Tetracyclic aromatic amide derivatives, their preparation methods and uses

Abstract

This invention relates to a tetracyclic aromatic amide derivative, its preparation method, and the pharmaceutical application of pharmaceutical compositions containing the derivative. Specifically, this invention relates to a tetracyclic aromatic amide derivative of general formula (I), its preparation method, its pharmaceutically usable salts, and their use as therapeutic agents, particularly DHX9 inhibitors, wherein the definitions of the substituents in general formula (I) are the same as those in the specification.

Description

[Technical Field]

[0001] This invention relates to a tetracyclic aromatic amide derivative, its preparation method, pharmaceutical compositions containing the derivative, and its use as a therapeutic agent, particularly as a DHX9 inhibitor. [Previous Technology]

[0002] DExH-box helicase 9 (DHX9) is a member of the DExD / H-box helicase family. It is an NTP-dependent helicase protein that can unwind RNA, DNA, and aberrant polynucleotide structures, and is therefore also known as nuclear DNA helicase II (NDH II) and RNA helicase A (RHA). The core domain of this family of helicases has a conserved Asp-Glu-Ile-His (DEIH) sequence, which is the core region for NTP binding and hydrolysis.

[0003] Because DHX9 lacks alkali selectivity, it can utilize all four NTPs to meet its energy requirements. It is a multi-domain, multifunctional protein that plays an important role in biological development, DNA replication, transcription, translation, repair, splicing, editing, RNA processing, transport, remodeling, and maintaining genome stability.

[0004] Due to its regulatory role in processes such as transcription and maintaining genome stability, DHX9 has been shown to be a key regulatory factor in various cancer types, participating in the regulation of genes associated with sustained proliferation signaling, evasion of growth inhibitors, evasion of apoptosis, angiogenesis, and metastasis—all of which are hallmarks of cancer. Specifically, microsatellite instability cancers, such as microsatellite instability (MSI) colorectal cancer, and tumors with defective mismatch repair (MMR), exhibit a strong dependence on DHX9.

[0005] In addition to its role in cancer, DHX9 is also associated with other diseases involving gene replication, translation, or regulation. These diseases include viral infections and autoimmune diseases.

[0006] There are no new drugs targeting DHX9 on the market, nor is there any information on clinical compounds. As a novel anti-tumor target, DHX9 has enormous potential for research, and it is essential to develop inhibitors targeting this target. [Summary of the Invention]

[0007] To address the above-mentioned technical problems, the present invention provides a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically usable salts thereof: wherein: X is selected from halogens; R1 is selected from C1-6 alkyl or 3-5 membered cycloalkyl; wherein the C1-6 alkyl or 3-5 membered cycloalkyl is optionally further substituted by one or more substituents selected from halogens, hydroxyl groups, cyano groups, C1-6 alkyl groups or C1-6 alkoxy groups; is a 5-membered heteroaryl group; X1 and X2 are each independently selected from CH, S or N, and X1 and X2 are not simultaneously S; X3 is selected from C or N; provided that when X3 is C, X1 and X2 are not simultaneously CH; W and Q are each independently selected from C or N; the cyclic C is selected from 5-6 membered heteroaryl or 4-7 membered heterocyclic group; Y and Z are each independently selected from CR2c or N; R2a is selected from hydrogen atom, cyano, halogen, hydroxyl, SF5, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, 3-8 heterocyclic, C6-10 aryl or 5-6 heteroaryl, wherein the C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, 3-8 heterocyclic, C6-10 aryl or 5-6 heteroaryl may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy; R2b are each independently selected from hydrogen atom, halogen, hydroxyl, cyano, C1-6 alkyl, amino, carboxyl or C1-6 alkyl, wherein the C1-6 alkyl or C1-6 alkoxy is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy; R2c are each independently selected from hydrogen atom, halogen, hydroxyl, cyano, C1-6 alkyl, amino, carboxyl, C1-6 alkoxy or -OCH2R3, wherein the C1-6 alkyl or C1-6 alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, C1-6 alkyl, C1-6 alkoxy or -OR3; R3 is independently selected from C3-8 cycloalkyl, C6-10 aryl, 5-6 heteroaryl, or 5-6 heterocyclic groups, wherein the C3-8 cycloalkyl, C6-10 aryl, 5-6 heteroaryl, or 5-6 heterocyclic group is optionally further substituted by one or more substituents selected from hydroxyl, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy; p is independently selected from 0, 1, or 2; q is independently selected from 0, 1, or 2; m is independently selected from 0, 1, or 2; n is independently selected from 0, 1, or 2.

[0008] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of general formula (II) or (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: wherein: Y and Z are each independently selected from CR2c or N; R2c are each independently selected from hydrogen atom, C1-6 alkoxy or -OCH2R3, wherein the C1-6 alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, C1-6 alkyl, C1-6 alkoxy or -OR3; R3 are each independently selected from C6-10 aryl, 5-6 heteroaryl or 5-6 heterocyclic group, wherein the C6-10 aryl, 5-6 heteroaryl or 5-6 heterocyclic group is optionally further substituted by one or more substituents selected from hydroxyl, halogen, cyano, C1-6 alkyl, C1-6 alkoxy; The rings C, W, Q, R1, X, R2a, R2b, p, q, m and n are defined as described in general formula (I).

[0009] A preferred embodiment of the present invention is a compound of general formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: m is 1 or 2 and n is 0.

[0010] A preferred embodiment of the present invention is a compound of general formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: m is 0 and n is 1.

[0011] A preferred embodiment of the present invention is a compound of general formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: W is N and Q is C.

[0012] A preferred embodiment of the present invention is a compound of general formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: W is C and Q is N.

[0013] A preferred embodiment of the present invention is a compound of general formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically usable salt thereof, wherein the ring C is selected from a 5-membered heteroaryl group, preferably a triazole, a tetrazolium or a pyrazole.

[0014] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the group is selected from the following groups:; R2c is defined as in general formula (I).

[0015] In a preferred embodiment of the present invention, a compound of general formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R2c is selected from C1-6 alkoxy or -OCH2R3, wherein the C1-6 alkoxy is optionally further substituted by one or more substituents selected from halogens; R3 is each independently selected from phenyl, 5-6-membered heteroaryl or 5-6-membered heterocyclic group, wherein the phenyl, 5-6-membered heteroaryl or 5-6-membered heterocyclic group is optionally further substituted by one or more substituents selected from hydroxyl, halogen, cyano, C1-6 alkyl or C1-6 alkoxy.

[0016] In a preferred embodiment of the present invention, a compound of general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R2c is selected from methoxy, trifluoromethoxy, ...

[0017] A preferred embodiment of the present invention is a compound of general formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X is selected from Cl or Br, preferably Cl.

[0018] A preferred embodiment of the present invention is a compound of general formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R1 is selected from methyl or ethyl.

[0019] In a preferred embodiment of the present invention, the compounds of the general formula are selected from: Compound numbering structure name Example 1 1-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-9H-benzo[c]thieno[3,2-e][1,2,4]triazolo[4,3-a]azepine-11-carboxamide 1-(benzyloxy)-N-(3-chloro-5-(methanesulfonylamino)phenyl)-9H-benzo[c]thieno[3,2-e][1,2,4]triazolo[4,3-a]aza-11-methamide Example 2 1-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-9H-benzo[f]thieno[2,3-d][1,2,4]triazolo[4,3-a]azepine-11-carboxamide 1-(benzyloxy)-N-(3-chloro-5-(methanesulfonylamino)phenyl)-9H-benzo[f]thiopheno[2,3-d][1,2,4]triazolo[4,3-a]aza-11-methamide Example 3 1-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]azepine-11-carboxamide 1-(benzyloxy)-N-(3-chloro-5-(methanesulfonylamino)phenyl)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]aza-11-methamide Example 4 N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]azepine-11-carboxamide N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]aza-11-methylamine Example 5 N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3-fluorobenzyl)oxy)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]azepine-11-carboxamide N-(3-chloro-5-(methanesulfonylamino)phenyl)-1-((3-fluorobenzyl)oxy)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]aza-11-methamide Example 6 1-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-9,10-dihydrobenzo[f]pyrrolo[1,2-d][1,2,4]triazolo[3,4-h][1,4]diazocine-13-carboxamide 1-(benzyloxy)-N-(3-chloro-5-(methanesulfonylamino)phenyl)-9,10-dihydrobenzo[f]pyrrolo[1,2-d][1,2,4]triazolo[3,4-h][1,4]diazoindene-13-methamide Example 7 N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3-fluorobenzyl)oxy)-9,10-dihydrobenzo[f]pyrrolo[1,2-d][1,2,4]triazolo[3,4-h][1,4]diazocine-13-carboxamide N-(3-chloro-5-(methanesulfonylamino)phenyl)-1-((3-fluorobenzyl)oxy)-9,10-dihydrobenzo[f]pyrrolo[1,2-d][1,2,4]triazolo[3,4-h][1,4]diazooct-13-methamide Example 8 N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]imidazo[1,2-a]pyrrolo[1,2-d][1,4]diazepine-12-carboxamide N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]imidazo[1,2-a]pyrrolo[1,2-d][1,4]diaza-12-methamide Example 9 N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]diazepine-12-carboxamide N-(3-chloro-5-(methylsulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]diazamine-12-methylamine Example 10 N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d]tetrazolo[1,5-a][1,4]diazepine-12-carboxamide N-(3-chloro-5-(methylsulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d]tetrazo[1,5-a][1,4]diazamine-12-methylamine Example 11 N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-6-oxo-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diazepine-12-carboxamide N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-6-oxo-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diaza-12-methylamine Example 12 N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diazepine-12-carboxamide N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diaza-12-methylamine Example 13 N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-6-oxo-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazino[4,3-a]pyrrolo[1,2-d][1,4]diazepine-13-carboxamide N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-6-oxo-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazin[4,3-a]pyrrolo[1,2-d][1,4]diaza-13-methamide Example 14 N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3-fluorobenzyl)oxy)-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazino[4,3-a]pyrrolo[1,2-d][1,4]diazepine-13-carboxamide N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3-fluorobenzyl)oxy)-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazin[4,3-a]pyrrolo[1,2-d][1,4]diaza-13-methamide Example 15 N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3-fluorobenzyl)oxy)-4b,7,8,10-tetrahydro-5H-benzo[c][1,4]oxazino[4,3-a]thieno[3,2-e]azepine-12-carboxamide N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3-fluorobenzyl)oxy)-4b,7,8,10-tetrahydro-5H-benzo[c][1,4]oxazin[4,3-a]thieno[3,2-e]aza-12-methamide Or its stereoisomers, tautomers, or medicinal salts thereof.

[0020] Note: If there is a difference between the drawn structure and the given name of the structure, the drawn structure will be given greater weight.

[0021] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of general formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

[0022] The present invention provides the use of a compound of general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a DHX9 inhibitor.

[0023] The present invention also provides the use of a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating DHX9-mediated diseases, wherein the DHX9-mediated diseases are preferably cancer, viral infections or autoimmune diseases, more preferably cancer; wherein the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic system cancer, breast cancer, brain cancer, skin cancer, lung cancer, blood cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft tissue cancer, kidney cancer and liver cancer, preferably colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic system cancer and gastric cancer.

[0024] The present invention also provides the use of a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating DHX9-mediated diseases, wherein the DHX9-mediated disease is preferably cancer, wherein the cancer is microsatellite instability (MSI) cancer, preferably highly microsatellite instability (MSI-H) cancer, more preferably highly microsatellite instability (MSI-H) colorectal cancer.

[0025] The present invention further provides the use of a compound of formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating cancer, viral infection or autoimmune disease.

[0026] The present invention provides the use of a compound of general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically usable salt or pharmaceutical composition thereof in the preparation of a medicament for treating colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic system cancer, breast cancer, brain cancer, skin cancer, lung cancer, blood cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft tissue cancer, kidney cancer and liver cancer, preferably in the preparation of a medicament for treating colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic system cancer and gastric cancer.

[0027] The present invention provides the use of a compound of general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating microsatellite instability (MSI) cancer, preferably in the preparation of a medicament for treating high microsatellite instability (MSI-H) cancer, more preferably in the preparation of a medicament for treating high microsatellite instability (MSI-H) colorectal cancer.

[0028] Detailed Description of the Invention

[0029] Unless otherwise stated, some terms used in this invention in the specification and claims are defined as follows:

[0030] When "alkyl" is used as a group or part of a group, it refers to an aliphatic hydrocarbon group comprising C1-C20 straight chains or branches. Preferably, it is a C1-C10 alkyl group, more preferably a C1-C6 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted.

[0031] "Alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. C2-C4 alkenyl is preferred. The alkenyl group may be optionally substituted or unsubstituted.

[0032] "Alynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which can be straight-chain or branched. C2-C10 alkynyl groups are preferred, C2-C6 alkynyl groups are more preferred, and C2-C4 alkynyl groups are most preferred. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl. The alkynyl group can be substituted or unsubstituted.

[0033] "alkylene" refers to a saturated C1-C20 straight-chain or branched aliphatic hydrocarbon group having two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, preferably a C1-C10 alkylene, more preferably a C1-C6 alkylene. Examples of alkylene groups include, but are not limited to, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,4-butylene, etc. Alkylenes may be substituted or unsubstituted.

[0034] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more cyclic atoms are carbon atoms, including monocyclic, polycyclic, fused, bridged, and spirocyclic groups, preferably having a 5- to 7-membered monocyclic or a 7- to 10-membered bicyclic or tricyclic ring. Examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclopentyl, and cyclobutyl. Cycloalkyl groups may be substituted or unsubstituted.

[0035] "Spirocycloalkyl" refers to a polycyclic group with 5 to 18 nucleotides, two or more cyclic structures, in which the monocyclic rings share a carbon atom (called a spiro atom) with each other, and contains one or more double bonds within the rings, but none of the rings has fully conjugated π electrons, and is an aromatic system. Preferably, it is 6 to 14 nucleotides, more preferably 7 to 10 nucleotides. Spirocycloalkyl is classified into monospiro, bispiro, or polyspirocycloalkyl according to the number of spiro atoms shared between the rings, preferably monospiro and bispirocycloalkyl, preferably 4 nucleotides / 5 nucleotides, 4 nucleotides / 6 nucleotides, 5 nucleotides / 5 nucleotides, or 5 nucleotides / 6 nucleotides. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, and spiro[2.4]heptyl.

[0036] "Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms, wherein one or more rings may contain one or more double bonds, but none of the rings has fully conjugated π electrons, preferably a 6- to 12-membered aromatic system, more preferably a 7- to 10-membered system. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, or tetradecahydrophenanthrene.

[0037] "Bridged cycloalkyl" refers to an aromatic system consisting of 5 to 18 nucleotides, containing two or more cyclic structures, sharing two non-directly connected carbon atoms, and one or more rings may contain one or more double bonds, but none of the rings has fully conjugated π electrons. Preferably, it consists of 6 to 12 nucleotides, more preferably 7 to 10 nucleotides. More preferably, it consists of 6 to 14 nucleotides, more preferably 7 to 10 nucleotides. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, and (1r,5r)-bicyclo[3.3.2]decyl.

[0038] The terms "heterocyclic group," "heterocyclic alkyl group," "heterocycle," or "heterocyclic" are used interchangeably in this application and all refer to non-aromatic heterocyclic groups that may contain 0, 1, or more double bonds, wherein one or more of the cyclic atoms are heteroatoms selected from nitrogen, oxygen, or S(O)r (where t is selected from 0, 1, or 2), including monocyclic, polycyclic, fused, bridged, and spirocyclic groups. Preferably, it has a 3- to 8-membered monocyclic ring (more preferably a 5- to 8-membered monocyclic ring) or a 7- to 10-membered bicyclic or tricyclic ring, which may contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heterocyclic groups" include, but are not limited to, morpholino, oxetyl, thiomorpholino, tetrahydrofurano, tetrahydropyrano, 1,1-dioxo-thiomorpholino, piperidino, 2-oxo-piperidino, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, hexahydropyrimidine, etc.; Heterocyclic groups may be substituted or unsubstituted.

[0039] "Spirocycloalkyl" refers to a polycyclic group with 5 to 18 members, having two or more cyclic structures, where the monocyclic rings share an atom with each other. The rings may contain 0, 1, or more double bonds, but none of the rings has fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen, or S(O)t (where t is selected from 0, 1, or 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups according to the number of shared spiro atoms between the rings, preferably monospirocycloalkyl and bispirocycloalkyl. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl groups. Non-limiting embodiments of "spirocyclocyclic groups" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, and 5-oxaspiro[2.4]heptyl.

[0040] "Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms. One or more rings may contain 0 or more double bonds, but none of the rings has fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen, or S(O)r (where t is selected from 0, 1, or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting embodiments of "fused heterocyclic group" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrol, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, and octahydrobenzo[b][1,4]dioxine.

[0041] "Bridged heterocyclic group" refers to a polycyclic group with 5 to 14 members, or 5 to 18 members, containing two or more ring structures, sharing two atoms that are not directly connected to each other. One or more rings may contain 0 or more double bonds, but none of the rings have fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen, or S(O)t (where t is selected from 0, 1, or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting embodiments of "bridged heterocyclic group" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

[0042] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be connected together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferably, the aryl group is a C6-C10 aryl group, more preferably phenyl and naphthyl, and most preferably naphthyl. The aryl group may be substituted or unsubstituted.

[0043] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic ring, 8- to 10-membered bicyclic ring or 12- to 14-membered tricyclic ring, which may contain 1 to 4 heteroatoms selected from nitrogen, oxygen or S(O)r (where r is selected from 0, 1 or 2). Examples of "heteroaryl" compounds include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo[m]dioxacyclopentenyl, benzo[thiophene], benzimidazolyl, indoleyl, isoyindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indoleyl, benzo[isothiazolyl], benzo[oxazolyl], benzo[isothiazolyl], isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4 - Triazolyl, pyridyl, pyrimidinyl, pyrazin-2(1H)-keto, pyrimidin-4(3H)-keto, pyridazin-3(2H)-keto, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridyl, 3H-imidazo[4,5-c]pyridyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furan[3,2-b]pyridyl, furan[2,3-c]pyridyl, thieno[2,3-c]pyridyl, benzofuranyl, benzo[b]thienoyl, 1H-pyrrolo[3,2-b]pyridyl, 2H-pyrrolo[3,4-c]pyridyl.

[0044] The heteroaryl group may be substituted or unsubstituted.

[0045] A "fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms, wherein at least one ring has a fully conjugated π electron aromatic system, and one or more rings may contain 0, 1, or more double bonds, but at least one ring does not have a fully conjugated π electron aromatic system, wherein the ring atoms are selected from 0, 1, or more heteroatoms selected from nitrogen, oxygen, or S(O)r (where r is selected from 0, 1, or 2), and the remaining ring atoms are carbon. Fused rings preferably include bicyclic, tricyclic, or tetracyclic fused rings, wherein bicyclic fused rings are preferably fused rings of aryl or heteroaryl groups with monocyclic heterocyclic groups or monocyclic cycloalkyl groups. Preferably, they are 6 to 16-membered, more preferably 8 to 10-membered bicyclic fused rings or 12 to 16-membered tricyclic fused rings. Examples of "fused rings" include, but are not limited to:

[0046] "Alkoxy" refers to a (alkyl-O-) group. Alkyl groups are defined herein. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0047] "Nitro" refers to the -NO2 group.

[0048] "Hydroxy" refers to the -OH group.

[0049] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0050] "Amino" refers to -NH2.

[0051] "Cyano" refers to -CN.

[0052] "Benzyl" refers to -CH2-phenyl.

[0053] "Carboxyl group" refers to -C(O)OH.

[0054] "Carboxylic acid ester group" refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, wherein the definitions of alkyl and cycloalkyl are as described above.

[0055] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group, wherein the definition of alkyl is as described above.

[0056] "Aminoalkyl" refers to an amino-substituted alkyl group, wherein the definition of alkyl is as described above.

[0057] "Halogenated alkyl" refers to halogen-substituted alkyl, wherein the definition of alkyl is as described above.

[0058] "Haloalkoxy" refers to halogen-substituted alkoxy groups, where the definition of alkoxy groups is as described above.

[0059] "DMSO" refers to dimethyl monoxide.

[0060] "BOC" refers to tert-butoxycarbonyl.

[0061] "Bn" refers to benzyl.

[0062] "THP" refers to 2-tetrahydropyranyl.

[0063] "TFA" refers to trifluoroacetic acid.

[0064] "Ts" refers to p-toluenesulfonyl.

[0065] A "leaving group" is an atom or functional group that breaks off from a larger molecule in a chemical reaction. It is a term used in nucleophilic substitution and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks off from the substrate molecule carrying a pair of electrons is called the leaving group. Groups that readily accept electrons and have a strong ability to accept negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break off from other molecules. This is because when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to combine with other atoms, and the tendency to exist in the form of anion (or electrically neutral leaving group) is enhanced. Common leaving groups include, but are not limited to, halogens, methanesulfonyl, -OTs, or -OH.

[0066] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0067] Unless otherwise specified, “substitution” or “substituted” as used in this specification means that the group can be substituted by one or more substituents selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, SF5, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester, =O, -OCH2R3', -C(O)R3', -C(O)OR3', -NHC(O)R3', -NHC(O)OR3', -NR4'R5', -C(O)NR4'R5', -S(O)2NR4'R5', -CH2NHC(O)OR3', -CH2NR4'R5' or -S(O)rR3'; R3' is independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R6', -C(O)OR6', -OC(O)R6', -NR7'R8', -C(O)NR7'R8', -SO2NR7'R8' or -NR7'C(O)R8'; R4' and R5' are each independently selected from hydrogen atom, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R6', -C(O)OR6', -OC(O)R6', -NR7'R8', -C(O)NR7'R8', -SO2NR7'R8' or -NR7'C(O)R8'; Alternatively, R4' and R5' together with the atoms they are attached to form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R6', -C(O)OR6', -OC(O)R6', -NR7'R8', -C(O)NR7'R8', -SO2NR7'R8' or -NR7'C(O)R8';R6', R7', and R8' are each independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, or carboxylic acid ester groups; r is selected from 0, 1, or 2.

[0068] The compounds of the present invention may contain asymmetric centers or chiral centers, and thus exist in different stereoisomer forms. It is contemplated that all stereoisomer forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, atropisomers, and geometric (conformal) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0069] Unless otherwise indicated, the structure described in this invention also includes all isomers of this structure (e.g., diastereomers, enantiomers, and trans-blocking isomers and geometric (conformal) isomers; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Therefore, individual stereoisomers of the compounds of this invention, as well as mixtures of enantiomers, mixtures of diastereomers, and mixtures of geometric (conformal) isomers, are all within the scope of this invention.

[0070] "Medicinal salts" refers to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use. Medicinal salts of compounds represented by general formula (I) can be metal salts or amine salts formed with suitable acids.

[0071] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby facilitating the absorption of the active ingredient and the exertion of its biological activity.

[0072] Method for synthesizing the compounds of the present invention

[0073] In order to achieve the objective of the present invention, the present invention adopts the following technical solution:

[0074] The present invention provides a method for preparing a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically usable salts thereof, the method comprising: a condensation reaction of a compound of general formula (IA) and a compound of general formula (IB), optionally followed by a substitution reaction, to obtain a compound of general formula (I) wherein: Y1 is selected from hydroxyl or chlorine; the rings C, X, R1, R2a, R2b, W, Q, X1, X2, X3, Y, Z, m, n, p and q are defined as in general formula (I).

Implementation Method

[0076] The following embodiments are used to further describe the present invention, but these embodiments are not intended to limit the scope of the present invention.

[0077] Example

[0078] Examples provide the preparation and related structural identification data of representative compounds represented by formula (I). It must be noted that the following examples are for illustrative purposes only and not for limiting the invention. ¹H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. ¹H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If coupling constants are provided, their units are Hz.

[0079] Mass spectrometry is obtained by LC / MS instrumentation, and the ionization method can be ESI or APCI.

[0080] The thin-layer chromatography silica gel plates used are Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used in thin-layer chromatography (TLC) have a size of 0.15mm~0.2mm, and the size used for thin-layer chromatography separation and purification of products is 0.4mm~0.5mm.

[0081] Column chromatography generally uses Yantai Huanghai silicone 200~300 mesh silicone as a carrier.

[0082] In the following examples, unless otherwise specified, all temperatures are in Celsius. Unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise specified, they are purchased from manufacturers including but not limited to Aldrich Chemical Company, ABCR GmbH & Co.KG, Acros Organics, Guangzan Chemical Technology Co., Ltd., and Jingyan Chemical Technology Co., Ltd.

[0083] CD3OD: Deuterated methanol.

[0084] CDCl3: Deuterated chloroform.

[0085] DMSO-d 6: Deuterated dimethyl monoxide.

[0086] Argon atmosphere refers to a reaction flask connected to an argon balloon with a volume of approximately 1L.

[0087] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0088] The compound was purified using silicone column chromatography and reversed-phase column chromatography. The eluent system was selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: ethyl acetate system; D: trifluoroacetic acid aqueous solution and acetonitrile system. The volume ratio of the solvent varied depending on the polarity of the compound, and small amounts of acidic or basic reagents, such as acetic acid or triethylamine, could be added for adjustment.

[0089] Example 1

[0090] 1-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-9H-benzo[c]thieno[3,2-e][1,2,4]triazolo[4,3-a]azepine-11-carboxamide

[0091] 1-(benzyloxy)-N-(3-chloro-5-(methanesulfonylamino)phenyl)-9H-benzo[c]thieno[3,2-e][1,2,4]triazolo[4,3-a]aza-11-methamide

[0092] Step 1

[0093] methyl 3-(benzyloxy)-2-bromobenzoate

[0094] Methyl 3-(benzyloxy)-2-bromobenzoate

[0095] Methyl 2-bromo-3-hydroxybenzoate 1a (1.00 g, 4.33 mmol, commercially available) was dissolved in N,N-dimethylformamide (1 mL) solution, and potassium carbonate (1.20 g, 8.66 mmol) and benzyl bromide (740.27 mg, 4.33 mmol) were added sequentially. After purging with nitrogen three times, the reaction was carried out at 25 °C for 3 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: system A) to give methyl 3-(benzyloxy)-2-bromobenzoate 1b (950 mg), yield 68%.

[0096] MS m / z (ESI): 321.0 [M+1]

[0097] Second Step

[0098] methyl 5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate

[0099] Methyl 5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylic acid ester

[0100] At 25 °C, triethylsilane (10.3 g, 88.1 mmol), tert-butyl carbamate (10.3 g, 88.1 mmol), and trifluoroacetic acid (6.70 g, 58.8 mmol) were added to a solution of methyl 5-aldehydethiophene-2-carboxylate 1c (5 g, 29.4 mmol, commercially available) in dichloromethane (50 mL) / acetonitrile (50 mL). The reaction was carried out at 25 °C for 18 hours. The mixture was poured into a saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (500 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: system A) to give methyl 5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylic acid 1d (7.0 g), yield 88%.

[0101] MS m / z (ESI): 215.9 [M+1-46]

[0102] Step 3

[0103] methyl 4-bromo-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate

[0104] 4-Bromo-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylic acid methyl ester

[0105] At 25°C, N-bromobutyldiamide (9.84 g, 55.28 mmol) was added to a solution of methyl 5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylic acid ester 1d (5.00 g, 18.4 mmol) in N,N-dimethylformamide (30 mL), and the reaction was carried out at 50°C for 18 hours. The mixture was poured into water (500 mL) and extracted with ethyl acetate (400 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: system A) to give methyl 4-bromo-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylic acid ester 1e (2.5 g), yield 39%.

[0106] MS m / z (ESI): 372.0 [M+23]

[0107] 1H NMR (400 MHz, DMSO-d 6) δ 7.75 (t, J = 6.0 Hz, 1H), 7.71 (s, 1H), 4.24 (d, J = 6.0 Hz, 2H), 3.82 (s, 3H), 1.41 (s, 9H).

[0108] Step 4

[0109] methyl 4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate

[0110] 4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylic acid methyl ester

[0111] Methyl 4-bromo-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylic acid ester 1e (1.5 g, 4.28 mmol) and methyl 3-(benzyloxy)-2-bromobenzoate ester 1b (1.58 g, 4.92 mmol) were dissolved in 1,4-dioxane (15 mL). Pinacol diboronate (3.26 g, 12.85 mmol), n-butyldi(1-adamantyl)phosphine (614.24 mg, 1.71 mmol), potassium carbonate (1.78 g, 12.85 mmol), palladium acetate (192.31 mg, 856.58 μmol), and water (3 mL) were added to the resulting solution. The reaction mixture was purged with nitrogen three times and stirred at 80°C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure and purified by silicone column chromatography (eluent: system A) to give methyl 4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylic acid 1f (800 mg), yield 36%.

[0112] MS m / z (ESI): 512.2 [M+1]

[0113] Step 5

[0114] methyl 5-(aminomethyl)-4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)thiophene-2-carboxylate

[0115] Methyl 5-(aminomethyl)-4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)thiophene-2-carboxylic acid ester

[0116] Methyl 4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylic acid 1f (1.6 g, 3.13 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (356.61 mg, 3.13 mmol, 5 mL) was added to the resulting solution. The reaction solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to obtain methyl 5-(aminomethyl)-4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)thiophene-2-carboxylic acid 1g, which was used directly in the next step.

[0117] MS m / z (ESI): 412.2 [M+1]

[0118] Step Six

[0119] methyl 10-(benzyloxy)-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate

[0120] Methyl 10-(benzyloxy)-6-oxo-5,6-dihydro-4H-benzo[c]thiopheno[3,2-e]aza-2-carboxylic acid ester

[0121] 1 g of methyl 5-(aminomethyl)-4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)thiophene-2-carboxylic acid was dissolved in toluene (13 mL), and N,N-diisopropylethylamine (6.03 g, 46.65 mmol, 8.13 mL) was added to the resulting solution. The reaction mixture was stirred at 70 °C for 12 hours. The resulting mixture was concentrated under reduced pressure and purified by silicone column chromatography (eluent: system A) to give methyl 10-(benzyloxy)-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]aza-2-carboxylic acid 1 h (960 mg), with a two-step yield of 80%.

[0122] MS m / z (ESI): 380.2 [M+1]

[0123] Step Seven

[0124] methyl 1-(benzyloxy)-9H-benzo[c]thieno[3,2-e][1,2,4]triazolo[4,3-a]azepine-11-carboxylate

[0125] 1-(benzyloxy)-9H-benzo[c]thiopheno[3,2-e][1,2,4]triazolo[4,3-a]aza-11-carboxylic acid methyl ester

[0126] Methyl 10-(benzyloxy)-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]aza-2-carboxylic acid 1h (50 mg, 0.132 mmol) was dissolved in o-dichlorobenzene (3 mL), and phosphorus oxychloride (60.6 mg, 0.395 mmol) and N,N-dimethylaniline (79.8 mg, 0.659 mmol) were added to the resulting solution. The reaction solution was stirred at 130°C for 2 hours. Methylhydrazine (63.3 mg, 1.05 mmol) and N,N-diisopropylethylamine (68.1 mg, 0.527 mmol) were added to the above reaction solution, and the mixture was stirred at 100°C for 18 hours to obtain the final product. The solution was added dropwise to a saturated sodium bicarbonate aqueous solution (15 mL), and the resulting mixed solution was diluted with water (50 mL). It was then extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: system A) to give methyl 1-(benzyloxy)-9H-benzo[c]thieno[3,2-e][1,2,4]triazolo[4,3-a]aza-11-carboxylic acid ester 1i (20 mg), yield 38%.

[0127] MS m / z (ESI): 404.0 [M+1]

[0128] Step 8

[0129] 1-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-9H-benzo[c]thieno[3,2-e][1,2,4]triazolo[4,3-a]azepine-11-carboxamide

[0130] 1-(benzyloxy)-N-(3-chloro-5-(methanesulfonylamino)phenyl)-9H-benzo[c]thieno[3,2-e][1,2,4]triazolo[4,3-a]aza-11-methylamine

[0131] Methyl 1-(benzyloxy)-9H-benzo[c]thieno[3,2-e][1,2,4]triazolo[4,3-a]aza-11-carboxylic acid 1i (30.0 mg, 0.0744 mmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide 1j (32.8 mg, 0.149 mmol, prepared according to published patent "WO2023154519") were dissolved in tetrahydrofuran (5 mL), and trimethylaluminum (2 M, 0.37 mL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 60 °C for 2 hours. The reaction solution was then slowly added dropwise to methanol (50 mL) to quench the reaction. The resulting mixed solution was concentrated under reduced pressure and purified by silicone column chromatography (eluent: system A). It was then separated by preparative liquid chromatography (separation column: AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 µm, 20 mL / min; mobile phase A: 0.05 % NH4HCO3 + H2O, mobile phase B: CH3CN) to obtain 1-(benzyloxy)-N-(3-chloro-5-(methanesulfonylamino)phenyl)-9H-benzo[c]thieno[3,2-e][1,2,4]triazolo[4,3-a]aza-11-methamide 1 (20 mg), yield 45%.

[0132] MS m / z (ESI): 592.2 [M+1]

[0133] 1H NMR (400 MHz, DMSO-d 6) δ 10.40 (s, 1H), 10.23 (s, 1H), 8.65 (s, 1H), 8.53 (s, 1H), 7.67 (dd, J = 8.0, 1.2 Hz, 1H), 7.64 – 7.56 (m, 3H), 7.56 - 7.47 (m, 3H), 7.31 - 7.21 (m, 3H), 6.96 (t, J = 2.0 Hz, 1H), 5.73 (s, 1H), 5.33 (s, 1H), 5.20 (s, 1H), 5.03 (s, 1H), 3.06 (s, 3H).

[0134] Example 2

[0135] 1-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-9H-benzo[f]thieno[2,3-d][1,2,4]triazolo[4,3-a]azepine-11-carboxamide

[0136] 1-(benzyloxy)-N-(3-chloro-5-(methanesulfonylamino)phenyl)-9H-benzo[f]thiopheno[2,3-d][1,2,4]triazolo[4,3-a]aza-11-methamide

[0137] Step 1

[0138] methyl 1-(benzyloxy)-9H-benzo[f]thieno[2,3-d][1,2,4]triazolo[4,3-a]azepine-11-carboxylate

[0139] 1-(benzyloxy)-9H-benzo[f]thiopheno[2,3-d][1,2,4]triazolo[4,3-a]aza-11-carboxylic acid methyl ester

[0140] Methyl 10-(benzyloxy)-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]aza-2-carboxylic acid 1h (150 mg, 0.395 mmol) was dissolved in o-dichlorobenzene (5 mL). Phosphorus oxychloride (182 mg, 1.19 mmol) and N,N-dimethylaniline (240 mg, 1.98 mmol) were added to the resulting solution. The reaction solution was stirred at 130 °C for 3 hours to obtain a green solution. Methylhydrazine (127 mg, 2.11 mmol, commercially available) and N,N-diisopropylethylamine (204 mg, 1.58 mmol) were added to the above reaction solution, and the mixture was stirred at 110 °C for 4 hours. The solution was added dropwise to a saturated sodium bicarbonate aqueous solution (15 mL). The resulting mixed solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was dried and concentrated under reduced pressure. The solution was purified by silicone column chromatography (eluent: system B) to give methyl 1-(benzyloxy)-9H-benzo[f]thieno[2,3-d][1,2,4]triazolo[4,3-a]aza-11-carboxylic acid ester 2a (50 mg), yield: 47%.

[0141] MS m / z (ESI): 404.1 [M+1]

[0142] Second Step

[0143] 1-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-9H-benzo[f]thieno[2,3-d][1,2,4]triazolo[4,3-a]azepine-11-carboxamide

[0144] 1-(benzyloxy)-N-(3-chloro-5-(methanesulfonylamino)phenyl)-9H-benzo[f]thieno[2,3-d][1,2,4]triazolo[4,3-a]aza-11-methamide

[0145] Methyl 1-(benzyloxy)-9H-benzo[f]thieno[2,3-d][1,2,4]triazolo[4,3-a]aza-11-carboxylic acid ester 2a (50.0 mg, 0.124 mmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide 1j (54.7 mg, 0.248 mmol) were dissolved in tetrahydrofuran (5 mL), and trimethylaluminum (2 M, 0.62 mL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 60 °C for 18 hours. The reaction was quenched by slowly adding the reaction solution to methanol (50 mL). The resulting mixed solution was concentrated under reduced pressure, purified by silicone column chromatography (eluent: system B), and then separated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 µm, 20 mL / min; mobile phase A: 0.05 % NH4HCO3 + H2O, mobile phase B: CH3CN) to give 1-(benzyloxy)-N-(3-chloro-5-(methanesulfonylamino)phenyl)-9H-benzo[f]thieno[2,3-d][1,2,4]triazolo[4,3-a]aza-11-methylamine 2 (40 mg), yield: 54%.

[0146] MS m / z (ESI): 592.2 [M+1]

[0147] 1H NMR (400 MHz, DMSO-d 6) δ 10.36 (s, 1H), 10.09 (s, 1H), 8.99 (s, 1H), 8.47 (s, 1H), 7.63 - 7.57 (m, 3H), 7.55 - 7.47 (m, 2H), 7.43 - 7.35 (m, 2H), 7.30 - 7.21 (m, 3H), 6.97 (t, J = 2.0 Hz, 1H), 5.38 (d, J = 12.0 Hz, 1H), 5.19 (d, J = 12.0 Hz, 1H), 4.59 (d, J = 15.6 Hz, 1H), 3.99 (d, J = 15.6 Hz (1H), 3.06 (s, 3H).

[0148] Example 3

[0149] 1-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]azepine-11-carboxamide

[0150] 1-(benzyloxy)-N-(3-chloro-5-(methanesulfonyl)phenyl)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]aza-11-methamide

[0151] Step 1

[0152] methyl 1-(benzyloxy)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]azepine-11-carboxylate

[0153] 1-(benzyloxy)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]aza-11-carboxylic acid methyl ester

[0154] Methyl 10-(benzyloxy)-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]aza-2-carboxylic acid 1h (150 mg, 0.395 mmol) was dissolved in o-dichlorobenzene (3 mL), and phosphorus oxychloride (182 mg, 1.19 mmol) and N,N-dimethylaniline (240 mg, 1.98 mmol) were added to the resulting solution. The reaction solution was stirred at 130 °C for 2 hours. Aminoacetaldehyde dimethyl acetal (333 mg, 3.16 mmol, commercially available) and N,N-diisopropylethylamine (204 mg, 1.58 mmol) were added to the above reaction solution, and the mixture was stirred at 120 °C for 18 hours. The solution was added dropwise to a saturated sodium bicarbonate aqueous solution (15 mL). The resulting mixed solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was dried and concentrated under reduced pressure. The solution was purified by silica gel column chromatography (eluent: system B) to give methyl 1-(benzyloxy)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]aza-11-carboxylic acid ester 3a (30 mg), yield: 19%.

[0155] MS m / z (ESI): 403.2 [M+1]

[0156] Step Two

[0157] 1-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]azepine-11-carboxamide

[0158] 1-(benzyloxy)-N-(3-chloro-5-(methanesulfonylamino)phenyl)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]aza-11-methamide

[0159] Methyl 1-(benzyloxy)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]aza-11-carboxylic acid ester 3a (30.0 mg, 0.0745 mmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide 1j (32.9 mg, 0.149 mmol) were dissolved in tetrahydrofuran (5 mL), and trimethylaluminum (2 M, 0.37 mL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 60 °C for 3 hours. The reaction was quenched by slowly adding the reaction solution to methanol (50 mL). The resulting mixed solution was concentrated under reduced pressure, purified by silicone column chromatography (eluent: system B), and then separated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 µm, 20 mL / min; mobile phase A: 0.05 % NH4HCO3 + H2O, mobile phase B: CH3CN) to give 1-(benzyloxy)-N-(3-chloro-5-(methanesulfonylamino)phenyl)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]azapyr-11-methamide 3 (6 mg), yield: 14%.

[0160] MS m / z (ESI): 591.2 [M+1]

[0161] 1H NMR (400 MHz, DMSO-d 6) δ 10.37 (s, 1H), 8.53 (s, 1H), 7.66 – 7.56 (m, 4H), 7.56 – 7.46 (m, 3H), 7.43 – 7.34 (m, 2H), 7.31 – 7.23 (m, 3H), 7.03 (s, 1H), 6.95 (s, 1H), 5.65 -5.49 (m, 1H), 5.40 - 5.12 (m, 2H), 5.03 - 4.87 (m, 1H), 3.04 (s, 3H).

[0162] According to the preparation method of Example 3 of the present invention, Examples 4-5 were prepared, and the specific structures and structural characterizations are as follows: Implementation Example Numbers and Structures MS m / z (ESI) 1 H NMR 4 627.0 [M+1] 1 1H NMR (400 MHz, DMSO-d6) δ10.39 (s, 1H), 8.58 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.41 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 6.4 Hz, 2H), 7.10 (t, J = 9.2 Hz, 1H), 7.04 (s, 1H), 6.95 (t, J = 2.0 Hz, 1H), 5.66 - 5.49 (m, 1H), 5.46 - 5.30 (m, 1H), 5.26 - 5.09 (m, 1H), 5.04 - 4.86 (m, 1H), 3.04 (s, 3H). 5 609.0[M+1] 1 1H NMR (400 MHz, DMSO-d6) δ10.40 (s, 1H), 8.56 (s, 1H), 7.66 – 7.59 (m, 3H), 7.51 (t, J = 8.0 Hz, 1H), 7.43 – 7.28 (m, 5H), 7.10 – 7.02 (m, 2H), 6.96 (t, J = 1.6 Hz, 1H), 5.57 (d, J = 13.2 Hz, 1H), 5.37 (d, J = 11.2 Hz, 1H), 5.19 (d, J = 11.2 Hz, 1H), 4.94 (d, J = 13.2 Hz, 1H), 3.06 (s, 3H).

[0163] Example 6

[0164] 1-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-9,10-dihydrobenzo[f]pyrrolo[1,2-d][1,2,4]triazolo[3,4-h][1,4]diazocine-13-carboxamide

[0165] 1-(benzyloxy)-N-(3-chloro-5-(methanesulfonylamino)phenyl)-9,10-dihydrobenzo[f]pyrrolo[1,2-d][1,2,4]triazolo[3,4-h][1,4]diazoindene-13-methamide

[0166] Step 1

[0167] methyl 5-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrole-3-carboxylate

[0168] Methyl 5-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrole-3-carboxylic acid ester

[0169] Methyl 5-bromo-1H-pyrrole-3-carboxylic acid 6a (4.0 g, 19.61 mmol) was dissolved in acetonitrile (400 mL), and cesium carbonate (19.16 g, 58.82 mmol) and tert-butyl (3-bromopropyl)carbamate 6b (8.79 g, 39.21 mmol, commercially available) were added. The mixture was stirred at 80 °C for 18 hours. The reaction solution was filtered, and the filter cake was washed with acetonitrile (50 mL × 3). After concentration, the mixture was purified by silica gel column chromatography (eluent: system A) to give methyl 5-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrole-3-carboxylic acid 6c (6.0 g), yield: 88.1%.

[0170] MS m / z (ESI): 290.9 [M+1-56]

[0171] Step Two

[0172] 3-(benzyloxy)-2-bromobenzoic acid

[0173] 3-(benzyloxy)-2-bromobenzoic acid

[0174] 20.0 g (68.70 mmol) of 3-(benzyloxy)-2-bromobenzaldehyde 6d was dissolved in acetonitrile (200 mL), and periodic acid (31.32 g, 137.39 mmol, commercially available) and pyridinium chlorochromate (296 mg, 1.37 mmol, commercially available) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (200 mL), extracted with ethyl acetate (200 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: system B) to give 9.7 g (3-(benzyloxy)-2-bromobenzoic acid 6e), yield: 45.9%.

[0175] MS m / z (ESI): 307.0 [M+1]

[0176] Step 3

[0177] methyl 3-(benzyloxy)-2-bromobenzoate

[0178] Methyl 3-(benzyloxy)-2-bromobenzoate

[0179] 3-(benzyloxy)-2-bromobenzoic acid 6e (9.7 g, 31.58 mmol) was dissolved in methanol (100 mL), and concentrated sulfuric acid (1.55 g, 15.79 mmol) was added. The mixture was stirred at 80°C for 12 hours. The reaction solution was concentrated under reduced pressure and purified by silicone column chromatography (eluent: system B) to give methyl 3-(benzyloxy)-2-bromobenzoate 6f (7.8 g), yield: 76.9%.

[0180] MS m / z (ESI): 321.0 [M+1]

[0181] Step 4

[0182] methyl 5-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrole-3-carboxylate

[0183] Methyl 5-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrole-3-carboxylic acid ester

[0184] Butyl di(1-adamantyl)phosphine (2.27 g, 6.34 mmol) and palladium acetate (711.28 mg, 3.17 mmol) were dissolved in 1,4-dioxane (60 mL). The resulting mixture was purged with nitrogen three times and stirred at room temperature for 30 minutes under nitrogen protection. Then, methyl 5-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrole-3-carboxylic acid 6c (5.5 g, 15.84 mmol) and methyl 3-(benzyloxy)-2-bromobenzoate 6f (6.11 g, 19.01 mmol), pinacol diboronate (6.03 g, 23.76 mmol), potassium carbonate (6.57 g, 47.52 mmol) and water (15 mL) were added to the mixture. The reaction solution was purged with nitrogen three times and stirred at 80 °C for 2 hours under nitrogen protection. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with dichloromethane (30 mL x 2). The filtrate was purified by silicone column chromatography (eluent: system A) to give 6 g (2.4 g) of methyl 5-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrole-3-carboxylic acid, yield: 29.8%.

[0185] MS m / z (ESI): 509.2 [M+1]

[0186] Step 5

[0187] methyl 1-(2-aminoethyl)-5-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-1H-pyrrole-3-carboxylate

[0188] Methyl 1-(2-aminoethyl)-5-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-1H-pyrrole-3-carboxylic acid ester

[0189] 6 g (4.0 g, 4.72 mmol) of methyl 5-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrole-3-carboxylic acid was dissolved in dichloromethane (40 mL), and trifluoroacetic acid (15 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by reverse-phase column chromatography (eluent: system D) to give 6 h (1.2 g) of methyl 1-(2-aminoethyl)-5-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-1H-pyrrole-3-carboxylic acid, yield: 62.2%.

[0190] MS m / z (ESI): 409.2 [M+1]

[0191] Step Six

[0192] methyl 12-(benzyloxy)-8-oxo-5,6,7,8-tetrahydrobenzo[f]pyrrolo[1,2-d][1,4]diazocine-2-carboxylate

[0193] 12-(benzyloxy)-8-oxo-5,6,7,8-tetrahydrobenzo[f]pyrrolo[1,2-d][1,4]diazoindene-2-carboxylic acid methyl ester

[0194] Methyl 1-(2-aminoethyl)-5-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-1H-pyrrole-3-carboxylic acid 6 h (400 mg, 979.32 μmol) was dissolved in dioxane (10 mL), and trimethylaluminum (2 M, 3.9 mL) was slowly added dropwise. The reaction solution was heated to 100 °C and stirred for 2 hours. The reaction solution was quenched by slow dropwise addition of methanol (20 mL), and the reaction solution was concentrated under reduced pressure and purified by silicone column chromatography (eluent: system B) to give methyl 12-(benzyloxy)-8-oxo-5,6,7,8-tetrahydrobenzo[f]pyrrolo[1,2-d][1,4]diazoindene-2-carboxylic acid 6i (250 mg), yield: 67.8%.

[0195] MS m / z (ESI): 377.2 [M+1]

[0196] Step Seven

[0197] methyl 1-(benzyloxy)-9,10-dihydrobenzo[f]pyrrolo[1,2-d][1,2,4]triazolo[3,4-h][1,4]diazocine-13-carboxylate

[0198] 2-(benzyloxy)-8-oxo-5,6,7,8-tetrahydrobenzo[f]pyrrolo[1,2-d][1,4]diazoinden-2-carboxylic acid

[0199] Methyl 12-(benzyloxy)-8-oxo-5,6,7,8-tetrahydrobenzo[f]pyrrolo[1,2-d][1,4]diazoindene-2-carboxylate 6i (100 mg, 0.266 mmol) was dissolved in toluene (5 mL). Phosphorus oxychloride (163 mg, 1.06 mmol) and N,N-dimethylaniline (96.6 mg, 0.797 mmol) were added to the resulting solution. The reaction mixture was stirred at 90 °C for 2 hours. Methylhydrazine (121 mg, 2.03 mmol) and N,N-diisopropylethylamine (131 mg, 1.01 mmol) were added to the above reaction mixture, and the mixture was stirred at 90 °C for 18 hours. The solution was added dropwise to a saturated sodium bicarbonate aqueous solution (15 mL). The resulting mixed solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was dried and concentrated under reduced pressure. It was purified by silicone column chromatography (eluent: system B) to give 12-(benzyloxy)-8-oxo-5,6,7,8-tetrahydrobenzo[f]pyrrolo[1,2-d][1,4]diazoindene-2-carboxylic acid 6j (30 mg), yield: 30%.

[0200] MS m / z (ESI): 401.1 [M+1]

[0201] Step 8

[0202] 1-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-9,10-dihydrobenzo[f]pyrrolo[1,2-d][1,2,4]triazolo[3,4-h][1,4]diazocine-13-carboxamide

[0203] 1-(benzyloxy)-N-(3-chloro-5-(methanesulfonylamino)phenyl)-9,10-dihydrobenzo[f]pyrrolo[1,2-d][1,2,4]triazolo[3,4-h][1,4]diazoindene-13-methamide

[0204] 12-(benzyloxy)-8-oxo-5,6,7,8-tetrahydrobenzo[f]pyrrolo[1,2-d][1,4]diazoindene-2-carboxylic acid 6j (30.0 mg, 0.0749 mmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide 1j (33.1 mg, 0.150 mmol) were dissolved in tetrahydrofuran (5 mL), and trimethylaluminum (2 M, 0.37 mL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 60 °C for 18 hours. The reaction solution was then slowly added dropwise to methanol (50 mL) to quench the reaction. The resulting mixed solution was concentrated under reduced pressure, purified by silicone column chromatography (eluent: system B), and then separated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 µm, 20 mL / min; mobile phase A: 0.05 % NH4HCO3 + H2O, mobile phase B: CH3CN) to give 1-(benzyloxy)-N-(3-chloro-5-(methanesulfonylamino)phenyl)-9,10-dihydrobenzo[f]pyrrolo[1,2-d][1,2,4]triazolo[3,4-h][1,4]diazoind-13-methamide 6 (10 mg), yield: 23%.

[0205] MS m / z (ESI): 589.2 [M+1]

[0206] 1H NMR (400 MHz, DMSO-d 6) δ 10.00 (s, 1H), 9.78 (s, 1H), 8.45 (s, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.66 (t, J = 1.6 Hz, 1H), 7.56 (t, J = 1.6 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.37 - 7.31 (m, 4H), 7.30 - 7.24 (m, 1H), 7.22 (d, J = 7.6 Hz, 1H), 6.88 (t, J = 1.6 Hz, 1H), 6.79 (d, J = 1.6 Hz, 1H), 5.20 (q, J = 12.8 Hz, 2H), 4.69 - 4.57 (m, 1H), 4.54 - 4.43 (m, 1H), 4.28 - 4.18 (m, 1H), 4.13 - 3.99 (m, 1H), 3.04 (s, 3H)

[0207] According to the preparation method of Embodiment 6 of the present invention, Embodiment 7 is prepared, and the specific structure and structural characteristics are as follows: Implementation Case Numbering and Structure MS m / z (ESI) 1 H NMR 7 607.1 [M+1] 1H NMR (400 MHz, DMSO-d6) δ9.99 (s, 1H), 9.79 (s, 1H), 8.45 (s, 1H), 7.75 (d,J= 1.6 Hz, 1H), 7.66 (t,J= 1.6 Hz, 1H), 7.61 – 7.51 (m, 2H), 7.44 – 7.30 (m, 2H), 7.24 (d,J= 7.2 Hz, 1H), 7.20 – 7.05 (m, 3H), 6.89 (t,J= 2.0 Hz, 1H), 6.82 (d,J= 1.6 Hz, 1H), 5.23 (dd,J= 27.6, 13.2 Hz, 2H), 4.73 – 4.58 (m, 1H), 4.55 – 4.42 (m, 1H), 4.31 – 4.17 (m, 1H), 4.16 – 3.98 (m, 1H), 3.05 (s, 3H).

[0208] Example 8

[0209] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]imidazo[1,2-a]pyrrolo[1,2-d][1,4]diazepine-12-carboxamide

[0210] N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]imidazo[1,2-a]pyrrolo[1,2-d][1,4]diaza-12-methylamine

[0211] Step 1

[0212] methyl 5-bromo-1-(2-methoxy-2-oxoethyl)-1H-pyrrole-3-carboxylate

[0213] Methyl 5-bromo-1-(2-methoxy-2-oxoethyl)-1H-pyrrole-3-carboxylic acid ester

[0214] Methyl 5-bromo-1H-pyrrole-3-carboxylic acid 6a (5.0 g, 24.51 mmol) and cesium carbonate (23.95 g, 73.52 mmol) were dissolved in acetonitrile (100 mL). Methyl bromoacetate (7.5 g, 49.01 mmol, commercially available) was added to the resulting mixture. The reaction solution was stirred at 80 °C for 18 hours. The reaction solution was filtered, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure and purified by silicone column chromatography (eluent: system A) to give methyl 5-bromo-1-(2-methoxy-2-oxyethyl)-1H-pyrrole-3-carboxylic acid 8a (4.0 g), yield: 59%.

[0215] MS m / z (ESI): 275.9 [M+1]

[0216] Step Two

[0217] 2-bromo-1-((3,5-difluorobenzyl)oxy)-3-nitrobenzene

[0218] 2-Bromo-1-((3,5-difluorobenzyl)oxy)-3-nitrobenzene

[0219] 2-Bromo-3-nitrophenol 8b (5 g, 22.94 mmol) was dissolved in acetonitrile (45 mL), and cesium carbonate (14.95 g, 45.87 mmol) and 3,5-difluorobenzyl chloride (5.59 g, 34.40 mmol, commercially available) were added to the resulting solution. The reaction mixture was stirred at 80 °C for 18 hours. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (50 mL). The resulting filtrate was concentrated under reduced pressure and purified by silicone column chromatography (eluent: system A) to give 2-bromo-1-((3,5-difluorobenzyl)oxy)-3-nitrobenzene 8c (6.7 g), yield: 85%.

[0220] MS m / z (ESI): no signal

[0221] Step 3

[0222] 2-bromo-3-((3,5-difluorobenzyl)oxy)aniline

[0223] 2-Bromo-3-((3,5-difluorobenzyl)oxy)aniline

[0224] 2-Bromo-1-((3,5-difluorobenzyl)oxy)-3-nitrobenzene 8c (6.7 g, 19.47 mmol), iron powder (3.26 g, 58.41 mmol), and ammonium chloride (3.12 g, 58.41 mmol) were dissolved in ethanol (120 mL), and water (40 mL) was added to the resulting mixture. The reaction solution was stirred at 90 °C for 18 hours. The reaction solution was filtered, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure and purified by silicone column chromatography (eluent: system A) to obtain 2-bromo-3-((3,5-difluorobenzyl)oxy)aniline 8d (5.0 g), yield: 82%.

[0225] MS m / z (ESI): 314.0 [M+1]

[0226] Step 4

[0227] methyl 11-((3,5-difluorobenzyl)oxy)-6-oxo-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[0228] 11-((3,5-difluorobenzyl)oxy)-6-oxo-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2-carboxylic acid methyl ester

[0229] 2-Bromo-3-((3,5-difluorobenzyl)oxy)aniline 8d (1 g, 3.18 mmol), methyl 5-bromo-1-(2-methoxy-2-oxoethyl)-1H-pyrrole-3-carboxylic acid 8a (1.76 g, 6.37 mmol), pinacol diboronate (2.43 g, 9.55 mmol), and potassium carbonate (1.32 g, 9.55 mmol) were dissolved in dioxane (10 mL) and water (2 mL). Methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (0.46 g, 0.64 mmol, commercially available)) was added to the resulting mixture. After purging with nitrogen three times, the reaction solution was stirred at 80 °C for 18 hours. The reaction solution was concentrated under reduced pressure and purified by silicone column chromatography (eluent: system A) to obtain methyl 1-((3,5-difluorobenzyl)oxy)-6-oxo-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2-carboxylic acid 8e (450 mg), yield: 35%.

[0230] MS m / z (ESI): 399.1 [M+1]

[0231] Step 5

[0232] methyl 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]imidazo[1,2-a]pyrrolo[1,2-d][1,4]diazepine-12-carboxylate

[0233] 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]imidazo[1,2-a]pyrrolo[1,2-d][1,4]diaza-12-carboxylic acid methyl ester

[0234] Methyl 1-((3,5-difluorobenzyl)oxy)-6-oxo-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2-carboxylic acid 8e (200 mg, 0.50 mmol) was dissolved in o-dichlorobenzene (5 mL), and phosphorus oxychloride (0.14 mL, 1.51 mmol) and N,N-dimethylaniline (304 mg, 2.51 mmol) were added to the resulting solution. The reaction solution was stirred at 130 °C for 2 hours. Aminoacetaldehyde dimethyl acetal (528 mg, 5.02 mmol, commercially available) and N,N-diisopropylethylamine (324 mg, 2.51 mmol) were added to the above reaction solution, and the mixture was stirred at 130 °C for 18 hours. The solution was added dropwise to water (100 mL), extracted with ethyl acetate (100 mL), the organic phase was dried and concentrated under reduced pressure, and purified by silicone column chromatography (eluent: system A) to give methyl 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]imidazo[1,2-a]pyrrolo[1,2-d][1,4]diaza-12-carboxylic acid 8f (110 mg), yield: 52%.

[0235] MS m / z (ESI): 422.1 [M+1]

[0236] Step Six

[0237] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]imidazo[1,2-a]pyrrolo[1,2-d][1,4]diazepine-12-carboxamide

[0238] N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]imidazo[1,2-a]pyrrolo[1,2-d][1,4]diaza-12-methamide

[0239] Methyl 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]imidazo[1,2-a]pyrrolo[1,2-d][1,4]diaza-12-carboxylic acid 8f (50 mg, 0.19 mmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide 1j (62.8 mg, 0.28 mmol) were dissolved in tetrahydrofuran (5 mL), and trimethylaluminum (1 M, 1.14 mL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 60 °C for 2 hours. The reaction solution was then slowly added dropwise to methanol (20 mL) to quench the reaction. The resulting mixed solution was concentrated under reduced pressure, purified by silicone column chromatography (eluent: system B), and then separated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 µm, 20 mL / min; mobile phase A: 0.05 % NH4HCO3 + H2O, mobile phase B: CH3CN) to obtain N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]imidazo[1,2-a]pyrrolo[1,2-d][1,4]diaza-12-methamide 8 (53.6 mg), yield: 46%.

[0240] MS m / z (ESI): 610.1 [M+1]

[0241] 1H NMR (400 MHz, DMSO-d 6) δ 10.00 (s, 1H), 9.84 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 2.0 Hz, 2H), 7.61 (t, J = 2.0 Hz, 1H), 7.53 (t, J = 8.2 Hz, 1H), 7.31 – 7.23 (m, 3H), 7.23 – 7.11 (m, 3H), 7.02 (d, J = 1.6 Hz, 1H), 6.89 (t, J = 2.0 Hz, 1H), 5.46 (d, J = 15.2 Hz, 1H), 5.40 (d, J = 13.2 Hz, 1H), 5.22 (d, J = 13.2 Hz, 1H), 5.01 (d, J = 15.2 Hz, 1H), 3.05 (s, 3H).

[0242] Example 9

[0243] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]diazepine-12-carboxamide

[0244] N-(3-chloro-5-(methylsulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]diazamine-12-methylamine

[0245] Step 1

[0246] methyl 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]diazepine-12-carboxylate

[0247] 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]diaza-12-carboxylic acid methyl ester

[0248] Methyl 1-((3,5-difluorobenzyl)oxy)-6-oxo-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2-carboxylic acid 8e (80 mg, 0.20 mmol) was dissolved in o-dichlorobenzene (5 mL), and phosphorus oxychloride (0.06 mL, 0.60 mmol) and N,N-dimethylaniline (122 mg, 1.00 mmol) were added to the resulting solution. The reaction solution was stirred at 130 °C for 2 hours. Methylhydrazine (121 mg, 2.01 mmol) and N,N-diisopropylethylamine (130 mg, 1.00 mmol) were added to the above reaction solution, and the mixture was stirred at 130 °C for 18 hours. The solution was added dropwise to water (100 mL), extracted with ethyl acetate (100 mL), and the organic phase was dried and concentrated under reduced pressure. After purification by silicone column chromatography (eluent: system A), methyl 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]diaza-12-carboxylic acid 9a (40 mg) was obtained, with a yield of 47%.

[0249] MS m / z (ESI): 423.2 [M+1]

[0250] Step Two

[0251] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]diazepine-12-carboxamide

[0252] N-(3-chloro-5-(methylsulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]diazamine-12-methylamine

[0253] Methyl 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]diaza-12-carboxylic acid 9a (40 mg, 0.09 mmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide 1j (31.4 mg, 0.14 mmol) were dissolved in tetrahydrofuran (2 mL), and trimethylaluminum (1 M, 0.47 mL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 60 °C for 2 hours. The reaction was quenched by slowly adding the reaction solution to methanol (20 mL). The resulting mixed solution was concentrated under reduced pressure, purified by silicone column chromatography (eluent: system B), and then separated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 µm, 20 mL / min; mobile phase A: 0.05 % NH4HCO3 + H2O, mobile phase B: CH3CN) to obtain N-(3-chloro-5-(methylsulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]diazamine-12-methylamine 9 (10.7 mg), yield: 18%.

[0254] MS m / z (ESI): 611.1 [M+1]

[0255] 1H NMR (400 MHz, DMSO-d 6) δ 10.02 (s, 1H), 9.90 (s, 1H), 9.08 (s, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.71 – 7.65 (m, 1H), 7.65 – 7.52 (m, 2H), 7.44 – 7.28 (m, 3H), 7.28 – 7.09 (m, 3H), 6.92 (t, J = 2.0 Hz, 1H), 5.80 (d, J = 15.2 Hz, 1H), 5.44 (d, J = 13.2 Hz, 1H), 5.31 – 5.13 (m, 2H), 3.07 (s, 3H).

[0256] Example 10

[0257] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d]tetrazolo[1,5-a][1,4]diazepine-12-carboxamide

[0258] N-(3-chloro-5-(methylsulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d]tetrazo[1,5-a][1,4]diazamine-12-methylamine

[0259] Step 1

[0260] methyl 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d]tetrazolo[1,5-a][1,4]diazepine-12-carboxylate

[0261] 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d]tetrazolo[1,5-a][1,4]diaza-12-carboxylic acid methyl ester

[0262] Methyl 1-((3,5-difluorobenzyl)oxy)-6-oxo-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2-carboxylic acid 8e (100 mg, 0.25 mmol) was dissolved in pyridine (2 mL), and diphenyl azidophosphate (138 mg, 0.50 mmol, commercially available) was added to the resulting solution. The reaction mixture was stirred at 120 °C for 18 hours. The solution was added dropwise to water (100 mL), extracted with ethyl acetate (100 mL), and the organic phase was dried and concentrated under reduced pressure. After purification by silicone column chromatography (eluent: system A), methyl 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d]tetrazo[1,5-a][1,4]diaza-12-carboxylic acid ester 10a (80 mg) was obtained, with a yield of 76%.

[0263] MS m / z (ESI): 424.1 [M+1]

[0264] Second Step

[0265] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d]tetrazolo[1,5-a][1,4]diazepine-12-carboxamide

[0266] N-(3-chloro-5-(methylsulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d]tetrazo[1,5-a][1,4]diazamine-12-methylamine

[0267] Methyl 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d]tetrazo[1,5-a][1,4]diaza-12-carboxylic acid ester 10a (80.0 mg, 0.19 mmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide 1j (62.6 mg, 0.28 mmol) were dissolved in tetrahydrofuran (2 mL), and trimethylaluminum (1 M, 1.13 mL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 60 °C for 2 hours. The reaction solution was then slowly added dropwise to methanol (20 mL) to quench the reaction. The resulting mixed solution was concentrated under reduced pressure, purified by silicone column chromatography (eluent: system B), and then separated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 µm, 20 mL / min; mobile phase A: 0.05 % NH4HCO3 + H2O, mobile phase B: CH3CN) to give N-(3-chloro-5-(methylsulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d]tetrazo[1,5-a][1,4]diazamine-12-methylamine 10 (40.7 mg), yield: 35%.

[0268] MS m / z (ESI): 612.1 [M+1]

[0269] 1H NMR (400 MHz, DMSO-d 6) δ 10.00 (s, 1H), 9.92 (s, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.69 – 7.62 (m, 2H), 7.62 – 7.55 (m, 2H), 7.46 (dd, J = 8.0, 1.2 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.28 – 7.11 (m, 3H), 6.90 (t, J = 2.0 Hz, 1H), 6.08 (bs, 1H), 5.37 (bs, 3H), 3.05 (s, 3H).

[0270] Example 11

[0271] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-6-oxo-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diazepine-12-carboxamide

[0272] N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-6-oxo-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diaza-12-methylamine

[0273] Step 1

[0274] methyl 5-bromo-1-(5-methoxy-2,5-dioxopentyl)-1H-pyrrole-3-carboxylate

[0275] Methyl 5-bromo-1-(5-methoxy-2,5-dioxopentyl)-1H-pyrrole-3-carboxylic acid ester

[0276] Methyl 5-bromo-1H-pyrrole-3-carboxylic acid 6a (1.00 g, 4.90 mmol) (XHB020) was dissolved in acetonitrile (20 mL). Methyl 5-bromo-4-oxopentanoate 11a (1.54 g, 7.35 mmol, commercially available) and potassium carbonate (3.19 g, 9.80 mmol) were added to the resulting solution. The reaction mixture was stirred at 60 °C for 1 hour. The system was filtered and concentrated under reduced pressure, then purified by silicone column chromatography (eluent: system A) to give methyl 5-bromo-1-(5-methoxy-2,5-dioxopentyl)-1H-pyrrole-3-carboxylic acid 11b (1.0 g), yield: 61%.

[0277] MS m / z (ESI): 332.0 [M+1]

[0278] Second Step

[0279] methyl 11-((3,5-difluorobenzyl)oxy)-6-(3-methoxy-3-oxopropyl)-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[0280] 11-((3,5-difluorobenzyl)oxy)-6-(3-methoxy-3-oxopropyl)-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2-carboxylic acid methyl ester

[0281] Methyl 11b of 5-bromo-1-(5-methoxy-2,5-dioxopentyl)-1H-pyrrole-3-carboxylic acid (820 mg, 2.47 mmol) was dissolved in 1,4-dioxane (20 mL). To the resulting solution, 8d of 2-bromo-3-((3,5-difluorobenzyl)oxy)aniline (1.61 g, 4.94 mmol), pinacol diborate (1.88 g, 7.41 mmol), n-butylbis(1-adamantyl)phosphine (354 mg, 0.988 mmol, commercially available), potassium carbonate (1.02 g, 7.41 mmol), palladium acetate (111 mg, 0.494 mmol), and water (2 mL) were added. The reaction mixture was purged with nitrogen three times and stirred at 80 °C for 18 hours under nitrogen protection. The resulting mixed solution was filtered and concentrated under reduced pressure, then purified by silicone column chromatography (eluent: system A) to give methyl 11-((3,5-difluorobenzyl)oxy)-6-(3-methoxy-3-oxopropyl)-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2-carboxylic acid 11c (300 mg), yield: 25%.

[0282] MS m / z (ESI): 469.1 [M+1]

[0283] Step 3

[0284] methyl 11-((3,5-difluorobenzyl)oxy)-6-(3-methoxy-3-oxopropyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[0285] 11-((3,5-difluorobenzyl)oxy)-6-(3-methoxy-3-oxopropyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2-carboxylic acid methyl ester

[0286] Methyl 11-((3,5-difluorobenzyl)oxy)-6-(3-methoxy-3-oxypropyl)-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2-carboxylic acid ester 11c (60 mg, 0.128 mmol) and 10% palladium on carbon (30 mg, 0.282 mmol) were dissolved in methanol (3 mL). After hydrogen purging, the reaction solution was placed at 25 °C for 18 hours. The mixed solution was filtered, and the filtrate was concentrated under reduced pressure to give methyl 11-((3,5-difluorobenzyl)oxy)-6-(3-methoxy-3-oxypropyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2-carboxylic acid ester 11d (40 mg), yield: 67%.

[0287] MS m / z (ESI): 471.1 [M+1]

[0288] Step 4

[0289] methyl 1-((3,5-difluorobenzyl)oxy)-6-oxo-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diazepine-12-carboxylate

[0290] 1-((3,5-difluorobenzyl)oxy)-6-oxo-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diaza-12-carboxylic acid methyl ester

[0291] Methyl 11d of 11-((3,5-difluorobenzyl)oxy)-6-(3-methoxy-3-oxopropyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2-carboxylic acid 11d (80 mg, 0.170 mmol) was dissolved in tetrahydrofuran (8 mL), and trimethylaluminum (2 M, 0.85 mL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 60 °C for 36 hours. The reaction solution was then quenched by slowly adding methanol (50 mL). The resulting mixed solution was concentrated under reduced pressure and purified by silicone column chromatography (eluent: system A) to give methyl 1-((3,5-difluorobenzyl)oxy)-6-oxo-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diaza-12-carboxylic acid ester 11e (50 mg), yield: 67%.

[0292] MS m / z (ESI): 439.0 [M+1]

[0293] Step 5

[0294] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-6-oxo-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diazepine-12-carboxamide

[0295] N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-6-oxo-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diaza-12-methamide

[0296] Methyl 1-((3,5-difluorobenzyl)oxy)-6-oxo-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diaza-12-carboxylic acid ester 11e (30 mg, 0.068 mmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide 1j (30.2 mg, 0.136 mmol) were dissolved in tetrahydrofuran (7 mL), and trimethylaluminum (2 M, 0.34 mL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 60 °C for 18 hours. The reaction solution was then slowly added dropwise to methanol (30 mL) to quench the reaction. The resulting mixed solution was concentrated under reduced pressure, purified by silicone column chromatography (eluent: system B), and then separated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 µm, 20 mL / min; mobile phase A: 0.05 % NH4HCO3 + H2O, mobile phase B: CH3CN) to obtain N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-6-oxo-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diaza-12-methamide 11 (13.5 mg), yield: 31%.

[0297] MS m / z (ESI): 627.1 [M+1]

[0298] 1H NMR (400 MHz, DMSO-d 6) δ 9.95 (s, 1H), 9.83 (s, 1H), 7.79 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.61 (s, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.23 – 7.11 (m, 4H), 7.07 (d, J = 1.6 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.89 (t, J = 2.0 Hz, 1H), 5.33 (d, J = 13.6 Hz, 1H), 5.19 (d, J = 13.6 Hz, 1H), 4.42 – 4.34 (m, 1H), 4.18 (d, J = 14.8 Hz, 1H), 4.04 (dd, J = 14.8, 4.8 Hz, 1H), 3.05 (s, 3H), 2.56 – 2.51 (m, 1H), 2.26 – 2.12 (m, 2H), 1.78 – 1.63 (m, 1H).

[0299] Implementation Example 12

[0300] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diazepine-12-carboxamide

[0301] N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diaza-12-methylamine

[0302] Step 1

[0303] methyl 1-((3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diazepine-12-carboxylate

[0304] 1-((3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diaza-12-carboxylic acid methyl ester

[0305] Methyl 1-((3,5-difluorobenzyl)oxy)-6-oxo-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diaza-12-carboxylic acid ester 11e (30.0 mg, 0.0684 mmol) was dissolved in boranetetrahydrofuran solution (3 mL, 1M), and the reaction solution was placed at 60 °C for 2 hours. The mixed solution was quenched dropwise with methanol (20 mL), and the solution was concentrated under reduced pressure. After purification by silicone column chromatography (eluent: system A), 1-((3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diaza-12-carboxylic acid methyl ester 12a (25 mg) was obtained, with a yield of 86%.

[0306] MS m / z (ESI): 425.2 [M+1]

[0307] Step Two

[0308] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diazepine-12-carboxamide

[0309] N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diaza-12-methylamine

[0310] Methyl 1-((3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diaza-12-carboxylic acid ester 12a (30 mg, 0.0707 mmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide 1j (44.0 mg, 0.199 mmol) were dissolved in tetrahydrofuran (5.0 mL), and trimethylaluminum (2 M, 0.35 mL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 60 °C for 2 hours. The reaction solution was then slowly added dropwise to methanol (30 mL) to quench the reaction. The resulting mixed solution was concentrated under reduced pressure, purified by silicone column chromatography (eluent: system B), and then separated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 µm, 20 mL / min; mobile phase A: 0.05 % NH4HCO3 + H2O, mobile phase B: CH3CN) to obtain N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diaza-12-methamide 12 (7.3 mg), yield: 17%.

[0311] MS m / z (ESI): 613.1 [M+1]

[0312] 1H NMR (400 MHz, DMSO-d 6) δ 9.84 (s, 1H), 9.78 (s, 1H), 7.67 (t, J = 2.0 Hz, 1H), 7.66 - 7.61 (m, 2H), 7.25 - 7.09 (m, 4H), 7.07 (d, J = 2.0 Hz, 1H), 6.89 (t, J = 2.0 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 5.20 (d, J = 13.6 Hz, 1H), 5.12 (d, J = 13.6 Hz, 1H), 4.22 (dd, J = 14.0, 2.6 Hz, 1H), 4.03 (dd, J = 14.0, 5.6 Hz, 1H), 3.50 - 3.41 (m, 1H), 3.31 - 3.23 (m, 2H), 3.06 (s, 3H), 2.11 - 2.00 (m, 1H), 1.98 – 1.87 (m, 1H), 1.87 – 1.77 (m, 1H), 1.70 – 1.57 (m, 1H).

[0313] Implementation Example 13

[0314] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-6-oxo-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazino[4,3-a]pyrrolo[1,2-d][1,4]diazepine-13-carboxamide

[0315] N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-6-oxo-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazin[4,3-a]pyrrolo[1,2-d][1,4]diazazo-13-methamide

[0316] Step 1

[0317] methyl 5-bromo-1-(2-hydroxy-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylate

[0318] Methyl 5-bromo-1-(2-hydroxy-3-methoxy-3-oxypropyl)-1H-pyrrole-3-carboxylic acid ester

[0319] Methyl 5-bromo-1H-pyrrole-3-carboxylic acid 6a (2.00 g, 9.80 mmol) (XHB20) was dissolved in acetonitrile (20 mL). 1,8-diazobisspirocyclic [5.4.0]undecyl-7-ene (4.48 g, 29.4 mmol, commercially available) and methyl 2,3-epoxypropionate 13a (2.50 g, 24.5 mmol, commercially available) were added to the resulting solution. The reaction mixture was stirred at 60 °C for 3 hours. The system was filtered and concentrated under reduced pressure, then purified by silicone column chromatography (eluent: system A) to give methyl 5-bromo-1-(2-hydroxy-3-methoxy-3-oxypropyl)-1H-pyrrole-3-carboxylic acid 13b (1.7 g), yield: 57%.

[0320] MS m / z (ESI): 306.0 [M+1]

[0321] Step Two

[0322] methyl 5-(2-amino-6-((3,5-difluorobenzyl)oxy)phenyl)-1-(2-hydroxy-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylate

[0323] Methyl 5-(2-amino-6-((3,5-difluorobenzyl)oxy)phenyl)-1-(2-hydroxy-3-methoxy-3-oxypropyl)-1H-pyrrole-3-carboxylic acid ester

[0324] Methyl 5-bromo-1-(2-hydroxy-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylic acid ester 13b (800 mg, 2.61 mmol) was dissolved in 1,4-dioxane (10 mL). To the resulting solution, 2-bromo-3-((3,5-difluorobenzyl)oxy)aniline 8d (1.07 g, 3.40 mmol), pinacol diborate (1.99 g, 7.84 mmol), n-butyldi(1-adamantyl)phosphine (375 mg, 1.05 mmol), potassium carbonate (1.08 g, 7.84 mmol), palladium acetate (117 mg, 0.523 mmol), and water (1 mL) were added. The reaction mixture was purged three times with nitrogen and stirred at 80 °C for 18 hours under nitrogen protection. The resulting mixed solution was filtered and concentrated under reduced pressure, and then purified by silicone column chromatography (eluent: system A) to give methyl 5-(2-amino-6-((3,5-difluorobenzyl)oxy)phenyl)-1-(2-hydroxy-3-methoxy-3-oxypropyl)-1H-pyrrole-3-carboxylic acid 13c (350 mg), yield: 29%.

[0325] MS m / z (ESI): 461.1 [M+1]

[0326] Step 3

[0327] methyl 5-(2-amino-6-((3,5-difluorobenzyl)oxy)phenyl)-1-(2-bromo-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylate

[0328] Methyl 5-(2-amino-6-((3,5-difluorobenzyl)oxy)phenyl)-1-(2-bromo-3-methoxy-3-oxypropyl)-1H-pyrrole-3-carboxylic acid ester

[0329] Methyl 5-(2-amino-6-((3,5-difluorobenzyl)oxy)phenyl)-1-(2-hydroxy-3-methoxy-3-oxypropyl)-1H-pyrrole-3-carboxylic acid ester 13c (500 mg, 1.09 mmol) was dissolved in tetrahydrofuran (20 mL). Carbon tetrabromide (540 mg, 1.63 mmol) and triphenylphosphine (854 mg, 3.26 mmol) were added to the resulting solution. The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain methyl 5-(2-amino-6-((3,5-difluorobenzyl)oxy)phenyl)-1-(2-bromo-3-methoxy-3-oxypropyl)-1H-pyrrole-3-carboxylic acid ester 13d (1.2 g), which was directly used in the next step of the reaction.

[0330] MS m / z (ESI): 523.2 [M+1]

[0331] Step Four

[0332] dimethyl 11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2,6-dicarboxylate

[0333] 11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2,6-dicarboxylic acid dimethyl ester

[0334] At 25 °C, cesium carbonate (374 mg, 1.15 mmol) was added to a tetrahydrofuran (10 mL) solution of methyl 5-(2-amino-6-((3,5-difluorobenzyl)oxy)phenyl)-1-(2-bromo-3-methoxy-3-oxypropyl)-1H-pyrrole-3-carboxylic acid ester 13d (1.2 g, crude). The reaction was carried out at 60 °C for 3 hours. The resulting mixed solution was filtered, concentrated under reduced pressure, and purified by silicone column chromatography (eluent: system A) to give 11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2,6-dicarboxylic acid dimethyl ester 13e (70 mg), yield: 15%.

[0335] MS m / z (ESI): 443.1 [M+1]

[0336] Step 5

[0337] methyl 11-((3,5-difluorobenzyl)oxy)-6-(hydroxymethyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[0338] 11-((3,5-difluorobenzyl)oxy)-6-(hydroxymethyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2-carboxylic acid methyl ester

[0339] At 25 °C, sodium borohydride (128 mg, 3.39 mmol) was added to a methanol (8.0 mL) solution of 11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2,6-dicarboxylic acid dimethyl ester 13e (300 mg, 0.678 mmol), and the reaction was carried out for 2 hours. The reaction solution was concentrated under reduced pressure and purified by silicone column chromatography (eluent: system A) to give 11-((3,5-difluorobenzyl)oxy)-6-(hydroxymethyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2-carboxylic acid methyl ester 13f (70 mg), yield: 25%.

[0340] MS m / z (ESI): 415.2 [M+1]

[0341] Step Six

[0342] methyl 1-((3,5-difluorobenzyl)oxy)-6-oxo-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazino[4,3-a]pyrrolo[1,2-d][1,4]diazepine-13-carboxylate

[0343] 1-((3,5-difluorobenzyl)oxy)-6-oxo-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazin[4,3-a]pyrrolo[1,2-d][1,4]diaza-13-carboxylic acid methyl ester

[0344] Methyl 11-((3,5-difluorobenzyl)oxy)-6-(hydroxymethyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2-carboxylic acid 13f (40 mg, 0.0965 mmol) was dissolved in tetrahydrofuran (6.0 mL). Methyl chloroacetate (62.9 mg, 0.579 mmol, commercially available) and potassium tert-butoxide (65.0 mg, 0.579 mmol) were added to the resulting solution. The reaction mixture was stirred at 25 °C for 2 hours. The resulting mixed solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was dried and concentrated under reduced pressure. After purification by silicone column chromatography (eluent: system A), 13 g (30 mg) of methyl 1-((3,5-difluorobenzyl)oxy)-6-oxo-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazin[4,3-a]pyrrolo[1,2-d][1,4]diaza-13-carboxylic acid was obtained, with a yield of 68%.

[0345] MS m / z (ESI): 455.0 [M+1]

[0346] 1H NMR (400 MHz, DMSO-d 6) δ 7.75 (d, J = 1.6 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.25 – 7.09 (m, 4H), 7.02 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 1.6 Hz, 1H), 5.32 (d, J = 13.2 Hz, 1H), 5.18 (d, J = 13.2 Hz, 1H), 4.44 – 4.31 (m, 1H), 4.24 – 4.14 (m, 3H), 3.96 (d, J = 16.8 Hz, 1H), 3.84 (dd, J = 14.8, 5.6 Hz, 1H), 3.73 (s, 3H), 3.48 (t, J = 12.0 Hz, 1H).

[0347] Step Seven

[0348] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-6-oxo-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazino[4,3-a]pyrrolo[1,2-d][1,4]diazepine-13-carboxamide

[0349] N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-6-oxo-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazin[4,3-a]pyrrolo[1,2-d][1,4]diaza-13-methamide

[0350] 13 g (20 mg, 0.0440 mmol) of methyl 1-((3,5-difluorobenzyl)oxy)-6-oxo-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazin[4,3-a]pyrrolo[1,2-d][1,4]diaza-13-carboxylic acid and 1 j (19.4 mg, 0.0880 mmol) of N-(3-amino-5-chlorophenyl)methanesulfonamide were dissolved in tetrahydrofuran (5 mL). Trimethylaluminum (2 M, 0.22 mL) was slowly added dropwise to the resulting mixture. The reaction mixture was stirred at 60 °C for 18 hours. The reaction was quenched by slowly adding the reaction mixture to methanol (30 mL). The resulting mixed solution was concentrated under reduced pressure, purified by silicone column chromatography (eluent: system B), and then separated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 µm, 20 mL / min; mobile phase A: 0.05 % NH4HCO3 + H2O, mobile phase B: CH3CN) to give N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3,5-difluorobenzyl)oxy)-6-oxo-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazin[4,3-a]pyrrolo[1,2-d][1,4]diaza-13-methamide 13 (12.7 mg), yield: 45%.

[0351] MS m / z (ESI): 643.2 [M+1]

[0352] 1H NMR (400 MHz, DMSO-d 6) δ 9.84 (s, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.60 (s, 1H), 7.41 (t, J = 8.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.20 - 7.11 (m, 3H), 7.08 (s, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.89 (s, 1H), 5.34 (d, J = 13.6 Hz, 1H), 5.19 (d, J = 13.6 Hz, 1H), 4.43 - 4.33 (m, 1H), 4.27 - 4.20 (m, 1H), 4.19 (s, 1H), 4.17 (d, J = 16.8 Hz, 1H), 3.95 (d, J = 16.8 Hz, 1H), 3.89 - 3.80 (m, 1H), 3.50 (t, J = 11.2 Hz, 1H), 3.04 (s, 3H).

[0353] Example 14

[0354] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3-fluorobenzyl)oxy)-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazino[4,3-a]pyrrolo[1,2-d][1,4]diazepine-13-carboxamide

[0355] N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3-fluorobenzyl)oxy)-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazin[4,3-a]pyrrolo[1,2-d][1,4]diaza-13-methamide

[0356] Step 1

[0357] 2-bromo-1-((3-fluorobenzyl)oxy)-3-nitrobenzene

[0358] 2-Bromo-1-((3-fluorobenzyl)oxy)-3-nitrobenzene

[0359] 2-Bromo-3-nitrophenol 8b (25 g, 114.68 mmol) was dissolved in acetonitrile (300 mL), and cesium carbonate (74.7 g, 229.35 mmol) and 3-fluorobenzyl bromide (32.5 g, 172.01 mmol, 21.10 mL) were added to the resulting solution. The reaction mixture was stirred at 25 °C for 18 hours. The resulting mixture was diluted with water (500 mL) and extracted with ethyl acetate (300 mL x 2). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-bromo-1-((3-fluorobenzyl)oxy)-3-nitrobenzene 14a, which was used directly in the next step.

[0360] MS m / z (ESI): no signal. [M+1]

[0361] Second Step

[0362] 2-bromo-3-((3-fluorobenzyl)oxy)aniline

[0363] 2-Bromo-3-((3-fluorobenzyl)oxy)aniline

[0364] 2-Bromo-1-((3-fluorobenzyl)oxy)-3-nitrobenzene 14a (28 g, 85.86 mmol) was dissolved in ethanol (400 mL). Iron powder (14.4 g, 257.58 mmol), ammonium chloride (13.8 g, 257.58 mmol), and water (200 mL) were added to the resulting solution. The reaction solution was stirred at 90 °C for 18 hours. The resulting mixed solution was filtered under reduced pressure, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was diluted with water (500 mL) and extracted with ethyl acetate (300 mL x 2). The extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silicone column chromatography (eluent: system A) to give 2-bromo-3-((3-fluorobenzyl)oxy)aniline 14b (23.6 g), yield: 93%.

[0365] MS m / z (ESI): 296.0 [M+1]

[0366] Step 3

[0367] methyl 5-(2-amino-6-((3-fluorobenzyl)oxy)phenyl)-1-(2-hydroxy-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylate

[0368] Methyl 5-(2-amino-6-((3-fluorobenzyl)oxy)phenyl)-1-(2-hydroxy-3-methoxy-3-oxypropyl)-1H-pyrrole-3-carboxylic acid ester

[0369] 2-Bromo-3-((3-fluorobenzyl)oxy)aniline 14b (4.02 g, 13.59 mmol) and 55-bromo-1-(2-hydroxy-3-methoxy-3-oxypropyl)-1H-pyrrole-3-carboxylic acid methyl ester 13b (3.2 g, 10.45 mmol) were dissolved in 1,4-dioxane (60 mL). Pinacol diboronate (7.96 g, 31.36 mmol), n-butyldi(1-adamantyl)phosphine (1.50 g, 4.18 mmol), palladium acetate (469.39 mg, 2.09 mmol), potassium carbonate (4.33 g, 31.36 mmol), and water (12 mL) were added to the resulting solution. The reaction solution was purged with nitrogen three times and stirred at 80 °C for 18 hours under nitrogen protection. The resulting mixed solution was filtered under reduced pressure, and the filter cake was washed with dichloromethane (20 mL x 2). The filtrate was concentrated under reduced pressure and purified by silicone column chromatography (eluent: system A) to give methyl 5-(2-amino-6-((3-fluorobenzyl)oxy)phenyl)-1-(2-hydroxy-3-methoxy-3-oxypropyl)-1H-pyrrole-3-carboxylic acid 14c (1.3 g), yield: 28%.

[0370] MS m / z (ESI): 443.2 [M+1]

[0371] Step Four

[0372] methyl 5-(2-amino-6-((3-fluorobenzyl)oxy)phenyl)-1-(2-bromo-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylate

[0373] Methyl 5-(2-amino-6-((3-fluorobenzyl)oxy)phenyl)-1-(2-bromo-3-methoxy-3-oxypropyl)-1H-pyrrole-3-carboxylic acid ester

[0374] Methyl 5-(2-amino-6-((3-fluorobenzyl)oxy)phenyl)-1-(2-hydroxy-3-methoxy-3-oxypropyl)-1H-pyrrole-3-carboxylic acid ester 14c (1.3 g, 2.94 mmol) was dissolved in tetrahydrofuran (20 mL). Triphenylphosphine (2.3 g, 8.81 mmol) and carbon tetrabromide (1.5 g, 4.41 mmol) were added to the resulting solution. The reaction mixture was stirred at 25 °C for 3 hours. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with tetrahydrofuran (5 mL x 2). The filtrate was collected to obtain methyl 5-(2-amino-6-((3-fluorobenzyl)oxy)phenyl)-1-(2-bromo-3-methoxy-3-oxypropyl)-1H-pyrrole-3-carboxylic acid ester 14d in tetrahydrofuran (20 mL). The solution can be used directly in the next step.

[0375] MS m / z (ESI): 505.1 [M+1]

[0376] Step 5

[0377] dimethyl 11-((3-fluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2,6-dicarboxylate

[0378] 11-((3-fluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2,6-dicarboxylic acid dimethyl ester

[0379] At room temperature, cesium carbonate (1.4 g, 2.77 mmol) was added to a tetrahydrofuran (20 mL) solution of methyl 5-(2-amino-6-((3-fluorobenzyl)oxy)phenyl)-1-(2-bromo-3-methoxy-3-oxypropyl)-1H-pyrrole-3-carboxylic acid ester 14d. The reaction mixture was stirred at 60 °C for 18 hours. The resulting mixture was filtered under reduced pressure, the filter cake was washed with methanol (5 mL x 2), the filtrate was concentrated under reduced pressure, and purified by silicone column chromatography (eluent: system A) to give 11-((3-fluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2,6-dicarboxylic acid dimethyl ester 14e (300 mg), yield: 25%.

[0380] MS m / z (ESI): 425.1 [M+1]

[0381] Step Six

[0382] methyl 11-((3-fluorobenzyl)oxy)-6-(hydroxymethyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[0383] 11-((3-fluorobenzyl)oxy)-6-(hydroxymethyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2-carboxylic acid methyl ester

[0384] 120 mg (282.74 μmol) of 11-((3-fluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2,6-dicarboxylic acid dimethyl ester 14f was dissolved in methanol (5 mL), and sodium borohydride (54 mg, 1.41 mmol) was added to the resulting solution. The reaction solution was stirred at 25 °C for 2 hours. The resulting mixture was concentrated under reduced pressure and purified by silicone column chromatography (eluent: system A) to give 90 mg (90 mg) of 11-((3-fluorobenzyl)oxy)-6-(hydroxymethyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2-carboxylic acid dimethyl ester 14f, yield: 80%.

[0385] MS m / z (ESI): 397.1 [M+1]

[0386] Step Seven

[0387] methyl 1-((3-fluorobenzyl)oxy)-6-oxo-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazino[4,3-a]pyrrolo[1,2-d][1,4]diazepine-13-carboxylate

[0388] 1-((3-fluorobenzyl)oxy)-6-oxo-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazin[4,3-a]pyrrolo[1,2-d][1,4]diaza-13-carboxylic acid methyl ester

[0389] Methyl 11-((3-fluorobenzyl)oxy)-6-(hydroxymethyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza-2-carboxylic acid 14f (100 mg, 252.26 μmol) was dissolved in tetrahydrofuran (5 mL). Methyl chloroacetate (164.26 mg, 1.51 mmol) and potassium tert-butoxide (169.84 mg, 1.51 mmol) were added to the resulting solution. The reaction mixture was stirred at 25 °C for 2 hours. The filtrate was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silicone column chromatography (eluent: system A) to give 14 g (80 mg) of methyl 1-((3-fluorobenzyl)oxy)-6-oxo-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazin[4,3-a]pyrrolo[1,2-d][1,4]diaza-13-carboxylic acid, yield: 73%.

[0390] MS m / z (ESI): 437.1 [M+1]

[0391] Step 8

[0392] methyl 1-((3-fluorobenzyl)oxy)-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazino[4,3-a]pyrrolo[1,2-d][1,4]diazepine-13-carboxylate

[0393] 1-((3-fluorobenzyl)oxy)-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazin[4,3-a]pyrrolo[1,2-d][1,4]diaza-13-carboxylic acid methyl ester

[0394] 14 g (70 mg, 160.39 μmol) of methyl 1-((3-fluorobenzyl)oxy)-6-oxo-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazin[4,3-a]pyrrolo[1,2-d][1,4]diaza-13-carboxylic acid was dissolved in a boranetetrahydrofuran complex (1 M, 2 mL). The reaction solution was stirred at 60 °C for 2 hours. The reaction solution was then slowly added dropwise to methanol (5 mL) to quench the reaction. The resulting mixed solution was concentrated under reduced pressure and purified by silicone column chromatography (eluent: system A) to give methyl 1-((3-fluorobenzyl)oxy)-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazin[4,3-a]pyrrolo[1,2-d][1,4]diaza-13-carboxylic acid 14h (40 mg), yield: 59%.

[0395] MS m / z (ESI): 423.1 [M+1]

[0396] Step Nine

[0397] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3-fluorobenzyl)oxy)-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazino[4,3-a]pyrrolo[1,2-d][1,4]diazepine-13-carboxamide

[0398] N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3-fluorobenzyl)oxy)-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazin[4,3-a]pyrrolo[1,2-d][1,4]diaza-13-methamide

[0399] Methyl 1-((3-fluorobenzyl)oxy)-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazin[4,3-a]pyrrolo[1,2-d][1,4]diaza-13-carboxylic acid ester 14h (40 mg, 98.90 μmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide 1j (32.74 mg, 148.35 μmol) were dissolved in tetrahydrofuran (1.5 mL), and trimethylaluminum (2 M, 395.59 μL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 60 °C for 18 hours. The reaction was quenched by slowly adding the reaction solution to methanol (10 mL). The resulting mixed solution was concentrated under reduced pressure, purified by silicone column chromatography (eluent: system B), and then separated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 µm, 20 mL / min; mobile phase A: 0.05 % NH4HCO3 + H2O, mobile phase B: CH3CN) to obtain N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3-fluorobenzyl)oxy)-6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazin[4,3-a]pyrrolo[1,2-d][1,4]diaza-13-methamide 14 (32 mg), yield: 53%.

[0400] MS m / z (ESI): 611.1 [M+1]

[0401] 1H NMR (400 MHz, DMSO-d 6) δ 10.00 (s, 1H), 9.80 (s, 1H), 7.70 (t, J = 1.6 Hz, 1H), 7.67 (d, J = 1.2 Hz, 1H), 7.63 (t, J = 1.6 Hz, 1H), 7.42 – 7.36 (m, 1H), 7.31 – 7.21 (m, 3H), 7.12 – 7.07 (m, 1H), 6.95 (d, J = 1.2 Hz, 1H), 6.92 – 6.89 (m, 2H), 6.81 (d, J = 8.0 Hz, 1H), 5.25 (d, J = 13.2 Hz, 1H), 5.13 (d, J = 13.2 Hz, 1H), 3.99 – 3.85 (m, 3H), 3.77 (d, J = 10.0 Hz, 1H), 3.29 – 3.23 (m, 4H), 3.06 (s, 3H), 2.86 (d, J = 10.8 Hz, 1H).

[0402] Example 15

[0403] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3-fluorobenzyl)oxy)-4b,7,8,10-tetrahydro-5H-benzo[c][1,4]oxazino[4,3-a]thieno[3,2-e]azepine-12-carboxamide

[0404] N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3-fluorobenzyl)oxy)-4b,7,8,10-tetrahydro-5H-benzo[c][1,4]oxazin[4,3-a]thieno[3,2-e]aza-12-methamide

[0405] Step 1

[0406] 2-bromo-3-((3-fluorobenzyl)oxy)benzaldehyde

[0407] 2-Bromo-3-((3-fluorobenzyl)oxy)benzaldehyde

[0408] At room temperature, cesium carbonate (121.56 g, 373.10 mmol) and 3-fluorobenzyl bromide (47.02 g, 248.73 mmol) were added to a solution of 2-bromo-3-hydroxybenzaldehyde 15a (25.0 g, 124.37 mmol, commercially available) in acetonitrile (250 mL), and the mixture was stirred for 18 hours. The reaction solution was poured into water (150 mL) and extracted with dichloromethane (200 mL × 3). After concentration, the solution was purified by silica gel column chromatography (eluent: system A) to give 2-bromo-3-((3-fluorobenzyl)oxy)benzaldehyde 15b (20.0 g), yield: 52.2%.

[0409] MS m / z (ESI): 309.0 [M+1]

[0410] Step Two

[0411] 3-(2-bromo-3-((3-fluorobenzyl)oxy)phenyl)morpholine

[0412] 3-(2-bromo-3-((3-fluorobenzyl)oxy)phenyl)morpholine

[0413] 2-Bromo-3-((3-fluorobenzyl)oxy)benzaldehyde 15b (250 mg, 0.800 mmol) was dissolved in dichloromethane (1.5 mL). To the resulting solution, (2-amino-ethoxy)methyl]tributyltinane 15c (294 mg, 0.800 mmol, commercially available), 2,6-dimethylpyridine (87 mg, 0.800 mmol, commercially available), copper(II) trifluoromethanesulfonate (292 mg, 0.800 mmol, commercially available), and hexafluoroisopropanol (1.5 mL, commercially available) were added. The reaction mixture was stirred at 25 °C for 16 hours. The resulting mixed solution was added to ammonia (2 mL) and extracted with dichloromethane (10 mL x 2). The extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silicone column chromatography (eluent: system A) to give 3-(2-bromo-3-((3-fluorobenzyl)oxy)phenyl)morpholine 15d (170 mg), yield: 57%.

[0414] MS m / z (ESI): 366.0 [M+1]

[0415] Step 3

[0416] methyl 4-bromo-5-((3-(2-bromo-3-((3-fluorobenzyl)oxy)phenyl)morpholino)methyl)thiophene-2-carboxylate

[0417] Methyl 14-bromo-5-((3-(2-bromo-3-((3-fluorobenzyl)oxy)phenyl)morpholino)methyl)thiophene-2-carboxylic acid ester

[0418] 3-(2-bromo-3-((3-fluorobenzyl)oxy)phenyl)morpholine 15d (170 mg, 0.460 mmol) was dissolved in dichloroethane (2 mL). Methyl 4-bromo-5-methoxythiophene-2-carboxylic acid 15e (231 mg, 0.920 mmol, commercially available), acetic acid (13.8 mg, 0.230 mmol), and sodium triacetoxyborohydride (147 mg, 0.690 mmol, commercially available) were added to the resulting solution. The reaction mixture was stirred at 25 °C for 16 hours. The reaction solution was concentrated under reduced pressure and purified by silicone column chromatography (eluent: system B) to give 15f (210 mg) of methyl 4-bromo-5-((3-(2-bromo-3-((3-fluorobenzyl)oxy)phenyl)morpholino)methyl)thiophene-2-carboxylic acid, yield: 75%.

[0419] MS m / z (ESI): 598.0 [M+1]

[0420] Step 4

[0421] methyl 1-((3-fluorobenzyl)oxy)-4b,7,8,10-tetrahydro-5H-benzo[c][1,4]oxazino[4,3-a]thieno[3,2-e]azepine-12-carboxylate

[0422] 1-((3-fluorobenzyl)oxy)-4b,7,8,10-tetrahydro-5H-benzo[c][1,4]oxazin[4,3-a]thieno[3,2-e]aza-12-carboxylic acid methyl ester

[0423] Methyl 4-bromo-5-((3-(2-bromo-3-((3-fluorobenzyl)oxy)phenyl)morpholino)methyl)thiophene-2-carboxylic acid ester 15f (210 mg, 0.350 mmol) was dissolved in 1,4-dioxane (2 mL). Pinacol diboronate (266 mg, 1.05 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonic acid (25.5 mg, 0.0300 mmol), potassium carbonate (145 mg, 1.05 mmol), and water (0.4 mL) were added to the resulting solution. The reaction mixture was purged with nitrogen three times and stirred at 80 °C for 16 hours under nitrogen protection. The resulting mixed solution was filtered under reduced pressure, and the filter cake was washed with dichloromethane (10 mL x 2). The resulting filtrate was concentrated under reduced pressure and purified by silicone column chromatography (eluent: system A) to give 15 g (75 mg) of methyl 1-((3-fluorobenzyl)oxy)-4b,7,8,10-tetrahydro-5H-benzo[c][1,4]oxazin[4,3-a]thieno[3,2-e]aza-12-carboxylic acid, yield: 48%.

[0424] MS m / z (ESI): 440.2 [M+1]

[0425] Step 5

[0426] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3-fluorobenzyl)oxy)-4b,7,8,10-tetrahydro-5H-benzo[c][1,4]oxazino[4,3-a]thieno[3,2-e]azepine-12-carboxamide

[0427] N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3-fluorobenzyl)oxy)-4b,7,8,10-tetrahydro-5H-benzo[c][1,4]oxazin[4,3-a]thieno[3,2-e]aza-12-methamide

[0428] 15 g (75.0 mg, 0.170 mmol) of methyl 1-((3-fluorobenzyl)oxy)-4b,7,8,10-tetrahydro-5H-benzo[c][1,4]oxazin[4,3-a]thieno[3,2-e]aza-12-carboxylic acid and 1 j (60.2 mg, 0.270 mmol) of N-(3-amino-5-chlorophenyl)methanesulfonamide were dissolved in tetrahydrofuran (1 mL). Trimethylaluminum (2 M, 0.54 mL, n-hexane solution) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 60 °C for 2 hours. The reaction was quenched by slowly adding the reaction solution to methanol (5 mL). The resulting mixed solution was concentrated under reduced pressure, purified by silicone column chromatography (eluent: system B), and then separated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 µm, 20 mL / min; mobile phase A: 0.05 % NH4HCO3 + H2O, mobile phase B: CH3CN) to give N-(3-chloro-5-(methanesulfonyl)phenyl)-1-((3-fluorobenzyl)oxy)-4b,7,8,10-tetrahydro-5H-benzo[c][1,4]oxazin[4,3-a]thieno[3,2-e]aza-12-methamide 15 (27 mg), yield: 31%.

[0429] MS m / z (ESI): 628.2 [M+1]

[0430] 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.50 (s, 1H), 7.65 (s, 2H), 7.41 (t, J = 8.0 Hz, 1H), 7.35 (dd, J = 8.0, 6.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 12.4 Hz, 2H), 6.98 (s, 1H), 5.33 (d, J = 12.8 Hz, 1H), 5.19 (d, J = 12.8 Hz, 1H), 4.04 (m, 1H), 3.91 – 3.72 (m, 3H), 3.69 (s, 1H), 3.08 (s, 3H), 2.89 – 2.59 (m, 4H).

[0431] Biological Evaluation

[0432] Test Example 1: Determination of the inhibitory effect of the compound of the present invention on the proliferation of CCRF-CEM cells

[0433] The following methods were used to determine the effect of the compounds of the present invention on the proliferation of CCRF-CEM cells. CCRF-CEM cells (MSI-H cells) were purchased from the Cell Bank of the Chinese Academy of Sciences and cultured in RPMI-1640 medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. Cell viability was determined using the CellTiter-Glo® Luminescent Cell Viability Assay Kit (Promega, catalog number G7573).

[0434] The experimental method was performed according to the kit instructions, and is briefly described below: The test compound was first dissolved in DMSO to prepare a 10 mM stock solution, which was then diluted with culture medium to prepare the test sample. The final concentration range of the compound was 10000 nM-1.52 nM. Cells in the logarithmic growth phase were seeded into 96-well cell culture plates at a density of 1000 cells per well. After adding the test compound, the plates were incubated at 37°C for 120 hours. After incubation, 50 μL of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes, and allowed to stand for 10 minutes. The luminescence values ​​of each well were then read using the Luminescence mode on a microplate reader. The percentage inhibition rate of the compound at each concentration point was calculated by comparing the values ​​with the control group (0.1% DMSO). Then, nonlinear regression analysis was performed in GraphPad Prism 9 software using the logarithm of compound concentration versus inhibition rate to obtain the IC50 value of the compound inhibiting cell proliferation, as shown in Table 1.

[0435] Table 1. IC50 data of the compounds of the present invention on the inhibition of CCRF-CEM cell proliferation. Example number IC 50 (nM) Example number IC 50 (nM) Example number IC 50 (nM) 1 2.3 8 0.9 12 21.6 2 3.1 9 1.4 14 28.6 3 4.3 10 1.8 15 2.7 4 0.9 11 2.9 ATX-968 85 Conclusion: The compound of this invention has a good inhibitory effect on the proliferation of CCRF-CEM cells (IC50 < 30 nM).

[0436] Note: The structure of ATX-968 (prepared according to Example 31 of published patent WO2023154519A1) is as follows:

[0437] Test Example 2: Determination of the inhibitory effect of the compound of the present invention on the proliferation of LS411N cells.

[0438] The following methods were used to determine the effect of the compounds of the present invention on the proliferation of LS411N cells. LS411N cells (MSI-H cells) were purchased from the American Type Culture Collection (ATCC) and cultured in RPMI-1640 medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. Cell viability was determined using the CellTiter-Glo® Luminescent Cell Viability Assay Kit (Promega, catalog number G7573).

[0439] The experimental method was performed according to the kit instructions, and is briefly described below: The test compound was first dissolved in DMSO to prepare a 10 mM stock solution, which was then diluted with culture medium to prepare the test sample. The final concentration range of the compound was 10000 nM-0.152 nM. Cells in the logarithmic growth phase were seeded into 96-well cell culture plates at a density of 1000 cells per well. After adding the test compound, the plates were incubated at 37°C for 120 hours. After incubation, 50 μL of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes, and allowed to stand for 10 minutes. The fluorescence values ​​of each well were then read using the Luminescence mode on a microplate reader. The percentage inhibition rate of the compound at each concentration point was calculated by comparing the values ​​with the control group (0.1% DMSO). Then, nonlinear regression analysis was performed in GraphPad Prism 9 software using the logarithm of compound concentration versus inhibition rate to obtain the IC50 value of the compound inhibiting cell proliferation, as shown in Table 2.

[0440] Table 2. IC50 data on the inhibitory effect of the compounds of this invention on the proliferation of LS411N cells. Example number IC 50 (nM) Example number IC 50 (nM) Example number IC 50 (nM) 1 28.2 8 21.9 15 4.0 2 9.5 9 28.8 ATX-968 112 3 4.9 10 13.0 4 10.7 12 23.1

[0441] Conclusion: The compound of the present invention has a good inhibitory effect on the proliferation of LS411N cells with an IC50 of <30 nM.

[0442] Test Example 3: Test on the inhibition of hDHX9 enzyme (ATPase) activity by the compounds of the present invention

[0443] The following method was used to determine the degree of inhibition of the compounds of the present invention on the activity of recombinant human DExH-box helicase 9 (hDHX9, ATPase) under in vitro conditions. This method uses the Promega ADP-Glo™ Kinase Assay kit (catalog number V9102). Detailed experimental procedures can be found in the kit's instruction manual.

[0444] The experimental procedure is briefly described as follows: The test compound was first dissolved in DMSO to prepare a stock solution, and then serially diluted using reaction buffer (40 mM HEPES, pH 7.5, 20 mM MgCl2, 0.01% Tween-20, 0.01% BSA, 1 mM DTT, 0.004 U / ml RNaseOUT™ Recombinant Ribonuclease Inhibitor). The final concentration range of the test compound in the reaction system was 10000 nM to 0.04 nM. hDHX9 protein was prepared using reaction buffer (expressed and purified by Nanjing Genscript Biotech Co., Ltd.), and the double-stranded RNA substrate of DHX9 was synthesized and annealed by Suzhou Genewise Biotech Co., Ltd. (Sequence 1: 5'- GAAUUAACCAAGGAAAAUAACAAGGACAGGGACCAGG-3' and Sequence 2: 5'- GCCUGGUCCCUGUCCUUGUUAUUUUCCUUGGUUAAUU-3'). The reaction was performed in 384-well microplates. First, the test compound and recombinant human DHX9 protein (final concentration 6.3 nM) were added to the wells and incubated at room temperature for 15 minutes. Then, double-stranded RNA sequence solution (final concentration 18.8 nM) and ATP solution (final concentration 30 μM, from ADP-Glo™ Kinase Assay kit component V915A) were added to the reaction mixture and incubated at room temperature for 45 minutes. Next, 5 μL of ADP-Glo ​​Reagent was added to the reaction mixture and incubated at room temperature for 50 minutes. Finally, 10 μL of Kinase Detection Reagent was added to the reaction mixture and incubated at room temperature for 30 minutes. After incubation, the chemiluminescence intensity of each well was measured using a microplate reader in Luminescence mode. The percentage inhibition rate of the compound at each concentration was calculated by comparing the ratio of luminescence intensity with that of the control group (0.1% DMSO). The IC50 value of the compound was obtained by nonlinear regression analysis of the compound concentration logarithm-inhibition rate using GraphPad Prism 9 software, as shown in Table 3.

[0445] Table 3 IC50 data of the compounds of the present invention inhibiting the activity of hDHX9 enzyme (ATPase). Example number IC 50 (nM) Example number IC 50 (nM) Example number IC 50 (nM) 1 0.2 8 9.6 14 21.3 2 1.3 9 2.8 15 19.2 3 9.1 10 15.1 6 1.4 11 12.4

[0446] Conclusion: The compound of this invention exhibits good inhibitory activity against hDHX9 enzyme (ATPase) with an IC50 < 30 nM. [Simplified Explanation of the Diagram]

[0075] None

Claims

1. A compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: which is a compound of general formula (II) or (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: wherein: X is selected from halogen; R1 is selected from methyl; one of W and Q is N and the other is C; the cyclic C is selected from 5-6-membered heteroaryl or 4-7-membered heterocyclic group; Y and Z are each independently selected from CR2c; R2a is selected from hydrogen atom, cyano, halogen, hydroxyl, SF5, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, 3-8-membered heterocyclic group, C6-10 aryl or 5-6-membered heteroaryl, wherein the C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, 3-8-membered heterocyclic group, C6-10 aryl or 5-6-membered heteroaryl group is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy; R2b are each independently selected from hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, amino, carboxyl, or C1-6 alkyl, wherein the C1-6 alkyl or C1-6 alkoxy is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, or C1-6 haloalkoxy; R2c are each independently selected from -OCH2R3; R3 are each independently selected from phenyl, wherein the phenyl is optionally further substituted by one or more substituents selected from halogen; p is each independently selected from O; q is each independently selected from O; m is each independently selected from 1 or 2; n is each independently selected from O.

2. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein: W represents N, and Q represents C.

3. The compound according to claim 1, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein: W represents C, and Q represents N.

4. The compound according to any one of claims 1-3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the ring C is selected from a 5-membered heteroaryl group.

5. The compound according to claim 4, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein ring C is selected from triazole, tetraazole, or pyrazole.

6. The compound according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the group is selected from the following: ; R2c is defined as described in claim 1.

7. The compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R2c is selected from , , or .

8. The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein X is selected from Cl.

9. The compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is: or.

10. A pharmaceutical composition comprising an effective dose of any one of claims 1 to 9 of the compound or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

11. Use of a compound as claimed in any one of claims 1 to 9, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, in the preparation of a DHX9 inhibitor.

12. Use of a compound or stereoisomer, tautomer or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 9, or a pharmaceutical composition according to claim 10, in the preparation of a medicament for treating DHX9-mediated diseases.

13. The use as described in claim 12, wherein the DHX9-mediated disease is cancer, viral infection, or autoimmune disease.

14. According to the use described in claim 13, the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic system cancer, breast cancer, brain cancer, skin cancer, lung cancer, blood cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft tissue cancer, kidney cancer, and liver cancer.

15. The use as described in claim 13, wherein the cancer is a microsatellite instability cancer.

16. The use as described in claim 15, wherein the cancer is a highly microsatellite unstable cancer.

17. The use as described in claim 15, wherein the cancer is highly microsatellite unstable colorectal cancer.

18. Use of a compound or stereoisomer, tautomer or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 9, or a pharmaceutical composition according to claim 10, in the preparation of a medicament for treating cancer, viral infection or autoimmune disease.