Aromatic amide derivative, and preparation method therefor and use thereof

Abstract

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

Description

Aromatic amide derivatives and their preparation method and use Technical Field

[0001] The present invention relates to an aromatic amide derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and use of the derivative as a therapeutic agent, in particular as a DHX9 inhibitor. Background Art

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

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

[0004] Due to its regulatory role in processes such as transcription and maintaining genomic stability, DHX9 has been shown to be a key regulator in multiple cancer types, participating in the regulation of genes associated with sustained proliferative signaling, evasion of growth suppressors, escape from 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 has been implicated in other diseases involving gene replication, translation, or regulation, including viral infections and autoimmune diseases.

[0006] There are no new DHX9 inhibitors on the market, nor is there any information on clinical compounds. As a novel anti-tumor target, DHX9 offers enormous potential for research, and the development of inhibitors targeting this target is highly desirable. Summary of the Invention

[0007] In order to solve the above technical problems, the present invention provides an aromatic amide derivative represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0008] in:

[0009] Ring A is selected from a tricyclic heteroaryl or a tricyclic fused ring;

[0010] X is selected from halogen;

[0011] R 1 Selected from C 1-6 Alkyl or 3-5 membered cycloalkyl; wherein the alkyl or cycloalkyl is optionally further substituted with one or more selected from halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent;

[0012] R 2 Each is independently selected from hydrogen, cyano, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, SF5, -O(CH2) t R A 、-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 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally further substituted by one or more deuterium atoms, halogen, nitro, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -OR A 、-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 a substituent;

[0013] Or, two R 2to form a -C(O) or cyclopropyl group with the same carbon atom to which it is attached;

[0014] R 3 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more hydroxyl groups, halogen groups, nitro groups, cyano groups, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, =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 a substituent;

[0015] R A is selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from 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 substituted by a substituent;

[0016] R 4 and R 5 Each is independently selected from hydrogen atom, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 6 、-C(O)OR 6 、-OC(O)R 6 、-NR 7 R 8 、-C(O)NR7 R 8 、-SO2NR 7 R 8 or -NR 7 C(O)R 8 substituted by a substituent;

[0017] Or, R 4 and R 5 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, 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 a substituent;

[0018] R 6 、R 7 and R 8 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

[0019] t is selected from 0 or 1;

[0020] n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; and

[0021] r is each independently 0, 1 or 2.

[0022] A preferred embodiment of the present invention provides a compound of formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from a 12-18 membered tricyclic fused ring or a 12-18 membered tricyclic heteroaryl, preferably a 12-16 membered tricyclic fused ring or a 12-14 membered tricyclic heteroaryl.

[0023] A preferred embodiment of the present invention provides a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein: R 2Selected from hydrogen atom, halogen, cyano, C 1-6 Alkyl, amino, SF5, -O(CH2) t R A 、-C(O)OR 3 、-NHC(O)R 3 or -C(O)R 3 , wherein the C 1-6 The alkyl group is optionally further substituted with one or more groups selected from deuterium atoms, halogen, cyano, C 1-6 Alkyl, -C(O)OR 6 OR A substituted by a substituent;

[0024] Or, two R 2 to form a -C(O) or cyclopropyl group with the same carbon atom to which it is attached;

[0025] R A Selected from hydrogen atoms, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group may be further substituted by one or more selected from hydroxy, halogen, cyano, -NR 7 R 8 、C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 substituted by an alkoxy substituent;

[0026] R 3 Selected from hydrogen atoms, C 3-8 Cycloalkyl, C 6-10 Aryl or C 1-6 Alkyl, wherein the C 3-8 Cycloalkyl, C 6-10 Aryl or C 1-6 The alkyl group is optionally further substituted with one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent;

[0027] R 6 Selected from hydrogen atoms or C 1-6 alkyl;

[0028] R 7 、R 8 Each independently selected from a hydrogen atom or C 1-6 alkyl;

[0029] t is selected from 0 or 1.

[0030] A preferred embodiment of the present invention provides a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein: R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, hydroxyl, cyano, C 1-6 Alkoxy, SF5, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0031] Or, two R 2 It forms a -C(O) with the same carbon atom to which it is attached.

[0032] A preferred embodiment of the present invention provides a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, which is a compound of formula (IIA) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0033] in:

[0034] is a 5-membered heteroaryl group;

[0035] X1 and X2 are each independently selected from CH, S or N, and X1 and X2 are not S at the same time;

[0036] X3 is selected from C or N; provided that when X3 is C, X1 and X2 are not CH at the same time;

[0037] Ring B is selected from a 5- to 8-membered heterocyclic group, a 6- to 10-membered aryl group, or a 5- to 6-membered heteroaryl group, wherein the heterocyclic group contains one or two double bonds;

[0038] Select single or double bonds as needed so that each atom thereof assumes a normal valence state;

[0039] Y and Z are each independently selected from CR a 、CHR a , O, N, or NR b ;

[0040] R 2a Selected from hydrogen atoms, C 3-8 Cycloalkyl, C 1-6 Alkyl or -C(O)R 3 , wherein the C 1-6 The alkyl group is optionally further substituted by one or more groups selected from deuterium atoms, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 6substituted by a substituent;

[0041] Or, two R 2a to form a -C(O) or cyclopropyl group with the same carbon atom to which it is attached;

[0042] R 2b Each independently selected from a hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 3 ; wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more substituents selected from hydroxy, halogen or cyano;

[0043] R a and R b Each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, amino, -NHC(O)R 3 or -O(CH2) t R A , wherein the C 1-6 The alkyl group is optionally further substituted with one or more radicals selected from halogen, cyano, C 1-6 Alkyl or -OR A substituted by a substituent;

[0044] R A Each independently selected from a hydrogen atom, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group may be further substituted by one or more selected from hydroxy, halogen, cyano, -NR 7 R 8 、C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 substituted by an alkoxy substituent;

[0045] R 3 Selected from hydrogen atoms, C 6-10 Aryl, C 3-8 Cycloalkyl or C 1-6 Alkyl, wherein the C 6-10 Aryl, C 3-8 Cycloalkyl or C 1-6 The alkyl group is optionally further substituted with one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6substituted by an alkoxy substituent;

[0046] R 6 Selected from hydrogen atoms or C 1-6 alkyl;

[0047] R 7 、R 8 Each independently selected from a hydrogen atom or C 1-6 alkyl;

[0048] t is selected from 0 or 1;

[0049] p is each independently selected from 0, 1, 2, 3, 4 or 5;

[0050] q is each independently selected from 0, 1 or 2;

[0051] R 1 and X are as defined in the general formula (I).

[0052] A preferred embodiment of the present invention provides a compound of formula (IIA) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound of formula (IIIA) or (IIIB) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

[0053] in:

[0054] Ring B is selected from a 5- to 8-membered heterocyclic group, wherein the heterocyclic group contains one or two double bonds;

[0055] Y and Z are each independently selected from CR a or N;

[0056] R 2a Selected from hydrogen atoms, C 1-6 Alkyl or -C(O)R 3 , wherein the C 1-6 The alkyl group is optionally further substituted with one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 6 substituted by a substituent;

[0057] Or, two R 2a to form a -C(O) or cyclopropyl group with the same carbon atom to which it is attached;

[0058] R 2b Each independently selected from a hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 3 ;

[0059] Ra Each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, amino, -NHC(O)R 3 or -O(CH2) t R A , wherein the C 1-6 The alkyl group is optionally further substituted with one or more radicals selected from halogen, cyano, C 1-6 Alkyl or -OR A substituted by a substituent;

[0060] R A Each independently selected from a hydrogen atom, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group may be further substituted by one or more selected from hydroxy, halogen, cyano, -NR 7 R 8 、C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 substituted by an alkoxy substituent;

[0061] R 3 Selected from hydrogen atoms, C 6-10 Aryl or C 1-6 Alkyl, wherein the C 6-10 Aryl or C 1-6 The alkyl group is optionally further substituted with one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent;

[0062] R 6 Selected from hydrogen atoms or C 1-6 alkyl;

[0063] R 7 、R 8 Each independently selected from a hydrogen atom or C 1-6 alkyl;

[0064] t is selected from 0 or 1;

[0065] p is each independently selected from 0, 1, 2, 3, 4 or 5;

[0066] R 1 and X are as defined in Formula (IIA).

[0067] A preferred embodiment of the present invention provides a compound of formula (IIA) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, which is a compound of formula (IIIC) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0068] in:

[0069] Y and Z are each independently selected from CHR a 、O、NR b ;

[0070] R 2a Selected from hydrogen atoms or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent;

[0071] R 2b Each independently selected from a hydrogen atom or C 1-6 alkyl;

[0072] R a and R b Each independently selected from hydrogen, halogen, hydroxyl, cyano or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent;

[0073] p is each independently selected from 0, 1 or 2;

[0074] q is each independently selected from 0, 1 or 2;

[0075] R 1 and X are as defined in Formula (IIA).

[0076] A preferred embodiment of the present invention provides a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, which is a compound of formula (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0077] in:

[0078] is a 5-membered heteroaryl group;

[0079] X1 and X2 are each independently selected from CH, S or N, and X1 and X2 are not S at the same time;

[0080] X3 is selected from C or N; provided that when X3 is C, X1 and X2 are not CH at the same time;

[0081] Ring B is selected from a 5- to 8-membered heterocyclic group, a 6- to 10-membered aryl group, or a 5- to 6-membered heteroaryl group, wherein the heterocyclic group contains one or two double bonds;

[0082] is a 6-membered heteroaryl or a 6-membered heterocyclic group;

[0083] Select single or double bonds as needed so that each atom thereof assumes a normal valence state;

[0084] Y and Z are each independently selected from CR a , O or NR b ;

[0085] R a Selected from hydrogen atom, halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl or alkoxy is optionally further substituted by one or more halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent;

[0086] R b Selected from hydrogen atoms or C 1-6 Alkyl, wherein the alkyl is optionally further substituted by one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent;

[0087] m is selected from 0, 1, 2 or 3;

[0088] R 1 、R 2 and X are as defined in the general formula (I).

[0089] A preferred embodiment of the present invention provides a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, which is a compound of formula (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0090] in:

[0091] Ring B is selected from a 5- to 8-membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein the heterocyclic group contains one or two double bonds;

[0092] Y and Z are each independently selected from CR a or N;

[0093] Ra Selected from hydrogen atom, halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted by one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent;

[0094] p is selected from 0, 1, 2 or 3;

[0095] R 1 、R 2 and X are as defined in the general formula (I).

[0096] A preferred embodiment of the present invention provides a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein: Selected from the following groups:

[0097] R 2 and n are as defined in the general formula (I).

[0098] A preferred embodiment of the present invention provides a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein: Selected from the following groups:

[0099] A preferred embodiment of the present invention provides a compound of formula (IIA) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein: Selected from the following groups:

[0100] R 2a Selected from hydrogen atoms, C 1-6 Alkyl, C 3-8 Cycloalkyl or -C(O)R 3 , wherein the C 1-6 The alkyl group is optionally further substituted with one or more groups selected from deuterium atoms, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 6 substituted by a substituent;

[0101] Or, two R 2a to form a -C(O) or cyclopropyl group with the same carbon atom to which it is attached;

[0102] R 2b Each independently selected from a hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 3 ;

[0103] R a Each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, amino, -NHC(O)R 3 or -O(CH2) t R A , wherein the C 1-6 The alkyl group is optionally further substituted with one or more radicals selected from halogen, cyano, C 1-6 Alkyl or -OR A substituted by a substituent;

[0104] R b Selected from hydrogen atoms or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more halogens;

[0105] R A Selected from hydrogen atoms, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group may be further substituted by one or more selected from hydroxy, halogen, cyano, -NR 7 R 8 、C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 substituted by an alkoxy substituent;

[0106] R 3 Selected from hydrogen atoms, C 6-10 Aryl, C 3-8 Cycloalkyl or C 1-6 Alkyl, wherein the C 6-10 Aryl, C 3-8 Cycloalkyl or C 1-6 The alkyl group is optionally further substituted with one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent;

[0107] R 6 Selected from hydrogen atoms or C 1-6 alkyl;

[0108] R 7 、R 8 Each independently selected from a hydrogen atom or C 1-6 alkyl;

[0109] t is selected from 0 or 1;

[0110] p is each independently selected from 0, 1, 2, 3, 4 or 5;

[0111] p' is each independently selected from 0, 1, 2, 3 or 4;

[0112] q is each independently selected from 0, 1 or 2.

[0113] A preferred embodiment of the present invention provides a compound of formula (IIA) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein: R 2a Selected from hydrogen atom, methyl, ethyl, isopropyl,

[0114] Or, two R 2a The same carbon atom to which it is attached forms a -C(O) or cyclopropyl group.

[0115] A preferred embodiment of the present invention provides a compound of formula (IIA) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein: R a Selected from hydrogen atom, hydroxyl, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, amino,

[0116] A preferred embodiment of the present invention provides a compound of formula (IIA) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein: q is 0.

[0117] A preferred embodiment of the present invention provides a compound of formula (IIA) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein: Selected from the following groups:

[0118] A preferred embodiment of the present invention provides a compound of formula (I), (II), (IIA), (III), (IIIA), (IIIB) or (IIIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein: X is selected from Cl or Br, preferably Cl.

[0119] A preferred embodiment of the present invention provides a compound of formula (I), (II), (IIA), (III), (IIIA), (IIIB) or (IIIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from methyl or ethyl.

[0120] In a preferred embodiment of the present invention, the compound described by the general formula is selected from:

[0121] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0122] Note: If there is a discrepancy between a drawn structure and the name given for that structure, the drawn structure will be given greater weight.

[0123] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of formula (I), (II), (IIA), (III), (IIIA), (IIIB) or (IIIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0124] The present invention provides a compound of formula (I), (II), (IIA), (III), (IIIA), (IIIB) or (IIIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., a pharmaceutical composition described in the aforementioned technical solutions) for use as a medicine (i.e., for use in treatment).

[0125] The present invention provides a compound of formula (I), (II), (IIA), (III), (IIIA), (IIIB) or (IIIC) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or its pharmaceutical composition (such as the pharmaceutical composition described in the aforementioned technical solutions) for use in preparing a DHX9 inhibitor.

[0126] The present invention also provides a use of a compound of formula (I), (II), (IIA), (III), (IIIA), (IIIB) or (IIIC) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., the pharmaceutical composition described in the aforementioned technical solution) 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 more preferably cancer; wherein the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic system cancer, breast cancer, brain cancer, skin cancer, lung cancer, blood cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft tissue cancer, kidney cancer and liver cancer, and preferably colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic system cancer and gastric cancer.

[0127] The present invention also provides a compound of general formula (I), (II), (IIA), (III), (IIIA), (IIIB) or (IIIC) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof (such as the pharmaceutical composition described in the aforementioned technical solution) for preparing a drug for treating a disease mediated by DHX9, wherein the disease mediated by DHX9 is preferably cancer, wherein the cancer is microsatellite instability (MSI) cancer, preferably microsatellite instability-high (MSI-H) cancer, and more preferably microsatellite instability-high (MSI-H) colorectal cancer.

[0128] The present invention further provides a compound of formula (I), (II), (IIA), (III), (IIIA), (IIIB) or (IIIC) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof (such as the pharmaceutical composition described in the aforementioned technical solutions) for use in preparing a medicament for treating cancer, viral infection or autoimmune disease.

[0129] The present invention provides a use of a compound of general formula (I), (II), (IIA), (III), (IIIA), (IIIB) or (IIIC) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., the pharmaceutical composition described in the aforementioned technical solution) in the preparation of a medicament for treating colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic system cancer, breast cancer, brain cancer, skin cancer, lung cancer, blood cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft tissue cancer, kidney cancer and liver cancer, preferably in the preparation of a medicament for treating colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic system cancer and gastric cancer.

[0130] The present invention provides a use of a compound of formula (I), (II), (IIA), (III), (IIIA), (IIIB) or (IIIC) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., the pharmaceutical composition described in the aforementioned technical solution) in preparing a medicament for treating microsatellite instability (MSI) cancer, preferably in preparing a medicament for treating microsatellite instability-high (MSI-H) cancer, and more preferably in preparing a medicament for treating microsatellite instability-high (MSI-H) colorectal cancer.

[0131] The present invention further provides a method for preventing and / or treating a disease mediated by DHX9, comprising administering to a patient a therapeutically effective dose of a compound of formula (I), (II), (IIA), (III), (IIIA), (IIIB) or (IIIC) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., the pharmaceutical composition described in the aforementioned technical solution); wherein the disease mediated by DHX9 is preferably cancer, viral infection or autoimmune disease, and more preferably cancer; wherein the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic system cancer, breast cancer, brain cancer, skin cancer, lung cancer, blood cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft tissue cancer, kidney cancer and liver cancer, and preferably colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic system cancer and gastric cancer; or the cancer is microsatellite instability (MSI) cancer, preferably microsatellite instability-high (MSI-H) cancer, and more preferably microsatellite instability-high (MSI-H) colorectal cancer.

[0132] The present invention further provides a method for preventing and / or treating cancer, viral infection or autoimmune disease, comprising administering to a patient a therapeutically effective dose of a compound of formula (I), (II), (IIA), (III), (IIIA), (IIIB) or (IIIC) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., the pharmaceutical composition described in the aforementioned technical solution); wherein the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic system cancer, breast cancer, brain cancer, skin cancer, lung cancer, blood cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft tissue cancer, kidney cancer and liver cancer, preferably colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic system cancer and gastric cancer; or the cancer is microsatellite instability (MSI) cancer, preferably microsatellite instability-high (MSI-H) cancer, more preferably microsatellite instability-high (MSI-H) colorectal cancer.

[0133] Detailed Description of the Invention

[0134] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0135] "Alkyl" when used as a group or a part of a group refers to a group comprising C1-C 20 A straight chain or branched aliphatic hydrocarbon group. Preferably C1-C 10 Alkyl, more preferably C1-C6 alkyl. 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. Alkyl can be substituted or unsubstituted.

[0136] "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 of which are not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. C2-C4 alkenyl is preferred. The alkenyl group may be optionally substituted or unsubstituted.

[0137] "Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which can be straight chain or branched. 10The alkynyl group of the present invention is substituted or unsubstituted. The alkynyl group of the present invention is substituted or unsubstituted.

[0138] "Alkylene" refers to a saturated C1-C 20 A straight-chain or branched aliphatic hydrocarbon group having two residues derived from the same carbon atom or two different carbon atoms of a parent alkane, preferably C1-C 10 Alkylene, more preferably C1-C6 alkylene. Examples of alkylene groups include, but are not limited to, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,4-butylene, etc. The alkylene group may be substituted or unsubstituted.

[0139] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more of the ring atoms is a carbon atom, including monocyclic, polycyclic, fused, bridged, and spirocyclic rings, preferably having a 5- to 7-membered monocyclic ring or a 7- to 10-membered bicyclic or tricyclic ring. Examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclopentyl, and cyclobutyl. Cycloalkyl groups may be substituted or unsubstituted.

[0140] "Spiroalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spiroalkyl is divided into single spiro, double spiro or multiple spiroalkyl groups, preferably single spiro and double spiroalkyl groups, preferably 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members. Non-limiting examples of "spiroalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl, etc.

[0141] "Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms. One or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron aromatic system. It is preferably 6- to 12-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, and more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of "fused cycloalkyl" include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, tetradecahydrophenanthrenyl, and the like.

[0142] "Bridged cycloalkyl" refers to an all-carbon polycyclic group with 5 to 18 members, containing two or more cyclic structures that share two non-directly connected carbon atoms. One or more rings may contain one or more double bonds, but none of the rings have completely conjugated π electrons. It is an aromatic system with preferably 6 to 12 members, more preferably 7 to 10 members. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl, and the like.

[0143] "Heterocyclyl", "heterocycloalkyl", "heterocycle" or "heterocyclic" are used interchangeably in this application and refer to non-aromatic heterocyclic groups that may contain zero, one or more double bonds in the ring, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms, including monocyclic, polycyclic, condensed, bridged and spirocyclic rings. Preferably there is a 5 to 8-membered monocyclic or 7 to 10-membered bicyclic or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetane, 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, hexahydropyrimidine, etc. The heterocyclic group may be substituted or unsubstituted.

[0144] "Spiro heterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the rings, which may contain 0, 1 or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r(wherein r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiro atoms between rings, spirocycloalkyl is divided into single spiro heterocyclic group, double spiro heterocyclic group or multiple spiro heterocyclic group, preferably single spiro heterocyclic group and double spiro heterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiro heterocyclic group. Non-limiting examples of "spiro heterocyclic group" 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, etc.

[0145] "Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms, one or more rings may contain zero, one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein t is selected from 0, 1 or 2) heteroatom, and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin (dioxine), etc.

[0146] "Bridged heterocyclic group" refers to a 5- to 14-membered, 5- to 18-membered polycyclic group containing two or more ring structures that share two atoms that are not directly connected to each other, one or more rings may contain zero, one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) t (wherein t is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include but are not limited to: 2-azabicyclo [2.2.1] heptyl, 2-azabicyclo [2.2.2] octyl, 2-azabicyclo [3.3.2] decyl, etc.

[0147] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused manner. The term "aryl" includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably, aryl is C6-C10 The aryl group is more preferably phenyl and naphthyl, and most preferably naphthyl. The aryl group may be substituted or unsubstituted.

[0148] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic ring, 8- to 10-membered bicyclic ring, or 12- to 14-membered tricyclic ring, which may contain 1 to 4 atoms 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, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4 -triazolyl, pyridyl, pyrimidinyl, pyrazin-2(1H)-onyl, pyrimidin-4(3H)-onyl, pyridazin-3(2H)-onyl, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furo[3,2-b]pyridinyl, furo[2,3-c]pyridinyl, thieno[2,3-c]pyridinyl, benzofuranyl, benzo[b]thienyl, 1H-pyrrolo[3,2-b]pyridinyl, 2H-pyrrolo[3,4-c]pyridinyl, etc. The heteroaryl group may be substituted or unsubstituted.

[0149] "Fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms, wherein at least one ring has a completely conjugated π-electron aromatic system, and at the same time, one or more rings may contain 0, 1 or more double bonds, but at least one ring does not have a completely conjugated π-electron aromatic system, wherein the ring atoms are selected from 0, 1 or more nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclyl or monocyclic cycloalkyl group. Preferably, it is a 6-16 membered, more preferably an 8-10 membered bicyclic fused ring or a 12-17 membered tricyclic fused ring. Examples of "fused ring" include but are not limited to:

[0150] "Alkoxy" refers to a group (alkyl-O-). Alkyl is defined herein. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0151] "Nitro" refers to a -NO2 group.

[0152] "Hydroxy" refers to an -OH group.

[0153] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0154] "Amino" refers to -NH2.

[0155] "Cyano" refers to -CN.

[0156] "Benzyl" refers to -CH2-phenyl.

[0157] "Carboxyl" refers to -C(O)OH.

[0158] "Carboxylate" refers to a -C(O)O-alkyl group or a -C(O)O-cycloalkyl group, wherein alkyl and cycloalkyl are as defined above.

[0159] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0160] "Aminoalkyl" refers to an alkyl group substituted with an amino group, wherein alkyl is as defined above.

[0161] "Haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.

[0162] "Haloalkoxy" refers to an alkoxy group substituted with a halogen group, wherein alkoxy is as defined above.

[0163] "DMSO" refers to dimethyl sulfoxide.

[0164] "BOC" refers to tert-butoxycarbonyl.

[0165] "Bn" refers to benzyl.

[0166] "THP" refers to 2-tetrahydropyranyl.

[0167] "TFA" refers to trifluoroacetic acid.

[0168] "Ts" refers to p-toluenesulfonyl.

[0169] "SF5" refers to sulfur pentafluoride.

[0170] "Leaving group", or leaving group, is an atom or functional group that breaks away from a larger molecule in a chemical reaction. It is a term used in nucleophilic substitution reactions 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 away from the substrate molecule with a pair of electrons is called the leaving group. Groups that easily accept electrons and have a strong ability to withstand negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break away from other molecules. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to bind to other atoms, and the tendency to exist as an anion (or an electrically neutral leaving group) is enhanced. Common leaving groups include but are not limited to halogens, methylsulfonyl, -OTs or -OH.

[0171] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0172] As used herein, "substituted" or "substituted", unless otherwise specified, means that a group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, SF5, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -O(CH2), m R A 、-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 ;

[0173] Alternatively, the two substituents and the same carbon atom to which they are attached form a cyclopropyl group;

[0174] R A is selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from 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 substituted by a substituent;

[0175] R 3 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more hydroxyl groups, halogen groups, nitro groups, cyano groups, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, =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 a substituent;

[0176] R 4 and R 5 Each is independently selected from hydrogen atom, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, 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 a substituent;

[0177] Or, R 4 and R 5 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, 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 a substituent;

[0178] R 6 、R 7 and R 8 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

[0179] r is selected from 0, 1 or 2;

[0180] m is selected from 0 or 1.

[0181] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0182] Unless otherwise indicated, structures depicted herein also encompass all isomers (e.g., diastereoisomers, enantiomers, and atropisomers, and geometric (conformational) isomeric forms of such structures; for example, R and S configurations at various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereoisomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (conformational) isomeric mixtures of the present compounds are within the scope of the invention.

[0183] "Pharmaceutically acceptable salts" refer to salts of the above compounds that retain their original biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of the compounds represented by general formula (I) may be metal salts or amine salts formed with suitable acids.

[0184] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0185] Synthesis method of the compound of the present invention

[0186] In order to achieve the purpose of the present invention, the present invention adopts the following technical solutions:

[0187] The present invention provides a method for preparing a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, the method comprising:

[0188] The compound of formula (IA) undergoes a condensation reaction with the compound (IB), and optionally further undergoes a substitution reaction to obtain the compound of formula (I)

[0189] in:

[0190] Y is selected from hydroxy or chlorine;

[0191] Ring A, X, R 1 、R 2 and n are as defined in the general formula (I). DETAILED DESCRIPTION

[0192] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0193] Example

[0194] The examples provide the preparation of representative compounds represented by formula (I) and related structural identification data. It must be noted that the following examples are used to illustrate the present invention rather than to limit the present invention.

[0195] 1 H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0196] Mass spectra were obtained using LC / MS, and the ionization method could be ESI or APCI.

[0197] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0198] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0199] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available raw materials and reagents are used directly without further purification, unless otherwise indicated. Commercial manufacturers include but are not limited to Aldrich Chemical Company, ABCR GmbH & Co.KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd.

[0200] CD3OD: deuterated methanol.

[0201] CDCl3: deuterated chloroform.

[0202] DMSO-d6: deuterated dimethyl sulfoxide.

[0203] Argon atmosphere means that the reaction bottle is connected to an argon balloon with a capacity of about 1 L.

[0204] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0205] The compound was purified using silica gel column chromatography and reverse phase column chromatography, with the eluent system selected from: A: petroleum ether and ethyl acetate; B: dichloromethane and methanol; C: dichloromethane: ethyl acetate; and D: aqueous trifluoroacetic acid and acetonitrile. The volume ratio of the solvents varied depending on the polarity of the compound and could be adjusted by adding a small amount of an acidic or alkaline reagent, such as acetic acid or triethylamine.

[0206] Example 1

[0207] N-(3-chloro-5-(methylsulfonamido)phenyl)-6H-thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxamide

[0208] N-(3-Chloro-5-(methylsulfonamido)phenyl)-6H-thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxamide

[0209] first step

[0210] methyl 4-bromo-5-(hydroxymethyl)thiophene-2-carboxylate

[0211] Methyl 4-bromo-5-(hydroxymethyl)thiophene-2-carboxylate

[0212] Methyl 4-bromo-5-formylthiophene-2-carboxylate 1a (800 mg, 3.21 mmol, commercially available) was dissolved in methanol (10 mL), and sodium acetate borohydride (2.04 g, 9.64 mmol) was added. The mixture was stirred at 25°C for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide methyl 4-bromo-5-(hydroxymethyl)thiophene-2-carboxylate 1b (800 mg) in a 99.2% yield.

[0213] MS m / z(ESI):251.0[M+1].

[0214] Step 2

[0215] methyl 5-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate

[0216] 5-(Hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic acid methyl ester

[0217] Methyl 4-bromo-5-(hydroxymethyl)thiophene-2-carboxylate 1b (400 mg, 1.59 mmol), pinacol diboron (606.79 mg, 2.39 mmol), and potassium acetate (312.68 mg, 3.19 mmol) were added to dioxane (5 mL), and the reaction mixture was purged with nitrogen three times. Under a nitrogen atmosphere, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (116.56 mg, 159.30 μmol) was added to the reaction mixture, and the temperature was raised to 90°C and stirred for 2 hours. The reaction mixture was filtered to obtain methyl 5-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate 1c (473 mg), which was used directly in the next reaction. MS m / z (ESI): 299.0 [M+1].

[0218] Step 3

[0219] methyl 5-(hydroxymethyl)-4-(3-hydroxypyridin-2-yl)thiophene-2-carboxylate

[0220] 5-(Hydroxymethyl)-4-(3-hydroxypyridin-2-yl)thiophene-2-carboxylic acid methyl ester

[0221] Methyl 5-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate 1c (473 mg), 2-bromopyridin-3-ol (204.25 mg, 1.17 mmol), and potassium carbonate (486.72 mg, 3.52 mmol) were added to dioxane (4 mL) and water (1 mL). The reaction mixture was purged with nitrogen three times. Under a nitrogen atmosphere, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (85.89 mg, 117.39 μmol) was added to the reaction mixture, which was heated to 90°C and stirred for 2 hours. After the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent: System A) to give methyl 5-(hydroxymethyl)-4-(3-hydroxypyridin-2-yl)thiophene-2-carboxylate 1d (130 mg) in a yield of 41.75%.

[0222] MS m / z(ESI):266.0[M+1].

[0223] Step 4

[0224] methyl 6H-thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxylate

[0225] 6H-thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxylic acid methyl ester

[0226] Methyl 5-(hydroxymethyl)-4-(3-hydroxypyridin-2-yl)thiophene-2-carboxylate 1d (130 mg, 490.04 μmol) and triphenylphosphine (385.59 mg, 1.47 mmol) were dissolved in tetrahydrofuran (6 mL), and the reaction mixture was purged with nitrogen three times. Diisopropyl azodicarboxylate (297.27 mg, 1.47 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: System A) to afford methyl 6H-thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxylate 1e (50 mg) in a yield of 41.26%.

[0227] MS m / z(ESI):248.0[M+1].

[0228] Step 5

[0229] 6H-thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxylic acid

[0230] 6H-Thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxylic acid

[0231] Methyl 6H-thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxylate 1e (50 mg, 202.21 μmol) was dissolved in tetrahydrofuran (1.5 mL) and water (0.5 mL). Lithium hydroxide monohydrate (12.73 mg, 303.31 μmol) was added and stirred at 25°C for 1 hour. After the reaction, the solvent was evaporated to give 6H-thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxylic acid 1f (70 mg) in a yield of 74.21%, which was used directly in the next reaction.

[0232] MS m / z(ESI):234.0[M+1].

[0233] Step 6

[0234] N-(3-chloro-5-(methylsulfonamido)phenyl)-6H-thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxamide

[0235] N-(3-Chloro-5-(methylsulfonamido)phenyl)-6H-thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxamide

[0236] O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (335.30 mg, 643.11 μmol) and N,N-diisopropylethylamine (83.12 mg, 643.11 μmol) were added to a solution of 6H-thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxylic acid 1f (50 mg, 214.37 μmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide 1g (70.96 mg, 321.55 μmol, prepared according to patent WO2023154519) in N,N-dimethylformamide (1 mL) at room temperature. The reaction mixture was reacted at 25°C for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH₄HCO₃ + H₂O, mobile phase B: CH₃CN) to afford N-(3-chloro-5-(methylsulfonamido)phenyl)-6H-thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxamide 1 (6 mg) in a 6.42% yield.

[0237] MS m / z(ESI):435.8[M+1].

[0238] 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),10.08(s,1H),8.57(s,1H),8.21(dd,J=4.8,1.2Hz,1H),7.70(t,J=1.6Hz,1H),7.68( d,J=1.6Hz,1H),7.38(dd,J=8.0,1.2Hz,1H),7.26(dd,J=8.0,4.8Hz,1H),6.96(t,J=2.0Hz,1H),5.57(s,2H),3.07(s,3H).

[0239] Example 2

[0240] N-(3-chloro-5-(methylsulfonamido)phenyl)-4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxamide

[0241] N-(3-Chloro-5-(methylsulfonamido)phenyl)-4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxamide

[0242] first step

[0243] methyl 5-bromo-4-(bromomethyl)thiophene-2-carboxylate

[0244] Methyl 5-bromo-4-(bromomethyl)thiophene-2-carboxylate

[0245] 5-Bromo-4-methylthiophene-2-carboxylic acid methyl ester 2a (3 g, 12.76 mmol, commercially available) and N-bromosuccinimide (2.04 g, 11.48 mmol) were added to carbon tetrachloride (30 mL), and the reaction mixture was purged with nitrogen three times. Under a nitrogen atmosphere, dibenzoyl peroxide (30.91 mg, 127.61 μmol) was added to the reaction mixture, and the temperature was raised to 80°C and stirred for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 5-Bromo-4-(bromomethyl)thiophene-2-carboxylic acid methyl ester 2b (4.1 g), which was used directly in the next reaction. MS m / z (ESI): 314.8 [M+1].

[0246] Step 2

[0247] methyl 5-bromo-4-(hydroxymethyl)thiophene-2-carboxylate

[0248] Methyl 5-bromo-4-(hydroxymethyl)thiophene-2-carboxylate

[0249] Methyl 5-bromo-4-(bromomethyl)thiophene-2-carboxylate 2b (6.7 g, 21.34 mmol) was dissolved in acetonitrile (60 mL) and water (20 mL). Potassium carbonate (8.85 g, 64.01 mmol) was added, and the mixture was heated to 60°C and stirred for 48 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: System A) to obtain methyl 5-bromo-4-(hydroxymethyl)thiophene-2-carboxylate 2c (1.3 g) in a yield of 24.26%.

[0250] MS m / z(ESI):252.9[M+1].

[0251] Step 3

[0252] methyl 5-bromo-4-(((2-bromopyridin-3-yl)oxy)methyl)thiophene-2-carboxylate

[0253] Methyl 5-bromo-4-(((2-bromopyridin-3-yl)oxy)methyl)thiophene-2-carboxylate

[0254] Methyl 5-bromo-4-(hydroxymethyl)thiophene-2-carboxylate 2c (350 mg, 1.39 mmol), 2-bromopyridin-3-ol (363.79 mg, 2.09 mmol), and triphenylphosphine (1.10 g, 4.18 mmol) were dissolved in tetrahydrofuran (20 mL). The reaction mixture was purged with nitrogen three times. Diisopropyl azodicarboxylate (845.56 mg, 4.18 mmol) was added dropwise at 0°C. The mixture was heated to 50°C and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: System A) to afford methyl 5-bromo-4-(((2-bromopyridin-3-yl)oxy)methyl)thiophene-2-carboxylate 2d (600 mg) in an 82.69% yield.

[0255] MS m / z(ESI):407.9[M+1].

[0256] Step 4

[0257] methyl 4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxylate

[0258] 4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxylic acid methyl ester

[0259] Compound 2d (750 mg, 1.84 mmol), pinacol diboronate (1.40 g, 5.53 mmol), bis(1-adamantyl)-butylphosphine (264.23 mg, 736.96 μmol), and potassium carbonate (1.27 g, 9.21 mmol) were dissolved in ethylene glycol dimethyl ether (10 mL) and water (1 mL). The reaction mixture was purged with nitrogen three times. Under a nitrogen atmosphere, palladium acetate (82.73 mg, 368.48 μmol) was added, and the mixture was heated to 80°C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: System A) to obtain methyl 4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxylate 2e (300 mg) in a 65.82% yield. MS m / z (ESI): 247.9 [M+1].

[0260] Step 5

[0261] 4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxylic acid

[0262] 4H-Thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxylic acid

[0263] 4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxylic acid methyl ester 2e (420 mg, 1.70 mmol) was dissolved in tetrahydrofuran (12 mL) and water (4 mL). Lithium hydroxide monohydrate (71.28 mg, 1.70 mmol) was added and stirred at 25°C for 1 hour. After the reaction, the pH was adjusted to a weakly acidic state with 1M hydrochloric acid solution. The mixture was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxylic acid 2f (270 mg) in a yield of 68.15%.

[0264] MS m / z(ESI):233.9[M+1].

[0265] Step 6

[0266] N-(3-chloro-5-(methylsulfonamido)phenyl)-4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxamide

[0267] N-(3-Chloro-5-(methylsulfonamido)phenyl)-4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxamide

[0268] O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.48 g, 2.83 mmol) and N,N-diisopropylethylamine (365.71 mg, 2.83 mmol) were added to a solution of 4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxylic acid 2f (220 mg, 943.22 μmol) and 1 g of N-(3-amino-5-chlorophenyl)methanesulfonamide (312.22 mg, 1.41 mmol) in N,N-dimethylformamide (1 mL) at room temperature. The reaction mixture was allowed to react at 25°C for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to give N-(3-chloro-5-(methylsulfonyl)phenyl)-4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxamide 2 (15 mg) in a yield of 3.65%.

[0269] MS m / z(ESI):436.0[M+1].

[0270] 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),10.09(s,1H),8.16(dd,J=4.8,1.4Hz,1H),7.91(s,1H),7.66(dt, J=21.8,1.8Hz,2H),7.32(ddd,J=12.8,8.2,3.0Hz,2H),6.97(t,J=1.8Hz,1H),5.48(s,2H),3.08(s,3H).

[0271] Example 3-4 was synthesized according to the synthesis method of Example 1-2 of the present invention. The spectrum parameters of Example 3-4 are shown in the following table:

[0272] Example 5

[0273] N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydrothieno[2',3':2,3]oxepino[4,5-b]pyridine-9-carboxamide

[0274] N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydrothieno[2',3':2,3]oxepin 4,5-b]pyridine-9-carboxamide

[0275] first step

[0276] (E)-2-bromo-3-(2-methoxyvinyl)pyridine

[0277] (E)-2-Bromo-3-(2-methoxyvinyl)pyridine

[0278] (Methoxymethyl)triphenylphosphonium chloride 5b (13.8 g, 40.3 mmol, commercially available) was added to tetrahydrofuran (50 mL). The reaction mixture was purged with nitrogen three times and cooled to -78°C. Lithium bistrimethylsilylamide (6.75 g, 40.3 mmol.1 mol in THF) was added dropwise to the reaction mixture. After stirring at -78°C for half an hour, 2-bromo-3-pyridinecarboxaldehyde 5a (5 g, 26.9 mmol, commercially available) was dissolved in tetrahydrofuran and slowly added dropwise to the reaction mixture. The mixture was stirred for 16 hours and then slowly allowed to return to room temperature. The reaction mixture was quenched with methanol at 0°C and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: System A) afforded (E)-2-bromo-3-(2-methoxyvinyl)pyridine 5c (2.1 g) in a 37% yield.

[0279] MS m / z(ESI):215.9[M+1].

[0280] Step 2

[0281] 2-(2-bromopyridin-3-yl)acetaldehyde

[0282] 2-(2-bromopyridin-3-yl)acetaldehyde

[0283] (E)-2-Bromo-3-(2-methoxyvinyl)pyridine 5c (2.1 g, 9.81 mmol) was added to a formic acid solution (5 mL) at room temperature. The mixture was heated to 90°C and allowed to react for 16 hours. The reaction solution was concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: System A) afforded 2-(2-bromopyridin-3-yl)acetaldehyde 5d (700 mg) in a 36% yield.

[0284] MS m / z(ESI):201.9[M+1].

[0285] Step 3

[0286] 2-(2-bromopyridin-3-yl)ethan-1-ol

[0287] 2-(2-Bromopyridin-3-yl)ethan-1-ol

[0288] Sodium borohydride (265 mg, 7.00 mmol) was added portionwise to a solution of 2-(2-bromopyridin-3-yl)ethanaldehyde 5d (700 mg, 3.50 mmol) in ethanol (10 mL) at room temperature. The reaction mixture was allowed to react at room temperature for 16 hours. The reaction mixture was quenched with methanol, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: System A) to afford 2-(2-bromopyridin-3-yl)ethan-1-ol 5e (430 mg) in a 61% yield.

[0289] MS m / z(ESI):204.0[M+1].

[0290] Step 4

[0291] methyl 4-bromo-5-methoxythiophene-2-carboxylate

[0292] Methyl 4-bromo-5-methoxythiophene-2-carboxylate

[0293] N-Bromosuccinimide (2.27 g, 12.8 mmol) was added to a solution of methyl 5-methoxy-2-thiophenecarboxylate 5f (2 g, 11.6 mmol, commercially available) in dichloromethane (50 mL) at room temperature. The reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: System A) to obtain methyl 4-bromo-5-methoxythiophene-2-carboxylate (5 g, 2.8 g) in a 96% yield.

[0294] MS m / z(ESI):251.0[M+1].

[0295] Step 5

[0296] methyl 5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate

[0297] 5-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic acid methyl ester

[0298] [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (291 mg, 0.4 mmol), pinacol diboron (2.63 g, 10.3 mmol), potassium acetate (1.56 g, 15.9 mmol), and methyl 4-bromo-5-methoxythiophene-2-carboxylate (5 g, 7.97 mmol) were added to dioxane (20 mL) at room temperature. The atmosphere was purged with nitrogen three times and the mixture was reacted at 100°C for 2 hours. The mixture was filtered, the filter cake rinsed with ethyl acetate (150 mL), and the filtrate concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: System A) afforded methyl 5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (5h) (1.0 g) in a 42% yield.

[0299] MS m / z(ESI):299.2[M+1].

[0300] Step 6

[0301] methyl 4-(3-(2-hydroxyethyl)pyridin-2-yl)-5-methoxythiophene-2-carboxylate

[0302] 4-(3-(2-hydroxyethyl)pyridin-2-yl)-5-methoxythiophene-2-carboxylic acid methyl ester

[0303] [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (156 mg, 0.21 mmol), 2-(2-bromopyridin-3-yl)ethan-1-ol 5e (430 mg, 2.13 mmol), potassium carbonate (588 mg, 4.26 mmol), and methyl 5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate 5h (825 mg, 2.77 mmol) were added to a mixture of dioxane (5 mL) and water (1 mL) at room temperature. The atmosphere was replaced with nitrogen three times, and the mixture was heated to 100°C and stirred for 16 hours. The mixture was filtered, the filter cake was rinsed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure. The product was separated and purified by silica gel column chromatography (eluent: System A) to give methyl 4-(3-(2-hydroxyethyl)pyridin-2-yl)-5-methoxythiophene-2-carboxylate 5i (500 mg) in an 80% yield.

[0304] MS m / z(ESI):294.0[M+1].

[0305] Step 7

[0306] methyl 5-hydroxy-4-(3-(2-hydroxyethyl)pyridin-2-yl)thiophene-2-carboxylate

[0307] 5-Hydroxy-4-(3-(2-hydroxyethyl)pyridin-2-yl)thiophene-2-carboxylic acid methyl ester

[0308] Aluminum trichloride (2.27 g, 17.1 mmol) was added to a solution of methyl 4-(3-(2-hydroxyethyl)pyridin-2-yl)-5-methoxythiophene-2-carboxylate 5i (500 mg, 1.70 mmol) in dichloromethane (20 mL) at room temperature for 48 hours. The reaction solution was poured into water and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: System A) afforded methyl 5-hydroxy-4-(3-(2-hydroxyethyl)pyridin-2-yl)thiophene-2-carboxylate 5j (300 mg) in a 63% yield.

[0309] MS m / z(ESI):280.0[M+1].

[0310] 1 H NMR (500MHz, DMSO-d6) δ10.20(s,1H),8.42(d,J=4.8Hz,1H),8.10(d,J=7.2Hz,1H),7.98(s,1 H),7.41–7.33(m,1H),4.90(s,1H),3.77(t,J=6.4Hz,2H),3.72(s,3H),3.06(t,J=6.4Hz,2H).

[0311] Step 8

[0312] methyl 5,6-dihydrothieno[2',3':2,3]oxepino[4,5-b]pyridine-9-carboxylate

[0313] 5,6-dihydrothieno[2',3':2,3]oxa Methyl benzo[4,5-b]pyridine-9-carboxylate

[0314] At room temperature, diisopropyl azodicarboxylate (586 mg, 2.90 mmol) was added to a solution of methyl 5-hydroxy-4-(3-(2-hydroxyethyl)pyridin-2-yl)thiophene-2-carboxylate 5j (270 mg, 0.97 mmol) and triphenylphosphine (760 mg, 2.90 mmol) in tetrahydrofuran (30 mL). The reaction mixture was allowed to react at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: System A) to obtain 5,6-dihydrothieno[2',3':2,3]oxepin. Methyl 4-bromo[4,5-b]pyridine-9-carboxylate 5k (230 mg), yield: 91%.

[0315] MS m / z(ESI):262.0[M+1].

[0316] Step 9

[0317] 5,6-dihydrothieno[2',3':2,3]oxepino[4,5-b]pyridine-9-carboxylic acid

[0318] 5,6-dihydrothieno[2',3':2,3]oxa 4,5-b]pyridine-9-carboxylic acid

[0319] At room temperature, lithium hydroxide monohydrate (111 mg, 2.64 mmol) was added to 5,6-dihydrothieno[2',3':2,3]oxazoline methyl pyridine-9-carboxylate 5k (230 mg, 0.88 mmol) was added to a mixture of tetrahydrofuran (3 mL), methanol (3 mL) and water (3 mL) and the reaction mixture was allowed to react at room temperature for 16 hours. The reaction mixture was adjusted to pH 6 with dilute hydrochloric acid and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5,6-dihydrothieno[2',3':2,3]oxepin 4-[4,5-b]pyridine-9-carboxylic acid 51 (230 mg), yield: 91%.

[0320] MS m / z(ESI):248.0[M+1].

[0321] Step 10

[0322] N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydrothieno[2',3':2,3]oxepino[4,5-b]pyridine-9-carboxamide

[0323] N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydrothieno[2',3':2,3]oxepin 4,5-b]pyridine-9-carboxamide

[0324] At 25 ° C, 5,6-dihydrothieno[2',3':2,3]oxa 5l (50.0 mg, 0.202 mmol) of pyridine-9-carboxylic acid and 1 g (89.3 mg, 0.404 mmol) of N-(3-amino-5-chlorophenyl)methanesulfonamide were added to N,N-dimethylformamide (5 mL), followed by (7-azabenzotriazole-1-oxy)tripyrrolidone hexafluorophosphate (211 mg, 0.404 mmol) and N,N-diisopropylethylamine (78.4 mg, 0.607 mmol). The mixture was reacted at 65°C for 18 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(3-chloro-5-(methylsulfonyl)phenyl)-5,6-dihydrothieno[2′,3′:2,3]oxepin [4,5-b]pyridine-9-carboxamide 5 (46 mg), yield: 51%. MS m / z (ESI): 450.2 [M+1].

[0325] 1 H NMR(400MHz, DMSO-d6)δ10.56(d,J=2.4Hz,1H),8.66(d,J=2.0Hz,1H),8.58–8.47(m,1H),7.73–7 .61(m,3H),7.28–7.20(m,1H),6.92(s,1H),4.62–4.48(m,2H),3.26–3.18(m,2H),3.067(s,3H).

[0326] Example 6

[0327] N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydrothieno[3',2':4,5]oxepino[3,2-b]pyridine-9-carboxamide

[0328] N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydrothieno[3',2':4,5]oxaplanin 2-[3,2-b]pyridine-9-carboxamide

[0329] first step

[0330] methyl 4-bromo-5-(2-hydroxyethyl)thiophene-2-carboxylate

[0331] 4-Bromo-5-(2-hydroxyethyl)thiophene-2-carboxylic acid methyl ester

[0332] Methyl 5-(2-hydroxyethyl)thiophene-2-carboxylate 6a (1.3 g, 6.98 mmol, commercially available) was added to N,N-dimethylformamide (15 mL), followed by N-bromosuccinimide (2.48 g, 13.96 mmol). The mixture was heated to 50°C and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: System A) to obtain methyl 4-bromo-5-(2-hydroxyethyl)thiophene-2-carboxylate 6b (900 mg) in a 48.36% yield.

[0333] MS (ESI) m / z: 264.9 [M+H].

[0334] 1H NMR (400MHz, DMSO-d6) δ7.70 (s, 1H), 3.81 (s, 3H), 3.63 (d, J = 6.4Hz, 2H), 2.93 (t, J = 6.4Hz, 2H).

[0335] Step 2

[0336] methyl 4-bromo-5-(2-((2-bromopyridin-3-yl)oxy)ethyl)thiophene-2-carboxylate

[0337] Methyl 4-bromo-5-((2-bromopyridin-3-yl)oxy)ethyl)thiophene-2-carboxylate

[0338] Methyl 4-bromo-5-(2-hydroxyethyl)thiophene-2-carboxylate 6b (700 mg, 2.64 mmol), 2-bromopyridin-3-ol (689.09 mg, 3.96 mmol), and triphenylphosphine (2.08 g, 7.92 mmol) were dissolved in tetrahydrofuran (20 mL). The reaction mixture was purged with nitrogen three times. Diisopropyl azodicarboxylate (1.60 g, 7.92 mmol) was added dropwise at 0°C, and the reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was concentrated under reduced pressure and separated by silica gel column chromatography (eluent: System A) to obtain methyl 4-bromo-5-((2-bromopyridin-3-yl)oxy)ethyl)thiophene-2-carboxylate 6c (1.2 g) in a yield of 78.39%.

[0339] MS (ESI) m / z: 421.7 [M+H].

[0340] Step 3

[0341] methyl 6,7-dihydrothieno[3',2':4,5]oxepino[3,2-b]pyridine-9-carboxylate

[0342] 6,7-dihydrothieno(3',2':4,5)oxa Methyl 3,2-pyridine-9-carboxylate

[0343] Methyl 4-bromo-5-((2-bromopyridin-3-yl)oxy)ethyl)thiophene-2-carboxylate 6c (880 mg, 2.09 mmol), pinacol diboron (1.59 g, 6.27 mmol), bis(1-adamantyl)-butylphosphine (299.70 mg, 835.90 μmol), and potassium carbonate (1.44 g, 10.45 mmol) were dissolved in ethylene glycol dimethyl ether (10 mL) and water (1 mL). The reaction mixture was purged with nitrogen three times. Under a nitrogen atmosphere, palladium acetate (93.83 mg, 417.95 μmol) was added, and the reaction mixture was stirred at 100°C for 2 hours. The reaction mixture was concentrated under reduced pressure and separated by silica gel column chromatography (eluent: System A) to afford 6,7-dihydrothieno(3',2':4,5)oxazolidinone. Methyl (3,2-b)pyridine-9-carboxylate 6d (270 mg), yield 49.45%.

[0344] MS (ESI) m / z: 261.9 [M+H].

[0345] Step 4

[0346] 6,7-dihydrothieno[3',2':4,5]oxepino[3,2-b]pyridine-9-carboxylic acid

[0347] 6,7-dihydrothieno(3',2':4,5)oxa 9-pyridine-3,2-b-carboxylic acid

[0348] 6,7-dihydrothieno(3',2':4,5)oxazoline Methyl 6d (3,2-b)pyridine-9-carboxylate (300 mg, 1.15 mmol) was dissolved in tetrahydrofuran (12 mL) and water (4 mL), and lithium hydroxide monohydrate (53.00 mg, 1.26 mmol) was added and stirred at 25°C for 1 hour. After the reaction, the pH was adjusted to weak acidity with 1M hydrochloric acid solution, and then extracted with dichloromethane (50 mL × 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 6,7-dihydrothieno(3',2':4,5)oxazoline. 2-[3,2-b]pyridine-9-carboxylic acid 6e (230 mg), yield 81.02%.

[0349] MS (ESI) m / z: 247.9 [M+H].

[0350] Step 5

[0351] N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydrothieno[3',2':4,5]oxepino[3,2-b]pyridine-9-carboxamide

[0352] N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydrothieno[3',2':4,5]oxaplanin 2-[3,2-b]pyridine-9-carboxamide

[0353] At room temperature, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.14 g, 2.18 mmol) and N,N-diisopropylethylamine (282.25 mg, 2.18 mmol) were added to 6,7-dihydrothieno(3',2':4,5)oxazol-1-yl. 6e (3,2-b)pyridine-9-carboxylic acid (180 mg, 727.95 μmol) and 1 g (240.96 mg, 1.09 mmol) of N-(3-amino-5-chlorophenyl)methanesulfonamide in N,N-dimethylformamide (1 mL) were added. The reaction mixture was allowed to react at 25°C for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydrothieno[3',2':4,5]oxazoline. [3,2-b]pyridine-9-carboxamide 6 (12 mg), yield 3.66%.

[0354] MS (ESI) m / z: 449.8 [M+H].

[0355] 1 H NMR (400MHz, DMSO-d6) δ10.67(s,1H),10.06(s,1H),8.86(s,1H),8.40(dd,J=4.4,1.6Hz,1H),7.81–7.64(m,2H),7.47(dd,J= 8.0,1.6Hz,1H),7.31(dd,J=8.0,4.4Hz,1H),6.95(t,J=2.0Hz,1H),4.39(t,J=4.8Hz,2H),3.46(t,J=4.8Hz,2H),3.07(s,3H).

[0356] Example 7

[0357] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxamide

[0358] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine 9-Methyl-2-nitropropane

[0359] first step

[0360] methyl 5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate

[0361] Methyl 5-(((tert-Butoxycarbonyl)amino)methyl)thiophene-2-carboxylate

[0362] To a solution of methyl 5-formylthiophene-2-carboxylate 7a (5 g, 29.4 mmol, commercially available) in dichloromethane (50 mL) and acetonitrile (50 mL) were added triethylsilane (10.3 g, 88.1 mmol), tert-butyl carbamate (10.3 g, 88.1 mmol), and trifluoroacetic acid (6.70 g, 58.8 mmol) at 25°C. The reaction was allowed to proceed at room temperature for 18 hours. The mixture was poured into saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: System A) to afford methyl 5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate 7b (7.0 g) in an 88% yield.

[0363] MS m / z(ESI):215.9[M+1].

[0364] Step 2

[0365] methyl 4-bromo-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate

[0366] Methyl 4-bromo-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate

[0367] To a solution of methyl 5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate 7b (5.00 g, 18.4 mmol) in N,N-dimethylformamide (30 mL) at 25°C was added N-bromosuccinimide (9.84 g, 55.28 mmol). The mixture was reacted at 50°C for 18 hours. The mixture was poured into water (500 mL) and extracted with ethyl acetate (400 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: System A) to afford methyl 4-bromo-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate 7c (2.5 g) in a 39% yield.

[0368] MS m / z(ESI):372.0[M+1].

[0369] 1 H NMR (400MHz, DMSO-d6) δ7.75(t,J=6.0Hz,1H),7.71(s,1H),4.24(d,J=6.0Hz,2H),3.82(s,3H),1.41(s,9H).

[0370] Step 3

[0371] methyl 5-(((tert-butoxycarbonyl)amino)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate

[0372] Methyl 5-(((tert-Butoxycarbonyl)amino)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate

[0373] To a solution of methyl 4-bromo-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate 7c (500 mg, 1.43 mmol) in 1,4-dioxane (10 mL) was added potassium acetate (420 mg, 4.28 mmol), biboronic acid pinacol bis(boron) (725 mg, 2.86 mmol), tris(dibenzylideneacetone)dipalladium (261 mg, 0.286 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (204 mg, 0.428 mmol) at 25°C. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 90°C for 1 hour. The mixture was filtered and concentrated under reduced pressure to give methyl 5-(((tert-butoxycarbonyl)amino)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate 7d (560 mg), which was used directly in the next reaction.

[0374] MS m / z(ESI):420.2[M+1].

[0375] Step 4

[0376] methyl 2-(2-(((tert-butoxycarbonyl)amino)methyl)-5-(methoxycarbonyl)thiophen-3-yl)nicotinate

[0377] To a mixed solution of methyl 5-(((tert-butoxycarbonyl)amino)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate 7d (570 mg, 1.43 mmol) and methyl 2-bromo-3-pyridinecarboxylate 7e (620 mg, 2.87 mmol, commercially available) in 1,4-dioxane (10 mL) and water (2 mL) were added 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (210 mg, 0.287 mmol) and potassium carbonate (595 mg, 4.30 mmol) at 25°C, and the mixture was heated to 90°C and reacted for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give methyl 2-(2-(((tert-butoxycarbonyl)amino)methyl)-5-(methoxycarbonyl)thiophen-3-yl)nicotinate 7f (500 mg) in a yield of 86%.

[0378] MS m / z(ESI):407.1[M+1].

[0379] Step 5

[0380] methyl 2-(2-(aminomethyl)-5-(methoxycarbonyl)thiophen-3-yl)nicotinate

[0381] 2-(2-(aminomethyl)-5-(methoxycarbonyl)thiophen-3-yl)nicotinate

[0382] To a solution of methyl 2-(2-(((tert-butoxycarbonyl)amino)methyl)-5-(methoxycarbonyl)thiophen-3-yl)nicotinate 7f (560 mg, 1.38 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL) and allowed to react at room temperature for 2 hours at 25°C. The mixture was concentrated under reduced pressure to afford methyl 2-(2-(aminomethyl)-5-(methoxycarbonyl)thiophen-3-yl)nicotinate 7g (420 mg), which was used directly in the next reaction.

[0383] MS m / z(ESI):306.9[M+1].

[0384] Step 6

[0385] methyl 5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylate

[0386] 5-Oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine -9-carboxylic acid methyl ester

[0387] At 25°C, N,N-diisopropylethylamine (1.05g, 8.16mmol) was added to a solution of 7g (500mg, 1.63mmol) of methyl 2-(2-(aminomethyl)-5-(methoxycarbonyl)thiophen-3-yl)nicotinate in toluene (5mL), and the mixture was reacted at 70°C for 18 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: System A) to obtain 5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine. -9-carboxylic acid methyl ester 7h (200 mg), yield: 45%.

[0388] MS m / z(ESI):275.0[M+1].

[0389] Step 7

[0390] 5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylic acid

[0391] 5-Oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine -9-carboxylic acid

[0392] At 25 ° C, 5-oxo-6,7-dihydro-5H-pyrido [3,2-c] thieno [3,2-e] azepine To a mixed solution of methyl 9-carboxylate 7h (130 mg, 0.474 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was added lithium hydroxide monohydrate (59.7 mg, 1.42 mmol) and reacted at 25°C for 2 hours. The mixture was concentrated under reduced pressure to obtain 5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine. -9-carboxylic acid 7i (120 mg), yield: 65.82%.

[0393] MS m / z(ESI):261.0[M+1].

[0394] Step 8

[0395] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxamide

[0396] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine -9-Formamide

[0397] At 25 ° C, 5-oxo-6,7-dihydro-5H-pyrido [3,2-c] thieno [3,2-e] azepine 9-Carboxylic acid 7i (130 mg, 0.499 mmol) and 1 g of N-(3-amino-5-chlorophenyl)methanesulfonamide (220 mg, 0.999 mmol) were added to N,N-dimethylformamide (5 mL), followed by (7-azabenzotriazole-1-oxy)tripyrrolidone hexafluorophosphate (521 mg, 0.999 mmol) and N,N-diisopropylethylamine (194 mg, 1.50 mmol). The temperature was raised to 65°C and the reaction was allowed to proceed for 18 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(3-chloro-5-(methylsulfonyl)phenyl)-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine -9-Carboxamide 7 (50 mg), yield: 22%.

[0398] MS m / z(ESI):463.0[M+1].

[0399] 1 H NMR (400MHz, DMSO-d6) δ10.64(s,1H),10.09(s,1H),8.84(dd,J=4.8,2.0Hz,1H),8.77(s,1H),8.62(d,J=1.6Hz,1H),8.30(dd ,J=8.0,1.6Hz,1H),7.74-7.67(m,2H),7.55(dd,J=8.0,4.8Hz,1H),6.97(t,J=2.0Hz,1H),4.31(d,J=6.0Hz,2H),3.08(s,3H).

[0400] Example 8

[0401] N-(3-chloro-5-(methylsulfonamido)phenyl)-6-methyl-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxamide

[0402] N-(3-Chloro-5-(methylsulfonamido)phenyl)-6-methyl-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine -9-Formamide

[0403] first step

[0404] methyl 6-methyl-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylate

[0405] 6-Methyl-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine -9-carboxylic acid methyl ester

[0406] At 0 ° C, 5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine To a solution of methyl 7h-9-carboxylate (150 mg, 0.547 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (45.6 mg, 1.09 mmol, 60% purity) and the mixture was allowed to react at 0°C for 0.5 hour. Methyl iodide (155 mg, 1.09 mmol) was added to the above solution and allowed to react at 25°C for 1 hour. The mixture was quenched with saturated aqueous ammonium chloride (5 mL), followed by addition of water (30 mL) and extraction with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: System A) to yield 6-methyl-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine. -9-carboxylic acid methyl ester 8a (130 mg), yield: 82%.

[0407] MS m / z(ESI):289.0[M+1].

[0408] Step 2

[0409] 6-methyl-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylic acid

[0410] 6-Methyl-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine -9-carboxylic acid

[0411] At 25 ° C, 6-methyl-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine To a mixture of tetrahydrofuran (5 mL) and water (2 mL) of methyl-9-carboxylate 8a (130 mg, 0.451 mmol) was added lithium hydroxide monohydrate (56.8 mg, 1.35 mmol) and the mixture was reacted at 25°C for 2 hours. The mixture was concentrated under reduced pressure to obtain 6-methyl-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine. -9-Carboxylic acid 8b (120 mg) was used directly in the next reaction.

[0412] MS m / z(ESI):275.0[M+1].

[0413] Step 3

[0414] N-(3-chloro-5-(methylsulfonamido)phenyl)-6-methyl-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxamide

[0415] N-(3-Chloro-5-(methylsulfonamido)phenyl)-6-methyl-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine -9-Formamide

[0416] At 25 ° C, 6-methyl-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine -9-carboxylic acid 8b (125 mg, 0.456 mmol), N-(3-amino-5-chlorophenyl)methanesulfonamide 1 g (201 mg, 0.911 mmol) were added to N,N-dimethylformamide (5 mL), followed by (7-azabenzotriazole-1-oxy)tripyrrolidone hexafluorophosphate (475 mg, 0.911 mmol) and N,N-diisopropylethylamine (177 mg, 1.37 mmol), and the temperature was raised to 65 ° C and the reaction was carried out for 3 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(3-chloro-5-(methylsulfonyl)phenyl)-6-methyl-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine -9-Carboxamide 8 (40 mg), yield: 18%.

[0417] MS m / z(ESI):477.0[M+1].

[0418] 1 H NMR (400MHz, DMSO-d6) δ10.64(s,1H),10.08(s,1H),8.82(dd,J=4.4,2.0Hz,1H),8.62(s,1H),8.28(dd,J=8.0,2.0Hz,1H),7.72( t,J=2.0Hz,1H),7.68(t,J=2.0Hz,1H),7.54(dd,J=8.0,4.8Hz,1H),6.96(t,J=2.0Hz,1H),4.59(s,2H),3.14(s,3H),3.08(s,3H).

[0419] Example 9

[0420] N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxamide

[0421] N-(3-Chloro-5-(methylsulfonamido)phenyl)-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine -9-Formamide

[0422] first step

[0423] methyl 6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylate

[0424] 6,7-Dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine -9-carboxylic acid methyl ester

[0425] At 25 ° C, 5-oxo-6,7-dihydro-5H-pyrido [3,2-c] thieno [3,2-e] azepine -9-carboxylic acid methyl ester 7h (500 mg, 1.82 mmol) was added to a tetrahydrofuran solution of borane (1 M, 10 mL) and the temperature was raised to 65 ° C for 1 hour. The system was quenched by adding methanol (20 mL) and the mixture was concentrated under reduced pressure to obtain 6,7-dihydro-5H-pyrido [3,2-c] thieno [3,2-e] azepine -9-Carboxylic acid methyl ester 9a (470 mg) was used directly in the next reaction.

[0426] MS m / z(ESI):261.0[M+1].

[0427] Step 2

[0428] 6-(tert-butyl)9-methyl 5,7-dihydro-6H-pyrido[3,2-c]thieno[3,2-e]azepine-6,9-dicarboxylate

[0429] 6-(tert-Butyl)9-methyl-5,7-dihydro-6H-pyrido[3,2-c]thieno[3,2-e]azepine -6,9-dicarboxylate

[0430] At 25 ° C, 6,7-dihydro-5H-pyrido [3,2-c] thieno [3,2-e] azepine To a solution of methyl 9-carboxylate 9a (470 mg, 1.81 mmol) in N,N-dimethylformamide (10 mL) were added N,N-diisopropylethylamine (700 mg, 5.42 mmol), di-tert-butyl dicarbonate (788 mg, 3.61 mmol), and 4-dimethylaminopyridine (22.1 mg, 0.181 mmol), and the mixture was stirred at room temperature for 18 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: System A) to obtain 6-(tert-butyl)9-methyl5,7-dihydro-6H-pyrido[3,2-c]thieno[3,2-e]azepine. -6,9-dicarboxylate 9b (300 mg), yield: 46%.

[0431] MS m / z(ESI):361.2[M+1].

[0432] Step 3

[0433] 6-(tert-butoxycarbonyl)-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylic acid

[0434] 6-(tert-Butyloxycarbonyl)-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine -9-carboxylic acid

[0435] At 25 ° C, 6-(tert-butyl) 9-methyl 5,7-dihydro-6H-pyrido [3,2-c] thieno [3,2-e] azepine To a solution of 6,9-dicarboxylate 9b (140 mg, 0.388 mmol) in tetrahydrofuran (2 mL) and water (1 mL) was added lithium hydroxide monohydrate (48.9 mg, 1.17 mmol) and the mixture was reacted at 25°C for 2 hours. The mixture was concentrated under reduced pressure to obtain 6-(tert-butyloxycarbonyl)-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine. -9-Carboxylic acid 9c (130 mg) was used directly in the next reaction.

[0436] MS m / z(ESI):347.0[M+1].

[0437] Step 4

[0438] tert-butyl 9-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-5,7-dihydro-6H-pyrido[3,2-c]thieno[3,2-e]azepine-6-carboxylate

[0439] 9-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-5,7-dihydro-6H-pyrido[3,2-c]thieno[3,2-e]azepine -6-carboxylic acid tert-butyl ester

[0440] At 25 ° C, 6-(tert-butyloxycarbonyl)-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine -9-Carboxylic acid 9c (130 mg, 0.375 mmol) and 1 g of N-(3-amino-5-chlorophenyl)methanesulfonamide (166 mg, 0.751 mmol) were added to N,N-dimethylformamide (5 mL), followed by (7-azabenzotriazole-1-oxy)tripyrrolidone hexafluorophosphate (391 mg, 0.751 mmol) and N,N-diisopropylethylamine (146 mg, 1.13 mmol). The reaction mixture was heated to 65°C and stirred for 3 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (eluent: System A) to give 9-((3-chloro-5-(methylsulfonylamino)phenyl)carbamoyl)-5,7-dihydro-6H-pyrido[3,2-c]thieno[3,2-e]azepine. -tert-Butyl 6-carboxylate 9d (70 mg), yield: 34%.

[0441] MS m / z(ESI):548.8[M+1].

[0442] Step 5

[0443] N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxamide

[0444] N-(3-Chloro-5-(methylsulfonamido)phenyl)-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine -9-Formamide

[0445] At 25 ° C, 9-((3-chloro-5-(methylsulfonyl)phenyl)carbamoyl)-5,7-dihydro-6H-pyrido[3,2-c]thieno[3,2-e]azepine was added. To a solution of tert-butyl-6-carboxylate 9d (50.0 mg, 0.0911 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) and the mixture was allowed to react at 25°C for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to afford N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine -9-Carboxamide 9 (10 mg), yield: 24%.

[0446] MS m / z(ESI):449.0[M+1].

[0447] 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),10.01(s,1H),8.76(s,1H),8.54(dd,J=4.8,1.6Hz,1H),7.69(dt,J=6.0,2.0Hz,2H ),7.63(dd,J=7.6,1.6Hz,1H),7.25(dd,J=7.6,4.8Hz,1H),6.93(t,J=2.0Hz,1H),4.34(s,2H),3.95(s,2H),3.09(s,3H).

[0448] Example 10

[0449] N-(3-chloro-5-(methylsulfonamido)phenyl)-6-methyl-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxamide

[0450] N-(3-Chloro-5-(methylsulfonamido)phenyl)-6-methyl-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine -9-Formamide

[0451] At 25 ° C, N-(3-chloro-5-(methylsulfonyl)phenyl)-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine To a solution of 9-carboxamide 9 (41.0 mg, 0.0913 mmol) in acetonitrile (3 mL) was added aqueous formaldehyde solution (37.1 mg, 0.0457 mmol, 37% purity) and the mixture was reacted at 25°C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was separated by preparative liquid phase separation (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to obtain N-(3-chloro-5-(methylsulfonyl)phenyl)-6-methyl-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine -9-Carboxamide 10 (10 mg), yield: 24%.

[0452] MS m / z(ESI):463.0[M+1].

[0453] 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),10.11(s,1H),8.74(s,1H),8.59(dd,J=4.8,1.6Hz,1H),7.74(dd,J=7.6,1.6Hz,1H), 7.70(dt,J=8.0,2.0Hz,2H),7.32(dd,J=7.6,4.8Hz,1H),6.95(s,1H),4.15(s,2H),3.85(s,2H),3.07(s,3H),2.33(s,3H).

[0454] Example 11

[0455] N-(3-chloro-5-(methylsulfonamido)phenyl)-6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxamide

[0456] N-(3-chloro-5-(methylsulfonamido)phenyl)-6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-Formamide

[0457] first step

[0458] methyl 2-(5-bromothiophen-2-yl)acetate

[0459] Methyl 2-(5-bromothiophen-2-yl)acetate

[0460] To a solution of methyl 2-thiopheneacetate 11a (10.0 g, 64.0 mmol) in N,N-dimethylformamide (50 mL) was added N-bromosuccinimide (13.7 g, 76.8 mmol) at 25°C. The mixture was allowed to react for 1 hour at 25°C. The mixture was poured into water (500 mL) and extracted with ethyl acetate (400 mL). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to afford methyl 2-(5-bromothiophen-2-yl)acetate 11b (10.0 g) in a 66% yield.

[0461] Step 2

[0462] methyl 5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate

[0463] 5-(2-methoxy-2-oxo)thiophene-2-carboxylic acid methyl ester

[0464] To a solution of methyl 2-(5-bromothiophen-2-yl)acetate 11b (3.60 g, 15.3 mmol) in methanol (20 mL) was added 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (1.14 g, 1.53 mmol) and triethylamine (4.65 g, 45.9 mmol) at 25°C. After carbon monoxide displacement, the reaction was continued at 70°C for 18 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to afford methyl 5-(2-methoxy-2-oxothiophene-2-carboxylate 11c (1.5 g) in a 46% yield.

[0465] MS m / z(ESI):215.0[M+1].

[0466] Step 3

[0467] methyl 4-bromo-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate

[0468] 4-Bromo-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylic acid methyl ester

[0469] To a solution of methyl 5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate 11c (1.80 g, 8.40 mmol) in trifluoroacetic acid (10 mL) and acetic acid (1 mL) was added N-bromosuccinimide (1.94 g, 10.9 mmol) at 25°C for 1 hour. The mixture was diluted with ethyl acetate (100 mL) and the pH was adjusted to 8-9 by dropwise addition of the ethyl acetate solution into saturated aqueous sodium bicarbonate. The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to afford methyl 4-bromo-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate 11d (1.2 g) in a 49% yield.

[0470] MS m / z(ESI):293.0 / 295.0[M+1].

[0471] 1 H NMR (400MHz, DMSO-d6) δ7.75(s,1H),4.02(s,2H),3.85(s,3H),3.68(s,3H).

[0472] Step 4

[0473] methyl 5-(2-methoxy-2-oxoethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate

[0474] 5-(2-methoxy-2-oxoethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic acid methyl ester

[0475] To a solution of methyl 4-bromo-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate 11d (3.70 g, 12.6 mmol) in 1,4-dioxane (30 mL) were added potassium acetate (3.72 g, 37.9 mmol), bipyraclostrobin (9.62 g, 37.9 mmol) and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (924 mg, 1.26 mmol) at 25°C. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 90°C for 4 h. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to give 5-(2-methoxy-2-oxoethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic acid methyl ester 11e (3.50 g) in a yield of 82%.

[0476] MS m / z(ESI):341.1[M+1].

[0477] Step 5

[0478] methyl 4-(3-aminopyridin-2-yl)-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate

[0479] 4-(3-aminopyridin-2-yl)-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylic acid methyl ester

[0480] To a mixed solution of methyl 5-(2-methoxy-2-oxoethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate 11e (3.25 g, 9.55 mmol) and 2-bromo-3-aminopyridine (3.31 g, 19.1 mmol) in 1,4-dioxane (30 mL) and water (6 mL) were added 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (698 mg, 0.955 mmol) and potassium carbonate (3.96 g, 28.7 mmol) at 90°C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to give methyl 4-(3-aminopyridin-2-yl)-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate 11f (1.60 g) in a yield of 55%.

[0481] MS m / z(ESI):307.0[M+1].

[0482] Step 6

[0483] methyl 6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylate

[0484] 6-Oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-carboxylic acid methyl ester

[0485] To a solution of methyl 4-(3-aminopyridin-2-yl)-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate 11f (300 mg, 0.979 mmol) in tetrahydrofuran (10 mL) was added a 2M solution of trimethylaluminum in n-hexane (2.0 mL) at 25°C and allowed to react for 1 hour at 25°C. The system was quenched with methanol, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain 6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine. -9-carboxylic acid methyl ester 11g (240mg), yield: 89%.

[0486] MS m / z(ESI):275.0[M+1].

[0487] Step 7

[0488] 6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylic acid

[0489] 6-Oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-carboxylic acid

[0490] At 25 ° C, 6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine 11 g (80.0 mg, 0.292 mmol) of methyl 9-carboxylate was added to a mixed solution of tetrahydrofuran (1.5 mL) and water (1.5 mL), and lithium hydroxide monohydrate (36.7 mg, 0.875 mmol) was added, and the mixture was reacted at 25°C for 18 hours. The mixture was concentrated under reduced pressure to obtain 6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine. -9-carboxylic acid 11h (75.0 mg) was directly used for the next step reaction.

[0491] MS m / z(ESI):261.0[M+1].

[0492] Step 8

[0493] N-(3-chloro-5-(methylsulfonamido)phenyl)-6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxamide

[0494] N-(3-chloro-5-(methylsulfonamido)phenyl)-6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-Formamide

[0495] At 25°C, 6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylic acid 11h (75.0 mg, 0.288 mmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide 1g (127 mg, 0.576 mmol) were added to N,N-dimethylformamide (5 mL). (7-Azabenzotriazole-1-oxy)tripyrrolidone hexafluorophosphate (300 mg, 0.576 mmol) and N,N-diisopropylethylamine (112 mg, 0.864 mmol) were added to the reaction solution. The mixture was reacted at 65°C for 2 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to give N-(3-chloro-5-(methylsulfonyl)phenyl)-6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-Carboxamide 11 (3.00 mg), yield: 2%.

[0496] MS m / z(ESI):463.0[M+1].

[0497] 1 H NMR (400MHz, DMSO-d6) δ10.57(s,1H),10.39(s,1H),8.57(s,1H),8.50(dd,J=4.4,1.6Hz,1H),7 .72–7.59(m,3H),7.46(dd,J=8.0,4.4Hz,1H),6.93(t,J=2.0Hz,1H),3.75(s,2H),3.03(s,3H).

[0498] Example 12

[0499] N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxamide

[0500] N-(3-Chloro-5-(methylsulfonamido)phenyl)-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-Formamide

[0501] first step

[0502] methyl 6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylate

[0503] 6,7-Dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-carboxylic acid methyl ester

[0504] At 25 ° C, 6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine 11 g (200 mg, 0.729 mmol) of methyl 9-carboxylate was added to a 1 M solution of borane in tetrahydrofuran (10 mL) and reacted at 65°C for 1 hour. The system was quenched with methanol (20 mL), and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain 6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-carboxylic acid methyl ester 12a (160 mg), yield: 84%.

[0505] MS m / z(ESI):261.0[M+1].

[0506] Step 2

[0507] 6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylic acid

[0508] 6,7-Dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-carboxylic acid

[0509] At 25 ° C, 6,7-dihydro-5H-pyrido [3,2-b] thieno [3,2-d] azepine -9-carboxylic acid methyl ester 12a (40.0 mg, 0.154 mmol) was added to a mixed solution of tetrahydrofuran (1 mL), methanol (2 mL) and water (1 mL), and lithium hydroxide monohydrate (19.3 mg, 0.461 mmol) was added and reacted at 25°C for 2 hours. The mixture was concentrated under reduced pressure to obtain 6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-Carboxylic acid 12b (40 mg) was used directly in the next step.

[0510] MS m / z(ESI):247.0[M+1].

[0511] Step 3

[0512] N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxamide

[0513] N-(3-Chloro-5-(methylsulfonamido)phenyl)-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-Formamide

[0514] At 25 ° C, 6,7-dihydro-5H-pyrido [3,2-b] thieno [3,2-d] azepine -9-Carboxylic acid 12b (40.0 mg, 0.162 mmol) and 1 g (71.7 mg, 0.325 mmol) of N-(3-amino-5-chlorophenyl)methanesulfonamide were added to N,N-dimethylformamide (4 mL), and (7-azabenzotriazole-1-oxy)tripyrrolidone hexafluorophosphate (169 mg, 0.325 mmol) and N,N-diisopropylethylamine (63.0 mg, 0.487 mmol) were added to the reaction solution, and the reaction was carried out at 65 ° C for 3 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (150 mL). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to obtain N-(3-chloro-5-(methylsulfonyl)phenyl)-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-Carboxamide 12 (11.0 mg), yield: 15%.

[0515] MS m / z(ESI):449.0[M+1].

[0516] 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),10.07(s,1H),8.84(s,1H),8.03(dd,J=4.4,1.6Hz,1H),7.71-7.69(m,2H),7.18(dd,J=8.0,1.6 Hz,1H),7.07(dd,J=8.0,4.4Hz,1H),6.94(t,J=2.0Hz,1H),6.48(t,J=4.4Hz,1H),3.38-3.33(m,2H),3.23-3.19(m,2H),3.07(s,3H).

[0517] Example 13

[0518] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxamide

[0519] N-(3-Chloro-5-(methylsulfonamido)phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-Formamide

[0520] first step

[0521] methyl 5-methyl-6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylate

[0522] 5-Methyl-6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-carboxylic acid methyl ester

[0523] At 25 ° C, 6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine To a solution of 11 g (50.0 mg, 0.183 mmol) of methyl 9-carboxylate in tetrahydrofuran (10 mL) was added iodomethane (51.8 mg, 0.365 mmol) and cesium carbonate (178 mg, 0.547 mmol), and the mixture was reacted at 50°C for 1 hour. The mixture was filtered and concentrated under reduced pressure to obtain 5-methyl-6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine. -9-Carboxylic acid methyl ester 13a (50.0 mg) was used directly in the next step. MS m / z (ESI): 289.0 [M+1].

[0524] Step 2

[0525] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxamide

[0526] N-(3-Chloro-5-(methylsulfonamido)phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-Formamide

[0527] At 25 ° C, 5-methyl-6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine Methyl 9-carboxylate 13a (50.0 mg, 0.173 mmol) and 1 g of N-(3-amino-5-chlorophenyl)methanesulfonamide (76.5 mg, 0.347 mmol) were added to tetrahydrofuran (10 mL). A 2 M solution of trimethylaluminum in n-hexane (0.86 mL) was added to the reaction mixture and the mixture was reacted at 60°C for 3 hours. The mixture was poured into methanol (50 mL) and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH₄HCO₃ + H₂O, mobile phase B: CH₃CN) to afford N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-Carboxamide 13 (10.0 mg), yield: 12%.

[0528] MS m / z(ESI):472.2[M+1].

[0529] 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),10.12(s,1H),8.69–8.49(m,2H),8.03(dd,J=8.4,1.2Hz,1H),7.71 -7.64(m,2H),7.55(dd,J=8.4,4.4Hz,1H),6.96(t,J=2.0Hz,1H),3.74(s,2H),3.27(s,3H),3.06(s,3H).

[0530] Example 14

[0531] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxamide

[0532] N-(3-Chloro-5-(methylsulfonamido)phenyl)-5-methyl-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-Formamide

[0533] first step

[0534] methyl 5-methyl-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylate

[0535] 5-Methyl-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-carboxylic acid methyl ester

[0536] At 25 ° C, 6,7-dihydro-5H-pyrido [3,2-b] thieno [3,2-d] azepine To a solution of methyl ester 12a (100 mg, 0.384 mmol) of methyl-9-carboxylate 12a in 1,2-dichloroethane (5 mL) were added aqueous formaldehyde (156 mg, 1.92 mmol, 37% purity), acetic acid (23.1 mg, 0.384 mmol), and sodium triacetylborohydride (244 mg, 1.15 mmol) and allowed to react at 25°C for 2 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (150 mL). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to afford 5-methyl-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine. -9-carboxylic acid methyl ester 14a (100 mg), yield: 95%.

[0537] MS m / z(ESI):275.0[M+1].

[0538] Step 2

[0539] 5-methyl-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylic acid

[0540] 5-Methyl-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-carboxylic acid

[0541] At 25 ° C, 5-methyl-6,7-dihydro-5H-pyrido [3,2-b] thieno [3,2-d] azepine -9-carboxylic acid methyl ester 14a (85.0 mg, 0.310 mmol) was added to a mixed solution of tetrahydrofuran (3 mL) and water (1.5 mL), and lithium hydroxide monohydrate (39.0 mg, 0.930 mmol) was added and reacted at 50°C for 2 hours. The mixture was concentrated under reduced pressure to obtain 5-methyl-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-Carboxylic acid 14b (80 mg) was used directly in the next step.

[0542] MS m / z(ESI):261.0[M+1].

[0543] Step 3

[0544] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxamide

[0545] N-(3-Chloro-5-(methylsulfonamido)phenyl)-5-methyl-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-Formamide

[0546] At 25 ° C, 5-methyl-6,7-dihydro-5H-pyrido [3,2-b] thieno [3,2-d] azepine -9-Carboxylic acid 14b (80.0 mg, 0.307 mmol) and 1 g of N-(3-amino-5-chlorophenyl)methanesulfonamide (136 mg, 0.615 mmol) were added to N,N-dimethylformamide (5 mL). (7-Azabenzotriazole-1-oxy)tripyrrolidone hexafluorophosphate (641 mg, 1.23 mmol) and N,N-diisopropylethylamine (238 mg, 1.84 mmol) were added to the reaction solution and reacted at 65°C for 3 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (150 mL). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to give N-(3-chloro-5-(methylsulfonyl)phenyl)-5-methyl-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine -9-Carboxamide 14 (10.0 mg), yield: 12%.

[0547] MS m / z(ESI):463.2[M+1].

[0548] 1H NMR (400MHz, DMSO-d6) δ10.61(s,1H),10.11(s,1H),8.81(s,1H),8.18(dd,J=4.4,1.6Hz,1H),7.72-7.69(m,2H),7.37(dd,J=8.4 ,1.6Hz,1H),7.23(dd,J=8.4,4.4Hz,1H),6.94(t,J=2.0Hz,1H),3.34-3.30(m,2H),3.30-3.26(m,2H),3.07(s,3H),2.99(s,3H).

[0549] Example 15

[0550] N-(3-chloro-5-(methylsulfonamido)phenyl)-10-methoxy-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxamide

[0551] N-(3-Chloro-5-(methylsulfonamido)phenyl)-10-methoxy-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-Formamide

[0552] first step

[0553] methyl 4-(2-amino-6-methoxyphenyl)-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate

[0554] 4-(2-amino-6-methoxyphenyl)-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylic acid methyl ester

[0555] Methyl 4-bromo-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate 11d (3.00 g, 10.23 mmol) was dissolved in a mixture of ethylene glycol dimethyl ether (30 mL) and water (3 mL) at room temperature. 2-Bromo-3-methoxyaniline 15a (6.20 g, 30.70 mmol), potassium carbonate (4.24 g, 30.70 mmol), bis(boron)-pinacol (12.99 g, 51.17 mmol), palladium acetate (459.53 mg, 2.05 mmol), and n-butyldi(1-adamantyl)phosphine (1.47 g, 4.09 mmol) were added sequentially. After nitrogen substitution three times, the reaction mixture was stirred at 80°C for 18 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give methyl 4-(2-amino-6-methoxyphenyl)-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate 15b (2.80 g) in a yield of 81%.

[0556] MS m / z(ESI):336.0[M+1].

[0557] Step 2

[0558] methyl 10-methoxy-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate

[0559] 10-Methoxy-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-carboxylic acid methyl ester

[0560] At room temperature, methyl 4-(2-amino-6-methoxyphenyl)-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate 15b (2.80 g, 8.35 mmol) was dissolved in toluene (15 mL), and N,N-diisopropylethylamine (6.47 g, 50.09 mmol) was added dropwise. After nitrogen substitution three times, the reaction temperature was raised to 100°C and the reaction was allowed to react for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to obtain 10-methoxy-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine. -2-Carboxylic acid methyl ester 15c (1.30 g), yield: 51%.

[0561] MS m / z(ESI):304.0[M+1].

[0562] Step 3

[0563] methyl 10-methoxy-6-methyl-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate

[0564] 10-Methoxy-6-methyl-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-carboxylic acid methyl ester

[0565] At room temperature, 10-methoxy-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-Carboxylic acid methyl ester 15c (280.00 mg, 0.92 mmol) was dissolved in tetrahydrofuran (3 mL) and cesium carbonate (902.27 mg, 2.77 mmol) and iodomethane (262.04 mg, 1.85 mmol) were added in sequence. After nitrogen substitution three times, the reaction was continued at 25°C for 3 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain 10-methoxy-6-methyl-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-carboxylic acid methyl ester 15d (220 mg), yield: 75%.

[0566] MS m / z(ESI):318.0[M+1].

[0567] Step 4

[0568] methyl 10-methoxy-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate

[0569] 10-Methoxy-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-carboxylic acid methyl ester

[0570] At room temperature, 10-methoxy-6-methyl-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-Carboxylic acid methyl ester 15d (200.00 mg, 0.63 mmol) was dissolved in tetrahydrofuran (2 mL) and borane-tetrahydrofuran (162.48 mg, 1.89 mmol, 1 M) was added dropwise. The mixture was reacted at 25°C for 1 hour. The reaction solution was poured into methanol (50 mL) and stirred at 50°C for 0.5 hour. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: System A) to obtain 10-methoxy-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-Carboxylic acid methyl ester 15e (125 mg), yield: 65%. MS m / z (ESI): 304.0 [M+1].

[0571] Step 5

[0572] N-(3-chloro-5-(methylsulfonamido)phenyl)-10-methoxy-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxamide

[0573] N-(3-Chloro-5-(methylsulfonamido)phenyl)-10-methoxy-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-Formamide

[0574] At room temperature, 10-methoxy-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine Methyl 2-carboxylate 15e (125.00 mg, 0.41 mmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide 1 g (90.90 mg, 0.41 mmol) were dissolved in tetrahydrofuran (1 mL), and a solution of trimethylaluminum in n-hexane (89.10 mg, 1.24 mmol, 1 M) was added dropwise. The reaction was allowed to proceed at 60°C for 18 hours. The reaction solution was poured into methanol (50 mL) for quenching and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to obtain N-(3-chloro-5-(methylsulfonyl)phenyl)-10-methoxy-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-Formamide 15 (106 mg), yield: 52%. MS m / z (ESI): 492.0 [M+1].

[0575] 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),10.17(s,1H),8.11(s,1H),7.64(dt,J=15.2,1.8Hz,2H),7.29(t,J=8.2Hz,1H),6.95( t,J=1.8Hz,1H),6.81(t,J=7.8Hz,2H),3.80(s,3H),3.42(t,J=6.6Hz,2H),3.06(s,3H),2.83(t,J=6.6Hz,2H),2.69(s,3H).

[0576] According to the preparation method of Example 15 of the present invention, Examples 16-18 were prepared, and their specific structures and structural characterizations are as follows:

[0577] Example 19

[0578] 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxamide

[0579] 10-(Benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-Formamide

[0580] first step

[0581] 1-(benzyloxy)-2-bromo-3-nitrobenzene

[0582] 1-(Benzyloxy)-2-bromo-3-nitrobenzene

[0583] 2-Bromo-3-nitrophenol 19a (1 g, 4.59 mmol) was dissolved in tetrahydrofuran (10 mL). Cesium carbonate (4.48 g, 13.76 mmol) and benzyl bromide (1.18 g, 6.88 mmol, 817.23 μL) were added to the resulting solution. The reaction solution was stirred at room temperature for 12 hours. The resulting mixed solution was filtered under reduced pressure, and the filter cake was washed with dichloromethane (5 mL x 3). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to provide 1-(benzyloxy)-2-bromo-3-nitrobenzene 19b (1.26 g) in an 89% yield.

[0584] MS m / z(ESI):308.0[M+1].

[0585] Step 2

[0586] 3-(benzyloxy)-2-bromoaniline

[0587] 3-(Benzyloxy)-2-bromoaniline

[0588] 1-(Benzyloxy)-2-bromo-3-nitrobenzene 19b (1.26 g, 4.09 mmol) was dissolved in ethanol (12 mL). Iron powder (685.15 mg, 12.27 mmol), ammonium chloride (656.20 mg, 12.27 mmol), and water (1.5 mL) were added to the resulting solution. The reaction mixture was purged with nitrogen three times and stirred at 90°C under nitrogen for 2 hours. The resulting mixed solution was filtered under reduced pressure, and the filter cake was washed with dichloromethane (5 mL x 3). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to provide 3-(benzyloxy)-2-bromoaniline 19c (1.0 g) in an 88% yield.

[0589] MS m / z(ESI):278.0[M+1].

[0590] Step 3

[0591] methyl 4-(2-amino-6-(benzyloxy)phenyl)-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate

[0592] 4-(2-amino-6-(benzyloxy)phenyl)-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylic acid methyl ester

[0593] 3-(Benzyloxy)-2-bromoaniline 19c (1 g, 3.60 mmol) and methyl 4-bromo-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate 11d (702.60 mg, 2.40 mmol) were dissolved in 1,4-dioxane (20 mL). To the resulting solution were added pinacol diboron (1.83 g, 7.19 mmol), n-butyldi(1-adamantyl)phosphine (343.75 mg, 958.74 μmol), potassium carbonate (993.77 mg, 7.19 mmol), palladium acetate (107.62 mg, 479.37 μmol) and water (2 mL). The reaction solution was replaced with nitrogen three times and stirred at 80°C under nitrogen protection for 1 hour. The resulting mixed solution was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: System A) to give methyl 4-(2-amino-6-(benzyloxy)phenyl)-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate 19d (900 mg) in a yield of 45%.

[0594] MS m / z(ESI):412.2[M+1].

[0595] Step 4

[0596] methyl 10-(benzyloxy)-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate

[0597] 10-(Benzyloxy)-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-carboxylic acid methyl ester

[0598] Methyl 4-(2-amino-6-(benzyloxy)phenyl)-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate 19d (800 mg, 972.12 μmol) was dissolved in tetrahydrofuran (8 mL). Trimethylaluminum in n-hexane (1 M, 9.72 mL) was slowly added dropwise to the resulting solution. The reaction solution was stirred at 60°C for 1 hour. The reaction solution was slowly added dropwise to methanol (20 mL). The resulting mixed solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to obtain 10-(benzyloxy)-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine. -2-Carboxylic acid methyl ester 19e (200 mg), yield: 54%. MS m / z (ESI): 380.0 [M+1].

[0599] Step 5

[0600] methyl 10-(benzyloxy)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate

[0601] 10-(Benzyloxy)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-carboxylic acid methyl ester

[0602] To borane tetrahydrofuran complex (1 M, 4 mL) was slowly added 10-(benzyloxy)-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-carboxylic acid methyl ester 19e (150 mg, 395.33 μmol), the reaction solution was stirred at 60°C for 1 hour, and the reaction solution was slowly added dropwise to methanol (20 mL) and stirred at 60°C for 1 hour. The resulting mixed solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to obtain 10-(benzyloxy)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-Carboxylic acid methyl ester 19f (100 mg), yield: 69%.

[0603] MS m / z(ESI):336.2[M+1].

[0604] Step 6

[0605] methyl 10-(benzyloxy)-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate

[0606] 10-(Benzyloxy)-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-carboxylic acid methyl ester

[0607] 10-(Benzyloxy)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine Methyl 19f-2-carboxylate (100 mg, 273.64 μmol) was dissolved in 1,2-dichloroethane (4.00 mL). Sodium triacetoxyborohydride (347.97 mg, 1.64 mmol), acetic acid (1.64 mg, 27.36 μmol, 1.57 μL), and aqueous formaldehyde (133.24 mg, 1.64 mmol, 122.24 μL, 37% purity) were added to the resulting solution. The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to afford 10-(benzyloxy)-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine. -2-carboxylic acid methyl ester 19g (90mg), yield: 86%.

[0608] MS m / z(ESI):380.2[M+1].

[0609] Step 7

[0610] 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxamide

[0611] 10-(Benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-Formamide

[0612] 10-(Benzyloxy)-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine 19 g (20 mg, 52.70 μmol) of methyl 2-carboxylate and 1 g (17.45 mg, 79.06 μmol) of N-(3-amino-5-chlorophenyl)methanesulfonamide were dissolved in tetrahydrofuran (1 mL). To the resulting mixed solution, a solution of trimethylaluminum in n-hexane (1 M, 527.05 μL) was slowly added dropwise. The reaction solution was stirred at 60 ° C for 1 hour. The reaction solution was slowly added dropwise to methanol (5 mL) to quench the reaction. The resulting mixed solution was concentrated under reduced pressure, and the residue was separated by preparative liquid phase separation (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 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-Formamide 19 (11 mg), yield: 36%.

[0613] MS m / z(ESI):568.2[M+1].

[0614] 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),10.14(s,1H),8.26(s,1H),7.63(dt,J=4.4,2.0Hz,2H),7.44(d,J=6.4Hz,2H),7.30–7.22(m,4H),6.95(t, J=2.0Hz,1H),6.90(d,J=8.0Hz,1H),6.81(d,J=8.0Hz,1H),5.14(s,2H),3.42(t,J=6.4Hz,2H),3.07(s,3H),2.84(t,J=6.4Hz,2H),2.71(s,3H).

[0615] According to the preparation method of Example 19 of the present invention, Examples 20-26 were prepared, and their specific structures and structural characterizations are as follows:

[0616] Example 27

[0617] N-(3-chloro-5-(methylsulfonamido)phenyl)-6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxamide

[0618] N-(3-chloro-5-(methylsulfonamido)phenyl)-6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine -10-formamide

[0619] first step

[0620] methyl 5-bromo-1-(2-methoxy-2-oxoethyl)-1H-pyrrole-3-carboxylate

[0621] 5-Bromo-1-(2-methoxy-2-oxoethyl)-1H-pyrrole-3-carboxylic acid methyl ester

[0622] Methyl 5-bromo-1H-pyrrole-3-carboxylate 27a (1.5 g, 7.35 mmol) and methyl bromoacetate (1.69 g, 11.03 mmol) were dissolved in acetonitrile (30 mL), followed by the addition of potassium carbonate (3.05 g, 22.06 mmol) and the reaction was allowed to react at room temperature for 12 hours. The reaction solution was filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to afford methyl 5-bromo-1-(2-methoxy-2-oxoethyl)-1H-pyrrole-3-carboxylate 27b (1.8 g) in an 88% yield.

[0623] MS m / z(ESI):276.0[M+1].

[0624] Step 2

[0625] methyl 6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxylate

[0626] 6-Oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]azepine -10-carboxylic acid methyl ester

[0627] Methyl 5-bromo-1-(2-methoxy-2-oxoethyl)-1H-pyrrole-3-carboxylate 27b (2 g, 2.09 mmol), 2-bromo-3-aminopyridine (3.76 g, 21.73 mmol), pinacol diboronate (5.52 g, 21.73 mmol), bis(1-adamantyl)-butylphosphine (1.04 g, 2.90 mmol), and potassium carbonate (5.01 g, 36.22 mmol) were dissolved in ethylene glycol dimethyl ether (20 mL) and water (4 mL). The reaction mixture was purged with nitrogen three times. Palladium acetate (325.28 mg, 1.45 mmol) was added under a nitrogen atmosphere, and the reaction was incubated at 80°C for 12 hours. The reaction solution was diluted with water and extracted with ethyl acetate (100 mL × 3). The extracts were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain 6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine -10-carboxylic acid methyl ester 27c (600 mg), yield: 32%.

[0628] MS m / z(ESI):258.2[M+1].

[0629] Step 3

[0630] N-(3-chloro-5-(methylsulfonamido)phenyl)-6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxamide

[0631] N-(3-chloro-5-(methylsulfonamido)phenyl)-6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine -10-formamide

[0632] 1 g (171.57 mg, 777.47 μmol) of N-(3-amino-5-chlorophenyl)methanesulfonamide was dissolved in tetrahydrofuran (1 mL) and toluene (1 mL), and a solution of trimethylaluminum in n-hexane (2 M, 583.10 μL) was added dropwise at 0°C, and then stirred at 25°C for 0.5 hours. Methyl 27c (100 mg, 388.74 μmol) of 1,0-dimethyl-1,0-carboxylate was added to the reaction solution, and the reaction was continued at 60°C for 1 hour. After the reaction, the product was quenched with methanol and dried by spin drying. The residue was purified by silica gel column chromatography (eluent: System A) and then separated by preparative liquid phase separation (AKZONOBEL Kromasil column; 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-(methylsulfonylamino)phenyl)-6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine. -10-Carboxamide 27 (7 mg), yield: 19%.

[0633] MS m / z(ESI):446.0[M+1].

[0634] 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),10.03(s,1H),9.98(s,1H),8.46(d,J=4.4Hz,1H),7.80(s,1H),7. 75(s,1H),7.67(s,1H),7.56(d,J=8.0Hz,1H),7.45–7.35(m,2H),6.90(s,1H),4.81(s,2H),3.07(s,3H).

[0635] Example 28

[0636] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxamide

[0637] N-(3-Chloro-5-(methylsulfonamido)phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine -10-formamide

[0638] first step

[0639] methyl 5-methyl-6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxylate

[0640] 5-Methyl-6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine -10-carboxylic acid methyl ester

[0641] 6-Oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine Methyl 27c (300 mg, 1.17 mmol) and potassium carbonate (322.35 mg, 2.33 mmol) were dissolved in N,N-dimethylformamide (5 mL), and iodomethane (248.29 mg, 1.75 mmol, 108.90 μL) was added, followed by reaction at room temperature for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate (50 mL × 3). The extracts were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain 5-methyl-6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine -10-carboxylic acid methyl ester 28a (300 mg), yield: 95%.

[0642] MS m / z(ESI):272.1[M+1].

[0643] Step 2

[0644] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxamide

[0645] N-(3-Chloro-5-(methylsulfonamido)phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine -10-formamide

[0646] 5-methyl-6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine Methyl 2-(3-amino-5-chlorophenyl)methanesulfonamide 28a (250 mg, 921.59 μmol) and 1 g (406.75 mg, 1.84 mmol) of N-(3-amino-5-chlorophenyl)methanesulfonamide were dissolved in tetrahydrofuran (2 mL) and toluene (2 mL). A solution of trimethylaluminum in n-hexane (2 M, 2.76 mL) was added dropwise at 0 °C, and the mixture was reacted at 60 °C for 3 h. After the reaction, the product was quenched with methanol and dried in spun-drying. The residue was purified by silica gel column chromatography (eluent: System A), and then separated by preparative liquid phase separation (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-(methylsulfonylamino)phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine -10-carboxamide 28 (92 mg), yield: 22%.

[0647] MS m / z(ESI):460.0[M+1].

[0648] 1 H NMR (400MHz, DMSO-d6) δ9.97(s,2H),8.54(dd,J=4.8,1.2Hz,1H),7.97(dd,J=8.0,1.2Hz,1H),7.84(d,J=1.6Hz,1H),7.73(t,J=1.6H z,1H),7.65(s,1H),7.50(dd,J=8.4,4.8Hz,1H),7.38(d,J=2.0Hz,1H),6.90(t,J=2.0Hz,1H),4.78(s,2H),3.28(s,3H),3.05(s,3H).

[0649] Example 29

[0650] N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxamide

[0651] N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine -10-formamide

[0652] first step

[0653] methyl 6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxylate

[0654] 6,7-Dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine -10-carboxylic acid methyl ester

[0655] 6-Oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine Methyl 27c-10-carboxylate (200 mg, 777.47 μmol) was dissolved in tetrahydrofuran (5 mL) and borane dimethyl sulfide (2 M, 9.72 mL) was added dropwise at 0°C, followed by reaction at room temperature for 1 hour. The reaction solution was quenched with methanol and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine -10-carboxylic acid methyl ester 29a (110 mg), yield: 58%.

[0656] MS m / z(ESI):244.0[M+1].

[0657] Step 2

[0658] N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxamide

[0659] N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine -10-formamide

[0660] 6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine -10-Carboxylic acid methyl ester 29a (90 mg, 369.97 μmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide 1 g (163.29 mg, 739.95 μmol) were dissolved in tetrahydrofuran (2 mL) and toluene (2 mL), and trimethylaluminum (2 M, 554.96 μL) was added dropwise at 0 ° C, and then reacted at 60 ° C for 3 hours. After the reaction, the product was quenched with methanol and dried in spun-drying. The residue was purified by silica gel column chromatography (eluent: System A) and then separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to obtain N-(3-chloro-5-(methylsulfonyl)phenyl)-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine -10-Carboxamide 29 (50 mg), yield: 31%. MS m / z (ESI): 432.1 [M+1].

[0661] 1 H NMR (400MHz, DMSO-d6) δ9.99 (s, 1H), 9.89 (s, 1H), 7.94 (dd, J = 4.0, 1.2Hz, 1H), 7.7 6(t,J=2.0Hz,1H),7.70(t,J=1.6Hz,1H),7.56(d,J=2.0Hz,1H),7.52(d,J=2.0Hz,1 H),7.11(dd,J=8.4,1.6Hz,1H),7.00(dd,J=8.4,4.4Hz,1H),6.89(t,J=1.6Hz,1H), 6.51(t,J=4.0Hz,1H),4.42–4.21(m,2H),3.46(dd,J=7.2,3.6Hz,2H),3.07(s,3H).

[0662] According to the preparation method of Example 29 of the present invention, Examples 30-34 were prepared, and their specific structures and structural characterizations are as follows:

[0663] Example 34

[0664] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-methoxy-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxamide

[0665] N-(3-Chloro-5-(methylsulfonamido)phenyl)-11-methoxy-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Formamide

[0666] first step

[0667] methyl 5-bromo-1-(2,2-dimethoxyethyl)-1H-pyrrole-3-carboxylate

[0668] 5-Bromo-1-(2,2-dimethoxyethyl)-1H-pyrrole-3-carboxylic acid methyl ester

[0669] Methyl 5-bromo-1H-pyrrole-3-carboxylate 27a (5.00 g, 24.5 mmol), 2-bromo-1,1-dimethoxyethane (8.28 g, 49.0 mmol), and cesium carbonate (24.0 g, 73.5 mmol) were added to acetonitrile (50 mL) at 25°C and reacted at 80°C for 18 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to give methyl 5-bromo-1-(2,2-dimethoxyethyl)-1H-pyrrole-3-carboxylate 34a (5.0 g) in a 70% yield.

[0670] MS m / z(ESI):292.0 / 294[M+1].

[0671] Step 2

[0672] methyl 5-bromo-1-(2-oxoethyl)-1H-pyrrole-3-carboxylate

[0673] 5-Bromo-1-(2-oxoethyl)-1H-pyrrole-3-carboxylic acid methyl ester

[0674] 5-Bromo-1-(2,2-dimethoxyethyl)-1H-pyrrole-3-carboxylic acid methyl ester 34a (1.00 g, 3.42 mmol) was added to trifluoroacetic acid (10 mL) at 25°C and reacted for 0.5 h. The system was concentrated under reduced pressure to afford 5-bromo-1-(2-oxoethyl)-1H-pyrrole-3-carboxylic acid methyl ester 34b (800 mg), which was used directly in the next step.

[0675] MS m / z(ESI):264.0 / 266[M+1].

[0676] Step 3

[0677] methyl 5-bromo-1-(2-((2-bromo-3-methoxyphenyl)amino)ethyl)-1H-pyrrole-3-carboxylate

[0678] 5-Bromo-1-(2-((2-bromo-3-methoxyphenyl)amino)ethyl)-1H-pyrrole-3-carboxylic acid methyl ester

[0679] Methyl 5-bromo-1-(2-oxoethyl)-1H-pyrrole-3-carboxylate 34b (700 mg, 2.84 mmol) was added to 1,2-dichloroethane (10 mL) at 25°C. Sodium acetate borohydride (1.81 g, 8.53 mmol), acetic acid (17.1 mg, 0.284 mmol), and 2-bromo-3-methoxyaniline (575 mg, 2.84 mmol) were added to the reaction mixture, and the mixture was allowed to react at 25°C for 18 hours. Methanol (20 mL) was added to the mixture, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give methyl 5-bromo-1-(2-((2-bromo-3-methoxyphenyl)amino)ethyl)-1H-pyrrole-3-carboxylate 34c (150 mg) in a 12% yield.

[0680] MS m / z(ESI):430.9 / 432.9 / 434.9[M+1].

[0681] Step 4

[0682] methyl 11-methoxy-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[0683] 11-Methoxy-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-carboxylic acid methyl ester

[0684] Methyl 5-bromo-1-(2-((2-bromo-3-methoxyphenyl)amino)ethyl)-1H-pyrrole-3-carboxylate 34c (140 mg, 0.324 mmol) was added to a mixed solution of 1,4-dioxane (5 mL) and water (1 mL) at 25°C. Palladium acetate (14.5 mg, 0.0648 mmol), pinacol diboron (247 mg, 0.972 mmol), potassium carbonate (134 mg, 0.972 mmol) and n-butyldi(1-adamantyl)phosphine (46.5 mg, 0.130 mmol) were added to the reaction solution, and the temperature was raised to 80°C under nitrogen for 18 h. The system was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to obtain 11-methoxy-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Carboxylic acid methyl ester 34d (80 mg), yield: 91%.

[0685] MS m / z(ESI):273.1[M+1].

[0686] Step 5

[0687] methyl 11-methoxy-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[0688] 11-Methoxy-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-carboxylic acid methyl ester

[0689] At 25 ° C, 11-methoxy-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-carboxylic acid methyl ester 34d (80 mg, 0.294 mmol) was added to methanol (5 mL), and aqueous formaldehyde solution (298 mg, 3.67 mmol, 0.27 mL, 37% purity) and palladium carbon (40.0 mg, 10% palladium content, 55% w / w water content) were added to the above reaction solution. The reaction was carried out at 25°C under a hydrogen atmosphere for 2 hours. The system was filtered and the filtrate was concentrated under reduced pressure to obtain 11-methoxy-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Carboxylic acid methyl ester 34e (80.0 mg) was used directly in the next step.

[0690] MS m / z(ESI):287.1[M+1].

[0691] Step 6

[0692] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-methoxy-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxamide

[0693] N-(3-Chloro-5-(methylsulfonamido)phenyl)-11-methoxy-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Formamide

[0694] At 25 ° C, 11-methoxy-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine Methyl 2-carboxylate 34e (50.0 mg, 0.175 mmol) and 1 g of N-(3-amino-5-chlorophenyl)methanesulfonamide (57.8 mg, 0.262 mmol) were added to tetrahydrofuran (10 mL). Trimethylaluminum in n-hexane solution (1 M, 0.87 mL) was added to the reaction mixture, and the mixture was reacted at 60°C for 18 h. The mixture was poured into methanol (50 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) and then separated by preparative liquid phase separation (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-(methylsulfonylamino)phenyl)-11-methoxy-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Carboxamide 34 (16 mg), yield: 19%.

[0695] MS m / z(ESI):475.2[M+1].

[0696] 1H NMR (400MHz, DMSO-d6) δ10.06(s,1H),9.75(s,1H),7.71(t,J=2.0Hz,1H),7.67(d,J=2.0Hz,1H),7.62(t,J=2.0Hz,1H),7.27(t,J=8.0Hz,1H),6.8 8(t,J=2.0Hz,1H),6.83–6.77(m,2H),6.74(d,J=8.0Hz,1H),4.01(t,J=6 .0Hz,2H),3.78(s,3H),3.35(d,J=6.0Hz,2H),3.05(s,3H),2.70(s,3H).

[0697] Example 35

[0698] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-methoxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[0699] N-(3-Chloro-5-(methylsulfonamido)phenyl)-11-methoxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide

[0700] first step

[0701] methyl 5-bromo-1-(2-hydroxyethyl)-1H-pyrrole-3-carboxylate

[0702] 5-Bromo-1-(2-hydroxyethyl)-1H-pyrrole-3-carboxylic acid methyl ester

[0703] Methyl 5-bromo-1H-pyrrole-3-carboxylate 27a (1.00 g, 4.90 mmol), 2-bromoethanol (9.19 g, 73.5 mmol), and cesium carbonate (24.0 g, 73.5 mmol) were added to acetonitrile (50 mL) at 25°C and reacted at 80°C for 18 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to give methyl 5-bromo-1-(2-hydroxyethyl)-1H-pyrrole-3-carboxylate 35a (900 mg) in a 74% yield.

[0704] MS m / z(ESI):247.9 / 249.9[M+1].

[0705] Step 2

[0706] methyl 5-bromo-1-(2-(2-bromo-3-methoxyphenoxy)ethyl)-1H-pyrrole-3-carboxylate

[0707] 5-Bromo-1-(2-(2-bromo-3-methoxyphenoxy)ethyl)-1H-pyrrole-3-carboxylic acid methyl ester

[0708] Methyl 5-bromo-1-(2-hydroxyethyl)-1H-pyrrole-3-carboxylate 35a (400 mg, 1.61 mmol), cyanomethylenetri-n-butylphosphine (973 mg, 4.03 mmol), and 2-bromo-3-methoxyphenol (491 mg, 2.42 mmol) were added to toluene (5 mL) at 25°C and reacted at 80°C for 2 hours. The system was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to give methyl 5-bromo-1-(2-(2-bromo-3-methoxyphenoxy)ethyl)-1H-pyrrole-3-carboxylate 35b (400 mg) in a 57% yield.

[0709] MS m / z(ESI):431.9 / 433.9 / 435.9[M+1].

[0710] Step 3

[0711] methyl 11-methoxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[0712] 11-Methoxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-carboxylic acid methyl ester

[0713] Methyl 5-bromo-1-(2-(2-bromo-3-methoxyphenoxy)ethyl)-1H-pyrrole-3-carboxylate 35b (400 mg, 0.927 mmol) was added to a mixture of 1,4-dioxane (10 mL) and water (2 mL) at 25°C. Palladium acetate (62.2 mg, 0.277 mmol), bis(pinacolato) borate (1.06 g, 4.16 mmol), potassium carbonate (574 mg, 4.16 mmol), and n-butyldi(1-adamantyl)phosphine (199 mg, 0.554 mmol) were added to the reaction mixture. The mixture was reacted at 80°C under nitrogen for 18 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to afford 11-methoxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine. -2-Carboxylic acid methyl ester 35c (200 mg), yield: 79%.

[0714] MS m / z(ESI):274.0[M+1].

[0715] Step 4

[0716] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-methoxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[0717] N-(3-Chloro-5-(methylsulfonamido)phenyl)-11-methoxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide

[0718] At 25 ° C, 11-methoxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine Methyl 2-carboxylate 35c (200 mg, 0.732 mmol) and 1 g (242 mg, 1.10 mmol) of N-(3-amino-5-chlorophenyl)methanesulfonamide were added to tetrahydrofuran (10 mL). Trimethylaluminum in n-hexane (2 M, 1.8 mL) was added to the reaction mixture and the mixture was reacted at 60°C for 18 h. The mixture was poured into methanol (50 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) and then separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to give N-(3-chloro-5-(methylsulfonyl)phenyl)-11-methoxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide 35 (60 mg), yield: 18%.

[0719] MS m / z(ESI):462.0[M+1].

[0720] 1H NMR (400MHz, DMSO-d6) δ10.07(s,1H),9.82(s,1H),7.78–7.68(m,2H),7.63(t,J=2.0Hz,1H),7.28(t,J=8.0Hz,1H),6.97-6.92(m ,2H),6.89(t,J=2.0Hz,1H),6.78(dd,J=8.0,1.2Hz,1H),4.42(t,J=6.0Hz,2H),4.15(t,J=6.0Hz,2H),3.83(s,3H),3.05(s,3H).

[0721] According to the preparation method of Example 35 of the present invention, Examples 36-37 were prepared, and the specific structures and structural characterizations are as follows:

[0722] Example 38

[0723] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-(phenoxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[0724] N-(3-Chloro-5-(methylsulfonamido)phenyl)-11-(phenoxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide

[0725] first step

[0726] 2-bromo-3-(hydroxymethyl)phenol

[0727] 2-Bromo-3-(hydroxymethyl)phenol

[0728] 2-Bromo-3-hydroxybenzaldehyde 38a (2.00 g, 9.95 mmol) was dissolved in methanol (30 mL) at room temperature, and sodium borohydride (1.13 g, 29.85 mmol) was added. The atmosphere was purged with nitrogen three times, and the reaction was continued at 25°C for 18 hours. The reaction solution was diluted with methanol (80 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 2-bromo-3-(hydroxymethyl)phenol 38b (1.78 g) in an 88% yield.

[0729] MS m / z(ESI):185.0 / 187.0[M+1].

[0730] Step 2

[0731] 2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenol

[0732] 2-Bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenol

[0733] 2-Bromo-3-(hydroxymethyl)phenol 38b (1.78 g, 8.77 mmol) was dissolved in dichloromethane (20 mL) at room temperature. Imidazole (1.19 g, 17.53 mmol) was added, followed by the dropwise addition of a solution of tert-butyldimethylsilyl chloride (1.45 g, 9.64 mmol) in dichloromethane (2 mL). The atmosphere was purged with nitrogen three times and the reaction was allowed to proceed at 25°C for 18 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to afford 2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenol 38c (1.5 g) in a 54% yield.

[0734] MS m / z(ESI):317.0 / 319.0[M+1].

[0735] Step 3

[0736] methyl 5-bromo-1-(2-(2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenoxy)ethyl)-1H-pyrrole-3-carboxylate

[0737] 5-Bromo-1-(2-(2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenoxy)ethyl)-1H-pyrrole-3-carboxylic acid methyl ester

[0738] 2-Bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenol 38c (959.27 mg, 3.02 mmol) and methyl 5-bromo-1-(2-hydroxyethyl)-1H-pyrrole-3-carboxylate 35a (500.00 mg, 2.02 mmol) were dissolved in toluene (10 mL) at room temperature. Cyanomethylethylenetri-n-butylphosphine (1.46 g, 6.05 mmol, 1.58 mL) was added dropwise. The atmosphere was purged with nitrogen three times, and the reaction was continued at 80°C for 18 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give methyl 5-bromo-1-(2-(2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenoxy)ethyl)-1H-pyrrole-3-carboxylate 38d (580 mg) in a 52% yield.

[0739] MS m / z(ESI):568.0 / 570.0 / 572.0[M+23].

[0740] Step 4

[0741] methyl 11-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[0742] 11-(((tert-Butyldimethylsilyl)oxy)methyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-carboxylic acid methyl ester

[0743] Methyl 5-bromo-1-(2-(2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenoxy)ethyl)-1H-pyrrole-3-carboxylate 38d (580.00 mg, 1.06 mmol) was dissolved in a mixed solution of ethylene glycol dimethyl ether (6 mL) and water (0.5 mL) at room temperature. Potassium carbonate (439.35 mg, 3.18 mmol), bis(boron)pinacol (807.25 mg, 3.18 mmol), palladium acetate (47.58 mg, 0.21 mmol) and n-butyldi(1-adamantyl)phosphine (151.97 mg, 0.42 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and the reaction was carried out at 80 °C for 1 hour. The reaction solution was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to obtain 11-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Carboxylic acid methyl ester 38e (327 mg), yield: 79%.

[0744] MS m / z(ESI):388.2[M+1].

[0745] Step 5

[0746] methyl 11-(hydroxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[0747] 11-(Hydroxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-carboxylic acid methyl ester

[0748] At room temperature, 11-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-carboxylic acid methyl ester 38e (277.00 mg, 0.71 mmol) was dissolved in dichloromethane (1 mL), and a solution of hydrogen chloride in ethyl acetate (1.2 mL, 4 M) was added dropwise. The reaction was allowed to react at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to obtain 11-(hydroxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Carboxylic acid methyl ester 38f (107 mg), yield: 55%.

[0749] MS m / z(ESI):274.2[M+1].

[0750] Step 6

[0751] methyl 11-(phenoxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[0752] 11-(Phenoxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-carboxylic acid methyl ester

[0753] At room temperature, 11-(hydroxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-carboxylic acid methyl ester 38f (107.00 mg, 0.39 mmol) and phenol (55.27 mg, 0.59 mmol) were dissolved in toluene (1 mL) and cyanomethylene tri-n-butylphosphine (283.50 mg, 1.17 mmol, 0.31 mL) was added dropwise. After nitrogen replacement three times, the reaction was carried out at 80 ° C for 18 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: A system) to obtain 11-(phenoxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-carboxylic acid methyl ester 38g (97mg), yield: 71%.

[0754] MS m / z(ESI):350.2[M+1].

[0755] Step 7

[0756] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-(phenoxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[0757] N-(3-Chloro-5-(methylsulfonamido)phenyl)-11-(phenoxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide

[0758] At room temperature, 11-(phenoxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine 38 g (97.00 mg, 0.28 mmol) of methyl 2-carboxylate and 1 g (61.27 mg, 0.28 mmol) of N-(3-amino-5-chlorophenyl)methanesulfonamide were dissolved in tetrahydrofuran (1 mL), and trimethylaluminum (80.00 mg, 1.11 mmol, 2 M) was added dropwise. The reaction was allowed to proceed at 60°C for 18 hours. The reaction solution was quenched by pouring into methanol (50 mL) and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (AKZONOBEL Kromasil column; 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)-11-(phenoxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide 38 (57 mg), yield: 38%.

[0759] MS m / z(ESI):538.2[M+1].

[0760] 1H NMR (400MHz, DMSO-d6) δ10.00(s,1H),9.84(s,1H),7.84(d,J=1.6Hz,1H),7. 66(t,J=1.6Hz,1H),7.60(t,J=1.6Hz,1H),7.46(dd,J=7.8,1.2Hz,1H),7.39( t,J=7.8Hz,1H),7.32–7.26(m,2H),7.19(dd,J=7.8,1.2Hz,1H),6.98-6.89(m ,5H),5.16(s,2H),4.43(t,J=5.8Hz,2H),4.17(t,J=5.8Hz,2H),3.05(s,3H).

[0761] According to the preparation method of Example 9 of the present invention, Examples 39-48 were prepared, and their specific structures and structural characterizations are as follows:

[0762] Example 49

[0763] N-(3-chloro-5-(methylsulfonamido)phenyl)-10-hydroxy-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxamide

[0764] N-(3-Chloro-5-(methylsulfonamido)phenyl)-10-hydroxy-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-Formamide

[0765] N-(3-chloro-5-(methylsulfonylamino)phenyl)-10-methoxy-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine 45 (125.00 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL) and the atmosphere was purged with nitrogen three times. Boron tribromide (185.67 mg, 0.74 mmol) was then added dropwise and the reaction was stirred at 25°C for 18 hours. The reaction solution was poured into methanol (50 mL) and stirred for 1 hour to quench the mixture. The mixture was filtered and concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH₄HCO₃ + H₂O, mobile phase B: CH₃CN) to afford N-(3-chloro-5-(methylsulfonyl)phenyl)-10-hydroxy-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine. -2-Carboxamide 49 (5 mg), yield: 8%.

[0766] MS m / z(ESI):492.0[M+1].

[0767] 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),10.20(s,1H),10.06(s,1H),8.53(s,1H),7.68(t,J=1.6Hz,1H),7.63(t,J=1.8Hz, 1H),7.31–7.22(m,2H),7.12(dd,J=7.8,1.6Hz,1H),6.95(t,J=1.6Hz,1H),4.47–4.28(m,2H),3.06(s,3H),3.05(s,3H).

[0768] Example 50

[0769] 10-amino-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxamide

[0770] 10-amino-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-Formamide

[0771] first step

[0772] methyl 4-bromo-5-(((tert-butoxycarbonyl)(methyl)amino)methyl)thiophene-2-carboxylate

[0773] Methyl 4-bromo-5-(((tert-butoxycarbonyl)(methyl)amino)methyl)thiophene-2-carboxylate

[0774] Methyl 4-bromo-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate 7c (5 g, 14.28 mmol) and cesium carbonate (9.30 g, 28.55 mmol) were dissolved in N,N-dimethylformamide (50 mL). To the resulting mixture was added iodomethane (6.08 g, 42.83 mmol, 2.67 mL), and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: System A) to afford methyl 4-bromo-5-(((tert-butoxycarbonyl)(methyl)amino)methyl)thiophene-2-carboxylate 50a (2.7 g) in a 52% yield.

[0775] MS m / z(ESI):386.0[M+1].

[0776] Step 2

[0777] methyl 5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate

[0778] Methyl 5-(((tert-Butoxycarbonyl)(methyl)amino)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate

[0779] Methyl 4-bromo-5-(((tert-butoxycarbonyl)(methyl)amino)methyl)thiophene-2-carboxylate 50a (500 mg, 1.37 mmol) and pinacol diboron (693.31 mg, 2.73 mmol) were dissolved in 1,4-dioxane (5 mL). To the resulting mixture were added tris(dibenzylideneacetone)dipalladium (250.01 mg, 273.02 μmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (195.23 mg, 409.53 μmol) and potassium acetate (401.93 mg, 4.10 mmol). The reaction solution was purged with nitrogen three times and stirred at 90 °C under nitrogen protection for 2 h. The reaction mixture was filtered to obtain a solution of methyl 5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate 50b, which was used directly in the next step. MS m / z (ESI): 434.2 [M+1].

[0780] Step 3

[0781] methyl 4-(2-amino-6-(methoxycarbonyl)phenyl)-5-(((tert-butoxycarbonyl)(methyl)amino)methyl)thiophene-2-carboxylate

[0782] Methyl 4-(2-amino-6-(methoxycarbonyl)phenyl)-5-(((tert-butoxycarbonyl)(methyl)amino)methyl)thiophene-2-carboxylate

[0783] To a solution of methyl 5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (50 mL) prepared in the previous step was added methyl 3-amino-2-bromobenzoate (335.59 mg, 1.46 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (177.89 mg, 243.12 μmol), potassium carbonate (504.02 mg, 3.65 mmol), and water (2 mL). The reaction mixture was purged with nitrogen three times and stirred at 90°C under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The extract was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: System A) to give methyl 4-(2-amino-6-(methoxycarbonyl)phenyl)-5-(((tert-butoxycarbonyl)(methyl)amino)methyl)thiophene-2-carboxylate 50c (154 mg) in a yield of 29%.

[0784] MS m / z(ESI):335.0[M+1].

[0785] Step 4

[0786] methyl 4-(2-amino-6-(methoxycarbonyl)phenyl)-5-((methylamino)methyl)thiophene-2-carboxylate

[0787] Methyl 4-(2-amino-6-(methoxycarbonyl)phenyl)-5-((methylamino)methyl)thiophene-2-carboxylate

[0788] Methyl 4-(2-amino-6-(methoxycarbonyl)phenyl)-5-(((tert-butoxycarbonyl)(methyl)amino)methyl)thiophene-2-carboxylate 50c (150 mg, 345.22 μmol) was dissolved in 4M hydrogen chloride in ethyl acetate (2 mL). The reaction was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure to afford the residue methyl 4-(2-amino-6-(methoxycarbonyl)phenyl)-5-((methylamino)methyl)thiophene-2-carboxylate 50d, which was used directly in the next step.

[0789] MS m / z(ESI):335.0[M+1].

[0790] Step 5

[0791] methyl 10-amino-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate

[0792] 10-amino-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-carboxylic acid methyl ester

[0793] 50 d of methyl 4-(2-amino-6-(methoxycarbonyl)phenyl)-5-((methylamino)methyl)thiophene-2-carboxylate was dissolved in tetrahydrofuran (2 mL). Triethylamine was slowly added dropwise to adjust the pH of the solution to 7. The resulting mixed solution was purged with nitrogen three times. Trimethylaluminum (86.23 mg, 1.20 mmol, 106.45 μL) was slowly added dropwise to the reaction solution at 0°C. The reaction solution was stirred at 60°C under nitrogen for 12 hours. The reaction solution was slowly added to methanol to quench the reaction. The product was concentrated, and the residue was purified by silica gel column chromatography (eluent: System A) to obtain 10-amino-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine. -2-carboxylic acid methyl ester 50e (60 mg), yield: 66%.

[0794] MS m / z(ESI):303.0[M+1].

[0795] Step 6

[0796] methyl 10-[bis(tert-butoxycarbonyl)amino]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepine-2-carboxylate

[0797] 10-[Bis(tert-butoxycarbonyl)amino]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepine -2-carboxylic acid methyl ester

[0798] 10-amino-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine Methyl 2-carboxylate 50e (60 mg, 198.45 μmol) was dissolved in tetrahydrofuran (2 mL). To the resulting mixture were added di-tert-butyl dicarbonate (86.62 mg, 396.89 μmol, 91.18 μL), 4-dimethylaminopyridine (2.42 mg, 19.84 μmol), and cesium carbonate (129.32 mg, 396.89 μmol). The reaction mixture was stirred at 65°C for 1 hour. The reaction mixture was filtered under reduced pressure, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: System A) to obtain 10-[bis(tert-butoxycarbonyl)amino]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepine. -2-carboxylic acid methyl ester 50f (69 mg), yield: 86%.

[0799] MS m / z(ESI):503.2[M+1].

[0800] Step 7

[0801] 10-[bis(tert-butoxycarbonyl)amino]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepine-2-carboxylic acid

[0802] 10-[Bis(tert-butoxycarbonyl)amino]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepine -2-carboxylic acid

[0803] 10-[bis(tert-butoxycarbonyl)amino]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepine Methyl 2-carboxylate 50f (69 mg, 137.29 μmol) was dissolved in tetrahydrofuran (2 mL) and water (1 mL). Lithium hydroxide monohydrate (11.52 mg, 274.58 μmol) was added to the resulting mixture. The reaction mixture was stirred at room temperature for 2 hours. After concentration, 10-[bis(tert-butoxycarbonyl)amino]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepine was obtained. -2-Carboxylic acid 50g, directly used in the next step.

[0804] MS m / z(ESI):489.0[M+1].

[0805] Step 8

[0806] tert-butyl N-tert-butoxycarbonyl-N-[2-[[3-chloro-5-(methanesulfonamido)phenyl]carbamoyl]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepin-10-yl]carbamate

[0807] N-tert-Butyloxycarbonyl-N-[2-[[3-chloro-5-(methylsulfonylamino)phenyl]carbamoyl]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepine -10-yl]carbamic acid tert-butyl ester

[0808] 10-[bis(tert-butoxycarbonyl)amino]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepine 50 g of 2-amino-2-carboxylic acid and 1 g (42.81 mg, 194.00 μmol) of N-(3-amino-5-chlorophenyl)methanesulfonamide were dissolved in N,N-dimethylformamide (1 mL). To the resulting mixed solution were added (7-azabenzotriazole-1-oxy)tripyrrolidone hexafluorophosphate (202.29 mg, 388.00 μmol) and N,N-diisopropylethylamine (100.29 mg, 776.00 μmol, 137.57 μL). The reaction mixture was stirred at 65°C for 2 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain N-tert-butyloxycarbonyl-N-[2-[[3-chloro-5-(methylsulfonylamino)phenyl]carbamoyl]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepine -10-yl]carbamic acid tert-butyl ester 50h (80 mg), yield: 89%.

[0809] MS m / z(ESI):691.1[M+1].

[0810] Step 9

[0811] 10-amino-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxamide

[0812] 10-amino-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-Formamide

[0813] N-tert-Butyloxycarbonyl-N-[2-[[3-chloro-5-(methylsulfonylamino)phenyl]carbamoyl]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepine tert-Butyl]-10-amino-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine was obtained by preparative liquid chromatography (HPLC) using a column called AKZONOBEL Kromasil (250 × 21.2 mm ID, 5 μm, 20 mL / min); mobile phase A: 0.05% NH₄HCO₃ + H₂O; mobile phase B: CH₃CN. -2-Formamide 50 (3 mg), yield: 5%.

[0814] MS m / z(ESI):491.0[M+1].

[0815] 1 H NMR (400MHz, DMSO-d6) δ10.46(s,1H),10.08(s,1H),8.46(s,1H),7.97(s,1H),7.16(t,J=8.0Hz,1H),7.05(dd,J=8.4,2.5Hz,1H),6. 97(dd,J=8.0,1.2Hz,1H),6.96–6.92(m,2H),6.01(s,2H),4.43(d,J=16.0Hz,1H),4.31(d,J=16.0Hz,1H),3.05(s,3H),3.01(s,3H).

[0816] Example 51

[0817] N-(3-chloro-5-(methylsulfonamido)phenyl)-10-cyano-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxamide

[0818] N-(3-Chloro-5-(methylsulfonamido)phenyl)-10-cyano-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-Formamide

[0819] first step

[0820] methyl 10-bromo-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate

[0821] 10-Bromo-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-carboxylic acid methyl ester

[0822] 10-amino-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine Methyl 2-carboxylate 50e (330 mg, 1.09 mmol) was dissolved in dimethyl sulfoxide (5 mL). To the resulting solution was added tert-butyl nitrite (337.65 mg, 3.27 mmol, 389.45 μL). The reaction mixture was purged with nitrogen three times and stirred at room temperature under nitrogen for 20 minutes. Cuprous bromide (469.71 mg, 3.27 mmol) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain 10-bromo-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine. -2-carboxylic acid methyl ester 51a (150 mg), yield: 37%.

[0823] MS m / z(ESI):366.0[M+1].

[0824] Step 2

[0825] methyl 10-cyano-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate

[0826] 10-cyano-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-carboxylic acid methyl ester

[0827] To 10-bromo-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine Methyl 2-carboxylate 51a (80 mg, 218.44 μmol) was dissolved in N,N-dimethylformamide (2 mL). Zinc cyanide (76.95 mg, 655.33 μmol) and tetrakis(triphenylphosphine)palladium (50.48 mg, 43.69 μmol) were added to the resulting solution. The reaction mixture was purged with nitrogen three times and stirred at 100°C under nitrogen for 3 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to afford 10-cyano-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine. -2-Carboxylic acid methyl ester 51b (60 mg), yield: 88%.

[0828] Step 3

[0829] 10-cyano-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylic acid

[0830] 10-cyano-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-carboxylic acid

[0831] 10-cyano-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-carboxylic acid methyl ester 51b (70 mg, 224.11 μmol) was dissolved in tetrahydrofuran (2 mL), lithium hydroxide monohydrate (18.81 mg, 448.23 μmol) and water (1 mL) were added to the resulting solution, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 10-cyano-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-Carboxylic acid 51c was used directly in the next step.

[0832] MS m / z(ESI):299.0[M+1].

[0833] Step 4

[0834] N-(3-chloro-5-(methylsulfonamido)phenyl)-10-cyano-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxamide

[0835] N-(3-Chloro-5-(methylsulfonamido)phenyl)-10-cyano-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-Formamide

[0836] 10-cyano-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-Carboxylic acid 51c and 1 g (76.56 mg, 346.95 μmol) of N-(3-amino-5-chlorophenyl)methanesulfonamide were dissolved in N,N-dimethylformamide (2 mL). To the resulting mixture were added (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (361.78 mg, 693.89 μmol) and N,N-diisopropylethylamine (179.36 mg, 1.39 mmol, 246.04 μL). The reaction mixture was stirred at 65°C for 2 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain N-(3-chloro-5-(methylsulfonylamino)phenyl)-10-cyano-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-Formamide 51 (46 mg), yield: 40%.

[0837] MS m / z(ESI):501.0[M+1].

[0838] 1 H NMR (400MHz, DMSO-d6) δ10.61(s,1H),10.11(s,1H),8.62(s,1H),8.19(dd,J=8.0,1.2Hz,1H),8.13(dd,J=8.0,1.2Hz,1H),7.75–7 .66(m,2H),7.61(t,J=1.6Hz,1H),6.99(t,J=2.0Hz,1H),4.61(d,J=16.0Hz,1H),4.45(d,J=16.0Hz,1H),3.08(s,3H),3.07(s,3H).

[0839] Example 52

[0840] 6-acetyl-10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxamide

[0841] 6-acetyl-10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-Formamide

[0842] first step

[0843] methyl 6-acetyl-10-(benzyloxy)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate

[0844] 6-Acetyl-10-(benzyloxy)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-carboxylic acid methyl ester

[0845] 10-(Benzyloxy)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine Methyl 19f-2-carboxylate (40 mg, 109.46 μmol) was dissolved in dichloromethane (1 mL). Triethylamine (33.23 mg, 328.37 μmol, 45.64 μL) was added to the resulting solution. The reaction solution was cooled to 0°C in an ice bath, followed by the addition of acetyl chloride (17.18 mg, 218.91 μmol, 15.57 μL). The reaction solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to yield 6-acetyl-10-(benzyloxy)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine. -Methyl 2-carboxylate 52a was used directly in the next step.

[0846] MS m / z(ESI):408.2[M+1].

[0847] Step 2

[0848] 6-acetyl-10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxamide

[0849] 6-acetyl-10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-Formamide

[0850] 6-acetyl-10-(benzyloxy)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine Methyl 2-carboxylate 52a and 1 g (64.99 mg, 294.49 μmol) of N-(3-amino-5-chlorophenyl)methanesulfonamide were dissolved in tetrahydrofuran (2 mL). To the resulting mixed solution, a solution of trimethylaluminum in n-hexane (2 M, 736.23 μL) was slowly added dropwise, and the reaction solution was stirred at 60°C for 1 h. The reaction solution was slowly added dropwise to methanol (5 mL) to quench the reaction, and the product was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and then separated by preparative liquid phase separation (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 6-acetyl-10-(benzyloxy)-N-(3-chloro-5-(methylsulfonyl)phenyl)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine -2-Formamide 52 (30 mg), yield: 34%.

[0851] MS m / z(ESI):596.1[M+1].

[0852] 1H NMR (400MHz, DMSO-d6) δ10.38(s,1H),10.07(s,1H),8.38(s,1H),7.68(t,J=1.6Hz, 1H),7.62(t,J=1.6Hz,1H),7.46(dd,J=14.8,7.2Hz,3H),7.34–7.24(m,4H),7.10(d, J=7.6Hz,1H),6.96(t,J=2.0Hz,1H),5.31(d,J=12.0Hz,1H),5.16(d,J=12.0Hz,1H), 4.84(m,1H),3.48(m,1H),3.12(m,1H),3.08(s,3H),2.78–2.69(m,1H),1.55(s,3H).

[0853] According to the preparation method of Example 52 of the present invention, Examples 53-54 were prepared, and the specific structures and structural characterizations are as follows:

[0854] According to the preparation method of Example 19 of the present invention, the specific structures and structural characterizations of Examples 55-57 are as follows:

[0855] Example 58

[0856] N-(3-chloro-5-(methylsulfonamido)phenyl)-5'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-c]thieno[3,2-e]azepine]-9'-carboxamide

[0857] N-(3-Chloro-5-(methylsulfonamido)phenyl)-5'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-c]thieno[3,2-e]azepine]-9'-carboxamide

[0858] first step

[0859] tert-butyl(1-(thiophen-2-yl)cyclopropyl)carbamate

[0860] tert-Butyl (1-(thiophen-2-yl)cyclopropyl)carbamate

[0861] 1-(Thiophen-2-yl)cyclopropane-1-carboxylic acid 58a (200 mg, 1.19 mmol, commercially available) and triethylamine (200 mg, 1.19 mmol) were dissolved in toluene (10 mL) and tert-butanol (2 mL). Diphenylphosphoryl azide (392.64 mg, 1.43 mmol) was added and reacted at 80°C under a nitrogen atmosphere for 12 hours. The reaction solution was diluted with water and extracted three times with dichloromethane (20 mL). The combined extracts were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: System A) afforded tert-butyl (1-(thiophen-2-yl)cyclopropyl)carbamate 58b (170 mg) in a 59% yield. MS m / z (ESI): 184.0 [M+1].

[0862] Step 2

[0863] tert-butyl(1-(5-bromothiophen-2-yl)cyclopropyl)carbamate

[0864] tert-Butyl (1-(5-bromothiophen-2-yl)cyclopropyl)carbamate

[0865] Tert-butyl (1-(thiophen-2-yl)cyclopropyl)carbamate 58b (1.1 g, 4.60 mmol) was dissolved in N,N-dimethylformamide (15 mL), followed by the addition of N-bromosuccinimide (1.23 g, 6.89 mmol) and allowed to react at room temperature for 2 hours. The reaction solution was diluted with water and extracted three times with ethyl acetate (50 mL). The combined extracts were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: System A) afforded tert-butyl (1-(5-bromothiophen-2-yl)cyclopropyl)carbamate 58c (1.3 g) in a 90% yield.

[0866] MS m / z(ESI):263.9[M+1].

[0867] Step 3

[0868] methyl 5-(1-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylate

[0869] 5-(1-((tert-Butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylic acid methyl ester

[0870] Tert-butyl (1-(5-bromothiophen-2-yl)cyclopropyl)carbamate 58c (500 mg, 1.57 mmol) and triethylamine (476.97 mg, 4.71 mmol) were dissolved in methanol (10 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (233.10 mg, 314.24 μmol) was added, and the mixture was reacted at 80°C under a carbon monoxide atmosphere for 2 hours. After completion of the reaction, the reaction solution was diluted with water and extracted three times with ethyl acetate (20 mL). The combined extracts were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: System A) gave methyl 5-(1-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylate 58d (180 mg) in an 81% yield.

[0871] MS m / z(ESI):242.0[M+1].

[0872] Step 4

[0873] methyl 4-bromo-5-(1-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylate

[0874] Methyl 4-bromo-5-(1-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylate

[0875] Methyl 5-(1-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylate 58d (1.5 g, 4.13 mmol) was dissolved in tetrahydrofuran (20 mL). Trimethylaluminum (2M, 12.38 mL) was added dropwise at 0°C, followed by reaction at 60°C for 12 hours. The reaction solution was quenched with methanol and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: System A) afforded methyl 4-bromo-5-(1-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylate 58e (400 mg) in a 29% yield.

[0876] MS m / z(ESI):332.0[M+1].

[0877] Step 5

[0878] methyl 2-(2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(methoxycarbonyl)thiophen-3-yl)nicotinate

[0879] 2-(2-(1-((tert-Butoxycarbonyl)amino)cyclopropyl)-5-(methoxycarbonyl)thiophen-3-yl)nicotinate

[0880] Methyl 4-bromo-5-(1-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylate 58e (250 mg, 664.42 μmol), methyl 2-bromonicotinate (287.07 mg, 1.33 mmol), pinacol diboronate (506.17 mg, 1.99 mmol), bis(1-adamantyl)-butylphosphine (95.29 mg, 265.77 μmol), and potassium carbonate (459.14 mg, 3.32 mmol) were dissolved in ethylene glycol dimethyl ether (10 mL) and water (2 mL). The reaction mixture was purged with nitrogen three times. Palladium acetate (29.83 mg, 132.88 μmol) was added under nitrogen, and the reaction mixture was incubated at 80°C for 1 hour. The reaction mixture was diluted with water and extracted three times with ethyl acetate (50 mL). The extracts were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: System A) afforded methyl 2-(2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(methoxycarbonyl)thiophen-3-yl)nicotinate 58f (170 mg) in a 59% yield.

[0881] MS m / z(ESI):433.2[M+1].

[0882] Step 6

[0883] methyl 2-(2-(1-aminocyclopropyl)-5-(methoxycarbonyl)thiophen-3-yl)nicotinate

[0884] 2-(2-(1-aminocyclopropyl)-5-(methoxycarbonyl)thiophen-3-yl)nicotinate

[0885] Methyl 2-(2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(methoxycarbonyl)thiophen-3-yl)nicotinate 58f (180 mg, 416.20 μmol) was dissolved in 4 M dioxane hydrochloride (10 mL) and reacted at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure to afford methyl 2-(2-(1-aminocyclopropyl)-5-(methoxycarbonyl)thiophen-3-yl)nicotinate 58g, which was used directly in the next step.

[0886] MS m / z(ESI):333.2[M+1].

[0887] Step 7

[0888] methyl 5'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-c]thieno[3,2-e]azepine]-9'-carboxylate

[0889] 5'-Oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-c]thieno[3,2-e]azepine]-9'-carboxylic acid methyl ester

[0890] 58 g of methyl 2-(2-(1-aminocyclopropyl)-5-(methoxycarbonyl)thiophen-3-yl)nicotinate was dissolved in tetrahydrofuran (5 mL). Trimethylaluminum (2M, 902.60 μL) was added dropwise at 0°C, and the mixture was allowed to react at 25°C for 1 hour. After completion of the reaction, the trimethylaluminum was quenched with methanol, and the product was purified by silica gel column chromatography (eluent: System A) to afford methyl 5'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-c]thieno[3,2-e]azepine]-9'-carboxylate 58h (55 mg) in a two-step yield of 40%.

[0891] MS m / z(ESI):301.0[M+1].

[0892] Step 8

[0893] 5'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-c]thieno[3,2-e]azepine]-9'-carboxylicacid

[0894] 5'-Oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-c]thieno[3,2-e]azepine]-9'-carboxylic acid

[0895] Methyl 5'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-c]thieno[3,2-e]azepine]-9'-carboxylate 58h (40 mg, 133.19 μmol) was dissolved in tetrahydrofuran (4 mL) and water (2 mL), and lithium hydroxide monohydrate (11.18 mg, 266.37 μmol) was added. The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to afford 5'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-c]thieno[3,2-e]azepine]-9'-carboxylic acid 58i, which was used directly in the next step.

[0896] MS m / z(ESI):287.0[M+1].

[0897] Step 9

[0898] N-(3-chloro-5-(methylsulfonamido)phenyl)-5'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-c]thieno[3,2-e]azepine]-9'-carboxamide

[0899] N-(3-Chloro-5-(methylsulfonamido)phenyl)-5'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-c]thieno[3,2-e]azepine]-9'-carboxamide

[0900] O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (136.58 mg, 261.96 μmol) and N,N-diisopropylethylamine (67.71 mg, 523.92 μmol) were added to a solution of 5'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-c]thieno[3,2-e]azepine]-9'-carboxylic acid 58i and 1 g of N-(3-amino-5-chlorophenyl)methanesulfonamide (70.96 mg, 321.55 μmol) in N,N-dimethylformamide (1 mL) at room temperature. The reaction mixture was reacted at 65°C for 1 hour. The reaction mixture was diluted with water and extracted three times with ethyl acetate (50 mL). The extracts were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to give N-(3-chloro-5-(methylsulfonamido)phenyl)-5'-oxo-5',6'-dihydrospiro[cyclopropane-1.7'-pyrido[3,2-c]thieno[3,2-e]azepine]-9'-carboxamide 58 (8 mg) in a 9% yield.

[0901] MS m / z(ESI):489.0[M+1].

[0902] 1H NMR (400MHz, DMSO-d6) δ10.64(s,1H),10.10(s,1H),9.17(s,1H),8.84(dd,J=4.8,1.6Hz,1H),8.62(s,1H),8.28(dd,J=8. 0,1.6Hz,1H),7.70(s,1H),7.66(s,1H),7.56(dd,J=8.0,4.8Hz,1H),6.96(s,1H),3.07(s,3H),1.29(s,2H),1.12(s,2H).

[0903] According to the preparation method of Example 58 of the present invention, Examples 59-60 were prepared, and their specific structures and structural characterizations are as follows:

[0904] Example 61

[0905] N-(3-chloro-5-(methylsulfonamido)phenyl)-6'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-b]thieno[3,2-d]azepine]-9'-carboxamide

[0906] N-(3-Chloro-5-(methylsulfonamido)phenyl)-6'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-b]thieno[3,2-d]azepine]-9'-carboxamide

[0907] first step

[0908] methyl 1-(thiophen-2-yl)cyclopropane-1-carboxylate

[0909] 1-(Thien-2-yl)cyclopropane-1-carboxylic acid methyl ester

[0910] 1-(Thiophen-2-yl)cyclopropane-1-carboxylic acid 58a (2 g, 11.89 mmol) was dissolved in N,N-dimethylformamide (20 mL). Sodium hydride (1.43 g, 35.67 mmol, 60% purity) was added portionwise at 0°C, followed by stirring at room temperature for 15 minutes. Iodomethane was then added dropwise to the reaction mixture, and the reaction was continued at room temperature for 1 hour. The reaction mixture was diluted with water and extracted three times with ethyl acetate (30 mL). The combined extracts were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: System A) afforded methyl 1-(thiophen-2-yl)cyclopropane-1-carboxylate 61a (1.9 g) in an 87% yield.

[0911] 1 H NMR (400MHz, DMSO-d6) δ7.19 (dd, J=5.2, 1.2Hz, 1H), 6.94 (dd, J=3.6, 1.2Hz, 1H), 6. 91(dd,J=4.8,3.6Hz,1H),3.67(s,3H),1.70(q,J=4.0Hz,2H),1.32(q,J=4.0Hz,2H).

[0912] Step 2

[0913] methyl 1-(5-bromothiophen-2-yl)cyclopropane-1-carboxylate

[0914] Methyl 1-(5-bromothiophen-2-yl)cyclopropane-1-carboxylate

[0915] Methyl 1-(thiophen-2-yl)cyclopropane-1-carboxylate 61a (500 mg, 2.74 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of N-bromosuccinimide (976.65 mg, 5.49 mmol) and allowed to react at room temperature for 1 hour. The reaction mixture was diluted with water and extracted three times with ethyl acetate (50 mL). The combined extracts were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: System A) afforded methyl 1-(5-bromothiophen-2-yl)cyclopropane-1-carboxylate 61b (460 mg) in a 64% yield.

[0916] MS m / z(ESI):261.0[M+1].

[0917] Step 3

[0918] methyl 5-(1-(methoxycarbonyl)cyclopropyl)thiophene-2-carboxylate

[0919] 5-(1-(Methoxycarbonyl)cyclopropyl)thiophene-2-carboxylic acid methyl ester

[0920] Methyl 1-(5-bromothiophen-2-yl)cyclopropane-1-carboxylate 61b (1.3 g, 4.98 mmol) and triethylamine (2.01 g, 19.91 mmol, 2.77 mL) were dissolved in methanol (20 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (738.56 mg, 995.65 μmol) was added and the mixture was reacted at 70°C under a carbon monoxide atmosphere for 2 hours. After completion of the reaction, the reaction solution was diluted with water and extracted three times with dichloromethane (100 mL). The combined extracts were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: System A) afforded methyl 5-(1-(methoxycarbonyl)cyclopropyl)thiophene-2-carboxylate 61c (300 mg) in a 75% yield.

[0921] MS m / z(ESI):241.0[M+1].

[0922] Step 4

[0923] methyl 4-bromo-5-(1-(methoxycarbonyl)cyclopropyl)thiophene-2-carboxylate

[0924] Methyl 4-bromo-5-(1-(methoxycarbonyl)cyclopropyl)thiophene-2-carboxylate

[0925] Methyl 5-(1-(methoxycarbonyl)cyclopropyl)thiophene-2-carboxylate 61c (300 mg, 1.25 mmol) was dissolved in trifluoroacetic acid (3 mL) and sulfuric acid (0.3 mL). N-bromosuccinimide (288.89 mg, 1.62 mmol) was then added and allowed to react at room temperature for 1 hour. The reaction mixture was adjusted with saturated sodium bicarbonate solution and extracted three times with ethyl acetate (50 mL). The combined extracts were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: System A) afforded methyl 4-bromo-5-(1-(methoxycarbonyl)cyclopropyl)thiophene-2-carboxylate 61d (300 mg) in a 75% yield.

[0926] MS m / z(ESI):321.0[M+1].

[0927] Step 5

[0928] methyl 4-(3-aminopyridin-2-yl)-5-(1-(methoxycarbonyl)cyclopropyl)thiophene-2-carboxylate

[0929] Methyl 4-(3-aminopyridin-2-yl)-5-(1-(methoxycarbonyl)cyclopropyl)thiophene-2-carboxylate

[0930] Methyl 4-bromo-5-(1-(methoxycarbonyl)cyclopropyl)thiophene-2-carboxylate 61d (700 mg, 2.19 mmol), 2-bromo-3-aminopyridine (758.89 mg, 4.39 mmol), pinacol diboron (1.67 g, 6.58 mmol), bis(1-adamantyl)-butylphosphine (314.54 mg, 877.27 μmol), and potassium carbonate (1.52 g, 10.97 mmol) were dissolved in ethylene glycol dimethyl ether (20 mL) and water (4 mL). The reaction mixture was purged with nitrogen three times. Under a nitrogen atmosphere, palladium acetate (98.48 mg, 438.64 μmol) was added, and the reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was diluted with water and extracted three times with dichloromethane (100 mL). The extracts were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: System A) gave methyl 4-(3-aminopyridin-2-yl)-5-(1-(methoxycarbonyl)cyclopropyl)thiophene-2-carboxylate 61e (590 mg) in 81% yield.

[0931] MS m / z(ESI):333.1[M+1].

[0932] Step 6

[0933] methyl 6'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-b]thieno[3,2-d]azepine]-9'-carboxylate

[0934] 6'-Oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-b]thieno[3,2-d]azepine]-9'-carboxylic acid methyl ester

[0935] Methyl 4-(3-aminopyridin-2-yl)-5-(1-(methoxycarbonyl)cyclopropyl)thiophene-2-carboxylate 61e (700 mg, 2.11 mmol) was dissolved in tetrahydrofuran (10 mL). Trimethylaluminum (2M, 8.42 mL) was added dropwise at 0°C, and the mixture was allowed to react at 60°C for 1 hour. After completion of the reaction, the trimethylaluminum was quenched with methanol, and the mixture was purified by silica gel column chromatography (eluent: System A) to afford methyl 6'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-b]thieno[3,2-d]azepine]-9'-carboxylate 61f (400 mg) in a 63% yield.

[0936] MS m / z(ESI):301.0[M+1].

[0937] Step 7

[0938] N-(3-chloro-5-(methylsulfonamido)phenyl)-6'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-b]thieno[3,2-d]azepine]-9'-carboxamide

[0939] N-(3-Chloro-5-(methylsulfonamido)phenyl)-6'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-b]thieno[3,2-d]azepine]-9'-carboxamide

[0940] Methyl 6'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-b]thieno[3,2-d]azepine]-9'-carboxylate 61f (30 mg, 99.89 μmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide 1 g (44.09 mg, 199.78 μmol) were dissolved in tetrahydrofuran (2 mL), and trimethylaluminum (2 M, 399.56 μL) was added dropwise at 0°C, followed by stirring at 60°C for 1 hour. After the reaction, trimethylaluminum was quenched with methanol and purified by silica gel column chromatography (eluent: System A), followed by preparative liquid separation (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-(methylsulfonylamino)phenyl)-6'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-b]thieno[3,2-d]azepine]-9'-carboxamide 61 (5 mg) in a 10% yield.

[0941] MS m / z(ESI):489.0[M+1].

[0942] 1 H NMR (400MHz, DMSO-d6) δ10.61(s,1H),10.42(s,1H),10.08(s,1H),8.55(s,1H),8.49(d,J=3.6Hz,1H),7.70(s,1H),7.67(s,1 H),7.63(d,J=7.6Hz,1H),7.46(dd,J=8.1,4.5Hz,1H),6.96(s,1H),3.07(s,3H),1.44(d,J=6.8Hz,2H),1.12(d,J=6.4Hz,2H).

[0943] According to the preparation method of Example 7 of the present invention, Example 62 was prepared. The specific structure and structural characterization are as follows:

[0944] Example 63

[0945] 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4,6-dihydrobenzo[c]thieno[3,2-e]oxepine-2-carboxamide

[0946] 10-(Benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4,6-dihydrobenzo[c]thieno[3,2-e]oxepin -2-Formamide

[0947] first step

[0948] (3-(benzyloxy)-2-bromophenyl)methanol

[0949] (3-(Benzyloxy)-2-bromophenyl)methanol

[0950] To a solution of 3-(benzyloxy)-2-bromobenzaldehyde 63a (1.00 g, 3.43 mmol) in methanol (20 mL) was added sodium borohydride (390 mg, 10.3 mmol) at 0°C and allowed to react at 25°C for 18 hours. The mixture was diluted with methanol (50 mL) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give (3-(benzyloxy)-2-bromophenyl)methanol 63b (900 mg) in 89% yield.

[0951] MS m / z(ESI):292 / 294.0[M+1].

[0952] Step 2

[0953] methyl 4-(2-(benzyloxy)-6-(hydroxymethyl)phenyl)-5-(hydroxymethyl)thiophene-2-carboxylate

[0954] Methyl 4-(2-(benzyloxy)-6-(hydroxymethyl)phenyl)-5-(hydroxymethyl)thiophene-2-carboxylate

[0955] (3-(Benzyloxy)-2-bromophenyl)methanol 63b (900 mg, 3.07 mmol) was dissolved in 1,4-dioxane (10 mL). To the resulting solution were added methyl 4-bromo-5-(hydroxymethyl)thiophene-2-carboxylate 1b (1.36 g, 5.18 mmol), pinacol diboron (3.03 g, 11.95 mmol), n-butyldi(1-adamantyl)phosphine (571 mg, 1.59 mmol), potassium carbonate (1.65 g, 12.0 mmol), palladium acetate (179 mg, 0.797 mmol), and water (1 mL). The reaction mixture was purged with nitrogen three times and stirred at 80°C under nitrogen for 2 hours. After filtration and concentration under reduced pressure, the crude product was purified by silica gel column chromatography (eluent: System A) to give methyl 4-(2-(benzyloxy)-6-(hydroxymethyl)phenyl)-5-(hydroxymethyl)thiophene-2-carboxylate 63c (1.20 g, 60% purity) in a 64% yield.

[0956] MS m / z(ESI):385.2[M+1].

[0957] Step 3

[0958] methyl 10-(benzyloxy)-4,6-dihydrobenzo[c]thieno[3,2-e]oxepine-2-carboxylate

[0959] 10-(Benzyloxy)-4,6-dihydrobenzo[c]thieno[3,2-e]oxepin -2-carboxylic acid methyl ester

[0960] Methyl 4-(2-(benzyloxy)-6-(hydroxymethyl)phenyl)-5-(hydroxymethyl)thiophene-2-carboxylate 63c (500 mg, 60% purity, 0.78 mmol) was dissolved in 1,4-dioxane (5 mL). Aqueous hydrobromic acid (2 mL, 24% w / w) was added to the resulting solution, and the mixture was stirred at 100°C for 20 minutes to give a yellow solution. The mixture was poured into water (60 mL) and extracted with ethyl acetate (60 mL). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 10-(benzyloxy)-4,6-dihydrobenzo[c]thieno[3,2-e]oxepin. -2-carboxylic acid methyl ester 63d (195 mg), yield: 68.3%.

[0961] MS m / z(ESI):367.2[M+1].

[0962] Step 4

[0963] 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4,6-dihydrobenzo[c]thieno[3,2-e]oxepine-2-carboxamide

[0964] 10-(Benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4,6-dihydrobenzo[c]thieno[3,2-e]oxepin -2-Formamide

[0965] 10-(Benzyloxy)-4,6-dihydrobenzo[c]thieno[3,2-e]oxepin Methyl 2-carboxylate 63d (60.0 mg, 0.164 mmol) and 1 g of N-(3-amino-5-chlorophenyl)methanesulfonamide (72.3 mg, 0.327 mmol) were dissolved in tetrahydrofuran (5.0 mL). Trimethylaluminum (2 M, 0.82 mL) was slowly added dropwise to the resulting mixture. The reaction mixture was stirred at 65°C for 2 hours. The reaction was then slowly added dropwise to methanol (50 mL) to quench the reaction. The resulting mixed solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A), followed by preparative liquid separation (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 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonyl)phenyl)-4,6-dihydrobenzo[c]thieno[3,2-e]oxepin -2-Formamide 63 (28.0 mg), yield: 31%.

[0966] MS m / z(ESI):555.2[M+1].

[0967] 1 H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.49(s,1H),7.67–7.58(m,2H),7.53–7.46(m,2H),7.44–7.36(m,1H),7.3 4-7.22(m,4H),7.17(d,J=7.2Hz,1H),6.97(t,J=2.0Hz,1H),5.25(s,2H),4.49(s,2H),4.29(s,2H),3.06(s,3H).

[0968] Example 64

[0969] 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4,5-dihydrobenzo[b]thieno[3,2-d]oxepine-2-carboxamide

[0970] 10-(Benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4,5-dihydrobenzo[b]thieno[3,2-d]oxepin -2-Formamide

[0971] first step

[0972] methyl 5-(2-(3-(benzyloxy)-2-bromophenoxy)ethyl)-4-bromothiophene-2-carboxylate

[0973] 5-(2-(3-(Benzyloxy)-2-bromophenoxy)ethyl)-4-bromothiophene-2-carboxylic acid methyl ester

[0974] At 25°C, (3-(Benzyloxy)-2-bromophenyl)methanol 63b (70.0 mg, 0.264 mmol) was added to toluene (5 mL). 3-(Benzyloxy)-2-bromophenol 6b (111 mg, 0.396 mmol) and cyanomethylenetri-n-butylphosphine (191 mg, 0.792 mmol) were added to the reaction mixture. The mixture was reacted at 90°C under nitrogen for 18 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to obtain methyl 5-(2-(3-(Benzyloxy)-2-bromophenoxy)ethyl)-4-bromothiophene-2-carboxylate 64a (220 mg, 40% purity). Yield: 63.6%.

[0975] MS m / z(ESI):525.0[M+1].

[0976] Step 2

[0977] methyl 10-(benzyloxy)-4,5-dihydrobenzo[b]thieno[3,2-d]oxepine-2-carboxylate

[0978] 10-(Benzyloxy)-4,5-dihydrobenzo[b]thieno[3,2-d]oxepin -2-carboxylic acid methyl ester

[0979] Methyl 5-(2-(3-(benzyloxy)-2-bromophenoxy)ethyl)-4-bromothiophene-2-carboxylate 64a (200.0 mg, 40% purity, 0.152 mmol) was dissolved in 1,4-dioxane (5 mL). To the resulting solution were added pinacol diboron (116 mg, 0.456 mmol), n-butyldi(1-adamantyl)phosphine (21.8 mg, 0.0608 mmol), potassium carbonate (63.0 mg, 0.456 mmol), palladium acetate (6.83 mg, 0.0304 mmol), and water (1 mL). The reaction mixture was purged with nitrogen three times and stirred at 80°C under nitrogen for 18 hours. The resulting mixed solution was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to obtain 10-(benzyloxy)-4,5-dihydrobenzo[b]thieno[3,2-d]oxepin. -2-Carboxylic acid methyl ester 64b (20.0 mg), yield: 36%.

[0980] MS m / z(ESI):367.2[M+1].

[0981] Step 3

[0982] 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4,5-dihydrobenzo[b]thieno[3,2-d]oxepine-2-carboxamide

[0983] 10-(Benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4,5-dihydrobenzo[b]thieno[3,2-d]oxepin -2-Formamide

[0984] 10-(Benzyloxy)-4,5-dihydrobenzo[b]thieno[3,2-d]oxepin Methyl 2-carboxylate 64b (20.0 mg, 0.0546 mmol) and 1 g of N-(3-amino-5-chlorophenyl)methanesulfonamide (24.1 mg, 0.109 mmol) were dissolved in tetrahydrofuran (3.0 mL). Trimethylaluminum (2 M, 0.27 mL) was slowly added dropwise to the resulting mixture. The reaction mixture was stirred at 65°C for 2 hours. The reaction was then slowly added dropwise to methanol (50 mL) to quench the reaction. The resulting mixed solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A), followed by preparative liquid separation (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 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonyl)phenyl)-4,5-dihydrobenzo[b]thieno[3,2-d]oxepin -2-Carboxamide 64 (5.0 mg), yield: 17%.

[0985] MS m / z(ESI):555.0[M+1].

[0986] 1H NMR (400MHz, DMSO-d6) δ10.32(s,1H),8.39(s,1H),7.59–7.51(m,2H),7.50–7.45(m,2H),7.32–7.22(m,4H),7.04(d,J=8.4H z,1H),6.91(t,J=2.0Hz,1H),6.83(d,J=8.0Hz,1H),5.20(s,2H),4.51(t,J=6.4Hz,2H),3.02(t,J=6.4Hz,2H),2.99(s,3H).

[0987] Example 65

[0988] 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxamide

[0989] 10-(Benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-Formamide

[0990] first step

[0991] methyl 3-(benzyloxy)-2-bromobenzoate

[0992] Methyl 3-(benzyloxy)-2-bromobenzoate

[0993] Methyl 2-bromo-3-hydroxybenzoate 65a (1.00 g, 4.33 mmol) was dissolved in N,N-dimethylformamide (1 mL), and potassium carbonate (1.20 g, 8.66 mmol) and benzyl bromide (740.27 mg, 4.33 mmol) were added sequentially. After nitrogen substitution three times, the mixture was reacted at 25°C for 3 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to afford methyl 3-(benzyloxy)-2-bromobenzoate 65b (950.00 mg) in a 68.3% yield.

[0994] MS m / z(ESI):321 / 323[M+1].

[0995] Step 2

[0996] methyl 4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-5-(((tert-

[0997] butoxycarbonyl)amino)methyl)thiophene-2-carboxylate

[0998] Methyl 4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate

[0999] Methyl 4-bromo-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate 7c (1.5 g, 4.28 mmol) and methyl 3-(benzyloxy)-2-bromobenzoate 65b (1.58 g, 4.92 mmol) were dissolved in 1,4-dioxane (15 mL). To the resulting solution were added pinacol diboron (3.26 g, 12.85 mmol), n-butyldi(1-adamantyl)phosphine (614.24 mg, 1.71 mmol), potassium carbonate (1.78 g, 12.85 mmol), palladium acetate (192.31 mg, 856.58 μmol), and water (3 mL). The reaction mixture was purged with nitrogen three times and stirred at 80°C for 12 hours. The resulting mixed solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to give methyl 4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate 65c (800 mg) in a yield of 36.5%.

[1000] MS m / z(ESI):512.2[M+1].

[1001] Step 3

[1002] methyl 5-(aminomethyl)-4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)thiophene-2-carboxylate

[1003] Methyl 5-(aminomethyl)-4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)thiophene-2-carboxylate

[1004] Methyl 4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate 65c (1.6 g, 3.13 mmol) was dissolved in dichloromethane (20 mL). Trifluoroacetic acid (356.61 mg, 3.13 mmol, 5 mL) was added to the resulting solution. The reaction solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to afford methyl 5-(aminomethyl)-4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)thiophene-2-carboxylate 65d, which was used directly in the next step.

[1005] MS m / z(ESI):412.2[M+1].

[1006] Step 4

[1007] methyl 10-(benzyloxy)-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate

[1008] 10-(Benzyloxy)-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-carboxylic acid methyl ester

[1009] The crude product of methyl 5-(aminomethyl)-4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)thiophene-2-carboxylate 65d was dissolved in toluene (13 mL). N,N-diisopropylethylamine (6.03 g, 46.65 mmol, 8.13 mL) was added to the resulting solution. The reaction solution was stirred at 70°C for 12 hours. The resulting mixed solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to obtain 10-(benzyloxy)-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine. -2-Carboxylic acid methyl ester 65e (960 mg), yield: 80.1%.

[1010] MS m / z(ESI):380.2[M+1].

[1011] Step 5

[1012] methyl 10-(benzyloxy)-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate

[1013] 10-(Benzyloxy)-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-carboxylic acid methyl ester

[1014] 10-(Benzyloxy)-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine Methyl 2-carboxylate 65e (100 mg, 0.264 mmol) was dissolved in borane tetrahydrofuran solution (5 mL), and the reaction mixture was placed at 60°C for 2 hours. The mixed solution was dropped into methanol (20 mL) to quench, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to obtain 10-(benzyloxy)-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-carboxylic acid methyl ester 65f (70.0 mg), yield: 62%.

[1015] MS m / z(ESI):366.2[M+1].

[1016] Step 6

[1017] 5-(tert-butyl)2-methyl 10-(benzyloxy)-4,6-dihydro-5H-benzo[c]thieno[3,2-e]azepine-2,5-dicarboxylate

[1018] 5-(tert-Butyl)2-methyl-10-(benzyloxy)-4,6-dihydro-5H-benzo[c]thieno[3,2-e]azepine -2,5-dicarboxylate

[1019] 10-(Benzyloxy)-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine Methyl 2-carboxylate 65f (90.0 mg, 0.246 mmol) was dissolved in dichloromethane (5 mL). Di-tert-butyl dicarbonate (108 mg, 0.493 mmol), 4-dimethylaminopyridine (3.01 mg, 0.0246 mmol), and N,N-diisopropylethylamine (95.5 mg, 0.739 mmol) were added to the reaction mixture. The reaction mixture was allowed to react at 25°C for 18 hours. The reaction mixture was diluted with water (100 mL) and the aqueous solution was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography (eluent: System A) to obtain 5-(tert-butyl)-2-methyl-10-(benzyloxy)-4,6-dihydro-5H-benzo[c]thieno[3,2-e]azepine. -2,5-dicarboxylate 65g (80.0mg), yield: 70%.

[1020] MS m / z(ESI):366.2[M+1-100].

[1021] Step 7

[1022] tert-butyl 10-(benzyloxy)-2-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-4,6-dihydro-5H-benzo[c]thieno[3,2-e]azepine-5-carboxylate

[1023] 10-(Benzyloxy)-2-((3-chloro-5-(methylsulfonylamino)phenyl)carbamoyl)-4,6-dihydro-5H-benzo[c]thieno[3,2-e]azepine -5-carboxylic acid tert-butyl ester

[1024] 5-(tert-butyl)2-methyl-10-(benzyloxy)-4,6-dihydro-5H-benzo[c]thieno[3,2-e]azepine 65 g (60.0 mg, 0.129 mmol) of 2,5-dicarboxylate and 1 g (56.9 mg, 0.258 mmol) of N-(3-amino-5-chlorophenyl)methanesulfonamide were dissolved in tetrahydrofuran (7.0 mL). Trimethylaluminum (2 M, 0.64 mL) was slowly added dropwise to the resulting mixed solution. The reaction solution was stirred at 60°C for 2 hours. The reaction was quenched by slowly adding methanol (50 mL). The resulting mixed solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to obtain 10-(benzyloxy)-2-((3-chloro-5-(methylsulfonylamino)phenyl)carbamoyl)-4,6-dihydro-5H-benzo[c]thieno[3,2-e]azepine. -tert-Butyl 5-carboxylate 65h (60.0 mg), yield: 71%.

[1025] Step 8

[1026] 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxamide

[1027] 10-(Benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-Formamide

[1028] 10-(benzyloxy)-2-((3-chloro-5-(methylsulfonylamino)phenyl)carbamoyl)-4,6-dihydro-5H-benzo[c]thieno[3,2-e]azepine Tert-butyl 65h-5-carboxylate (60.0 mg, 0.0917 mmol) was dissolved in dichloromethane (4.0 mL), and trifluoroacetic acid (1.0 mL) was slowly added dropwise to the resulting mixture. The mixture was allowed to react at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure and then separated by preparative liquid chromatography (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH₄HCO₃ + H₂O, mobile phase B: CH₃CN) to afford 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine. -2-Formamide 65 (32.0 mg), yield: 63%.

[1029] MS m / z(ESI):554.2[M+1].

[1030] 1 H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.42(s,1H),8.18(s,1H),7.66(dt,J=8.0,2.0Hz,2H),7.50–7.43(m,2H),7.37 –7.19(m,5H),7.07(dd,J=7.6,1.2Hz,1H),6.97(t,J=2.0Hz,1H),5.21(s,2H),3.74(s,2H),3.54(s,2H),3.08(s,3H).

[1031] Example 66

[1032] 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxamide

[1033] 10-(Benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-Formamide

[1034] first step

[1035] methyl 10-(benzyloxy)-5-methyl-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate

[1036] 10-(Benzyloxy)-5-methyl-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-carboxylic acid methyl ester

[1037] 10-(Benzyloxy)-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine Methyl 2-carboxylate 65f (70 mg, 0.192 mmol) was dissolved in 1,2-dichloroethane (5 mL). Aqueous formaldehyde (77.7 mg, 0.958 mmol) and sodium triacetylborohydride (122 mg, 0.575 mmol) were added to the resulting solution. The reaction mixture was stirred at 25°C for 2 hours. The mixture was quenched with methanol, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to afford 10-(benzyloxy)-5-methyl-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine. -2-Carboxylic acid methyl ester 66a (50.0 mg), yield: 69%.

[1038] MS m / z(ESI):380.2[M+1].

[1039] Step 2

[1040] 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxamide

[1041] 10-(Benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine -2-Formamide

[1042] 10-(Benzyloxy)-5-methyl-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine Methyl 2-carboxylate 66a (60.0 mg, 0.156 mmol) and 1 g of N-(3-amino-5-chlorophenyl)methanesulfonamide (68.7 mg, 0.311 mmol) were dissolved in tetrahydrofuran (5.0 mL). Trimethylaluminum (2 M, 0.78 mL) was slowly added dropwise to the resulting mixture. The reaction mixture was stirred at 60°C for 2 hours. The reaction was then slowly added dropwise to methanol (50 mL) to quench the reaction. The resulting mixed solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A), followed by preparative liquid separation (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 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonylamino)phenyl)-5-methyl-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine. -2-Formamide 66 (7.0 mg), yield: 8%.

[1043] MS m / z(ESI):568.2[M+1].

[1044] 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),10.01(s,1H),8.43(s,1H),7.59(d,J=2.0Hz,1H),7.56(s,1H),7.49–7.44(m,2H),7.37–7.27(m, 3H),7.26-7.18(m,2H),7.08(d,J=7.6Hz,1H),6.93(t,J=2.0Hz,1H),5.21(s,2H),3.46(s,2H),3.22(s,2H),3.02(s,3H),2.33(s,3H).

[1045] Example 67

[1046] 11-benzamido-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[1047] 11-Benzamido-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide

[1048] first step

[1049] methyl 1-(2-(3-amino-2-bromophenoxy)ethyl)-5-bromo-1H-pyrrole-3-carboxylate

[1050] 1-(2-(3-amino-2-bromophenoxy)ethyl)-5-bromo-1H-pyrrole-3-carboxylic acid methyl ester

[1051] 3-Amino-2-bromophenol 67a (1.8 g, 9.57 mmol, commercially available) and methyl 5-bromo-1-(2-hydroxyethyl)-1H-pyrrole-3-carboxylate 35a (4.75 g, 19.15 mmol) were dissolved in toluene (20 mL). To the resulting solution was added cyanomethylenetri-n-butylphosphine (6.93 g, 28.72 mmol, 7.62 mL). The reaction mixture was stirred at 80°C for 2 hours. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to afford methyl 1-(2-(3-amino-2-bromophenoxy)ethyl)-5-bromo-1H-pyrrole-3-carboxylate 67b (1.88 g) in a yield of 46.9%.

[1052] MS m / z(ESI):417.0[M+1].

[1053] Step 2

[1054] methyl 11-amino-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1055] 11-Amino-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-carboxylic acid methyl ester

[1056] Methyl 1-(2-(3-amino-2-bromophenoxy)ethyl)-5-bromo-1H-pyrrole-3-carboxylate 67b (1.88 g, 4.50 mmol) was dissolved in ethylene glycol dimethyl ether (30 mL) and water (6.0 mL). To the resulting solution were added pinacol diboron (3.43 g, 13.49 mmol), n-butyldi(1-adamantyl)phosphine (644.9 mg, 1.80 mmol), potassium carbonate (1.86 g, 13.49 mmol), and palladium acetate (201.91 mg, 899.35 μmol). The reaction mixture was purged with nitrogen three times and then heated to 70°C with stirring for 18 hours. The obtained mixed solution was filtered under reduced pressure, and the filter cake was washed with dichloromethane (30 mL × 3). The obtained filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: A system) to obtain 11-amino-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Carboxylic acid methyl ester 67c (250 mg, 71.7% purity), yield: 15.4%.

[1057] MS m / z(ESI):259.1[M+1].

[1058] Step 3

[1059] methyl 11-benzamido-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1060] 11-Benzamido-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-carboxylic acid methyl ester

[1061] 11-amino-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine Methyl 2-carboxylate 67c (111.6 mg, 71.7% purity, 309.751 μmol) was dissolved in dichloromethane (40 mL). Triethylamine (94.03 mg, 129.16 μL) and benzoyl chloride (43.54 mg, 309.75 μmol, 35.98 μL) were added to the resulting solution. The reaction mixture was stirred at 25°C for 18 hours. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to afford 11-benzamido-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine. -2-Carboxylic acid methyl ester 67d (80 mg), yield: 71.2%.

[1062] MS m / z(ESI):363.1[M+1].

[1063] Step 4

[1064] 11-benzamido-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[1065] 11-Benzamido-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide

[1066] 11-Benzamido-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine Methyl 2-carboxylate 67d (20 mg, 55.19 μmol) and 1 g of N-(3-amino-5-chlorophenyl)methanesulfonamide (24.36 mg, 110.38 mmol) were dissolved in tetrahydrofuran (1 mL). Trimethylaluminum (2 M, 275.95 μL) was slowly added dropwise to the resulting mixture. The reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was then slowly added dropwise to methanol (10 mL) to quench the reaction. The obtained mixed solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A), and then separated by preparative liquid phase separation (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 11-benzamido-N-(3-chloro-5-(methylsulfonylamino)phenyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide 67 (12.56 mg), yield: 41.3%.

[1067] MS m / z(ESI):551.1[M+1].

[1068] 1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),9.86(s,1H),9.80(s,1H),7.90(d,J=7.4Hz,2H ),7.81(d,J=1.7Hz,1H),7.65(t,J=1.8Hz,1H),7.59–7.54(m,2H),7.51(dt,J=10.7 ,5.5Hz,3H),7.38(t,J=8.0Hz,1H),7.09(dd,J=8.0,1.0Hz,1H),6.92(d,J=1.7Hz,1 H),6.89(t,J=1.9Hz,1H),4.46(t,J=5.9Hz,2H),4.21(d,J=5.1Hz,2H),3.05(s,3H).

[1069] Example 68

[1070] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxamide

[1071] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Formamide

[1072] first step

[1073] 2-bromo-1-((3,5-difluorobenzyl)oxy)-3-nitrobenzene

[1074] 2-Bromo-1-((3,5-difluorobenzyl)oxy)-3-nitrobenzene

[1075] Potassium carbonate (24.88 g, 180.00 mmol) and 1-(bromomethyl)-3,5-difluorobenzene 68a (12.55 g, 60.60 mmol) were added to a solution of 2-bromo-3-nitrophenol 19a (13.08 g, 60 mmol) in acetonitrile (150 mL) at room temperature. The mixture was heated to 70°C and stirred for 4 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford 2-bromo-1-((3,5-difluorobenzyl)oxy)-3-nitrobenzene 68b (19.5 g) in a 94.5% yield.

[1076] 1H NMR (400MHz, DMSO-d6) δ7.67–7.53(m,2H),7.51–7.44(m,1H),7.30-7.18(m,3H),5.35(s,2H).

[1077] Step 2

[1078] 2-bromo-3-((3,5-difluorobenzyl)oxy)aniline

[1079] 2-Bromo-3-((3,5-difluorobenzyl)oxy)aniline

[1080] Iron powder (11.68 g, 209.24 mmol) and ammonium chloride (11.19 g, 209.24 mmol) were added to a mixture of 2-bromo-1-((3,5-difluorobenzyl)oxy)-3-nitrobenzene 68b (18 g, 52.31 mmol) in water (100 mL) and ethanol (200 mL). The mixture was heated at 80°C with stirring for 2 hours. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to provide 2-bromo-3-((3,5-difluorobenzyl)oxy)aniline 68c (13.00 g) in a yield of 79.1%.

[1081] MS m / z(ESI):316.0[M+1].

[1082] Step 3

[1083] methyl 11-((3,5-difluorobenzyl)oxy)-6-oxo-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[1084] 11-((3,5-difluorobenzyl)oxy)-6-oxo-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-carboxylic acid methyl ester

[1085] Palladium acetate (571 mg, 2.55 mmol) and n-butyldi(1-adamantyl)phosphine (1.83 g, 5.09 mmol) were added to dioxane (200 mL) at room temperature. After argon replacement, the mixture was stirred for 10 minutes. Subsequently, 2-bromo-3-((3,5-difluorobenzyl)oxy)aniline 68c (4.00 g, 12.73 mmol), methyl 5-bromo-1-(2-methoxy-2-oxoethyl)-1H-pyrrole-3-carboxylate 27b (4.22 g, 15.28 mmol), pinacol diboron (6.47 g, 25.47 mmol), potassium carbonate (5.28 g, 38.20 mmol) and water (20 mL) were added. After argon replacement, the mixture was heated at 100°C and stirred for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, water (50 mL), ethyl acetate (100 mL) and petroleum ether (50 mL) were added, stirred for 30 minutes, filtered, and the filter cake was dried under vacuum to obtain 11-((3,5-difluorobenzyl)oxy)-6-oxo-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-carboxylic acid methyl ester 68d (1.80 g), yield: 35.5%.

[1086] MS m / z(ESI):399.1[M+1].

[1087] Step 4

[1088] methyl 11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[1089] 11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-carboxylic acid methyl ester

[1090] Borane dimethyl sulfide complex (312.56 mg, 22.59 mmol, 2M tetrahydrofuran solution) was added to 11-((3,5-difluorobenzyl)oxy)-6-oxo-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine A solution of methyl 2-carboxylate 68d (4.5 g, 11.30 mmol) in tetrahydrofuran (80 mL) was heated at 60°C with stirring for 1 hour. Methanol (10 mL) was slowly added dropwise to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was 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]diazepine -2-Carboxylic acid methyl ester 68e (3.5 g), yield: 80.6%.

[1091] MS m / z(ESI):385.1[M+1].

[1092] Step 5

[1093] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxamide

[1094] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Formamide

[1095] At room temperature, trimethylaluminum (1.59 g, 22.11 mmol, 2M tetrahydrofuran) was added dropwise to a mixture of 1 g (585 mg, 2.65 mmol) of N-(3-amino-5-chlorophenyl)methanesulfonamide and 11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine. A solution of methyl ester 68e (850 mg, 2.21 mmol) of methyl-2-carboxylate 68e in tetrahydrofuran (20 mL) was replaced with argon and heated under reflux with stirring for 2 hours. Methanol (10 mL) was slowly added dropwise to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain N-(3-chloro-5-(methylsulfonylamino)phenyl)-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Formamide 68 (596 mg), yield: 45.9%.

[1096] MS m / z(ESI):573.2[M+1].

[1097] 1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),9.74(s,1H),7.69(s,1H),7.64(s,1H),7.62(s,1H),7.19–7.07(m,3H),7.06–6.98( m,2H),6.89(s,1H),6.50(t,J=8.3Hz,2H),5.73(s,1H),5.13(s,2H),4.23–4.03(m,2H),3.54-3.45(m,2H),3.06(s,3H).

[1098] Example 69

[1099] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-7-formyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxamide

[1100] N-(3-Chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-7-formyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Formamide

[1101] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Formamide 68 (50 mg, 87.26 μmol) was added to a formic acid solution (1 mL), heated at 100°C and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid phase separation (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain N-(3-chloro-5-(methylsulfonyl)phenyl)-11-((3,5-difluorobenzyl)oxy)-7-formyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Formamide 69 (14 mg), yield: 26.4%.

[1102] MS m / z(ESI):603.0[M+1].

[1103] 1 H NMR (400MHz, DMSO-d6) δ10.00(s,1H),9.85(s,1H),8.09(s,1H),7.77(s,1H),7.67(s,1H),7.63(s,1H),7.44(t,J=8.1Hz,1H),7 .28(d,J=8.5Hz,1H),7.15(d,J=7.0Hz,3H),7.10–7.00(m,2H),6.90(s,1H),5.27(s,2H),4.20(s,2H),4.02(s,2H),3.06(s,3H).

[1104] Example 70

[1105] 7-acetyl-N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxamide

[1106] 7-Acetyl-N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Formamide

[1107] first step

[1108] methyl 7-acetyl-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[1109] 7-Acetyl-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylic acid methyl ester

[1110] Under ice bath, acetyl chloride (15 mg, 195.12 μmol) was added dropwise to 11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine A solution of methyl 7-acetyl-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate 68e (50 mg, 130.08 μmol) and N,N-diisopropylethylamine (50 mg, 390.24 μmol) in dichloromethane (2 mL) was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to afford methyl 7-acetyl-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate 70a (50 mg) in a 90.9% yield.

[1111] MS m / z(ESI):427.1[M+1].

[1112] Step 2

[1113] 7-acetyl-N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxamide

[1114] 7-Acetyl-N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Formamide

[1115] Trimethylaluminum (85 mg, 1.17 mmol) was added dropwise to a solution of 1 g (31 mg, 140.71 μmol) of N-(3-amino-5-chlorophenyl)methanesulfonamide and methyl 7-acetyl-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate 70a (50 mg, 117.26 μmol) in tetrahydrofuran (3 mL) at room temperature. After argon replacement, the mixture was heated under reflux with stirring for 2 hours. The reaction mixture was slowly added dropwise with dilute hydrochloric acid solution (2 mL, 1 M) to quench the reaction, and ethyl acetate was added for extraction (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative liquid phase separation (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 7-acetyl-N-(3-chloro-5-(methylsulfonyl)phenyl)-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Formamide 70 (35 mg), yield: 47.1%.

[1116] MS m / z(ESI):615.1[M+1].

[1117] 1 H NMR (400MHz, DMSO-d6) δ9.98(s,1H),9.83(s,1H),7.74(d,J=1.5Hz,1H),7.69(t,J=1.6Hz,1H ),7.65–7.58(m,1H),7.45(t,J=8.1Hz,1H),7.28(d,J=8.4Hz,1H),7.18–7.06(m,5H),6.89(t ,J=1.8Hz,1H),5.35(d,J=13.3Hz,1H),5.21(d,J=13.3Hz,1H),4.88(td,J=12.8,6.0Hz,1H), 4.43–4.26(m,1H),3.82–3.65(m,1H),3.36(dd,J=13.1,5.0Hz,1H),3.06(s,3H),1.53(s,3H).

[1118] Example 71

[1119] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxamide

[1120] NN-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Formamide

[1121] first step

[1122] methyl 11-((3,5-difluorobenzyl)oxy)-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[1123] 11-((3,5-difluorobenzyl)oxy)-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-carboxylic acid methyl ester

[1124] At room temperature, iodomethane (52 mg, 364.23 μmol) was added dropwise to 11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine A solution of methyl-2-carboxylate 68e (70 mg, 182.11 μmol) and potassium carbonate (75 mg, 546.34 μmol) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 6 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to obtain 11-((3,5-difluorobenzyl)oxy)-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Carboxylic acid methyl ester 71a (61 mg), yield: 84.1%.

[1125] MS m / z(ESI):399.1[M+1].

[1126] Step 2

[1127] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxamide

[1128] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Formamide

[1129] At room temperature, trimethylaluminum (127 mg, 1.76 mmol) was added dropwise to a mixture of 1 g (47 mg, 210.84 μmol) of N-(3-amino-5-chlorophenyl)methanesulfonamide and 11-((3,5-difluorobenzyl)oxy)-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine. A solution of methyl-2-carboxylate 71a (70 mg, 175.70 μmol) in tetrahydrofuran (10 mL) was replaced with argon and heated under reflux with stirring for 2 hours. The reaction solution was slowly added dropwise with dilute hydrochloric acid solution (2 mL, 1 M) to quench the reaction, and ethyl acetate was added for extraction (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative liquid phase separation (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain N-(3-chloro-5-(methylsulfonyl)phenyl)-11-((3,5-difluorobenzyl)oxy)-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Formamide 71 (25 mg), yield: 24.2%.

[1130] MS m / z(ESI):587.1[M+1].

[1131] 1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),9.76(s,1H),7.74–7.68(m,2H),7.67–7 .62(m,1H),7.27(t,J=8.2Hz,1H),7.12(t,J=7.3Hz,3H),6.94(d,J=1.6Hz,1H ),6.89(t,J=1.7Hz,1H),6.84(d,J=8.3Hz,1H),6.78(d,J=8.1Hz,1H),5.17(s ,2H),4.02(t,J=5.8Hz,2H),3.37(t,J=5.9Hz,2H),3.06(s,3H),2.71(s,3H).

[1132] Example 72

[1133] N-(3-chloro-5-(methylsulfonamido)phenyl)-7-cyclopropyl-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxamide

[1134] N-(3-Chloro-5-(methylsulfonamido)phenyl)-7-cyclopropyl-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Formamide

[1135] first step

[1136] methyl 7-cyclopropyl-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[1137] 7-cyclopropyl-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylic acid methyl ester

[1138] At room temperature, (1-ethoxycyclopropyloxy)-trimethylsilane (79 mg, 455.28 μmol) was added to 11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine A solution of methyl 7-cyclopropyl-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate 68e (50 mg, 130.08 μmol) and acetic acid (78 mg, 1.30 mmol) in methanol (3 mL) was stirred at room temperature for 10 minutes. Sodium borohydride (41 mg, 650.41 μmol) was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was then heated at 60°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to afford methyl 7-cyclopropyl-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate 72a (48 mg) in an 86.9% yield.

[1139] MS m / z(ESI):425.1[M+1].

[1140] Step 2

[1141] N-(3-chloro-5-(methylsulfonamido)phenyl)-7-cyclopropyl-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxamide

[1142] N-(3-Chloro-5-(methylsulfonamido)phenyl)-7-cyclopropyl-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Formamide

[1143] To a solution of 1 g (32 mg, 145.49 μmol) of N-(3-amino-5-chlorophenyl)methanesulfonamide and methyl 7-cyclopropyl-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate 72a (51.46 mg, 121.25 μmol) in tetrahydrofuran (3 mL) was added dropwise trimethylaluminum (87 mg, 1.21 mmol) at room temperature. The atmosphere was replaced with argon and the mixture was heated under reflux with stirring for 2 h. The reaction solution was slowly added dropwise with dilute hydrochloric acid solution (2 mL, 1 M) to quench the reaction, and ethyl acetate was added for extraction (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative liquid phase separation (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain N-(3-chloro-5-(methylsulfonyl)phenyl)-7-cyclopropyl-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine -2-Formamide 72 (25 mg), yield 28.2%.

[1144] MS m / z(ESI):613.2[M+1].

[1145] 1 H NMR (400MHz, DMSO-d6) δ9.99(s,1H),9.77(s,1H),7.66(d,J=19.8Hz,3H),7.27(t,J=7.6Hz,1H),7.11(s,4H),6.90(s, 2H),6.82(d,J=7.9Hz,1H),5.15(s,2H),4.68(s,1H),4.03(s,2H),3.52(s,2H),3.06(s,3H),0.63(s,2H),0.11(s,2H).

[1146] Example 73

[1147] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[1148] N-(3-Chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide

[1149] first step

[1150] 3-(benzyloxy)-2-bromophenol

[1151] 3-(Benzyloxy)-2-bromophenol

[1152] 2-Bromobenzene-1,3-diol 73a (1.00 g, 5.29 mmol) was dissolved in acetonitrile (10 mL) at room temperature. Potassium carbonate (1.46 g, 10.58 mmol) and benzyl bromide (542.95 mg, 3.17 mmol) were added sequentially, and the mixture was allowed to react at 25°C for 2 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 3-(benzyloxy)-2-bromophenol 73b (533 mg) in a 36.1% yield.

[1153] MS m / z(ESI):279.0 / 281.0[M+1].

[1154] Step 2

[1155] methyl 1-(2-(3-(benzyloxy)-2-bromophenoxy)ethyl)-5-bromo-1H-pyrrole-3-carboxylate

[1156] 1-(2-(3-(Benzyloxy)-2-bromophenoxy)ethyl)-5-bromo-1H-pyrrole-3-carboxylic acid methyl ester

[1157] At room temperature, methyl 5-bromo-1-(2-hydroxyethyl)-1H-pyrrole-3-carboxylate 35a (200.0 mg, 0.81 mmol) was dissolved in toluene (2 mL). 3-(benzyloxy)-2-bromophenol 73b (247.5 mg, 0.89 mmol) and cyanomethylenetri-n-butylphosphine (583.7 mg, 2.42 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and the mixture was allowed to react at 80°C for 18 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to afford methyl 1-(2-(3-(benzyloxy)-2-bromophenoxy)ethyl)-5-bromo-1H-pyrrole-3-carboxylate 73c (150 mg) in a 36.5% yield.

[1158] MS m / z(ESI):508.0 / 510.0 / 512.0[M+1].

[1159] Step 3

[1160] methyl 11-(benzyloxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1161] 11-(Benzyloxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-carboxylic acid methyl ester

[1162] Compound 73c (150.0 mg, 0.29 mmol) was dissolved in ethylene glycol dimethyl ether (4 mL) and water (0.5 mL) at room temperature. Potassium carbonate (122.0 mg, 0.88 mmol), bis(boron) pinacol (224.4 mg, 0.88 mmol), palladium acetate (13.3 mg, 0.06 mmol), and n-butyldi(1-adamantyl)phosphine (42.2 mg, 0.12 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and the reaction was continued at 80°C for 18 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain 11-(benzyloxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine. -2-carboxylic acid methyl ester 73d (72 mg), yield: 69.9%.

[1163] MS m / z(ESI):350.0[M+1].

[1164] Step 4

[1165] methyl 11-hydroxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1166] 11-Hydroxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-carboxylic acid methyl ester

[1167] 11-(Benzyloxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine Methyl 2-carboxylate 73d (800 mg, 2.29 mmol) was dissolved in methanol (20 mL). Palladium / carbon (10%) (1.00 g, 9.40 mmol) was added to the resulting solution. The reaction solution was replaced with hydrogen three times and stirred at room temperature under a hydrogen atmosphere for 12 hours. The resulting mixed solution was filtered under reduced pressure, and the filter cake was washed with methanol (50 mL × 3). The filtrate was concentrated under reduced pressure, and petroleum ether / ethyl acetate (30 mL, 3:1) was added and stirred for 30 minutes. The mixture was filtered and the filter cake was dried to obtain 11-hydroxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine. -2-Carboxylic acid methyl ester 73e (300 mg), yield: 50.5%.

[1168] MS m / z(ESI):260.2[M+1].

[1169] Step 5

[1170] methyl 11-((3,5-difluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1171] 11-((3,5-difluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-carboxylic acid methyl ester

[1172] 11-Hydroxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine Methyl 2-carboxylate 73e (2.0 g, 7.71 mmol) was dissolved in tetrahydrofuran (40 mL). Cesium carbonate (5.0 g, 15.43 mmol) and 1-(chloromethyl)-3,5-difluorobenzene (2.5 g, 15.43 mmol, 1.94 mL) were added to the resulting solution. The reaction mixture was stirred at 60°C for 12 hours. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with methanol (5 mL × 3). The mixture was stirred with petroleum ether / ethyl acetate (30 mL, 10:1) for 30 minutes, filtered, and the filter cake was dried to obtain 11-((3,5-difluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine. -2-Carboxylic acid methyl ester 73f (2.8 g), yield: 94.2%.

[1173] MS m / z(ESI):386.2[M+1].

[1174] Step 6

[1175] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[1176] N-(3-Chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide

[1177] 11-((3,5-difluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine Methyl 2-carboxylate 73f (200 mg, 519.00 μmol) and 1 g of N-(3-amino-5-chlorophenyl)methanesulfonamide (229.1 mg, 1.04 mmol) were dissolved in tetrahydrofuran (4 mL). Trimethylaluminum (2 M, 2.08 mL) was slowly added dropwise to the resulting mixture. The reaction mixture was stirred at 60°C for 2 hours. The reaction was quenched by slowly adding methanol (10 mL). The resulting mixed solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A), and then separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to obtain N-(3-chloro-5-(methylsulfonyl)phenyl)-11-((3,5-difluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide 73 (80 mg), yield: 26.8%.

[1178] MS m / z(ESI):574.2[M+1].

[1179] 1H NMR (400MHz, DMSO-d6) δ10.00(s,1H),9.84(s,1H),7.77(d,J=1.6Hz,1H),7.70(t,J =1.6Hz,1H),7.65(t,J=1.6Hz,1H),7.29(t,J=8.0Hz,1H),7.18–7.13(m,3H),7.08( d,J=1.6Hz,1H),6.99(dd,J=8.0,1.2Hz,1H),6.90(t,J=2.0Hz,1H),6.83(dd,J=8.0 ,0.4Hz,1H),5.24(s,2H),4.44(t,J=5.6Hz,2H),4.16(t,J=5.6Hz,2H),3.06(s,3H).

[1180] Example 74

[1181] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3-cyano-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[1182] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3-cyano-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide

[1183] first step

[1184] methyl 11-((3-bromo-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1185] 11-((3-bromo-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-carboxylic acid methyl ester

[1186] 11-Hydroxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine Methyl 2-carboxylate 73e (100 mg, 385.72 μmol) was dissolved in tetrahydrofuran (3 mL). Cesium carbonate (251.35 mg, 771.44 μmol) and 3-fluoro-5-bromobenzyl bromide (206.68 mg, 771.44 μmol, commercially available) were added to the resulting solution. The reaction mixture was stirred at 60°C for 3 hours. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with dichloromethane (20 mL × 3). The filtrate was stirred with petroleum ether / ethyl acetate (30 mL, 3:1) for 30 minutes, filtered, and the filter cake was dried to obtain 11-((3-bromo-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine. -2-Carboxylic acid methyl ester 74a (160 mg), yield: 92.9%.

[1187] MS m / z(ESI):446.0 / 448.0[M+1].

[1188] Step 2

[1189] methyl 11-((3-cyano-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1190] 11-((3-cyano-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-carboxylic acid methyl ester

[1191] 11-((3-bromo-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine Methyl 2-carboxylate 74a (80 mg, 179.27 μmol) was dissolved in N,N-dimethylformamide (2 mL). Zinc cyanide (63.15 mg, 537.80 μmol) and tetrakis(triphenylphosphine)palladium (41.43 mg, 35.85 μmol) were added to the resulting solution. The reaction mixture was purged with nitrogen three times and stirred at 90°C under nitrogen for 3 hours. The resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 2). The extract was allowed to stand to precipitate a solid, which was filtered and dried to yield 11-((3-cyano-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine. -2-Carboxylic acid methyl ester 74b (50 mg), yield: 71.1%.

[1192] MS m / z(ESI):393.2[M+1].

[1193] Step 3

[1194] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3-cyano-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[1195] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3-cyano-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide

[1196] 11-((3-cyano-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine Methyl 2-carboxylate 74b (40 mg, 101.94 μmol) and 1 g of N-(3-amino-5-chlorophenyl)methanesulfonamide (44.99 mg, 203.88 μmol) were dissolved in tetrahydrofuran (1 mL). Trimethylaluminum (2 M, 407.77 μL) was slowly added dropwise to the resulting mixture. The reaction mixture was stirred at 60°C for 2 hours. The reaction was then slowly added dropwise to methanol (10 mL) to quench the reaction. The resulting mixed solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A), and then separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to obtain N-(3-chloro-5-(methylsulfonyl)phenyl)-11-((3-cyano-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide 74 (6 mg), yield: 10.1%.

[1197] MS m / z(ESI):581.1[M+1].

[1198] 1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),9.81(s,1H),7.80–7.77(m,1H),7.76(d,J=1.6Hz,1H),7 .73(t,J=1.6Hz,1H),7.69(t,J=1.6Hz,1H),7.67–7.64(m,1H),7.61(t,J=1.6Hz,1H),7.30(t, J=8.0Hz,1H),7.09(d,J=1.6Hz,1H),7.00(dd,J=8.0,0.8Hz,1H),6.88(t,J=2.0Hz,1H),6.84( dd,J=8.0,0.8Hz,1H),5.28(s,2H),4.44(t,J=6.0Hz,2H),4.16(t,J=6.0Hz,2H),3.04(s,3H).

[1199] Example 75

[1200] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3-(dimethylamino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[1201] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3-(dimethylamino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide

[1202] first step

[1203] methyl 11-((3-((tert-butoxycarbonyl)amino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1204] 11-((3-((tert-Butoxycarbonyl)amino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-carboxylic acid methyl ester

[1205] 11-((3-bromo-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine Methyl 2-carboxylate 74a (60 mg, 134.45 μmol) and tert-butyl carbamate (47.25 mg, 403.35 μmol) were dissolved in 1,4-dioxane (2 mL). Cesium carbonate (131.42 mg, 403.35 μmol), tris(dibenzylideneacetone)dipalladium (12.31 mg, 13.44 μmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (15.56 mg, 26.89 μmol) were added to the resulting solution. The reaction mixture was purged with nitrogen three times and stirred at 100°C under nitrogen for 3 hours. The obtained mixed solution was filtered under reduced pressure, and the filter cake was washed with dichloromethane (10 mL × 2). The obtained filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: System A) to obtain 11-((3-((tert-butoxycarbonyl)amino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Carboxylic acid methyl ester 75a (60 mg), yield: 92.5%.

[1206] MS m / z(ESI):483.2[M+1].

[1207] Step 2

[1208] methyl 11-((3-amino-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1209] 11-((3-amino-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-carboxylic acid methyl ester

[1210] 11-((3-((tert-Butoxycarbonyl)amino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine Methyl 2-carboxylate 75a (60 mg, 124.35 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (14.18 mg, 124.35 μmol, 0.5 mL) was added to the resulting solution. The reaction mixture was stirred at 25°C for 1 hour. The resulting mixture was concentrated under reduced pressure to afford 11-((3-amino-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Carboxylic acid methyl ester 75b was used directly in the next step of synthesis.

[1211] MS m / z(ESI):383.2[M+1].

[1212] Step 3

[1213] methyl 11-((3-(dimethylamino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1214] 11-((3-(Dimethylamino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-carboxylic acid methyl ester

[1215] 11-((3-amino-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine Methyl 2-carboxylate 75b was dissolved in N,N-dimethylformamide (2 mL). Potassium carbonate (65.06 mg, 470.73 μmol) and iodomethane (222.72 mg, 1.57 mmol, 97.68 μL) were added to the resulting solution. The reaction mixture was stirred at 25°C for 12 hours. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with dichloromethane (5 mL x 2). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to obtain 11-((3-(dimethylamino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine. -2-Carboxylic acid methyl ester 75c (20 mg), yield: 39.2%.

[1216] MS m / z(ESI):411.2[M+1].

[1217] Step 4

[1218] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3-(dimethylamino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[1219] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3-(dimethylamino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide

[1220] 11-((3-(dimethylamino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine Methyl 2-carboxylate 75c (20 mg, 48.73 μmol) and 1 g of N-(3-amino-5-chlorophenyl)methanesulfonamide (21.51 mg, 97.46 μmol) were dissolved in tetrahydrofuran (1 mL). Trimethylaluminum (2 M, 194.91 μL) was slowly added dropwise to the resulting mixture. The reaction mixture was stirred at 60°C for 2 hours. The reaction was quenched by slowly adding methanol (5 mL). The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to afford N-(3-chloro-5-(methanesulfonamido)phenyl)-11-((3-(dimethylamino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine. -2-Formamide 75 (9 mg), yield: 30.8%.

[1221] MS m / z(ESI):599.1[M+1].

[1222] 1H NMR (400MHz, DMSO-d6) δ10.00(s,1H),9.84(s,1H),7.76(d,J=1.6Hz,1H),7.69(t,J=1.6Hz,1H) ,7.64(t,J=1.6Hz,1H),7.28(t,J=8.0Hz,1H),7.06(d,J=1.6Hz,1H),7.01(d,J=8.4Hz,1H),6.8 9(t,J=2.0Hz,1H),6.81(d,J=8.0Hz,1H),6.63(s,1H),6.45(d,J=8.8Hz,1H),6.37(dt,J=12.8, 2.0Hz,1H),5.14(s,2H),4.43(t,J=6.0Hz,2H),4.16(t,J=6.0Hz,2H),3.06(s,3H),2.84(s,6H).

[1223] Example 76

[1224] 11-((3-amino-5-fluorobenzyl)oxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[1225] 11-((3-amino-5-fluorobenzyl)oxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide

[1226] first step

[1227] tert-butyl(3-(((2-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepin-11-yl)oxy)methyl)-5-fluorophenyl)carbamate

[1228] (3-(((2-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -11-yl)oxy)methyl)-5-fluorophenyl)carbamic acid tert-butyl ester

[1229] 11-((3-((tert-Butoxycarbonyl)amino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine Methyl 2-carboxylate 75a (60 mg, 124.35 μmol) and 1 g of N-(3-amino-5-chlorophenyl)methanesulfonamide (54.88 mg, 248.70 μmol) were dissolved in tetrahydrofuran (1.5 mL). Trimethylaluminum (2 M, 497.41 μL) was slowly added dropwise to the resulting mixture. The reaction mixture was stirred at 60°C for 2 hours. The reaction was quenched by slowly adding methanol (10 mL). The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to obtain (3-(((2-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine tert-Butyl-1-yl)oxy)methyl)-5-fluorophenyl)carbamate 76a (30 mg), yield: 35.9%.

[1230] MS m / z(ESI):693.2[M+23].

[1231] Step 2

[1232] 11-((3-amino-5-fluorobenzyl)oxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[1233] 11-((3-amino-5-fluorobenzyl)oxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide

[1234] (3-(((2-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine Tert-butyl 11-((3-amino-5-fluorobenzyl)oxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine was obtained by preparative liquid chromatography (HPLC) using an AKZONOBEL Kromasil column (250 × 21.2 mm ID, 5 μm, 20 mL / min, mobile phase A: 0.05% NH4HCO3 + H2O, mobile phase B: CH3CN). The product was 11-((3-amino-5-fluorobenzyl)oxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine. -2-Formamide 76 (10 mg), yield: 29.3%.

[1235] MS m / z(ESI):571.1[M+1].

[1236] 1 H NMR (400MHz, DMSO-d6) δ10.00(s,1H),9.85(s,1H),7.76(d,J=1.6Hz,1H),7.71(t,J=1.6Hz,1H),7.63( t,J=1.6Hz,1H),7.25(t,J=8.0Hz,1H),7.03(d,J=1.6Hz,1H),6.94(dd,J=8.0,0.4Hz,1H),6.89(t,J=2 .0Hz,1H),6.79(dd,J=8.0,0.4Hz,1H),6.46(t,J=1.6Hz,1H),6.33(dt,J=8.8,2.4Hz,1H),6.22(dt,J= 11.6, 2.0Hz, 1H), 5.41 (s, 2H), 5.06 (s, 2H), 4.43 (t, J = 5.6Hz, 2H), 4.16 (t, J = 5.6Hz, 2H), 3.05 (s, 3H).

[1237] Example 77

[1238] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,3-difluorocyclopentyl)methoxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[1239] N-(3-Chloro-5-(methylsulfonamido)phenyl)-11-((3,3-difluorocyclopentyl)methoxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide

[1240] first step

[1241] methyl 11-((3,3-difluorocyclopentyl)methoxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1242] 11-((3,3-difluorocyclopentyl)methoxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-carboxylic acid methyl ester

[1243] 11-Hydroxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine Methyl 2-carboxylate 73e (30 mg, 115.72 μmol) and 3,3-difluorocyclopentylmethanol (31.51 mg, 231.43 μmol) were dissolved in toluene (1 mL). Cyanomethylethylenetri-n-butylphosphine (83.78 mg, 347.15 μmol, 90.97 μL) was added to the resulting solution. The reaction mixture was stirred at 80°C for 2 hours. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to obtain 11-((3,3-difluorocyclopentyl)methoxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine. -2-Carboxylic acid methyl ester 77a (35 mg), yield: 80.1%.

[1244] MS m / z(ESI):378.2[M+1].

[1245] Step 2

[1246] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,3-difluorocyclopentyl)methoxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[1247] N-(3-Chloro-5-(methylsulfonamido)phenyl)-11-((3,3-difluorocyclopentyl)methoxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide

[1248] 11-((3,3-difluorocyclopentyl)methoxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine Methyl 2-carboxylate 77a (60 mg, 158.99 μmol) and 1 g of N-(3-amino-5-chlorophenyl)methanesulfonamide (70.17 mg, 317.98 μmol) were dissolved in tetrahydrofuran (2 mL). Trimethylaluminum (2 M, 635.96 μL) was slowly added dropwise to the resulting mixture. The reaction mixture was stirred at 60°C for 2 hours. The reaction was then slowly added dropwise to methanol (10 mL) to quench the reaction. The obtained mixed solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A), and then separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to obtain N-(3-chloro-5-(methylsulfonyl)phenyl)-11-((3,3-difluorocyclopentyl)methoxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine -2-Formamide 77 (25 mg), yield: 27.7%.

[1249] MS m / z(ESI):566.1[M+1].

[1250] 1 H NMR (400MHz, DMSO-d6) δ10.00(s,1H),9.82(s,1H),7.75(d,J=1.6Hz,1H),7.69(t,J=1. 6Hz,1H),7.63(t,J=1.6Hz,1H),7.26(t,J=8.0Hz,1H),6.95–6.91(m,2H),6.89(t,J=2.0 Hz,1H),6.79(dd,J=8.0,0.8Hz,1H),4.43(t,J=6.0Hz,2H),4.15(t,J=6.0Hz,2H),3.99 (d,J=6.4Hz,2H),3.05(s,3H),2.62–2.54(m,1H),2.29–1.93(m,5H),1.70–1.60(m,1H).

[1251] According to the preparation method of Example 77 of the present invention, Examples 78-85 were prepared, and their specific structures and structural characterizations are as follows:

[1252] According to the preparation method of Example 73 of the present invention, Examples 86-99 were prepared, and their specific structures and structural characterizations are as follows:

[1253] According to the preparation method of Example 69 of the present invention, Example 101 was prepared. The specific structure and structural characterization are as follows:

[1254] According to the preparation method of Example 70 of the present invention, Examples 102-105 were prepared, and their specific structures and structural characterizations are as follows:

[1255] According to the preparation method of Example 68 of the present invention, Examples 106-111 were prepared, and their specific structures and structural characterizations are as follows:

[1256] According to the preparation method of Example 71 of the present invention, Examples 112-133 were prepared, and their specific structures and structural characterizations are as follows:

[1257] According to the preparation method of Example 67 of the present invention, Examples 134-135 were prepared, and their specific structures and structural characterizations are as follows:

[1258] According to the preparation method of Example 63 of the present invention, Examples 136-138 were prepared, and their specific structures and structural characterizations are as follows:

[1259] According to the preparation method of Example 64 of the present invention, Examples 139-142 were prepared, and their specific structures and structural characterizations are as follows:

[1260] According to the preparation method of Example 65 of the present invention, Examples 143-146 were prepared, and their specific structures and structural characterizations are as follows:

[1261] According to the preparation method of Example 66 of the present invention, Examples 147-150 were prepared, and their specific structures and structural characterizations are as follows:

[1262] According to the preparation method of Example 68 of the present invention, Examples 151-154 were prepared, and their specific structures and structural characterizations are as follows:

[1263] According to the preparation method of Example 19 of the present invention, Examples 155-158 were prepared, and their specific structures and structural characterizations are as follows:

[1264] Biological evaluation

[1265] Test Example 1: Determination of CCRF-CEM cell proliferation inhibition by the compounds of the present invention

[1266] The following method was used to determine the effect of the compounds of the present invention on CCRF-CEM cell proliferation. CCRF-CEM cells (MSI-H cells) were purchased from the cell bank of the Chinese Academy of Sciences and cultured in RPMI-1640 medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. Cell viability was measured by The assay was performed using the Luminescent Cell Viability Assay Kit (Promega, Cat. No. G7573).

[1267] The experimental method was performed according to the steps in the kit instructions, which are briefly described as follows: the test compound was first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with culture medium to prepare the test sample. The final concentration of the compound ranged from 10000nM to 1.52nM. Cells in the logarithmic growth phase were seeded into 96-well cell culture plates at a density of 1000 cells per well, and then the test compound was added and cultured in a 37°C air incubator for 120 hours. After the culture was completed, 50μL of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes and then allowed to stand for 10 minutes. The luminescence value of each well of the sample was then read using the Luminescence mode on the microplate reader. The percentage inhibition rate of the compound at each concentration point was calculated by comparing it with the value of the control group (0.1% DMSO). The nonlinear regression analysis of the compound concentration logarithm-inhibition rate was then performed in GraphPad Prism 9 software to obtain the IC value of the compound for inhibiting cell proliferation. 50 Values ​​are shown in Table 1.

[1268] Table 1 IC of the compounds of the present invention against CCRF-CEM cell proliferation inhibition 50 data

[1269] Conclusion: The compounds of the present invention have an IC inhibitory effect on CCRF-CEM cell proliferation. 50 <100nM, with good inhibitory effect.

[1270] Note: The structure of ATX-968 (prepared according to Example 31 of patent publication WO2023154519A1) is as follows:

[1271] Test Example 2: Determination of the Inhibitory Effect of the Compounds of the Invention on LS411N Cell Proliferation

[1272] The following method was used to determine the effect of the compounds of the present invention on LS411N cell proliferation. LS411N cells (MSI-H cells) were purchased from the American Type Culture Collection (ATCC) and cultured in RPMI-1640 medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. Cell viability was measured by The assay was performed using the Luminescent Cell Viability Assay Kit (Promega, Cat. No. G7573).

[1273] The experimental method was performed according to the steps in the kit instructions, which are briefly described as follows: the test compound was first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with culture medium to prepare the test sample. The final concentration of the compound ranged from 10000nM to 0.152nM. Cells in the logarithmic growth phase were seeded into 96-well cell culture plates at a density of 1000 cells per well, and then the test compound was added and cultured in a 37°C air incubator for 120 hours. After the culture was completed, 50μL of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes and then allowed to stand for 10 minutes. The luminescence value of each well of the sample was then read using the Luminescence mode on the microplate reader. The percentage inhibition rate of the compound at each concentration point was calculated by comparing it with the value of the control group (0.1% DMSO). The nonlinear regression analysis of the compound concentration logarithm-inhibition rate was then performed in GraphPad Prism 9 software to obtain the IC value of the compound in inhibiting cell proliferation. 50 Values ​​are shown in Table 2.

[1274] Table 2 IC values ​​of the compounds of the present invention for inhibition of LS411N cell proliferation 50 data

[1275] Conclusion: The compounds of the present invention have an IC value of 1.0 for the proliferation of LS411N cells. 50 <100nM, with good inhibitory effect.

[1276] Test Example 3: Test on the Inhibition of hDHX9 Enzyme (ATPase) Activity by the Compounds of the Invention

[1277] The following method is used to determine the degree of inhibition of the compound of the present invention on the activity of recombinant human DExH-box helicase 9 (hDHX9, ATPase) under in vitro conditions. This method uses Promega's ADP-Glo TM Kinase Assay Kit (Cat. No. V9102). Detailed experimental procedures can be found in the kit instructions.

[1278] The experimental process is briefly described as follows: the test compound was first dissolved in DMSO to prepare a stock solution, and then the reaction buffer (40mM HEPES, pH7.5, 20mM MgCl2, 0.01% Tween-20, 0.01% BSA, 1mM DTT, 0.004U / ml RNaseOUT TMRecombinant Ribonuclease Inhibitor) was used for gradient dilution, and the final concentration of the test compound in the reaction system ranged from 10,000 nM to 0.04 nM; hDHX9 protein was prepared using reaction buffer (commissioned to Nanjing GenScript Biotechnology Co., Ltd. for expression and purification), and the double-stranded RNA substrate of DHX9 was commissioned to Suzhou Jinweizhi Biotechnology Co., Ltd. for synthesis and annealing (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 recombinant human DHX9 protein (final concentration 6.3 nM) were added to the wells and incubated at room temperature for 15 minutes. Subsequently, the double-stranded RNA sequence solution (final concentration 18.8 nM) and ATP solution (final concentration 30 μM, from ADP-Glo) were added to the reaction solution. TM Kinase Assay kit component V915A) and incubate at room temperature for 45 minutes. Subsequently, 5 μL ADP-Glo ​​Reagent was added to the reaction system and incubated at room temperature for 50 minutes. Thereafter, 10 μL Kinase Detection Reagent was added to the reaction system and incubated at room temperature for 30 minutes. After the incubation, the chemiluminescence intensity value of each well was measured in the luminescence mode of the microplate reader. The percentage inhibition rate of the compound at each concentration was calculated by comparing the luminescence intensity ratio with the control group (0.1% DMSO), and the nonlinear regression analysis of the compound concentration-inhibition rate was performed using GraphPad Prism 9 software to obtain the IC value of the compound. 50 Values ​​are shown in Table 3.

[1279] Table 3 IC values ​​of the compounds of the present invention for inhibiting hDHX9 enzyme (ATPase) activity 50 data

[1280] Conclusion: The IC values ​​of the compounds of the present invention for inhibiting hDHX9 enzyme (ATPase) activity are 50 <100nM, with good inhibitory effect.

[1281] Test Example 4: Pharmacokinetics of the Compounds of the Invention in Mice

[1282] 1. Experimental Purpose

[1283] ICR mice were used as test animals. After oral administration of the control compound ATX-968 and the compound of the present invention, the drug concentrations in plasma at different time points were determined by LC / MS / MS to study the pharmacokinetic characteristics of the compound of the present invention in mice.

[1284] 2. Experimental plan

[1285] 2.1 Experimental drugs and animals;

[1286] Reference compounds ATX-968, compounds 68 and 73.

[1287] ICR mice, male, 32.8-38.0 g, were purchased from Weitonglihua Laboratory Animal Technology Co., Ltd.

[1288] 2.2 Drug preparation

[1289] Weigh an appropriate amount of the test compound and sequentially add appropriate amounts of DMA (N,N-dimethylacetamide), 30% Solutol HS15 (30% polyethylene glycol-15 hydroxystearate), and saline (normal saline). Vortex mix thoroughly by ultrasonication to prepare a 1 mg / mL dosing formulation. DMA:30% Solutol HS15:Saline = 10:10:80 (v / v / v).

[1290] 2.3 Administration

[1291] ICR mice in each test compound group (9 mice in each group) were fasted overnight and then orally administered (PO, compound dosage of 10 mg / kg, administration volume of 10 mL / kg), and were fed 4 hours after administration.

[1292] 3. Operation

[1293] Approximately 0.1 mL of blood was collected intraorbitally before dosing and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours after dosing. Whole blood samples were placed in tubes containing EDTA-K2 for anticoagulant treatment. After collection, the blood samples were placed on ice and centrifuged at 1500 g for 10 minutes to separate the plasma. The collected plasma was stored at –40 to –20°C until analysis.

[1294] LC-MS / MS was used to determine the content of the test compound in mouse plasma after oral administration.

[1295] 4. Pharmacokinetic parameter results

[1296] The pharmacokinetic parameters of the test compounds are shown in Table 4 below.

[1297] Table 4 Pharmacokinetic parameters of the test compounds in mice

[1298] Test Example 5: Efficacy test of the compound of the present invention in mice

[1299] 1. Purpose of the experiment

[1300] The anti-tumor effects of the control compound ATX-968 and the present compounds 68 and 73 were evaluated in the LS411N human cecal cancer subcutaneous xenograft BALB / c nude mouse animal model.

[1301] 2. Experimental Animals

[1302] BALB / c nude mice, female, 6–7 weeks old, were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd. Animal production license number: SCXK(Su)2023-0009, animal qualification certificate number: No. B202409230909.

[1303] 3. Preparation of test substances

[1304] The vehicle control group was given DMA:Solutol HS15:20% HP-β-CD=10:10:80 (v / v / v).

[1305] ATX-968: Weigh an appropriate amount of ATX-968 and sequentially add appropriate amounts of DMA, Solutol HS15, and 20% HP-β-CD. Mix thoroughly by ultrasonic vortexing to prepare a 20 mg / mL dosing formulation. DMA, Solutol HS15, and 20% HP-β-CD are in a ratio of 10:10:80 (v:v:v).

[1306] Compound 68: An appropriate amount of compound 68 was weighed and added sequentially with appropriate amounts of DMA, Solutol HS15, and 20% HP-β-CD. The mixture was vortexed and ultrasonically mixed to prepare a 10 mg / mL dosing formulation. The ratio of DMA, Solutol HS15, and 20% HP-β-CD was 10:10:80 (v:v:v).

[1307] Compound 73: An appropriate amount of compound 73 was weighed and added sequentially with appropriate amounts of DMA, Solutol HS15, and 20% HP-β-CD. The mixture was vortexed and ultrasonically mixed to prepare a 10 mg / mL dosing formulation. The ratio of DMA, Solutol HS15, and 20% HP-β-CD was 10:10:80 (v:v:v).

[1308] 4. LS411N Cell Culture

[1309] LS411N human cecal cancer cells were cultured in RPMI Medium 1640 supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin-amphotericin B. Exponentially growing LS411N cells were harvested and resuspended in a 1:1 mixture of PBS and Matrigel to a suitable concentration for subcutaneous tumor inoculation on the right side of the back of BALB / c nude mice.

[1310] 5. Animal Inoculation and Grouping

[1311] Female BALB / c nude mice were subcutaneously inoculated with approximately 4.0 × 10 6 LS411N cells. When the average tumor volume reaches approximately 100-250mm 3 The mice were randomly divided into groups according to tumor size, with 6 mice in each group.

[1312] 6. Animal Medication and Observation

[1313] Each group of animals was given the test substance orally (po) twice a day at a fixed time according to the animal body weight. The first dose began on the day of grouping and continued for 21 consecutive days. The animal body weight was recorded every day.

[1314] Group 1 (G1), vehicle control group;

[1315] Group 2 (G2) received oral administration of ATX-968 at a dose of 200 mg / kg twice a day (BID);

[1316] Group 3 (G3) was orally administered with compound 68 at a dose of 100 mg / kg twice a day (BID);

[1317] Group 3 (G4) was orally administered with compound 73 at a dose of 100 mg / kg twice a day (BID);

[1318] The formation of tumors at the inoculation site of each group of animals was observed, and the tumor volume was measured twice a week. The tumor volume (TV), relative tumor volume (RTV), relative tumor proliferation rate (T / C), and relative tumor inhibition rate (TGI) were calculated as follows:

[1319] (1)TV(tumor volume)=1 / 2×a×b 2 , where a and b represent the length and width of the tumor, respectively;

[1320] (2)RTV(relative tumor volume)=V t / V0, where V0 is the tumor volume measured during grouping, V t is the tumor volume at each measurement;

[1321] (3) T / C (%) = T RTV / C RTV × 100%, where T RTV is the RTV of the treatment group, C RTV is the RTV of the vehicle control group;

[1322] (4) TGI% = (1-T / C) × 100%; where T and C are the relative tumor volumes of the treatment group and the vehicle control group at a specific time point, respectively.

[1323] 7. Results

[1324] As shown in Table 5.

[1325] Table 5 Pharmacodynamic analysis of the test compounds in each group in the LS411N human cecal cancer subcutaneous transplant tumor model

[1326] Note: Data are expressed as “mean ± standard error”;

[1327] Conclusion: Under the conditions set in this experiment, in the LS411N human cecal cancer subcutaneous transplant mouse animal model, compared with the solvent and ATX-968 at a dose of 200 mg / kg, compounds 68 and 73 of the present invention showed more significant tumor growth inhibition effects at a lower dose (100 mg / kg).

Claims

1. A compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts: in: Ring A is selected from a tricyclic heteroaryl or a tricyclic fused ring; X is selected from halogen; R 1 Selected from C 1-6 Alkyl or 3-5 membered cycloalkyl; wherein the alkyl or cycloalkyl is optionally further substituted with one or more selected from halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent; R 2 Each is independently selected from hydrogen, cyano, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, SF5, -O(CH2) t R A 、-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 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally further substituted by one or more deuterium atoms, halogen, nitro, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -OR A 、-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 a substituent; Or, two R 2 to form a -C(O) or cyclopropyl group with the same carbon atom to which it is attached; R 3 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more hydroxyl groups, halogen groups, nitro groups, cyano groups, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, =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 a substituent; R A is selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from 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 substituted by a substituent; R 4 and R 5 Each is independently selected from hydrogen atom, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, 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 a substituent; Or, R 4 and R 5 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, 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 a substituent; R 6 、R 7 and R 8 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group; t is selected from 0 or 1; n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; and r is each independently 0, 1 or 2.

2. The compound according to claim 1, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from a 12- to 18-membered tricyclic condensed ring or a 12- to 18-membered tricyclic heteroaryl group, and is preferably a 12- to 16-membered tricyclic condensed ring or a 12- to 14-membered tricyclic heteroaryl group.

3. The compound according to claim 1 or 2, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R 2 Selected from hydrogen atom, halogen, cyano, C 1-6 Alkyl, amino, SF5, -O(CH2) t R A 、-C(O)OR 3 、-NHC(O)R 3 or -C(O)R 3 , wherein the C 1-6 The alkyl group is optionally further substituted with one or more groups selected from deuterium atoms, halogen, cyano, C 1-6 Alkyl, -C(O)OR 6 OR A substituted by a substituent; Or, two R 2 to form a -C(O) or cyclopropyl group with the same carbon atom to which it is attached; R A Selected from hydrogen atoms, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group may be further substituted by one or more selected from hydroxy, halogen, cyano, -NR 7 R 8 、C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 substituted by an alkoxy substituent; R 3 Selected from hydrogen atoms, C 3-8 Cycloalkyl, C 6-10 Aryl or C 1-6 Alkyl, wherein the C 3-8 Cycloalkyl, C 6-10 Aryl or C 1-6 The alkyl group is optionally further substituted with one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent; R 6 Selected from hydrogen atoms or C 1-6 alkyl; R 7 、R 8 Each independently selected from a hydrogen atom or C 1-6 alkyl; t is selected from 0 or 1.

4. The compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, hydroxyl, cyano, C 1-6 Alkoxy, SF5, C 1-6 Haloalkyl or C 1-6 haloalkoxy; Or, two R 2 It forms a -C(O) with the same carbon atom to which it is attached.

5. The compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, which is a compound according to general formula (IIA), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof: in: is a 5-membered heteroaryl group; X1 and X2 are each independently selected from CH, S or N, and X1 and X2 are not S at the same time; X3 is selected from C or N; provided that when X3 is C, X1 and X2 are not CH at the same time; Ring B is selected from a 5- to 8-membered heterocyclic group, a 6- to 10-membered aryl group, or a 5- to 6-membered heteroaryl group, wherein the heterocyclic group contains one or two double bonds; Select single or double bonds as needed so that each atom thereof assumes a normal valence state; Y and Z are each independently selected from CR a 、CHR a , O, N, or NR b ; R 2a Selected from hydrogen atoms, C 3-8 Cycloalkyl, C 1-6 Alkyl or -C(O)R 3 , wherein the C 1-6 The alkyl group is optionally further substituted with one or more groups selected from deuterium atoms, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 6 substituted by a substituent; Or, two R 2a to form a -C(O) or cyclopropyl group with the same carbon atom to which it is attached; R 2b Each independently selected from a hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 3 ; wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more substituents selected from hydroxy, halogen or cyano; R a and R b Each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, amino, -NHC(O)R 3 or -O(CH2) t R A , wherein the C 1-6 The alkyl group is optionally further substituted with one or more radicals selected from halogen, cyano, C 1-6 Alkyl or -OR A substituted by a substituent; R A Each independently selected from a hydrogen atom, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group may be further substituted by one or more selected from hydroxy, halogen, cyano, -NR 7 R 8 、C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 substituted by an alkoxy substituent; R 3 Selected from hydrogen atoms, C 6-10 Aryl, C 3-8 Cycloalkyl or C 1-6 Alkyl, wherein the C 6-10 Aryl, C 3-8 Cycloalkyl or C 1-6 The alkyl group is optionally further substituted with one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent; R 6 Selected from hydrogen atoms or C 1-6 alkyl; R 7 、R 8 Each independently selected from a hydrogen atom or C 1-6 alkyl; t is selected from 0 or 1; p is each independently selected from 0, 1, 2, 3, 4 or 5; q is each independently selected from 0, 1 or 2; R 1 and X is as defined in claim 1.

6. The compound according to claim 5, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, which is a compound or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof represented by general formula (IIIA) or (IIIB): in: Ring B is selected from a 5- to 8-membered heterocyclic group, wherein the heterocyclic group contains one or two double bonds; Y and Z are each independently selected from CR a or N; R 2a Selected from hydrogen atoms, C 1-6 Alkyl or -C(O)R 3 , wherein the C 1-6 The alkyl group is optionally further substituted with one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 6 substituted by a substituent; Or, two R 2a to form a -C(O) or cyclopropyl group with the same carbon atom to which it is attached; R 2b Each independently selected from a hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 3 ; R a Each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, amino, -NHC(O)R 3 or -O(CH2) t R A , wherein the C 1-6 The alkyl group is optionally further substituted with one or more radicals selected from halogen, cyano, C 1-6 Alkyl or -OR A substituted by a substituent; R A Each independently selected from a hydrogen atom, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group may be further substituted by one or more selected from hydroxy, halogen, cyano, -NR 7 R 8 、C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 substituted by an alkoxy substituent; R 3 Selected from hydrogen atoms, C 6-10 Aryl or C 1-6 Alkyl, wherein the C 6-10 Aryl or C 1-6 The alkyl group is optionally further substituted with one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent; R 6 Selected from hydrogen atoms or C 1-6 alkyl; R 7 、R 8 Each independently selected from a hydrogen atom or C 1-6 alkyl; t is selected from 0 or 1; p is each independently selected from 0, 1, 2, 3, 4 or 5; R 1 and X is as defined in claim 5.

7. The compound according to claim 5, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, which is a compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt according to general formula (IIIC): in: Y and Z are each independently selected from CHR a 、O、NR b ; R 2a Selected from hydrogen atoms or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent; R 2b Each independently selected from a hydrogen atom or C 1-6 alkyl; R a and R b Each independently selected from hydrogen, halogen, hydroxyl, cyano or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent; p is each independently selected from 0, 1 or 2; q is each independently selected from 0, 1 or 2; R 1 and X is as defined in claim 5.

8. The compound according to any one of claims 1 to 4, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, which is a compound according to general formula (II), or its stereoisomer, tautomer, or pharmaceutically acceptable salt: in: is a 5-membered heteroaryl group; X1 and X2 are each independently selected from CH, S or N, and X1 and X2 are not S at the same time; X3 is selected from C or N; provided that when X3 is C, X1 and X2 are not CH at the same time; Ring B is selected from a 5- to 8-membered heterocyclic group, a 6- to 10-membered aryl group, or a 5- to 6-membered heteroaryl group, wherein the heterocyclic group contains one or two double bonds; is a 6-membered heteroaryl or a 6-membered heterocyclic group; Select single or double bonds as needed so that each atom thereof assumes a normal valence state; Y and Z are each independently selected from CR a , O or NR b ; R a Selected from hydrogen atoms, halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl or alkoxy is optionally further substituted by one or more halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent; R b Selected from hydrogen atoms or C 1-6 Alkyl, wherein the alkyl is optionally further substituted by one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent; m is selected from 0, 1, 2 or 3; R 1 、R 2 and X is as defined in claim 1.

9. The compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, which is a compound according to general formula (III), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof: in: Ring B is selected from a 5- to 8-membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein the heterocyclic group contains one or two double bonds; Y and Z are each independently selected from CR a or N; R a Selected from hydrogen atoms, halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted by one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent; p is selected from 0, 1, 2 or 3; R 1 、R 2 and X is as defined in claim 1.

10. The compound according to any one of claims 1 to 4, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: Selected from the following groups: R 2 and n are as defined in claim 1.

11. The compound according to claim 10, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: Selected from the following groups:

12. The compound according to claim 5, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: Selected from the following groups: R 2a Selected from hydrogen atoms, C 1-6 Alkyl, C 3-8 Cycloalkyl or -C(O)R 3 , wherein the C 1-6 The alkyl group is optionally further substituted with one or more groups selected from deuterium atoms, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 6 substituted by a substituent; Or, two R 2a to form a -C(O) or cyclopropyl group with the same carbon atom to which it is attached; R 2b Each independently selected from a hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 3 ; R a Each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, amino, -NHC(O)R 3 or -O(CH2) t R A , wherein the C 1-6 The alkyl group is optionally further substituted with one or more radicals selected from halogen, cyano, C 1-6 Alkyl or -OR A substituted by a substituent; R b Selected from hydrogen atoms or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more halogens; R A Selected from hydrogen atoms, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group may be further substituted by one or more selected from hydroxy, halogen, cyano, -NR 7 R 8 、C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 substituted by an alkoxy substituent; R 3 Selected from hydrogen atoms, C 6-10 Aryl, C 3-8 Cycloalkyl or C 1-6 Alkyl, wherein the C 6-10 Aryl, C 3-8 Cycloalkyl or C 1-6 The alkyl group is optionally further substituted with one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent; R 6 Selected from hydrogen atoms or C 1-6 alkyl; R 7 、R 8 Each independently selected from a hydrogen atom or C 1-6 alkyl; t is selected from 0 or 1; p is each independently selected from 0, 1, 2, 3, 4 or 5; p' is each independently selected from 0, 1, 2, 3 or 4; q is each independently selected from 0, 1 or 2.

13. The compound according to claim 12, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R 2a Selected from hydrogen atom, methyl, ethyl, isopropyl, Or, two R 2a The same carbon atom to which it is attached forms a -C(O) or cyclopropyl group.

14. The compound according to claim 12, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R a Selected from hydrogen atom, hydroxyl, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, amino, 15. The compound according to claim 12, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: q is 0.

16. The compound according to any one of claims 12 to 15, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: Selected from the following groups:

17. The compound according to any one of claims 1 to 16, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: X is selected from Cl or Br, preferably Cl.

18. The compound according to any one of claims 1 to 17, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from methyl or ethyl.

19. The compound according to any one of claims 1 to 18, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: The compound is:

20. A pharmaceutical composition comprising an effective dose of the compound according to any one of claims 1 to 19, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or a combination thereof.

21. Use of the compound according to any one of claims 1 to 19, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 20, in the preparation of a DHX9 inhibitor.

22. Use of a compound according to any one of claims 1 to 19, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, 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 more preferably cancer; further preferably, the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic system cancer, breast cancer, brain cancer, skin cancer, lung cancer, blood cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft tissue cancer, kidney cancer, and liver cancer, and further preferably colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic system cancer, and gastric cancer.

23. The use according to claim 22, wherein the cancer is microsatellite instability cancer, preferably microsatellite instability-high cancer, and further preferably microsatellite instability-high colorectal cancer.

24. Use of a compound according to any one of claims 1 to 19, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, in the preparation of a medicament for treating cancer, viral infection, or autoimmune disease, preferably, wherein the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic system cancer, breast cancer, brain cancer, skin cancer, lung cancer, blood cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft tissue cancer, kidney cancer, and liver cancer, and further preferably, the cancer is colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic system cancer, and gastric cancer.

25. The use according to claim 24, wherein the cancer is microsatellite instability cancer, preferably microsatellite instability-high cancer, and further preferably microsatellite instability-high colorectal cancer.