-20-membered heteroaryl contain 1, 2 or 3 heteroatoms independently selected from O, N and S or heteroatoms selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -S(=O)(=NH)-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- and -S(=O)N(H)-.

[0029] In some embodiments of the present invention, the structure of the compound represented by formula (I) is as shown in formula (I-1) or (I-2):

[0030] In some embodiments of the present invention, R is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -CHO, -COOH, -C(=O)NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkyl-C 1-6 Alkoxy-, C 1-6 Alkyl-C 1-6 Alkylthio-, C 1-6 Alkyl-C 1-6 Alkylamino-, -C 1-6 Alkyl -OH, -C 1-6 Alkyl group -NH2, -C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-C(=O)-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl, -C 1-6 Alkyl-NH-S(=O)2-C 1-6 Alkyl, C 3-6Cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, thiophene, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, or thiaranyl.

[0031] The C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkyl-C 1-6 Alkoxy-, C 1-6 Alkyl-C 1-6 Alkylthio-, C 1-6 Alkyl-C 1-6 Alkylamino-, -C 1-6 Alkyl -OH, -C 1-6 Alkyl group -NH2, -C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-C(=O)-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl, -C 1-6 Alkyl-NH-S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, thiophenyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, and thiaranyl may be optionally substituted with 1, 2, or 3 R's;

[0032] Other variables are as defined in this invention.

[0033] In some embodiments of the present invention, R is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -CHO, -COOH, -C(=O)NH2, -CH3, -CF3, -CHF2, -CH2F, -CF2Cl, -CF2Br, -CF2I, -OCH3, -NHCH3 or -N(CH3)2.

[0034] In some embodiments of the present invention, L1 is selected from single bonds, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C 1-6 Alkyl-C 1-6 Alkoxy-, -C1-6 Alkyl-C 1-6 Alkylthio-, -C 1-6 Alkyl-C 1-6 Alkylamino-,-C(=O)-C 1-6 Alkyl-, -C 1-6 Alkyl-C(=O)-C 1-6 Alkyl-, -NH-C(=O)-C 1-6 Alkyl-, -C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl-, -NH-S(=O)2-C 1-6 Alkyl- or -C 1-6 Alkyl-NH-S(=O)2-C 1-6 alkyl-,

[0035] The C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C 1-6 Alkyl-C 1-6 Alkoxy-, -C 1-6 Alkyl-C 1-6 Alkylthio-, -C 1-6 Alkyl-C 1-6 Alkylamino-,-C(=O)-C 1-6 Alkyl-, -C 1-6 Alkyl-C(=O)-C 1-6 Alkyl-, -NH-C(=O)-C 1-6 Alkyl-, -C 1- 6alkyl-NH-C(=O)-C 1-6 Alkyl-, -NH-S(=O)2-C 1-6 Alkyl- and -C 1-6 Alkyl-NH-S(=O)2-C 1-6 Alkyl groups are optionally substituted with one, two, or three Rs;

[0036] Other variables are as defined in this invention.

[0037] In some embodiments of the present invention, L1 is selected from single bonds, -CH2-, -CF2-, ...

[0038] In some embodiments of the present invention, L1 is selected from single bonds, -CH2-,

[0039] In some embodiments of the present invention, R1 is selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, azacyclobutane, tetrahydropyrrolyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, thiophenyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, or thiaranyl.

[0040] The C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, azacyclobutyl, tetrahydropyrrolyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridinyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazine, pyranyl, furanyl, thiazolyl, oxazolyl, and thiaranyl may be substituted with 1, 2, or 3 Rs.

[0041] Other variables are as defined in this invention.

[0042] In some embodiments of the present invention, R1 is selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -CH3, -C2H5,

[0043] In some embodiments of the present invention, the structural unit L1-R1 is selected from...

[0044] In some embodiments of the present invention, the structural unit L1-R1 is selected from...

[0045] In some embodiments of the present invention, R b1 Each occurrence is independently selected from -H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino or C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino and C 3-6 The cycloalkyl group may be optionally substituted with 1, 2 or 3 Rs; other variables are as defined in this invention.

[0046] In some embodiments of the present invention, R b2Each occurrence is independently selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio and C 1-6 The alkylamino group may be optionally substituted with 1, 2, or 3 Rs; other variables are as defined in this invention.

[0047] In some embodiments of the present invention, L2 is selected from single bonds, -O-, -S-, -NH-, -CH2-, -CF2-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2- or

[0048] In some embodiments of the present invention, R2 is selected from C. 3-12 Cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, thiophene, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, or thiaranyl.

[0049] The C 3-12 Cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, thiophenyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, and thiaranyl may be substituted with 1, 2, or 3 Rs.

[0050] Other variables are as defined in this invention.

[0051] In some embodiments of the present invention, R2 is selected from...

[0052] In some embodiments of the present invention, the structural unit -L2-R2 is selected from...

[0053] In some embodiments of the present invention, L3 is selected from single bonds, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C 1-6 Alkyl-C 1-6 Alkoxy-, -C 1-6 Alkyl-C 1-6 Alkylthio-, -C 1-6 Alkyl-C 1-6 Alkylamino-,-C(=O)-C 1-6 Alkyl-, -C1-6 Alkyl-C(=O)-C 1-6 Alkyl-, -NH-C(=O)-C 1-6 Alkyl-, -C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl-, -NH-S(=O)2-C 1-6 Alkyl- or -C 1-6 Alkyl-NH-S(=O)2-C 1-6 alkyl-,

[0054] The C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C 1-6 Alkyl-C 1-6 Alkoxy-, -C 1-6 Alkyl-C 1-6 Alkylthio-, -C 1-6 Alkyl-C 1-6 Alkylamino-,-C(=O)-C 1-6 Alkyl-, -C 1-6 Alkyl-C(=O)-C 1-6 Alkyl-, -NH-C(=O)-C 1-6 Alkyl-, -C 1- 6alkyl-NH-C(=O)-C 1-6 Alkyl-, -NH-S(=O)2-C 1-6 Alkyl- and -C 1-6 Alkyl-NH-S(=O)2-C 1-6 Alkyl groups are optionally substituted with one, two, or three Rs;

[0055] Other variables are as defined in this invention.

[0056] In some embodiments of the present invention, L3 is selected from single bonds, -CH2-,

[0057] In some embodiments of the present invention, R3 is selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -COOH, -C(=O)NH2, C 1- 6-alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-12 Cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, thiophene, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, or thiaranyl.

[0058] The C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-12 Cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, thiophenyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, and thiaranyl may be substituted with 1, 2, or 3 Rs.

[0059] Other variables are as defined in this invention.

[0060] In some embodiments of the present invention, R3 is selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -COOH, -C(=O)NH2, -CH3, -CF2H, -C2H5, -OCH3, -OCF2H, -OC(CH3)3,

[0061] In some embodiments of the present invention, the structural unit -L3-R3 is selected from -CH3, -C2H5,

[0062] In some embodiments of the present invention, R5 is selected from -F, -Cl, -Br, -I, -CN, or C. 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally substituted with 1, 2, or 3 Rs; other variables are as defined in this invention.

[0063] In some embodiments of the present invention, R6 is selected from C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio and C 1-6 The alkylamino group may be optionally substituted with 1, 2, or 3 Rs; other variables are as defined in this invention.

[0064] In some embodiments of the present invention, R7 is selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, C 1-12 Alkyl, C 1-12 Heteroalkyl, C 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl, wherein C 1-12 Alkyl, C 1-12 Heteroalkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic alkyl groups may be optionally substituted with 1, 2 or 3 Rs; other variables are as defined in this invention.

[0065] In some embodiments of the present invention, R8 is selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, C 1-12 Alkyl, C 1-12 Heteroalkyl, C 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl, wherein C 1-12 Alkyl, C 1-12 Heteroalkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic alkyl groups may be optionally substituted with 1, 2 or 3 Rs; other variables are as defined in this invention.

[0066] The present invention also provides compounds of the following formula, their optical isomers, or pharmacologically acceptable salts thereof, selected from...

[0067] In some embodiments of the present invention, the above-mentioned compound, its optical isomer, or its pharmacologically acceptable salt is selected from...

[0068] In another aspect, the invention also provides a pharmaceutical composition. In some embodiments of the invention, the pharmaceutical composition protects the aforementioned compound, its optical isomers, or pharmaceutically acceptable salts thereof.

[0069] In some embodiments of the present invention, the above-mentioned pharmaceutical composition further comprises pharmaceutical excipients.

[0070] In another aspect, the present invention also provides the use of the above-described compounds, their optical isomers, or pharmaceutically acceptable salts thereof, or the above-described pharmaceutical compositions in the preparation of medicaments for treating tumor-related diseases.

[0071] The purpose of this invention is to provide a compound or its stereoisomers, deuterated compounds, solvent compounds, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals as WRN inhibitors, intermediates thereon, and preparation methods thereof, as well as their use in the preparation of medicaments for treating microsatellite-related diseases with high instability.

[0072] In some embodiments of the present invention, tumor-related diseases are one or more of the diseases associated with solid tumors.

[0073] The compounds of this invention can be used alone or in combination with other chemotherapeutic agents, targeted therapies, or immunotherapies for the treatment of various tumors, especially malignant tumors with microsatellite instability (MSI), or malignant tumors with mismatch repair deficient (dMMR), or those with a high level of TA. n Malignant tumors with repetitive sequences include, but are not limited to, colorectal cancer, gastric cancer, endometrial cancer, and ovarian cancer.

[0074] Definitions and Explanations

[0075] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0076] The term “pharmacologically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0077] The term "pharmacologically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a specific substituent, as discovered in this invention, with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmacologically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of acid in a solution or a suitable inert solvent. Examples of pharmacologically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and also include salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0078] The pharmacologically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0079] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0080] Unless otherwise stated, the terms "tautomer" or "tautomer form" refer to isomers with different functional groups in dynamic equilibrium at room temperature, capable of rapidly interconverting into each other. Tautomers can be chemically equilibrated if possible (e.g., in solution). For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions involving the rearrangement of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the tautomers pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0081] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0082] "Optional" or "optionally" means that the event or condition described below may occur but is not required to occur, and the description includes both the scenario in which said event or condition occurs and the scenario in which said event or condition does not occur.

[0083] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on the basis of chemical feasibility.

[0084] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by one, two, or three Rs, the group can optionally be substituted by up to three Rs, and each case has an independent option for R. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound. For example, Can be selected wait.

[0085] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected, for example... When L2 represents a single bond, it means that the structure is actually A hyphen ("-") not between two letters or symbols indicates the connection site of a substituent. For example, C 1- 6-alkyl carbonyl - refers to a carbonyl group connected to the rest of the molecule via a carbonyl group. 1-6 Alkyl groups. However, when the linking site of the substituent is obvious to those skilled in the art, such as halogen substituents, the "-" may be omitted.

[0086] Unless otherwise stated, when the group valence bond is marked with a dashed line At times, for example, in In the diagram, the dashed line represents the connection point between the group and other parts of the molecule.

[0087] When the listed substituents do not specify which atom they are attached to the substituted group, such substituents can be bonded to any of their atoms. For example, a pyridinium substituent can be attached to the substituted group by any carbon atom on the pyridine ring.

[0088] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linking group L is at this time The phenyl and cyclopentyl groups can be connected in the same direction as the reading order from left to right to form the structure. Alternatively, the phenyl and cyclopentyl groups can be connected in the reverse order of reading from left to right to form the phenyl group. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0089] Unless otherwise specified, the number of atoms on a ring indicates the number of atoms constituting the ring itself in compounds formed by atomic bonds (such as monocyclic compounds, fused ring compounds, spirocyclic compounds, bridged ring compounds, cross-linked compounds, carbocyclic compounds, and heterocyclic compounds). The number of atoms on a ring is usually defined as the ring's atom count; for example, a "4-6 membered ring" refers to a ring with 4-6 atoms arranged around it. When a ring is substituted with a substituent, the atoms contained in the substituent are not included in the ring-forming atoms. Unless otherwise specified, benzene is a 6-membered ring, naphthalene is a 10-membered ring, and thiophene is a 5-membered ring.

[0090] Unless otherwise specified, the term "alkyl" means a saturated hydrocarbon group containing a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof, which may represent a straight-chain and / or branched alkyl group, and may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). Unless otherwise specifically stated in the specification, alkyl groups may optionally be substituted.

[0091] Unless otherwise specified, the term "C" 1-20 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 20 carbon atoms. The C 1-20 Alkyl groups include C 1-19 C 1-15 C 1-10 C 1-5 C 1-4 C 2-20 C 2-12 C 2-6 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-20Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, sec-butyl, n-pentyl, n-hexyl, 1-methylhexyl, n-nonyl, n-decyl, adamantyl, n-undecyl, n-dodecyl, 2-ethyldodecyl, 2-butyldodecyl, n-eicosyl, methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, 1,7-heptylene, 1,8-octylene, 1,9-nonylene, 1,10-decylene, 1,12-dodecylene, 1,14-tetradecylene, 1,16-hexadecylene, 1,18-octadecylene, 1,20-eicosylene, etc.

[0092] Unless otherwise specified, the term "C" 1-6 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 Alkyl groups include C 1-5 C 1-4 C 2-6 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-6 Examples of alkyl groups include, but are not limited to, methyl (“Me”), ethyl (“Et”), propyl such as n-propyl (“n-Pr”) or isopropyl (“i-Pr”), butyl such as n-butyl (“n-Bu”), isobutyl (“i-Bu”), sec-butyl (“s-Bu”) or tert-butyl (“t-Bu”), pentyl, hexyl, methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, etc.

[0093] Unless otherwise specified, the term "alkenyl" refers to a compound containing at least one unsaturated site, i.e., a carbon-carbon sp group. 2 The double-bonded hydrocarbon group can represent a straight-chain and / or branched alkenyl group, where branching refers to one or more alkyl groups, such as methyl, ethyl, or propyl, attached to the straight-chain alkenyl chain. It can be monovalent, divalent, or polyvalent. Unless otherwise specified in the specification, the alkenyl group may optionally be substituted.

[0094] Unless otherwise specified, "C 2-12 "Alkenyl" is used to denote a hydrocarbon group consisting of 2 to 12 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon double bond. The carbon-carbon double bond can be located at any position within the group. The C... 2-12 Alkenes include C 2-11 C 2-10 C 2-5 C 2-4 C 3-20 C 4-12 C 5-6 Alkenes, etc.; they can be monovalent, divalent, or polyvalent. C2-12 Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, n-butenyl, 3-methylbut-2-enyl, pentenyl, hexenyl, butadienyl, pentodienyl, hexadienyl, octenyl, decenyl, n-undecenyl, vinylidene, propenylidene, sec-butenylidene, 2-methylbutenylidene, etc.

[0095] Unless otherwise specified, "C 2-6 "Alkenyl" is used to denote a hydrocarbon group consisting of 2 to 6 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon double bond. The carbon-carbon double bond can be located at any position within the group. The C... 2-6 Alkenes include C 2-4 C 2-3 C4, C3, and C2 alkenyl groups, etc.; they can be monovalent, divalent, or polyvalent. 2-6 Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, vinylidene, propenylidene, sec-butenyl, etc.

[0096] Unless otherwise specified, "-CH=C 3-20 "Cycloalkyl" is used to indicate a compound with one carbon atom and C. 3-20 A group in which a cycloalkyl group is linked by a double bond can be represented structurally as follows: Ring A is selected from C. 3-20 Cycloalkyl. For example, "-CH=C3 cycloalkyl" indicates...

[0097] Unless otherwise specified, the term "alkynyl" refers to a hydrocarbon group containing at least one unsaturated site, i.e., a carbon-carbon sp triple bond, which can represent a straight-chain and / or branched alkynyl group. A branched group refers to one or more alkyl groups, such as methyl, ethyl, or propyl, attached to the straight-chain alkynyl group. It can be monovalent, divalent, or polyvalent. Unless specifically stated in the specification, the alkynyl group may optionally be substituted.

[0098] Unless otherwise specified, the term "C" 2-12 "Alkyne" is used to denote a straight-chain or branched hydrocarbon group consisting of 2 to 12 carbon atoms containing at least one carbon-carbon triple bond, which can be located at any position within the group. 2-12 Alkyne groups include C 2-11 C 2-10 C 2-5 C 2-4 C 3-20 C 4-12 C 5-6 Alkyne groups, etc.; they can be monovalent, divalent, or polyvalent. C 2-12Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, ethynylene, propynylene, penynyl, penynylene, 1-butynyl, butyrynyl, cyclopropylethynyl, 3-methyl-2-pentynylene, etc.

[0099] Unless otherwise specified, the term "C" 2-6 "Alkyne" is used to denote a hydrocarbon group consisting of 2 to 6 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon triple bond. The carbon-carbon triple bond can be located at any position within the group. It can be monovalent, divalent, or polyvalent. The C... 2- 6-Alkyne group includes C 2-5 C 2-4 C 2-3 C2, C 2-6 C6 and C5 acetylinyl groups, etc. C 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, ethynylene, propynylene, penynyl, and penynylene.

[0100] Unless otherwise specified, the term "heteroalkyl" on its own or in combination with another term refers to a stable straight-chain or branched alkyl group or a combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heterogroup, wherein the "alkyl" in "alkyl group" is defined as described above. In some embodiments, the heteroatom is selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heterogroup is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. In some embodiments, the heteroalkyl is C 1-20 Heteroalkyl; in some embodiments, the heteroalkyl group is C10. 1-6 Heteroalkyl; in other embodiments, the heteroalkyl group is C10. 1-3Heteroalkyl groups. Heteroatoms or heteroatomic groups can be located at any internal position of a heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule. Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -CH2-S-CH2-CH3, -CH2-CH2, -S(=O)-CH3, -CH2-CH2-S(=O)2-CH3, etc.; at most two heteroatoms can be consecutive, for example, -CH2-NH-OCH3. Unless otherwise specified in the specification, heteroalkyl groups may optionally be substituted. Unless otherwise specified, the term "alkoxy" refers to an alkyl group connected to the remainder of the molecule by one oxygen atom, wherein "alkyl" in "alkyl group" is defined as described above. Unless otherwise specified in the specification, alkoxy groups may optionally be substituted.

[0101] Unless otherwise specified, the term "C" 1-6 "Alkoxy" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-6 Alkoxy groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, and C3 alkoxy groups, etc. 1- Examples of 6-alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy, methyleneoxy, ethoxy, propoxy, butoxy, pentylene, etc.

[0102] Unless otherwise specified, the term "C" 1-4 "Alkoxy" refers to alkyl groups containing 1 to 4 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-4 Alkoxy groups include C 1-3 C 1-2 C 2-4 C4 and C3 alkoxy groups, etc. 1-6Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), methyleneoxy, ethoxy, propoxy, butoxy, etc.

[0103] Unless otherwise specified, the term "C" 1-3 "Alkoxy" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 C 2-3 C3 and C2 alkoxy groups, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), methyleneoxy, ethoxy, propoxy, etc.

[0104] Unless otherwise specified, the term "amino" can be monovalent. Bivalent Or multiple prices

[0105] Unless otherwise specified, the term "alkylamino" refers to an alkyl group attached to the remainder of a molecule by an amino group as defined above, wherein "alkyl" in "alkyl group" is defined as described above. Alkylamino groups may optionally be substituted unless specifically stated in the specification.

[0106] Unless otherwise specified, the term "C" 1-6 "Alkylamino" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule via an amino group. The C 1-6 Alkylamino groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, C3, and C2 alkylamino groups, etc. 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, etc.

[0107] Unless otherwise specified, the term "C" 1-4 "Alkylamino" refers to alkyl groups containing 1 to 4 carbon atoms that are attached to the rest of the molecule via an amino group. The C 1-4 Alkylamino groups include C 1-3 C 1-2 C2-4 C4, C3, and C2 alkylamino groups, etc. C 1-4 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, etc.

[0108] Unless otherwise specified, the term "C" 1-3 "Alkylamino" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule via an amino group. The C 1-3 Alkylamino groups include C 1-2 C3 and C2 alkylamino groups, etc. C 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, etc.

[0109] Unless otherwise specified, the term "alkylthio" refers to an alkyl group attached to the remainder of the molecule by a sulfur atom, wherein the "alkyl" in "alkyl group" is defined as described above. Unless specifically stated otherwise in the specification, the alkylthio group may optionally be substituted.

[0110] Unless otherwise specified, the term "C" 1-6 "Alkylthio" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule via a sulfur atom. The C 1-6 Alkyl thio groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, C3, and C2 alkylthio groups, etc. C 1- Examples of 6-alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, etc.

[0111] Unless otherwise specified, the term "C" 1-4 "Alkylthio" refers to alkyl groups containing 1 to 4 carbon atoms that are attached to the rest of the molecule via a sulfur atom. The C 1-4 Alkyl thio groups include C 1-3 C 1-2 C 2-4 C4, C3, and C2 alkylthio groups, etc. C 1-4Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, etc.

[0112] Unless otherwise specified, the term "C" 1-3 "Alkylthio" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule via a sulfur atom. The C 1-3 Alkyl thio groups include C 1-3 C 1-2 And C3 alkylthio groups, etc. C 1-3 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, etc.

[0113] Unless otherwise specified, the term "cycloalkyl" refers to a stable, non-aromatic monocyclic or polycyclic saturated hydrocarbon group consisting of carbon and hydrogen atoms, which may include fused, spirocyclic, and / or bridged ring systems. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, but are not limited to, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. 4-6 "Cycloalkyl" indicates a cycloalkyl group having 4-6 carbon atoms in the ring. Similarly, "C 3-4 "Cycloalkyl" refers to a cycloalkyl group having 3-4 carbon atoms in the ring. Unless otherwise specified in the specification, the cycloalkyl group may be optionally substituted.

[0114] Unless otherwise specified, "C 3-20 "Cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon group having 3-20 ring carbon atoms, for example 3-15 ring carbon atoms, for example 3-6 ring carbon atoms; it can be monovalent, divalent, or polyvalent. C 3-20 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0115] Unless otherwise specified, "C 3-6 "Cycloalkyl" refers to a saturated monocyclic or bicyclic hydrocarbon group having 3-6 ring carbon atoms, for example 3-5 ring carbon atoms, for example 3-4 ring carbon atoms; it can be monovalent, divalent, or polyvalent. C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0116] Unless otherwise specified, "C 4-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms, which can be monocyclic or bicyclic. 4-6 Cycloalkyl groups include C 4-5 C 5-6C4, C5, and C6 cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. 4-6 Examples of cycloalkyl groups include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0117] Unless otherwise specified, the term "heterocyclic alkyl" means a non-aromatic saturated cyclic group existing as a monocyclic, fused, spirocyclic, and / or bridged ring, wherein at least one ring atom is a heteroatom or heteroatomic group, and the remainder are carbon atoms; in some embodiments, the heteroatom is selected independently from B, O, N, and S each time it appears, wherein the nitrogen and sulfur atoms are optionally oxidized (i.e., NO and S(O)). p (p is 1 or 2), the nitrogen heteroatom is optionally quaternized, and in other embodiments, each occurrence of the heterogroup is independently selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. The heteroatom or heterogroup can be located at any internal position of the heterocyclic alkyl group, including the position where the heterocyclic alkyl group is connected to the rest of the molecule. In some embodiments, the heterocyclic alkyl group is a 3-20-membered heterocyclic alkyl group; in some embodiments, the heterocyclic alkyl group is a 3-10-membered heterocyclic alkyl group; in other embodiments, the heterocyclic alkyl group is a 3-6-membered heterocyclic alkyl group. Unless otherwise specifically stated in the specification, the heterocyclic alkyl group may optionally be substituted. Unless otherwise specified, the term "3-6 membered heterocyclic alkyl" on its own or in combination with other terms respectively refers to a saturated cyclic group consisting of 3 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from B, O, S, and N or heteroatomic groups as described above, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p(where p is 1 or 2). It includes monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused, and bridged rings. Furthermore, regarding the "3-6 membered heterocyclic alkyl," heteroatoms or heterogroups can be located at any internal position of the heterocyclic alkyl group, including positions that can occupy the connection between the heterocyclic alkyl group and the rest of the molecule. The 3-6 membered heterocyclic alkyl groups include 5-6, 4, 5, and 6 membered heterocyclic alkyl groups, etc. Examples of 3-6 membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl or homopiperidinyl, etc.

[0118] Unless otherwise specified, the term "cycloalkenyl" in this invention refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group composed of carbon and hydrogen atoms, having one or more carbon-carbon splines. 2 Double bonds, which may include fused rings, spiro rings, and / or bridged ring systems. Monocyclic cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc. Polycyclic cycloalkenyl groups include, but are not limited to, bicyclic [2.2.1]hept-2-enyl, etc. Unless otherwise specified in the specification, cycloalkenyl groups may optionally be substituted. "C 3-7 "Cycloalkenyl" includes C3, C4, C5, C6, and C7 cycloalkenyl groups. Examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, and cyclohexenyl.

[0119] Unless otherwise specified, the term "heterocyclic alkenyl" in this invention refers to a cyclic alkenyl group comprising a plurality of heteroatoms or heterogroups, wherein in some embodiments, each heteroatom is independently selected from B, O, N, and S, wherein nitrogen and sulfur atoms are optionally oxidized (i.e., NO and S(O)). p(p is 1 or 2), the nitrogen heteroatom is optionally quaternized, and in other embodiments, each heteroatom group is independently selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. "5-6 membered heterocyclic alkenyl" alone or in combination with other terms respectively represents an unsaturated cyclic group consisting of 5 to 6 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from B, O, S, and N or heteroatom groups as described above, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). Examples of heterocyclic alkenyl groups include, but are not limited to, those mentioned above. Unless otherwise specified in the specification, the heterocyclic alkenyl group may optionally be substituted.

[0120] Unless otherwise specified, when a substituent attached to ring A can connect with ring A to form a ring, it means that the substituent can connect to any site on ring A to form a new ring together with ring A, including fused rings, spirocyclic rings, or bridged rings; wherein ring A can be selected from cycloalkyl, heterocyclic alkyl, cycloalkenyl, heterocyclic alkenyl, aryl, heteroaryl, etc. as described above. For example, when R in the text can be related to... Connect to form a 6-membered ring, the embodiments of which include, but are not limited to, those of the following. wait.

[0121] Unless otherwise specified, C n-n+m Or C n -C n+m This includes any specific case with n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It also includes any range from n to n+m, such as C 1-12 Including C 1-3 C 1-6 C 1-9 C 3-6 C 3-9 C 3-12 C 6-9 C 6-12 and C 9-12Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings, etc.

[0122] Unless otherwise specified, the term "aryl" refers to a hydrocarbon cyclic group comprising at least one aromatic ring. In this invention, the aryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, spirocyclic, and / or bridged ring systems. Aryl groups include, but are not limited to, benzene, naphthalene, anthracene, fluoranthene, phenanthrene, benzo[a]phenanthrene, dinaphthalene-2, tetraphenylene, pyrene, benzo[a]pyrene, acenaphthene, fluorene, and their derivatives. Unless specifically stated in the specification, the aryl group may optionally be substituted.

[0123] Unless otherwise specified, the term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, containing 1 to 3 heteroatoms; more preferably 5- or 6-membered, containing 1 to 3 heteroatoms; non-limiting examples include pyrazolyl, imidazolyl, furanyl, thiophene, thiazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc. The heteroaryl group can be attached to the rest of the molecule via heteroatoms or carbon atoms. The heteroaryl ring can be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include: Examples of heteroaryl compounds include triazine, pyridine, pyrimidine, imidazole, furan, thiophene, benzofuran, benzothiophene, indole, carbazole, pyrroloimidazole, pyrrolopyrrole, thiophenolopyrrole, thiophenolothiophene, furanolopyrrole, furanolofuran, thiophenolofuran, benzoisoxazole, benzoisothiazol, quinoline, isoquinoline, o-diazonine, quinoxaline, phenanthridine, primidine, quinazoline, quinazolinone, dibenzothiophene, dibenzofuran, carbazole and their derivatives. Unless otherwise specified in the specification, heteroaryl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

[0124] As used in this invention, the term "substituted" means that in any of the above-mentioned groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl), at least one hydrogen atom is substituted by a non-hydrogen atom bond, said non-hydrogen atom including but not limited to halogen atoms (such as F, Cl, Br, I), oxygen-containing groups (such as hydroxyl, alkoxy, ester), sulfur-containing groups (such as thiol, thioalkyl, sulfone, sulfonyl, sulfoxide), nitrogen-containing groups (such as amino, amide, alkylamino, dialkylamino, arylamino, aryl-alkyl-amino, diarylamino, N-oxide, imide, enamino), silicon-containing groups (such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl), and other heteroatoms in various other groups.

[0125] The term "substituted" as used in this invention also means that one or more hydrogen atoms in any of the above-mentioned groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkathioyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl) are substituted by a higher-order bond (such as a double or triple bond) of a heteroatom, for example, oxygen in carbonyl, carboxyl, and ester groups, and nitrogen in imine, oxime, hydrazone, and nitrile groups. For example, "substituted" means that one or more hydrogen atoms in any of the above-mentioned groups are replaced by -NR. g R h -NR g C(=O)R h -NR g C(=O)NR g R h -NR g C(=O)OR h -NR g SO2R h -OC(=O)NR g R h -OR g -SR g -SOR g SO2R g -OSO2R g -SO2OR g =NSO2R g With -SO2NR g R h Substitution. "Substituted" can also mean that one or more hydrogen atoms in any of the above groups are replaced by -C(=O)R g -C(=O)OR g -C(=O)NR g R h -CH2SO2R g -CH2SO2NRg R h Replacement. The R g With R h The groups, whether identical or different, are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl-alkyl, heteroaryl, N-heteroaryl, and heteroaryl-alkyl. "Substituted" may also indicate that one or more hydrogen atoms in any of the above groups are substituted with amino, cyano, hydroxyl, imino, nitro, oxo, thio, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl-alkyl, heteroaryl, N-heteroaryl, and heteroaryl-alkyl. Additionally, each of the above substituents may optionally be substituted with one or more of the above substituents.

[0126] Those skilled in the art will understand that some compounds of formula (I) may contain one or more chiral centers, and thus have two or more stereoisomers. Therefore, the compounds of the present invention may exist as a single stereoisomer (e.g., enantiomer, diastereomer) and mixtures thereof in any proportion, such as racemates, and, where appropriate, as tautomers and geometric isomers.

[0127] As used in this article, "stereoisomer" refers to compounds that have the same chemical composition but differ in the spatial arrangement of atoms or groups. Stereoisomers include enantiomers, diastereomers, and conformational isomers.

[0128] The term "enantiomer" as used in this article refers to two stereoisomers of a compound that are non-overlapping mirror images of each other.

[0129] As used herein, the term "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis and chromatography such as HPLC.

[0130] Stereochemical definitions and conventions can be found in SP Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in an optically active form, meaning they possess the ability to rotate the plane of polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l, or (+) and (-), are used to indicate the symbol for rotating the plane of polarized light, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers can also be called enantiomers, and mixtures of such isomers are often called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur in chemical reactions or methods where there is no stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two optically inactive enantiomers.

[0131] Racemic mixtures can be used in their original form or resolved into individual isomers. Resolution yields stereochemically pure compounds or mixtures enriched with one or more isomers. Methods for isomer separation are well-known (see Allinger NL and Eliel EL, "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), including physical methods such as chromatography using chiral adsorbents. Individual chiral isomers can be prepared from chiral precursors. Alternatively, a single isomer can be chemically separated from a mixture by forming a diastereomeric salt with a chiral acid (e.g., a single enantiomer of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), the salt is fractionally crystallized, and one or both of the separated bases are then released. This process can optionally be repeated to obtain one or two isomers that substantially do not contain the other isomer, i.e., the desired stereoisomers with an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% by weight. Alternatively, as is well known to those skilled in the art, a racemic compound can be covalently attached to a chiral compound (auxiliary compound) to obtain a diastereomeric isomer.

[0132] As used herein, the terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can be interconverted via low-energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions via the recombination of some bonding electrons.

[0133] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0134] Undefined technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. Detailed Implementation

[0135] The present application is described in detail below with reference to embodiments, but this does not imply any adverse limitations on the present application. The present application has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific implementations of the present application without departing from the spirit and scope thereof.

[0136] Example 1: Synthesis of Compound H1

[0137] Step 1: Synthesis of Compounds 1-2

[0138] Compound 1-1 (3 g) was dissolved in carbon tetrachloride (50 mL), and N-chlorosuccinimide (2.22 g) was added. The reaction was carried out at room temperature for 4 hours. LC-MS showed the formation of the target product. The reaction solution was directly filtered, and the organic phase was concentrated to dryness. The resulting crude compound 1-2 (3 g) was used directly in the next step. LC-MS (ESI) [M+H] + =233.0.

[0139] Step 2: Synthesis of compounds 1-3

[0140] Compound 1-2 (3 g) was dissolved in acetic acid (10 mL) and hydrogen peroxide (10 mL), and the mixture was heated at 70 °C for half an hour. LC-MS showed the formation of the target product. The reaction solution was directly concentrated, diluted with ethyl acetate, washed with saturated sodium bicarbonate, extracted, and separated. The organic phase was mixed and passed through a column (PE:EA = 1:1) to give compound 1-3 (228 mg). LC-MS (ESI) [M+H] + =264.8.

[0141] Step 3: Synthesis of compounds 1-5

[0142] Compounds 1-3 (265.66 mg) were dissolved in tetrahydrofuran (10 mL) under ice-water bath conditions. Sodium hydride (44.16 mg, 60% purity) was slowly added, and the mixture was stirred for 20 minutes. Then, compound 1-4 (200 mg) was added, and the reaction was carried out at 25°C for 2 hours. LC-MS showed product formation. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and filtered through a column (PE:EA = 10-100%) to give compound 1-5 (134 mg). LC-MS (ESI) [M+Ht-Bu] + =254.2.

[0143] Step 4: Synthesis of compounds 1-6

[0144] Compounds 1-5 (130 mg) were dispersed in a mixed solvent of dichloromethane (5 mL) and trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LC-MS until complete. The reaction solution was directly concentrated to obtain compound 1-6 (85 mg). The crude product was used directly in the next step. LC-MS (ESI) [M+H] + =209.9.

[0145] Step 5: Synthesis of compound H1

[0146] Compounds 1-6 (90 mg), N,N-diisopropylethylamine (166.41 mg, 224.28 μL), compounds 1-7 (144.33 mg), and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (194.31 mg) were dissolved in dichloromethane (10 mL). The mixture was stirred for 16 hours, and the reaction was monitored by LCMS until complete. Compound H1 (93 mg) was prepared by reverse-phase chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25℃; gradient: 70%-95% acetonitrile in 12 min; flow rate: 30 mL / min).

[0147] LC-MS(ESI)[M+H] + =472.0.

[0148] 1 H NMR(400MHz, DMSO-d6)δ9.02(s,1H),8.95(d,J=8.0Hz,1H),7.50(t,J=7.9Hz,2H),7.37–7.29(m,3H),7.16(d,J=8.8Hz,1 H), 4.56 (q, J = 8.1Hz, 1H), 3.21 (s, 3H), 1.86 (t, J = 19.0Hz, 3H), 1.29–1.17 (m, 1H), 0.59–0.48 (m, 2H), 0.48–0.37 (m, 2H).

[0149] J1 and K1 were obtained by separation (separation conditions: mobile phase: A: Supercritical CO2; B: MeOH (+0.1% 7.0 mol / L Ammonia in MeOH); chromatographic column: Column specifications: 250×30mm, 10μm; column temperature: 25℃; gradient: A:B = 90:10; flow rate: 140mL / min.

[0150] J1: SFC retention time t = 2.065 min;

[0151] LC-MS(ESI)[M+H] + =472.1;

[0152] 1 H NMR (400MHz, DMSO-d) 6) δ9.02(s,1H),8.94(d,J=8.0Hz,1H),7.53–7.45(m,2H),7.33(dd,J=8.0,4.3Hz,3H),7.16(d,J=8.8Hz,1H),4.56 (q,J=8.0Hz,1H),3.21(s,3H),1.85(t,J=19.0Hz,3H),1.25–1.22(m,1H),0.56–0.51(m,2H),0.47–0.42(m,2H).

[0153] K1: SFC retention time t = 1.816 min;

[0154] LC-MS(ESI)[M+H] + =472.1;

[0155] 1 H NMR(400MHz, DMSO-d6)δ9.02(s,1H),8.94(d,J=7.9Hz,1H),7.50(t,J=7.9Hz,2H),7.36–7.28(m,3H),7.16(d,J=8.8Hz,1 H), 4.56 (q, J = 8.1Hz, 1H), 3.21 (s, 3H), 1.85 (t, J = 19.0Hz, 3H), 1.25–1.20 (m, 1H), 0.59–0.51 (m, 2H), 0.47–0.44 (m, 2H).

[0156] Example 2 Synthesis of compound H2

[0157] Step 1: Synthesis of Compound 2-2

[0158] Compound 2-1 (10 g) was dissolved in tetrahydrofuran (125 mL) under dry ice and ethanol bath conditions. Lithium di(trimethylsilyl)amino (1 M) was slowly added, and the mixture was stirred for 30 minutes. Then, 18.87 g of 1-chloromethyl-4-fluoro-1,4-diazobicyclo2,2,2-octanebis(tetrafluoroborate) salt was added. After 5 minutes, N,N-dimethylformamide (75 mL) was added. The reaction was carried out at 0 °C for 4 hours. LC-MS showed product formation. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, and filtered through a column (PE:EA = 10-100%) to obtain compound 2-2 (3.8 g). LC-MS (ESI) [M+H] +=249.0.

[0159] Step 2: Synthesis of compounds 2-3

[0160] Compound 2-2 (1.25 g) was dissolved in tetrahydrofuran (25 mL) under ice-water bath conditions. Sodium hydride (220.81 mg, 60% purity) was added, and the reaction proceeded for 0.5 hours. Compound 1-4 (1 g) was then added, and the mixture was heated to room temperature for 2 hours. LC-MS showed the reaction was complete. The reaction was quenched with saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The sample was then passed through a column (PE:EA = 0-50%) to obtain compound 2-3 (0.58 g). LC-MS (ESI) [M+Ht-Bu] + =238.0.

[0161] Step 3: Synthesis of compounds 2-4

[0162] Compound 2-3 (200 mg) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL), and stirred at room temperature for 4 hours. The reaction was monitored by LC-MS until complete. The reaction solution was directly concentrated to obtain compound 2-4 (85 mg), and the crude product was used directly in the next step. LC-MS (ESI) [M+H] + =194.0.

[0163] Step 4: Synthesis of compound H2

[0164] Compounds 2-4 (18 mg), N,N-diisopropylethylamine (36.12 mg, 48.67 μL), compounds 1-7 (31.32 mg), and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (42.17 mg) were dissolved in dichloromethane (10 mL). The mixture was stirred for 16 hours, and the reaction was monitored by LCMS until complete. Compound H2 (11 mg) was obtained by reverse-phase chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25℃; gradient: 70%-95% acetonitrile in 14 min; flow rate: 30 mL / min).

[0165] LC-MS(ESI)[M+H] + =456.2.

[0166] 1H NMR(400MHz, DMSO-d6)δ9.02(s,1H),8.94(d,J=8.0Hz,1H),7.50(t,J=7.9Hz,2H),7.37–7.27(m,3H),6.33(dd,J=34.3,8.9H z,1H),4.47(q,J=8.3Hz,1H),3.26(s,3H),1.86(t,J=19.0Hz,3H),1.31–1.17(m,1H),0.58–0.46(m,2H),0.48–0.32(m,2H).

[0167] J2 and K2 were obtained by separation (separation conditions: mobile phase: A: Supercritical CO2; B: MeOH (+0.2% 7.0 mol / L Ammonia in MeOH); chromatographic column: Column specifications: 250×25mm, 10μm; column temperature: 25℃; gradient: A:B = 85:15; flow rate: 120mL / min.

[0168] J2: SFC retention time t = 2.382 min;

[0169] LC-MS(ESI)[M+H] + =456.1;

[0170] 1 H NMR(400MHz, DMSO-d6)δ9.01(s,1H),8.93(d,J=8.0Hz,1H),7.56–7.45(m,2H),7.39–7.29(m,3H),6.42–6.24(m,1H), 4.47(q,J=8.1Hz,1H),3.25(s,3H),1.85(t,J=19.0Hz,3H),1.24–1.22(m,1H),0.60–0.48(m,2H),0.48–0.34(m,2H).

[0171] K2: SFC retention time t = 1.853 min;

[0172] LC-MS(ESI)[M+H] + =456.1;

[0173] 1H NMR(400MHz, DMSO-d6)δ9.01(s,1H),8.93(d,J=7.8Hz,1H),7.53–7.46(m,2H),7.37–7.30(m,3H),6.40–6.26(m,1H),4.47(q,J =8.4Hz,1H),3.25(s,3H),1.85(t,J=19.0Hz,3H),1.30–1.18(m,1H),1.24–1.21(m,1H),0.57–0.50(m,2H),0.46–0.33(m,2H).

[0174] Example 3 Synthesis of compound H3

[0175] Synthesis of compound H3

[0176] Compounds 1-6 (70 mg), N,N-diisopropylethylamine (129.43 mg, 174.44 μL), compound 3-1 (122.68 mg), and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (151.13 mg) were dissolved in dichloromethane (10 mL), stirred for 16 hours, and the reaction was monitored by LCMS until complete. The mixture was purified by silica gel column chromatography (PE / EA = 3 / 1-2 / 1) to give compound H3 (115 mg).

[0177] LC-MS(ESI)[M+H] + =498.0.

[0178] 1 H NMR(400MHz, DMSO-d6)δ9.02(s,1H),8.96(d,J=8.0Hz,1H),7.53–7.46(m,2H),7.36–7.28(m,3H),7.15(d,J=8.8Hz, 1H), 4.56 (q, J = 8.1Hz, 1H), 3.22 (s, 3H), 1.69–1.55 (m, 1H), 1.28–1.17 (m, 1H), 0.66–0.47 (m, 6H), 0.46–0.38 (m, 2H).

[0179] J3 and K3 were obtained by separation (separation conditions: mobile phase: A: Supercritical CO2; B: MeOH (+0.1% 7.0 mol / L Ammonia in MeOH); chromatographic column: Column specifications: 250×25mm, 10μm; column temperature: 25℃; gradient: A:B = 80:20; flow rate: 120mL / min.

[0180] J3: SFC retention time t = 3.364 min;

[0181] LC-MS(ESI)[M+H] + =498.1;

[0182] 1 H NMR(400MHz, DMSO-d6)δ9.01(s,1H),8.94(d,J=7.9Hz,1H),7.53–7.46(m,2H),7.36–7.29(m,3H),7.15(d,J=8.8Hz, 1H), 4.56 (q, J = 8.2Hz, 1H), 3.21 (s, 3H), 1.69–1.55 (m, 1H), 1.24–1.19 (m, 1H), 0.63–0.48 (m, 6H), 0.48–0.39 (m, 2H).

[0183] K3: SFC retention time t = 2.026 min;

[0184] LC-MS(ESI)[M+H] + =498.1;

[0185] 1 H NMR(400MHz, DMSO-d6)δ9.01(s,1H),8.94(d,J=7.9Hz,1H),7.53–7.46(m,2H),7.38–7.29(m,3H),7.15(d,J=8.8Hz, 1H), 4.56 (q, J = 8.1Hz, 1H), 3.21 (s, 3H), 1.69–1.55 (m, 1H), 1.23–1.19 (m, 1H), 0.65–0.49 (m, 6H), 0.49–0.37 (m, 2H).

[0186] Example 4 Synthesis of compound H4

[0187] Synthesis of compound H4

[0188] Compound 2-4 (67 mg), N,N-diisopropylethylamine (134.43 mg, 181.18 μL), compound 3-1 (127.43 mg), and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (156.97 mg) were dissolved in dichloromethane (10 mL), stirred for 16 hours, and the reaction was monitored by LCMS until complete. The mixture was purified by silica gel column chromatography (PE / EA = 3 / 1-2 / 1) to give compound H4 (92 mg).

[0189] LC-MS(ESI)[M+H]+ =482.0.

[0190] 1 H NMR(400MHz, DMSO-d6)δ9.02(s,1H),8.95(d,J=7.9Hz,1H),7.55–7.44(m,2H),7.38–7.27(m,3H),6.33(dd,J=34.3,8.9 Hz,1H),4.48(q,J=8.3Hz,1H),3.26(s,3H),1.69–1.58(m,1H),1.29–1.20(m,1H),0.68–0.46(m,6H),0.45–0.30(m,2H).

[0191] J4 and K4 were obtained by separation (separation conditions: mobile phase: A: Supercritical CO2; B: ETOH (+0.2% 7.0 mol / L Ammonia in MeOH); chromatographic column: Column specifications: 250×30mm, 10μm; column temperature: 25℃; gradient: A:B = 85:15; flow rate: 120mL / min.

[0192] J4: SFC retention time t = 1.884 min;

[0193] LC-MS(ESI)[M+H] + =481.9;

[0194] 1 H NMR(400MHz, DMSO-d6)δ9.00(s,1H),8.93(d,J=7.9Hz,1H),7.53–7.46(m,2H),7.37–7.27(m,3H),6.32(dd,J=34.3,8.9 Hz,1H),4.47(q,J=8.3Hz,1H),3.25(s,3H),1.69–1.54(m,1H),1.26–1.22(m,1H),0.64–0.50(m,6H),0.48–0.32(m,2H).

[0195] K4: SFC retention time t = 1.499 min;

[0196] LC-MS(ESI)[M+H] + =481.9;

[0197] 1H NMR(400MHz, DMSO-d6)δ9.00(s,1H),8.93(d,J=7.9Hz,1H),7.54–7.45(m,2H),7.37–7.28(m,3H),6.32(dd,J=34.3,8.9 Hz,1H),4.47(q,J=8.1Hz,1H),3.25(s,3H),1.69–1.54(m,1H),1.30–1.18(m,1H),0.64–0.50(m,6H),0.47–0.34(m,2H).

[0198] Example 5: Synthesis of Compound H5

[0199] Step 1: Synthesis of Compound 5-1

[0200] Compound 1-1 (2.0 g) was dissolved in carbon tetrachloride (20 mL), and NBS (1.80 g) was added. The mixture was stirred at room temperature for 4 hours. LC-MS monitoring was performed. The reaction mixture was diluted with DCM (10 mL), filtered through diatomaceous earth, and the filtrate was washed with sodium thiosulfate solution (10 mL), followed by washing with saturated brine (10 mL). The solution was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (0-50% EA / PE) to obtain compound 5-1 (1.30 g). 1 H NMR (400MHz, Chloroform-d) δ5.02 (d, J = 11.8 Hz, 1H), 4.34–4.22 (m, 4H), 2.42 (d, J = 1.0 Hz, 3H), 1.44–1.34 (m, 6H).

[0201] Step 2: Synthesis of compound 5-2

[0202] Compound 5-1 (0.1 g) was dissolved in DCM (3 mL), and mCPBA (155.68 mg) was added. The mixture was stirred at room temperature for 2 hours. LC-MS monitoring was performed. Saturated sodium bicarbonate solution (5 mL) was added to the reaction mixture, followed by dichloromethane (10 mL). Extraction was performed, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain the crude product. Column chromatography (0-100% EA / PE) yielded compound 5-2 (0.052 g). LC-MS (ESI) [M+H] + =309.0.

[0203] Step 3: Synthesis of compound 5-3

[0204] Compound 5-2 (50 mg) was dissolved in THF (2 mL), sodium hydride (7.12 mg) was added, and the mixture was stirred for 10 minutes. Then, compound 1-4 (32.23 mg) was added, and the mixture was stirred at room temperature for 2 hours. LC-MS analysis was performed. After the reaction was complete, saturated ammonium chloride aqueous solution (10 mL) was added, followed by extraction with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (0-40% EA / PE) to give compound 5-3 (48 mg). LC-MS (ESI) [M+H] + =298.0.

[0205] Step 4: Synthesis of compound 5-4

[0206] Compound 5-3 (48 mg) was dissolved in DCM (2 mL), and TFA (15.45 mg, 2 mL) was added. The mixture was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. The solution was then concentrated to dryness to give compound 5-4 (0.06 g, crude product, TFA salt). LC-MS (ESI) [M+H] + =254.0.

[0207] Step 5: Synthesis of compound H5

[0208] Compounds 1-7 (45.79 mg) and compounds 5-4 (0.06 g, TFA) were added to DCM (2 mL). While stirring, HATU (80.15 mg) and DIPEA (105.60 mg, 142.32 μL) were added. The mixture was stirred at room temperature for 30 minutes, and monitored by LCMS. Preparative HPLC was used for separation and purification (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Pntulips ZZ-C18 10 μm 250 × 20 mm; column temperature: 25℃; gradient: 50%-70% acetonitrile in 8 min; flow rate: 30 mL / min) to obtain H5 (30 mg).

[0209] LC-MS(ESI)[M+H] + =516.0.

[0210] 1 H NMR(400MHz, DMSO-d6)δ9.02(s,1H),8.95(d,J=8.0Hz,1H),7.53–7.46(m,2H),7.38–7.29(m,4H ),4.59–4.49(m,1H),3.20(s,3H),1.86(t,J=19.0Hz,3H),1.28–1.23(m,1H),0.56–0.40(m,4H).

[0211] Example 6 Synthesis of compound H8

[0212] Step 1: Synthesis of Compound 6-1

[0213] Compound 1-1 (0.50 g) was dissolved in THF (4.75 mL). Under ice bath conditions, BuLi (403.97 mg) was added, and the mixture was stirred for 15 minutes. Then, methyl iodide (716.38 mg, 314.20 μL) was added, and the mixture was allowed to return to room temperature naturally. The mixture was stirred for 1–2 hours, and the reaction was monitored by LC-MS. Ethyl acetate (20 mL) and saturated ammonium chloride (20 mL) were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give crude compound 6-1 (0.5 g). 1 HNMR(400MHz,Chloroform-d)δ4.24–4.15(m,4H),2.79–2.70(m,1H),2.29–2.28(m,3H),1.51–1.43(m,3H),1.37–1.32(m,6H).

[0214] Step 2: Synthesis of compound 6-2

[0215] Compound 6-1 (0.4 g) was dissolved in acetic acid (3 mL), and hydrogen peroxide (3 mL) was added. The mixture was stirred at room temperature for 30 minutes, then heated to 70 °C and stirred for 16 hours. LC-MS monitoring showed the target product peak. Saturated sodium bicarbonate (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the crude product was purified by column chromatography (5-10% MeOH in DCM) to give compound 6-2 (0.1 g). LC-MS (ESI) [M+H] + =245.0.

[0216] Step 3: Synthesis of compound 6-3

[0217] Compound 6-2 (100 mg) was dissolved in THF (2 mL), sodium hydride (18.01 mg) was added, and the mixture was stirred for 10 minutes. Then, compound 1-4 (81.58 mg) was added, and the mixture was stirred at room temperature for 2 hours. LCMS analysis was performed. The mixture was extracted with ethyl acetate (20 mL) after adding saturated ammonium chloride (10 mL). The organic phase was collected, concentrated, and purified by column chromatography (0-40% EA / PE) to obtain compound 6-3 (52 mg).

[0218] Step 4: Synthesis of compound 6-4

[0219] Compound 6-3 (50 mg) was dissolved in DCM (1 mL), and TFA (7.88 mg, 1 mL) was added. The mixture was stirred at room temperature for 1 hour. LC-MS monitoring showed the reaction was complete. The solution was directly concentrated and evaporated to dryness to give compound 6-4 (25 mg, crude product, TFA salt). LC-MS (ESI) [M+H] + =189.9.

[0220] Step 5: Synthesis of compound H8

[0221] Compounds 1-7 (55.48 mg) and 6-4 (60 mg, crude) were dissolved in DCM (2 mL), and HATU (97.35 mg) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until complete. The solution was directly evaporated to dryness and set aside for later use. The solution was purified by reverse-phase chromatography (preparation method: column: Pntulips ZZ-C18 10 μm 250 × 20 mm; column temperature: 25 °C; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio 50%-95% in 12 min; flow rate 30 mL / min) to obtain H8 (40 mg).

[0222] LC-MS(ESI)[M+H] + =452.2.

[0223] 1 H NMR(400MHz, DMSO-d6)δ8.98(s,1H),8.88(d,J=8.0Hz,1H),7.52–7.46(m,2H),7.35–7.28(m,3H),6.60–6.57(m,1H), 4.45–4.42(m,1H),2.97(s,3H),2.10(d,J=1.4Hz,3H),1.86(t,J=19.0Hz,3H),1.21–1.13(m,1H),0.52–0.33(m,4H).

[0224] Example 7 Synthesis of compound H21

[0225] Step 1: Synthesis of compound H21

[0226] Compound 7-1 (40 mg) was dissolved in dichloromethane (3 mL), followed by the addition of HATU (60.93 mg) and N,N-diisopropylethylamine (34.79 mg). The reaction was carried out at 20 °C for 10 min, followed by the addition of compound 2-4 (26.01 mg). The reaction was carried out at 20 °C for 1 h. LC-MS showed the product as the main peak. The mixture was extracted three times with water and dichloromethane, and the organic phase was evaporated to dryness. The solution was prepared (preparation method: column: Agilent 10Prep-C18250×21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% TFA)-acetonitrile; acetonitrile ratio 40%-82% in 16.2 min; flow rate 35 mL / min) to give H21 (16.28 mg).

[0227] LC-MS(ESI)[M+H] + =473.0.

[0228] 1 H NMR (400MHz, DMSO-d6) δ8.92(d,J=8.0Hz,1H),8.23(d,J=12.0Hz,1H),7.49–7.39(m,2H),7.29–7.21(m,3H),6.32(dd,J=32.0,8 .0Hz,1H),4.43(q,J=8.0Hz,1H),3.24(s,3H),1.79(t,J=20.0Hz,3H),1.28–1.17(m,1H),0.58–0.46(m,2H),0.46–0.32(m,2H).

[0229] J21 and K21 were separated (separation conditions: mobile phase: A: Supercritical CO2; B: Methanol (0.1% NH3H2O); column: ChiralPak IG; column size: 250×30mm, 10μm; column temperature: 38℃; gradient: A:B = 90:10; flow rate: 120mL / min).

[0230] J21: SFC retention time t = 2.110 min;

[0231] LC-MS(ESI)[M+H]+=473.0;

[0232] 1H NMR (400MHz, DMSO-d6) δ8.94(d,J=8.0Hz,1H),8.24(d,J=8.0Hz,1H),7.52–7.40(m,2H),7.32–7.18(m,3H),6.32(dd,J=36.0,8 .0Hz,1H),4.44(q,J=8.0Hz,1H),3.25(s,3H),1.79(t,J=20.0Hz,3H),1.31–1.16(m,1H),0.58–0.45(m,2H),0.45–0.29(m,2H).

[0233] K21: SFC retention time t = 1.987 min;

[0234] LC-MS(ESI)[M+H]+=473.0;

[0235] 1 H NMR (400MHz, DMSO-d6) δ8.94(d,J=8.0Hz,1H),8.24(d,J=8.0Hz,1H),7.48–7.41(m,2H),7.28–7.21(m,3H),6.32(dd,J=32.0,8 .0Hz,1H),4.43(q,J=8.0Hz,1H),3.25(s,3H),1.81(t,J=16.0Hz,3H),1.31–1.16(m,1H),0.59–0.46(m,2H),0.44–0.31(m,2H).

[0236] Example 8 Synthesis of compound H23

[0237] Step 1: Synthesis of compound H23

[0238] Compound 8-1 (140 mg), compound 2-4 (96.88 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (208.06 mg), and N,N-diisopropylethylamine (194.39 mg, 261.99 μL) were dissolved in dichloromethane (9.98 mL). The reaction was stirred at room temperature for 1 hour, and the product was detected by LCMS. The product was quenched with water, extracted with dichloromethane, and dried over anhydrous sodium sulfate. The crude product was obtained by rotary evaporation and prepared by liquid chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×30 mm; column temperature: 25℃; gradient: 60%-95% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain compound H23 (87 mg).

[0239] LCMS(ESI)[M+H] + =455.2.

[0240] 1 H NMR (400MHz, DMSO-d6) δ8.87(d,J=8.0Hz,1H),8.76(s,1H),7.57–7.53(m,2H),7.38–7.35(m,1H),7.30–7.28(m,2H),6.85(s,1H),6 .29(dd,J=34.0Hz,J=8.8Hz,1H),4.47(q,J=8.4Hz,1H),3.24(s,3H),1.93(t,J=19.2Hz,3H),1.20–1.17(m,1H),0.52–0.34(m,4H).

[0241] Example 9: Synthesis of Compound H26

[0242] Step 1: Synthesis of compound H26

[0243] Compound 9-1 (60 mg) was dissolved in dichloromethane (5 mL), followed by the addition of HATU (88.27 mg) and N,N-diisopropylethylamine (81.83 mg, 110.28 μL). The reaction was carried out at 20 °C for 10 min, and then compound 2-4 (40.78 mg) was added, and the reaction was stirred for 1 h. The desired product was observed as the main peak in the LCMS reaction. The product was extracted three times with water and dichloromethane, and the organic phase was evaporated to dryness. (Preparation method: chromatographic column: Agilent 10Prep-C18 250 × 21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% TFA)-acetonitrile; acetonitrile ratio 35%-79% in 16.2 min; flow rate 35 mL / min) to obtain H26 (31.22 mg).

[0244] LC-MS(ESI)[M+H] + =460.2.

[0245] 1H NMR(400MHz, DMSO-d6)δ8.83(s,1H),8.71(d,J=8.0Hz,1H),7.52–7.44(m,2H), 7.33–7.26(m,3H),6.36(dd,J=32.0,8.0Hz,1H),4.47(q,J=8.0Hz,1H),3.25(s ,3H),3.18–3.06(m,1H),1.92–1.80(m,2H),1.72–1.60(m,2H),1.58–1.47(m,4 H),1.29–1.18(m,1H),0.59–0.48(m,2H),0.47–0.39(m,1H),0.39–0.31(m,1H).

[0246] Example 10 Synthesis of compound H29

[0247] Step 1: Synthesis of compound H29

[0248] Compound 10-1 (46 mg), compound 2-4 (31.16 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (60.84 mg), and N,N-diisopropylethylamine (62.52 mg, 84.27 μL) were dissolved in dichloromethane (5 mL). The reaction was stirred at room temperature for 1 hour, and the product was detected by LCMS. The product was quenched with water, extracted with dichloromethane, and dried over anhydrous sodium sulfate to obtain a crude product. The crude product was then prepared by liquid chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25℃; gradient: 40%-95% acetonitrile in 12.1 min; flow rate: 30 mL / min) to obtain compound H29 (25.84 mg).

[0249] LCMS(ESI)[M+H] + =461.2.

[0250] 1 H NMR (400MHz, DMSO-d6) δ9.01 (s, 1H), 8.93 (d, J = 8.0Hz, 1H), 6.33 (dd, J = 34.4Hz, J = 8.8Hz, 1H), 4.47 (q, J=8.0Hz,1H),3.25(s,3H),1.90–1.80(m,3H),1.26–1.22(m,1H),0.54–0.52(m,2H),0.44–0.35(m,2H).

[0251] Example 11 Synthesis of compound H30

[0252] Step 1: Synthesis of Compound 11-3

[0253] Compound 11-2 (1.33 g) was dissolved in anhydrous tetrahydrofuran (50 mL), sodium hydride (825 mg, 60% purity) was added, and the mixture was stirred at room temperature for 20 minutes. Compound 11-1 (3 g) was then added, and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was poured into a saturated ammonium chloride solution and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0–6% elution) to obtain compound 11-3 (1.83 g). LCMS (ESI) [M+H] + =283.2.

[0254] Step 2: Synthesis of compound 11-4

[0255] Compound 11-3 (1.73 g) was dissolved in anhydrous acetonitrile (20 mL), and a solution of sulfonyl chloride (4.13 g) in dichloromethane (20 mL) was added at 0 °C. After the addition was complete, the mixture was allowed to react overnight at room temperature. The reaction solution was poured into an ice-cold saturated sodium bicarbonate solution and extracted twice with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting with ethyl acetate / petroleum ether = 0–5%) to give compound 11-4 (1.3 g). LCMS (ESI) [M+H] + =271.0.

[0256] Step 3: Synthesis of Compounds 11-6

[0257] Compound 11-4 (1.25 g) was dissolved in 1,4-dioxane (20 mL) and water (5 mL). Compound 11-5 (888 mg), anhydrous potassium phosphate (1.96 g), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (298 mg) were added. After purging with nitrogen three times, the mixture was reacted at 90 °C for 3 hours. The reaction solution was concentrated and extracted with an ethyl acetate / water system. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0–5% elution) to obtain compound 11-6 (690 mg). LCMS (ESI) [M+H] + =277.2.

[0258] Step 4: Synthesis of compounds 11-7

[0259] Compound 11-6 (640 mg) was dissolved in tetrahydrofuran (12 mL) and water (6 mL), and sodium periodate (2.48 g) and potassium osmium tetroxide dihydrate (72 mg) were added. The mixture was reacted overnight at 35 °C. A solid precipitated, which was filtered. The filtrate was concentrated to remove the tetrahydrofuran, and then extracted with an ethyl acetate / water system. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0–13% elution) to give compound 11-7 (440 mg). LCMS (ESI) [M+H] + =279.1.

[0260] Step 5: Synthesis of compounds 11-8

[0261] Compound 11-7 (430 mg) was dissolved in anhydrous dichloromethane (6 mL), and diethylaminosulfur trifluoride (4.88 g, 4 mL) was added. The mixture was reacted overnight at room temperature. The reaction solution was slowly added dropwise to a saturated sodium thiosulfate aqueous solution with stirring. The mixture was extracted with a dichloromethane / water system, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting with ethyl acetate / petroleum ether = 0–8%) to give compound 11-8 (410 mg). LCMS (ESI) [M+H] + =301.1.

[0262] Step 6: Synthesis of compounds 11-9

[0263] Compound 11-8 (360 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of lithium hydroxide monohydrate (503 mg) in water (5 mL) was added. The mixture was reacted at room temperature for 2 hours. The pH of the reaction solution was adjusted to 1 with 0.5 M HCl, and the mixture was extracted with an ethyl acetate / water system. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0–40% elution) to give compound 11-9 (189 mg). LCMS (ESI) [M+H] + =273.0. 1 H NMR (400MHz, DMSO-d6) δ13.47(s,1H),8.97(s,1H),5.61–5.53(m,1H),2.08–1.93(m,5H),1.83–1.67(m,4H),1.67–1.52(m,2H).

[0264] Step 7: Synthesis of compound H30

[0265] Compound 11-9 (50 mg) was dissolved in anhydrous dichloromethane (2 mL), and N,N-diisopropylethylamine (119 mg, 159.95 μL) and compound 2-4 (80 mg, TFA) were added. The mixture was stirred at room temperature for 5 minutes, and then N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (76 mg) was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with dichloromethane, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by HPLC (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2mm; column temperature: 25℃; gradient: 60%-95% acetonitrile in 14min; flow rate: 30mL / min) to obtain H30 (40mg).

[0266] LCMS(ESI)[M+H] + =448.2.

[0267] 1 H NMR(400MHz,Chloroform-d)δ9.30(s,1H),7.98(d,J=6.4Hz,1H),6.12(dd,J=32.2,8.6Hz,1H),5.87–5.80(m,1H),4.39–4.27(m,1H),3.07(s,3H) ,2.21–2.10(m,2H),2.02(t,J=18.5,17.9Hz,3H),1.97–1.90(m,2H),1.8 6–1.77(m,4H),1.17–1.08(m,1H),0.74–0.66(m,2H),0.51–0.44(m,2H).

[0268] Example 12 Synthesis of compound H42

[0269] Step 1: Synthesis of Compound 12-2

[0270] Compound 12-1 (900 mg) was dissolved in anhydrous tetrahydrofuran (50 mL), sodium hydride (550 mg, 60% purity) was added, and the mixture was stirred at room temperature for 20 minutes. Compound 11-1 (2.99 g) was then added, and the mixture was allowed to react at room temperature for 2 hours. The reaction solution was poured into a saturated ammonium chloride solution and extracted with an ethyl acetate / water system. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0–5% elution) to obtain compound 12-2 (1.55 g). LCMS (ESI) [M+H] + =295.1.

[0271] Step 2: Synthesis of Compound 12-3

[0272] Compound 12-2 (1.5 g) was dissolved in anhydrous acetonitrile (15 mL), and a solution of sulfonyl chloride (3.44 g, 2.06 mL) in anhydrous dichloromethane (15 mL) was added at 0 °C. After the addition was complete, the mixture was left at room temperature for 3 hours. The reaction solution was poured into ice-cold saturated sodium bicarbonate solution, extracted twice with dichloromethane, and the organic phase was washed once with ice-cold saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting with ethyl acetate / petroleum ether = 0–4%) to give compound 12-3 (1.35 g). LCMS (ESI) [M+H] + =283.0.

[0273] Step 3: Synthesis of Compounds 12-5

[0274] Compound 12-3 (1.36 g) was dissolved in 1,4-dioxane (40 mL) and water (10 mL). Compound 11-5 (3.55 g), anhydrous potassium phosphate (6.63 g), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (465 mg) were added. After purging with nitrogen three times, the mixture was reacted at 100 °C for 24 hours. The reaction solution was concentrated and extracted with an ethyl acetate / water system. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0–3% elution) to give compound 12-5 (273 mg). LCMS (ESI) [M+H] + =289.4.

[0275] Step 4: Synthesis of Compounds 12-6

[0276] Compound 12-5 (220 mg) was dissolved in tetrahydrofuran (12 mL) and water (6 mL), and sodium periodate (2.45 g) and potassium osmium tetroxide dihydrate (47.5 mg) were added. The mixture was reacted at 35 °C for 6 hours. A solid precipitated, which was filtered. The filtrate was extracted with an ethyl acetate / water system, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0–8% elution) to give compound 12-6 (123 mg). LCMS (ESI) [M+H] + =291.1.

[0277] Step 5: Synthesis of compounds 12-7

[0278] Compound 12-6 (123 mg) was dissolved in anhydrous dichloromethane (1.5 mL), and diethylaminosulfur trifluoride (1.17 g, 958.63 μL) was added. The mixture was allowed to react overnight at room temperature. The reaction solution was slowly added dropwise to a saturated sodium thiosulfate solution, and the mixture was extracted twice with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 12-7 (140 mg, crude product). LCMS (ESI) [M+H] + =313.2.

[0279] Step 6: Synthesis of compounds 12-8

[0280] Compound 12-7 (120 mg) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide monohydrate (97 mg) in water (2 mL) was added. The mixture was reacted at room temperature for 2 hours. The reaction solution was diluted with water and washed once with ethyl acetate. The ethyl acetate phase was discarded. The aqueous phase was adjusted to pH 1 with 0.5 M dilute hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, filtered through anhydrous sodium sulfate, and the filtrate was concentrated and dried under vacuum to give compound 12-8 (90 mg). LCMS (ESI) [M+H] + =285.0.

[0281] Step 7: Synthesis of compound H42

[0282] Compound 12-8 (32 mg) was dissolved in anhydrous dichloromethane (938.72 μL), and N,N-diisopropylethylamine (73 mg, 98.04 μL) and compound 2-4 (38 mg, TFA) were added. The mixture was stirred at room temperature for 5 minutes, and then N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (51 mg) was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with dichloromethane, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by HPLC (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2mm; column temperature: 25℃; gradient: 60%-95% acetonitrile in 14min; flow rate: 30mL / min) to obtain H42 (15mg).

[0283] LCMS(ESI)[M+H] + =460.2.

[0284] 1H NMR(400MHz,Chloroform-d)δ9.29(s,1H),7.90(d,J=6.4Hz,1H),6.12(dd,J=32.1,8.6Hz,1H),5.93–5.68(m,1H),4.42–4.23(m,1H),3.07(s,3 H),2.57–2.39(m,2H),2.13–1.96(m,5H),1.51–1.42(m,2H),1.20–1.10 (m,1H),0.80–0.63(m,3H),0.49(d,J=5.3Hz,2H),0.36(d,J=4.6Hz,1H).

[0285] Example 13 Synthesis of compound H44

[0286] Step 1: Synthesis of Compound 13-2

[0287] Compound 1-3 (95.84 mg) was dissolved in tetrahydrofuran (8 mL), and sodium hydride (14.07 mg, 60% purity) was added at 0 °C. The reaction was stirred at 0 °C for 30 minutes. Then, compound 13-1 (50 mg) was dissolved in tetrahydrofuran (8 mL) and injected into the above solution. The reaction was brought back to room temperature and stirred for 30 minutes. LCMS analysis showed product formation. The product was quenched with water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was evaporated to dryness and then subjected to column chromatography with a petroleum ether / ethyl acetate ratio of 2 / 1 to give intermediate 13-2 (50 mg). LCMS (ESI) [M-55] + =228.0.

[0288] Step 2: Synthesis of compound 13-3

[0289] Compound 13-2 (50 mg) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (60.27 mg) was added at room temperature. The reaction was stirred at room temperature for 2 hours, and the product was detected by LCMS. Intermediate 13-3 (32 mg) was directly evaporated to dryness. LCMS (ESI) [M+H] + =184.0.

[0290] Step 3: Synthesis of compound H44

[0291] Compounds 1-7 (48.83 mg), 13-3 (32 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (65.73 mg), and N,N-diisopropylethylamine (67.56 mg, 91.05 μL) were dissolved in dichloromethane (5 mL). The reaction was stirred at room temperature for 1 hour, and the product was detected by LCMS. The product was quenched with water, extracted with dichloromethane, and dried over anhydrous sodium sulfate to obtain a crude product. The crude product was then prepared by liquid chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25℃; gradient: 60%-95% acetonitrile in 11 min; flow rate: 30 mL / min) to obtain compound H44 (4.95 mg).

[0292] LCMS(ESI)[M+H] + =446.0.

[0293] 1 H NMR(400MHz, DMSO-d6)δ9.03(s,1H),8.99(d,J=7.8Hz,1H),7.51–7.47(m,2H),7.34–7.30(m,3H),7 .13(d,J=8.4Hz,1H),4.94–4.92(m,1H),3.20(s,3H),1.85(t,J=18.8Hz,3H),1.37(d,J=6.8Hz,3H).

[0294] Example 14 Synthesis of compound H45

[0295] Step 1: Synthesis of Compound 14-2

[0296] Oxaloyl chloride (737.74 mg) was dissolved in dichloromethane (5 mL), and the mixture was cooled to -78 °C. Then, a solution of dimethyl sulfoxide (825.71 mg) in dichloromethane (5 mL) was slowly added, and the reaction was allowed to proceed at this temperature for 20 minutes. Next, a solution of compound 14-2 (1 g) dissolved in dichloromethane (5 mL) was slowly added, and the reaction was allowed to proceed for 30 minutes. Finally, triethylamine (1.60 g) was added, and the reaction was allowed to proceed at this temperature for 1 hour. New spots appeared on the TLC plate. The reaction was quenched with potassium dihydrogen phosphate solution, followed by extraction three times with dichloromethane and water. The organic phase was evaporated to dryness and purified by silica gel (ethyl acetate: petroleum ether = 0-100%) to obtain the target compound 14-2 (1 g, crude). LC-MS (ESI) [M+H] + =131.9.

[0297] Step 2: Synthesis of compound 14-3

[0298] Compound 1-3 (300 mg) was dissolved in THF (10 mL), followed by the addition of sodium hydride (68.00 mg). The reaction was carried out at 20 °C for 20 minutes, and then compound 14-2 (212.23 mg) was added, followed by another 20 minutes of reaction. The reaction was quenched with water, and part of the solvent was concentrated. The mixture was then extracted three times with water and dichloromethane. The organic phase was evaporated to dryness and purified by silica gel (ethyl acetate: petroleum ether = 0-40%) to give the target compound 14-3 (100 mg). LC-MS (ESI) [M+H] + =242.0.

[0299] Step 3: Synthesis of Compounds 14-4

[0300] Compound 14-4 (80 mg) was dissolved in dichloromethane (5 mL), followed by the addition of trifluoroacetic acid (1 mL), and the reaction was carried out at 20 °C for 1 hour. The solution was directly evaporated to dryness, and then further evaporated using an oil pump to obtain target compound 5 (60 mg, crude product). LC-MS (ESI) [M+H] + =198.0.

[0301] Step 4: Synthesis of compound H45

[0302] Compounds 1-7 (60 mg) were dissolved in a mixture of dichloromethane (4 mL) and N,N-dimethylacetamide (1 mL), followed by the addition of HATU (97.70 mg) and triethylamine (86.66 mg). The reaction was carried out at 20 °C for 10 min, followed by the addition of compound 14-4 (42.33 mg). The reaction was then carried out at 20 °C for 1 h. LC-MS showed the desired product as the main peak. The product was extracted three times with water and dichloromethane, and the organic phase was evaporated to dryness. The solution was prepared by (preparation method: column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25 °C; mobile phase: water (0.1% TFA)-acetonitrile; acetonitrile ratio 45%-70% in 16.2 min; flow rate 35 mL / min) to obtain the target compound H45 (39.78 mg).

[0303] LC-MS(ESI)[M+H] + =460.0.

[0304] 1H NMR (400MHz, DMSO-d6) δ9.01 (s, 1H), 8.83 (d, J = 8.0Hz, 1H), 7.57-7.45 (m, 2H), 7.37 -7.25(m,3H),6.66(d,J=12.0Hz,1H),5.51-5.33(m,1H),3.37(s,3H),1.86(t,J=20.0Hz,3H),1.79-1.58(m,2H),0.93(t,J=8.0Hz,3H).

[0305] Example 15 Synthesis of compound H46

[0306] Step 1: Synthesis of Compound 15-2

[0307] Compound 1-3 (77.84 mg) was dissolved in tetrahydrofuran (8 mL), and sodium hydride (14.07 mg, 60% purity) was added at 0 °C. The reaction was stirred at 0 °C for 30 minutes. Then, compound 15-1 (50 mg) was dissolved in tetrahydrofuran (8 mL) and injected into the above solution. The reaction was brought back to room temperature and stirred for 30 minutes. LCMS analysis showed product formation. The product was quenched with water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was evaporated to dryness and then subjected to column chromatography with a petroleum ether / ethyl acetate ratio of 2 / 1 to give intermediate 15-2 (58 mg). LCMS (ESI) [M-55] + =268.0.

[0308] Step 2: Synthesis of Compound 15-3

[0309] Compound 15-2 (58 mg) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (61.27 mg) was added at room temperature. The reaction was stirred at room temperature for 2 hours, and the product was detected by LCMS. Intermediate 15-3 (40 mg) was directly evaporated to dryness. LCMS (ESI) [M+H] + =224.0.

[0310] Step 1: Synthesis of compound H46

[0311] Compounds 1-7 (25.05 mg), 15-3 (20 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (33.73 mg), and N,N-diisopropylethylamine (34.66 mg, 46.71 μL) were dissolved in dichloromethane (5 mL). The reaction was stirred at room temperature for 1 hour, and the product was detected by LCMS. The product was quenched with water, extracted with dichloromethane, and dried over anhydrous sodium sulfate. The crude product was obtained by rotary evaporation and prepared by liquid chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25℃; gradient: 60%-95% acetonitrile in 11 min; flow rate: 30 mL / min) to obtain compound H46 (7.87 mg).

[0312] LCMS(ESI)[M+H] + =486.2.

[0313] 1 H NMR(400MHz, DMSO-d6)δ9.00(s,1H),8.89(d,J=8.4Hz,1H),7.52–7.48(m,2H),7.34–7.30(m,3H ), 6.95 (d, J = 9.2Hz, 1H), 4.98–4.92 (m, 1H), 3.21 (s, 3H), 2.68–2.65 (m, 1H), 1.94–1.74 (m, 9H).

[0314] Example 16 Synthesis of compound H57

[0315] Step 1: Synthesis of compound H57

[0316] Compound 8-1 (40 mg), compounds 1-6 (32.74 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (59.45 mg), and N,N-diisopropylethylamine (55.54 mg, 74.85 μL) were dissolved in dichloromethane (5 mL). The reaction was stirred at room temperature for 1 hour, and the product was detected by LCMS. The product was quenched with water, extracted with dichloromethane, and dried over anhydrous sodium sulfate. The crude product was obtained by rotary evaporation and prepared by liquid chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×30 mm; column temperature: 25℃; gradient: 60%-95% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain compound H57 (21.04 mg).

[0317] LCMS(ESI)[M+H]+ =471.0.

[0318] 1 H NMR (400MHz, DMSO-d6) δ8.89(d,J=8.0Hz,1H),8.78(s,1H),7.56(dd,J=8.5,7.3Hz,2H),7.39(d,J=7.4Hz,1H),7.34–7.22(m,2H),7 .13(d,J=8.8Hz,1H),6.86(s,1H),4.57(q,J=8.1Hz,1H),3.21(s,3H),1.94(t,J=19.2Hz,3H),1.23–1.18(m,1H),0.42–0.40(m,4H).

[0319] Example 17 Synthesis of Compound H61

[0320] Step 1: Synthesis of compound H61

[0321] Compound 17-1 (45 mg), compound 1-6 (32.80 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (62.12 mg), and N,N-diisopropylethylamine (63.84 mg, 86.04 μL) were dissolved in dichloromethane (5 mL). The reaction was stirred at room temperature for 1 hour, and the product was detected by LCMS. The product was quenched with water, extracted with dichloromethane, and dried over anhydrous sodium sulfate to obtain a crude product. The crude product was then prepared by liquid chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25℃; gradient: 60%-95% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain compound H61 (9.75 mg).

[0322] LCMS(ESI)[M+H] + =465.2.

[0323] 1H NMR (400MHz, DMSO-d6) δ8.67(s,1H),8.18(d,J=8.0Hz,1H),7.46–7.44(m,2H),7.31–7.27(m,4H),4.49(q,J=8.4Hz,1H),3.39(s,3H),3. 20(s,3H),3.06(s,1H),2.74(s,1H),1.27–1.27(m,1H),0.83–0.82(m,1.4H),0.50–0.48(m,1.6H),0.41–0.38(m,2H),0.36–0.35(m,2H).

[0324] Example 18 Synthesis of compound H62

[0325] Step 1: Synthesis of compound H62

[0326] Compound 18-1 (30 mg), compound 1-6 (19.92 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (39.39 mg), and N,N-diisopropylethylamine (40.49 mg, 54.56 μL) were dissolved in dichloromethane (5 mL). The reaction was stirred at room temperature for 1 hour, and the product was detected by LCMS. The product was quenched with water, extracted with dichloromethane, and dried over anhydrous sodium sulfate. The crude product was obtained by rotary evaporation and prepared by liquid chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25℃; gradient: 60%-95% acetonitrile in 11 min; flow rate: 30 mL / min) to obtain compound H62 (6 mg).

[0327] LCMS(ESI)[M+H] + =479.0.

[0328] 1 H NMR(400MHz, DMSO-d6)δ8.69(s,1H),8.18(d,J=8.1Hz,1H),7.47(dd,J=8.5,7.3Hz,2H),7.34–7.25(m,4H),5.01(s,0.6H),4.50(q, J=8.4Hz,1H),4.21(s,0.6H),3.21(s,3H),2.96(s,1.5H),2.60(s,1.5H),1.30–1.28(m,1H),1.08–1.07(m,6H),0.95–0.39(m,4H).

[0329] Example 19 Synthesis of compound H64

[0330] Step 1: Synthesis of compound H64

[0331] Compound 11-9 (42 mg) was dissolved in anhydrous dichloromethane (2 mL), and N,N-diisopropylethylamine (80 mg, 107.49 μL) and compound 1-6 (50 mg, TFA) were added. The mixture was stirred at room temperature for 5 minutes, and then N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (64 mg) was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with dichloromethane, washed once with water, and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by HPLC (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2mm; column temperature: 25℃; gradient: 60%-95% acetonitrile in 14min; flow rate: 30mL / min) to obtain H64 (48mg).

[0332] LCMS(ESI)[M+H] + =464.0.

[0333] 1 H NMR(400MHz,Chloroform-d)δ9.30(s,1H),8.00(d,J=6.2Hz,1H),6.95(d,J=8.9Hz,1H),5.86–5.80(m,1H),4.38–4.29(m,1H),3.08(s,3H),2.20–2. 09(m,2H),2.04(t,J=18.5Hz,3H),1.97–1.89(m,2H),1.87–1.78(m,4H),1 .17–1.09(m,1H),0.73–0.66(m,2H),0.61–0.53(m,1H),0.50–0.42(m,1H).

[0334] Example 20 Synthesis of compound H68

[0335] Step 1: Synthesis of compound H68

[0336] Compound 20-1 (30.11 mg) and compounds 1-6 (23.27 mg) were dissolved in DCM. HATU (54.44 mg) and DIPEA (71.73 mg, 96.67 μL) were added, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS until complete. Saturated ammonium chloride (10 mL) and dichloromethane (20 mL) were added, and the mixture was extracted. The organic phase was concentrated. The target compound H68 (20 mg) was obtained by preparative separation and purification (preparation method: mobile phase: water (0.1% FA)-acetonitrile; chromatographic column: Pntulips ZZ-C18 10 μm 250 × 20 mm; column temperature: 25℃; mobile phase acetonitrile ratio 50%-95% in 11 min; flow rate 30 mL / min).

[0337] LC-MS(ESI)[M+H] + =463.2.

[0338] 1 H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.20(d,J=8.1Hz,1H),7.49–7.40(m,2H),7.32–7.21(m,4H),4.48(q,J=8.4Hz ,1H),4.07–3.74(m,4H),3.20(s,3H),2.27–2.17(m,2H),1.30–1.23(m,1H),0.55–0.44(m,2H),0.44–0.33(m,2H).

[0339] Example 21 Synthesis of compound H69

[0340] Step 1: Synthesis of compound H69

[0341] Compound 21-1 (30.11 mg) and compounds 1-6 (23.27 mg) were dissolved in DCM. HATU (54.44 mg) and DIPEA (71.73 mg, 96.67 μL) were added. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS until complete. Saturated ammonium chloride (10 mL) and dichloromethane (20 mL) were added, followed by extraction. The organic phase was concentrated, and the mixture was purified by preparative separation (preparation method: mobile phase: water (0.1% FA)-acetonitrile; column: Pntulips ZZ-C18 10 μm 250 × 20 mm; column temperature: 25℃; mobile phase acetonitrile ratio 40%-95% in 14 min; flow rate 30 mL / min) to obtain H69 (4 mg). LC-MS (ESI) [M+H] + =477.4.

[0342] 1H NMR(400MHz, DMSO-d6)δ8.68(s,1H),8.17(d,J=8.1Hz,1H),7.49–7.42(m,2H),7.33–7.26(m,4H),4.52–4.45(m, 1H),3.51–3.43(m,2H),3.21(s,3H),3.12–3.05(m,2H),1.89–1.75(m,4H),1.32–1.25(m,1H),0.53–0.33(m,4H).

[0343] Example 22 Synthesis of compound H71

[0344] Step 1: Synthesis of compound H71

[0345] Compound 12-8 (37 mg) was dissolved in anhydrous dichloromethane (2 mL), and N,N-diisopropylethylamine (84 mg, 113.36 μL) and compound 1-6 (44.4 mg, TFA) were added. The mixture was stirred at room temperature for 5 minutes, and then N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (59 mg) was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with dichloromethane, washed once with water, and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by HPLC (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2mm; column temperature: 25℃; gradient: 60%-95% acetonitrile in 14min; flow rate: 30mL / min) to obtain H71 (37mg).

[0346] LCMS(ESI)[M+H] + =476.2.

[0347] 1H NMR(400MHz,Chloroform-d)δ9.29(s,1H),7.93(d,J=6.0Hz,1H),6.96(dd,J=8.9 ,4.6Hz,1H),5.83(t,J=6.9Hz,1H),4.40–4.29(m,1H),3.08(s,3H),2.58–2.39(m, 2H),2.11(s,1H),2.08(s,1H),2.07–1.97(m,3H),1.50–1.44(m,2H),1.21–1.13(m ,1H),0.78–0.65(m,3H),0.60–0.54(m,1H),0.52–0.44(m,1H),0.41–0.30(m,1H).

[0348] Example 23 Synthesis of compound H72

[0349] Step 1: Synthesis of compound H72

[0350] Compounds 1-6 (40 mg), N,N-diisopropylethylamine (73.96 mg, 99.68 μL), compound 23-1 (61.66 mg), and 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (86.36 mg) were dissolved in dichloromethane (10 mL) and stirred for 16 hours. The reaction was monitored by LC-MS until complete. The solution was prepared by reverse-phase chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25℃; gradient: 75%-95% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain H72 (49.53 mg). LC-MS (ESI) [M+H] + =515.2.

[0351] 1 H NMR(400MHz, DMSO-d6)δ8.95(d,J=8.0Hz,1H),8.24(d,J=9.7Hz,1H),7.50–7.37(m,2H),7.29–7.19(m,3H),7.1 4(d,J=8.8Hz,1H),4.53(q,J=8.1Hz,1H),3.21(s,3H),1.62–1.52(m,1H),1.28–1.17(m,1H),0.62–0.37(m,8H).

[0352] Example 24 Synthesis of compound H73

[0353] Step 1: Synthesis of compound H73

[0354] Compound 23-1 (36 mg), compound 2-4 (30.13 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (42.01 mg), and N,N-diisopropylethylamine (43.18 mg, 58.19 μL) were dissolved in dichloromethane (5 mL). The reaction was stirred at room temperature for 1 hour, and the product was detected by LCMS. The product was quenched with water, extracted with dichloromethane, and dried over anhydrous sodium sulfate. The crude product was obtained by rotary evaporation and prepared by liquid chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25℃; gradient: 40%-95% acetonitrile in 14 min; flow rate: 30 mL / min) to obtain compound H73 (20.37 mg).

[0355] LCMS(ESI)[M+H] + =499.2.

[0356] 1 H NMR (400MHz, DMSO-d6) δ8.92(d,J=8.0Hz,1H),8.21(d,J=9.60Hz,1H),7.45–7.41(m,2H),7.25–7.22(m,3H),6.31(dd,J=34.0Hz ,J=8.8Hz,1H),4.47(q,J=8.4Hz,1H),3.24(s,3H),1.59–1.55(m,1H),1.23–1.19(m,1H),0.58–0.49(m,6H),0.40–0.35(m,2H).

[0357] Example 25 Synthesis of compound H75

[0358] Step 1: Synthesis of compound H75

[0359] Compound 25-1 (46 mg), compound 2-4 (31.83 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (62.15 mg), and N,N-diisopropylethylamine (63.87 mg, 86.08 μL) were dissolved in dichloromethane (5 mL). The reaction was stirred at room temperature for 1 hour, and the product was detected by LCMS. The product was quenched with water, extracted with dichloromethane, and dried over anhydrous sodium sulfate. The crude product was obtained by rotary evaporation and prepared by liquid chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25℃; gradient: 40%-95% acetonitrile in 14 min; flow rate: 30 mL / min) to obtain compound H75 (21.15 mg).

[0360] LCMS(ESI)[M+H] + =455.2.

[0361] 1 H NMR (400MHz, DMSO-d6) δ8.84(d,J=8.0Hz,1H),8.23(d,J=7.8Hz,1H),7.51–7.43(m,3H),7.27–7.23(m,3H),6.32(dd, J=34.4Hz, J=8.8Hz, 1H), 4.48 (q, J=8.4Hz, 1H), 3.24 (s, 3H), 1.81–1.71 (m, 3H), 1.23–1.21 (m, 1H), 0.53–0.34 (m, 4H).

[0362] J75 and K75 were obtained by separation (separation conditions: mobile phase: A: Supercritical CO2; B: IPA (+0.1% 7.0 mol / L Ammonia in MeOH); column: Column specifications: 250×25mm, 10μm; column temperature: 25℃; gradient: A:B = 90:10; flow rate: 140mL / min.

[0363] J75: SFC retention time t = 2.818 min;

[0364] LC-MS(ESI)[M+H]+=455.2;

[0365] 1H NMR (400MHz, DMSO-d6) δ8.84(d,J=8.1Hz,1H),8.23(d,J=7.7Hz,1H),7.51(d ,J=7.7Hz,1H),7.47–7.43(m,2H),7.26(dd,J=10.7,4.5Hz,3H),6.32(dd,J= 34.4,8.9Hz,1H),4.48(q,J=8.4Hz,1H),3.24(s,3H),1.76(t,J=19.0Hz,3H) ,1.23–1.21(m,1H),0.52–0.50(m,2H),0.49–0.42(m,1H),0.41–0.36(m,1H).

[0366] K75: SFC retention time t = 1.994 min;

[0367] LC-MS(ESI)[M+H]+=455.2;

[0368] 1 H NMR (400MHz, DMSO-d6) δ8.83(d,J=8.0Hz,1H),8.23(d,J=7.7Hz,1H),7.50(d,J=7.7Hz,1H),7.47–7.43(m,2H),7.25(t,J=7.6Hz,3H),6.32(dd,J=34. 4,8.9Hz,1H),4.48(q,J=8.2Hz,1H),3.24(s,3H),1.76(t,J=19.0Hz,3H),1 .23–1.21(m,1H),0.51–0.50(m,2H),0.49–0.49(m,1H),0.42–0.41(m,1H).

[0369] Example 26 Synthesis of compound H76

[0370] Step 1: Synthesis of compound H76

[0371] Compound 26-1 (50 mg) was dissolved in DCM (131.71 mL), and compound 2-4 (57.07 mg, TFA), HATU (91.40 mg), and DIPEA (96.34 mg, 129.84 μL) were added. The mixture was stirred at room temperature for 16 hours. LCMS showed the presence of the target product. The reaction solution was added to water (10 mL), extracted with dichloromethane (10 mL), and the organic phase was concentrated. Preparative separation and purification were performed (preparation method: mobile phase: water (0.1% FA)-acetonitrile; chromatographic column: Pntulips ZZ-C18 10 μm 250 × 20 mm; column temperature: 25 °C; mobile phase acetonitrile ratio 40%-95% in 14 min; flow rate 30 mL / min) to obtain H76 (30 mg).

[0372] LC-MS(ESI)[M+H] + =444.2.

[0373] 1 H NMR(400MHz, CDCl3-d)δ8.11(d,J=8.0Hz,1H),7.93(d,J=6.9Hz,1H),7.43–7.37(m,2H),7.2 4–7.18(m,1H),7.16–7.12(m,1H),7.07–7.01(m,2H),6.78(d,J=1.6Hz,1H),6.07(dd,J=32. 6,8.6Hz,1H),4.40–4.32(m,1H),3.01(s,3H),2.49(d,J=6.9Hz,2H),1.06–0.96(m,1H),0.9 2–0.85(m,1H),0.58–0.52(m,1H),0.52–0.44(m,3H),0.41–0.29(m,2H),0.15–0.09(m,2H).

[0374] Example 27 Synthesis of compound H77

[0375] Step 1: Synthesis of compound H77

[0376] Compound 27-1 (70 mg), compound 2-4 (49.68 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (96.98 mg), and N,N-diisopropylethylamine (99.67 mg, 134.33 μL) were dissolved in dichloromethane (8 mL). The reaction was stirred at room temperature for 2 hours, and the product was detected by LCMS. The product was quenched with water, extracted with dichloromethane, and dried over anhydrous sodium sulfate to obtain a crude product. The crude product was then prepared by liquid chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25℃; gradient: 50%-95% acetonitrile in 12.1 min; flow rate: 30 mL / min) to obtain compound H77 (23.13 mg).

[0377] LCMS(ESI)[M+H] + 448.2.

[0378] 1 H NMR(400MHz, DMSO-d6)δ8.86(s,1H),8.73(d,J=8.0Hz,1H),7.50–7.46(m,2H),7.31–7.27(m,3H),6.35(dd,J=34.4Hz,J=8.8Hz ,1H),4.49–4.47(m,1H),3.26(s,3H),1.25–1.23(m,1H),1.16(s,9H),0.52–0.50(m,2H),0.43–0.42(m,1H),0.35–0.35(m,1H).

[0379] Example 28 Synthesis of compound H78

[0380] Step 1: Synthesis of compound H78

[0381] Compound 28-1 (30 mg), compound 2-4 (31.30 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (43.66 mg), and N,N-diisopropylethylamine (44.87 mg, 60.47 μL) were dissolved in dichloromethane (5 mL). The reaction was stirred at room temperature for 2 hours, and the product was detected by LCMS. The product was quenched with water, extracted with dichloromethane, and dried over anhydrous sodium sulfate. The crude product was obtained by rotary evaporation and prepared by liquid chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25℃; gradient: 50%-95% acetonitrile in 12.1 min; flow rate: 30 mL / min) to obtain compound H78 (12.4 mg).

[0382] LCMS(ESI)[M+H] + =435.2.

[0383] 1 H NMR(400MHz, DMSO-d6)δ8.69(s,1H),8.16(d,J=8.4Hz,1H),7.49–7.45(m,2H),7.31–7.27(m,3H),6.48(dd,J=34.8Hz,J=9.2Hz,1H),4 .45–4.39(m,1H),3.25(s,3H),3.10(s,3H),2.78(s,3H),1.29–1.26(m,1H),0.51–0.49(m,2H),0.43–0.39(m,1H),0.30–0.28(m,1H).

[0384] Example 29 Synthesis of compound H79

[0385] Step 1: Synthesis of Compound 29-2

[0386] Compound 29-1 (2 g) was dissolved in methanol (20 mL), and concentrated sulfuric acid (10 mL) was slowly added. The mixture was stirred at 80°C for 16 hours. LC-MS monitoring showed the disappearance of the starting material, with the target product as the main peak. The reaction solution was dried, diluted with saturated sodium bicarbonate and ethyl acetate, extracted, and the organic phase was dried to obtain 29-2 (1.8 g). LC-MS (ESI) [M+H] + =194.4.

[0387] Step 2: Synthesis of compound 29-3

[0388] 1.5 g of 29-2 was dissolved in 10 mL of dichloromethane under ice-water bath conditions. 1.89 g of m-chloroperoxybenzoic acid (85% purity) was slowly added, and the reaction was carried out at 25°C for 16 hours. LC-MS showed a small amount of reactant remaining, with the target product as the main peak. The reaction solution was washed successively with saturated sodium thiosulfate aqueous solution and saturated sodium carbonate aqueous solution. Extraction and separation were performed, and the organic phase was mixed and passed through a column (PE:EA = 1:1) to obtain intermediate 29-3 (0.9 g). LC-MS (ESI) [M+H] + =210.2.

[0389] Step 3: Synthesis of compound 29-4

[0390] 29-3 (900 mg) was dissolved in phosphorus oxychloride (50 mL), stirred at 95 °C for 16 hours, and monitored by LC-MS until the reaction was complete, with the main peak indicating the target product. The reaction solution was directly dried, diluted with saturated sodium bicarbonate aqueous solution and ethyl acetate, extracted, and the organic phase was concentrated to dryness to obtain 29-4 (500 mg). LC-MS (ESI) [M+H] + =228.2.

[0391] Step 4: Synthesis of Compounds 29-5

[0392] 29-4 (200 mg), phenol (99.20 mg), and cesium carbonate (571.84 mg) were dissolved in N,N-dimethylformamide (10 mL). The mixture was stirred at 95 °C for 16 hours. LC-MS monitoring showed that the reaction was essentially complete and the target product was present. The reaction solution was directly mixed and passed through a column (PE:EA = 4:1) to obtain 29-5 (50 mg). LC-MS (ESI) [M+H] + =286.0.

[0393] Step 5: Synthesis of compounds 29-6

[0394] Dissolve 29-5 (40 mg) and lithium hydroxide (10.07 mg) in water (10 mL) and methanol (10 mL), stir at 25 degrees for 4 hours, monitor the disappearance of the starting material by LCMS, the main peak is the target product, quench the reaction with dilute hydrochloric acid and ethyl acetate, extract and separate the liquid, concentrate the organic phase to dryness to obtain 29-6 (30 mg).

[0395] LC-MS(ESI)[M+H] + =272.1.

[0396] Step 6: Synthesis of compound H79

[0397] Compound 29-6 (30 mg), compound 2-4 (21.37 mg), 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (62.57 mg), and N,N-diisopropylethylamine (42.87 mg, 57.78 μL) were dissolved in dichloromethane (10 mL) and stirred for 4 hours. The reaction was monitored by LCMS until complete. The reaction solution was diluted with water and ethyl acetate, extracted, and the organic phase was concentrated to dryness. The solution was then prepared by reverse-phase chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25℃; gradient: 60%-95% acetonitrile in 14 min; flow rate: 30 mL / min) to obtain H79 (16 mg).

[0398] LC-MS(ESI)[M+H] + =447.4.

[0399] 1 H NMR (400MHz, DMSO-d6) δ8.63(d,J=8.2Hz,1H),8.08(d,J=7.8Hz,1H),7.52–7.36(m,2H),7.29–7.15(m,4H),6.37(dd,J=34.6,9.0Hz ,1H),4.48(q,J=8.5Hz,1H),3.24(s,3H),1.29–1.19(m,1H),1.13(s,9H),0.55–0.45(m,2H),0.45–0.38(m,1H),0.37–0.30(m,1H).

[0400] Example 30 Synthesis of compound H24

[0401] Step 1: Synthesis of Compound 30-2

[0402] Compound 30-1 (5.5 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (1.31 g), potassium phosphate (11.41 g), and potassium isopropenyltrifluoroborate (3.18 g) were added to a flask, followed by 1,4-dioxane (20 mL) and water (1 mL). The mixture was heated to 90 °C and reacted for 2 hours. The reaction was monitored by LC-MS. After the reaction was complete, ethyl acetate (50 mL) and water (30 mL) were added directly. The organic phase was washed with saturated brine (20 mL), concentrated, mixed, and purified by column chromatography (0-10% EA in PE) to obtain compound 30-2 (4.8 g). LC-MS (ESI) [M+H] + =269.0.

[0403] Step 2 Synthesis of compound 30-3

[0404] Compound 30-2 (2 g) was dissolved in tetrahydrofuran (100 mL), water (30 mL), potassium osmium tetroxide dihydrate (54.93 mg), and sodium periodate (4.78 g). The mixture was stirred at room temperature for 2 hours. LC-MS showed the starting material disappeared. The mixture was filtered through diatomaceous earth, and the filtrate was washed with saturated brine (30 mL × 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (0-10% EAIN PE) to give compound 30-3 (0.97 g). LC-MS (ESI) [M+H] + =271.0.

[0405] Step 3: Synthesis of compound 30-4

[0406] Compound 30-3 (100 mg) was dissolved in dichloromethane (5 mL). Under ice bath conditions, diethylaminotrifluoride (2.45 g, 2.04 mL) was added. After the addition was complete, the mixture was stirred at room temperature for 3 hours, and monitored by LC-MS. The reaction solution was then added dropwise to ice water. After the addition was complete, the mixture was extracted with dichloromethane (20 mL). The organic phase was washed with saturated brine (10 mL), stirred until dry, and purified by column chromatography (0-7% EA in PE) to obtain compound 30-4 (84 mg). LC-MS (ESI) [M+H] + =293.0.

[0407] Step 4: Synthesis of compound 30-5

[0408] Compound 30-4 (84 mg) was dissolved in water (0.5 mL), and an aqueous solution of lithium hydroxide (24.14 mg) (0.5 mL) was added. The mixture was stirred at 37 °C for 1 hour. After the reaction was complete as monitored by LC-MS, acetic acid (1 mL) was added, and the mixture was extracted with water (10 mL) and ethyl acetate (15 mL). The organic phase was washed with saturated brine (10 mL), and the organic phase was directly evaporated to dryness. Toluene was used to remove water, giving crude compound 30-5 (85 mg). LC-MS (ESI) [M+H] + =279.0.

[0409] Step 5: Synthesis of compound H24

[0410] Compound 30-5 (80 mg) was dissolved in dichloromethane (3 mL), and compound 2-4 (100 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (163.88 mg) and N,N-diisopropylethylamine (186 mg) were added. The mixture was stirred at room temperature for 1 hour and monitored by LC-MS. After the reaction was complete, the solution was concentrated, diluted with acetonitrile, and prepared by reverse-phase chromatography (preparation method: column: Pntulips ZZ-C18 10 μm 250×20 mm; column temperature: 25℃; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio of mobile phase 30%-70% in 12 min; flow rate 30 mL / min) to obtain H24 (90 mg).

[0411] LC-MS(ESI)[M+H] + =454.0.

[0412] 1 H NMR(400MHz, CDCl3-d)δ8.25(d,J=8.1Hz,1H),7.97(d,J=6.8Hz,1H),7.47–7.40(m,2H),7.36–7.31(m,1H),7.29–7.22(m,1H),7.11–6.99(m,3H) ,6.10(dd,J=32.5,8.6Hz,1H),4.40–4.32(m,1H),3.02(s,3H),1.85(t, J=18.2Hz,3H),1.09–1.01(m,1H),0.62–0.48(m,2H),0.44–0.31(m,2H).

[0413] J24 and K24 were obtained by separation (separation conditions: mobile phase: A: Supercritical CO2; B: Ethanol; column: ChiralPak IG; column size: 250×30mm ID, 10μm; column temperature: 38℃; gradient: A:B = 80:20; flow rate: 120mL / min).

[0414] J24: SFC retention time t = 2.912 min;

[0415] LC-MS(ESI)[M+H]+=454.1;

[0416] 1H NMR(400MHz, CDCl3)δ8.25(dd,J=8.2,1.0Hz,1H),7.97(d,J=6.8Hz,1H),7.49–7.38(m,2H),7.38–7.31(m,1H),7.10–6.98(m,3H),6 .13–6.02(m,1H),4.41–4.31(m,1H),3.02(s,3H),1.85(t,J=18.2Hz,3H),1.11–0.98(m,1H),0.64–0.46(m,2H),0.45–0.29(m,2H).

[0417] K24: SFC retention time t = 2.738 min;

[0418] LC-MS(ESI)[M+H]+=454.1;

[0419] 1H NMR (400MHz, CDCl3) δ8.28–8.22(m,1H),7.97(d,J=6.8Hz,1H),7.47–7.39(m,2H),7.37–7.32(m,1H),7.26–7.23(m,1H),7.09–6.99(m,3H),6.10( dd,J=32.5,8.6Hz,1H),4.41–4.32(m,1H),3.02(s,3H),1.85(t,J=18.2H z,3H),1.04(m,J=8.6,4.7Hz,1H),0.61–0.47(m,2H),0.42–0.31(m,2H).

[0420] Example 31 Synthesis of compound H28

[0421] Step 1: Synthesis of compound H28

[0422] Compound 18-1 (60 mg) and compound 2-4 (50 mg) were dissolved in dichloromethane (5 mL), and then O-(7-azabenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (95.29 mg) and N,N-diisopropylethylamine (26.99 mg, 36.37 μL) were added. The reaction was carried out at 20 °C for 1 hour. The mixture was extracted three times with water and dichloromethane, and the organic phase was evaporated to dryness. The solution was prepared (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 °C; gradient: 60%-80% acetonitrile in 14.2 min; flow rate: 30 mL / min) to obtain H28 (38.04 mg).

[0423] LC-MS(ESI)[M+H]+=463.2.

[0424] 1H NMR (400MHz, DMSO-d6) δ8.69 (s, 1H), 8.14 (d, J = 8.0Hz, 1H), 7.50–7.43 (m, 2H), 7. 32–7.26(m,3H),6.47(dd,J=36.0,8.0Hz,1H),5.01(s,0.5H),4.43(q,J=8.0Hz,1H ),4.20(s,0.5H),3.25(s,3H),2.95(s,1.5H),2.59(s,1.5H),1.35–1.23(m,1H),1 .07(s,3H),0.94(s,3H),0.55–0.47(m,2H),0.45–0.38(m,1H),0.35–0.25(m,1H).

[0425] Example 32 Synthesis of compound H80

[0426] Step 1: Synthesis of compound 32-2

[0427] Phenol (8.40 g, 7.85 mL) was dissolved in N,N-dimethylformamide (100 mL), cooled to 0 °C, and then sodium hydride (3.93 g, 60% purity) was added. The reaction was carried out at 20 °C for 30 minutes. Then, compound 32-1 (10.0 g) was added, and the reaction was carried out at room temperature for 1 hour. LC-MS showed the target product molecular weight. The reaction solution was slowly added to ice water, followed by ethyl acetate. The mixture was extracted three times, and the organic phase was evaporated to dryness and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-10%) to give target compound 32-2 (5.4 g). LC-MS (ESI) [M+H] + =340.0.

[0428] Step 2: Synthesis of compound 32-3

[0429] Compound 32-2 (1 g) was dissolved in N,N-dimethylformamide (4 mL), followed by the addition of dimethylamine tetrahydrofuran solution (2 mL, 2 M). The reaction was carried out in a microwave tube at 100 °C in an oil bath for 1 hour. LC-MS showed the target product as the main peak. The mixture was extracted three times with water and ethyl acetate, and the organic phase was evaporated to dryness and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-40%) to give compound 32-3 (350 mg, crude product). LC-MS (ESI) [M+H] + =291.2.

[0430] Step 3: Synthesis of compound 32-4

[0431] Compound 32-3 (300 mg) was dissolved in a mixed solution of tetrahydrofuran (3 mL), methanol (3 mL), and water (1 mL), followed by the addition of lithium hydroxide (74.25 mg). The reaction was carried out at 65 °C for 16 hours. LC-MS showed the desired product as the main peak. Part of the solvent was concentrated, and the mixture was extracted three times with water and dichloromethane. The organic phase was evaporated to dryness and subjected to reversed-phase column chromatography (acetonitrile:water = 0-65%) to give compound 32-4 (120 mg). LC-MS (ESI) [M+H] + =277.2.

[0432] Step 4: Synthesis of compound H80

[0433] Compound 32-4 (50 mg) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of O-(7-azabenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (82.58 mg) and N,N-diisopropylethylamine (70.17 mg). The reaction was carried out at 20 °C for 5 min, followed by the addition of compound 2-4 (41.97 mg). The reaction was then carried out at 50 °C for 1 h. LC-MS showed the desired product as the main peak. The product was extracted three times with water and dichloromethane, and the organic phase was evaporated to dryness. The mixture was then prepared by reverse-phase chromatography (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25 °C; gradient: 40%-60% acetonitrile in 14.1 min; flow rate: 30 mL / min) to obtain H80 (24.94 mg).

[0434] LC-MS(ESI)[M+H] + =452.4.

[0435] 1 H NMR (400MHz, DMSO-d6) δ8.27(d,J=8.0Hz,1H),7.81(d,J=16.0Hz,1H),7.47–7.38(m,2H),7.28–7.17(m,3H),6.48(dd,J=36.0,12.0Hz,1H ), 4.38(q,J=8.0Hz,1H),3.24(s,3H),2.91(d,J=4.0Hz,6H),1.34–1.22(m,1H),0.54–0.42(m,2H),0.42–0.33(m,1H),0.34–0.24(m,1H).

[0436] Example 33 Synthesis of compound H81

[0437] Step 1: Synthesis of compound 33-2

[0438] Compound 33-1 (3 g) and phenol (1.12 g) were dissolved in N,N-dimethylformamide (50 mL), and potassium carbonate (2.14 g) was added. The mixture was heated to 85 °C and reacted for 16 hours. After the reaction was complete, the reaction solution was poured into water (150 mL), and ethyl acetate (50 mL) was added for extraction. The organic phase was washed with water (50 mL × 2), then with saturated brine (30 mL). The organic phase was directly mixed and purified by column chromatography (1-3% EA / PE) to obtain the target compound 33-2 (1.79 g). LC-MS (ESI) [M+H] + =325.0.

[0439] Step 2 Synthesis of compound 33-3

[0440] Compound 33-2 (250 mg) was dissolved in 1,4-dioxane (3 mL) and water (1 mL). Potassium 2-isopropenyltrifluoroborate (170.70 mg), potassium carbonate (212.22 mg), and Pd(dppf)Cl2 (56.21 mg) were added. Nitrogen gas was purged several times, and the mixture was heated to 100 °C for 3 hours. LC-MS monitoring showed complete conversion to product. The reaction solution was cooled to room temperature, and ethyl acetate (30 mL) and water (20 mL) were added. The organic phase was washed with saturated brine (20 mL), concentrated, and purified by column chromatography (0-10% EA / PE) to obtain the target compound 33-3 (100 mg). LC-MS (ESI) [M+H] + =287.0.

[0441] Step 3: Synthesis of compound 33-4

[0442] Compound 33-3 (1 g) was dissolved in tetrahydrofuran (20 mL), water (15 mL), and potassium osmium tetroxide (21.75 mg) was added, followed by sodium periodate (2.26 g). The mixture was stirred at room temperature for 3 hours, and monitored by LC-MS. After the reaction was complete, the mixture was filtered through diatomaceous earth, ethyl acetate (20 mL) was added, and the mixture was washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 33-4 (1 g). LC-MS (ESI) [M+H] + =289.2.

[0443] Step 4: Synthesis of Compounds 33-5

[0444] Compound 33-4 (1 g) was placed in a flask, and diethylaminosulfur trifluoride (DAST) (5 mL) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was slowly added dropwise to water for further processing. The mixture was extracted with dichloromethane (30 mL), and the organic phase was washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography to obtain crude compound 33-5 (0.9 g). LC-MS (ESI) [M+H] + =311.2.

[0445] Step 5: Synthesis of compounds 33-6

[0446] Compound 33-5 (0.75 g) was dissolved in tetrahydrofuran (5 mL) and water (2 mL). Lithium hydroxide monohydrate (203.05 mg) was added, and the mixture was stirred at room temperature for 1 hour. LC-MS showed complete reaction. After finishing, acetic acid (1 mL) was added, the organic solvent was evaporated, ethyl acetate (20 mL) was added, and the mixture was washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain crude compound 33-6 (720 mg). LC-MS (ESI) [M+H] + =297.0.

[0447] Step 6: Synthesis of compound H81

[0448] Compounds 33-6 (95 mg) and 2-4 (98.21 mg) were dissolved in dichloromethane (2 mL), and HATU (157.28 mg) and N,N-diisopropylethylamine (207.23 mg, 279.29 μL) were added. The mixture was stirred at room temperature for 2 hours. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated. The crude product was sent for reverse-phase preparation and separated by HPLC (preparation method: column: Pntulips ZZ-C18 10 μm 250×20 mm; column temperature: 25℃; mobile phase: water (0.1% FA)-acetonitrile; acetonitrile ratio 30%-95% in 12 min; flow rate 30 mL / min) to obtain the target compound H81 (15 mg).

[0449] LC-MS(ESI)[M+H] + =472.2.

[0450] 1H NMR (400MHz, CDCl3-d) δ8.01–7.93(m,2H),7.46–7.40(m,2H),7.26–7.22(m,1H),7.09(d,J=5.9Hz,1H),7.05–7.00(m,2H),6.07(dd,J =32.5,8.6Hz,1H),4.32(q,J=8.4Hz,1H),3.02(s,3H),1.96(t,J=1.2Hz,3H),1.07–0.98(m,1H),0.60–0.46(m,2H),0.40–0.29(m,2H).

[0451] H81 and J81 were obtained by separation (separation conditions: mobile phase: A: Supercritical CO2; B: Ethanol; column: ChiralPak AY; column size: 250×30mm ID, 10μm; column temperature: 38℃; gradient: A:B = 90:10; flow rate: 120mL / min).

[0452] J81: SFC retention time t = 2.403 min;

[0453] LC-MS(ESI)[M+H] + =472.2;

[0454] 1 H NMR (400MHz, DMSO-d6) δ8.82–8.77(m,1H),7.66–7.58(m,1H),7.44–7.34(m,2H),7.18–7.10(m,2H),7.05–6.95(m,2H),6.21(dd ,J=34.3,9.0Hz,1H),4.29(q,J=8.5Hz,1H),3.21(s,3H),1.99(t,3H),0.47-0.43(m,1H),0.40–0.32(m,1H),0.26-0.23(m,2H).

[0455] K81: SFC retention time t = 2.247 min;

[0456] LC-MS(ESI)[M+H] + =472.2;

[0457] 1H NMR(400MHz, CDCl3-d)δ8.28–8.22(m,1H),7.97(d,J=6.8Hz,1H),7.47–7 .39(m,2H),7.37–7.32(m,1H),7.26–7.23(m,1H),7.09–6.99(m,3H),6.10 (dd,J=32.5,8.6Hz,1H),4.41–4.32(m,1H),3.02(s,3H),1.85(t,J=18.2 Hz, 3H), 1.04 (m, J = 8.6, 4.7Hz, 1H), 0.61–0.47 (m, 2H), 0.42–0.31 (m, 2H).

[0458] Experimental Example 1: WRN Helicase Activity Detection Experiment

[0459] 1. Experimental apparatus

[0460] The instrument information used in this experiment is shown in Table 1.

[0461] Table 1

[0462] 2. Experimental Materials

[0463] The WRN enzyme used in the experiment had a His-TEV tag at its N-terminus, was expressed in eukaryotic cells, and had a purity of 90%. The two single-stranded DNA molecules used for detection were labeled with BHQ2 and Cy5, respectively. When the two fluorescent molecules came close together (when the DNA was in a double-stranded state), no fluorescent signal was detected due to the quenching effect. WRN has helicase activity, which can untangle double-stranded DNA to form single strands, thereby generating a fluorescent signal. Information on other reagents and consumables required for the experiment is shown in Table 2.

[0464] Table 2

[0465] 3. Experimental Methods

[0466] Two labeled single-stranded DNA strands were annealed to form double-stranded DNA. Annealing buffer: 12 mM Tris (pH 8.0), 300 mM NaCl, 12 mM MgCl2, 2 mM DTT. Annealing program: 95 °C, 5 min.

[0467] 2×WRNase (20 nM) was prepared using a buffer containing 0.2 mM ATP (50 mM Tris (pH 7.5), 100 mM NaCl, 2 mM MgCl2, 0.01% Tween-20, 1 mM DTT, 0.003% BSA). 2× substrate (200 nM double-stranded DNA, 2000 nM capture DNA, 3.8 mM ATP) was prepared using a buffer. The test compound was dissolved to 10 mM in DMSO and serially diluted using 96-well V plates. 0.5 μL of the compound was added to 25 μL of 2×WRNase and incubated at room temperature for 4 h. 25 μL of 2× substrate was added, and the reaction was incubated at room temperature for 30 min. Detection was performed using a microplate reader with excitation at 620 nm and emission at 685 nm.

[0468] 4. Data Analysis

[0469] Concentration-effect curves were fitted using GraphPad Prism 8 software, and the IC50 concentration of the compound at which 50% inhibition was achieved was calculated. 50 First, the percentage inhibition rate corresponding to each compound concentration was calculated. Then, the concentration-response curve was fitted using the "log(inhibitor) vs. normalized response - Variable slope" equation in GraphPad Prism 8 software to obtain the IC50. 50 .

[0470] Inhibition rate (%) = (Average fluorescence intensity of positive control wells - Fluorescence intensity of compound wells) / (Average fluorescence intensity of positive control wells - Average fluorescence intensity of negative control wells) × 100

[0471] Positive control: 25 μL 2× WRN enzyme + 0.5 μL DMSO + 25 μL 2× substrate

[0472] Negative control: 25 μL 2× buffer + 0.5 μL DMSO + 25 μL 2× substrate

[0473] The experimental results are shown in Table 3. In Table 3, IC... 50 The classification is as follows: "++++" represents 10nM <IC 50 <100nM, "++++" represents 100nM <IC 50 <400nM, "++" represents 400nM <IC 50 <1000nM, "++" represents 1000nM <IC 50 <5000nM, "+" represents IC 50 >5000nM.

[0474] Table 3

[0475] Experiment Example 2: Cell Proliferation Experiment

[0476] 1. Experimental apparatus

[0477] The instrument information used in this experiment is shown in Table 4.

[0478] Table 4

[0479] 2. Experimental Materials

[0480] The information on other reagents and consumables required for this experiment is shown in Table 5.

[0481] Table 5

[0482] 3. Experimental Methods

[0483] HCT116 and SW620 cells were seeded at a density of 800 cells / well in 96-well cell culture plates and cultured overnight at 37°C. The test compounds, serially diluted with DMSO, were added, and after 5 days of incubation, cell viability was assessed using the CellTiter-Glo reagent kit. CellTiter-Glo reagent was equilibrated to room temperature, and an appropriate amount was added to the cell culture plate, incubated with shaking at room temperature for 12 minutes. The luminescence signal was detected using a microplate reader.

[0484] 4. Data Analysis

[0485] The luminescence signal values ​​of DMSO-treated wells and cell-free wells were used as negative and positive controls, respectively, to calculate the inhibitory rate of the compound on cell proliferation. The concentration-inhibition rate curve was fitted using the "log(inhibitor) vs. normalized response – Variable slope" equation in GraphPad Prism 8 software to obtain the IC50. 50 .

[0486] Inhibition rate (%) = [1 - (luminescence intensity of compound wells - average luminescence intensity of positive control wells) / (average luminescence intensity of negative control wells - average luminescence intensity of positive control wells)] × 100

[0487] The experimental results are shown in Table 6. In Table 6, IC... 50 The classification is as follows: "++++" represents 10nM <IC 50 <40nM, where "++++" represents 40nM <IC 50 <200nM, "++" represents 200nM <IC 50 <1000nM, "++" represents 1000nM <IC 50<25000nM, "+" represents IC 50 >25000nM.

[0488] Test results show that the compound of the present invention has an inhibitory effect on the proliferation of MSI-H colorectal cancer cell lines SW48 and HCT116, but has no inhibitory effect on the proliferation of MSS SW620 cells.

[0489] Table 6

[0490] Experimental Example 3: γ-H 2AX Induction Experiment

[0491] 1. Experimental apparatus

[0492] The instrument information used in this experiment is shown in Table 7.

[0493] Table 7

[0494] 2. Experimental Materials

[0495] The information on other reagents and consumables required for this experiment is shown in Table 8.

[0496] Table 8

[0497] 3. Experimental Methods

[0498] SW48, HCT116, and SW620 cells were seeded into 96-well cell culture plates at a density of 10,000-25,000 cells / well and cultured overnight at 37°C. The test compounds were added in serially diluted DMSO and incubated for 2-3 days. γ-H2AX levels were detected using HTRF Phospho-H2AX (SER139) Detection Kits. 4×Lysis buffer and Detection buffer were equilibrated to room temperature. 4×Lysis buffer was prepared as 1×Lysis buffer using ddH2O. After aspirating the culture medium, 50 μL of 1×Lysis buffer was added to each well and lysed at room temperature for 30 minutes with shaking. 16 μL of the lysis buffer was transferred to a 384-well plate, and 4 μL of diluted mixed antibody was added (Phospho-H2AX d2 antibody and Phospho-H2AX Eu Cryptate antibody were diluted 20-fold using Detection buffer, and then the two antibodies were mixed 1:1 by volume). Incubate at room temperature for 2–24 hours, and detect fluorescence signals at 655 nm and 615 nm using a microplate reader. Simultaneously, set up parallel treatment plates and use the CellTiter-Glo reagent kit to detect cell viability. Equilibrate the CellTiter-Glo reagent to room temperature, add an appropriate amount to the cell plate, and shake at room temperature for 12 minutes. Detect the fluorescence signal using a microplate reader.

[0499] The concentration-HTRF ratio curve was fitted using the "log(agonist) vs. response – Variable slope (four parameters)" equation in GraphPad Prism 8 software to obtain the EC value. 50 .

[0500] Cell viability (%) = (Cellular fluorescence intensity in compound wells / Average fluorescence intensity in DMSO control wells) × 100

[0501] HTRF Ratio = (665nm fluorescence signal value / 615nm fluorescence signal value) × 10 4 / Cell viability

[0502] The experimental results are shown in Table 9. In Table 9, EC... 50 The classification is as follows: "++++" represents 100nM <EC 50 <600nM, "++" represents 600nM <EC 50 <1200nM, "++" represents 1200nM <EC 50 <10000nM, "+" represents EC50 >10000nM.

[0503] Test results show that the compound of the present invention has good activity in inducing MSI cells to produce γ-H2AX and has good selectivity for MSS cells.

[0504] Table 9

[0505] Example 4 Pharmacokinetic Evaluation

[0506] (I) Pharmacokinetics in mice

[0507] 1. Experimental Objective

[0508] Male ICR mice were used as test animals. Examples J2, J21, J75, Comparative Example 1 and Comparative Example 2 were administered intravenously and by gavage, respectively. The drug concentration in plasma at different time points was determined by LC-MS / MS to study the pharmacokinetic characteristics of the compound of the present invention in mice.

[0509] The chemical structure of Comparative Example 1 is as follows: See Example 235 of WO2024010782A1; the chemical structure of Comparative Example 2 is as follows: See Example 87 of WO2024010782A1 for reference.

[0510] 2. Experimental Design

[0511] 2.1 Experimental drugs and animals

[0512] Experimental reagents: Examples J2, J21, J75, Comparative Examples 1 and 2;

[0513] Animals: Male SPF-grade ICR mice, 26-28g, purchased from Shanghai Shengchang Biotechnology Co., Ltd.

[0514] 2.2 Drug Preparation

[0515] Weigh appropriate amounts of Examples J2, J21, J75, Comparative Example 1, and Comparative Example 2, dissolve them in an appropriate amount of DMSO, and prepare a stock solution with a concentration of 20.0 mg / mL. Add an appropriate amount of solubilol, sonicate for 2 min, vortex for 2 min, then add an appropriate amount of saline, vortex for 2 min, sonicate for 2 min, and obtain a colorless, clear, pH 6 intravenous administration solution of 0.2 mg / mL, which is used for animal administration in the 1 MPa intravenous administration group.

[0516] Weigh appropriate amounts of Examples J2, J21, J75, Comparative Example 1, and Comparative Example 2, dissolve them in an appropriate amount of DMSO, and prepare a stock solution with a concentration of 20.0 mg / mL. Add an appropriate amount of solubilol, sonicate for 2 min, vortex for 2 min, add an appropriate amount of saline, vortex for 2 min, sonicate for 5 min, and obtain a colorless, clear oral administration solution with pH=6 of 1.0 mg / mL, which is used to administer the solution to animals in the 10 mpk oral administration group.

[0517] 2.3 Administration

[0518] Mice in the test compound intravenous administration group (n=3) were fasted overnight and then administered the compound intravenously (dose 1.0 mg / kg, administration volume 5 mL / kg). They were fed 4 hours after administration.

[0519] Mice in the test compound oral administration group (n=3) were fasted overnight and then administered the compound orally by gavage (dose 10.0 mg / kg, administration volume 10 mL / kg). They were fed 4 hours after administration.

[0520] 3. Operation

[0521] Before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration, 0.05 mL of blood was collected into 1.5 mL EP tubes containing heparin sodium. The collected whole blood was vortexed twice to mix it, placed on wet ice, and centrifuged at 8000 rpm for 5 min at 4°C within 1 hour. The supernatant plasma was collected and stored at -80°C until processing and analysis.

[0522] The levels of the target compound in mouse plasma after administration were determined by LC-MS / MS.

[0523] 4. Pharmacokinetic Parameter Results

[0524] The experimental results of intravenous administration are shown in Table 10.

[0525] Table 10

[0526] The results of the oral administration experiment are shown in Table 11.

[0527] Table 11

[0528] (II) Rat Pharmacokinetic Tests

[0529] 1. Experimental Objective

[0530] Male SD rats were used as test animals. They were administered the drugs in Examples J21, J75, Comparative Example 1 and Comparative Example 2 via intravenous and gavage, respectively. The drug concentration in plasma at different time points was determined by LC-MS / MS to study the pharmacokinetic characteristics of the compounds of the present invention in mice.

[0531] 2. Experimental Design

[0532] 2.1 Experimental drugs and animals

[0533] Experimental reagents: Example J21, Example J75, Comparative Example 1 and Comparative Example 2;

[0534] Animals: Male SPF-grade SD rats, 170-180g, purchased from Shanghai Jihui Experimental Animal Co., Ltd.

[0535] 2.2 Drug Preparation

[0536] Weigh appropriate amounts of Examples J21, J75, Comparative Example 1, and Comparative Example 2, dissolve them in an appropriate amount of DMSO, and prepare a stock solution with a concentration of 20.0 mg / mL. Add an appropriate amount of solubilol, sonicate for 2 min, vortex for 2 min, then add an appropriate amount of saline, vortex for 2 min, sonicate for 2 min, to obtain a colorless, clear, pH=6 intravenous administration solution of 0.2 mg / mL, which was used for animal administration in the 1 MPa intravenous administration group.

[0537] Weigh appropriate amounts of Examples J21, J75, Comparative Example 1, and Comparative Example 2, dissolve them in an appropriate amount of DMSO, and prepare a stock solution with a concentration of 20.0 mg / mL. Add an appropriate amount of solubilol, sonicate for 2 min, vortex for 2 min, then add an appropriate amount of saline, vortex for 2 min, sonicate for 2 min, to obtain a colorless, clear oral administration solution with pH=6 of 1.0 mg / mL, which is used to administer the solution to animals in the 10 mpk oral administration group.

[0538] 2.3 Administration

[0539] Mice in the test compound intravenous administration group (n=3) were fasted overnight and then administered the compound intravenously (dose 1.0 mg / kg, administration volume 5 mL / kg). They were fed 4 hours after administration.

[0540] Mice in the test compound oral administration group (n=3) were fasted overnight and then administered the compound orally by gavage (dose 10.0 mg / kg, administration volume 10 mL / kg). They were fed 4 hours after administration.

[0541] 3. Operation

[0542] Before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration, 0.05 mL of blood was collected into 1.5 mL EP tubes containing heparin sodium. The collected whole blood was vortexed twice to mix it, placed on wet ice, and centrifuged at 8000 rpm for 5 min at 4°C within 1 hour. The supernatant plasma was collected and stored at -80°C until processing and analysis.

[0543] The content of the target compound in rat plasma after administration was determined by LC-MS / MS.

[0544] 4. Pharmacokinetic Parameter Results

[0545] The experimental results of intravenous administration are shown in Table 12.

[0546] Table 12

[0547] The results of the oral administration experiment are shown in Table 13.

[0548] Table 13

[0549] The exemplary embodiments of the present invention have been described above. It should be understood that the scope of protection of this application is not limited to the exemplary embodiments described above. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the scope of protection of this application.

Claims

1. The compound represented by formula (Ⅰ), its optical isomer, or its pharmacologically acceptable salt, in, X is selected from CR7 or N; Z is selected from CR8 or N; L1 is selected from single bonds, C 1-20 Alkyl or C 1-20 Heteroalkyl, the C 1-20 Alkyl and C 1-20 The heteroalkyl group may be optionally substituted with 1, 2 or 3 Rs; L2 is selected from single bond, -O-, -S-, -N(R) b1 )-、-C(R b2 -2-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2- or L3 is selected from single bonds, C 1-20 Alkyl or C 1-20 Heteroalkyl, the C 1-20 Alkyl and C 1-20 The heteroalkyl group may be optionally substituted with 1, 2 or 3 Rs; T is selected from O or N(R) b1 ); R1 is selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 heteroaryl, wherein C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl and 5-20 heteroaryl groups may be substituted by 1, 2 or 3 Rs; R2 is selected from C 6-20 Aryl, 5-20 heteroaryl, C 3-20 Cycloalkyl or 3-20 membered heterocycloalkyl, wherein C 6-20 Aryl, 5-20 heteroaryl, C 3-20 Cycloalkyl and 3-20 membered heterocyclic alkyl groups may be optionally substituted with 1, 2 or 3 Rs; R3 is selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -COOH, -C(=O)NH2, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 heteroaryl, wherein C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl and 5-20 heteroaryl groups may be substituted by 1, 2 or 3 Rs; R4 is selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl or 3-20 membered heterocycloalkyl, wherein C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl and 3-20 membered heterocyclic alkyl groups may be optionally substituted with 1, 2 or 3 Rs; R5 is selected from -F, -Cl, -Br, -I, -CN, or C. 1-20 Alkyl, the C 1-20 Alkyl groups may be optionally substituted with 1, 2, or 3 Rs; R6 is selected from C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl or 3-20 membered heterocycloalkyl, wherein C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl and 3-20 membered heterocyclic alkyl groups may be optionally substituted with 1, 2 or 3 Rs; R7 and R8 are independently selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, and C, respectively. 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl or 3-20 membered heterocycloalkyl, wherein C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl and 3-20 membered heterocyclic alkyl groups may be optionally substituted with 1, 2 or 3 Rs; R b1 Each occurrence is independently selected from -H, C 1-12 Alkyl, C 1-12 Heteroalkyl, C 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl, wherein C 1-12 Alkyl, C 1-12 Heteroalkyl, C 3-12 Cycloalkyl and 3-12 membered heterocycloalkyl groups may be optionally substituted with 1, 2 or 3 Rs; R b2 Each occurrence is independently selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, C 1-12 Alkyl or C 1-12 Heteroalkyl, the C 1- 12 Alkyl and C 1-12 The heteroalkyl group may be optionally substituted with 1, 2 or 3 Rs; Each occurrence of R is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -CHO, -COOH, -C(=O)NH2, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 heteroaryl, wherein C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 The aryl group and 5-20 heteroaryl group are optionally substituted by 1, 2 or 3 R's; each time R' appears, it is independently selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CH3, -CF3, -C2H5, -CN, -SF5, -CHO, -COOH or -C(=O)NH2; The above C 1-12 Heteroalkyl, C 1-20 Heteroalkyl, 3-12-membered heterocyclic alkyl, 3-20-membered heterocyclic alkyl and 5-20-membered heteroaryl contain 1, 2 or 3 heteroatoms independently selected from O, N and S or heteroatoms selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -S(=O)(=NH)-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- and -S(=O)N(H)-.

2. The compound according to claim 1, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, The structure of the compound represented by formula (Ⅰ) is shown in formula (Ⅰ-1) or (Ⅰ-2):

3. The compound according to claim 1 or 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -CHO, -COOH, -C(=O)NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkyl-C 1-6 Alkoxy-, C 1-6 Alkyl-C 1-6 Alkylthio-, C 1-6 Alkyl-C 1-6 Alkylamino-, -C 1- 6-alkyl-OH, -C 1-6 Alkyl group -NH2, -C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-C(=O)-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl, -C 1-6 Alkyl-NH-S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, thiophene, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, or thiaranyl. The C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkyl-C 1-6 Alkoxy-, C 1-6 Alkyl-C 1-6 Alkylthio-, C 1-6 Alkyl-C 1-6 Alkylamino-, -C 1-6 Alkyl -OH, -C 1-6 Alkyl group -NH2, -C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-C(=O)-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl, -C 1-6 Alkyl-NH-S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, thiophene, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, and thiaranyl may be optionally substituted with 1, 2, or 3 R's.

4. The compound according to claim 3, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R is independently selected from -H, -D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SF5, -CHO, -COOH, -C(=O)NH2, -CH3, -CF3, -CHF2, -CH2F, -CF2Cl, -CF2Br, -CF2I, -OCH3, -NHCH3, or -N(CH3)2.

5. The compound according to claim 1 or 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, L1 is selected from single bonds, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C 1-6 Alkyl-C 1-6 Alkoxy-, -C 1-6 Alkyl-C 1-6 Alkylthio-, -C 1-6 Alkyl-C 1-6 Alkylamino-,-C(=O)-C 1-6 Alkyl-, -C 1-6 Alkyl-C(=O)-C 1-6 Alkyl-, -NH-C(=O)-C 1-6 Alkyl-, -C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl-, -NH-S(=O)2-C 1-6 Alkyl- or -C 1-6 Alkyl-NH-S(=O)2-C 1-6 alkyl-, The C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C 1-6 Alkyl-C 1-6 Alkoxy-, -C 1-6 Alkyl-C 1-6 Alkylthio-, -C 1-6 Alkyl-C 1-6 Alkylamino-,-C(=O)-C 1-6 Alkyl-, -C 1-6 Alkyl-C(=O)-C 1-6 Alkyl-, -NH-C(=O)-C 1-6 Alkyl-, -C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl-, -NH-S(=O)2-C 1-6 Alkyl- and -C 1-6 Alkyl-NH-S(=O)2-C 1-6 Alkyl groups are optionally substituted with 1, 2, or 3 Rs.

6. The compound according to claim 5, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, L1 is selected from single bonds, -CH2-, -CF2-、 7. The compound according to claim 1 or 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R1 is selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, azacyclobutane, tetrahydropyrrolyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, thiophenyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, or thiaranyl. The C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, azacyclobutyl, tetrahydropyrrolyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridinyl, pyrazinyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, and thiaranyl are optionally substituted with 1, 2, or 3 Rs.

8. The compound according to claim 7, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R1 is selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -CH3, -C2H5.

9. The compound according to claim 1 or 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, Structural unit - L1-R1 is selected from 10. The compound according to claim 1 or 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R b1 Each occurrence is independently selected from -H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino or C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino and C 3-6 The cycloalkyl group may be optionally substituted with 1, 2 or 3 Rs; and / or R b2 Each occurrence is independently selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio and C 1-6 The alkylamino group can be optionally substituted with 1, 2 or 3 Rs.

11. The compound of claim 10, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, L2 is selected from single bonds, -O-, -S-, -NH-, -CH2-, -CF2-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2- or 12. The compound according to claim 1 or 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R2 is selected from C 3-12 Cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, thiophene, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, or thiaranyl. The C 3-12 Cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, and thiaranyl may be substituted with 1, 2, or 3 Rs.

13. The compound according to claim 12, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R2 is selected from 14. The compound according to claim 1 or 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, Structural unit - L2-R2 is selected from 15. The compound according to claim 1 or 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, L3 is selected from single bonds, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C 1-6 Alkyl-C 1-6 Alkoxy-, -C 1-6 Alkyl-C 1-6 Alkylthio-, -C 1-6 Alkyl-C 1-6 Alkylamino-,-C(=O)-C 1-6 Alkyl-, -C 1-6 Alkyl-C(=O)-C 1-6 Alkyl-, -NH-C(=O)-C 1-6 Alkyl-, -C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl-, -NH-S(=O)2-C 1-6 Alkyl- or -C 1-6 Alkyl-NH-S(=O)2-C 1-6 alkyl-, The C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C 1-6 Alkyl-C 1-6 Alkoxy-, -C 1-6 Alkyl-C 1-6 Alkylthio-, -C 1-6 Alkyl-C 1-6 Alkylamino-,-C(=O)-C 1-6 Alkyl-, -C 1-6 Alkyl-C(=O)-C 1-6 Alkyl-, -NH-C(=O)-C 1-6 Alkyl-, -C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl-, -NH-S(=O)2-C 1-6 Alkyl- and -C 1-6 Alkyl-NH-S(=O)2-C 1-6 Alkyl groups are optionally substituted with 1, 2, or 3 Rs.

16. The compound of claim 15, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, L3 is selected from single bonds, -CH2-, 17. The compound according to claim 1 or 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R3 is selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -COOH, -C(=O)NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-12 Cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, thiophene, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, or thiaranyl. The C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-12 Cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, and thiaranyl may be substituted with 1, 2, or 3 Rs.

18. The compound of claim 17, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R3 is selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -COOH, -C(=O)NH2, -CH3, -CF2H, -C2H5, -OCH3, -OCF2H, -OC(CH3)3.

19. The compound according to claim 1 or 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, Structural unit -L3-R3 is selected from -CH3, -C2H5, 20. The compound according to claim 1 or 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R5 is selected from -F, -Cl, -Br, -I, -CN, or C. 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted with 1, 2 or 3 Rs.

21. The compound according to claim 1 or 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R6 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio and C 1-6 The alkylamino group can be optionally substituted with 1, 2 or 3 Rs.

22. A compound of the following formula, its optical isomer, or a pharmacologically acceptable salt thereof, selected from...

23. The compound of claim 22, its optical isomer, or a pharmacologically acceptable salt thereof, wherein the compound is selected from...

24. A pharmaceutical composition, wherein, It includes the compound of any one of claims 1 to 23, its optical isomer, or a pharmaceutically acceptable salt thereof.

25. The use of the compound of any one of claims 1 to 23, its optical isomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 24 in the preparation of a medicament for treating tumor-related diseases.

26. The application according to claim 25, wherein, The tumors are malignant tumors with high microsatellite instability, malignant tumors with mismatch repair defects, or tumors with a large number of (TA) detected. n Malignant tumors with repetitive sequences.

27. The application according to claim 25, wherein, The tumor-related diseases mentioned are one or more of the diseases associated with solid tumors.

28. The application according to claim 25, wherein, The tumor-related diseases include one or more of colorectal cancer, gastric cancer, endometrial cancer, and ovarian cancer.

Images