Tetracyclic aromatic amide derivative, and preparation method therefor and use thereof

Abstract

The present invention relates to a tetracyclic aromatic amide derivative, a preparation method therefor, and the pharmaceutical use of a pharmaceutical composition containing the derivative. Specifically, the present invention relates to a tetracyclic aromatic amide derivative as represented by general formula (I), a preparation method therefor and a pharmaceutically acceptable salt thereof, and the use thereof as a therapeutic agent, especially a DHX9 inhibitor, wherein the definition of each substituent in general formula (I) is the same as that defined in the description.

Description

Tetranuclear aromatic amide derivatives, processes for their preparation and uses thereof TECHNICAL FIELD

[0001] The present application relates to a tetranuclear aromatic amide derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and the use thereof as a therapeutic agent, particularly as a DHX9 inhibitor. BACKGROUND

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

[0003] Since DHX9 lacks base selectivity, DHX9 can use all four NTPs to meet its energy needs, and is a multi-domain, multifunctional protein that plays an important role in biological development, DNA replication, transcription, translation, repair, splicing, editing, RNA processing, transport, reconstitution, and maintenance of genomic stability.

[0004] Due to its regulatory role in processes such as transcription and maintenance of genomic stability, DHX9 has been shown to be a key regulator in multiple cancer types, and is involved in the regulation of genes associated with persistent proliferation signaling, evasion of growth suppressors, evasion of apoptosis, angiogenesis and metastasis, all of which are hallmarks of cancer. Specifically, microsatellite unstable cancers, such as microsatellite instability (MSI) colorectal cancer, and tumors with defective mismatch repair (MMR) show 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 is no new drug on the market for inhibitors targeting DHX9, and there is no clinical compound information. As a brand new antitumor target, there is a huge exploration space for the research of DHX9 target, and it is necessary to develop inhibitors targeting the target. SUMMARY

[0007] To solve the above technical problems, the present application provides a compound represented by general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0008] wherein: X is selected from halogen;

[0009] R 1 is selected from C 1-6 alkyl or 3-5 membered cycloalkyl; wherein said C 1-6 alkyl or 3-5 membered cycloalkyl is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, C 1-6 alkyl or C 1-6 alkoxy;

[0010] is 5-membered heteroaryl;

[0011] X1and X2are each independently selected from CH, S or N, and X1and X2are not simultaneously S,

[0012] X3is selected from C or N; provided that when X3is C, X1and X2are not simultaneously CH;

[0013] W and Q are each independently selected from C or N;

[0014] ring C is selected from 5-6 membered heteroaryl or 4-7 membered heterocyclyl;

[0015] Y and Z are each independently selected from CR 2c or N;

[0016] R 2a is selected from hydrogen atom, cyano, halogen, hydroxy, SF5, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0017] R 2b is each independently selected from hydrogen atom, halogen, hydroxy, cyano, C 1-6 alkyl, amino, carboxy or C 1-6 alkyl, wherein said C 1-6 alkyl or C 1-6 alkoxy is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Substituents of haloalkoxy groups;

[0018] R 2c Each is independently selected from hydrogen atom, halogen, hydroxyl group, cyano group, C 1-6 Alkyl, amino, carboxyl, C 1-6 Alkyl group or -OCH2R 3 The C mentioned therein 1-6 Alkyl or C 1-6 Alkyl groups may optionally be further selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, etc. 1-6 Alkyl, C 1-6 Alkoxy or -OR 3 The substituents are replaced;

[0019] R 3 Each is independently selected from C 3-8 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic, wherein the C 3-8 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, or 5-6 membered heterocyclic group may be further selected by one or more groups selected from hydroxyl, halogen, cyano, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0020] p can be independently selected from 0, 1, or 2;

[0021] Each q is independently selected from 0, 1, or 2;

[0022] m is independently selected from 0, 1, or 2;

[0023] n can be independently selected from 0, 1, or 2.

[0024] 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 compound is of general formula (II) or (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0025] in:

[0026] Y and Z are each independently selected from CR 2c Or N;

[0027] R 2c Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl group or -OCH2R 3 The C mentioned therein1-6 alkoxy is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy or -OR 3 ;

[0028] R 3 each independently is selected from the group consisting of C 6-10 aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, wherein said C 6-10 aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy;

[0029] ring C, W, Q, R 1 , X, R 2a , R 2b , p, q, m and n are as defined in general formula (I).

[0030] It is a preferred embodiment of the present application that the compound according to general formula (I), (II) or (III), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2 and n is 0.

[0031] It is a preferred embodiment of the present application that the compound according to general formula (I), (II) or (III), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein m is 0 and n is 1.

[0032] It is a preferred embodiment of the present application that the compound according to general formula (I), (II) or (III), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein W is N and Q is C.

[0033] It is a preferred embodiment of the present application that the compound according to general formula (I), (II) or (III), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein W is C and Q is N.

[0034] It is a preferred embodiment of the present application that the compound according to general formula (I), (II) or (III), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein ring C is selected from 5-membered heteroaryl, preferably triazol, tetrazol or pyrazol.

[0035] It is a preferred embodiment of the present application that the compound according to general formula (I), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of:

[0036] R 2cR1is as defined in general formula (I).

[0037] In a preferred embodiment of the present application, a compound according to general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 2c is selected from C 1-6 alkyl or -OCH2R 3 wherein said C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen;

[0038] R 3 each independently is selected from phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, wherein said phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl is optionally further substituted by one or more substituents selected from hydroxy, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy;

[0039] In a preferred embodiment of the present application, a compound according to general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, R 2c is selected from methoxy, trifluoromethoxy,

[0040] In a preferred embodiment of the present application, a compound according to general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein X is selected from Cl or Br, preferably Cl.

[0041] In a preferred embodiment of the present application, a compound according to general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from methyl or ethyl.

[0042] In a preferred embodiment of the present application, a compound according to general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, is selected from:

[0043] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0044] Note: If there is a discrepancy between the drawn structure and the name given to that structure, the drawn structure will control.

[0045] Further, the present application provides a pharmaceutical composition comprising an effective amount of a compound of general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0046] The present application provides use of a compound of general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a DHX9 inhibitor.

[0047] The present application also provides use of a compound of general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating a disease mediated by DHX9, wherein the disease mediated by DHX9 is preferably cancer, viral infection or autoimmune disease, and further preferably cancer; and wherein the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic 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, and preferably colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic cancer and gastric cancer.

[0048] The present application also provides use of a compound of general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating a disease mediated by DHX9, wherein the disease mediated by DHX9 is preferably cancer, and wherein the cancer is microsatellite instability (MSI) cancer, preferably high microsatellite instability (MSI-H) cancer, and more preferably high microsatellite instability (MSI-H) colorectal cancer.

[0049] The present application further provides use of a compound of general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating cancer, viral infection or autoimmune disease.

[0050] The present application provides use of a compound of general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic 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, and preferably in the preparation of a medicament for treating colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic cancer and gastric cancer.

[0051] 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.

[0052] Detailed description of the invention

[0053] Unless otherwise stated, some terms used in this specification and claims are defined as follows:

[0054] When "alkyl" is used as a group or part of a group, it refers to a group consisting of C1-C2. 20 Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C. 10 Alkyl groups, more preferably C1-C6 alkyl groups. 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.

[0055] "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. Preferably C2-C4 alkenyl. The alkenyl group may be optionally substituted or unsubstituted.

[0056] "Alkyne group" refers to an aliphatic hydrocarbon group containing a single carbon-carbon triple bond, which can be straight-chain or branched. C2-C is preferred. 10 The alkynyl group is preferred, more preferably C2-C6 alkynyl, and most preferably C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl. The alkynyl group may be substituted or unsubstituted.

[0057] "Alkylene" refers to saturated C1-C 20 A 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 C1-C.10 Alkylene, more preferably Ci-C6alkylene. Examples of alkylene groups include, but are not limited to, methylene, 1,1-ethylidene, 1,2-ethylidene, 1,1- propylidene, 1,2-propylidene, 1,3-propylidene, 1,4-butylidene, and the like. Alkylene groups can be substituted or unsubstituted.

[0058] "Cycloalkyl" refers to non-aromatic cyclic alkyl groups in which one or more ring-forming atoms are carbon atoms, including monocyclic, polycyclic, fused, bridged, and spirocyclic rings, preferably having 5 to 7 membered monocyclic or 7 to 10 membered bicyclic or tricyclic rings. Examples of "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclobutyl. Cycloalkyl groups can be substituted or unsubstituted.

[0059] "Spiroalkyl" refers to a polycyclic group of 5 to 18 membered, two or more cyclic structures, and single rings share one carbon atom (called a spiro atom) with each other, the rings contain 1 or more double bonds, but none of the rings has a fully conjugated π-electron aromatic system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. According to the number of spiro atoms shared between the rings, spiroalkyl is divided into single-, double-, or multi-spiroalkyl, preferably single- and double-spiroalkyl, preferably 4 / 5-, 4 / 6-, 5 / 5-, or 5 / 6-membered. Non-limiting examples of "spiroalkyl" groups include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

[0060] "Fused ring alkyl" refers to a all-carbon polycyclic group of 5 to 18 membered, containing two or more cyclic structures share a pair of carbon atoms with each other, one or more rings can contain one or more double bonds, but none of the rings has a fully conjugated π-electron aromatic system, preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyl, preferably bicyclic or tricyclic, more preferably 5 / 5- or 5 / 6- membered bicyclic alkyl. Non-limiting examples of "fused ring alkyl" groups include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decalinyl, or tetradecahydrophenanthryl.

[0061] "Bicyclic ring alkyl" refers to a 5- to 18-membered, all-carbon polycyclic ring group containing two or more cyclic structures that share two non-adjacent carbon atoms with each other, one or more of the rings can contain one or more double bonds, but no ring has a fully conjugated pi-electron system that is aromatic, preferably 6- to 12-membered, more preferably 7- to 10-membered. Preferably 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings that make up the ring system, it can be referred to as a bicyclic, tricyclic, tetracyclic, or polycyclic bicyclic ring alkyl group, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bicyclic ring alkyl" groups 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, (1r,5r)-bicyclo[3.3.2]decyl.

[0062] "Heterocyclyl," "heterocycloalkyl," "heterocycle," or "heterocyclic" are used interchangeably herein and refer to a non-aromatic ring group that can contain 0, 1, or multiple double bonds within the ring, one or more ring atoms selected from nitrogen, oxygen, or S(O) r (wherein t is selected from 0, 1, or 2) heteroatoms, including mono-, poly-, fused-, bridged-, and spiro- rings. Preferably 3- to 8-membered monocyclic (more preferably 5- to 8-membered monocyclic) or 7- to 10-membered bicyclic or tricyclic rings, which can contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heterocyclyl" groups include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, hexahydropyrimidinyl,

[0063] The heterocyclyl group can be substituted or unsubstituted.

[0064] "Spiroheterocyclyl" refers to a 5- to 18-membered, polycyclic ring group containing two or more cyclic structures that share a single atom between the rings, the rings can contain 0, 1, or multiple double bonds within the ring, but no ring has a fully conjugated pi-electron system that is aromatic, one or more of the ring atoms is selected from nitrogen, oxygen, or S(O) theteroatoms, the remainder of the ring atoms being carbon. Preferably 6- to 14- membered, more preferably 7- to 10-membered. Spiroheterocyclyl groups are classified as mono-, bi- or polyspiroheterocyclyl groups, preferably mono- and bi- spiroheterocyclyl groups, according to the number of spiro atoms shared between rings. More preferably 4 / 4-, 4 / 5-, 3 / 5-, 3 / 6-, 4 / 6-, 5 / 5- or 5 / 6- membered monospiroheterocyclyl groups. Non-limiting examples of "spiroheterocyclyl 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, 5-oxaspiro[2.4]heptyl.

[0065] "Heteroaromatic" means a fully carbon-based polycyclic ring system containing two or more cyclic structures sharing one pair of atoms with each other, one or more rings can contain 0, one or more double bonds, but none of the rings has a fully conjugated π-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r heteroatoms, the remainder of the ring atoms being carbon. Preferably 6- to 14- membered, more preferably 7- to 10-membered. According to the number of rings making up the group, the fused heterocyclyl group can be bicyclic, tricyclic, tetracyclic or polycyclic, preferably bicyclic or tricyclic, more preferably 5 / 5- or 5 / 6- bicyclic fused heterocyclyl groups. Non-limiting examples of "fused heterocyclyl groups" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-lH-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][l,4]dioxine.

[0066] "Bridged heterocyclyl" means a 5- to 14-membered, 5- to 18-membered, polycyclic ring system containing two or more cyclic structures sharing two non-adjacent atoms with each other, one or more rings can contain 0, one or more double bonds, but none of the rings has a fully conjugated π-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) t heteroatoms, the remainder of the ring atoms being carbon. Preferably 6- to 14- membered, more preferably 7- to 10-membered. According to the number of rings making up the group, the fused heterocyclyl group can be bicyclic, tricyclic, tetracyclic or polycyclic, preferably bicyclic or tricyclic, more preferably 5 / 5- or 5 / 6- bicyclic fused heterocyclyl groups. Non-limiting examples of "fused heterocyclyl groups" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-lH-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][l,4]dioxine.

[0067] "Aryl" means a carbocyclic aromatic ring system containing one or two rings, wherein the rings can be connected together in a fused manner. The term "aryl" includes mono- or bicyclic aromatic groups such as the aromatic groups of phenyl, naphthyl, tetrahydronaphthyl. Preferably aryl is C6-C10 Aryl, more preferably aryl is phenyl and naphthyl, most preferably naphthyl. Aryl can be substituted or unsubstituted.

[0068] "Heteroaryl" means an aromatic 5- to 6-membered monocyclic, 8- to 10-membered bicyclic, or 12- to 14-membered tricyclic ring which can contain 1 to 4 heteroatoms selected from nitrogen, oxygen, or S(O) r (wherein r is selected from 0, 1, or 2) heteroatoms. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridinyl, 2-oxo-l,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzoimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl, isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, pyridyl, pyrimidinyl, pyrazin-2(lH)-onyl, pyrimidin-4(3H)-onyl, pyridazin-3(2H)-onyl, lH-indolyl, lH-benzo[d]imidazolyl, lH-pyrrolo[2,3-c]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furano[3,2-b]pyridinyl, furano[2,3-c]pyridinyl, thieno[2,3-c]pyridinyl, benzofuranyl, benzo[b]thiophenyl, lH-pyrrolo[3,2-b]pyridinyl, 2H-pyrrolo[3,4-c]pyridinyl,

[0069] Heteroaryl can be substituted or unsubstituted.

[0070] "Fused ring" means a polycyclic group in which two or more cyclic structures share a pair of atoms with each other, at least one of which rings has a fully conjugated pi-electron aromatic system, while one or more rings can contain 0, 1, or multiple double bonds, but at least one ring does not have a fully conjugated pi-electlectron aromatic system, wherein the ring atoms are selected from 0, 1, or multiple heteroatoms selected from nitrogen, oxygen, or S(O) r (wherein r is selected from 0, 1, or 2) heteroatoms, with the remaining ring atoms being carbon. Fused rings preferably include bicyclic, tricyclic, or tetracyclic fused rings, with bicyclic fused rings preferably being a fused ring of aryl or heteroaryl with monocyclic heterocyclyl or monocyclic cycloalkyl. Preferred 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 ring" include, but are not limited to:

[0071] "Alkoxy" means a group of the formula (alkyl-O-). Alkyl is as defined above. Preferably, the alkoxy group is C1-C6alkoxy. Examples include, but are not limited to, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, t-butyloxy, and the like.

[0072] "Carboxy" means a -C(O)OH group.

[0073] "Halo" means fluoro, chloro, bromo, and iodo.

[0074] "Amino" means -NH2.

[0075] "Cyano" means -CN.

[0076] "Benzyl" means -CH2-phenyl.

[0077] "Carboxy" means a -C(O)OH group.

[0078] "Carboxy" means a -C(O)OH group.

[0079] "Carboxy" means a -C(O)OH group.

[0080] "Hydroxyalkyl" means an alkyl group as defined above substituted with a hydroxyl group.

[0081] "Aminoalkyl" means an alkyl group as defined above substituted with an amino group.

[0082] "Haloalkyl" means an alkyl group as defined above substituted with a halogen.

[0083] "Haloalkoxy" means an alkoxy group as defined above substituted with a halogen.

[0084] "DMSO" means dimethyl sulfoxide.

[0085] "BOC" means tert-butoxycarbonyl.

[0086] "Bn" means benzyl.

[0087] "THP" means 2-tetrahydropyranyl.

[0088] "TFA" means trifluoroacetic acid.

[0089] "Ts" means p-toluenesulfonyl.

[0090] A "leaving group," or simply a group, is an atom or functional group that breaks off from a larger molecule in a chemical reaction. It's 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 with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to accept negative charges are desirable 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 a smaller pKa means the leaving group doesn't need to bond with other atoms and has a stronger tendency to exist as an anion (or an electrically neutral leaving group). Common leaving groups include, but are not limited to, halogens, methanesulfonyl groups, -OTs, or -OH.

[0091] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and 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).

[0092] Unless otherwise specified, the terms "substitution" or "substituted" in this specification refer to the substitution of a group by one or more groups selected from the following: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, SF5, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester, =O, -OCH2R 3’ -C(O)R 3’ -C(O)OR 3’ -NHC(O)R 3’ -NHC(O)OR 3’ -NR 4’ R 5’ -C(O)NR 4’ R 5’ -S(O)2NR 4’ R 5’ -CH2NHC(O)OR 3’ -CH2NR 4’ R 5’ or -S(O) r R 3’ The substituents are replaced;

[0093] R 3’Each is independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 6’ -C(O)OR 6’ -OC(O)R 6’ -NR 7’ R 8’ -C(O)NR 7’ R 8’ -SO2NR 7’ R 8’ or -NR 7’ C(O)R 8’ The substituents are replaced;

[0094] R 4’ and R 5’ Each is 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 selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 6’ -C(O)OR 6’ -OC(O)R 6’ -NR 7’ R 8’ -C(O)NR 7’ R 8’ -SO2NR 7’ R 8’ or -NR 7’ C(O)R 8’ The substituents are replaced;

[0095] Or, R 4’ and R 5’ The atoms bonded to them together 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 Furthermore, the 4-8 membered heterocyclic group may optionally be further selected from one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 6’ -C(O)OR 6’ -OC(O)R 6’ -NR 7’ R 8’ -C(O)NR 7’ R 8’, -SO2NR 7’ R 8’ or -NR 7’ C(O)R 8’ substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate;

[0096] R 6’ , R 7’ and R 8’ are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate;

[0097] r is selected from 0, 1 or 2.

[0098] The compounds of the present application can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present application, including but not limited to, diastereomeric, enantiomeric, and atropisomeric forms and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present application.

[0099] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (such as diastereomeric, enantiomeric, and atropisomeric forms and geometric (conformational) isomers) and tautomeric forms of the structure; for example, structures having R and S configurations, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (conformational) mixtures of the present compounds are within the scope of the present application.

[0100] "Pharmaceutically acceptable salt" refers to those salts which retain the biological activity of the parent compound and which are suitable for medical use. The pharmaceutically acceptable salts of the compounds of Formula (I) can be metal salts, amine salts with suitable acids.

[0101] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein or physiologically acceptable salts or prodrugs thereof with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to an organism and to facilitate absorption of the active ingredient.

[0102] Synthesis of the compounds of the present application

[0103] In order to achieve the purposes of the present application, the present application adopts the following technical solutions:

[0104] The present application provides a preparation method of a compound of general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which comprises:

[0105] The compound of general formula (IA) is subjected to condensation reaction with the compound of general formula (IB), and optionally further subjected to substitution reaction to obtain the compound of general formula (I)

[0106] wherein:

[0107] Y1is selected from hydroxyl or chloro;

[0108] ring C, X, R 1 , R 2a , R 2b , W, Q, X1, X2, X3, Y, Z, m, n, p and q are as defined in general formula (I). DETAILED DESCRIPTION

[0109] The present application is further described below in connection with the following examples, which are not intended to limit the scope of the present application.

[0110] Examples

[0111] The examples below give the preparation of representative compounds of formula (I) and related structure identification data. It must be understood that the examples below are intended to illustrate the present application and not to limit it. 1 H NMR spectra were recorded on a Bruker instrument (400 MHz) and chemical shifts are expressed in ppm using tetramethylsilane as internal standard (0.00 ppm). 1 H NMR spectra were recorded on a Bruker instrument (400 MHz) and chemical shifts are expressed in ppm using tetramethylsilane as internal standard (0.00 ppm).

[0112] Mass spectra were recorded on LC / MS instrument, and ionization mode can be ESI or APCI.

[0113] Thin layer chromatography silica gel plates were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used in thin layer chromatography (TLC) had a thickness of 0.15 mm to 0.2 mm, and the silica gel plates used in thin layer chromatography separation and purification of products had a thickness of 0.4 mm to 0.5 mm.

[0114] Column chromatography generally used Yantai Huanghai silica gel 200-300 mesh silica gel as carrier.

[0115] In the following examples, all temperatures are in degrees Celsius, unless otherwise indicated, and all starting materials and reagents are commercially available or synthesized according to known procedures, and are used without further purification, unless otherwise indicated, and are purchased from commercial suppliers including, but not limited to, Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Broadpharm Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd., unless otherwise indicated.

[0116] CD3OD: deuterated methanol.

[0117] CDCl3: deuterated chloroform.

[0118] DMSO-d6: deuterated dimethyl sulfoxide.

[0119] Argon atmosphere means that the reaction bottle is connected to an argon balloon with a volume of about 1 L.

[0120] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0121] The compounds are purified by silica gel column chromatography and reverse phase column chromatography, and the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: ethyl acetate; D: trifluoroacetic acid aqueous solution and acetonitrile system. The volume ratio of the solvents is different according to the polarity of the compounds, and a small amount of acidic or basic reagent can also be added for adjustment, such as acetic acid or triethylamine, etc.

[0122] Example 1

[0123] 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

[0124] 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 -11-carboxamide

[0125] First step

[0126] methyl 3-(benzyloxy)-2-bromobenzoate

[0127] methyl 3-(benzyloxy)-2-bromobenzoate

[0128] Methyl 2-bromo-3-hydroxybenzoate 1a (1.00 g, 4.33 mmol, commercial) was dissolved in N,N-dimethylformamide (1 mL) solution, potassium carbonate (1.20 g, 8.66 mmol) and benzyl bromide (740.27 mg, 4.33 mmol) were added successively. After nitrogen replacement for three times, the reaction was reacted at 25 °C for 3 hours. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was 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: A system) to obtain methyl 3-(benzyloxy)-2-bromobenzoate 1b (950 mg) in a yield of 68%.

[0129] MS m / z (ESI): 321.0 [M+1]

[0130] Second step

[0131] Methyl 5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate

[0132] Methyl 5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate

[0133] Methyl 5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate

[0134] MS m / z (ESI): 215.9 [M+1-46]

[0135] Third step

[0136] Methyl 4-bromo-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate

[0137] 4-bromo-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylic acid methyl ester

[0138] To a solution of methyl 5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2- carboxylate 1d (5.00 g, 18.4 mmol) in N,N-dimethylformamide (30 mL) was added N- bromosuccinimide (9.84 g, 55.28 mmol) at 25 °C and the reaction was carried out at 50 °C for 18 h. The mixture was poured into water (500 mL) and extracted with ethyl acetate (400 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification was performed by silica gel column chromatography (eluent: A system) to give 4-bromo-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylic acid methyl ester 1e (2.5 g) in 39% yield.

[0139] MS m / z (ESI): 372.0 [M+23]

[0140] 1 H NMR (400 MHz, DMSO-d6) d 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).

[0141] Fourth step

[0142] methyl

[0143] 4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate

[0144] 4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate

[0145] Methyl 4-bromo-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2- carboxylate 1e (1.5 g, 4.28 mmol) and methyl 3-(benzyloxy)-2-bromobenzoate 1b (1.58 g, 4.92 mmol) were dissolved in 1,4-dioxane (15 mL), to the resulting solution was added pinacol diborane (3.26 g, 12.85 mmol), n-butyl bis(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). The reaction was purged with nitrogen for 3 times and stirred at 80 °C for 12 h under nitrogen. The reaction was concentrated under reduced pressure, purified by silica gel column chromatography (eluent: A system) to give methyl 4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-5-(((tert- butoxycarbonyl)amino)methyl)thiophene-2-carboxylate 1f (800 mg), yield 36%.

[0146] MS m / z (ESI): 512.2 [M+1]

[0147] Fifth step

[0148] methyl 5-(aminomethyl)-4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)thiophene-2-carboxylate

[0149] methyl 5-(aminomethyl)-4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)thiophene-2-carboxylate

[0150] Methyl 4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-5-(((tert- butoxycarbonyl)amino)methyl)thiophene-2-carboxylate 1f (1.6 g, 3.13 mmol) was dissolved in dichloromethane (20 mL), to the resulting solution was added trifluoroacetic acid (356.61 mg, 3.13 mmol, 5 mL). The reaction was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give methyl 5-(aminomethyl)-4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)thiophene-2-carboxylate 1g, which was used directly in the next step.

[0151] MS m / z (ESI): 412.2 [M+1]

[0152] Sixth step

[0153] methyl 10-(benzyloxy)-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate

[0154] 10-(benzyloxy)-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylic acid -2-carboxylic acid methyl ester

[0155] Methyl 10-(benzyloxy)-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate was prepared according to the procedure described in Example 1, Step 1, using methyl 5-(aminomethyl)-4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)thiophene-2-carboxylate 1g (960 mg, 2.22 mmol) and N,N-diisopropylethylamine (1.20 mL, 6.66 mmol, 1.10 g). The resulting mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (eluent: A system) to give methyl 10-(benzyloxy)-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate 1h (960 mg), 80% yield over two steps. -2-carboxylic acid methyl ester 1h (960 mg), 80% yield over two steps.

[0156] MS m / z (ESI): 380.2 [M+1]

[0157] Seventh step

[0158] methyl 1-(benzyloxy)-9H-benzo[c]thieno[3,2-e][1,2,4]triazolo[4,3-a]azepine-11-carboxylate

[0159] 1-(benzyloxy)-9H-benzo[c]thieno[3,2-e][1,2,4]triazolo[4,3-a]azepine-11-carboxylic acid -11-carboxylic acid methyl ester

[0160] Methyl 1-(benzyloxy)-9H-benzo[c]thieno[3,2-e][1,2,4]triazolo[4,3-a]azepine-11-carboxylate was prepared according to the procedure described in Example 1, Step 1, using methyl 10-(benzyloxy)-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate 1h (960 mg, 2.53 mmol) and N,N-diisopropylethylamine (1.20 mL, 6.66 mmol, 1.10 g). The resulting mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (eluent: A system) to give methyl 1-(benzyloxy)-9H-benzo[c]thieno[3,2-e][1,2,4]triazolo[4,3-a]azepine-11-carboxylate 1i (960 mg), 80% yield over two steps. -2-carboxylic acid methyl ester 1h (50 mg, 0.132 mmol) was dissolved in o-dichlorobenzene (3 mL), to the resulting solution was added phosphorous oxychloride (60.6 mg, 0.395 mmol) and N,N-dimethylaniline (79.8 mg, 0.659 mmol). The reaction was stirred at 130 °C for 2 hours. Formhydrazide (63.3 mg, 1.05 mmol) and N,N-diisopropylethylamine (68.1 mg, 0.527 mmol) were added to the above reaction, which was stirred at 100 °C for 18 hours. The solution was dropped into saturated aqueous sodium bicarbonate solution (15 mL), the resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, which was purified by silica gel column chromatography (eluent: A system) to give 1-(benzyloxy)-9H-benzo[c]thieno[3,2-e][1,2,4]triazolo[4,3-a]azepine-11-carboxylic acid methyl ester 1i (20 mg, 38% yield). -11-carboxylic acid methyl ester 1i (20 mg), yield 38%.

[0161] MS m / z (ESI): 404.0 [M+1]

[0162] Eighth step

[0163] 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

[0164] 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 -11-carboxamide

[0165] 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 - 11-carboxylic acid methyl ester 1i (30.0 mg, 0.0744 mmol) and N-(3-amino-5- chlorophenyl)methanesulfonamide 1j (32.8 mg, 0.149 mmol, prepared according to the published patent “WO2023154519”) were dissolved in tetrahydrofuran (5 mL), to the resulting mixture was slowly added trimethylaluminum (2 M, 0.37 mL). The reaction was stirred at 60 °C for 2 hours. The reaction was slowly added to methanol (50 mL) to quench the reaction. The resulting mixture was concentrated under reduced pressure, then purified by silica gel column chromatography (eluent: system A) and then purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3 + H2O, mobile phase B: CH3CN) to give 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 - 11-carboxamide 1 (20 mg) in 45% yield.

[0166] MS m / z (ESI): 592.2 [M+1]

[0167] 1 H NMR (400 MHz, DMSO-d6) 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).

[0168] Example 2

[0169] 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

[0170] 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 - 11-carboxamide

[0171] First Step

[0172] 1-(benzyloxy)-9H-benzo[f]thieno[2,3-d][1,2,4]triazolo[4,3-a]azepine-11-carboxylate

[0173] 1-(benzyloxy)-9H-benzo[f]thieno[2,3-d][1,2,4]triazolo[4,3-a]azepine-11-carboxylate -11-carboxylate

[0174] 1-(benzyloxy)-9H-benzo[f]thieno[2,3-d][1,2,4]triazolo[4,3-a]azepine-11-carboxylate -2-carboxylate 1h (150 mg, 0.395 mmol) was dissolved in o-dichlorobenzene (5 mL) and to the resulting solution was added phosphorous oxychloride (182 mg, 1.19 mmol) and N,N-dimethylaniline (240 mg, 1.98 mmol). The reaction was stirred at 130 °C for 3 hours to give a green solution. Formohydrazide (127 mg, 2.11 mmol, commercially available) and N,N-diisopropylethylamine (204 mg, 1.58 mmol) were added to the above reaction and stirred at 110 °C for 4 hours. The solution was added dropwise to saturated aqueous sodium bicarbonate solution (15 mL) and the resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was dried and concentrated under reduced pressure and purified by silica gel column chromatography (eluent: system B) to give 1-(benzyloxy)-9H-benzo[f]thieno[2,3-d][1,2,4]triazolo[4,3-a]azepine-11-carboxylate -11-carboxylate 2a (50 mg), yield: 47%.

[0175] MS m / z (ESI): 404.1 [M+1]

[0176] Second Step

[0177] 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

[0178] 1-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-9H-benzo[f]thieno[2,3- d][1,2,4]triazolo[4,3-a]azepine - 11 -formamide

[0179] 1-(benzyloxy)-9H-benzo[f]thieno[2,3-d][1,2,4]triazolo[4,3-a]azepine -11-carboxylic acid methyl 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), to the resulting mixture solution was slowly added trimethylaluminum (2 M, 0.62 mL). The reaction solution was stirred at 60 °C for 18 hours. The reaction solution was slowly added to methanol (50 mL) to quench the reaction. The resulting mixture solution was concentrated under reduced pressure, purified with silica gel column chromatography (eluent: system B), and further purified with preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3 + H2O, mobile phase B: CH3CN) to obtain 1-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-9H- benzo[f]thieno[2,3-d][1,2,4]triazolo[4,3-a]azepine -11-formamide 2 (40 mg), yield: 54%. MS m / z (ESI): 592.2 [M+1]

[0180] 1 H NMR (400 MHz, DMSO-d6) 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).

[0181] Example 3

[0182] 1-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]azepine-11-carboxamide

[0183] 1-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]azepine-11-carboxamide -11-carboxamide

[0184] First step

[0185] methyl 1-(benzyloxy)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]azepine-11-carboxylate

[0186] 1-(benzyloxy)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]azepine -11-carboxylic acid methyl ester

[0187] 10-(benzyloxy)-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-carboxylic acid methyl ester 1h (150 mg, 0.395 mmol) was dissolved in o-dichlorobenzene (3 mL) and to the resulting solution was added phosphorus oxychloride (182 mg, 1.19 mmol) and N,N-dimethylaniline (240 mg, 1.98 mmol). The reaction was stirred at 130 °C for 2 hours. To the reaction was added semicarbazide (333 mg, 3.16 mmol, commercially available) and N,N-diisopropylethylamine (204 mg, 1.58 mmol) and stirred at 120 °C for 18 hours. The solution was added dropwise to saturated aqueous sodium bicarbonate solution (15 mL) and the resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was dried and concentrated under reduced pressure and purified by silica gel column chromatography (eluent: system B) to give 1-(benzyloxy)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]azepine -11-carboxylic acid methyl ester 3a (30 mg), yield: 19%.

[0188] MS m / z (ESI): 403.2 [M+1]

[0189] Second step

[0190] 1-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]azepine-11-carboxamide

[0191] 1-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]azepine-11-carboxamide -11-carboxamide

[0192] 1-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]azepine-11-carboxamide -11-carboxamide 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 was stirred at 60 °C for 3 h. The reaction was quenched by slowly adding dropwise to methanol (50 mL). The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: system B) and then by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3 + H2O, mobile phase B: CH3CN) to give 1-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-9H-benzo[c]imidazo[1,2-a]thieno[3,2-e]azepine-11-carboxamide -11-carboxamide 3 (6 mg), yield: 14%.

[0193] MS m / z (ESI): 591.2 [M+1]

[0194] 1 H NMR (400 MHz, DMSO-d6) 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).

[0195] Example 4-5 were prepared according to the preparation method of Example 3 of the present application, the specific structures and structural characterization are as follows:

[0196] Example 6

[0197] 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

[0198] 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

[0199] First step

[0200] methyl 5-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrole-3-carboxylate

[0201] methyl 5-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrole-3-carboxylate

[0202] Methyl 5-bromo-1H-pyrrole-3-carboxylate 6a (4.0 g, 19.61 mmol) was dissolved in acetonitrile (400 mL), 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, and stirred at 80°C for 18 hours. The reaction solution was filtered, the filter cake was washed with acetonitrile (50 mL x 3), concentrated, and then purified by silica gel column chromatography (eluent: A system) to obtain methyl 5-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrole-3-carboxylate 6c (6.0 g), yield: 88.1%.

[0203] MS m / z (ESI): 290.9 [M+1-56]

[0204] Second step

[0205] 3-(benzyloxy)-2-bromobenzoic acid

[0206] 3-(benzyloxy)-2-bromobenzoic acid

[0207] To 3-(benzyloxy)-2-bromobenzaldehyde 6d (20.0 g, 68.70 mmol) was dissolved in acetonitrile (200 mL), and added periodic acid (31.32 g, 137.39 mmol, commercially available) and pyridinium chlorochromate (296 mg, 1.37 mmol, commercially available). Stirring at room temperature for 2 hours. The reaction was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: system B) to obtain 3-(benzyloxy)-2-bromobenzoic acid 6e (9.7 g), yield: 45.9%.

[0208] MS m / z (ESI): 307.0 [M+1]

[0209] Third step

[0210] methyl 3-(benzyloxy)-2-bromobenzoate

[0211] 3-(benzyloxy)-2-bromobenzoic acid methyl ester

[0212] To 3-(benzyloxy)-2-bromobenzoic acid 6e (9.7 g, 31.58 mmol) was dissolved in methanol (100 mL), and added concentrated sulfuric acid (1.55 g, 15.79 mmol), and stirred at 80°C for 12 hours. The reaction was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: system B) to obtain 3-(benzyloxy)-2-bromobenzoic acid methyl ester 6f (7.8 g), yield: 76.9%.

[0213] MS m / z (ESI): 321.0 [M+1]

[0214] Fourth step

[0215] methyl

[0216] 5-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrole-3-carboxylate

[0217] 5-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrole-3-carboxylate

[0218] Butylbis(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 ester 6c (5.5 g, 15.84 mmol), 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 mixture was purged with nitrogen three times and stirred at 80 °C for 2 hours under nitrogen protection. The resulting mixed solution was filtered under reduced pressure, and the filter cake was washed with dichloromethane (30 mL x 2). The resulting filtrate was purified by silica gel 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%.

[0219] MS m / z(ESI): 509.2 [M+1]

[0220] Step 5

[0221] methyl

[0222] 1-(2-aminoethyl)-5-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-1H-pyrrole-3-carboxylate

[0223] 1-(2-aminoethyl)-5-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-1H-pyrrole-3-carboxylic acid methyl ester

[0224] 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%.

[0225] MS m / z(ESI): 409.2 [M+1]

[0226] Sixth step

[0227] methyl

[0228] 12-(benzyloxy)-8-oxo-5,6,7,8-tetrahydrobenzo[f]pyrrolo[1,2-d][1,4]diazocine-2-carboxylate

[0229] 12-(benzyloxy)-8-oxo-5,6,7,8-tetrahydrobenzo[f]pyrrolo[1,2-d][1,4]diazocine-2-carboxylate

[0230] Methyl 1-(2-aminoethyl)-5-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-1H-pyrrole-3-carboxylate 6h (400 mg, 979.32 μmol) was dissolved in dioxane (10 mL), and trimethylaluminum (2 M, 3.9 mL) was added dropwise slowly. The reaction was heated to 100 °C and stirred for 2 hours. The reaction was quenched by slowly adding methanol (20 mL) dropwise, and the reaction was concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: system B) gave methyl 12-(benzyloxy)-8-oxo-5,6,7,8-tetrahydrobenzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate 6i (250 mg), in a yield of 67.8%.

[0231] MS m / z (ESI): 377.2 [M+1]

[0232] Seventh step

[0233] methyl

[0234] 1-(benzyloxy)-9,10-dihydrobenzo[f]pyrrolo[1,2-d][1,2,4]triazolo[3,4-h][1,4]diazocine-13-carboxylate

[0235] 2-(benzyloxy)-8-oxo-5,6,7,8-tetrahydrobenzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylic acid

[0236] Methyl 12-(benzyloxy)-8-oxo-5,6,7,8-tetrahydrobenzo[f]pyrrolo[l,2- d][l,4]diazocine-2-carboxylate 6i (100 mg, 0.266 mmol) was dissolved in toluene (5 mL) and to the resulting solution was added phosphorous oxychloride (163 mg, 1.06 mmol) and N,N-dimethylaniline (96.6 mg, 0.797 mmol). The reaction was stirred at 90 °C for 2 h. Formylhydrazine (121 mg, 2.03 mmol) and N,N-diisopropylethylamine (131 mg, 1.01 mmol) were added to the reaction and stirred at 90 °C for 18 h. The solution was added dropwise to saturated aqueous sodium bicarbonate (15 mL) and the resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was dried and concentrated under reduced pressure and purified by silica gel column chromatography (eluent: system B) to give 12-(benzyloxy)-8-oxo-5,6,7,8-tetrahydrobenzo[f]pyrrolo[l,2- d][l,4]diazocine-2-carboxylic acid 6j (30 mg), yield: 30%.

[0237] MS m / z (ESI): 401.1 [M+1]

[0238] Eighth Step

[0239] 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

[0240] 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

[0241] To a solution of 12-(benzyloxy)-8-oxo-5,6,7,8-tetrahydrobenzo[f]pyrrolo[l,2- d][l,4]diazepine-2-carboxylic acid 6j (30.0 mg, 0.0749 mmol) and N-(3-amino-5- chlorophenyl)methanesulfonamide lj (33.1 mg, 0.150 mmol) in tetrahydrofuran (5 mL), trimethylaluminum (2 M, 0.37 mL) was added dropwise slowly. The reaction was stirred at 60 °C for 18 h. The reaction was quenched by adding dropwise slowly into methanol (50 mL). The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: system B) and then by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3 + H2O, mobile phase B: CH3CN) to give l-(benzyloxy)-N-(3-chloro-5- (methanesulfonamido)phenyl)-9,10-dihydrobenzo[f]pyrrolo[l,2-d][l,2,4]triazolo[3,4- h][l,4]diazepine-13-carboxamide 6 (10 mg), yield: 23%.

[0242] MS m / z (ESI): 589.2 [M+1]

[0243] 1 H NMR (400 MHz, DMSO-d6) 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)

[0244] Example 7 was prepared according to the procedure described in Example 6 of the present application. The structure and structure characterization are as follows:

[0245] Example 8

[0246] 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

[0247] 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 -12-carboxamide

[0248] First step

[0249] methyl 5-bromo-1-(2-methoxy-2-oxoethyl)-1H-pyrrole-3-carboxylate

[0250] methyl 5-bromo-1-(2-methoxy-2-oxoethyl)-1H-pyrrole-3-carboxylate

[0251] Methyl 5-bromo-l-(2-methoxy-2-oxoethyl)-lH-pyrrole-3-carboxylate 8a (4.0 g) was prepared from methyl 5-bromo-lH-pyrrole-3-carboxylate 6a (5.0 g, 24.51 mmol) and cesium carbonate (23.95 g, 73.52 mmol) in acetonitrile (100 mL) by adding methyl bromoacetate (7.5 g, 49.01 mmol, commercially available) to the resulting mixture solution. The reaction was stirred at 80 °C for 18 hours. The reaction was filtered, the filter cake was washed with ethyl acetate (50 mL), and the resulting filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: A system) to give methyl 5-bromo-l-(2-methoxy-2-oxoethyl)-lH-pyrrole-3-carboxylate 8a (4.0 g) in 59% yield.

[0252] MS m / z (ESI): 275.9 [M+1]

[0253] Second step

[0254] 2-bromo-1-((3,5-difluorobenzyl)oxy)-3-nitrobenzene

[0255] 2-bromo-1-((3,5-difluorobenzyl)oxy)-3-nitrobenzene

[0256] 2-Bromo-3-nitrophenol 8b (5 g, 22.94 mmol) was dissolved in acetonitrile (45 mL). 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 silica gel column chromatography (eluent: system A) to give 2-bromo-1-((3,5-difluorobenzyl)oxy)-3-nitrobenzene 8c (6.7 g), yield: 85%.

[0257] MS m / z(ESI): no signal

[0258] Step 3

[0259] 2-bromo-3-((3,5-difluorobenzyl)oxy)aniline

[0260] 2-Bromo-3-((3,5-difluorobenzyl)oxy)aniline

[0261] 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 silica gel column chromatography (eluent: system A) to give 2-bromo-3-((3,5-difluorobenzyl)oxy)aniline 8d (5.0 g), yield: 82%.

[0262] MS m / z(ESI): 314.0 [M+1]

[0263] Step 4

[0264] methyl

[0265] 11-((3,5-difluorobenzyl)oxy)-6-oxo-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[0266] 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

[0267] 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). To the resulting mixture, 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. After purging with nitrogen three times, the reaction mixture was stirred at 80 °C for 18 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: system A) to obtain 1-((3,5-difluorobenzyl)oxy)-6-oxo-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza 2-Carboxylic acid methyl ester 8e (450 mg), yield: 35%.

[0268] MS m / z(ESI): 399.1 [M+1]

[0269] Step 5

[0270] methyl

[0271] 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]imidazo[1,2-a]pyrrolo[1,2-d][1,4]diazepine-12-carboxylate

[0272] 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]imidazo[1,2-a]pyrrolo[1,2-d][1,4]diaza methyl 1,2-carboxylate

[0273] 1-((3,5-difluorobenzyl)oxy)-6-oxo-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza -2-carboxylic acid methyl ester 8e (200 mg, 0.50 mmol) was dissolved in o-dichlorobenzene (5 mL), to the resulting solution was added phosphorous oxychloride (0.14 mL, 1.51 mmol) and N,N-dimethylaniline (304 mg, 2.51 mmol). The reaction 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 and stirred at 130 °C for 18 hours. The solution was dropped into water (100 mL) and extracted with ethyl acetate (100 mL), the organic phase was dried and concentrated under reduced pressure, purified by silica gel column chromatography (eluent: system A) to give 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]imidazo[1,2-a]pyrrolo[1,2-d][1,4]diazepine-12-carboxylic acid methyl ester 8f (110 mg), yield: 52%. -12-carboxylic acid methyl ester 8f (110 mg), yield: 52%.

[0274] MS m / z (ESI): 422.1 [M+1]

[0275] Sixth step

[0276] 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

[0277] 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 -12-carboxamide

[0278] 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 Methyl 1,2-carboxylate 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 was quenched by slowly adding the reaction solution to methanol (20 mL). The resulting mixed solution was concentrated under reduced pressure, purified by silica gel 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-(methanesulfonamide)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]imidazo[1,2-a]pyrrolo[1,2-d][1,4]diaza -12-Formamide 8 (53.6 mg), yield: 46%.

[0279] MS m / z(ESI): 610.1 [M+1]

[0280] 1 H NMR (400MHz, DMSO-d6) δ10.00(s,1H),9.84(s,1H),7.84(d,J=2.0Hz,1H),7.66(d,J =2.0Hz,2H),7.61(t,J=2.0Hz,1H),7.53(t,J=8.2Hz,1H),7.31–7.23(m,3H),7.23– 7.11(m,3H),7.02(d,J=1.6Hz,1H),6.89(t,J=2.0Hz,1H),5.46(d,J=15.2Hz,1H),5 .40(d,J=13.2Hz,1H),5.22(d,J=13.2Hz,1H),5.01(d,J=15.2Hz,1H),3.05(s,3H).

[0281] Example 9

[0282] 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

[0283] 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 -12-carboxamide

[0284] First step

[0285] methyl

[0286] 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]diazepine-12-carboxylate

[0287] 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]diazepine-12-carboxylate -12-carboxamide

[0288] 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]diazepine-12-carboxylate -2-carboxylate 8e (80 mg, 0.20 mmol) was dissolved in o-dichlorobenzene (5 mL), to the resulting solution was added phosphorous oxychloride (0.06 mL, 0.60 mmol) and N,N-dimethylaniline (122 mg, 1.00 mmol). The reaction was stirred at 130 °C for 2 hours. Formylhydrazide (121 mg, 2.01 mmol) and N,N-diisopropylethylamine (130 mg, 1.00 mmol) were added to the reaction, which was stirred at 130 °C for 18 hours. The solution was dropped into water (100 mL), extracted with ethyl acetate (100 mL), the organic phase was dried and concentrated under reduced pressure, purified by silica gel column chromatography (eluent: A system) to obtain 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]diazepine-12-carboxamide -12-carboxamide 9a (40 mg), yield: 47%.

[0289] MS m / z (ESI): 423.2 [M+1]

[0290] Second step

[0291] 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

[0292] 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 -12-carboxamide

[0293] 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 -12-carboxamide 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 was stirred at 60 °C for 2 hours. The reaction was quenched by slowly adding dropwise to methanol (20 mL). The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: system B) and then by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3 + H2O, mobile phase B: CH3CN) to give 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 -12-carboxamide 9 (10.7 mg), yield: 18%.

[0294] MS m / z (ESI): 611.1 [M+1]

[0295] 1H NMR (400 MHz, DMSO-d6) 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).

[0296] Example 10

[0297] 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

[0298] 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 -12-carboxamide

[0299] First Step

[0300] methyl

[0301] 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d]tetrazolo[1,5-a][1,4]diazepine-12-carboxylate

[0302] 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d]tetrazolo[1,5-a][1,4]diazepine-12-carboxylate -12-carboxylate

[0303] 1-((3,5-difluorobenzyl)oxy)-6-oxo-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine 1-2-carboxylic acid methyl ester 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), dried, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: system A) to give 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d]tetrazolo[1,5-a][1,4]diaza 12-Carboxylic acid methyl ester 10a (80 mg), yield: 76%.

[0304] MS m / z(ESI): 424.1 [M+1]

[0305] Step 2

[0306] 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

[0307] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d]tetrazolo[1,5-a][1,4]diazide -12-formamide

[0308] 1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d]tetrazolo[1,5-a][1,4]diaza Methyl 1,2-carboxylate 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 was quenched by slowly adding the reaction solution to methanol (20 mL). The resulting mixed solution was concentrated under reduced pressure, purified by silica gel 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-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-9H-benzo[f]pyrrolo[1,2-d]tetrazolo[1,5-a][1,4]diazide -12-Formamide 10 (40.7 mg), yield: 35%.

[0309] MS m / z(ESI): 612.1 [M+1]

[0310] 1 H NMR (400MHz, DMSO-d6) δ10.00(s,1H),9.92(s,1H),7.92(d,J=2.0Hz,1H),7.69–7.62(m,2H),7.62–7.55(m,2H),7.46(dd,J =8.0,1.2Hz,1H),7.41(d,J=2.0Hz,1H),7.28–7.11(m,3H),6.90(t,J=2.0Hz,1H),6.08(bs,1H),5.37(bs,3H),3.05(s,3H).

[0311] Example 11

[0312] 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

[0313] 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-2-carboxamide -12-carboxamide

[0314] First Step

[0315] methyl 5-bromo-1-(5-methoxy-2,5-dioxopentyl)-1H-pyrrole-3-carboxylate

[0316] 5-bromo-1-(5-methoxy-2,5-dioxopentyl)-1H-pyrrole-3-carboxylic acid methyl ester

[0317] Methyl 5-bromo-1H-pyrrole-3-carboxylate 6a (1.00 g, 4.90 mmol) (XHB020) was dissolved in acetonitrile (20 mL), to the resulting solution was added methyl 5-bromo-4-oxo-pentanoate 11a (1.54 g, 7.35 mmol, commercially available) and potassium carbonate (3.19 g, 9.80 mmol). The reaction was stirred at 60 °C for 1 hour. The system was filtered and concentrated under reduced pressure, purified by silica gel column chromatography (eluent: A system) to give methyl 5-bromo-1-(5-methoxy-2,5-dioxopentyl)-1H-pyrrole-3-carboxylate 11b (1.0 g), yield: 61%.

[0318] MS m / z (ESI): 332.0 [M+1]

[0319] Second Step

[0320] methyl

[0321] 11-((3,5-difluorobenzyl)oxy)-6-(3-methoxy-3-oxopropyl)-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[0322] 11-((3,5-difluorobenzyl)oxy)-6-(3-methoxy-3-oxopropyl)-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate -2-carboxylic acid methyl ester

[0323] Methyl 5-bromo-1-(5-methoxy-2,5-dioxopentyl)-1H-pyrrole-3-carboxylic acid ester 11b (820 mg, 2.47 mmol) was dissolved in 1,4-dioxane (20 mL). To the resulting solution, 2-bromo-3-((3,5-difluorobenzyl)oxy)aniline 8d (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 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, then purified by silica gel column chromatography (eluent: system A) to obtain 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 11c (300mg), yield: 25%.

[0324] MS m / z(ESI): 469.1 [M+1]

[0325] Step 3

[0326] methyl

[0327] 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

[0328] 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

[0329] 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 11c (60 mg, 0.128 mmol) and palladium on carbon 10% (30 mg, 0.282 mmol) were dissolved in methanol (3 mL), after hydrogen replacement, 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 obtain 11-((3,5-difluorobenzyl)oxy)-6-(3-methoxy-3-oxopropyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-12-carboxylic acid methyl ester -2-carboxylic acid methyl ester 11d (40 mg), yield: 67%.

[0330] MS m / z (ESI): 471.1 [M+1]

[0331] Fourth step

[0332] methyl

[0333] 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

[0334] 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 -12-carboxylic acid methyl ester

[0335] 11-((3,5-difluorobenzyl)oxy)-6-(3-methoxy-3-oxopropyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-12-carboxylic acid methyl ester -2-carboxylic acid methyl ester 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 mixed solution. The reaction solution was stirred at 60 °C for 36 hours. The reaction solution was slowly added dropwise to methanol (50 mL) to quench the reaction. The resulting mixed solution was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: A system) to obtain 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-carboxylic acid methyl ester -12-carboxylic acid methyl ester 11e (50 mg), yield: 67%.

[0336] MS m / z (ESI): 439.0 [M+1]

[0337] Fifth step

[0338] 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

[0339] 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 -12-carboxamide

[0340] 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 -12-carboxamide 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 was stirred at 60 °C for 18 h. The reaction was quenched by slowly adding dropwise to methanol (30 mL). The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: system B) and then by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3 + H2O, mobile phase B: CH3CN) to give 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 -12-carboxamide 11 (13.5 mg), yield: 31%.

[0341] MS m / z (ESI): 627.1 [M+1]

[0342] 1H NMR (400 MHz, DMSO-d6) 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).

[0343] Example 12

[0344] 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

[0345] 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 -12-formamide

[0346] First step

[0347] methyl

[0348] 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

[0349] 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 - 12-carboxylic acid methyl ester

[0350] 1-((3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'- d][1,4]diazepine-12-carboxylic acid methyl ester - 12-carboxylic acid methyl ester 11e (30.0 mg, 0.0684 mmol) was dissolved in borane tetrahydrofuran solution (3 mL, 1M), and the reaction solution was placed at 60 °C for 2 hours. After the mixed solution was dropped into methanol (20 mL) to quench, the solution was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: A system) to obtain 1-((3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'- d][1,4]diazepine-12-carboxylic acid methyl ester - 12-carboxylic acid methyl ester 12a (25 mg)], yield: 86%.

[0351] MS m / z (ESI): 425.2 [M+1]

[0352] Second step

[0353] 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

[0354] 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 - 12-carboxamide

[0355] 1-((3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydro-6H-benzo[f]dipyrrolo[1,2-a:1',2'- d][1,4]diazepine-12-carboxylic acid methyl ester - 12-carboxylic acid methyl 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), to the resulting mixture solution was slowly added trimethylaluminum (2 M, 0.35 mL). The reaction solution was stirred at 60 °C for 2 hours. The reaction solution was slowly added to methanol (30 mL) to quench the reaction. The resulting mixture solution was concentrated under reduced pressure, purified with silica gel column chromatography (eluent: system B), and further purified with preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3 + H2O, mobile phase B: CH3CN) to give N-(3-chloro-5- (methanesulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydro-6H- benzo[f]dipyrrolo[1,2-a:1',2'-d][1,4]diazepine-5(6H)-carboxamide 12j (7.3 mg, 17% yield). - 12-carboxamide 12 (7.3 mg), yield: 17%.

[0356] MS m / z (ESI): 613.1 [M+1]

[0357] 1 H NMR (400 MHz, DMSO-d6) 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).

[0358] Example 13

[0359] 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

[0360] 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 -13-carboxamide

[0361] First step

[0362] methyl 5-bromo-1-(2-hydroxy-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylate

[0363] methyl 5-bromo-1-(2-hydroxy-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylate

[0364] Methyl 5-bromo-l-(2-hydroxy-3-methoxy-3-oxopropyl)-lH-pyrrole-3-carboxylate 13b was prepared according to the procedure described for the preparation of methyl 5-bromo-l-(2-hydroxy-3-methoxy-3-oxopropyl)-lH-pyrrole-3-carboxylate 13b, using methyl 5-bromo-lH-pyrrole-3-carboxylate 6a (2.00 g, 9.80 mmol) and 2,3-epoxypropionic acid methyl ester 13a (2.50 g, 24.5 mmol).

[0365] MS m / z (ESI): 306.0 [M+1]

[0366] Second step

[0367] methyl

[0368] 5-(2-amino-6-((3,5-difluorobenzyl)oxy)phenyl)-1-(2-hydroxy-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylate

[0369] 5-(2-amino-6-((3,5-difluorobenzyl)oxy)phenyl)-1-(2-hydroxy-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylate

[0370] Methyl 5-(2-amino-6-((3,5-difluorobenzyl)oxy)phenyl)-1-(2-hydroxy-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylate 13c was prepared according to the procedure described in Example 1, Step 4, using methyl 5-bromo-1-(2-hydroxy-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylate 13b (800 mg, 2.61 mmol) and 2-bromo-3-((3,5-difluorobenzyl)oxy)aniline 8d (1.07 g, 3.40 mmol). The reaction mixture was stirred at 80 °C for 18 h under nitrogen. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: A system) to give methyl 5-(2-amino-6-((3,5-difluorobenzyl)oxy)phenyl)-1-(2-hydroxy-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylate 13c (350 mg, 29% yield).

[0371] MS m / z (ESI): 461.1 [M+1]

[0372] Third Step

[0373] methyl

[0374] 5-(2-amino-6-((3,5-difluorobenzyl)oxy)phenyl)-1-(2-bromo-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylate

[0375] 5-(2-amino-6-((3,5-difluorobenzyl)oxy)phenyl)-1-(2-bromo-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylate

[0376] 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.

[0377] MS m / z(ESI): 523.2 [M+1]

[0378] Step 4

[0379] dimethyl

[0380] 11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2,6-dicarboxylate

[0381] 11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza Dimethyl 2,6-dicarboxylic acid ester

[0382] 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-pyrrolo-3-carboxylic acid ester 13d (1.2 g, crude) and reacted at 60°C for 3 hours. The resulting mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: system A) to obtain 11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza Dimethyl 2,6-dicarboxylate 13e (70 mg), yield: 15%.

[0383] MS m / z(ESI): 443.1 [M+1]

[0384] Step 5

[0385] methyl

[0386] 11-((3,5-difluorobenzyl)oxy)-6-(hydroxymethyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[0387] 11-((3,5-difluorobenzyl)oxy)-6-(hydroxymethyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate -2-carboxylic acid methyl ester

[0388] 25 °C, to a solution of 11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2,6-dicarboxylic acid dimethyl ester 13e (300 mg, 0.678 mmol) in methanol (8.0 mL) was added sodium borohydride (128 mg, 3.39 mmol) and the reaction was stirred for 2 h. The reaction was concentrated under reduced pressure and purified by column chromatography on silica gel (eluent: system A) to give 11-((3,5-difluorobenzyl)oxy)-6-(hydroxymethyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylic acid methyl ester 13f (70 mg), yield: 25%. -2-carboxylic acid methyl ester -2-carboxylic acid methyl ester

[0389] MS m / z (ESI): 415.2 [M+1]

[0390] Sixth step

[0391] methyl

[0392] 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

[0393] 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 -13-carboxylic acid methyl ester

[0394] 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 -2-carboxylate 13f (40 mg, 0.0965 mmol) was dissolved in tetrahydrofuran (6.0 mL), to the resulting solution was added methyl chloroacetate (62.9 mg, 0.579 mmol, commercially available) and potassium tert-butoxide (65.0 mg, 0.579 mmol). The reaction was stirred at 25 °C for 2 hours. The resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL), the organic phase was dried and concentrated under reduced pressure, purified by silica gel column chromatography (eluent: A system) to give 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-carboxylic acid methyl ester 13g (30 mg), yield: 68%. -13-carboxylate 13g (30 mg), yield: 68%.

[0395] MS m / z (ESI): 455.0 [M+1]

[0396] 1 H NMR (400 MHz, DMSO-d6) 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).

[0397] Seventh step

[0398] 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

[0399] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-6-oxo- 6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazepino[4,3-a]pyrrolo[1,2-d][1,4]diazepine - 13-carboxylic acid methyl ester

[0400] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-6-oxo- 6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazepino[4,3-a]pyrrolo[1,2-d][1,4]diazepine - 13-carboxylic acid methyl ester 13g (20 mg, 0.0440 mmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide 1j (19.4 mg, 0.0880 mmol) were dissolved in tetrahydrofuran (5 mL), to the resulting mixture solution was slowly added trimethylaluminum (2 M, 0.22 mL). The reaction was stirred at 60 °C for 18 hours. The reaction was quenched by slowly adding to methanol (30 mL). The resulting mixture was concentrated under reduced pressure, purified by silica gel column chromatography (eluent: system B), and then separated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3 + H2O, mobile phase B: CH3CN) to give N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((3,5-difluorobenzyl)oxy)-6-oxo- 6,7,9a,10-tetrahydro-9H-benzo[f][1,4]oxazepino[4,3-a]pyrrolo[1,2-d][1,4]diazepine - 13-carboxylic acid methyl ester 13 (12.7 mg), yield: 45%.

[0401] MS m / z (ESI): 643.2 [M+1]

[0402] 1H NMR (400 MHz, DMSO-d6) 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).

[0403] Example 14

[0404] 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

[0405] 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 -13-carboxamide

[0406] First Step

[0407] 2-bromo-1-((3-fluorobenzyl)oxy)-3-nitrobenzene

[0408] 2-bromo-1-((3-fluorobenzyl)oxy)-3-nitrobenzene

[0409] To a solution of 2-bromo-3-nitrophenol 8b (25 g, 114.68 mmol) in acetonitrile (300 mL) was added cesium carbonate (74.7 g, 229.35 mmol) and 3-fluorobenzyl bromide (32.5 g, 172.01 mmol, 21.10 mL). The reaction was stirred at 25 °C for 18 h. The resulting mixture was diluted with water (500 mL) and extracted with ethyl acetate (300 mL x 2). The organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-bromo-1-((3-fluorobenzyl)oxy)-3-nitrobenzene 14a which was used directly in the next step.

[0410] MS m / z (ESI): no signal. [M+1]

[0411] Second step

[0412] 2-bromo-3-((3-fluorobenzyl)oxy)aniline

[0413] 2-bromo-3-((3-fluorobenzyl)oxy)aniline

[0414] To a solution of 2-bromo-1-((3-fluorobenzyl)oxy)-3-nitrobenzene 14a (28 g, 85.86 mmol) in ethanol (400 mL) was added iron powder (14.4 g, 257.58 mmol), ammonium chloride (13.8 g, 257.58 mmol) and water (200 mL). The reaction was stirred at 90 °C for 18 h. The resulting mixture 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 organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: A system) gave 2-bromo-3-((3-fluorobenzyl)oxy)aniline 14b (23.6 g) in 93% yield.

[0415] MS m / z (ESI): 296.0 [M+1]

[0416] Third step

[0417] methyl

[0418] 5-(2-amino-6-((3-fluorobenzyl)oxy)phenyl)-1-(2-hydroxy-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylate

[0419] 5-(2-amino-6-((3-fluorobenzyl)oxy)phenyl)-1-(2-hydroxy-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylic acid methyl ester

[0420] To a solution of 2-bromo-3-((3-fluorobenzyl)oxy)aniline 14b (4.02 g, 13.59 mmol) and 55-bromo-1-(2-hydroxy-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylic acid methyl ester 13b (3.2 g, 10.45 mmol) in 1,4-dioxane (60 mL) was added pinacol diborane (7.96 g, 31.36 mmol), n-butyl bis(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). The reaction was purged with nitrogen for 3 times and stirred at 80 °C for 18 h under nitrogen. The resulting mixture was filtered under reduced pressure, the filter cake was washed with dichloromethane (20 mL x 2), the resulting filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: A system) to give 5-(2-amino-6-((3-fluorobenzyl)oxy)phenyl)-1-(2-hydroxy-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylic acid methyl ester 14c (1.3 g), yield: 28%.

[0421] MS m / z (ESI): 443.2 [M+1]

[0422] Fourth step

[0423] methyl

[0424] 5-(2-amino-6-((3-fluorobenzyl)oxy)phenyl)-1-(2-hydroxy-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylic acid methyl ester

[0425] 5-(2-amino-6-((3-fluorobenzyl)oxy)phenyl)-1-(2-hydroxy-3-methoxy-3-oxopropyl)-1H-pyrrole-3-carboxylic acid methyl ester

[0426] 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 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, which was used directly in the next step.

[0427] MS m / z (ESI): 505.1 [M+1]

[0428] Step 5

[0429] dimethyl

[0430] 11-((3-fluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2,6-dicarboxylate

[0431] 11-((3-fluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza Dimethyl 2,6-dicarboxylic acid ester

[0432] Cesium carbonate (1.4 g, 2.77 mmol) was added to a 20 mL solution of methyl 5-(2-amino-6-((3-fluorobenzyl)oxy)phenyl)-1-(2-bromo-3-methoxy-3-oxypropyl)-1H-pyrrolo-3-carboxylic acid ester 14d in tetrahydrofuran. 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 silica gel column chromatography (eluent: system A) to give 11-((3-fluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diaza Dimethyl 2,6-dicarboxylate 14e (300 mg), yield: 25%. MS m / z (ESI): 425.1 [M+1]

[0433] Step 6

[0434] methyl

[0435] 11-((3-fluorobenzyl)oxy)-6-(hydroxymethyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[0436] 11-((3-Fluorobenzyl)oxy)-6-(hydroxymethyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate -2-carboxylic acid methyl ester

[0437] 11-((3-Fluorobenzyl)oxy)-6-(hydroxymethyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate -2,6-dicarboxylic acid dimethyl ester 14e (120 mg, 282.74 μmol) 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 solution was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: A system) to obtain 11-((3-fluorobenzyl)oxy)-6-(hydroxymethyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate -2-carboxylic acid methyl ester 14f (90 mg), yield: 80%.

[0438] MS m / z (ESI): 397.1 [M+1]

[0439] Seventh Step

[0440] methyl

[0441] 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

[0442] 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 -13-carboxylic acid methyl ester

[0443] 11-((3-Fluorobenzyl)oxy)-6-(hydroxymethyl)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate -2-carboxylate 14f (100 mg, 252.26 μmol) was dissolved in tetrahydrofuran (5 mL), to the resulting solution was added methyl chloroacetate (164.26 mg, 1.51 mmol) and potassium tert-butoxide (169.84 mg, 1.51 mmol). The reaction was stirred at 25 °C for 2 hours. The resulting 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 silica gel column chromatography (eluent: A system) to give 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 (70 mg, 160.39 μmol, 63.7% yield) as a white solid. -13-carboxylate 14g (80 mg), yield: 73%.

[0444] MS m / z (ESI): 437.1 [M+1]

[0445] Eighth step

[0446] methyl

[0447] 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

[0448] 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 -13-carboxylate

[0449] 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 -13-carboxylate 14g (70 mg, 160.39 μmol) was dissolved in borane tetrahydrofuran complex (1 M, 2 mL). The reaction was stirred at 60 °C for 2 hours. The reaction was quenched by slowly dropping into methanol (5 mL). The resulting mixture was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: A system) to give 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 (70 mg, 160.39 μmol, 63.7% yield) as a white solid. - 13-carboxylic acid methyl ester 14h (40 mg), yield: 59%.

[0450] MS m / z (ESI): 423.1 [M+1]

[0451] Ninth step

[0452] 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

[0453] 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 - 13-carboxamide

[0454] 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 - 13-carboxylic acid methyl 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 was stirred at 60 °C for 18 hours. The reaction was quenched by slowly adding dropwise to methanol (10 mL). The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: system B) and then by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3 + H2O, mobile phase B: CH3CN) to give 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 - 13-carboxamide 14 (32 mg), yield: 53%.

[0455] MS m / z (ESI): 611.1 [M+1]

[0456] 1 H NMR (400 MHz, DMSO-d6) 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).

[0457] Example 15

[0458] 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

[0459] 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 -12-carboxamide

[0460] First Step

[0461] 2-bromo-3-((3-fluorobenzyl)oxy)benzaldehyde

[0462] 2-bromo-3-((3-fluorobenzyl)oxy)benzaldehyde

[0463] To a solution of 2-bromo-3-hydroxybenzaldehyde 15a (25.0 g, 124.37 mmol, commercially available) in acetonitrile (250 mL) was added cesium carbonate (121.56 g, 373.10 mmol) and 3-fluorobenzyl bromide (47.02 g, 248.73 mmol) at room temperature and stirred for 18 h. The reaction mixture was poured into water (150 mL) and extracted with dichloromethane (200 mL x 3). After concentration, purification by silica gel column chromatography (eluent: system A) gave 2-bromo-3-((3-fluorobenzyl)oxy)benzaldehyde 15b (20.0 g) in 52.2% yield.

[0464] MS m / z (ESI): 309.0 [M+1]

[0465] Second step

[0466] 3-(2-bromo-3-((3-fluorobenzyl)oxy)phenyl)morpholine

[0467] 3-(2-bromo-3-((3-fluorobenzyl)oxy)phenyl)morpholine

[0468] To a solution of 2-bromo-3-((3-fluorobenzyl)oxy)benzaldehyde 15b (250 mg, 0.800 mmol) in dichloromethane (1.5 mL) was added [2-(2-amino-ethoxy)methyl]tributylstannane 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). The reaction mixture was stirred at 25 °C for 16 h. The resulting mixture was added to aqueous ammonia (2 mL) and extracted with dichloromethane (10 mL x 2). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: system A) gave 3-(2-bromo-3-((3-fluorobenzyl)oxy)phenyl)morpholine 15d (170 mg) in 57% yield.

[0469] MS m / z (ESI): 366.0 [M+1]

[0470] Third step

[0471] methyl

[0472] 4-bromo-5-((3-(2-bromo-3-((3-fluorobenzyl)oxy)phenyl)morpholino)methyl)thiophene-2-carboxylate

[0473] 4-bromo-5-((3-(2-bromo-3-((3-fluorobenzyl)oxy)phenyl)morpholino)methyl)thiophene-2-carboxylic acid methyl ester

[0474] Methyl 4-bromo-5-((3-(2-bromo-3-((3-fluorobenzyl)oxy)phenyl)morpholino)methyl)thiophene-2-carboxylate 15f was prepared from 3-(2-bromo-3-((3-fluorobenzyl)oxy)phenyl)morpholine 15d (170 mg, 0.460 mmol) following the procedure for the preparation of 4-bromo-5-((3-(2-bromo-3-((3-fluorobenzyl)oxy)phenyl)morpholino)methyl)thiophene-2-carboxylic acid methyl ester 15f. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (eluent: system B) to give 4-bromo-5-((3-(2-bromo-3-((3-fluorobenzyl)oxy)phenyl)morpholino)methyl)thiophene-2-carboxylic acid methyl ester 15f (210 mg, 75% yield).

[0475] MS m / z (ESI): 598.0 [M+1]

[0476] Fourth step

[0477] methyl

[0478] 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

[0479] 1-((3-Fluorobenzyl)oxy)-4b,7,8,10-tetrahydro-5H-benzo[c][1,4]oxazino[4,3-a]thieno[3,2-e]azepine-12-carboxylic acid methyl ester

[0480] ​Methyl 4-bromo-5-((3-(2-bromo-3-((3-fluorobenzyl)oxy)phenyl)morpholino)methyl)thiophene-2-carboxylate 15f (210 mg, 0.350 mmol) was dissolved in 1,4-dioxane (2 mL), to the resulting solution was added pinacol diborane (266 mg, 1.05 mmol), [n-butyldi(1-adamantyl)phosphine]methanesulfonic acid (2-amino-1,1'- biphenyl-2-yl)palladium(II) (25.5 mg, 0.0300 mmol), potassium carbonate (145 mg, 1.05 mmol) and water (0.4 mL). The reaction was purged with nitrogen for 3 times and stirred at 80 °C for 16 h under nitrogen. The resulting mixture was filtered under reduced pressure, the filter cake was washed with dichloromethane (10 mL x 2), the resulting filtrate was concentrated under reduced pressure, purified by silica gel column chromatography (eluent: A system) to give 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 15g (75 mg), yield: 48%.

[0481] MS m / z (ESI): 440.2 [M+1]

[0482] Fifth step

[0483] 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

[0484] 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 -12-carboxamide

[0485] 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 ​- 12-carboxylic acid methyl ester 15g (75.0 mg, 0.170 mmol) and N-(3-amino-5- chlorophenyl)methanesulfonamide 1j (60.2 mg, 0.270 mmol) were dissolved in tetrahydrofuran (1 mL), and trimethylaluminum (2 M, 0.54 mL, n-hexane solution) was slowly added dropwise to the resulting mixed solution. The reaction solution was stirred at 60 °C for 2 hours. The reaction solution was slowly added dropwise to methanol (5 mL) to quench the reaction. The resulting mixed solution was concentrated under reduced pressure, purified by silica gel column chromatography (eluent: B system), and further purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3 + H2O, mobile phase B: CH3CN) to obtain N-(3-chloro-5- (methanesulfonamido)phenyl)-1-((3-fluorobenzyl)oxy)-4b,7,8,10-tetrahydro-5H- benzo[c][1,4]oxazepino[4,3-a]thieno[3,2-e]azepine - 12-carboxamide 15 (27 mg), yield: 31%.

[0486] MS m / z (ESI): 628.2 [M+1]

[0487] 1 H 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).

[0488] Biological evaluation

[0489] Test Example 1, Inhibition of CCRF-CEM cell proliferation by compounds of the present application

[0490] The following method was used to determine the effect of compounds of the present application on CCRF-CEM cell proliferation. CCRF-CEM cells (MSI-H cells) were purchased from the Chinese Academy of Sciences Cell Bank and cultured in RPMI-1640 medium containing 10% fetal bovine serum, 100 U of penicillin, and 100 μg / mL of streptomycin. Cell viability was determined by The Luminescent Cell Viability Assay kit (Promega, Cat# G7573) was used to determine the cell viability.

[0491] The experimental procedure was performed according to the kit instruction, briefly described as follows: the test compound was first dissolved in DMSO to prepare a 10 mM stock solution, then diluted with culture medium to prepare test samples, and the final concentration of the compound ranged from 10000 nM to 1.52 nM. Cells in the logarithmic growth phase were inoculated into a 96-well cell culture plate at a density of 1000 cells per well, then incubated in a 37°C air incubator for 120 hours after adding the test compound. After the incubation, 50 μL of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes, and then incubated for 10 minutes. Then the luminescence value of each well was read on a microplate reader using the Luminescence mode. The percentage inhibition of the compound at each concentration point was calculated by comparing the value with the control group (0.1% DMSO), and then the compound concentration-log-inhibition was subjected to non-linear regression analysis in GraphPad Prism 9 software to obtain the IC 50 value of the compound for inhibiting cell proliferation, as shown in Table 1.

[0492] Table 1 IC 50 data of the compound of the present application for inhibiting the proliferation of CCRF-CEM cells

[0493] Conclusion: The compound of the present application has a good inhibitory effect on the IC 50 <30 nM.

[0494] Note: The structure of ATX-968 (prepared according to Example 31 of the published patent WO2023154519A1) is as follows:

[0495] Test Example 2, determination of the inhibitory effect of the compound of the present application on the proliferation of LS411N cells

[0496] The following method was used to determine the effect of the compound of the present application 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 of penicillin and 100 μg / mL of streptomycin. Cell viability was determined by The Luminescent Cell Viability Assay kit (Promega, Cat# G7573) was used to determine the cell viability.

[0497] The experimental method is operated according to the steps of the kit instruction, and the brief description is as follows: the test compound is first dissolved in DMSO to prepare a 10 mM stock solution, then diluted with culture medium to prepare a test sample, and the final concentration of the compound is in the range of 10000 nM-0.152 nM. Cells in the logarithmic growth phase are inoculated into a 96-well cell culture plate at a density of 1000 cells per well, then after adding the test compound, incubated in a 37°C air incubator for 120 hours. After the incubation is completed, 50 μL of CellTiter-Glo detection solution is added to each well, shaken for 5 minutes, then placed for 10 minutes, then the luminescence value of each well of the sample is read on the enzyme label instrument using the Luminescence mode. The percentage inhibition rate of the compound at each concentration point is calculated by comparing the value with the control group (0.1% DMSO), and then the compound concentration logarithm-inhibition rate is nonlinearly regressed in the GraphPad Prism 9 software to obtain the IC 50 value of the compound for inhibiting cell proliferation, see Table 2.

[0498] Table 2 IC 50 data of the compound of the present application for inhibiting the proliferation of LS411N cells

[0499] Conclusion: The compound of the present application has a good inhibitory effect on the IC 50 <30 nM. Test Example 3, Test of the compound of the present application for inhibiting the activity of hDHX9 enzyme (ATPase)

[0500] The following method is used to determine the degree of inhibition of the compound of the present application on the activity of recombinant human DExH-box helicase 9 (hDHX9, ATPase) under in vitro conditions. This method uses the ADP-Glo TM Kinase Assay kit (product number V9102) of Promega Company. For detailed experimental operation, please refer to the kit instruction.

[0501] The experimental procedure is briefly described as follows: the test compound is first dissolved in DMSO to prepare a stock solution, then the 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 TMRecombinant Ribonuclease Inhibitor) were gradient diluted, and the final concentration of the test compound in the reaction system was 10000 nM-0.04 nM; the hDHX9 protein was prepared using a reaction buffer (expressed and purified by Nanjing Kingsriver Biotechnology Co., Ltd.), and the double-stranded RNA substrate of DHX9 was synthesized and annealed by Suzhou Jinyuizhi Biotechnology Co., Ltd. (Sequence 1: 5'-GAAUUAACCAAGGAAAAUAACAAGGACAGGGACCAGG-3' and Sequence 2: 5'-GCCUGGUCCCUGUCCUUGUUAUUUUCCUUGGUUAAUU-3'). The reaction was carried out in a 384-well microplate. First, the test compound and the recombinant human DHX9 protein (final concentration 6.3 nM) were added to the well and incubated at room temperature for 15 minutes, then the double-stranded RNA sequence solution (final concentration 18.8 nM) and ATP solution (final concentration 30 μM, from ADP-Glo TM Kinase Assay kit component V915A) were added to the reaction system and incubated at room temperature for 45 minutes. Then 5 μL of ADP-Glo Reagent was added to the reaction system and incubated at room temperature for 50 minutes. Then 10 μL of Kinase Detection Reagent was added to the reaction system and incubated at room temperature for 30 minutes. After incubation, the chemiluminescence intensity value of each well was determined by a luminometer in luminescence mode. The percentage inhibition of the compound at each concentration was calculated by comparing the luminescence intensity ratio with the control group (0.1% DMSO), and the IC 50 value of the compound was obtained by nonlinear regression analysis of the compound concentration logarithm-inhibition rate by GraphPad Prism 9 software, as shown in Table 3.

[0502] Table 3 IC 50 data of the compounds of the present application on hDHX9 enzyme (ATPase)

[0503] Conclusion: The compounds of the present application have good inhibitory effect on hDHX9 enzyme (ATPase) with IC 50 <30 nM.

Claims

1. A compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: wherein: X is selected from halogen; R 1 selected from C 1-6 alkyl or 3- to 5-membered cycloalkyl; wherein said C 1-6 alkyl or 3- to 5-membered cycloalkyl is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, C 1-6 alkyl or C 1-6 alkoxy; is a 5-membered heteroaryl; X1and X2are each independently selected from CH, S or N, and X1and X2are not simultaneously S, X3is selected from C or N; provided that when X3is C, X1and X2are not simultaneously CH; W and Q are each independently selected from C or N; Ring C is selected from a 5-6 membered heteroaryl or a 4-7 membered heterocyclyl; Y and Z are each independently selected from CR 2c or N; R 2a selected from the group consisting of hydrogen atom, cyano, halogen, hydroxyl, SF5, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl are optionally further substituted by one or more substituents selected from the group consisting of hydroxyl, halogen, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; R 2b each independently is selected from a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a C 1-6 alkyl group, an amino group, a carboxyl group or a C 1-6 alkyl group, wherein said C 1-6 alkyl group or C 1-6 alkoxy group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen, a nitro group, a cyano group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkyl group or a C 1-6 haloalkoxy group; R 2c each independently is selected from a hydrogen atom, halogen, hydroxyl, cyano, C 1-6 alkyl, amino, carboxyl, C 1-6 alkoxy or -OCH2R 3 wherein said C 1-6 alkyl or C 1-6 alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy or -OR 3 ; R 3 each independently selected from C 3-8 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, wherein said C 3-8 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl are optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy; each p is independently selected from 0, 1 or 2; each q is independently selected from 0, 1 or 2; each m is independently selected from 0, 1 or 2; each n is independently selected from 0, 1 or 2.

2. The compound according to claim 1, which is a compound according to general formula (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof: ###0002### (II) (III) wherein: Y and Z are each independently selected from CR 2c or N; R 2c Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl group or -OCH2R 3 The C mentioned therein 1-6 Alkyl groups may optionally be further selected from one or more halogens, hydroxyl groups, cyano groups, C6 groups, etc. 1-6 Alkyl, C 1-6 Alkoxy or -OR 3 The substituents are replaced; R 3 each independently is selected from C 6-10 aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, wherein said C 6-10 aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy; C, W, Q, R 1 , X, R 2a , R 2b , p, q, m and n are as defined in claim 1.

3. The compound according to claim 1 or 2, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: m is 1 or 2, and n is 0.

4. The compound according to claim 1 or 2, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: m is 0, and n is 1.

5. The compound according to any one of claims 1-4, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: W is N, and Q is C.

6. The compound according to any one of claims 1-4, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: W is C, and Q is N.

7. The compound according to any one of claims 1-6, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from a 5-membered heteroaryl, preferably triazole, tetrazole or pyrazole.

8. The compound according to claim 1, wherein is selected from the group consisting of: R 2c The definition is as in claim 1.

9. The compound according to any one of claims 1-8, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2c is selected from C 1-6 alkoxy or -OCH2R 3 wherein said C 1-6 alkoxy is optionally further substituted with one or more selected from halo; R 3 each independently is selected from phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, wherein said phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy; 10. The compound according to claim 9, wherein R is selected from the group consisting of methoxy, trifluoromethoxy, and 2c ​ 11. The compound according to any one of claims 1-10, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein X is selected from CI or Br, preferably CI.

12. The compound according to any one of claims 1 to 11, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 1 is selected from methyl or ethyl.

13. The compound according to any one of claims 1 to 12, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound is:

13. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1-12, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

14. Use of a compound according to any one of claims 1-12, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for the manufacture of a DHX9 inhibitor.

15. Use of a compound according to any one of claims 1-12, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for the treatment of a disease mediated by DHX9, wherein the disease mediated by DHX9 is preferably cancer, viral infection or autoimmune disease, further preferably cancer; still further preferably, the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic 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, more preferably colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic cancer and gastric cancer.

16. The use according to claim 15, wherein the cancer is a microsatellite instability cancer, preferably a high microsatellite instability cancer, further preferably a high microsatellite instability colorectal cancer.

17. Use of a compound according to any one of claims 1 to 12, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for the treatment of cancer, viral infection or autoimmune disease, preferably wherein the cancer is selected from the group consisting of colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic 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, further preferably the cancer is colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic cancer and gastric cancer.

18. Use according to claim 17, wherein the cancer is a microsatellite unstable cancer, preferably a high microsatellite unstable cancer, further preferably a high microsatellite unstable colorectal cancer.

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