Aromatic amide derivatives, methods for their preparation, and uses

Abstract

The present invention relates to aromatic amide derivatives, methods for preparing the same, and the use of pharmaceutical compositions containing derivatives in the medical field. Specifically, the present invention relates to Formula I, i.e. [Chemical Formula I] The present invention relates to an aromatic amide derivative as shown in the table, a method for preparing the same, a pharmaceutically acceptable salt thereof, and the same therapeutic agent, in particular as a DHX9 inhibitor, wherein the definitions of each substituent of Formula I are the same as those defined in the present specification.

Description

Technology Field

[0001] The present invention relates to an aromatic amide derivative, a method for preparing the same, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, particularly as a DHX9 inhibitor. Background Technology

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

[0003] DHX9 is a multidomain and multifunctional protein that can meet energy requirements by utilizing all four types of NTPs due to defects in base selectivity, and plays an important role in biological development, DNA replication, transcription, translation, repair, cleavage and editing, RNA processing, transport, remodeling, and maintaining genomic stability.

[0004] DHX9 has been proven to be a key regulator in many types of cancer due to its transcriptional regulatory and genomic stability maintenance functions, and is involved in gene regulation associated with sustained proliferative signaling, evasion of growth inhibitors, evasion of apoptosis, angiogenesis, and metastasis (all of which correspond to hallmarks of cancer). In particular, microsatellite instability cancers, such as microsatellite instability (MSI) colorectal cancer and MMR tumors, show a strong dependence on DHX9.

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

[0006] To date, no new DHX9-targeting inhibitor drugs have received market approval, and there is no information available regarding clinical compounds. Since the DHX9 target, a novel anti-tumor target, holds immense research potential, the development of DHX9-targeting inhibitors is urgent. means of solving the problem

[0007] In order to solve the above technical problem, the present invention uses the formula I, i.e.

[0008] [Chemical Formula I]

[0009]

[0010] Provides an aromatic amide derivative as shown in, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0011] Ring A is selected from tricyclic heteroaryl or tricyclic fusion rings;

[0012] X is selected from halogens;

[0013] R 1 C 1-6 Selected from alkyl or ternary to pentary cycloalkyl, wherein the alkyl or cycloalkyl is a halogen, hydroxyl, cyano, C 1-6 alkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from the alkoxy;

[0014] Each R 2 is independently a hydrogen atom, cyano, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclil, 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)NR4 R 5 , -S(O)2NR 4 R 5 , -CH2NHC(O)OR 3 , -CH2NR 4 R 5 or -S(O) r R 3 Selected from, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclil, aryl, or heteroaryl is a deuterium atom, halogen, nitro, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclil, 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 Optionally additionally substituted with one or more substituents selected from; or

[0015] 2 Rs 2 It forms -C(O) or cyclopropyl with the same carbon to which these groups are attached;

[0016] Each R 3 is independently selected from hydrogen atoms, alkyl, cycloalkyl, heterocyclil, aryl, or heteroaryl, wherein alkyl, cycloalkyl, heterocyclil, aryl, or heteroaryl is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclil, 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 R8 or -NR 7 C(O)R 8 Optionally additionally substituted with one or more substituents selected from;

[0017] R A is selected from hydrogen atoms, alkyl, cycloalkyl, heterocyclil, aryl, or heteroaryl, wherein alkyl, cycloalkyl, heterocyclil, aryl, or heteroaryl is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclil, 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 Optionally additionally substituted with one or more substituents selected from;

[0018] R 4 and R 5 Each is independently selected from hydrogen atom, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclil, aryl, or heteroaryl, wherein alkyl, alkoxy, cycloalkyl, heterocyclil, aryl, or heteroaryl is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclil, 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 Optionally additionally substituted with one or more substituents selected from; or

[0019] R 4 and R 5 These groups form a 4- to 8-membered heterocyclile together with the atoms to which they are attached, wherein the 4- to 8-membered heterocyclile has one or more N, O, or S(O) r Containing, the 4- to 8-membered heterocyclile is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclile, 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 Optionally additionally substituted with one or more substituents selected from;

[0020] R 6 , R 7 and R 8 Each is independently selected from a hydrogen atom, alkyl, amino, cycloalkyl, heterocyclil, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclil, aryl, or heteroaryl is optionally additionally substituted with one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclil, aryl, heteroaryl, carboxyl, or carboxylate groups;

[0021] t is selected from 0 or 1;

[0022] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0023] Each r is independently 0, 1, or 2.

[0024] A preferred solution of the present invention provides a compound as shown in Formula I, wherein ring A is selected from a 12- to 18-membered tricyclic fusion ring or a 12- to 18-membered tricyclic heteroaryl, preferably a 12- to 16-membered tricyclic fusion ring or a 12- to 14-membered tricyclic heteroaryl, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0025] A preferred solution of the present invention is R 2 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 Selected from, but C 1-6 Alkyl groups consist of deuterium atoms, halogens, cyanos, and C 1-6 Alkyl, -C(O)OR 6 or -OR A Optionally additionally substituted with one or more substituents selected from; or

[0026] 2 Rs 2 These groups form -C(O) or cyclopropyl together with the same carbon atom to which they are attached;

[0027] R A is a hydrogen atom, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Selected from aryl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclil, wherein C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 6-membered heteroaryls, or 5- to 6-membered heterocyclils are hydroxyl, halogen, cyano, -NR 7 R 8 , C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6Optionally additionally substituted with one or more substituents selected from the alkoxy;

[0028] R 3 Silver is a hydrogen atom, C 3-8 Cycloalkyl, C 6-10 Aryl or C 1-6 Selected from alkyl, wherein C 3-8 Cycloalkyl, C 6-10 Aryl or C 1-6 Alkyl groups are halogens, hydroxyl groups, cyano groups, C 1-6 alkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from the alkoxy;

[0029] R 6 It is a hydrogen atom or C 1-6 Selected from alkyls;

[0030] R 7 and R 8 Each independently consists of a hydrogen atom or C 1-6 Selected from alkyls;

[0031] t provides a compound as shown in Formula I, selected from 0 or 1, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0032] A preferred solution of the present invention is R 2 is a hydrogen atom, halogen, C 1-6 Alkyl, hydroxyl, cyano, C 1-6 Alkoxy, SF5, C 1-6 Haloalkyl or C 1-6 Selected from haloalkoxy; or

[0033] 2 Rs 2 It provides a compound as shown in Formula I, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, in which these groups form a -C(O) group with the same carbon atom to which they are attached.

[0034] A preferred solution of the present invention is a compound as shown in Formula I, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, of Formula IIA, i.e.

[0035] [Chemical Formula IIA]

[0036]

[0037] Provides a compound as shown in, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0038] is a 5-membered heteroaryl;

[0039] X1 and X2 are each independently selected from CH, S, or N, and X1 and X2 are not simultaneously S;

[0040] X3 is selected from C or N, wherein when X3 is C, X1 and X2 are not simultaneously CH;

[0041] Ring B is selected from 5- to 8-membered heterocyclils, 6- to 10-membered aryls, or 5- to 6-membered heteroaryls, wherein the heterocyclil contains one or two double bonds;

[0042] It is selected from single or double bonds as needed, and each of its atoms exists in a normal valence state;

[0043] Y and Z are each independently CR a , CHR a , O, N, or NR b Selected from;

[0044] R 2a is a hydrogen atom, C 3-8 Cycloalkyl, C 1-6 Alkyl or -C(O)R 3 Selected from, but C 1-6 Alkyl atoms are deuterium atoms, halogens, hydroxyl, cyano, C 1-6 Alkyl, C 1-6Alkoxy or -C(O)OR 6 Optionally additionally substituted with one or more substituents selected from; or

[0045] 2 Rs 2a It forms -C(O) or cyclopropyl with the same carbon atom to which these groups are attached;

[0046] Each R 2b is independently a hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 3 Selected from, but C 1-6 alkyl or C 1-6 The alkoxy is optionally additionally substituted with one or more substituents selected from hydroxyl, halogen, or cyano;

[0047] R a and R b Each independently consists of a hydrogen atom, halogen, cyano, and C 1-6 Alkyl, amino, -NHC(O)R 3 or -O(CH2) t R A Selected from, but C 1-6 Alkyl groups are halogens, cyanos, C 1-6 alkyl or -OR A Optionally additionally substituted with one or more substituents selected from;

[0048] Each R A is independently a hydrogen atom, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Selected from aryl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclil, wherein C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 6-membered heteroaryls, or 5- to 6-membered heterocyclils are hydroxyl, halogen, cyano, -NR 7 R 8 , C 1-6 Alkyl, C 1-6 Haloalkyl or C1-6 Optionally additionally substituted with one or more substituents selected from the alkoxy;

[0049] R 3 is a hydrogen atom, C 6-10 Aril, C 3-8 Cycloalkyl or C 1-6 Selected from alkyl, wherein C 6-10 Aril, C 3-8 Cycloalkyl or C 1-6 Alkyl groups are halogens, hydroxyl groups, cyano groups, C 1-6 alkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from the alkoxy;

[0050] R 6 It is a hydrogen atom or C 1-6 Selected from alkyls;

[0051] R 7 and R 8 Each independently consists of a hydrogen atom or C 1-6 Selected from alkyls;

[0052] t is selected from 0 or 1;

[0053] Each p is independently selected from 0, 1, 2, 3, 4, or 5;

[0054] Each q is independently selected from 0, 1, or 2;

[0055] R 1 and X are as defined in Chemical Formula I.

[0056] A preferred solution of the present invention is a compound as shown in formula IIA, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein formula IIIA or IIIB, i.e.

[0057] [Chemical Formula IIIA]

[0058]

[0059] [Chemical Formula IIIB]

[0060]

[0061] Provides a compound as shown in, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0062] Ring B is selected from 5- to 8-membered heterocyclils, wherein the heterocyclil contains one or two double bonds;

[0063] Y and Z are each independently CR a or selected from N;

[0064] R 2a is a hydrogen atom, C 1-6 Alkyl or -C(O)R 3 Selected from, but C 1-6 Alkyl groups are halogens, hydroxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 6 Optionally additionally substituted with one or more substituents selected from; or

[0065] 2 Rs 2a It forms -C(O) or cyclopropyl with the same carbon atom to which these groups are attached;

[0066] Each R 2b is independently a hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 3 Selected from;

[0067] Each R a is independently a hydrogen atom, halogen, cyano, C 1-6 Alkyl, amino, -NHC(O)R 3 or -O(CH2) t R A Selected from, but C 1-6 Alkyl groups are halogens, cyanos, C 1-6 alkyl or -OR A Optionally additionally substituted with one or more substituents selected from;

[0068] Each RA is independently a hydrogen atom, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Selected from aryl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclil, wherein C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 6-membered heteroaryls, or 5- to 6-membered heterocyclils are hydroxyl, halogen, cyano, -NR 7 R 8 , C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from the alkoxy;

[0069] R 3 is a hydrogen atom, C 6-10 Aryl or C 1-6 Selected from alkyl, wherein C 6-10 Aryl or C 1-6 Alkyl groups are halogens, hydroxyl groups, cyano groups, C 1-6 alkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from the alkoxy;

[0070] R 6 It is a hydrogen atom or C 1-6 Selected from alkyls;

[0071] R 7 and R 8 Each independently consists of a hydrogen atom or C 1-6 Selected from alkyls;

[0072] t is selected from 0 or 1;

[0073] Each p is independently selected from 0, 1, 2, 3, 4, or 5;

[0074] R 1 and X are as defined in the chemical formula IIA.

[0075] A preferred solution of the present invention is a compound as shown in formula IIA, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, of formula IIIC, i.e.

[0076] [Chemical Formula IIIC]

[0077]

[0078] Provides a compound as shown in, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0079] Y and Z are independently CHR a , O or NR b Selected from;

[0080] R 2a is a hydrogen atom or C 1-6 Selected from alkyl, wherein C 1-6 Alkyl groups are halogens, hydroxyl groups, cyano groups, C 1-6 alkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from the alkoxy;

[0081] Each R 2b is independently a hydrogen atom or C 1-6 Selected from alkyls;

[0082] R a and R b Each is independently a hydrogen atom, halogen, hydroxyl, cyano, or C 1-6 Selected from alkyl, wherein C 1-6 Alkyl groups are halogens, hydroxyl groups, cyano groups, C 1-6 alkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from the alkoxy;

[0083] Each p is independently selected from 0, 1, or 2;

[0084] Each q is independently selected from 0, 1, or 2;

[0085] R1 and X are as defined in the chemical formula IIA.

[0086] A preferred solution of the present invention is a compound as shown in Formula I, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, of Formula II, i.e.

[0087] [Chemical Formula II]

[0088]

[0089] Provides a compound as shown in, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0090] is a 5-membered heteroaryl;

[0091] X1 and X2 are each independently selected from CH, S, or N, and X1 and X2 are not simultaneously S;

[0092] X3 is selected from C or N, wherein when X3 is C, X1 and X2 are not simultaneously CH;

[0093] Ring B is selected from 5- to 8-membered heterocyclils, 6- to 10-membered aryls, or 5- to 6-membered heteroaryls, wherein the heterocyclil contains one or two double bonds;

[0094] is a 6-membered heteroaryl or a 6-membered heterocyclil;

[0095] It is selected from single or double bonds as needed, and each of its atoms exists in a normal valence state;

[0096] Y and Z are each independently CR a , O or NR b Selected from;

[0097] R a is a hydrogen atom, halogen, hydroxyl, cyano, C 1-6 alkyl or C1-6 Selected from alkoxy, wherein the alkyl or alkoxy group is a halogen, hydroxyl, cyano, C 1-6 alkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from the alkoxy;

[0098] R b is a hydrogen atom or C 1-6 Selected from alkyl, wherein the alkyl is a halogen, hydroxyl, cyano, C 1-6 alkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from the alkoxy;

[0099] m is selected from 0, 1, 2, or 3;

[0100] R 1 , R 2 and X are as defined in Chemical Formula I.

[0101] A preferred solution of the present invention is a compound as shown in Formula I, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, of Formula III, i.e.

[0102] [Chemical Formula III]

[0103]

[0104] Provides a compound as shown in, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0105] Ring B is selected from 5- to 8-membered heterocyclles or 5- to 6-membered heteroaryls, wherein the heterocyclles contain one or two double bonds;

[0106] Y and Z are each independently CR a or selected from N;

[0107] R a is a hydrogen atom, halogen, hydroxyl, cyano, C 1-6 alkyl or C 1-6 Selected from alkoxy, but C1-6 alkyl or C 1-6 Alkoxy is a halogen, hydroxyl, cyano, C 1-6 alkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from the alkoxy;

[0108] p is selected from 0, 1, 2, or 3;

[0109] R 1 , R 2 and X are as defined in Chemical Formula I.

[0110] A preferred solution of the present invention provides a compound as shown in Formula I, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein is the following elements, that is

[0111]

[0112] Selected from;

[0113] R 2 and n are as defined in Chemical Formula I.

[0114] A preferred solution of the present invention provides a compound as shown in Formula I, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein is the following elements, that is

[0115]

[0116]

[0117] Selected from.

[0118] A preferred solution of the present invention provides a compound as shown in Formula IIA, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein is the following elements, that is

[0119]

[0120]

[0121] Selected from;

[0122] R 2a is a hydrogen atom, C 1-6 Alkyl, C 3-8 Cycloalkyl or -C(O)R 3 Selected from, but C 1-6 Alkyl atoms are deuterium atoms, halogens, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 6 Optionally additionally substituted with one or more substituents selected from; or

[0123] 2 Rs 2a It forms -C(O) or cyclopropyl with the same carbon atom to which these groups are attached;

[0124] Each R 2b is independently a hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 3 Selected from;

[0125] Each R a is independently a hydrogen atom, halogen, cyano, C 1-6 Alkyl, amino, -NHC(O)R 3 or -O(CH2) t R A Selected from, but C 1-6 Alkyl groups are halogens, cyanos, C 1-6 alkyl or -OR A Optionally additionally substituted with one or more substituents selected from;

[0126] R b is a hydrogen atom or C 1-6 Selected from alkyl, wherein C 1-6 The alkyl group is optionally additionally substituted with one or more halogens;

[0127] R A is a hydrogen atom, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10Selected from aryl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclil, wherein C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 6-membered heteroaryls, or 5- to 6-membered heterocyclils are hydroxyl, halogen, cyano, -NR 7 R 8 , C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from the alkoxy;

[0128] R 3 is a hydrogen atom, C 6-10 Aril, C 3-8 Cycloalkyl or C 1-6 Selected from alkyl, wherein C 6-10 Aril, C 3-8 Cycloalkyl or C 1-6 Alkyl groups are halogens, hydroxyl groups, cyano groups, C 1-6 alkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from the alkoxy;

[0129] R 6 It is a hydrogen atom or C 1-6 Selected from alkyls;

[0130] R 7 and R 8 Each independently consists of a hydrogen atom or C 1-6 Selected from alkyls;

[0131] t is selected from 0 or 1;

[0132] Each p is independently selected from 0, 1, 2, 3, 4, or 5;

[0133] Each p' is independently selected from 0, 1, 2, 3, or 4;

[0134] Each q is independently selected from 0, 1, or 2.

[0135] A preferred solution of the present invention provides a compound as shown in formula IIA, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 2a is a hydrogen atom, methyl, ethyl, isopropyl, Selected from; or

[0136] 2 Rs 2a These groups form -C(O) or cyclopropyl with the same carbon atom to which they are attached.

[0137] A preferred solution of the present invention provides a compound as shown in formula IIA, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R a is a hydrogen atom, hydroxyl, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, amino,

[0138]

[0139] Selected from.

[0140] A preferred solution of the present invention provides a compound as shown in formula IIA, in which q is 0, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0141] A preferred solution of the present invention is The following types, that is

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149] Provides a compound as shown in Formula IIA selected from, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0150] A preferred solution of the present invention provides a compound as shown in formulas I, II, IIA, III, IIIA, IIIB, or IIIC, wherein X is selected from Cl or Br, preferably Cl, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0151] A preferred solution of the present invention is R 1 This provides a compound as shown in Formula I, II, IIA, III, IIIA, IIIB, or IIIC selected from methyl or ethyl, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0152] In a preferred solution of the present invention, the compound as shown in the formula is selected from the following, or its stereoisomers, its tautomers, or pharmaceutically acceptable salts:

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183] Note: In the event of a difference between the diagrammed structure and the given name of the structure, the diagrammed structure will prevail.

[0184] The present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition contains an effective dose of a compound as shown in formulas I, II, IIA, III, IIIA, IIIB, or IIIC, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.

[0185] The present invention provides a use as a medicine (referred to as a use for treatment) of a compound as shown in Formulas I, II, IIA, III, IIIA, IIIB, or IIIC, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., a pharmaceutical composition described in the above technical solution).

[0186] The present invention provides a use in the preparation of a DHX9 inhibitor of a compound as shown in formulas I, II, IIA, III, IIIA, IIIB or IIIC, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., a pharmaceutical composition described in the above technical solution).

[0187] The present invention provides a use in manufacturing a medicine for treating a DHX9-mediated disease, wherein a compound as shown in formulas I, II, IIA, III, IIIA, IIIB or IIIC, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., a pharmaceutical composition described in the above technical solution), wherein the DHX9-mediated disease is preferably a cancer, a viral infection or an autoimmune disease, more preferably a cancer, and the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic cancer, breast cancer, brain cancer, skin cancer, lung cancer, blood cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft tissue cancer, kidney cancer and liver cancer, and preferably selected from colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic cancer and gastric cancer.

[0188] The present invention provides a use in preparing a medicine for treating a DHX9-mediated disease, wherein a compound as shown in formulas I, II, IIA, III, IIIA, IIIB or IIIC, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., a pharmaceutical composition described in the above technical solution), wherein the DHX9-mediated disease is preferably cancer, and the cancer is microsatellite instability (MSI) cancer, preferably microsatellite high instability (MSI-H) cancer, more preferably microsatellite high instability (MSI-H) colorectal cancer.

[0189] The present invention provides a use of a compound as shown in Formulas I, II, IIA, III, IIIA, IIIB, or IIIC, or a stereoisomer thereof, a tautomeric isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., a pharmaceutical composition described in the above technical solution) in the preparation of a medicine for treating cancer, viral infection, or autoimmune disease.

[0190] The present invention provides a use in manufacturing a medicine for treating colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic cancer, breast cancer, brain cancer, skin cancer, lung cancer, blood cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft tissue cancer, kidney cancer, and liver cancer, preferably a use in manufacturing a medicine for treating colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic cancer, and gastric cancer, of a compound as shown in formulas I, II, IIA, III, IIIA, IIIB, or IIIC, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., a pharmaceutical composition described in the above technical solution).

[0191] The present invention provides a use of a compound as shown in formulas I, II, IIA, III, IIIA, IIIB, or IIIC, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., a pharmaceutical composition described in the above technical solution) in manufacturing a medicine for treating microsatellite instability (MSI) cancer, preferably in manufacturing a medicine for treating microsatellite high instability (MSI-H) cancer, and more preferably in manufacturing a medicine for treating microsatellite high instability (MSI-H) colorectal cancer.

[0192] The present invention further provides a method for preventing and / or treating a DHX9-mediated disease, comprising the step of administering to a patient a therapeutically effective amount of a compound as shown in Formulas I, II, IIA, III, IIIA, IIIB, or IIIC, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., a pharmaceutical composition described in the above technical solution), wherein the DHX9-mediated disease is preferably a cancer, a viral infection, or an autoimmune disease, more preferably a cancer, and the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic cancer, breast cancer, brain cancer, skin cancer, lung cancer, blood cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft tissue cancer, kidney cancer, and liver cancer, preferably colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic cancer, and gastric cancer, or the cancer is a microsatellite instability (MSI) cancer. Preferably, microsatellite high instability (MSI-H) cancer, and more preferably, microsatellite high instability (MSI-H) colorectal cancer.

[0193] The present invention further provides a method for preventing and / or treating cancer, viral infection or autoimmune disease, comprising the step of administering to a patient a therapeutically effective amount of a compound as shown in Formulas I, II, IIA, III, IIIA, IIIB, or IIIC, or a stereoisomer thereof, a tautomeric isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., a pharmaceutical composition described in the above technical solution), wherein the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic cancer, breast cancer, brain cancer, skin cancer, lung cancer, blood cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft tissue cancer, kidney cancer, and liver cancer, preferably from colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic cancer, and gastric cancer, or the cancer is microsatellite instability (MSI) cancer, preferably microsatellite hyperstability (MSI-H) cancer, and more preferably It is microsatellite high instability (MSI-H) colorectal cancer. Specific details for implementing the invention

[0194] Unless otherwise specified, some terms used in this specification and the claims of the present invention are defined as follows.

[0195] "Alkyl" refers to a group that, when taken as one or part of a group, has a C1-C 20 It refers to an aliphatic hydrocarbon group containing a straight chain or having a branched chain. Preferably, the alkyl is C1-C 10 The alkyl group is alkyl, and more preferably, the alkyl is a 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, and 2,3-dimethylbutyl. The alkyl group may or may not be substituted.

[0196] "Alkenyl" refers to an alkyl group as defined above, composed of at least two carbon atoms and at least one carbon-carbon double bond, representative examples of which are vinyl, 1-propene, 2-propene, 1-, 2- or 3-butenyl and Includes, but is not limited to, the following. Preferably, the alkenyl is a C2-C4 alkenyl. The alkenyl may be optionally substituted or may not be substituted.

[0197] "Alkynyl" refers to an aliphatic hydrocarbon group containing one carbon-carbon triple bond and may be straight or branched. Preferably, the alkynyl is C2-C 10It is an alkynyl, more preferably the alkynyl is a C2-C6 alkynyl, and most preferably the alkynyl is a C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethinyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl. The alkynyl may or may not be substituted.

[0198] "Alkylene" refers to a group having two residues derived by removing two hydrogen atoms from the same carbon or two different carbon atoms of a parent alkane, preferably C1-C 10 Saturated C1-C that is an alkylene, more preferably a C1-C6 alkylene 20 It refers to a straight-chain or branched-chain aliphatic hydrocarbon group. Examples of alkylene groups include, but are not limited to, methylene, 1,1-ethylidene, 1,2-ethylidene, 1,1-propylidene, 1,2-propylidene, 1,3-propylidene, and 1,4-butylidene. The alkylene may or may not be substituted.

[0199] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more ring-forming atoms comprise a monocyclic ring, a polycyclic ring, a fused ring, a crosslinked ring, and a spirocyclic ring, preferably a carbon atom 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. The cycloalkyl group may or may not be substituted.

[0200] "Spiroalkyl" refers to a 5- to 18-membered polycyclic group having two or more cyclic structures, wherein one ring shares one carbon atom (referred to as a spiro atom), and the ring contains one or more double bonds, but none of the rings have a total conjugated π-electron aromatic system. Preferably, the spiroalkyl is 6 to 14 members, and more preferably, the spiroalkyl is 7 to 10 members. The spiroalkyl is classified into mono-, di-, or poly-spiroalkyl depending on the number of spiro-atoms shared between the rings, preferably mono- or di-spiroalkyl, and preferably 4 / 5, 4 / 6, 5 / 5, or 5 / 6. Non-limiting examples of "spiroalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, and spiro[2.4]heptyl.

[0201] "Fused cycloalkyl" refers to a 5- to 18-membered all-carbon polycyclic group in which two or more cyclic structures share a pair of carbon atoms, and one or more rings may contain one or more double bonds, but none of the rings have an all-conjugated π-electron aromatic system. Preferably, the fused cycloalkyl is 6- to 12-membered, and more preferably, the fused cycloalkyl is 7- to 10-membered. Depending on the number of constituent rings, the fused cycloalkyl may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably as a bicyclic or tricyclic fused cycloalkyl, and more preferably as a 5-membered / 5-membered or 5-membered / 6-membered bicycloalkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl-1-alkenyl, bicyclo[3.2.0]heptyl, decahydronaphthyl and tetrahydrophenyl.

[0202] "Cross-linked cycloalkyl" refers to a 5- to 18-membered all-carbon polycyclic group in which two or more cyclic structures share two carbon atoms that are not directly connected to each other, and one or more rings may contain one or more double bonds, but none of the rings have an all-conjugated π-electron aromatic system. Preferably, the cross-linked cycloalkyl is 6 to 12 members, and more preferably, the cross-linked cycloalkyl is 7 to 10 members. Preferably, the cross-linked cycloalkyl is 6 to 14 members, and more preferably, the cross-linked cycloalkyl is 7 to 10 members. Depending on the number of constituent rings, the cross-linked cycloalkyl can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic cross-linked cycloalkyls, preferably bicyclic, tricyclic, or tetracyclic cross-linked cycloalkyls, and more preferably bicyclic or tricyclic cross-linked cycloalkyls. Non-limiting examples of "crosslinked cycloalkyl" include, but are not limited to, (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl and (1r,5r)-bicyclo[3.3.2]decyl.

[0203] "Heterocyclil," "heterocycloalkyl," "heterocycle," or "heterocyclic" may be used interchangeably in this application, each of these terms referring to a non-aromatic heterocyclil, the ring may contain zero, one or more double bonds, one or more ring-forming atoms being nitrogen, oxygen, or S(O) rThe heteroatom (wherein r is selected from 0, 1, or 2) is selected from the non-aromatic heterocyclile, and the heterocyclile comprises a monocyclic ring, a polycyclic ring, a fused ring, a cross-linked ring, and a spirocyclic ring. Preferably, the heterocyclile is a 5- to 8-membered monocyclic ring or a 7- to 10-membered bicyclic or tricyclic ring that may contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heterocyclil" include mopolinil, oxetanil, thiomopolinil, tetrohydrofuranil, tetrahydropyranil, 1,1-dioxo-thiomopolinil, piperidinil, 2-oxopiperidinil, pyrrolidinil, 2-oxopyrrolidinil, piperazine-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinil, hexahydropyrimidine, Includes, but is not limited to, the following. Heterocycliles may or may not be substituted.

[0204] "Spiro-heterocyclile" refers to a 5- to 18-membered polycyclic group having two or more cyclic structures in which the rings share one atom with each other, and the rings may contain zero, one, or more double bonds, but no ring has a total conjugated π-electron aromatic system, and one or more ring atoms are nitrogen, oxygen, or S(O) rThe heteroatom (wherein r is selected from 0, 1, or 2) is selected, and the remaining ring atom is carbon. Preferably, the spiro-heterocyclile is 6 to 14 members, and more preferably, the spiro-heterocyclile is 7 to 10 members. The spiro-heterocyclile is classified into mono-, di-, or poly-spiro-heterocycliles depending on the number of atoms shared between the rings, preferably mono- and di-spiro-heterocycliles, and more preferably 4 / 4, 4 / 5, 3 / 5, 3 / 6, 4 / 6, 5 / 5, or 5 / 6 mono-spiro-heterocycliles. Non-limiting examples of "spiro-heterocyclil" include, but are not limited to, 1,7-dioxane[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5] and 5-oxaspiro[2.4]heptyl.

[0205] "Fused heterocyclile" refers to an all-carbon polycyclic group in which two or more cyclic structures share a pair of atoms, wherein one or more rings may contain zero, one, or more double bonds, but no ring has an entirely conjugated π-electron aromatic system, and one or more ring atoms are heteroatoms of nitrogen, oxygen, or S(O). r(wherein r is selected from 0, 1, or 2), and the remaining ring atoms are carbon. Preferably, the fused heterocyclile is 6 to 14 members, and more preferably, the fused heterocyclile is 7 to 10 members. Depending on the number of constituent rings, the fused heterocyclile may be classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocycliles, preferably bicyclic or tricyclic fused heterocycliles, and more preferably 5 / 5 or 5 / 6 bicyclic fused heterocycliles. Non-limiting examples of "fused heterocycliles" include, but are not limited to, octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl and octahydrobenzo[b][1,4]dioxine.

[0206] "Cross-linked heterocyclile" refers to 5- to 14-membered and 5- to 18-membered polycyclic groups in which two or more cyclic structures share two atoms that are not directly connected to each other, and one or more rings may contain zero, one or more double bonds, but no ring has a total conjugated π-electron aromatic system, and one or more ring atoms are heteroatoms of nitrogen, oxygen, or S(O) r(wherein r is selected from 0, 1, or 2), and the remaining ring atoms are carbon. Preferably, the cross-linked heterocyclile is 6 to 14 members, and more preferably, the cross-linked heterocyclile is 7 to 10 members. Depending on the number of constituent rings, the cross-linked heterocyclile may be classified into bicyclic, tricyclic, tetracyclic, or polycyclic cross-linked heterocycliles, preferably bicyclic, tricyclic, or tetracyclic cross-linked heterocycliles, and more preferably bicyclic or tricyclic cross-linked heterocycliles. Non-limiting examples of "cross-linked heterocycliles" include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

[0207] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be connected together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryls, such as aromatic groups, namely phenyl, naphthyl, and tetrahydronaphthyl. Preferably, the aryl is C6-C 10 It is an aryl, more preferably the aryl is phenyl and naphthyl, and most preferably the aryl is naphthyl. The aryl may or may not be substituted.

[0208] "Heteroaryl" means nitrogen, oxygen, or S(O) rIt refers to an aromatic 5-6 member monocyclic ring, 8-10 member bicyclic ring, or 12-14 member tricyclic ring that may contain 1 to 4 heteroatoms selected from (where r in the formula is selected from 0, 1, or 2). Examples of "heteroaryl" include furil, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazollyl, pyrrolyl, pyrazolyl, triazolyl, tetrazollyl, thiazolyl, isothiazollyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothiophenyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl, indazollyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, isothiazollyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, pyridyl, pyrimidinyl, Pyrazine-2(1H)-keto, pyrimidine-4(3H)-keto, pyridazine-3(2H)-keto, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridyl, 3H-imidazo[4,5-c]pyridyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furan[3,2-b]pyridyl, furan[2,3-c]pyridyl, thieno[2,3-c]pyridyl, benzofuryl, benzo[b]thienyl, 1H-pyrrolo[3,2-b]pyridyl, 2H-pyrrolo[3,4-c]pyridyl and Includes, but is not limited to, etc. Heteroaryls may or may not be substituted.

[0209] A "fusion ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms, and at least one ring has a completely conjugated π-electron aromatic system. Meanwhile, one or more rings may contain zero, one, or more double bonds, but at least one ring does not have a completely conjugated π-electron aromatic system, and zero, one, or more ring atoms are heteroatoms, i.e., nitrogen, oxygen, or S(O) r(wherein r is selected from 0, 1, or 2), and the remaining ring is carbon. The fusion ring preferably comprises a bicyclic or tricyclic fusion ring, wherein the bicyclic fusion ring is preferably a fusion ring of an aryl or heteroaryl and a monocyclic heterocyclic or monocyclic cycloalkyl. Preferably, the fusion ring is 6 to 16 members, and more preferably, the fusion ring is an 8 to 10-membered bicyclic fusion ring or a 12 to 17-membered tricyclic fusion ring. Examples of "fusion rings" include

[0210]

[0211]

[0212] It includes, but is not limited to.

[0213] "Alkoxy" refers to a (alkyl-O-) group, wherein alkyl is defined as in the present invention. C1-C6 alkoxy is preferred. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0214] "Nitro" refers to the -NO2 group.

[0215] "Hydroxyl" refers to the -OH group.

[0216] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[0217] "Amino" refers to -NH2.

[0218] "Cyano" refers to -CN.

[0219] "Benzyl" refers to -CH2-phenyl.

[0220] "Carboxyl" refers to -C(O)OH.

[0221] "Carboxylate group" refers to -C(O)O-alkyl or -C(O)O-cycloalkyl as defined above, alkyl and cycloalkyl.

[0222] "Hydroxyalkyl" refers to a hydroxyl-substituted alkyl as defined above.

[0223] "Aminoalkyl" refers to an amino-substituted alkyl group as defined above.

[0224] "Haloalkyl" refers to a halogen-substituted alkyl group as defined above.

[0225] "Halloalkoxy" refers to a halogen-substituted alkoxy as defined above.

[0226] "DMSO" refers to dimethyl sulfoxyhydrate.

[0227] "BOC" refers to tert-butoxycarbonyl.

[0228] "Bn" refers to benzyl.

[0229] "THP" refers to 2-tetrahydropyranil.

[0230] "TFA" refers to trifluoroacetic acid.

[0231] "Ts" refers to p-toluenesulfonyl.

[0232] SF 5" Lan refers to pentafluorosulfanil.

[0233] A "leaving group" is an atom or functional group that separates from a larger molecule in a chemical reaction; this is a term used in nucleophilic substitution and elimination reactions. In nucleophilic substitution reactions, the reactant attacked by the nucleophilic reagent is called the substrate, and the atom or group of atoms that decays from the substrate molecule along with an electron pair is called the leaving group. A group that readily accepts electrons and strongly retains a negative charge is a superior leaving group. When the pKa of the conjugate acid of the leaving group is lower, the leaving group will separate more easily from the other molecule. This is because, when the pKa of the conjugate acid is lower, the corresponding leaving group does not need to bond with another atom, and its tendency to exist in the form of an anion (or an electrically neutral leaving group) also increases. Common leaving groups include, but are not limited to, halogens, methanesulfonyls, -OTs, or -OHs.

[0234] "Substituted" refers to a case where one or more hydrogen atoms in a group, preferably up to five hydrogen atoms, more preferably one to three hydrogen atoms, are independently substituted with a corresponding number of substituents. Substituents exist only in their possible chemical positions, and it is obvious that a person skilled in the art can determine possible or impossible substitutions (by experiment or theory) without excessive effort. For example, an amino or hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (e.g., an olefin bond).

[0235] In the specification, "substituted" or "substituted" means, unless otherwise specified, that any group is an alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, SF5, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclil, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate group, =O, -O(CH2) m RA , -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 It can be substituted with one or more elements selected from; or

[0236] Two substituents form a cyclopropyl with the same carbon atom to which these substituents are attached, wherein

[0237] R A is selected from hydrogen atoms, alkyl, cycloalkyl, heterocyclil, aryl, or heteroaryl, wherein alkyl, cycloalkyl, heterocyclil, aryl, or heteroaryl is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclil, 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 Optionally additionally substituted with one or more substituents selected from;

[0238] Each R 3is independently selected from hydrogen atoms, alkyl, cycloalkyl, heterocyclil, aryl, and heteroaryl, wherein alkyl, cycloalkyl, heterocyclil, aryl, or heteroaryl is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclil, 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 Optionally additionally substituted with one or more substituents selected from;

[0239] R 4 and R 5 Each is independently selected from hydrogen atom, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclil, aryl, or heteroaryl, wherein alkyl, alkoxy, cycloalkyl, heterocyclil, aryl, or heteroaryl is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclil, 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 Optionally additionally substituted with one or more substituents selected from; or

[0240] R 4 and R 5These groups form a 4- to 8-membered heterocyclile together with the atoms to which they are attached, wherein the 4- to 8-membered heterocyclile has one or more N, O, or S(O) r Containing, the 4- to 8-membered heterocyclile is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclile, 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 Optionally additionally substituted with one or more substituents selected from;

[0241] R 6 , R 7 and R 8 Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclil, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclil, aryl, or heteroaryl is optionally additionally substituted with one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclil, aryl, heteroaryl, carboxyl, or carboxylate groups;

[0242] r is selected from 0, 1, or 2;

[0243] m refers to the case where it is selected from 0 or 1.

[0244] Since the compounds of the present invention may contain asymmetric centers or chiral centers, they exist as different stereoisomer forms. All stereoisomer forms of the compounds of the present invention include, but are not limited to, diastereomers, enantiomers, atropy-isomers, geometric (structural) isomers, and mixtures thereof, such as racemic mixtures, all of which fall within the scope of the present invention.

[0245] Unless otherwise specified, the structures described in the present invention further comprise all isomers of the structures (e.g., diastereomers, enantiomers, atropy isomers, and geometric (structural) isomer forms, e.g., R and S stereoconfigurations of asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) structural isomers). Therefore, monostereomers, enantiomer mixtures, diastereomer mixtures, and geometric (structural) isomer mixtures of the compounds of the present invention are all within the scope of the present invention.

[0246] "Pharmaceuticalally acceptable salts" refers to some salts of the above compounds that can retain their original biological activity and are suitable for medical use. Pharmaceutically acceptable salts of compounds as shown in Formula I may be amine salts or metal salts formed with suitable acids.

[0247] The term “pharmaceutical composition” refers to a mixture containing one or more of the compounds described herein or their physiologically acceptable salts or prodrugs and other chemical components, and other components, such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration into an organism that is favorable for the absorption of the active ingredient, thereby enabling biological activity.

[0248] Method for synthesizing the compound of the present invention

[0249] To achieve the objective of the present invention, the following technical solution is used in the present invention.

[0250] The present invention provides a method for preparing a compound as shown in Formula I, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0251]

[0252] A step of carrying out a condensation reaction on a compound as shown in Formula IA and a compound as shown in Formula IB, and optionally additionally performing a substitution reaction to obtain a compound as shown in Formula I, wherein

[0253] Y is selected from hydroxyl or chlorine;

[0254] Rings A, X, R 1 , R 2 and n are as defined in Chemical Formula I.

[0255] Description of exemplary implementation

[0256] The present invention will be described in more detail below with reference to embodiments, but such embodiments are not intended to limit the scope of the invention.

[0257] Implementation example

[0258] Data regarding the preparation of a compound as shown in Chemical Formula I, which is a representative compound, and related structural verification are presented in the embodiments. The following embodiments are used to illustrate the invention and are not intended to limit the invention.

[0259] 1 The 1H NMR spectrum is measured by a Bruker instrument (400 MHz), and the chemical shift is expressed in ppm. Tetramethylsilane is used as an internal standard (0.00 ppm). 1In the notation for ¹H NMR, s represents a single peak, d represents a double peak, t represents a triple peak, m represents a multiple peak, br represents peak expansion, dd represents a double peak of a double peak, and dt represents a double peak of a triple peak. When a coupling constant is provided, the unit of the coupling constant is Hz.

[0260] The mass spectrum is measured with an LC / MS instrument, and the ionization mode can be ESI or APCI.

[0261] The silica gel plates used for thin-layer chromatography were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, the silica gel plates used for thin-layer chromatography (TLC) adopted specifications of 0.15 mm to 0.2 mm, and the products separated and purified by thin-layer chromatography adopted specifications of 0.4 mm to 0.5 mm.

[0262] In column chromatography, 200 to 300 mesh silica gel from Yantai Huanghai is generally used as a carrier.

[0263] In the following embodiments, unless otherwise specified, all temperatures are in degrees Celsius. Unless otherwise specified, various starting materials and reagents are commercially available or synthesized according to known methods, and commercially available raw materials and reagents are used directly without further purification. Unless otherwise specified, manufacturers of commercially available raw materials and reagents include, but are not limited to, Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd., Jingyan Chemical Technology Co., Ltd., etc.

[0264] CD3OD: Deuterium-added methanol

[0265] CDCl3: Deuterium-added chloroform

[0266] DMSO-d6: Deuterium-added dimethyl sulfoxyhydrate

[0267] An argon atmosphere means a state in which the reaction flask is connected to an argon balloon with a volume of about 1 L.

[0268] Unless otherwise specified in the embodiments, the solution in reaction refers to an aqueous solution.

[0269] The compound is purified by silica gel column chromatography and reverse-phase column chromatography, and the eluent system is selected from A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane:ethyl acetate; and D: aqueous trifluoroacetic acid and acetonitrile system. The volume ratio of the solvent depends on the polarity of the compound and may be adjusted by adding a small amount of acidic or basic reagent, such as acetic acid or triethylamine.

[0270] Example 1

[0271] N-(3-chloro-5-(methylsulfonamido)phenyl)-6H-thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxamide

[0272]

[0273] Step 1

[0274] Methyl 4-bromo-5-(hydroxymethyl)thiophene-2-carboxylate

[0275] Methyl 4-bromo-5-formylthiophene-2-carboxylate 1a800 mg (3.21 mmol, commercially available) was dissolved in methanol (10 mL), to which sodium boroacetoxyhydrogenate (2.04 g, 9.64 mmol) was added, and 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 phase was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield methyl 4-bromo-5-(hydroxymethyl)thiophene-2-carboxylate 1b (800 mg) was obtained (yield 99.2%).

[0276] MS m / z(ESI): 251.0 [M+1].

[0277] Step 2

[0278] Methyl 5-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate

[0279] Methyl 4-bromo-5-(hydroxymethyl)thiophene-2-carboxylate 1b (400 mg, 1.59 mmol), bis(pinacoleto)diborone (606.79 mg, 2.39 mmol), and potassium acetate (312.68 mg, 3.19 mmol) were added to dioxane (5 mL). Nitrogen purging was performed three times on the reaction solution. Under nitrogen protection, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (116.56 mg, 159.30 μmol) was added to the reaction solution. The mixture was heated to 90°C and stirred for 2 hours. The reaction solution was filtered, and the result was methyl 5-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate 1c (473 mg) was obtained, which was used directly in the next step of the reaction.

[0280] MS m / z(ESI): 299.0 [M+1].

[0281] Step 3

[0282] Methyl 5-(hydroxymethyl)-4-(3-hydroxypyridine-2-yl)thiophene-2-carboxylate

[0283] Methyl 5-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate 1c (473 mg), bis(pinacoleto)diborone (204.25 mg, 1.17 mmol), and potassium acetate (486.72 mg, 3.52 mmol) were added to 1,4-dioxane (4 mL) and water (1 mL). Nitrogen purging was performed three times on the reaction solution. Under nitrogen protection, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (85.89 mg, 117.39 μmol) was added to the reaction solution. The mixture was heated to 90°C and stirred for 2 hours. After the reaction was complete, the reaction solution was diluted with water and then extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent: System A), resulting in methyl 5-(hydroxymethyl)-4-(3-hydroxypyridine-2-yl)thiophene-2-carboxylate 1d (130 mg) (yield 41.75%) was obtained.

[0284] MS m / z(ESI): 266.0 [M+1].

[0285] Step 4

[0286] Methyl 6H-thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxylate

[0287] Methyl 5-(hydroxymethyl)-4-(3-hydroxypyridine-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). Nitrogen purging was performed three times on the reaction solution. At 0°C, diisopropyl azodicarboxylate (297.27 mg, 1.47 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction solution under reduced pressure, separation and purification were performed by silica gel column chromatography (eluent: System A), resulting in methyl 6H-thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxylate. 1e (50 mg) (yield 41.26%) was obtained.

[0288] MS m / z(ESI): 248.0 [M+1].

[0289] Step 5

[0290] 6H-thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxylic acid

[0291] 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), then lithium hydroxide monohydrate (12.73 mg, 303.31 μmol) was added, and the mixture was stirred at 25°C for 1 hour. After the reaction was complete, the solvent was removed by rotary evaporation, and as a result, 6H-thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxylic acid 1f (70 mg) (yield 74.21%) was obtained, which was used directly in the next step of the reaction.

[0292] MS m / z(ESI): 234.0 [M+1].

[0293] Step 6

[0294] N-(3-chloro-5-(methylsulfonamido)phenyl)-6H-thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxamide

[0295] At room temperature O -(7-azabenchotriazole-1-yl)- N,N,N',N '-tetramethyluronium hexafluorophosphate (335.30 mg, 643.11 μmol) and N,N - Diisopropylethylamine (83.12 mg, 643.11 μmol), N,N - 6H-thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxylic acid in dimethylformamide (1 mL) 1f (50 mg, 214.37 μmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g (70.96 mg, 321.55 μmol, prepared according to International Patent Publication WO2023154519) was added to the solution. The reaction solution was allowed to react at 25°C for 3 hours. The reaction solution was diluted with water and then extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. As a result of separating the residue by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O; and mobile phase B: CH3CN), N-(3-chloro-5-(methylsulfonamido)phenyl)-6H-thieno[3',2':4,5]pyrano[3,2-b]pyridine-8-carboxamide 1 (6 mg) (yield 6.42%) was obtained.

[0296] MS m / z(ESI): 435.8 [M+1].

[0297] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ10.59(s, 1H), 10.08(s, 1H), 8.57(s, 1H), 8.21(dd, J = 4.8, 1.2 Hz, 1H), 7.70(t, J= 1.6 Hz, 1H), 7.68(d, J = 1.6 Hz, 1H), 7.38(dd, J = 8.0, 1.2 Hz, 1H), 7.26(dd, J = 8.0, 4.8 Hz, 1H), 6.96(t, J = 2.0 Hz, 1H), 5.57(s, 2H), 3.07(s, 3H).

[0298] Example 2

[0299] N-(3-chloro-5-(methylsulfonamido)phenyl)-4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxamide

[0300]

[0301] Step 1

[0302] Methyl 5-bromo-4-(bromomethyl)thiophene-2-carboxylate

[0303] Methyl 5-bromo-4-methylthiophene-2-carboxylate 2a (3 g, 12.76 mmol, commercially available) and N Bromosuccinimide (2.04 g, 11.48 mmol) was added to carbon tetrachloride (30 mL). Nitrogen purging was performed three times on the reaction solution. Dibenzoyl peroxide (30.91 mg, 127.61 μmol) was added to the reaction solution under nitrogen protection, the mixture was heated to 80°C, and stirred for 18 hours. The reaction solution was diluted with water and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure, resulting in methyl 5-bromo-4-(bromomethyl)thiophene-2-carboxylate 2b (4.1 g) was obtained, which was used directly in the next step of the reaction.

[0304] MS m / z(ESI): 314.8 [M+1].

[0305] Step 2

[0306] Methyl 5-bromo-4-(hydroxymethyl)thiophene-2-carboxylate

[0307] 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), after which potassium carbonate (8.85 g, 64.01 mmol) was added. The mixture was then heated to 60°C and stirred for 48 hours. The reaction solution was concentrated under reduced pressure and then separated and purified by silica gel column chromatography (eluent: System A). As a result, methyl 5-bromo-4-(hydroxymethyl)thiophene-2-carboxylate 2c (1.3 g) (yield 24.26%) was obtained.

[0308] MS m / z(ESI): 252.9 [M+1].

[0309] Step 3

[0310] Methyl 5-bromo-4-(((2-bromopyridine-3-yl)oxy)methyl)thiophene-2-carboxylate

[0311] Methyl 5-bromo-4-(hydroxymethyl)thiophene-2-carboxylate 2c 350 mg (1.39 mmol), 2-bromopyridine-3-ol (363.79 mg, 2.09 mmol), and triphenylphosphine (1.10 g, 4.18 mmol) were dissolved in tetrahydrofuran (20 mL). Nitrogen purging was performed three times on the reaction solution. At 0°C, diisopropyl azodicarboxylate (845.56 mg, 4.18 mmol) was added dropwise, the mixture was heated to 50°C, and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (eluent: System A). The result was methyl 5-bromo-4-(((2-bromopyridine-3-yl)oxy)methyl)thiophene-2-carboxylate 2d (600 mg) (yield 82.69%) was obtained.

[0312] MS m / z(ESI): 407.9 [M+1].

[0313] Step 4

[0314] Methyl 4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxylate

[0315] compound 2d (750 mg, 1.84 mmol), bis(pinacoleto)diborone (1.40 g, 5.53 mmol), di(1-adamantyl)-butylphosphine (264.23 mg, 736.96 μmol), and potassium carbonate (1.27 g, 9.21 mmol) were dissolved in 1,2-dimethoxyethane (10 mL) and water (1 mL). Nitrogen purging was performed three times on the reaction solution. Palladium acetate (II) (82.73 mg, 368.48 μmol) was added under nitrogen protection, and then the mixture was heated to 80°C and stirred for 2 hours. After concentrating the reaction solution under reduced pressure and separating and purifying it by silica gel column chromatography (eluent: System A), methyl 4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxylate 2e (300 mg) (yield 65.82%) was obtained.

[0316] MS m / z(ESI): 247.9 [M+1].

[0317] Step 5

[0318] 4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxylic acid

[0319] Methyl 4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxylate 2e(420 mg, 1.70 mmol) was dissolved in tetrahydrofuran (12 mL) and water (4 mL), after which lithium hydroxide monohydrate (71.28 mg, 1.70 mmol) was added, and the mixture was stirred at 25°C for 1 hour. After the reaction was complete, a 1 M hydrochloric acid solution was added to adjust the pH to weakly acidic. Then, the mixture was extracted with dichloromethane (20 mL x 3), dried with anhydrous sodium sulfate, and concentrated under reduced pressure to yield 4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxylic acid 2f (270 mg) (yield 68.15%) was obtained.

[0320] MS m / z(ESI): 233.9 [M+1].

[0321] Step 6

[0322] N-(3-chloro-5-(methylsulfonamido)phenyl)-4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxamide

[0323] At room temperature O -(7-azabenchotriazole-1-yl)- N,N,N',N '-tetramethyluronium hexafluorophosphate (1.48 g, 2.83 mmol) and N,N - Diisopropylethylamine (365.71 mg, 2.83 mmol), N,N 4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxylic acid in dimethylformamide (1 mL) 2f (220 mg, 943.22 μmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g(312.22 mg, 1.41 mmol) was added to the solution. The reaction solution was allowed to react at 25°C for 3 hours. The reaction solution was diluted with water and then extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was separated by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O; and mobile phase B: CH3CN), and the result was N-(3-chloro-5-(methylsulfonamido)phenyl)-4H-thieno[2',3':4,5]pyrano[3,2-b]pyridine-2-carboxamide 2 (15 mg) (yield 3.65%) was obtained.

[0324] MS m / z(ESI): 436.0 [M+1].

[0325] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ10.55(s, 1H), 10.09(s, 1H), 8.16(dd, J = 4.8, 1.4 Hz, 1H), 7.91(s, 1H), 7.66(dt, J = 21.8, 1.8 Hz, 2H), 7.32(ddd, J = 12.8, 8.2, 3.0 Hz, 2H), 6.97(t, J = 1.8 Hz, 1H), 5.48(s, 2H), 3.08(s, 3H).

[0326] Examples 3 and 4 were synthesized according to the synthesis method of Examples 1 and 2 of the present invention. The separation parameters of Examples 3 and 4 are shown in the table below:

[0327]

[0328] Example 5

[0329] N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydrothieno[2',3':2,3]oxepino[4,5-b]pyridine-9-carboxamide

[0330]

[0331] Step 1

[0332] (E)-2-bromo-3-(2-methoxyvinyl)pyridine

[0333] (Methoxymethyl)triphenylphosphonium chloride 5b (13.8 g, 40.3 mmol, commercially available) was added to tetrahydrofuran (50 mL). Nitrogen purging was performed three times on the reaction solution, after which it was cooled to -78°C. Lithium bis(trimethylsilyl)amide (6.75 g, 40.3 mmol, 1 mol / L in THF) was added dropwise to the reaction solution, and the mixture was stirred at -78°C for 0.5 hours. Subsequently, 2-bromo-3-pyridinecarbaldehydride 5a (5 g, 26.9 mmol, commercially available) was dissolved in tetrahydrofuran and then slowly added dropwise to the reaction solution. The mixture was stirred for 16 hours, after which the temperature was gradually raised to room temperature. The reaction solution was quenched with methanol at 0°C, concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (eluent: System A). As a result, (E)-2-bromo-3-(2-methoxyvinyl)pyridine 5c (2.1 g) (yield 37%) was obtained.

[0334] MS m / z(ESI): 215.9 [M+1].

[0335] Step 2

[0336] 2-(2-bromopyridine-3-yl)acetaldehyde

[0337] (E)-2-bromo-3-(2-methoxyvinyl)pyridine at room temperature 5c(2.1 g, 9.81 mmol) was added to a formic acid solution (5 mL). The mixture was heated to 90°C and allowed to proceed for 16 hours. After concentrating the reaction solution under reduced pressure, separation and purification were performed by silica gel column chromatography (eluent: System A), resulting in 2-(2-bromopyridine-3-yl)acetaldehyde 5d (700 mg) (yield 36%) was obtained.

[0338] MS m / z(ESI): 201.9 [M+1].

[0339] Step 3

[0340] 2-(2-bromopyridine-3-yl)ethanol-1-ol

[0341] Sodium borohydride (265 mg, 7.00 mmol) at room temperature, 2-(2-bromopyridine-3-yl)acetaldehyde in ethanol (10 mL) 5d (700 mg, 3.50 mmol) was added in portions to the solution. The reaction solution was allowed to react at room temperature for 16 hours. The reaction solution was quenched with methanol, concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (eluent: System A), resulting in 2-(2-bromopyridine-3-yl)ethanol-1-ol 5e (430 mg) (yield 61%) was obtained.

[0342] MS m / z(ESI): 204.0 [M+1].

[0343] Step 4

[0344] Methyl 4-bromo-5-methoxythiophene-2-carboxylate

[0345] At room temperature N -Bromosuccinimide (2.27 g, 12.8 mmol) in dichloromethane (50 mL) methyl 5-methoxy-2-thiophenecarboxylate 5f(2 g, 11.6 mmol, commercially available) was added to the solution. The reaction solution was allowed to react at room temperature for 2 hours. After concentrating the reaction solution under reduced pressure, separation and purification were performed by silica gel column chromatography (eluent: System A), resulting in methyl 4-bromo-5-methoxythiophene-2-carboxylate 5g (2.8 g) (yield 96%) was obtained.

[0346] MS m / z(ESI): 251.0 [M+1].

[0347] Step 5

[0348] Methyl 5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate

[0349] At room temperature [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (291 mg, 0.4 mmol), bis(pinacoleto)diborone (2.63 g, 10.3 mmol), potassium acetate (1.56 g, 15.9 mmol), and methyl 4-bromo-5-methoxythiophene-2-carboxylate 5g (2 g, 7.97 mmol) was added to dioxane (20 mL). Nitrogen purging was performed three times on the mixture, and the mixture was allowed to react at 100°C for 2 hours. After filtering the mixture, the filter cake was rinsed with ethyl acetate (150 mL), the filtrate was concentrated under reduced pressure, and separation and purification by silica gel column chromatography (eluent: System A) resulted in methyl 5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate 5h (1.0 g) (yield 42%) was obtained.

[0350] MS m / z(ESI): 299.2 [M+1].

[0351] Step 6

[0352] Methyl 4-(3-(2-hydroxyethyl)pyridine-2-yl)-5-methoxythiophene-2-carboxylate

[0353] [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (156 mg, 0.21 mmol), 2-(2-bromopyridine-3-yl)ethanol-1-ol at room temperature 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) was added to a mixed solution of dioxane (5 mL) and water (1 mL). Nitrogen purging was performed three times on this mixture, heated to 100°C, and stirred for 16 hours. The mixture was filtered, the filter cake was rinsed with ethyl acetate (50 mL), the filtrate was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (eluent: System A). The result was methyl 4-(3-(2-hydroxyethyl)pyridine-2-yl)-5-methoxythiophene-2-carboxylate 5i (500 mg) (yield 80%) was obtained.

[0354] MS m / z(ESI): 294.0 [M+1].

[0355] Step 7

[0356] Methyl 5-hydroxy-4-(3-(2-hydroxyethyl)pyridine-2-yl)thiophene-2-carboxylate

[0357] At room temperature, aluminum trichloride (2.27 g, 17.1 mmol) in dichloromethane (20 mL) methyl 4-(3-(2-hydroxyethyl)pyridine-2-yl)-5-methoxythiophene-2-carboxylate 5iIt was added to a solution of (500 mg, 1.70 mmol). The reaction solution was allowed to react at room temperature for 48 hours. After pouring the reaction solution into water, it was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent: System A), resulting in methyl 5-hydroxy-4-(3-(2-hydroxyethyl)pyridine-2-yl)thiophene-2-carboxylate 5j (300 mg) (yield 63%) was obtained.

[0358] MS m / z(ESI): 280.0 [M+1].

[0359] 1 ¹H NMR(500 MHz, DMSO- d 6) δ10.20(s, 1H), 8.42(d, J = 4.8 Hz, 1H), 8.10(d, J = 7.2 Hz, 1H), 7.98(s, 1H), 7.41 - 7.33(m, 1H), 4.90(s, 1H), 3.77(t, J = 6.4 Hz, 2H), 3.72(s, 3H), 3.06(t, J = 6.4 Hz, 2H).

[0360] Step 8

[0361] Methyl 5,6-Dihydrothieno[2',3':2,3]oxepino[4,5-b]pyridine-9-carboxylate

[0362] At room temperature, diisopropyl azodicarboxylate (586 mg, 2.90 mmol) in tetrahydrofuran (30 mL) methyl 5-hydroxy-4-(3-(2-hydroxyethyl)pyridine-2-yl)thiophene-2-carboxylate 5jIt was added to a solution of (270 mg, 0.97 mmol) and triphenylphosphine (760 mg, 2.90 mmol). The reaction solution was allowed to react at room temperature for 16 hours. After concentrating the reaction solution under reduced pressure, separation and purification were performed by silica gel column chromatography (eluent: System A), resulting in methyl 5,6-dihydrothieno[2',3':2,3]oxepino[4,5-b]pyridine-9-carboxylate 5k (230 mg) (yield 91%) was obtained.

[0363] MS m / z(ESI): 262.0 [M+1].

[0364] Step 9

[0365] 5,6-Dihydrothieno[2',3':2,3]oxepino[4,5-b]pyridine-9-carboxylic acid

[0366] At room temperature, lithium hydroxide monohydrate (111 mg, 2.64 mmol) was mixed with methyl 5,6-dihydrothieno[2',3':2,3]oxepino[4,5-b]pyridine-9-carboxylate in tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). 5k It was added to a mixed solution of (230 mg, 0.88 mmol). The reaction solution was allowed to react at room temperature for 16 hours. Dilute hydrochloric acid was added to the reaction solution to adjust the pH to 6, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to yield 5,6-dihydrothieno[2',3':2,3]oxepino[4,5-b]pyridine-9-carboxylic acid 5l (230 mg) (yield 91%) was obtained.

[0367] MS m / z(ESI): 248.0 [M+1].

[0368] Step 10

[0369] N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydrothieno[2',3':2,3]oxepino[4,5-b]pyridine-9-carboxamide

[0370] 5,6-Dihydrothieno[2',3':2,3]oxepino[4,5-b]pyridine-9-carboxylic acid at 25°C 5l (50.0 mg, 0.202 mmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g (89.3 mg, 0.404 mmol) N , N - It was added to dimethylformamide (5 mL). Subsequently, (7-azabenzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (211 mg, 0.404 mmol) and N , N Diisopropylethylamine (78.4 mg, 0.607 mmol) was added, and the mixture was allowed to react at 65°C for 18 hours. The mixture was poured into water (50 mL) and then extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. As a result of separating the residue by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, and mobile phase B: CH3CN), N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydrothieno[2',3':2,3]oxepino[4,5-b]pyridine-9-carboxamide 5 (46 mg) (yield 51%) was obtained.

[0371] MS m / z(ESI): 450.2 [M+1].

[0372] 1 ¹H NMR(400 MHz, DMSO- d 6) δ10.56(d, J = 2.4 Hz, 1H), 8.66(d,J = 2.0 Hz, 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).

[0373] Example 6

[0374] N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydrothieno[3',2':4,5]oxepino[3,2-b]pyridine-9-carboxamide

[0375]

[0376] Step 1

[0377] Methyl 4-bromo-5-(2-hydroxyethyl)thiophene-2-carboxylate

[0378] Methyl 5-(2-hydroxyethyl)thiophene-2-carboxylate 6a 1.3 g, 6.98 mmol, commercially available methyl 4-bromo-5-(2-hydroxyethyl)thiophene-2-carboxylate was added to 15 mL of N,N-dimethylformamide, followed by the addition of N-bromosuccinimide (2.48 g, 13.96 mmol). The mixture was heated to 50°C and stirred for 12 hours. The reaction solution was concentrated under reduced pressure and separated and purified by silica gel column chromatography (eluent: System A). 6b (900 mg) (yield 48.36%) was obtained.

[0379] MS(ESI) m / z: 264.9 [M+H].

[0380] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ7.70(s, 1H), 3.81(s, 3H), 3.63(d, J = 6.4 Hz, 2H), 2.93(t, J = 6.4 Hz, 2H).

[0381] Step 2

[0382] Methyl 4-bromo-5-(2-((2-bromopyridine-3-yl)oxy)ethyl)thiophene-2-carboxylate

[0383] Methyl 4-bromo-5-(2-hydroxyethyl)thiophene-2-carboxylate 6b (700 mg, 2.64 mmol), 2-bromopyridine-3-ol (689.09 mg, 3.96 mmol), and triphenylphosphine (2.08 g, 7.92 mmol) were dissolved in tetrahydrofuran (20 mL). Nitrogen purging was performed three times on the reaction solution. At 0°C, diisopropyl azodicarboxylate (1.60 g, 7.92 mmol) was added dropwise, and the reaction solution was stirred at 50°C for 1 hour. After concentrating the reaction solution under reduced pressure, separation by silica gel column chromatography (eluent: System A) revealed methyl 4-bromo-5-(2-((2-bromopyridine-3-yl)oxy)ethyl)thiophene-2-carboxylate 6c (1.2 g) (yield 78.39%) was obtained.

[0384] MS(ESI) m / z: 421.7 [M+H].

[0385] Step 3

[0386] Methyl 6,7-Dihydrothieno[3',2':4,5]oxepino[3,2-b]pyridine-9-carboxylate

[0387] Methyl 4-bromo-5-(2-((2-bromopyridine-3-yl)oxy)ethyl)thiophene-2-carboxylate 6c(880 mg, 2.09 mmol), bis(pinacoleto)diborone (1.59 g, 6.27 mmol), di(1-adamantyl)-butylphosphine (299.70 mg, 835.90 μmol), and potassium carbonate (1.44 g, 10.45 mmol) were dissolved in 1,2-dimethoxyethane (10 mL) and water (1 mL). Nitrogen purging was performed three times on the reaction solution. Palladium acetate (II) (93.83 mg, 417.95 μmol) was added under nitrogen protection, and the reaction solution was stirred at 100°C for 2 hours. After concentrating the reaction solution under reduced pressure and separating it by silica gel column chromatography (eluent: System A), the result was methyl 6,7-dihydrothieno[3',2':4,5]oxepino[3,2-b]pyridine-9-carboxylate 6d (270 mg) (yield 49.45%) was obtained.

[0388] MS(ESI) m / z: 261.9 [M+H].

[0389] Step 4

[0390] 6,7-Dihydrothieno[3',2':4,5]oxepino[3,2-b]pyridine-9-carboxylic acid

[0391] Methyl 6,7-Dihydrothieno[3',2':4,5]oxepino[3,2-b]pyridine-9-carboxylate 6d (300 mg, 1.15 mmol) was dissolved in tetrahydrofuran (12 mL) and water (4 mL), and then lithium hydroxide monohydrate (53.00 mg, 1.26 mmol) was added, and the mixture was stirred at 25°C for 1 hour. After the reaction was complete, a 1 M hydrochloric acid solution was added to adjust the pH to weakly acidic, and then the mixture was extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to yield 6,7-dihydrothieno[3',2':4,5]oxepino[3,2-b]pyridine-9-carboxylic acid 6e(230 mg) (yield 81.02%) was obtained.

[0392] MS(ESI) m / z: 247.9 [M+H].

[0393] Step 5

[0394] N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydrothieno[3',2':4,5]oxepino[3,2-b]pyridine-9-carboxamide

[0395] At room temperature, O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.14 g, 2.18 mmol) and N,N-diisopropylethylamine (282.25 mg, 2.18 mmol) in N,N-dimethylformamide (1 mL) 6,7-dihydrothieno[3',2':4,5]oxepino[3,2-b]pyridine-9-carboxylic acid 6e (180 mg, 727.95 μmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide 1g (240.96 mg, 1.09 mmol) was added to the solution. The reaction solution was allowed to react at 25°C for 3 hours. The reaction solution was diluted with water and then extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was separated by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, and mobile phase B: CH3CN), and the result was N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydrothieno[3',2':4,5]oxepino[3,2-b]pyridine-9-carboxamide 6 (12 mg) (yield 3.66%) was obtained.

[0396] MS(ESI) m / z: 449.8 [M+H].

[0397] 1¹H NMR(400 MHz, DMSO- d 6 ) δ10.67(s, 1H), 10.06(s, 1H), 8.86(s, 1H), 8.40(dd, J = 4.4, 1.6 Hz, 1H), 7.81 - 7.64(m, 2H), 7.47(dd, J = 8.0, 1.6 Hz, 1H), 7.31(dd, J = 8.0, 4.4 Hz, 1H), 6.95(t, J = 2.0 Hz, 1H), 4.39(t, J = 4.8 Hz, 2H), 3.46(t, J = 4.8 Hz, 2H), 3.07(s, 3H).

[0398] Example 7

[0399] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxamide

[0400]

[0401] Step 1

[0402] Methyl 5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate

[0403] At 25°C, triethylsilane (10.3 g, 88.1 mmol), tert-butyl carbamate (10.3 g, 88.1 mmol), and trifluoroacetic acid (6.70 g, 58.8 mmol) were mixed with methyl 5-formylthiophene-2-carboxylate in dichloromethane (50 mL) and acetonitrile (50 mL). 7aAfter adding to a mixed solution of (5 g, 29.4 mmol, commercially available), the mixture was allowed to react at room temperature for 18 hours. The mixture was poured into a saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with a saturated solution of sodium chloride, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent: System A), resulting in methyl 5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate 7b (7.0 g) (yield 88%) was obtained.

[0404] MS m / z(ESI): 215.9 [M+1].

[0405] Step 2

[0406] Methyl 4-bromo-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate

[0407] At 25℃ N -Bromosuccinimide (9.84 g, 55.28 mmol), N , N - Methyl 5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate in dimethylformamide (30 mL) 7b (5.00 g, 18.4 mmol) was added to the solution. The mixture was allowed to react 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 phase was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (eluent: System A). The result was methyl 4-bromo-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate 7c (2.5 g) (yield 39%) was obtained.

[0408] MS m / z(ESI): 372.0 [M+1].

[0409] 1 ¹H NMR(400 MHz, DMSO- d 6) δ7.75(t, J = 6.0 Hz, 1H), 7.71(s, 1H), 4.24(d, J = 6.0 Hz, 2H), 3.82(s, 3H), 1.41(s, 9H).

[0410] Step 3

[0411] methyl 5-(((tert-butoxycarbonyl)amino)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate

[0412] At 25°C, potassium acetate (420 mg, 4.28 mmol), bis(pinacoleto)diborone (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) were mixed with methyl 4-bromo-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate in 1,4-dioxane (10 mL). 7c (500 mg, 1.43 mmol) was added to the solution. Nitrogen purging was performed on the mixture three times, and then it was allowed to react at 90°C for 1 hour. The mixture was filtered and concentrated under reduced pressure, resulting in methyl 5-(((tert-butoxycarbonyl)amino)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate 7d (560 mg) was obtained, which was used directly in the next step of the reaction.

[0413] MS m / z(ESI): 420.2 [M+1].

[0414] Step 4

[0415] methyl 2-(2-(((tert-butoxycarbonyl)amino)methyl)-5-(methoxycarbonyl)thiophene-3-yl)nicotinate

[0416] At 25°C, [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (210 mg, 0.287 mmol) and potassium carbonate (595 mg, 4.30 mmol) were mixed with methyl 5-(((tert-butoxycarbonyl)amino)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate in 1,4-dioxane (10 mL) and water (2 mL). 7d (570 mg, 1.43 mmol) and methyl 2-bromo-3-pyridinecarboxylate 7e After adding to a mixed solution of (620 mg, 2.87 mmol, commercially available), the mixture was heated to 90°C and allowed to react for 2 hours. The reaction solution was filtered and concentrated under reduced pressure, resulting in methyl 2-(2-(((tert-butoxycarbonyl)amino)methyl)-5-(methoxycarbonyl)thiophene-3-yl)nicotinate 7f (500 mg) (yield 86%) was obtained.

[0417] MS m / z(ESI): 407.1 [M+1].

[0418] Step 5

[0419] Methyl 2-(2-(aminomethyl)-5-(methoxycarbonyl)thiophene-3-yl)nicotinate

[0420] At 25°C, trifluoroacetic acid (2 mL) in dichloromethane (4 mL) methyl 2-(2-(((tert-butoxycarbonyl)amino)methyl)-5-(methoxycarbonyl)thiophene-3-yl)nicotinate 7f (560 mg, 1.38 mmol) was added to the solution, and the mixture was allowed to react at room temperature for 2 hours. As a result of concentrating the mixture under reduced pressure, methyl 2-(2-(aminomethyl)-5-(methoxycarbonyl)thiophene-3-yl)nicotinate 7g (420 mg) was obtained, which was used directly in the next step of the reaction.

[0421] MS m / z(ESI): 306.9 [M+1].

[0422] Step 6

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

[0424] At 25℃ N , N - Diisopropylethylamine (1.05 g, 8.16 mmol) in toluene (5 mL) methyl 2-(2-(aminomethyl)-5-(methoxycarbonyl)thiophene-3-yl)nicotinate 7g After adding to a solution of (500 mg, 1.63 mmol), the mixture was allowed to react at 70°C for 18 hours. The mixture was concentrated under reduced pressure and then separated and purified by silica gel column chromatography (eluent: System A), resulting in methyl 5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylate 7h (200 mg) (yield 45%) was obtained.

[0425] MS m / z(ESI): 275.0 [M+1].

[0426] Step 7

[0427] 5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylic acid

[0428] At 25°C, lithium hydroxide monohydrate (59.7 mg, 1.42 mmol) was methyl 5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylate in tetrahydrofuran (5 mL) and water (2 mL). 7h After adding to a mixed solution of (130 mg, 0.474 mmol), the mixture was allowed to react at 25°C for 2 hours. As a result of concentrating the mixture under reduced pressure, 5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylic acid 7i(120 mg) (yield 65.82%) was obtained.

[0429] MS m / z(ESI): 261.0 [M+1].

[0430] Step 8

[0431] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxamide

[0432] 5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylic acid at 25°C 7i (130 mg, 0.499 mmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g (220 mg, 0.999 mmol) N , N - Added to dimethylformamide (5 mL). Subsequently, (7-azabenzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (521 mg, 0.999 mmol) and N , N After adding diisopropylethylamine (194 mg, 1.50 mmol), the mixture was heated to 65°C and allowed to react for 18 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. As a result of separating the residue by preliminary liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, and mobile phase B: CH3CN), N-(3-chloro-5-(methylsulfonamido)phenyl)-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxamide 7 (50 mg) (yield 22%) was obtained.

[0433] MS m / z(ESI): 463.0 [M+1].

[0434] 1 ¹H NMR(400 MHz, DMSO- d 6) δ10.64(s, 1H), 10.09(s, 1H), 8.84(dd, J = 4.8, 2.0 Hz, 1H), 8.77(s, 1H), 8.62(d, J = 1.6 Hz, 1H), 8.30(dd, J = 8.0, 1.6 Hz, 1H), 7.74 - 7.67(m, 2H), 7.55(dd, J = 8.0, 4.8 Hz, 1H), 6.97(t, J = 2.0 Hz, 1H), 4.31(d, J = 6.0 Hz, 2H), 3.08(s, 3H).

[0435] Example 8

[0436] 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

[0437]

[0438] Step 1

[0439] Methyl 6-methyl-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylate

[0440] Sodium hydride (45.6 mg, 1.09 mmol, 60% purity) at 0℃, N,N - Methyl 5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylate in dimethylformamide (5 mL) 7hIt was added to a solution of (150 mg, 0.547 mmol), and the mixture was allowed to react at 0°C for 0.5 hours. Iodomethane (155 mg, 1.09 mmol) was added to the solution, and the mixture was allowed to react at 25°C for 1 hour. The mixture was quenched with a saturated aqueous ammonium chloride solution (5 mL), water (30 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent: System A), resulting in methyl 6-methyl-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylate 8a (130 mg) (yield 82%) was obtained.

[0441] MS m / z(ESI): 289.0 [M+1].

[0442] Step 2

[0443] 6-methyl-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylic acid

[0444] At 25°C, lithium hydroxide monohydrate (56.8 mg, 1.35 mmol) was methyl 6-methyl-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylate in tetrahydrofuran (5 mL) and water (2 mL). 8a It was added to a mixed solution of (130 mg, 0.451 mmol), and the mixture was allowed to react at 25°C for 2 hours. As a result of concentrating the mixture under reduced pressure, 6-methyl-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylic acid 8b (120 mg) was obtained, which was used directly in the next step of the reaction.

[0445] MS m / z(ESI): 275.0 [M+1].

[0446] Step 3

[0447] 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

[0448] 6-methyl-5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylic acid at 25°C 8b (125 mg, 0.456 mmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g (201 mg, 0.911 mmol) N , N - It was added to dimethylformamide (5 mL). Subsequently, (7-azabenzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (475 mg, 0.911 mmol) and N , N After adding diisopropylethylamine (177 mg, 1.37 mmol), the mixture was heated to 65°C and allowed to react for 3 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. As a result of separating the residue by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, and mobile phase B: CH3CN), 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 8 (40 mg) (yield 18%) was obtained.

[0449] MS m / z(ESI): 477.0 [M+1].

[0450] 1¹H NMR(400 MHz, DMSO- d 6) δ10.64(s, 1H), 10.08(s, 1H), 8.82(dd, J = 4.4, 2.0 Hz, 1H), 8.62(s, 1H), 8.28(dd, J = 8.0, 2.0 Hz, 1H), 7.72(t, J = 2.0 Hz, 1H), 7.68(t, J = 2.0 Hz, 1H), 7.54(dd, J = 8.0, 4.8 Hz, 1H), 6.96(t, J = 2.0 Hz, 1H), 4.59(s, 2H), 3.14(s, 3H), 3.08(s, 3H).

[0451] Example 9

[0452] N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxamide

[0453]

[0454] Step 1

[0455] Methyl 6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylate

[0456] Methyl 5-oxo-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylate at 25°C 7h (500 mg, 1.82 mmol) was added to a borane solution in tetrahydrofuran (1 M, 10 mL), the mixture was heated to 65°C, and allowed to react for 1 hour. The system was quenched with methanol (20 mL), and the mixture was concentrated under reduced pressure, resulting in methyl 6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylate 9a (470 mg) was obtained, which was used directly in the next step of the reaction.

[0457] MS m / z(ESI): 261.0 [M+1].

[0458] Step 2

[0459] 6-(tert-butyl)9-methyl 5,7-dihydro-6H-pyrido[3,2-c]thieno[3,2-e]azepine-6,9-diccarboxylate

[0460] At 25℃ N,N - Diisopropylethylamine (700 mg, 5.42 mmol), di-tert-butyl bicarbonate (788 mg, 3.61 mmol) and 4-dimethylaminopyridine (22.1 mg, 0.181 mmol) N , N - Methyl 6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylate in dimethylformamide (10 mL) 9a (470 mg, 1.81 mmol) was added to the solution, 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 x 3). The combined organic phase was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent: System A). The result was 6-(tert-butyl)9-methyl 5,7-dihydro-6H-pyrido[3,2-c]thieno[3,2-e]azepine-6,9-dicarboxylate 9b (300 mg)(46%) was obtained.

[0461] MS m / z(ESI): 361.2 [M+1].

[0462] Step 3

[0463] 6-(tert-butoxycarbonyl)-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylic acid

[0464] At 25°C, lithium hydroxide monohydrate (48.9 mg, 1.17 mmol) was mixed with 6-(tert-butyl)9-methyl 5,7-dihydro-6H-pyrido[3,2-c]thieno[3,2-e]azepine-6,9-dicarboxylate in tetrahydrofuran (2 mL) and water (1 mL). 9b It was added to a solution of (140 mg, 0.388 mmol), and the mixture was allowed to react at 25°C for 2 hours. As a result of concentrating the mixture under reduced pressure, 6-(tert-butoxycarbonyl)-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylic acid 9c (130 mg) was obtained, which was used directly in the next step of the reaction.

[0465] MS m / z(ESI): 347.0 [M+1].

[0466] Step 4

[0467] tert-butyl 9-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-5,7-dihydro-6H-pyrido[3,2-c]thieno[3,2-e]azepine-6-carboxylate

[0468] 6-(tert-butoxycarbonyl)-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxylic acid at 25°C 9c (130 mg, 0.375 mmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g (166 mg, 0.751 mmol) N , N - It was added to dimethylformamide (5 mL). Subsequently, (7-azabenzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (391 mg, 0.751 mmol) and N , NAfter adding diisopropylethylamine (146 mg, 1.13 mmol), the 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 phase was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent: System A). The result was tert-butyl 9-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-5,7-dihydro-6H-pyrido[3,2-c]thieno[3,2-e]azepine-6-carboxylate 9d (70 mg) (yield 34%) was obtained.

[0469] MS m / z(ESI): 548.8 [M+1].

[0470] Step 5

[0471] N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxamide

[0472] tert-butyl 9-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-5,7-dihydro-6H-pyrido[3,2-c]thieno[3,2-e]azepine-6-carboxylate in dichloromethane (3 mL) in trifluoroacetic acid (1 mL) at 25°C 9d It was added to a solution of (50.0 mg, 0.0911 mmol), 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. The residue was separated by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), and the result showed 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%) was obtained.

[0473] MS m / z(ESI): 449.0 [M+1].

[0474] 1 ¹H NMR(400 MHz, DMSO- d 6) δ10.62(s, 1H), 10.01(s, 1H), 8.76(s, 1H), 8.54(dd, J = 4.8, 1.6 Hz, 1H), 7.69(dt, J = 6.0, 2.0 Hz, 2H), 7.63(dd, J = 7.6, 1.6 Hz, 1H), 7.25(dd, J = 7.6, 4.8 Hz, 1H), 6.93(t, J = 2.0 Hz, 1H), 4.34(s, 2H), 3.95(s, 2H), 3.09(s, 3H).

[0475] Example 10

[0476] N-(3-chloro-5-(methylsulfonamido)phenyl)-6-methyl-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxamide

[0477]

[0478] At 25°C, an aqueous formaldehyde solution (37.1 mg, 0.0457 mmol, purity 37%) containing N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxamide in acetonitrile (3 mL) 9(41.0 mg, 0.0913 mmol) was added to the solution, and the mixture was allowed to react at 25°C for 2 hours. The mixture was concentrated under reduced pressure. The residue was separated by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), and the result showed N-(3-chloro-5-(methylsulfonamido)phenyl)-6-methyl-6,7-dihydro-5H-pyrido[3,2-c]thieno[3,2-e]azepine-9-carboxamide 10 (10 mg) (yield 24%) was obtained.

[0479] MS m / z(ESI): 463.0 [M+1].

[0480] 1 ¹H NMR(400 MHz, DMSO- d 6) δ10.63(s, 1H), 10.11(s, 1H), 8.74(s, 1H), 8.59(dd, J = 4.8, 1.6 Hz, 1H), 7.74(dd, J = 7.6, 1.6 Hz, 1H), 7.70(dt, J = 8.0, 2.0 Hz, 2H), 7.32(dd, J = 7.6, 4.8 Hz, 1H), 6.95(s, 1H), 4.15(s, 2H), 3.85(s, 2H), 3.07(s, 3H), 2.33(s, 3H).

[0481] Example 11

[0482] N-(3-chloro-5-(methylsulfonamido)phenyl)-6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxamide

[0483]

[0484] Step 1

[0485] Methyl acetate 2-(5-bromothiophene-2-yl)

[0486] At 25°C, N-bromosuccinimide (13.7 g, 76.8 mmol) was mixed with 2-methyl thiophene acetate in N,N-dimethylformamide (50 mL). 11a After adding to the solution (10.0 g, 64.0 mmol), the mixture was allowed to react at 25°C for 1 hour. The mixture was poured into water (500 mL) and extracted with ethyl acetate (400 mL). The organic phase was washed with a saturated sodium chloride solution (50 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 2-(5-bromothiophene-2-yl)acetate. 11b (10.0 g) (yield 66%) was obtained.

[0487] Step 2

[0488] Methyl 5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate

[0489] At 25°C, [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.14 g, 1.53 mmol) and triethylamine (4.65 g, 45.9 mmol) were mixed in 2-(5-bromothiophene-2-yl)methyl acetate in methanol (20 mL). 11b After adding to a solution of (3.60 g, 15.3 mmol), carbon monoxide purging was performed on the system, followed by allowing the reaction to proceed 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), and the result was methyl 5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate 11c (1.5 g) (yield 46%) was obtained.

[0490] MS m / z(ESI): 215.0 [M+1].

[0491] Step 3

[0492] Methyl 4-bromo-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate

[0493] At 25°C, N-bromosuccinimide (1.94 g, 10.9 mmol) was mixed with methyl 5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate in trifluoroacetic acid (10 mL) and acetic acid (1 mL). 11c (1.80 g, 8.40 mmol) was added to the solution, and the mixture was allowed to react at 25°C for 1 hour. The mixture was diluted with ethyl acetate (100 mL), and then the ethyl acetate solution was added dropwise to a saturated aqueous sodium bicarbonate solution to adjust the pH to 8–9. The organic phase was washed with a saturated sodium chloride solution (50 mL), dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 4-bromo-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate 11d (1.2 g) (yield 49%) was obtained.

[0494] MS m / z(ESI): 293.0 / 295.0 [M+1].

[0495] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ7.75(s, 1H), 4.02(s, 2H), 3.85(s, 3H), 3.68(s, 3H).

[0496] Step 4

[0497] Methyl 5-(2-methoxy-2-oxoethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate

[0498] At 25°C, potassium acetate (3.72 g, 37.9 mmol), bis(pinacoleto)diborone (9.62 g, 37.9 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (924 mg, 1.26 mmol) were mixed with methyl 4-bromo-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate in 1,4-dioxane (30 mL). 11dIt was added to a solution of (3.70 g, 12.6 mmol). Nitrogen purging was performed on the mixture three times, and it was allowed to react at 90°C for 4 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 5-(2-methoxy-2-oxoethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate 11e (3.50 g) (yield 82%) was obtained.

[0499] MS m / z(ESI): 341.1 [M+1].

[0500] Step 5

[0501] Methyl 4-(3-aminopyridine-2-yl)-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate

[0502] At 25°C, [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (698 mg, 0.955 mmol) and potassium carbonate (3.96 g, 28.7 mmol) were mixed with methyl 5-(2-methoxy-2-oxoethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate in 1,4-dioxane (30 mL) and water (6 mL). 11e It was added to a mixed solution of (3.25 g, 9.55 mmol) and 2-bromo-3-aminopyridine (3.31 g, 19.1 mmol), and the mixture was allowed to react at 90°C for 2 hours. The reaction solution was filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 4-(3-aminopyridine-2-yl)-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate 11f (1.60 g) (yield 55%) was obtained.

[0503] MS m / z(ESI): 307.0 [M+1].

[0504] Step 6

[0505] Methyl 6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylate

[0506] At 25°C, a solution of trimethylaluminum in n-hexane (2 M, 2.0 mL) in tetrahydrofuran (10 mL) methyl 4-(3-aminopyridine-2-yl)-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate 11f It was added to a solution of (300 mg, 0.979 mmol), and the mixture was allowed to react at 25°C for 1 hour. After quenching the system with methanol, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylate 11g (240 mg) (yield 89%) was obtained.

[0507] MS m / z(ESI): 275.0 [M+1].

[0508] Step 7

[0509] 6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylic acid

[0510] Methyl 6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylate at 25°C 11g (80.0 mg, 0.292 mmol) was added to a mixed solution of tetrahydrofuran (1.5 mL) and water (1.5 mL), and then lithium hydroxide monohydrate (36.7 mg, 0.875 mmol) was added to this, and the mixture was allowed to react at 25°C for 18 hours. As a result of concentrating the mixture under reduced pressure, 6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylic acid 11h (75.0 mg) was obtained, which was used directly in the next step of the reaction.

[0511] MS m / z(ESI): 261.0 [M+1].

[0512] Step 8

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

[0514] 6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylic acid at 25°C 11h (75.0 mg, 0.288 mmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g (127 mg, 0.576 mmol) was added to N,N-dimethylformamide (5 mL), and then (7-azabenzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (300 mg, 0.576 mmol) and N,N-diisopropylethylamine (112 mg, 0.864 mmol) were added to the reaction solution. The mixture was allowed to react at 65°C for 2 hours. The mixture was poured into water (50 mL) and then extracted with ethyl acetate (100 mL). The organic phase was washed with a saturated sodium chloride solution (50 mL), dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. As a result of separating the residue by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), N-(3-chloro-5-(methylsulfonamido)phenyl)-6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxamide 11 (3.00 mg) (yield 2%) was obtained.

[0515] MS m / z(ESI): 463.0 [M+1].

[0516] 1 ¹H NMR(400 MHz, DMSO- d6 ) δ10.57(s, 1H), 10.39(s, 1H), 8.57(s, 1H), 8.50(dd, J = 4.4, 1.6 Hz, 1H), 7.72 - 7.59(m, 3H), 7.46(dd, J = 8.0, 4.4 Hz, 1H), 6.93(t, J = 2.0 Hz, 1H), 3.75(s, 2H), 3.03(s, 3H).

[0517] Example 12

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

[0519]

[0520] Step 1

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

[0522] Methyl 6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylate at 25°C 11g (200 mg, 0.729 mmol) was added to a borane solution in tetrahydrofuran (1 M, 10 mL), and the mixture was allowed to react 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), and the result was methyl 6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylate 12a (160 mg) (yield 84%) was obtained.

[0523] MS m / z(ESI): 261.0 [M+1].

[0524] Step 2

[0525] 6,7-Dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylic acid

[0526] Methyl 6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylate at 25°C 12a (40.0 mg, 0.154 mmol) was added to a mixed solution of tetrahydrofuran (1 mL), methanol (2 mL), and water (1 mL), after which lithium hydroxide monohydrate (19.3 mg, 0.461 mmol) was added, and the mixture was allowed to react at 25°C for 2 hours. The mixture was concentrated under reduced pressure, and as a result, 6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylic acid 12b (40 mg) was obtained, which was used directly in the next step of the reaction.

[0527] MS m / z(ESI): 247.0 [M+1].

[0528] Step 3

[0529] N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxamide

[0530] 6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylic acid at 25°C 12b (40.0 mg, 0.162 mmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g (71.7 mg, 0.325 mmol) N,N - Added to dimethylformamide (4 mL), then (7-azabenzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (169 mg, 0.325 mmol) and N,NDiisopropylethylamine (63.0 mg, 0.487 mmol) was added to the reaction solution, and the mixture was allowed to react at 65°C for 3 hours. The mixture was poured into water (100 mL) and then extracted with ethyl acetate (150 mL). The organic phase was washed with a saturated sodium chloride solution (50 mL), dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. As a result of separating the residue by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxamide 12 (11.0 mg) (yield 15%) was obtained.

[0531] MS m / z(ESI): 449.0 [M+1].

[0532] 1 ¹H NMR(400 MHz, DMSO- d 6) δ10.60(s, 1H), 10.07(s, 1H), 8.84(s, 1H), 8.03(dd, J = 4.4, 1.6 Hz, 1H), 7.71 - 7.69(m, 2H), 7.18(dd, J = 8.0, 1.6 Hz, 1H), 7.07(dd, J = 8.0, 4.4 Hz, 1H), 6.94(t, J = 2.0 Hz, 1H), 6.48(t, J = 4.4 Hz, 1H), 3.38 - 3.33(m, 2H), 3.23 - 3.19(m, 2H), 3.07(s, 3H).

[0533] Example 13

[0534] 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

[0535]

[0536] Step 1

[0537] Methyl 5-methyl-6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylate

[0538] At 25°C, methyl 6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylate in tetrahydrofuran (10 mL) with iodomethane (51.8 mg, 0.365 mmol) and cesium carbonate (178 mg, 0.547 mmol). 11g It was added to a solution of (50.0 mg, 0.183 mmol), and the mixture was allowed to react at 50°C for 1 hour. After filtering the mixture and concentrating it under reduced pressure, the result was methyl 5-methyl-6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylate 13a (50.0 mg) was obtained, which was used directly in the next step.

[0539] MS m / z(ESI): 289.0 [M+1].

[0540] Step 2

[0541] 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

[0542] Methyl 5-methyl-6-oxo-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylate at 25°C 13a (50.0 mg, 0.173 mmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g(76.5 mg, 0.347 mmol) was added to tetrahydrofuran (10 mL), then a trimethylaluminum solution in n-hexane (2 M, 0.86 mL) was added to the reaction solution, and the mixture was allowed to react at 60°C for 3 hours. The mixture was poured into methanol (50 mL) and concentrated under reduced pressure. As a result of separating the residue by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), 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%) was obtained.

[0543] MS m / z(ESI): 472.2 [M+1].

[0544] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ10.59(s, 1H), 10.12(s, 1H), 8.69 - 8.49(m, 2H), 8.03(dd, J = 8.4, 1.2 Hz, 1H), 7.71 - 7.64(m, 2H), 7.55(dd, J = 8.4, 4.4 Hz, 1H), 6.96(t, J = 2.0 Hz, 1H), 3.74(s, 2H), 3.27(s, 3H), 3.06(s, 3H).

[0545] Example 14

[0546] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxamide

[0547]

[0548] Step 1

[0549] Methyl 5-methyl-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylate

[0550] At 25°C, aqueous formaldehyde solution (156 mg, 1.92 mmol, purity 37%), acetic acid (23.1 mg, 0.384 mmol), and sodium triacetoxyborohydride (244 mg, 1.15 mmol) were mixed with methyl 6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylate in 1,2-dichloroethane (5 mL). 12a (100 mg, 0.384 mmol) was added to the solution, and the mixture was 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 a saturated sodium chloride solution (50 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 5-methyl-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylate 14a (100 mg) (yield 95%) was obtained.

[0551] MS m / z(ESI): 275.0 [M+1].

[0552] Step 2

[0553] 5-methyl-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylic acid

[0554] Methyl 5-methyl-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylate at 25°C 14a(85.0 mg, 0.310 mmol) was added to a mixed solution of tetrahydrofuran (3 mL) and water (1.5 mL), and then lithium hydroxide monohydrate (39.0 mg, 0.930 mmol) was added, after which the mixture was allowed to react at 50°C for 2 hours. The mixture was concentrated under reduced pressure, and as a result, 5-methyl-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylic acid 14b (80 mg) was obtained, which was used directly in the next step.

[0555] MS m / z(ESI): 261.0 [M+1].

[0556] Step 3

[0557] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxamide

[0558] 5-methyl-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxylic acid at 25°C 14b (80.0 mg, 0.307 mmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g (136 mg, 0.615 mmol) N , N - Added to dimethylformamide (5 mL), and then (7-azabenzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (641 mg, 1.23 mmol) and N , NDiisopropylethylamine (238 mg, 1.84 mmol) was added to the reaction solution, and the mixture was allowed to react at 65°C for 3 hours. The mixture was poured into water (100 mL) and then extracted with ethyl acetate (150 mL). The organic phase was washed with a saturated sodium chloride solution (50 mL), dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. As a result of separating the residue by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-6,7-dihydro-5H-pyrido[3,2-b]thieno[3,2-d]azepine-9-carboxamide 14 (10.0 mg) (yield 12%) was obtained.

[0559] MS m / z(ESI): 463.2 [M+1].

[0560] 1 ¹H NMR(400 MHz, DMSO- d 6) δ10.61(s, 1H), 10.11(s, 1H), 8.81(s, 1H), 8.18(dd, J = 4.4, 1.6 Hz, 1H), 7.72 - 7.69(m, 2H), 7.37(dd, J = 8.4, 1.6 Hz, 1H), 7.23(dd, J = 8.4, 4.4 Hz, 1H), 6.94(t, J = 2.0 Hz, 1H), 3.34 - 3.30(m, 2H), 3.30 - 3.26(m, 2H), 3.07(s, 3H), 2.99(s, 3H).

[0561] Example 15

[0562] N-(3-chloro-5-(methylsulfonamido)phenyl)-10-methoxy-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxamide

[0563]

[0564] Step 1

[0565] Methyl 4-(2-amino-6-methoxyphenyl)-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate

[0566] Methyl 4-bromo-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate at room temperature 11d (3.00 g, 10.23 mmol) was dissolved in a mixed solution of 1,2-dimethoxyethane (30 mL) and water (3 mL), and then 2-bromo-3-methoxyaniline was added thereto 15a (6.20 g, 30.70 mmol), potassium carbonate (4.24 g, 30.70 mmol), bis(pinacoleto)diborone (12.99 g, 51.17 mmol), palladium(II) acetate (459.53 mg, 2.05 mmol), and di(1-adamantyl)-n-butylphosphine (1.47 g, 4.09 mmol) were added sequentially. Nitrogen purging was performed three times on the mixture, followed by carrying out the reaction 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), and the result was methyl 4-(2-amino-6-methoxyphenyl)-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate 15b (2.80 g) (yield 81%) was obtained.

[0567] MS m / z(ESI): 336.0 [M+1].

[0568] Step 2

[0569] Methyl 10-methoxy-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate

[0570] Methyl 4-(2-amino-6-methoxyphenyl)-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate at room temperature 15b(2.80 g, 8.35 mmol) was dissolved in toluene (15 mL), and then N,N-diisopropylethylamine (6.47 g, 50.09 mmol) was added dropwise. Nitrogen purging was performed on the mixture three times, then heated to 100°C and allowed to react for 18 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 10-methoxy-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate 15c (1.30 g) (yield 51%) was obtained.

[0571] MS m / z(ESI): 304.0 [M+1].

[0572] Step 3

[0573] Methyl 10-methoxy-6-methyl-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate

[0574] Methyl 10-methoxy-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate at room temperature 15c (280.00 mg, 0.92 mmol) was dissolved in a 3 mL tetrahydrofuran solution, to which cesium carbonate (902.27 mg, 2.77 mmol) and iodomethane (262.04 mg, 1.85 mmol) were sequentially added. Nitrogen purging was performed three times on the mixture, followed by the reaction being carried out at 25°C for 3 hours. The reaction solution was filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 10-methoxy-6-methyl-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate 15d (220 mg) (yield 75%) was obtained.

[0575] MS m / z(ESI): 318.0 [M+1].

[0576] Step 4

[0577] Methyl 10-methoxy-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate

[0578] Methyl 10-methoxy-6-methyl-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate at room temperature 15d (200.00 mg, 0.63 mmol) was dissolved in a 2 mL tetrahydrofuran solution, to which borane-tetrahydrofuran (1 M, 1.89 mmol, 162.48 mg) was added dropwise, and the reaction was carried out at 25°C for 1 hour. The reaction solution was poured into 50 mL of methanol, stirred at 50°C for 0.5 hours, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 10-methoxy-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate 15e (125 mg) (yield 65%) was obtained.

[0579] MS m / z(ESI): 304.0 [M+1].

[0580] Step 5

[0581] N-(3-chloro-5-(methylsulfonamido)phenyl)-10-methoxy-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxamide

[0582] Methyl 10-methoxy-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate at room temperature 15e (125.00 mg, 0.41 mmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g(90.90 mg, 0.41 mmol) was dissolved in a tetrahydrofuran (1 mL) solution, and then a trimethylaluminum solution in n-hexane (1 M, 1.24 mmol, 89.10 mg) was added dropwise. The reaction was carried out at 60°C for 18 hours. To quench the reaction, the solution was poured into methanol (50 mL) and then concentrated under reduced pressure. As a result of separating the residue by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), N-(3-chloro-5-(methylsulfonamido)phenyl)-10-methoxy-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxamide 15 (106 mg) (yield 52%) was obtained.

[0583] MS m / z(ESI): 492.0 [M+1].

[0584] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ 10.31(s, 1H), 10.17(s, 1H), 8.11(s, 1H), 7.64(dt, J = 15.2, 1.8 Hz, 2H), 7.29(t, J = 8.2 Hz, 1H), 6.95(t, J = 1.8 Hz, 1H), 6.81(t, J = 7.8 Hz, 2H), 3.80(s, 3H), 3.42(t, J = 6.6 Hz, 2H), 3.06(s, 3H), 2.83(t, J = 6.6 Hz, 2H), 2.69(s, 3H).

[0585] The compounds of Examples 16 to 18 were prepared according to the method of Example 15 of the present invention, and the specific structures and results of structural characterization are presented below:

[0586]

[0587]

[0588] Example 19

[0589] 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxamide

[0590]

[0591] Step 1

[0592] 1-(benzyloxy)-2-bromo-3-nitrobenzene

[0593] 2-Bromo-3-nitrophenol 19a 1 g (4.59 mmol) was dissolved in tetrahydrofuran (10 mL), and then 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, and the reaction solution was stirred at room temperature for 12 hours. The resulting mixture was filtered under reduced pressure, the filter cake was washed with dichloromethane (5 mL x 3), and the resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and 1-(benzyloxy)-2-bromo-3-nitrobenzene 19b (1.26 g) (yield 89%) was obtained.

[0594] MS m / z(ESI): 308.0 [M+1].

[0595] Step 2

[0596] 3-(benzyloxy)-2-bromoaniline

[0597] 1-(benzyloxy)-2-bromo-3-nitrobenzene 19b(1.26 g, 4.09 mmol) was dissolved in ethanol (12 mL), and then 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. Nitrogen purging was performed three times on the reaction solution, and the mixture was stirred at 90°C for 2 hours under nitrogen protection. The resulting mixture was filtered under reduced pressure, the filter cake was washed with dichloromethane (5 mL x 3), and the resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and 3-(benzyloxy)-2-bromoaniline 19c (1.0 g) (yield 88%) was obtained.

[0598] MS m / z(ESI): 278.0 [M+1].

[0599] Step 3

[0600] Methyl 4-(2-amino-6-(benzyloxy)phenyl)-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate

[0601] 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) was dissolved in 1,4-dioxane (20 mL), and then bis(pinacoleto)diborone (1.83 g, 7.19 mmol), di(1-adamantyl)-n-butylphosphine (343.75 mg, 958.74 μmol), potassium carbonate (993.77 mg, 7.19 mmol), palladium(II) acetate (107.62 mg, 479.37 μmol), and water (2 mL) were added to the resulting solution. Nitrogen purging was performed on the reaction solution three times, and then the mixture was stirred for 1 hour at 80°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and then purified by silica gel column chromatography (eluent: System A), resulting in methyl 4-(2-amino-6-(benzyloxy)phenyl)-5-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate 19d (900 mg) (yield 45%) was obtained.

[0602] MS m / z(ESI): 412.2 [M+1].

[0603] Step 4

[0604] Methyl 10-(benzyloxy)-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate

[0605] 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), and then a solution of trimethylaluminum in n-hexane (1 M, 9.72 mL) was slowly added dropwise to the resulting solution, and the reaction solution was stirred at 60°C for 1 hour. The reaction solution was slowly added dropwise to methanol (20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 10-(benzyloxy)-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate 19e(200 mg) (yield 54%) was obtained.

[0606] MS m / z(ESI): 380.0 [M+1].

[0607] Step 5

[0608] Methyl 10-(benzyloxy)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate

[0609] Methyl 10-(benzyloxy)-5-oxo-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate 19e (150 mg, 395.33 μmol) was slowly added to a borane-tetrahydrofuran complex (1 M, 4 mL). The reaction solution was stirred at 60°C for 1 hour, then the reaction solution was slowly added dropwise to methanol (20 mL) and stirred at 60°C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 10-(benzyloxy)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate 19f (100 mg) (yield 69%) was obtained.

[0610] MS m / z(ESI): 336.2 [M+1].

[0611] Step 6

[0612] Methyl 10-(benzyloxy)-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate

[0613] Methyl 10-(benzyloxy)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate 19fSodium triacetoxyborohydride (100 mg, 273.64 μmol) was dissolved in 1,2-dichloroethane (4.00 mL), and then sodium triacetoxyborohydride (347.97 mg, 1.64 mmol), acetic acid (1.64 mg, 27.36 μmol, 1.57 μL), and an aqueous formaldehyde solution (133.24 mg, 1.64 mmol, 122.24 μL, purity 37%) were added to the resulting solution, after which the reaction solution was stirred at room temperature for 12 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 10-(benzyloxy)-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate 19g (90 mg) (yield 86%) was obtained.

[0614] MS m / z(ESI): 380.2 [M+1].

[0615] Step 7

[0616] 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxamide

[0617] Methyl 10-(benzyloxy)-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate 19g (20 mg, 52.70 μmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g(17.45 mg, 79.06 μmol) was dissolved in tetrahydrofuran (1 mL), and then a solution of trimethylaluminum in n-hexane (1 M, 527.05 μL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 60°C for 1 hour, and then the reaction solution was slowly added dropwise to methanol (5 mL) to rapidly cool the reaction. The resulting mixture was concentrated under reduced pressure. As a result of purifying the residue by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH₃CN), 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-6-methyl-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxamide 19 (11 mg) (yield 36%) was obtained.

[0618] MS m / z(ESI): 568.2 [M+1].

[0619] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ10.28(s, 1H), 10.14(s, 1H), 8.26(s, 1H), 7.63(dt, J = 4.4, 2.0 Hz, 2H), 7.44(d, J = 6.4 Hz, 2H), 7.30 - 7.22(m, 4H), 6.95(t, J = 2.0 Hz, 1H), 6.90(d, J = 8.0 Hz, 1H), 6.81(d, J = 8.0 Hz, 1H), 5.14(s, 2H), 3.42(t, J = 6.4 Hz, 2H), 3.07(s, 3H), 2.84(t, J = 6.4 Hz, 2H), 2.71(s, 3H).

[0620] The compounds of Examples 20 to 26 were prepared according to the method of Example 19 of the present invention, and their specific structures and structural characterization results are presented below:

[0621]

[0622]

[0623] Example 27

[0624] 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

[0625]

[0626] Step 1

[0627] Methyl 5-bromo-1-(2-methoxy-2-oxoethyl)-1H-pyrrole-3-carboxylate

[0628] Methyl 5-bromo-1H-pyrrole-3-carboxylate 27a (1.5 g, 7.35 mmol) and methyl acetate bromide (1.69 g, 11.03 mmol) were dissolved in acetonitrile (30 mL), to which potassium carbonate (3.05 g, 22.06 mmol) was added, and the mixture was allowed to react at room temperature for 12 hours. The reaction solution was filtered through diatomite and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 5-bromo-1-(2-methoxy-2-oxoethyl)-1H-pyrrole-3-carboxylate 27b (1.8 g) (yield 88%) was obtained.

[0629] MS m / z(ESI): 276.0 [M+1].

[0630] Step 2

[0631] Methyl 6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxylate

[0632] 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), bis(pinacoleto)diborone (5.52 g, 21.73 mmol), di(1-adamantyl)-butylphosphine (1.04 g, 2.90 mmol), and potassium carbonate (5.01 g, 36.22 mmol) were dissolved in 1,2-dimethoxyethane (20 mL) and water (4 mL). Nitrogen purging was performed three times on the reaction solution. Palladium(II) acetate (325.28 mg, 1.45 mmol) was added under nitrogen protection, and the reaction was carried out at 80°C for 12 hours. After diluting the reaction solution with water, it was extracted with ethyl acetate (100 mL x 3). After combining the extracts, they were washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxylate 27c (600 mg) (yield 32%) was obtained.

[0633] MS m / z(ESI): 258.2 [M+1].

[0634] Step 3

[0635] 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

[0636] N -(3-amino-5-chlorophenyl)methanesulfonamide 1g(171.57 mg, 777.47 μmol) was dissolved in tetrahydrofuran (1 mL) and toluene (1 mL), and then trimethylaluminum solution in n-hexane (2 M, 583.10 μL) was added dropwise at 0°C, and the mixture was stirred at 25°C for 0.5 hours. Methyl 6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxylate was added to the reaction solution. 27c After adding (100 mg, 388.74 μmol), the mixture was allowed to react at 60°C for 1 hour. After the reaction was complete, the reaction solution was quenched with methanol and then evaporatively dried. The residue was purified by silica gel column chromatography (eluent: System A) and further separated by pre-liquid chromatography (column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), resulting in 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 27 (7 mg) (yield 19%) was obtained.

[0637] MS m / z(ESI): 446.0 [M+1].

[0638] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ10.50(s, 1H), 10.03(s, 1H), 9.98(s, 1H), 8.46(d, J = 4.4 Hz, 1H), 7.80(s, 1H), 7.75(s, 1H), 7.67(s, 1H), 7.56(d, J = 8.0 Hz, 1H), 7.45 - 7.35(m, 2H), 6.90(s, 1H), 4.81(s, 2H), 3.07(s, 3H).

[0639] Example 28

[0640] 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

[0641]

[0642] Step 1

[0643] Methyl 5-methyl-6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxylate

[0644] Methyl 6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxylate 27c (300 mg, 1.17 mmol) and potassium carbonate (322.35 mg, 2.33 mmol) N,N After dissolving in dimethylformamide (5 mL), iodomethane (248.29 mg, 1.75 mmol, 108.90 μL) was added, and the mixture was allowed to react at room temperature for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate (50 mL x 3). The extracts were combined, washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 5-methyl-6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxylate 28a (300 mg) (yield 95%) was obtained.

[0645] MS m / z(ESI): 272.1 [M+1].

[0646] Step 2

[0647] 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

[0648] Methyl 5-methyl-6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxylate 28a (250 mg, 921.59 μmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g (406.75 mg, 1.84 mmol) was dissolved in tetrahydrofuran (2 mL) and toluene (2 mL), and then trimethylaluminum solution in n-hexane (2 M, 2.76 mL) was added dropwise at 0°C, and the mixture was allowed to react at 60°C for 3 hours. After the reaction was complete, the reaction solution was quenched with methanol and then evaporated. The residue was purified by silica gel column chromatography (eluent: System A) and then further separated by pre-liquid chromatography (column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), resulting in 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 28 (92 mg) (yield 22%) was obtained.

[0649] MS m / z(ESI): 460.0 [M+1].

[0650] 1 ¹H NMR(400 MHz, DMSO- d 6) δ9.97(s, 2H), 8.54(dd, J = 4.8, 1.2 Hz, 1H), 7.97(dd, J = 8.0, 1.2 Hz, 1H), 7.84(d, J = 1.6 Hz, 1H), 7.73(t, J = 1.6 Hz, 1H), 7.65(s, 1H), 7.50(dd, J = 8.4, 4.8 Hz, 1H), 7.38(d, J = 2.0 Hz, 1H), 6.90(t, J = 2.0 Hz, 1H), 4.78(s, 2H), 3.28(s, 3H), 3.05(s, 3H).

[0651] Example 29

[0652] N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxamide

[0653]

[0654] Step 1

[0655] Methyl 6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxylate

[0656] Methyl 6-oxo-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxylate 27c 200 mg (777.47 μmol) was dissolved in 5 mL of tetrahydrofuran, and then 9.72 mL of dimethylborane sulfide was added dropwise at 0°C, after which the mixture was allowed to react 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), and the result was methyl 6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxylate 29a (110 mg) (yield 58%) was obtained.

[0657] MS m / z(ESI): 244.0 [M+1].

[0658] Step 2

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

[0660] Methyl 6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxylate 29a (90 mg, 369.97 μmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g (163.29 mg, 739.95 μmol) was dissolved in tetrahydrofuran (2 mL) and toluene (2 mL), then trimethylaluminum (2 M, 554.96 μL) was added dropwise at 0°C, and the mixture was allowed to react at 60°C for 3 hours. After the reaction was complete, the reaction solution was quenched with methanol and then evaporated. The residue was purified by silica gel column chromatography (eluent: System A) and then further separated by pre-liquid chromatography (column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), resulting in N-(3-chloro-5-(methylsulfonamido)phenyl)-6,7-dihydro-5H-pyrido[2,3-f]pyrrolo[1,2-d][1,4]diazepine-10-carboxamide 29 (50 mg) (yield 31%) was obtained.

[0661] MS m / z(ESI): 432.1 [M+1].

[0662] 1 ¹H NMR(400 MHz, DMSO- d 6) δ9.99(s, 1H), 9.89(s, 1H), 7.94(dd, J = 4.0, 1.2 Hz, 1H), 7.76(t, J = 2.0 Hz, 1H), 7.70(t, J = 1.6 Hz, 1H), 7.56(d, J = 2.0 Hz, 1H), 7.52(d, J = 2.0 Hz, 1H), 7.11(dd, J = 8.4, 1.6 Hz, 1H), 7.00(dd, J = 8.4, 4.4 Hz, 1H), 6.89(t, J = 1.6 Hz, 1H), 6.51(t, J = 4.0 Hz, 1H), 4.42 - 4.21(m, 2H), 3.46(dd, J = 7.2, 3.6 Hz, 2H), 3.07(s, 3H).

[0663] The compounds of Examples 30 to 34 were prepared according to the method of Example 29 of the present invention, and their specific structures and structural characterization results are presented below:

[0664]

[0665] Example 34

[0666] 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

[0667]

[0668] Step 1

[0669] Methyl 5-bromo-1-(2,2-dimethoxyethyl)-1H-pyrrole-3-carboxylate

[0670] Methyl 5-bromo-1H-pyrrole-3-carboxylate at 25℃ 27a5.00 g, 24.5 mmol of methyl 5-bromo-1-(2,2-dimethoxyethyl)-1H-pyrrole-3-carboxylate was added to acetonitrile (50 mL) and the mixture was allowed to react at 80°C for 18 hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 5-bromo-1-(2,2-dimethoxyethyl)-1H-pyrrole-3-carboxylate 34a (5.0 g) (yield 70%) was obtained.

[0671] MS m / z(ESI): 292.0 / 294 [M+1].

[0672] Step 2

[0673] Methyl 5-bromo-1-(2-oxoethyl)-1H-pyrrole-3-carboxylate

[0674] Methyl 5-bromo-1-(2,2-dimethoxyethyl)-1H-pyrrole-3-carboxylate at 25°C 34a (1.00 g, 3.42 mmol) was added to trifluoroacetic acid (10 mL), and the mixture was allowed to react at 25°C for 0.5 hours. As a result of concentrating the system under reduced pressure, methyl 5-bromo-1-(2-oxoethyl)-1H-pyrrole-3-carboxylate 34b (800 mg) was obtained, 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] Methyl 5-bromo-1-(2-oxoethyl)-1H-pyrrole-3-carboxylate at 25°C 34b700 mg (2.84 mmol) was added to 1,2-dichloroethane (10 mL), and then sodium boroacetoxyhydrogenate (1.81 g, 8.53 mmol), acetic acid (17.1 mg, 0.284 mmol), and 2-bromo-3-methoxycyaniline (575 mg, 2.84 mmol) were added to the reaction solution, and the mixture was allowed to react at 25°C for 18 hours. After adding methanol (20 mL) to the system, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 5-bromo-1-(2-((2-bromo-3-methoxyphenyl)amino)ethyl)-1H-pyrrole-3-carboxylate 34c (150 mg) (yield 12%) was obtained.

[0679] MS m / z(ESI): 430.9 / 432.9 / 434.9 [M+1].

[0680] Step 4

[0681] Methyl 11-methoxy-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[0682] Methyl 5-bromo-1-(2-((2-bromo-3-methoxyphenyl)amino)ethyl)-1H-pyrrole-3-carboxylate at 25°C 34cAfter adding (140 mg, 0.324 mmol) to a mixed solution of 1,4-dioxane (5 mL) and water (1 mL), palladium(II) acetate (14.5 mg, 0.0648 mmol), bis(pinacoleto)diborone (247 mg, 0.972 mmol), potassium carbonate (134 mg, 0.972 mmol), and di(1-adamantyl)-n-butylphosphine (46.5 mg, 0.130 mmol) were added to the reaction solution. The mixture was heated to 80°C under nitrogen protection and then allowed to proceed for 18 hours. The system was filtered and then concentrated under reduced pressure. As a result of purifying the residue by silica gel column chromatography (eluent: System A), methyl 11-methoxy-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate 34d (80 mg) (yield 91%) was obtained.

[0683] MS m / z(ESI): 273.1 [M+1].

[0684] Step 5

[0685] Methyl 11-methoxy-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[0686] Methyl 11-methoxy-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate at 25°C 34d (80 mg, 0.294 mmol) was dissolved in methanol (5 mL), and then an aqueous formaldehyde solution (298 mg, 3.67 mmol, 0.27 mL, purity 37%) and carbonaceous palladium (40.0 mg, Pd content 10%, moisture content 55% w / w) were added to the reaction solution. The mixture was allowed to react at 25°C for 2 hours under a hydrogen atmosphere. After filtering the system, the filtrate was concentrated under reduced pressure, resulting in methyl 11-methoxy-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate 34e(80.0 mg) was obtained, which was used directly in the next step.

[0687] MS m / z(ESI): 287.1 [M+1].

[0688] Step 6

[0689] 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

[0690] Methyl 11-methoxy-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate at 25°C 34e (50.0 mg, 0.175 mmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g (57.8 mg, 0.262 mmol) was added to tetrahydrofuran (10 mL), and then a trimethylaluminum solution in n-hexane (1 M, 0.87 mL) was added to the reaction solution, and the mixture was allowed to react at 60°C for 18 hours. The mixture was poured into methanol (50 mL) and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) and then further separated by pre-liquid chromatography (column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), resulting in 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 34 (16 mg) (yield 19%) was obtained.

[0691] MS m / z(ESI): 475.2 [M+1].

[0692] 1 ¹H NMR(400 MHz, DMSO- d6) δ10.06(s, 1H), 9.75(s, 1H), 7.71(t, J = 2.0 Hz, 1H), 7.67(d, J = 2.0 Hz, 1H), 7.62(t, J = 2.0 Hz, 1H), 7.27(t, J = 8.0 Hz, 1H), 6.88(t, J = 2.0 Hz, 1H), 6.83 - 6.77(m, 2H), 6.74(d, J = 8.0 Hz, 1H), 4.01(t, J = 6.0 Hz, 2H), 3.78(s, 3H), 3.35(d, J = 6.0 Hz, 2H), 3.05(s, 3H), 2.70(s, 3H).

[0693] Example 35

[0694] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-methoxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[0695]

[0696] Step 1

[0697] Methyl 5-bromo-1-(2-hydroxyethyl)-1H-pyrrole-3-carboxylate

[0698] Methyl 5-bromo-1H-pyrrole-3-carboxylate at 25℃ 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), and the mixture was allowed to react at 80 °C for 18 hours. The system was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 5-bromo-1-(2-hydroxyethyl)-1H-pyrrole-3-carboxylate 35a (900 mg) (yield 74%) was obtained.

[0699] MS m / z(ESI): 247.9 / 249.9 [M+1].

[0700] Step 2

[0701] Methyl 5-bromo-1-(2-(2-bromo-3-methoxyphenoxy)ethyl)-1H-pyrrole-3-carboxylate

[0702] Methyl 5-bromo-1-(2-hydroxyethyl)-1H-pyrrole-3-carboxylate at 25°C 35a methyl 5-bromo-1-(2-(2-bromo-3-methoxyphenoxy)ethyl)-1H-pyrrole-3-carboxylate (400 mg, 1.61 mmol), cyanomethylene tributylphosphorane (973 mg, 4.03 mmol), and 2-bromo-3-methoxyphenol (491 mg, 2.42 mmol) were added to toluene (5 mL), and the mixture was allowed to react at 80 °C for 2 hours. The system was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 5-bromo-1-(2-(2-bromo-3-methoxyphenoxy)ethyl)-1H-pyrrole-3-carboxylate 35b (400 mg) (yield 57%) was obtained.

[0703] MS m / z(ESI): 431.9 / 433.9 / 435.9 [M+1].

[0704] Step 3

[0705] Methyl 11-methoxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[0706] Methyl 5-bromo-1-(2-(2-bromo-3-methoxyphenoxy)ethyl)-1H-pyrrole-3-carboxylate at 25°C 35bAfter adding (400 mg, 0.927 mmol) to a mixed solution of 1,4-dioxane (10 mL) and water (2 mL), palladium(II) acetate (62.2 mg, 0.277 mmol), bis(pinacoleto)diborone (1.06 g, 4.16 mmol), potassium carbonate (574 mg, 4.16 mmol), and di(1-adamantyl)-n-butylphosphine (199 mg, 0.554 mmol) were added to the reaction solution. The mixture was allowed to react for 18 hours at 80°C under nitrogen protection. After filtering the system, it was concentrated under reduced pressure. As a result of purifying the residue by silica gel column chromatography (eluent: System A), methyl 11-methoxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 35c (200 mg) (yield 79%) was obtained.

[0707] MS m / z(ESI): 274.0 [M+1].

[0708] Step 4

[0709] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-methoxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[0710] Methyl 11-methoxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate at 25°C 35c (200 mg, 0.732 mmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g(242 mg, 1.10 mmol) was added to tetrahydrofuran (10 mL), and then a trimethylaluminum solution in n-hexane (2 M, 1.8 mL) was added to the reaction solution, and the mixture was allowed to react at 60°C for 18 hours. The mixture was poured into methanol (50 mL) and concentrated under reduced pressure. After purifying the residue by silica gel column chromatography (eluent: System A), and then further separating it by pre-liquid chromatography (column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), N-(3-chloro-5-(methylsulfonamido)phenyl)-11-methoxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide 35 (60 mg) (yield 18%) was obtained.

[0711] MS m / z(ESI): 462.0 [M+1].

[0712] 1 ¹H NMR(400 MHz, DMSO- d 6) δ10.07(s, 1H), 9.82(s, 1H), 7.78 - 7.68(m, 2H), 7.63(t, J = 2.0 Hz, 1H), 7.28(t, J = 8.0 Hz, 1H), 6.97 - 6.92(m, 2H), 6.89(t, J = 2.0 Hz, 1H), 6.78(dd, J = 8.0, 1.2 Hz, 1H), 4.42(t, J = 6.0 Hz, 2H), 4.15(t, J = 6.0 Hz, 2H), 3.83(s, 3H), 3.05(s, 3H).

[0713] The compounds of Examples 36 and 37 were prepared according to the method of Example 35 of the present invention, and the specific structures and structural characterization results are presented below:

[0714]

[0715] Example 38

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

[0717]

[0718] Step 1

[0719] 2-Bromo-3-(hydroxymethyl)phenol

[0720] 2-bromo-3-hydroxybenzaldehyde at room temperature 38a Sodium borohydride (1.13 g, 29.85 mmol) was dissolved in methanol (30 mL), and then sodium borohydride was added. Nitrogen purging was performed three times on the mixture, and the reaction was carried out at 25°C for 18 hours. The reaction solution was diluted in methanol (80 mL) and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and as a result, 2-bromo-3-(hydroxymethyl)phenol 38b (1.78 g) (yield 88%) was obtained.

[0721] MS m / z(ESI): 185.0 / 187.0 [M+1].

[0722] Step 2

[0723] 2-Bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenol

[0724] 2-bromo-3-(hydroxymethyl)phenol at room temperature 38b(1.78 g, 8.77 mmol) was dissolved in dichloromethane (20 mL), and then imidazole (1.19 g, 17.53 mmol) was added. Next, a solution of tert-butyldimethylsilyl chloride (1.45 g, 9.64 mmol) in dichloromethane (2 mL) was added dropwise. After performing nitrogen purging on the mixture three times, the reaction was carried out 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 phase was washed with a saturated sodium chloride solution (50 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was 2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenol 38c (1.5 g) (yield 54%) was obtained.

[0725] MS m / z(ESI): 317.0 / 319.0 [M+1].

[0726] Step 3

[0727] Methyl 5-bromo-1-(2-(2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenoxy)ethyl)-1H-pyrrole-3-carboxylate

[0728] 2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenol at room temperature 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) was dissolved in toluene (10 mL), and then cyanomethylene tributylphosphorane (1.46 g, 6.05 mmol, 1.58 mL) was added dropwise. Nitrogen purging was performed on the mixture three times, and 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: System A), and the result was methyl 5-bromo-1-(2-(2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenoxy)ethyl)-1H-pyrrole-3-carboxylate 38d (580 mg) (yield 52%) was obtained.

[0729] MS m / z(ESI): 568.0 / 570.0 / 572.0 [M+23].

[0730] Step 4

[0731] Methyl 11-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[0732] methyl 5-bromo-1-(2-(2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenoxy)ethyl)-1H-pyrrole-3-carboxylate at room temperature 38d(580.00 mg, 1.06 mmol) was dissolved in a mixed solution of 1,2-dimethoxyethane (6 mL) and water (0.5 mL), and then potassium carbonate (439.35 mg, 3.18 mmol), bis(pinacoleto)diborone (807.25 mg, 3.18 mmol), palladium(II) acetate (47.58 mg, 0.21 mmol), and di(1-adamantyl)-n-butylphosphine (151.97 mg, 0.42 mmol) were added sequentially. Nitrogen purging was performed three times on the mixture, and the reaction was then carried out at 80°C for 1 hour. The reaction solution was filtered and then concentrated under reduced pressure. As a result of purifying the residue by silica gel column chromatography (eluent: System A), methyl 11-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 38e (327 mg) (yield 79%) was obtained.

[0733] MS m / z(ESI): 388.2 [M+1].

[0734] Step 5

[0735] Methyl 11-(hydroxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[0736] methyl 11-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate at room temperature 38e (277.00 mg, 0.71 mmol) was dissolved in dichloromethane (1 mL), and then a solution of hydrogen chloride in ethyl acetate (4 M, 1.2 mL) was added dropwise. The reaction was carried out at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 11-(hydroxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 38f(107 mg) (yield 55%) was obtained.

[0737] MS m / z(ESI): 274.2 [M+1].

[0738] Step 6

[0739] Methyl 11-(phenoxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[0740] Methyl 11-(hydroxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate at room temperature 38f After dissolving (107.00 mg, 0.39 mmol) and phenol (55.27 mg, 0.59 mmol) in a 1 mL toluene solution, cyanomethylene tributylphosphorane (283.50 mg, 1.17 mmol, 0.31 mL) was added dropwise. Nitrogen purging was performed three times on the mixture, followed by the reaction being 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: System A), and the result was methyl 11-(phenoxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 38g (97 mg) (yield 71%) was obtained.

[0741] MS m / z(ESI): 350.2 [M+1].

[0742] Step 7

[0743] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-(phenoxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[0744] Methyl 11-(phenoxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate at room temperature 38g (97.00 mg, 0.28 mmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g(61.27 mg, 0.28 mmol) was dissolved in a tetrahydrofuran (1 mL) solution, and then trimethylaluminum (80.00 mg, 1.11 mmol, 2 M) was added dropwise. The reaction was carried out at 60°C for 18 hours. The reaction solution was poured into methanol (50 mL) and quenched, and then concentrated under reduced pressure. As a result of separating the residue by preliminary liquid chromatography (column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), N-(3-chloro-5-(methylsulfonamido)phenyl)-11-(phenoxymethyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide 38 (57 mg) (yield 38%) was obtained.

[0745] MS m / z(ESI): 538.2 [M+1].

[0746] 1H NMR (400 MHz, DMSO- d 6 ) δ 10.00(s, 1H), 9.84(s, 1H), 7.84(d, J = 1.6 Hz, 1H), 7.66(t, J = 1.6 Hz, 1H), 7.60(t, J = 1.6 Hz, 1H), 7.46(dd, J = 7.8, 1.2 Hz, 1H), 7.39(t, J = 7.8 Hz, 1H), 7.32 - 7.26(m, 2H), 7.19(dd, J = 7.8, 1.2 Hz, 1H), 6.98-6.89(m, 5H), 5.16(s, 2H), 4.43(t, J = 5.8 Hz, 2H), 4.17(t, J = 5.8 Hz, 2H), 3.05(s, 3H).

[0747] The compounds of Examples 39 to 48 were prepared according to the method of Example 9 of the present invention, and the specific structures and structural characterization results are presented below:

[0748]

[0749]

[0750]

[0751] Example 49

[0752] 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

[0753]

[0754] N-(3-chloro-5-(methanesulfonamido)phenyl)-10-methoxy-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxamide 45 (125.00 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL). Nitrogen purging was performed on the mixture three times, and then boron tribromide (185.67 mg, 0.74 mmol) was added dropwise. The reaction was carried out at 25°C for 18 hours. The reaction solution was poured into methanol (50 mL), stirred for 1 hour for quenching, filtered, and then concentrated under reduced pressure. As a result of separating the residue by preliminary liquid chromatography (column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), 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 49 (5 mg) (yield 8%) was obtained.

[0755] MS m / z(ESI): 492.0 [M+1].

[0756] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ 10.51(s, 1H), 10.20(s, 1H), 10.06(s, 1H), 8.53(s, 1H), 7.68(t, J = 1.6 Hz, 1H), 7.63(t, J = 1.8 Hz, 1H), 7.31 - 7.22(m, 2H), 7.12(dd, J = 7.8, 1.6 Hz, 1H), 6.95(t, J = 1.6 Hz, 1H), 4.47 - 4.28(m, 2H), 3.06(s, 3H), 3.05(s, 3H).

[0757] Example 50

[0758] 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

[0759]

[0760] Step 1

[0761] Methyl 4-bromo-5-(((tert-butoxycarbonyl)(methyl)amino)methyl)thiophene-2-carboxylate

[0762] 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) N,NIt was dissolved in dimethylformamide (50 mL), and then methyl iodide (6.08 g, 42.83 mmol, 2.67 mL) was added to the resulting mixture, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (100 mL x 3). The extract was dried with anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 4-bromo-5-(((tert-butoxycarbonyl)(methyl)amino)methyl)thiophene-2-carboxylate 50a (2.7 g) (yield 52%) was obtained.

[0763] MS m / z(ESI): 386.0 [M+1].

[0764] Step 2

[0765] methyl 5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate

[0766] Methyl 4-bromo-5-(((tert-butoxycarbonyl)(methyl)amino)methyl)thiophene-2-carboxylate 50a (500 mg, 1.37 mmol) and bis(pinacoleto)diborone (693.31 mg, 2.73 mmol) were dissolved in 1,4-dioxane (5 mL), and then 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) were added to the resulting mixture. Nitrogen purging was performed three times on the reaction solution, and the mixture was stirred at 90°C for 2 hours under nitrogen protection. As a result of filtering the reaction solution, methyl 5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate 50bA solution of was obtained, which was used directly in the next step.

[0767] MS m / z(ESI): 434.2 [M+1].

[0768] Step 3

[0769] methyl 4-(2-amino-6-(methoxycarbonyl)phenyl)-5-(((tert-butoxycarbonyl)(methyl)amino)methyl)thiophene-2-carboxylate

[0770] Methyl 3-amino-2-bromobenzoate (335.59 mg, 1.46 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (177.89 mg, 243.12 μmol), potassium carbonate (504.02 mg, 3.65 mmol), and water (2 mL) were mixed with methyl 5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate 50b It was added to the solution. Nitrogen purging was performed three times on the reaction solution, and the mixture was stirred at 90°C for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, diluted with water (20 mL), and extracted with ethyl acetate (30 mL x 3). The extract was dried with anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 4-(2-amino-6-(methoxycarbonyl)phenyl)-5-(((tert-butoxycarbonyl)(methyl)amino)methyl)thiophene-2-carboxylate 50c (154 mg) (yield 29%) was obtained.

[0771] MS m / z(ESI): 335.0 [M+1].

[0772] Step 4

[0773] Methyl 4-(2-amino-6-(methoxycarbonyl)phenyl)-5-((methylamino)methyl)thiophene-2-carboxylate

[0774] 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 a hydrogen chloride solution (2 mL, 4 M) in ethyl acetate, and the reaction solution was stirred at room temperature for 6 hours. As a result of concentrating the reaction solution under reduced pressure, methyl 4-(2-amino-6-(methoxycarbonyl)phenyl)-5-((methylamino)methyl)thiophene-2-carboxylate 50d The residue was obtained and was used directly in the next step.

[0775] MS m / z(ESI):335.0 [M+1].

[0776] Step 5

[0777] Methyl 10-amino-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate

[0778] Methyl 4-(2-amino-6-(methoxycarbonyl)phenyl)-5-((methylamino)methyl)thiophene-2-carboxylate 50d [The substance] was dissolved in tetrahydrofuran (2 mL), and triethylamine was slowly added dropwise to adjust the pH of the solution to 7. Nitrogen purging was performed three times on the resulting mixture, and 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 for 12 hours under nitrogen protection at 60°C. The reaction solution was slowly added to a methanol solution for quenching, and the mixture was concentrated. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 10-amino-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate 50e (60 mg) (yield 66%) was obtained.

[0779] MS m / z(ESI): 303.0 [M+1].

[0780] Step 6

[0781] Methyl 10-[bis(tert-butoxycarbonyl)amino]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepine-2-carboxylate

[0782] Methyl 10-amino-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate 50e After dissolving (60 mg, 198.45 μmol) in tetrahydrofuran (2 mL), di-tert-butyl bicarbonate (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) were added to the resulting mixture, and the reaction solution was stirred at 65°C for 1 hour. After filtering the reaction solution under reduced pressure, the filter cake was washed with ethyl acetate, and the filtrate was concentrated. As a result of purifying the residue by silica gel column chromatography (eluent: System A), methyl 10-[bis(tert-butoxycarbonyl)amino]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepine-2-carboxylate 50f (69 mg) (yield 86%) was obtained.

[0783] MS m / z(ESI): 503.2 [M+1].

[0784] Step 7

[0785] 10-[bis(tert-butoxycarbonyl)amino]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepine-2-carboxylic acid

[0786] Methyl 10-[bis(tert-butoxycarbonyl)amino]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepine-2-carboxylate 50f(69 mg, 137.29 μmol) was dissolved in tetrahydrofuran (2 mL) and water (1 mL), and then lithium hydroxide monohydrate (11.52 mg, 274.58 μmol) was added to the resulting mixture. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain 10-[bis(tert-butoxycarbonyl)amino]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepine-2-carboxylic acid 50g This was obtained and was used directly in the next step.

[0787] MS m / z(ESI): 489.0 [M+1].

[0788] Step 8

[0789] Carbamate tert-butyl N-tert-butoxycarbonyl-N-[2-[[3-chloro-5-(methanesulfonamido)phenyl]carbamoyl]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepine-10-yl]

[0790] 10-[bis(tert-butoxycarbonyl)amino]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepine-2-carboxylic acid 50g and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g (42.81 mg, 194.00 μmol) N,N - Dissolved in dimethylformamide (1 mL), and then in the resulting mixture, (7-azabenzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (202.29 mg, 388.00 μmol) and N , N--Diisopropylethylamine (100.29 mg, 776.00 μmol, 137.57 μL) was added. The reaction solution was stirred at 65°C for 2 hours. The reaction solution was diluted with water (10 mL) and then extracted with ethyl acetate (20 mL x 3). The extract was dried with anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was tert-butyl N-tert-butoxycarbonyl-N-[2-[[3-chloro-5-(methanesulfonamido)phenyl]carbamoyl]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepine-10-yl] 50h (80 mg) (yield 89%) was obtained.

[0791] MS m / z(ESI): 691.1 [M+1].

[0792] Step 9

[0793] 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

[0794] Carbamate tert-butyl N-tert-butoxycarbonyl-N-[2-[[3-chloro-5-(methanesulfonamido)phenyl]carbamoyl]-5-methyl-6-oxo-4H-thieno[2,3-d][2]benzazepine-10-yl] 50h(80 mg, 115.74 μmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (13.20 mg, 115.74 μmol, 1 mL) was added to the resulting mixture. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was separated by pre-liquid chromatography (column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), and the result was 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 50 (3 mg) (yield 5%) was obtained.

[0795] MS m / z(ESI): 491.0 [M+1].

[0796] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ10.46(s, 1H), 10.08(s, 1H), 8.46(s, 1H), 7.97(s, 1H), 7.16(t, J = 8.0 Hz, 1H), 7.05(dd, J = 8.4, 2.5 Hz, 1H), 6.97(dd, J = 8.0, 1.2 Hz, 1H), 6.96 - 6.92(m, 2H), 6.01(s, 2H), 4.43(d, J = 16.0 Hz, 1H), 4.31(d, J = 16.0 Hz, 1H), 3.05(s, 3H), 3.01(s, 3H).

[0797] Example 51

[0798] 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

[0799]

[0800] Step 1

[0801] Methyl 10-bromo-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate

[0802] Methyl 10-amino-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate 50e (330 mg, 1.09 mmol) was dissolved in dimethyl sulfoxyhydrate (5 mL), and then tert-butyl nitrite (337.65 mg, 3.27 mmol, 389.45 μL) was added to the resulting solution. Nitrogen purging was performed three times on the reaction solution, and the mixture was stirred for 20 minutes under nitrogen protection at room temperature. Copper bromide (469.71 mg, 3.27 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (100 mL) and then extracted with ethyl acetate (30 mL x 3). The extract was dried with anhydrous sodium sulfate and then concentrated under reduced pressure. As a result of purifying the residue by silica gel column chromatography (eluent: System A), methyl 10-bromo-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate 51a (150 mg) (yield 37%) was obtained.

[0803] MS m / z(ESI): 366.0 [M+1].

[0804] Step 2

[0805] Methyl 10-cyano-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate

[0806] Methyl 10-bromo-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate 51a (80 mg, 218.44 μmol) N,NAfter dissolving in 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. Nitrogen purging was performed three times on the reaction solution, and the mixture was stirred at 100°C for 3 hours under nitrogen protection. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The extract was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 10-cyano-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate 51b (60 mg) (yield 88%) was obtained.

[0807] Step 3

[0808] 10-cyano-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylic acid

[0809] Methyl 10-cyano-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate 51b (70 mg, 224.11 μmol) was dissolved in tetrahydrofuran (2 mL), and then lithium hydroxide monohydrate (18.81 mg, 448.23 μmol) and water (1 mL) were added to the resulting solution. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and as a result, 10-cyano-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylic acid 51c This was obtained and was used directly in the next step.

[0810] MS m / z(ESI): 299.0 [M+1].

[0811] Step 4

[0812] 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

[0813] 10-cyano-5-methyl-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylic acid 51c and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g (76.56 mg, 346.95 μmol) N,N It was dissolved in dimethylformamide (2 mL). To the resulting mixture, (7-azabenzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (361.78 mg, 693.89 μmol) and N,N - Diisopropylethylamine (179.36 mg, 1.39 mmol, 246.04 μL) was added. The reaction solution was stirred at 65°C for 2 hours. The reaction solution was diluted with water (20 mL) and then extracted with ethyl acetate (30 mL x 3). The extract was dried with anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and as a result, 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 51 (46 mg) (yield 40%) was obtained.

[0814] MS m / z(ESI): 501.0 [M+1].

[0815] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ10.61(s, 1H), 10.11(s, 1H), 8.62(s, 1H), 8.19(dd, J = 8.0, 1.2 Hz, 1H), 8.13(dd, J = 8.0, 1.2 Hz, 1H), 7.75 - 7.66(m, 2H), 7.61(t,J = 1.6 Hz, 1H), 6.99(t, J = 2.0 Hz, 1H), 4.61(d, J = 16.0 Hz, 1H), 4.45(d, J = 16.0 Hz, 1H), 3.08(s, 3H), 3.07(s, 3H).

[0816] Example 52

[0817] 6-acetyl-10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxamide

[0818]

[0819] Step 1

[0820] Methyl 6-acetyl-10-(benzyloxy)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate

[0821] Methyl 10-(benzyloxy)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate 19f (40 mg, 109.46 μmol) was dissolved in dichloromethane (1 mL), and then 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, and then acetyl chloride (17.18 mg, 218.91 μmol, 15.57 μL) was added. The reaction solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure, yielding methyl 6-acetyl-10-(benzyloxy)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate 52a was obtained, This was used directly in the next step.

[0822] MS m / z(ESI): 408.2 [M+1].

[0823] Step 2

[0824] 6-acetyl-10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxamide

[0825] Methyl 6-acetyl-10-(benzyloxy)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxylate 52a and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g (64.99 mg, 294.49 μmol) was dissolved in tetrahydrofuran (2 mL), and then trimethylaluminum solution in n-hexane (2 M, 736.23 μL) was added dropwise to the resulting mixture. The reaction solution was stirred at 60°C for 1 hour. The reaction solution was slowly added dropwise to methanol (5 mL) for quenching, and the mixture was concentrated under reduced pressure. After purifying the residue by silica gel column chromatography (eluent: System A), and then further separating it by pre-liquid chromatography (column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), the result was 6-acetyl-10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydro-4H-benzo[b]thieno[3,2-d]azepine-2-carboxamide 52 (30 mg) (yield 34%) was obtained.

[0826] MS m / z(ESI): 596.1 [M+1].

[0827] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ10.38(s, 1H), 10.07(s, 1H), 8.38(s, 1H), 7.68(t, J = 1.6 Hz, 1H), 7.62(t, J = 1.6 Hz, 1H), 7.46(dd, J= 14.8, 7.2 Hz, 3H), 7.34 - 7.24(m, 4H), 7.10(d, J = 7.6 Hz, 1H), 6.96(t, J = 2.0 Hz, 1H), 5.31(d, J = 12.0 Hz, 1H), 5.16(d, J = 12.0 Hz, 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).

[0828] The compounds of Examples 53 and 54 were prepared according to the method of Example 52 of the present invention, and the specific structures and structural characterization results are presented below:

[0829]

[0830] The compounds of Examples 55 to 57 were prepared according to the method of Example 19 of the present invention, and the specific structures and structural characterization results are presented below:

[0831]

[0832] Example 58

[0833] 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

[0834]

[0835] Step 1

[0836] tert-butyl(1-(thiophene-2-yl)cyclopropyl carbamate

[0837] 1-(thiophene-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), to which diphenylphosphorazidate (392.64 mg, 1.43 mmol) was added. The mixture was then allowed to react at 80°C for 12 hours under a nitrogen atmosphere. The reaction solution was diluted with water and extracted three times with dichloromethane (20 mL). The extracts were combined, washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), resulting in tert-butyl carbamate(1-(thiophene-2-yl)cyclopropyl) 58b (170 mg) (yield 59%) was obtained.

[0838] MS m / z(ESI): 184.0 [M+1].

[0839] Step 2

[0840] tert-butyl(1-(5-bromothiophene-2-yl)cyclopropyl carbamate

[0841] tert-butyl(1-(thiophene-2-yl)cyclopropyl carbamate 58b (1.1 g, 4.60 mmol) N,N - Dissolve in dimethylformamide (15 mL), and then here N Bromosuccinimide (1.23 g, 6.89 mmol) was added. The mixture was 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 extracts were combined, washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was tert-butyl carbamate (1-(5-bromothiophene-2-yl)cyclopropyl) 58c (1.3 g) (yield 90%) was obtained.

[0842] MS m / z(ESI): 263.9 [M+1].

[0843] Step 3

[0844] Methyl 5-(1-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylate

[0845] tert-butyl(1-(5-bromothiophene-2-yl)cyclopropyl carbamate 58c 500 mg (1.57 mmol) and triethylamine (476.97 mg, 4.71 mmol) were dissolved in methanol (10 mL), to which [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (233.10 mg, 314.24 μmol) was added. The mixture was then allowed to react at 80°C for 2 hours under a carbon monoxide atmosphere. After the reaction was complete, the reaction solution was diluted with water and extracted three times with ethyl acetate (20 mL). The extracts were combined, washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 5-(1-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylate 58d (180 mg) (yield 81%) was obtained.

[0846] MS m / z(ESI): 242.0 [M+1].

[0847] Step 4

[0848] Methyl 4-bromo-5-(1-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylate

[0849] Methyl 5-(1-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylate 58d1.5 g (4.13 mmol) was dissolved in tetrahydrofuran (20 mL), and then trimethylaluminum (2 M, 12.38 mL) was added dropwise at 0 °C. The mixture was then allowed to react at 60 °C for 12 hours. The reaction solution was quenched with methanol and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 4-bromo-5-(1-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylate 58e (400 mg) (yield 29%) was obtained.

[0850] MS m / z(ESI): 332.0 [M+1].

[0851] Step 5

[0852] Methyl nicotinate 2-(2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(methoxycarbonyl)thiophene-3-yl)

[0853] Methyl 4-bromo-5-(1-((tert-butoxycarbonyl)amino)cyclopropyl)thiophene-2-carboxylate 58e(250 mg, 664.42 μmol), 2-methyl bromonicotinate (287.07 mg, 1.33 mmol), bis(pinacoleto)diborone (506.17 mg, 1.99 mmol), di(1-adamantyl)-butylphosphine (95.29 mg, 265.77 μmol), and potassium carbonate (459.14 mg, 3.32 mmol) were dissolved in 1,2-dimethoxyethane (10 mL) and water (2 mL). Nitrogen purging was performed three times on the reaction solution. Palladium (II) acetate (29.83 mg, 132.88 μmol) was added under nitrogen protection, and the reaction solution was allowed to react at 80°C for 1 hour. The reaction solution was diluted with water and then extracted three times with ethyl acetate (50 mL). After combining the extracts, they were washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl nicotinate 2-(2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(methoxycarbonyl)thiophene-3-yl) 58f (170 mg) (yield 59%) was obtained.

[0854] MS m / z(ESI): 433.2 [M+1].

[0855] Step 6

[0856] Methyl nicotinate 2-(2-(1-aminocyclopropyl)-5-(methoxycarbonyl)thiophene-3-yl)

[0857] Methyl nicotinate 2-(2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(methoxycarbonyl)thiophene-3-yl) 58f (180 mg, 416.20 μmol) was dissolved in 4 M hydrogen chloride in 10 mL of dioxane, and the mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and as a result, methyl nicotinate 2-(2-(1-aminocyclopropyl)-5-(methoxycarbonyl)thiophene-3-yl) 58gThis was obtained and was used directly in the next step.

[0858] MS m / z(ESI): 333.2 [M+1].

[0859] Step 7

[0860] Methyl 5'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-c]thieno[3,2-e]azepine]-9'-carboxylate

[0861] Methyl nicotinate 2-(2-(1-aminocyclopropyl)-5-(methoxycarbonyl)thiophene-3-yl) at 0℃ 58g After dissolving it in tetrahydrofuran (5 mL), trimethylaluminum (2 M, 902.60 mL) was added dropwise. The mixture was then allowed to react at 25°C for 1 hour. After the reaction was complete, the trimethylaluminum was quenched with methanol. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 5'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-c]thieno[3,2-e]azepine]-9'-carboxylate 58h (55 mg) was obtained, and the second-stage yield was 40%.

[0862] MS m / z(ESI): 301.0 [M+1].

[0863] Step 8

[0864] 5'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-c]thieno[3,2-e]azepine]-9'-carboxylic acid

[0865] 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 then lithium hydroxide monohydrate (11.18 mg, 266.37 μmol) was added. The mixture was then allowed to react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the result was 5'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-c]thieno[3,2-e]azepine]-9'-carboxylic acid 58i This was obtained and was used directly in the next step.

[0866] MS m / z(ESI): 287.0 [M+1].

[0867] Step 9

[0868] 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

[0869] At room temperature O -(7-azabenchotriazole-1-yl)- N,N,N',N '-tetramethyluronium hexafluorophosphate (136.58 mg, 261.96 μmol) and N,N - Diisopropylethylamine (67.71 mg, 523.92 μmol) N,N - 5'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-c]thieno[3,2-e]azepine]-9'-carboxylic acid in dimethylformamide (1 mL) 58i and N -(3-amino-5-chlorophenyl)methanesulfonamide 1gIt was added to a solution of (70.96 mg, 321.55 μmol), and the reaction solution was allowed to react at 65°C for 1 hour. After diluting the reaction solution with water, it was extracted three times with ethyl acetate (50 mL). The extracts were combined, washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. As a result of separating the residue by pre-liquid chromatography (column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), 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) (yield 9%) was obtained.

[0870] MS m / z(ESI): 489.0 [M+1].

[0871] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ10.64(s, 1H), 10.10(s, 1H), 9.17(s, 1H), 8.84(dd, J = 4.8, 1.6 Hz, 1H), 8.62(s, 1H), 8.28(dd, J = 8.0, 1.6 Hz, 1H), 7.70(s, 1H), 7.66(s, 1H), 7.56(dd, J = 8.0, 4.8 Hz, 1H), 6.96(s, 1H), 3.07(s, 3H), 1.29(s, 2H), 1.12(s, 2H).

[0872] The compounds of Examples 59 and 60 were prepared according to the method of Example 58 of the present invention, and the specific structures and structural characterization results are presented below:

[0873]

[0874] Example 61

[0875] 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

[0876]

[0877] Step 1

[0878] Methyl 1-(thiophene-2-yl)cyclopropane-1-carboxylate

[0879] 1-(thiophene-2-yl)cyclopropane-1-carboxylic acid at 0℃ 58a (2 g, 11.89 mmol) N,N After dissolving in dimethylformamide (20 mL), sodium hydride (1.43 g, 35.67 mmol, 60% purity) was added in small amounts. The mixture was then stirred at room temperature for 15 minutes. Next, methyl iodide was added dropwise to the reaction solution, and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was diluted with water and extracted three times with ethyl acetate (30 mL). The extracts were combined, washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 1-(thiophene-2-yl)cyclopropane-1-carboxylate 61a (1.9 g) (yield 87%) was obtained.

[0880] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ7.19(dd, J = 5.2, 1.2 Hz, 1H), 6.94(dd, J = 3.6, 1.2 Hz, 1H), 6.91(dd, J = 4.8, 3.6 Hz, 1H), 3.67(s, 3H), 1.70(q, J = 4.0 Hz, 2H), 1.32(q, J = 4.0 Hz, 2H).

[0881] Step 2

[0882] Methyl 1-(5-bromothiophene-2-yl)cyclopropane-1-carboxylate

[0883] Methyl 1-(thiophene-2-yl)cyclopropane-1-carboxylate 61a (500 mg, 2.74 mmol) N,N - After dissolving in dimethylformamide (5 mL), here N Bromosuccinimide (976.65 mg, 5.49 mmol) was added. The mixture was allowed to react at room temperature for 1 hour. The reaction solution was diluted with water and extracted three times with ethyl acetate (50 mL). The extracts were combined, washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the results showed methyl 1-(5-bromothiophene-2-yl)cyclopropane-1-carboxylate 61b (460 mg) (yield 64%) was obtained.

[0884] MS m / z(ESI): 261.0 [M+1].

[0885] Step 3

[0886] Methyl 5-(1-(methoxycarbonyl)cyclopropyl)thiophene-2-carboxylate

[0887] Methyl 1-(5-bromothiophene-2-yl)cyclopropane-1-carboxylate 61bmethyl 5-(1-(methoxycarbonyl)cyclopropyl)thiophene-2-carboxylate) (1.3 g, 4.98 mmol) and triethylamine (2.01 g, 19.91 mmol, 2.77 mL) were dissolved in methanol (20 mL), to which [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (738.56 mg, 995.65 μmol) was added. The mixture was then allowed to react at 70°C for 2 hours under a carbon monoxide atmosphere. After the reaction was complete, the reaction solution was diluted with water and extracted three times with dichloromethane (100 mL). The extracts were combined, washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 5-(1-(methoxycarbonyl)cyclopropyl)thiophene-2-carboxylate 61c (300 mg) (yield 75%) was obtained.

[0888] MS m / z(ESI): 241.0 [M+1].

[0889] Step 4

[0890] Methyl 4-bromo-5-(1-(methoxycarbonyl)cyclopropyl)thiophene-2-carboxylate

[0891] 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), and then to NBromosuccinimide (288.89 mg, 1.62 mmol) was added. The mixture was allowed to react at room temperature for 1 hour. The pH of the reaction solution was adjusted to a basic pH using a saturated sodium bicarbonate solution, and then extracted three times with ethyl acetate (50 mL). The extracts were combined, washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 4-bromo-5-(1-(methoxycarbonyl)cyclopropyl)thiophene-2-carboxylate 61d (300 mg) (yield 75%) was obtained.

[0892] MS m / z(ESI): 321.0 [M+1].

[0893] Step 5

[0894] Methyl 4-(3-aminopyridine-2-yl)-5-(1-(methoxycarbonyl)cyclopropyl)thiophene-2-carboxylate

[0895] 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), bis(pinacoleto)diborone (1.67 g, 6.58 mmol), di(1-adamantyl)-butylphosphine (314.54 mg, 877.27 μmol), and potassium carbonate (1.52 g, 10.97 mmol) were dissolved in 1,2-dimethoxyethane (20 mL) and water (4 mL). Nitrogen purging was performed three times on the reaction solution. Palladium acetate (II) (98.48 mg, 438.64 μmol) was added under nitrogen protection, and the reaction solution was stirred at 70°C for 2 hours. After diluting the reaction solution with water, it was extracted three times with dichloromethane (100 mL). The extracts were combined, washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 4-(3-aminopyridine-2-yl)-5-(1-(methoxycarbonyl)cyclopropyl)thiophene-2-carboxylate 61e (590 mg) (yield 81%) was obtained.

[0896] MS m / z(ESI): 333.1 [M+1].

[0897] Step 6

[0898] Methyl 6'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-b]thieno[3,2-d]azepine]-9'-carboxylate

[0899] Methyl 4-(3-aminopyridine-2-yl)-5-(1-(methoxycarbonyl)cyclopropyl)thiophene-2-carboxylate at 0°C 61e(700 mg, 2.11 mmol) was dissolved in tetrahydrofuran (10 mL), and then trimethylaluminum (2 M, 8.42 mL) was added dropwise. The mixture was then allowed to react at 60°C for 1 hour. After the reaction was complete, the trimethylaluminum was quenched with methanol. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 6'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-b]thieno[3,2-d]azepine]-9'-carboxylate 61f (400 mg) (yield 63%) was obtained.

[0900] MS m / z(ESI): 301.0 [M+1].

[0901] Step 7

[0902] 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

[0903] Methyl 6'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrido[3,2-b]thieno[3,2-d]azepine]-9'-carboxylate at 0°C 61f (30 mg, 99.89 μmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide 1g(44.09 mg, 199.78 μmol) was dissolved in tetrahydrofuran (2 mL), and then trimethylaluminum (2 M, 399.56 μL) was added dropwise. The mixture was then stirred at 60°C for 1 hour. After the reaction was complete, the trimethylaluminum was quenched with methanol. The residue was purified by silica gel column chromatography (eluent: System A) and then further separated by pre-liquid chromatography (column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), resulting in 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 61 (5 mg) (yield 10%) was obtained.

[0904] MS m / z(ESI): 489.0 [M+1].

[0905] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ10.61(s, 1H), 10.42(s, 1H), 10.08(s, 1H), 8.55(s, 1H), 8.49(d, J = 3.6 Hz, 1H), 7.70(s, 1H), 7.67(s, 1H), 7.63(d, J = 7.6 Hz, 1H), 7.46(dd, J = 8.1, 4.5 Hz, 1H), 6.96(s, 1H), 3.07(s, 3H), 1.44(d, J = 6.8 Hz, 2H), 1.12(d, J = 6.4 Hz, 2H).

[0906] The compound of Example 62 was prepared according to the method of Example 7 of the present invention, and the specific structure and the results of structural characterization are presented below:

[0907]

[0908] Example 63

[0909] 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4,6-dihydrobenzo[c]thieno[3,2-e]oxepin-2-carboxamide

[0910]

[0911] Step 1

[0912] (3-(benzyloxy)-2-bromophenyl)methanol

[0913] Sodium borohydride (390 mg, 10.3 mmol) in methanol (20 mL) at 0°C 3-(benzyloxy)-2-bromobenzaldehyde 63a (1.00 g, 3.43 mmol) was added to the solution, and the mixture was 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), and as a result, (3-(benzyloxy)-2-bromophenyl)methanol 63b (900 mg) (yield 89%) was obtained.

[0914] MS m / z(ESI): 292 / 294.0 [M+1].

[0915] Step 2

[0916] Methyl 4-(2-(benzyloxy)-6-(hydroxymethyl)phenyl)-5-(hydroxymethyl)thiophene-2-carboxylate

[0917] (3-(benzyloxy)-2-bromophenyl)methanol 63b Dissolve (900 mg, 3.07 mmol) in 1,4-dioxane (10 mL), and then add methyl 4-bromo-5-(hydroxymethyl)thiophene-2-carboxylate to the resulting solution 1b(1.36 g, 5.18 mmol), bis(pinacoleto)diborone (3.03 g, 11.95 mmol), di(1-adamanthyl)-n-butylphosphine (571 mg, 1.59 mmol), potassium carbonate (1.65 g, 12.0 mmol), palladium(II) acetate (179 mg, 0.797 mmol), and water (1 mL) were added. Nitrogen purging was performed on the reaction solution three times, followed by stirring at 80°C for 2 hours under nitrogen protection. The reaction solution was filtered and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A), and the result was methyl 4-(2-(benzyloxy)-6-(hydroxymethyl)phenyl)-5-(hydroxymethyl)thiophene-2-carboxylate 63c (1.20 g, 60% purity) was obtained. The yield was 64%.

[0918] MS m / z(ESI): 385.2 [M+1].

[0919] Step 3

[0920] Methyl 10-(benzyloxy)-4,6-dihydrobenzo[c]thieno[3,2-e]oxepin-2-carboxylate

[0921] Methyl 4-(2-(benzyloxy)-6-(hydroxymethyl)phenyl)-5-(hydroxymethyl)thiophene-2-carboxylate 63c500 mg (purity 60%, 0.78 mmol) was dissolved in 1,4-dioxane (5 mL), and then an aqueous hydrobromide solution (2 mL, 24% w / w) was added to the resulting solution. The mixture was stirred at 100°C for 20 minutes, resulting in a yellow solution. The mixture was poured into water (60 mL) and extracted with ethyl acetate (60 mL). The combined organic phase was washed with a saturated sodium chloride solution (50 mL), dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The unrefined product was purified by silica gel column chromatography (eluent: System A), yielding methyl 10-(benzyloxy)-4,6-dihydrobenzo[c]thieno[3,2-e]oxepin-2-carboxylate 63d (195 mg) (yield 68.3%) was obtained.

[0922] MS m / z(ESI): 367.2 [M+1].

[0923] Step 4

[0924] 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4,6-dihydrobenzo[c]thieno[3,2-e]oxepin-2-carboxamide

[0925] Methyl 10-(benzyloxy)-4,6-dihydrobenzo[c]thieno[3,2-e]oxepin-2-carboxylate 63d (60.0 mg, 0.164 mmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g(72.3 mg, 0.327 mmol) was dissolved in tetrahydrofuran (5.0 mL), and then trimethylaluminum (2 M, 0.82 mL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 65°C for 2 hours. The reaction solution was slowly added dropwise to methanol (50 mL) to quench the reaction. The resulting mixture was concentrated under reduced pressure. Subsequently, the crude product was purified by silica gel column chromatography (eluent: System A) and then further separated by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH₃CN), resulting in 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4,6-dihydrobenzo[c]thieno[3,2-e]oxepin-2-carboxamide 63 (28.0 mg) (yield 31%) was obtained.

[0926] MS m / z(ESI): 555.2 [M+1].

[0927] 1 ¹H NMR(400 MHz, DMSO- d 6) 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), 7.34 - 7.22(m, 4H), 7.17(d, J = 7.2 Hz, 1H), 6.97(t, J = 2.0 Hz, 1H), 5.25(s, 2H), 4.49(s, 2H), 4.29(s, 2H), 3.06(s, 3H).

[0928] Example 64

[0929] 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4,5-dihydrobenzo[b]thieno[3,2-d]oxepin-2-carboxamide

[0930]

[0931] Step 1

[0932] Methyl 5-(2-(3-(benzyloxy)-2-bromophenoxy)ethyl)-4-bromothiophene-2-carboxylate

[0933] (3-(benzyloxy)-2-bromophenyl)methanol at 25℃ 63b (70.0 mg, 0.264 mmol) was added to toluene (5 mL), and then 3-(benzyloxy)-2-bromophenol was added to the reaction solution. 6b (111 mg, 0.396 mmol) and cyanomethylenetri-n-butylphosphorane (191 mg, 0.792 mmol) were added. The mixture was allowed to react at 90°C for 18 hours under nitrogen protection. The system was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A), and the result was methyl 5-(2-(3-(benzyloxy)-2-bromophenoxy)ethyl)-4-bromothiophene-2-carboxylate 64a (220 mg, 40% purity) was obtained. The yield was 63.6%.

[0934] MS m / z(ESI): 525.0 [M+1].

[0935] Step 2

[0936] Methyl 10-(benzyloxy)-4,5-dihydrobenzo[b]thieno[3,2-d]oxepin-2-carboxylate

[0937] 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), and then bis(pinacoleto)diborone (116 mg, 0.456 mmol), di(1-adamantyl)-n-butylphosphine (21.8 mg, 0.0608 mmol), potassium carbonate (63.0 mg, 0.456 mmol), palladium(II) acetate (6.83 mg, 0.0304 mmol), and water (1 mL) were added to the resulting solution. Nitrogen purging was performed three times on the reaction solution, and the mixture was stirred at 80°C for 18 hours under nitrogen protection. The resulting mixture was filtered and then concentrated under reduced pressure. As a result of purifying the crude product by silica gel column chromatography (eluent: System A), methyl 10-(benzyloxy)-4,5-dihydrobenzo[b]thieno[3,2-d]oxepin-2-carboxylate 64b (20.0 mg) (yield 36%) was obtained.

[0938] MS m / z(ESI): 367.2 [M+1].

[0939] Step 3

[0940] 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4,5-dihydrobenzo[b]thieno[3,2-d]oxepin-2-carboxamide

[0941] Methyl 10-(benzyloxy)-4,5-dihydrobenzo[b]thieno[3,2-d]oxepin-2-carboxylate 64b (20.0 mg, 0.0546 mmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g(24.1 mg, 0.109 mmol) was dissolved in tetrahydrofuran (3.0 mL), and then trimethylaluminum (2 M, 0.27 mL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 65°C for 2 hours. The reaction was quenched by slowly adding methanol (50 mL) to the reaction solution. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) and then further separated by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH₃CN), resulting in 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4,5-dihydrobenzo[b]thieno[3,2-d]oxepin-2-carboxamide 64 (5.0 mg) (yield 17%) was obtained.

[0942] MS m / z(ESI): 555.0 [M+1].

[0943] 1 ¹H NMR(400 MHz, DMSO- d 6) 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 = 8.4 Hz, 1H), 6.91(t, J = 2.0 Hz, 1H), 6.83(d, J = 8.0 Hz, 1H), 5.20(s, 2H), 4.51(t, J = 6.4 Hz, 2H), 3.02(t, J = 6.4 Hz, 2H), 2.99(s, 3H).

[0944] Example 65

[0945] 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxamide

[0946]

[0947] Step 1

[0948] Methyl 3-(benzyloxy)-2-bromobenzoate

[0949] Methyl 2-bromo-3-hydroxybenzoate 65a (1.00 g, 4.33 mmol) was dissolved in an N,N-dimethylformamide (1 mL) solution, to which potassium carbonate (1.20 g, 8.66 mmol) and benzyl bromide (740.27 mg, 4.33 mmol) were sequentially added. After performing nitrogen purging on the mixture three times, the reaction was carried out at 25°C for 3 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A), resulting in methyl 3-(benzyloxy)-2-bromobenzoate 65b (950.00 mg) (yield 68.3%) was obtained.

[0950] MS m / z(ESI): 321 / 323 [M+1].

[0951] Step 2

[0952] Methyl 4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate

[0953] 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) was dissolved in 1,4-dioxane (15 mL), and then bis(pinacoleto)diborone (3.26 g, 12.85 mmol), di(1-adamantyl)-n-butylphosphine (614.24 mg, 1.71 mmol), potassium carbonate (1.78 g, 12.85 mmol), palladium(II) acetate (192.31 mg, 856.58 μmol), and water (3 mL) were added to the resulting solution. Nitrogen purging was performed on the reaction solution three times, followed by stirring at 80°C for 12 hours. The resulting mixture was concentrated under reduced pressure. As a result of purifying the crude product by silica gel column chromatography (eluent: System A), methyl 4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)-5-(((tert-butoxycarbonyl)amino)methyl)thiophene-2-carboxylate 65c (800 mg) (yield 36.5%) was obtained.

[0954] MS m / z(ESI): 512.2 [M+1].

[0955] Step 3

[0956] Methyl 5-(aminomethyl)-4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)thiophene-2-carboxylate

[0957] 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), and then 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, yielding methyl 5-(aminomethyl)-4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)thiophene-2-carboxylate 65d ...was obtained, which was used directly in the next step.

[0958] MS m / z(ESI): 412.2 [M+1].

[0959] Step 4

[0960] Methyl 10-(benzyloxy)-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate

[0961] Methyl 5-(aminomethyl)-4-(2-(benzyloxy)-6-(methoxycarbonyl)phenyl)thiophene-2-carboxylate 65d Dissolve the unpurified product in toluene (13 mL), and then in the resulting solution N,N - Diisopropylethylamine (6.03 g, 46.65 mmol, 8.13 mL) was added. The reaction solution was stirred at 70°C for 12 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A), and the result was methyl 10-(benzyloxy)-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate 65e (960 mg) (yield 80.1%) was obtained.

[0962] MS m / z(ESI): 380.2 [M+1].

[0963] Step 5

[0964] Methyl 10-(benzyloxy)-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate

[0965] Methyl 10-(benzyloxy)-6-oxo-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate 65e(100 mg, 0.264 mmol) was dissolved in a borane solution (5 mL) in tetrahydrofuran. The reaction solution was allowed to react at 60°C for 2 hours. The mixture was added to methanol (20 mL) to quench the reaction, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A), and the result was methyl 10-(benzyloxy)-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate 65f (70.0 mg) (yield 62%) was obtained.

[0966] MS m / z(ESI): 366.2 [M+1].

[0967] Step 6

[0968] 5-(tert-butyl) 2-methyl 10-(benzyloxy)-4,6-dihydro-5H-benzo[c]thieno[3,2-e]azepine-2,5-diccarboxylate

[0969] Methyl 10-(benzyloxy)-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate 65f (90.0 mg, 0.246 mmol) was dissolved in dichloromethane (5 mL), and then di-tert-butyl bicarbonate (108 mg, 0.493 mmol), 4-dimethylaminopyridine (3.01 mg, 0.0246 mmol), and to the reaction solution N,N Diisopropylethylamine (95.5 mg, 0.739 mmol) was added. The reaction solution was allowed to react at 25°C for 18 hours. The reaction solution was diluted with water (100 mL), and the aqueous solution was extracted with ethyl acetate (100 mL). The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated. The crude product was then purified by silica gel column chromatography (eluent: System A), resulting in 5-(tert-butyl) 2-methyl 10-(benzyloxy)-4,6-dihydro-5H-benzo[c]thieno[3,2-e]azepine-2,5-dicarboxylate 65g(80.0 mg) (yield 70%) was obtained.

[0970] MS m / z(ESI): 366.2 [M+1-100].

[0971] Step 7

[0972] tert-butyl 10-(benzyloxy)-2-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-4,6-dihydro-5H-benzo[c]thieno[3,2-e]azepine-5-carboxylate

[0973] 5-(tert-butyl) 2-methyl 10-(benzyloxy)-4,6-dihydro-5H-benzo[c]thieno[3,2-e]azepine-2,5-diccarboxylate 65g (60.0 mg, 0.129 mmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g (56.9 mg, 0.258 mmol) was dissolved in tetrahydrofuran (7.0 mL), and then trimethylaluminum (2 M, 0.64 mL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 60°C for 2 hours. The reaction was quenched by slowly adding methanol (50 mL) to the reaction solution. The resulting mixture was concentrated under reduced pressure. Subsequently, the crude product was purified by silica gel column chromatography (eluent: System A), and the result was tert-butyl 10-(benzyloxy)-2-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-4,6-dihydro-5H-benzo[c]thieno[3,2-e]azepine-5-carboxylate 65h (60.0 mg) (yield 71%) was obtained.

[0974] Step 8

[0975] 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxamide

[0976] Tert-butyl 10-(benzyloxy)-2-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-4,6-dihydro-5H-benzo[c]thieno[3,2-e]azepine-5-carboxylate 65h (60.0 mg, 0.0917 mmol) was dissolved in dichloromethane (4.0 mL), and then 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. After concentrating the reaction solution under reduced pressure, separation was performed by pre-liquid chromatography (column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), and the result was 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxamide 65 (32.0 mg) (yield 63%) was obtained.

[0977] MS m / z(ESI): 554.2 [M+1].

[0978] 1 ¹H NMR(400 MHz, DMSO- d 6) δ10.44(s, 1H), 8.42(s, 1H), 8.18(s, 1H), 7.66(dt, J = 8.0, 2.0 Hz, 2H), 7.50 - 7.43 (m, 2H), 7.37 - 7.19 (m, 5H), 7.07 (dd, J = 7.6, 1.2 Hz, 1H), 6.97(t, J = 2.0 Hz, 1H), 5.21(s, 2H), 3.74(s, 2H), 3.54(s, 2H), 3.08(s, 3H).

[0979] Example 66

[0980] 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxamide

[0981]

[0982] Step 1

[0983] Methyl 10-(benzyloxy)-5-methyl-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate

[0984] Methyl 10-(benzyloxy)-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate 65f (70 mg, 0.192 mmol) was dissolved in 1,2-dichloroethane (5 mL), and then an aqueous formaldehyde solution (77.7 mg, 0.958 mmol) and sodium triacetoxyborohydride (122 mg, 0.575 mmol) were added to the resulting solution. The reaction solution was stirred at 25°C for 2 hours. After adding the mixture to methanol for quenching, the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A), and the result was methyl 10-(benzyloxy)-5-methyl-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate 66a (50.0 mg) (yield 69%) was obtained.

[0985] MS m / z(ESI): 380.2 [M+1].

[0986] Step 2

[0987] 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxamide

[0988] Methyl 10-(benzyloxy)-5-methyl-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxylate 66a (60.0 mg, 0.156 mmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g(68.7 mg, 0.311 mmol) was dissolved in tetrahydrofuran (5.0 mL), and then trimethylaluminum (2 M, 0.78 mL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 60°C for 2 hours. The reaction was quenched by slowly adding methanol (50 mL) to the reaction solution. The resulting mixture was concentrated under reduced pressure. Next, the crude product was purified by silica gel column chromatography (eluent: System A) and then further separated by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH₃CN), resulting in 10-(benzyloxy)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-5,6-dihydro-4H-benzo[c]thieno[3,2-e]azepine-2-carboxamide 66 (7.0 mg) (yield 8%) was obtained.

[0989] MS m / z(ESI): 568.2 [M+1].

[0990] 1 ¹H NMR(400 MHz, DMSO- d 6) δ10.39(s, 1H), 10.01(s, 1H), 8.43(s, 1H), 7.59(d, J = 2.0 Hz, 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 = 7.6 Hz, 1H), 6.93(t, J = 2.0 Hz, 1H), 5.21(s, 2H), 3.46(s, 2H), 3.22(s, 2H), 3.02(s, 3H), 2.33(s, 3H).

[0991] Example 67

[0992] 11-Benzamido-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[0993]

[0994] Step 1

[0995] Methyl 1-(2-(3-amino-2-bromophenoxy)ethyl)-5-bromo-1H-pyrrole-3-carboxylate

[0996] 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) was dissolved in toluene (20 mL), and then cyanomethylene tri-n-butylphosphorane (6.93 g, 28.72 mmol, 7.62 mL) was added to the resulting solution. The reaction solution was stirred at 80 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. Subsequently, the crude product was purified by silica gel column chromatography (eluent: System A), and the result was methyl 1-(2-(3-amino-2-bromophenoxy)ethyl)-5-bromo-1H-pyrrole-3-carboxylate 67b (1.88 g) (yield 46.9%) was obtained.

[0997] MS m / z(ESI): 417.0 [M+1].

[0998] Step 2

[0999] Methyl 11-amino-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1000] Methyl 1-(2-(3-amino-2-bromophenoxy)ethyl)-5-bromo-1H-pyrrole-3-carboxylate 67b(1.88 g, 4.50 mmol) was dissolved in dimethoxyethane (30 mL) and water (6.0 mL), and then bis(pinacoleto)diboron (3.43 g, 13.49 mmol), di(1-adamantyl)-n-butylphosphine (644.9 mg, 1.80 mmol), potassium carbonate (1.86 g, 13.49 mmol), and palladium(II) acetate (201.91 mg, 899.35 μmol) were added to the resulting solution. Nitrogen purging was performed three times on the reaction solution, heated to 70°C, and stirred for 18 hours. The resulting mixture was filtered under reduced pressure, the filter cake was washed with dichloromethane (30 mL x 3), the resulting filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: System A) to obtain methyl 11-amino-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 67c (250 mg, purity 71.7%) (yield 15.4%) was obtained.

[1001] MS m / z(ESI): 259.1 [M+1].

[1002] Step 3

[1003] Methyl 11-benzamido-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1004] Methyl 11-amino-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 67c(111.6 mg, purity 71.7%, 309.751 μmol) was dissolved in dichloromethane (40 mL), and then 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 solution was stirred at 25°C for 18 hours. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A), and the result was methyl 11-benzamido-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 67d (80 mg) (yield 71.2%) was obtained.

[1005] MS m / z(ESI): 363.1 [M+1].

[1006] Step 4

[1007] 11-Benzamido-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[1008] Methyl 11-benzamido-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 67d (20 mg, 55.19 μmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide 1g(24.36 mg, 110.38 μmol) was dissolved in tetrahydrofuran (1 mL), and then trimethylaluminum (2 M, 275.95 μL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 60°C for 2 hours. The reaction solution was slowly added dropwise to methanol (10 mL) to quench the reaction. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) and then further separated by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), resulting in 11-benzamido-N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide 67( 12.56 mg) (yield 41.3%) was obtained.

[1009] MS m / z(ESI): 551.1 [M+1].

[1010] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ9.98(s, 1H), 9.86(s, 1H), 9.80(s, 1H), 7.90(d, J = 7.4 Hz, 2H), 7.81(d, J = 1.7 Hz, 1H), 7.65(t, J = 1.8 Hz, 1H), 7.59 - 7.54(m, 2H), 7.51(dt, J = 10.7, 5.5 Hz, 3H), 7.38(t, J = 8.0 Hz, 1H), 7.09(dd, J = 8.0, 1.0 Hz, 1H), 6.92(d, J = 1.7 Hz, 1H), 6.89(t, J = 1.9 Hz, 1H), 4.46(t, J= 5.9 Hz, 2H), 4.21(d, J = 5.1 Hz, 2H), 3.05(s, 3H).

[1011] Example 68

[1012] 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

[1013]

[1014] Step 1

[1015] 2-Bromo-1-((3,5-Difluorobenzyl)oxy)-3-nitrobenzene

[1016] Potassium carbonate (24.88 g, 180.00 mmol) and 1-(bromomethyl)-3,5-difluorobenzene at room temperature 68a (12.55 g, 60.60 mmol) 2-bromo-3-nitrophenol in acetonitrile (150 mL) 19a (13.08 g, 60 mmol) was added to the solution, the mixture was heated to 70°C, and stirred for 4 hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, resulting in 2-bromo-1-((3,5-difluorobenzyl)oxy)-3-nitrobenzene 68b (19.5 g) (yield 94.5%) was obtained.

[1017] 1H NMR (400 MHz, DMSO- d 6 ) δ7.67-7.53(m, 2H), 7.51-7.44(m, 1H), 7.30-7.18(m, 3H), 5.35(s, 2H).

[1018] Step 2

[1019] 2-Bromo-3-((3,5-difluorobenzyl)oxy)aniline

[1020] Iron powder (11.68 g, 209.24 mmol) and ammonium chloride (11.19 g, 209.24 mmol) in water (100 mL) and ethanol (200 mL) 2-bromo-1-((3,5-difluorobenzyl)oxy)-3-nitrobenzene 68b After adding to a mixed solution of (18 g, 52.31 mmol), the mixture was heated to 80°C and stirred for 2 hours. The reaction solution was filtered, and the filtrate was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with a saturated sodium chloride solution (100 mL x 2), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, resulting in 2-bromo-3-((3,5-difluorobenzyl)oxy)aniline 68c (13.00 g) (yield 79.1%) was obtained.

[1021] MS m / z(ESI): 316.0 [M+1].

[1022] Step 3

[1023] Methyl 11-((3,5-difluorobenzyl)oxy)-6-oxo-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[1024] Palladium(II) acetate (571 mg, 2.55 mmol) and di(1-adamantyl)-n-butylphosphine (1.83 g, 5.09 mmol) were added to dioxane (200 mL) at room temperature. Argon purging was performed on the mixture, followed by stirring 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), bis(pinacoleto)diborone (6.47 g, 25.47 mmol), potassium carbonate (5.28 g, 38.20 mmol), and water (20 mL) were added. After performing argon purging on the mixture, it was heated to 100°C and stirred for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water (50 mL), ethyl acetate (100 mL), and petroleum ether (50 mL) were added to this, and the mixture was stirred for 30 minutes. After filtration, the filter cake was dried under vacuum, resulting in methyl 11-((3,5-difluorobenzyl)oxy)-6-oxo-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate 68d (1.80 g) (yield 35.5%) was obtained.

[1025] MS m / z(ESI): 399.1 [M+1].

[1026] Step 4

[1027] Methyl 11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[1028] Borane-dimethyl sulfide complex (312.56 mg, 22.59 mmol, 2 M tetrahydrofuran solution) in tetrahydrofuran (80 mL) methyl 11-((3,5-difluorobenzyl)oxy)-6-oxo-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate 68dAfter adding to a solution of (4.5 g, 11.30 mmol), the mixture was heated to 60°C and stirred for 1 hour. Methanol (10 mL) was slowly added dropwise, the reaction was quenched, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate 68e (3.5 g) (yield 80.6%) was obtained.

[1029] MS m / z(ESI): 385.1 [M+1].

[1030] Step 5

[1031] 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

[1032] At room temperature, trimethylaluminum (1.59 g, 22.11 mmol, 2 M tetrahydrofuran) in tetrahydrofuran (20 mL) N -(3-amino-5-chlorophenyl)methanesulfonamide 1g (585 mg, 2.65 mmol) and methyl 11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate 68e It was added dropwise to a solution of (850 mg, 2.21 mmol). After performing argon purging on the mixture, it was heated, refluxed, and stirred 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), and as a result, 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-carboxamide68 (596 mg) (yield 45.9%) was obtained.

[1033] MS m / z(ESI): 573.2 [M+1].

[1034] 1 H NMR (400 MHz, DMSO-d6) δ 9.96(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 = 8.3 Hz, 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).

[1035] Example 69

[1036] 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

[1037]

[1038] 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 at room temperature 68(50 mg, 87.26 μmol) was added to a formic acid solution (1 mL), the mixture was heated to 100°C, and stirred for 4 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was separated and purified by pre-liquid chromatography (column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, and mobile phase B: CH3CN), and the result was 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 69 (14 mg) (yield 26.4%) was obtained.

[1039] MS m / z(ESI): 603.0 [M+1].

[1040] 1 ¹H NMR(400 MHz, DMSO- d 6) 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 = 8.1 Hz, 1H), 7.28(d, J = 8.5 Hz, 1H), 7.15(d, J = 7.0 Hz, 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).

[1041] Example 70

[1042] 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

[1043]

[1044] Step 1

[1045] Methyl 7-acetyl-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[1046] Acetyl chloride (15 mg, 195.12 μmol) in dichloromethane (2 mL) in an ice bath, methyl 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) were added dropwise to the solution, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was 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) (yield 90.9%) was obtained.

[1047] MS m / z(ESI): 427.1 [M+1].

[1048] Step 2

[1049] 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

[1050] At room temperature, trimethylaluminum (85 mg, 1.17 mmol) in tetrahydrofuran (3 mL) N-(3-amino-5-chlorophenyl)methanesulfonamide 1g (31 mg, 140.71 μmol) 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) was added dropwise to the solution. Argon purging was performed on the mixture, then heated, refluxed, and stirred for 2 hours. A dilute hydrochloric acid solution (2 mL, 1 M) was slowly added dropwise to the reaction solution and the reaction was quenched, and ethyl acetate was added for extraction (5 mL x 3). The organic phases were combined, washed with a saturated sodium chloride solution (5 mL x 2), dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was separated and purified by preliminary liquid chromatography (column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, and mobile phase B: CH3CN), resulting in 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 70 (35 mg) (yield 47.1%) was obtained.

[1051] MS m / z(ESI): 615.1 [M+1].

[1052] 1 ¹H NMR(400 MHz, DMSO- d 6) δ9.98(s, 1H), 9.83(s, 1H), 7.74(d, J = 1.5 Hz, 1H), 7.69(t, J = 1.6 Hz, 1H), 7.65 - 7.58(m, 1H), 7.45(t, J = 8.1 Hz, 1H), 7.28(d, J = 8.4 Hz, 1H), 7.18 - 7.06(m, 5H), 6.89(t, J = 1.8 Hz, 1H), 5.35(d, J = 13.3 Hz, 1H), 5.21(d, J = 13.3 Hz, 1H), 4.88(td, J= 12.8, 6.0 Hz, 1H), 4.43 - 4.26(m, 1H), 3.82 - 3.65(m, 1H), 3.36(dd, J = 13.1, 5.0 Hz, 1H), 3.06(s, 3H), 1.53(s, 3H).

[1053] Example 71

[1054] 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

[1055]

[1056] Step 1

[1057] Methyl 11-((3,5-difluorobenzyl)oxy)-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[1058] At room temperature, methyl 11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate in N,N-dimethylformamide (3 mL) with iodomethane (52 mg, 364.23 μmol). 68e (70 mg, 182.11 μmol) and potassium carbonate (75 mg, 546.34 μmol) were added dropwise to the solution, and the mixture was stirred at room temperature for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 11-((3,5-difluorobenzyl)oxy)-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate 71a (61 mg) (yield 84.1%) was obtained.

[1059] MS m / z(ESI): 399.1 [M+1].

[1060] Step 2

[1061] 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

[1062] At room temperature, trimethylaluminum (127 mg, 1.76 mmol) in tetrahydrofuran (10 mL) N-(3-amino-5-chlorophenyl)methanesulfonamide 1g (47 mg, 210.84 μmol) and methyl 11-((3,5-difluorobenzyl)oxy)-7-methyl-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate 71a (70 mg, 175.70 μmol) was added dropwise to the solution. Argon purging was performed on the mixture, then heated, refluxed, and stirred for 2 hours. A dilute hydrochloric acid solution (2 mL, 1 M) was slowly added dropwise to the reaction solution and the reaction was quenched, and ethyl acetate was added for extraction (10 mL x 3). After combining the organic phases, they were washed with a saturated sodium chloride solution (10 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by preliminary liquid chromatography (Column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; Mobile phase A: 0.05% TFA+H2O, and Mobile phase B: CH3CN), resulting in 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 71 (25 mg) (yield 24.2%) was obtained.

[1063] MS m / z(ESI): 587.1 [M+1].

[1064] 1 ¹H NMR(400 MHz, 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 = 8.2 Hz, 1H), 7.12(t, J = 7.3 Hz, 3H), 6.94(d, J = 1.6 Hz, 1H), 6.89(t, J = 1.7 Hz, 1H), 6.84(d, J = 8.3 Hz, 1H), 6.78(d, J = 8.1 Hz, 1H), 5.17(s, 2H), 4.02(t, J = 5.8 Hz, 2H), 3.37(t, J = 5.9 Hz, 2H), 3.06(s, 3H), 2.71(s, 3H).

[1065] Example 72

[1066] 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

[1067]

[1068] Step 1

[1069] Methyl 7-cyclopropyl-11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate

[1070] (1-ethoxycyclopropoxy)-trimethylsilane (79 mg, 455.28 μmol) in methanol (3 mL) at room temperature methyl 11-((3,5-difluorobenzyl)oxy)-6,7-dihydro-5H-benzo[f]pyrrolo[1,2-d][1,4]diazepine-2-carboxylate 68eSodium borohydride (41 mg, 650.41 μmol) was added to a solution of (50 mg, 130.08 μmol) and acetic acid (78 mg, 1.30 mmol), and the mixture was stirred at room temperature for 10 minutes, after which sodium borohydride was added. The mixture was stirred at room temperature for 30 minutes, then heated to 60°C and stirred for 16 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was 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) (yield 86.9%) was obtained.

[1071] MS m / z(ESI): 425.1 [M+1].

[1072] Step 2

[1073] 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

[1074] At room temperature, trimethylaluminum (87 mg, 1.21 mmol) in tetrahydrofuran (3 mL) N-(3-amino-5-chlorophenyl)methanesulfonamide 1g (32 mg, 145.49 μmol) 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) was added dropwise to the solution. After argon purging the mixture, it was heated, refluxed, and stirred for 2 hours. The reaction solution was slowly added dropwise to a dilute hydrochloric acid solution (2 mL, 1 M) and the reaction was quenched, and ethyl acetate was added for extraction (5 mL x 3). The organic phases were combined, washed with a saturated sodium chloride solution (5 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by preliminary liquid chromatography (column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, and mobile phase B: CH3CN), resulting in 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 72 (25 mg) (yield 28.2%) was obtained.

[1075] MS m / z(ESI): 613.2 [M+1].

[1076] 1 ¹H NMR(400 MHz, DMSO- d 6) δ9.99(s, 1H), 9.77(s, 1H), 7.66(d, J = 19.8 Hz, 3H), 7.27(t, J = 7.6 Hz, 1H), 7.11(s, 4H), 6.90(s, 2H), 6.82(d, J = 7.9 Hz, 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).

[1077] Example 73

[1078] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[1079]

[1080] Step 1

[1081] 3-(benzyloxy)-2-bromophenol

[1082] 2-bromobenzene-1,3-diol at room temperature 73a 1.00 g (5.29 mmol) was dissolved in acetonitrile (10 mL), to which potassium carbonate (1.46 g, 10.58 mmol) and benzyl bromide (542.95 mg, 3.17 mmol) were sequentially added, and the mixture was allowed to react at 25°C for 2 hours. The reaction solution was filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was 3-(benzyloxy)-2-bromophenol 73b (533 mg) (yield 36.1%) was obtained.

[1083] MS m / z(ESI): 279.0 / 281.0 [M+1].

[1084] Step 2

[1085] Methyl 1-(2-(3-(benzyloxy)-2-bromophenoxy)ethyl)-5-bromo-1H-pyrrole-3-carboxylate

[1086] Methyl 5-bromo-1-(2-hydroxyethyl)-1H-pyrrole-3-carboxylate at room temperature 35a (200.0 mg, 0.81 mmol) was dissolved in a toluene (2 mL) solution, and then 3-(benzyloxy)-2-bromophenol was added thereto. 73b(247.5 mg, 0.89 mmol) and cyanomethylene tri-n-butylphosphorane (583.7 mg, 2.42 mmol) were added sequentially. Nitrogen purging was performed on the mixture three times, followed by allowing the reaction to proceed 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), and the results showed methyl 1-(2-(3-(benzyloxy)-2-bromophenoxy)ethyl)-5-bromo-1H-pyrrole-3-carboxylate 73c (150 mg) (yield 36.5%) was obtained.

[1087] MS m / z(ESI): 508.0 / 510.0 / 512.0 [M+1].

[1088] Step 3

[1089] Methyl 11-(benzyloxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1090] Compounds at room temperature 73c (150.0 mg, 0.29 mmol) was dissolved in a solution of 1,2-dimethoxyethane (4 mL) and water (0.5 mL), and then potassium carbonate (122.0 mg, 0.88 mmol), bis(pinacoleto)diborone (224.4 mg, 0.88 mmol), palladium(II) acetate (13.3 mg, 0.06 mmol), and di(1-adamantyl)-n-butylphosphine (42.2 mg, 0.12 mmol) were added sequentially. Nitrogen purging was performed on the mixture three times, and then the reaction was allowed to proceed at 80°C for 18 hours. The reaction solution was filtered and then concentrated under reduced pressure. As a result of purifying the residue by silica gel column chromatography (eluent: System A), methyl 11-(benzyloxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 73d (72 mg) (yield 69.9%) was obtained.

[1091] MS m / z(ESI): 350.0 [M+1].

[1092] Step 4

[1093] Methyl 11-hydroxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1094] Methyl 11-(benzyloxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 73d 800 mg (2.29 mmol) was dissolved in methanol (20 mL), and then palladium carbonate (10%) (1.00 g, 9.40 mmol) was added to the resulting solution. Hydrogen purging was performed on the reaction solution three times, followed by stirring for 12 hours under a hydrogen atmosphere at room temperature. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with methanol (50 mL x 3). The resulting filtrate was concentrated under reduced pressure, petroleum ether / ethyl acetate (30 mL, 3:1) was added, the mixture was stirred for 30 minutes, and then filtered. The filter cake was dried, and the result was methyl 11-hydroxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 73e (300 mg) (yield 50.5%) was obtained.

[1095] MS m / z(ESI): 260.2 [M+1].

[1096] Step 5

[1097] Methyl 11-((3,5-difluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1098] Methyl 11-hydroxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 73e2.0 g, 7.71 mmol of cesium carbonate was dissolved in 40 mL of tetrahydrofuran, and then 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 solution 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 x 3). After adding petroleum ether / ethyl acetate (30 mL, 10:1), the mixture was stirred for 30 minutes and then filtered. The filter cake was dried to obtain methyl 11-((3,5-difluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 73f (2.8 g) (yield 94.2%) was obtained.

[1099] MS m / z(ESI): 386.2 [M+1].

[1100] Step 6

[1101] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[1102] Methyl 11-((3,5-difluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 73f (200 mg, 519.00 μmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide 1g(229.1 mg, 1.04 mmol) was dissolved in tetrahydrofuran (4 mL), and then trimethylaluminum (2 M, 2.08 μL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 60°C for 2 hours. The reaction solution was slowly added dropwise to methanol (10 mL) to quench the reaction. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) and further separated by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), resulting in N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,5-difluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide 73( 80 mg) (yield 26.8%) was obtained.

[1103] MS m / z(ESI): 574.2 [M+1].

[1104] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ10.00(s, 1H), 9.84(s, 1H), 7.77(d, J = 1.6 Hz, 1H), 7.70(t, J = 1.6 Hz, 1H), 7.65(t, J = 1.6 Hz, 1H), 7.29(t, J = 8.0 Hz, 1H), 7.18 - 7.13(m, 3H), 7.08(d, J = 1.6 Hz, 1H), 6.99(dd, J = 8.0, 1.2 Hz, 1H), 6.90(t, J = 2.0 Hz, 1H), 6.83(dd, J = 8.0, 0.4 Hz, 1H), 5.24(s, 2H), 4.44(t, J= 5.6 Hz, 2H), 4.16(t, J = 5.6 Hz, 2H), 3.06(s, 3H).

[1105] Example 74

[1106] 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

[1107]

[1108] Step 1

[1109] Methyl 11-((3-bromo-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1110] Methyl 11-hydroxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 73e Cesium carbonate (251.35 mg, 771.44 μmol) was dissolved in tetrahydrofuran (3 mL), and then 3-bromo-5-fluorobenzyl bromide (206.68 mg, 771.44 μmol, commercially available) was added to the resulting solution. The reaction solution was stirred at 60°C for 3 hours. The resulting mixture was filtered under reduced pressure, and then the filter cake was washed with dichloromethane (20 mL x 3). Petroleum ether / ethyl acetate (30 mL, 3:1) was added to the resulting filtrate, and then the mixture was stirred for 30 minutes and filtered. As a result of drying the filter cake, methyl 11-((3-bromo-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 74a (160 mg) (yield 92.9%) was obtained.

[1111] MS m / z(ESI): 446.0 / 448.0 [M+1].

[1112] Step 2

[1113] Methyl 11-((3-cyano-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1114] Methyl 11-((3-bromo-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 74a (80 mg, 179.27 μmol) N,N After dissolving in 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. Nitrogen purging was performed three times on the reaction solution, followed by stirring at 90°C for 3 hours under nitrogen protection. The resulting mixture was diluted with water (20 mL) and then extracted with ethyl acetate (15 mL x 2). After allowing the extract to stand, a solid precipitated; this was filtered and dried to obtain methyl 11-((3-cyano-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 74b (50 mg) (yield 71.1%) was obtained.

[1115] MS m / z(ESI): 393.2 [M+1].

[1116] Step 3

[1117] 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

[1118] Methyl 11-((3-cyano-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 74b (40 mg, 101.94 μmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g(44.99 mg, 203.88 μmol) was dissolved in tetrahydrofuran (1 mL), and then trimethylaluminum (2 M, 407.77 μL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 60°C for 2 hours. The reaction solution was slowly added dropwise to methanol (10 mL) to quench the reaction. The resulting mixture was concentrated under reduced pressure. After purifying the crude product by silica gel column chromatography (eluent: System A) and then further separating it by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), 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 74( 6 mg) (yield 10.1%) was obtained.

[1119] MS m / z(ESI): 581.1 [M+1].

[1120] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ9.95(s, 1H), 9.81(s, 1H), 7.80 - 7.77(m, 1H), 7.76(d, J = 1.6 Hz, 1H), 7.73(t, J = 1.6 Hz, 1H), 7.69(t, J = 1.6 Hz, 1H), 7.67 - 7.64(m, 1H), 7.61(t, J = 1.6 Hz, 1H), 7.30(t, J = 8.0 Hz, 1H), 7.09(d, J = 1.6 Hz, 1H), 7.00(dd, J = 8.0, 0.8 Hz, 1H), 6.88(t, J = 2.0 Hz, 1H), 6.84(dd,J = 8.0, 0.8 Hz, 1H), 5.28(s, 2H), 4.44(t, J = 6.0 Hz, 2H), 4.16(t, J = 6.0 Hz, 2H), 3.04(s, 3H).

[1121] Example 75

[1122] 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

[1123]

[1124] Step 1

[1125] Methyl 11-((3-((tert-butoxycarbonyl)amino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1126] Methyl 11-((3-bromo-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 74aCesium carbonate (60 mg, 134.45 μmol) and tert-butyl carbamate (47.25 mg, 403.35 μmol) were dissolved in 1,4-dioxane (2 mL), and then cesium carbonate (131.42 mg, 403.35 μmol), tris(dibenzylideneacetone)dipalladium (12.31 mg, 13.44 μmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthen (15.56 mg, 26.89 μmol) were added to the resulting solution. Nitrogen purging was performed three times on the reaction solution, and the mixture was stirred at 100°C for 3 hours under nitrogen protection. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with dichloromethane (10 mL x 2). The filtrate was concentrated under reduced pressure. As a result of purifying the residue by silica gel column chromatography (eluent: System A), methyl 11-((3-((tert-butoxycarbonyl)amino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 75a (60 mg) (yield 92.5%) was obtained.

[1127] MS m / z(ESI): 483.2 [M+1].

[1128] Step 2

[1129] Methyl 11-((3-amino-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1130] Methyl 11-((3-((tert-butoxycarbonyl)amino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 75a(60 mg, 124.35 μmol) was dissolved in dichloromethane (1 mL), and then trifluoroacetic acid (14.18 mg, 124.35 μmol, 0.5 mL) was added to the resulting solution. The reaction solution was stirred at 25°C for 1 hour. The resulting mixture was concentrated under reduced pressure, and the result was methyl 11-((3-amino-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 75b A was obtained, which was used directly in the next step of the synthesis.

[1131] MS m / z(ESI): 383.2 [M+1].

[1132] Step 3

[1133] Methyl 11-((3-(dimethylamino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1134] Methyl 11-((3-amino-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 75b cast N,N It was dissolved in dimethylformamide (2 mL), and then 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 solution 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. The residue was separated and purified by silica gel column chromatography (eluent: System A), and the result was methyl 11-((3-(dimethylamino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 75c (20 mg) (yield 39.2%) was obtained.

[1135] MS m / z(ESI): 411.2 [M+1].

[1136] Step 4

[1137] 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

[1138] Methyl 11-((3-(dimethylamino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 75c (20 mg, 48.73 μmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g (21.51 mg, 97.46 μmol) was dissolved in tetrahydrofuran (1 mL), and then trimethylaluminum (2 M, 194.91 μL) was added dropwise to the resulting mixture. The reaction solution was stirred at 60°C for 2 hours. The reaction was quenched by slowly adding methanol (5 mL) to the reaction solution. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was 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 75 (9 mg) (yield 30.8%) was obtained.

[1139] MS m / z(ESI): 599.1 [M+1].

[1140] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ10.00(s, 1H), 9.84(s, 1H), 7.76(d, J = 1.6 Hz, 1H), 7.69(t, J = 1.6 Hz, 1H), 7.64(t, J = 1.6 Hz, 1H), 7.28(t,J = 8.0 Hz, 1H), 7.06(d, J = 1.6 Hz, 1H), 7.01(d, J = 8.4 Hz, 1H), 6.89(t, J = 2.0 Hz, 1H), 6.81(d, J = 8.0 Hz, 1H), 6.63(s, 1H), 6.45(d, J = 8.8 Hz, 1H), 6.37(dt, J = 12.8, 2.0 Hz, 1H), 5.14(s, 2H), 4.43(t, J = 6.0 Hz, 2H), 4.16(t, J = 6.0 Hz, 2H), 3.06(s, 3H), 2.84(s, 6H).

[1141] Example 76

[1142] 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

[1143]

[1144] Step 1

[1145] carbamate tert-butyl(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)

[1146] Methyl 11-((3-((tert-butoxycarbonyl)amino)-5-fluorobenzyl)oxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 75a (60 mg, 124.35 μmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g(54.88 mg, 248.70 μmol) was dissolved in tetrahydrofuran (1.5 mL), and then trimethylaluminum (2 M, 497.41 μL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 60°C for 2 hours. The reaction was quenched by slowly adding methanol (10 mL) to the reaction solution. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was tert-butyl carbamate (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) 76a (30 mg) (yield 35.9%) was obtained.

[1147] MS m / z(ESI): 693.2 [M+23].

[1148] Step 2

[1149] 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

[1150] carbamate tert-butyl(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) 76a(40 mg, 59.60 μmol) was dissolved in dichloromethane (1 mL), and then trifluoroacetic acid (6.80 mg, 59.60 μmol, 0.5 mL) was added to the resulting solution. The reaction solution was stirred at 25°C for 1 hour. The resulting mixture was concentrated under reduced pressure and separated by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), resulting in 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 76 (10 mg) (yield 29.3%) was obtained.

[1151] MS m / z(ESI): 571.1 [M+1].

[1152] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ10.00(s, 1H), 9.85(s, 1H), 7.76(d, J = 1.6 Hz, 1H), 7.71(t, J = 1.6 Hz, 1H), 7.63(t, J = 1.6 Hz, 1H), 7.25(t, J = 8.0 Hz, 1H), 7.03(d, J = 1.6 Hz, 1H), 6.94(dd, J = 8.0, 0.4 Hz, 1H), 6.89(t, J = 2.0 Hz, 1H), 6.79(dd, J = 8.0, 0.4 Hz, 1H), 6.46(t, J = 1.6 Hz, 1H), 6.33(dt, J = 8.8, 2.4 Hz, 1H), 6.22(dt, J= 11.6, 2.0 Hz, 1H), 5.41(s, 2H), 5.06(s, 2H), 4.43(t, J = 5.6 Hz, 2H), 4.16(t, J = 5.6 Hz, 2H), 3.05(s, 3H).

[1153] Example 77

[1154] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,3-difluorocyclopentyl)methoxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[1155]

[1156] Step 1

[1157] Methyl 11-((3,3-difluorocyclopentyl)methoxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate

[1158] Methyl 11-hydroxy-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 73e (30 mg, 115.72 μmol) and (3,3-difluorocyclopentyl)methanol (31.51 mg, 231.43 μmol) were dissolved in toluene (1 mL), and then cyanomethylene tri-n-butylphosphorane (83.78 mg, 347.15 μmol, 90.97 μL) was added to the resulting solution. The reaction solution was stirred at 80°C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A), and the result was methyl 11-((3,3-difluorocyclopentyl)methoxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 77a (35 mg) (yield 80.1%) was obtained.

[1159] MS m / z(ESI): 378.2 [M+1].

[1160] Step 2

[1161] N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,3-difluorocyclopentyl)methoxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide

[1162] Methyl 11-((3,3-difluorocyclopentyl)methoxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxylate 77a (60 mg, 158.99 μmol) and N -(3-amino-5-chlorophenyl)methanesulfonamide 1g (70.17 mg, 317.98 μmol) was dissolved in tetrahydrofuran (2 mL), and then trimethylaluminum (2 M, 635.96 μL) was slowly added dropwise to the resulting mixture. The reaction solution was stirred at 60°C for 2 hours. The reaction was quenched by slowly adding methanol (10 mL) to the reaction solution. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) and then further separated by pre-liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, and mobile phase B: CH3CN), resulting in N-(3-chloro-5-(methylsulfonamido)phenyl)-11-((3,3-difluorocyclopentyl)methoxy)-5,6-dihydrobenzo[f]pyrrolo[1,2-d][1,4]oxazepine-2-carboxamide 77 (25 mg) (yield 27.7%) was obtained.

[1163] MS m / z(ESI): 566.1 [M+1].

[1164] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ10.00(s, 1H), 9.82(s, 1H), 7.75(d, J = 1.6 Hz, 1H), 7.69(t,J = 1.6 Hz, 1H), 7.63(t, J = 1.6 Hz, 1H), 7.26(t, J = 8.0 Hz, 1H), 6.95 - 6.91(m, 2H), 6.89(t, J = 2.0 Hz, 1H), 6.79(dd, J = 8.0, 0.8 Hz, 1H), 4.43(t, J = 6.0 Hz, 2H), 4.15(t, J = 6.0 Hz, 2H), 3.99(d, J = 6.4 Hz, 2H), 3.05(s, 3H), 2.62-2.54(m, 1H), 2.29 - 1.93(m, 5H), 1.70-1.60(m, 1H).

[1165] The compounds of Examples 78 to 85 were prepared according to the method of Example 77 of the present invention, and their specific structures and structural characterization results are presented below:

[1166]

[1167]

[1168]

[1169] The compounds of Examples 86 to 99 were prepared according to the method of Example 73 of the present invention, and their specific structures and structural characterization results are presented below:

[1170]

[1171]

[1172]

[1173]

[1174] The compound of Example 101 was prepared according to the method of Example 69 of the present invention, and the specific structure and structural characteristic results are presented below:

[1175]

[1176] The compounds of Examples 102 to 105 were prepared according to the method of Example 70 of the present invention, and their specific structures and structural characterization results are presented below:

[1177]

[1178]

[1179] The compounds of Examples 106 to 111 were prepared according to the method of Example 68 of the present invention, and their specific structures and structural characterization results are presented below:

[1180]

[1181]

[1182] The compounds of Examples 112 to 133 were prepared according to the method of Example 71 of the present invention, and their specific structures and structural characterization results are presented below:

[1183]

[1184]

[1185]

[1186]

[1187]

[1188] The compounds of Examples 134 and 135 were prepared according to the method of Example 67 of the present invention, and their specific structures and structural characterization results are presented below:

[1189]

[1190] The compounds of Examples 136 to 138 were prepared according to the method of Example 63 of the present invention, and their specific structures and structural characterization results are presented below:

[1191]

[1192] The compounds of Examples 139 to 142 were prepared according to the method of Example 64 of the present invention, and their specific structures and structural characterization results are presented below:

[1193]

[1194] The compounds of Examples 143 to 146 were prepared according to the method of Example 65 of the present invention, and their specific structures and structural characterization results are presented below:

[1195]

[1196] The compounds of Examples 147 to 150 were prepared according to the method of Example 66 of the present invention, and their specific structures and structural characterization results are presented below:

[1197]

[1198] The compounds of Examples 151 to 154 were prepared according to the method of Example 68 of the present invention, and their specific structures and structural characterization results are presented below:

[1199]

[1200] The compounds of Examples 155 to 158 were prepared according to the method of Example 19 of the present invention, and their specific structures and structural characterization results are presented below:

[1201]

[1202] Biological evaluation

[1203] Test Example 1. Determination of the inhibitory effect of the compound of the present invention on CCRF-CEM cell proliferation

[1204] The effect of the compounds of the present invention on CCRF-CEM cell proliferation was determined by the following method. 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 / mL penicillin, and 100 μg / mL streptomycin. Cell viability was determined using the CellTiter-Glo® Luminescent Cell Viability Assay Kit (Promega, Cat. No. G7573).

[1205] The experimental method was carried out according to the steps of the kit usage instructions, which are briefly described as follows. The test compound was first dissolved in DMSO to prepare a 10 mM stock solution, and this stock solution was diluted with the aforementioned medium to prepare the test samples; the final concentration of the compound ranged from 10,000 nM to 1.52 nM. Cells in the log growth phase were seeded into 96-well cell culture plates at a density of 1,000 cells per well. Subsequently, the test compound was added, and the cells were incubated in a 37°C air incubator for 120 hours. After the incubation was complete, 50 μL of CellTiter-Glo assay reagent was added to each well, the plates were shaken for 5 minutes, and then left to stand for 10 minutes. Afterward, the luminescence values ​​of the samples in each well were read using a microplate reader in luminescence mode. The compound inhibition rate (%) at each concentration was calculated by comparing the read luminescence values ​​with the numerical values ​​of the control group (0.1% DMSO), and the IC50 of the compound for cell proliferation inhibition was determined by performing a non-linear regression analysis based on the concentration log-inhibition rate using GraphPad Prism 9 software. 50 The values ​​were calculated, and the results can be seen in Table 1.

[1206]

[1207] Conclusion: The compounds of the present invention have a relatively excellent inhibitory effect (IC) on CCRF-CEM cell proliferation.50 It showed < 100 nM).

[1208] Note: The structure of ATX-968 (manufactured in Example 31 according to International Patent Publication WO2023154519A1) is as follows:

[1209]

[1210] Test Example 2: Determination of the inhibitory effect of the compound of the present invention on LS411N cell proliferation

[1211] The effect of the compounds of the present invention on LS411N cell proliferation was determined by the following method. 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 / mL penicillin, and 100 μg / mL streptomycin. Cell viability was determined using the CellTiter-Glo® Luminescent Cell Viability Assay kit (Promega, Cat. No. G7573).

[1212] The experimental method was performed according to the steps of the kit usage instructions, which are briefly described below. The test compound was first dissolved in DMSO to prepare a 10 mM stock solution, and this stock solution was diluted with the aforementioned medium to prepare the test samples. The final concentration of the compound ranged from 10,000 nM to 0.152 nM. Cells in the log growth phase were seeded into 96-well cell culture plates at a density of 1,000 cells per well. After adding the test compound, the cells were incubated in a 37°C air incubator for 120 hours. Once incubation was complete, 50 μL of CellTiter-Glo assay reagent was added to each well, the plates were shaken for 5 minutes, and then left to stand for 10 minutes. Subsequently, the luminescence values ​​of each well containing the samples were read using a microplate reader in luminescence mode. The compound inhibition rate (%) at each concentration was calculated by comparing the read luminescence values ​​with the numerical values ​​of the control group (0.1% DMSO), and a non-linear regression analysis based on the log-inhibition rate of the compound concentration was performed using GraphPad Prism 9 software to determine the IC50 of the compound regarding cell proliferation inhibition. 50 The values ​​were calculated, and the results can be seen in Table 2.

[1213]

[1214] Conclusion: The compound of the present invention has a relatively excellent inhibitory effect (IC) on LS411N cell proliferation. 50 It showed < 100 nM).

[1215] Test Example 3. Test of the inhibitory effect of the compound of the present invention on the hDHX9 enzyme (ATPase).

[1216] The degree of in vitro inhibition of the compound of the present invention on the activity of recombinant human DExH-box helicase 9 (hDHX9, ATPase) was determined by the following method. This method includes Promega’s ADP-Glo TM The Kinase Test Kit (Cat. No. V9102) was used. The kit instructions were referenced for detailed experimental procedures.

[1217] The experimental procedure is briefly described as follows. The test compound was first dissolved in DMSO to prepare a stock solution, and then reaction buffer (40 mM HEPES, pH 7.5, 20 mM MgCl₂, 0.01% Tween-20, 0.01% BSA, 1 mM DTT, 0.004 U / mL RNase OUT) TM The test compound was serially diluted with a recombinant ribonuclease inhibitor, and the final concentration of the test compound in the reaction system ranged from 10,000 nM to 0.04 nM. The hDHX9 protein (expression and purification commissioned to Nanjing GenScript Biotechnology Co., Ltd.) was prepared using reaction buffer, and the double-stranded RNA substrate for DHX9 was synthesized and annealed by Suzhou GENEWIZ Biotechnology Co., Ltd., and their sequences are as follows: Sequence 1: 5'-GAAUUAACCAAGGAAAAUAACAAGGACAGGGACCAGG-3' and Sequence 2: 5'-GCCUGGUCCCUGUCCUUGUUAUUUUCCUUGGUUAAUU-3'). The reaction was performed on a 384-well microplate. 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, double-stranded RNA solution (final concentration 18.8 nM) and ATP solution (final concentration 30 μM, ADP-Glo TMA component derived from Component V915A of the kinase assay kit was added to the reaction solution, and the mixture was incubated at room temperature for 45 minutes. Next, 5 μL of ADP-Glo ​​reagent was added to the reaction system, and the mixture was incubated at room temperature for 50 minutes. Then, 10 μL of kinase detection reagent was added to the reaction system, and the mixture was incubated at room temperature for 30 minutes. After the incubation was completed, the chemiluminescence intensity values ​​for each well were determined using a micro-plate reader in luminescence mode. The confirmed luminescence intensity ratio was compared with the luminescence intensity ratio of the control group (0.1% DMSO) to calculate the compound inhibition rate (%) at each concentration. Subsequently, a non-linear regression analysis based on the compound concentration log-inhibition rate was performed using GraphPad Prism 9 software to determine the IC of the compound. 50 Values ​​were obtained, and the results can be seen in Table 3.

[1218]

[1219] Conclusion: The compound of the present invention has a superior inhibitory effect (IC) on hDHX9 enzyme (ATPase) activity. 50 It showed < 100 nM).

[1220] Test Example 4. Pharmacokinetic evaluation of the compound of the present invention in mice

[1221] 1. Experimental Objective

[1222] ICR mice were used as test animals and the control compound ATX-968 and the compound of the present invention were administered intragastically. Afterward, the plasma drug concentrations were determined at different time points using the LC / MS / MS method, and the in vivo pharmacokinetic profile of the compound of the present invention in mice was investigated.

[1223] 2. Experimental Design

[1224] 2.1 Experimental Drugs and Animals

[1225] Control compound ATX-968 and compounds 68 and 73.

[1226] ICR mouse (male, 32.8 g ~ 38.0 g, purchased from Vital River Laboratory Animal Technology Co., Ltd.)

[1227] 2.2 Drug Manufacturing

[1228] After weighing the titration amount of the test compound, DMA (N,N-dimethylacetamide), 30% Solutol HS15 (30% polyethylene glycol-15 hydroxystearate), and saline solution were added sequentially. The mixture was mixed by sonication and vortexing to prepare a 1 mg / mL dosage formulation, in which case the ratio of DMA, 30% Solutol HS15, and saline solution was 10:10:80 (v / v / v).

[1229] 2.3 Administration

[1230] ICR mice (9 per group) of each compound group were fasted overnight the day before, and then the compound was administered gastrically (PO) (compound dosage = 10 mg / kg, compound volume = 10 mL / kg), and food was provided 4 hours after administration.

[1231] 3. Work

[1232] Approximately 0.1 mL of blood was collected via the orbital vein before administration and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours after administration, and the collected whole blood samples were transferred into EDTA-K2-containing anticoagulant tubes. The collected blood samples were placed on ice, and plasma was subsequently separated by centrifugation (centrifugation conditions: 1500 g, 10 min). The collected plasma was stored at -40°C to -20°C until analysis.

[1233] The plasma content of the test compound administered intragastrically to mice was determined by LC-MS / MS.

[1234] 4. Results of pharmacokinetic parameters

[1235] The pharmacokinetic parameters of the compound under test can be found in Table 4 below.

[1236]

[1237] Test Example 5. Pharmacodynamic test of the compound of the present invention in mice

[1238] 1. Experimental Objective

[1239] The antitumor effects of the control compound ATX-968 and compounds 68 and 73 of the present invention were evaluated in a BALB / c nude mouse model, i.e., an LS411N human appendicitis subcutaneous xenograft model.

[1240] 2. Experimental animals

[1241] BALB / c nude mouse (female, 6–7 weeks old, purchased from Jiangsu Gempharmatech Biotechnology Co., Ltd., animal production license number: SCXK(Su) 2023-0009, and animal certificate of conformity number: No. B202409230909)

[1242] 3. Preparation of Test Compound

[1243] The vehicle control group was administered with DMA : Solutol HS 15 : 20% HP-β-CD (10 : 10 : 80 (v / v / v)).

[1244] ATX-968: After weighing an appropriate amount of ATX-968, an appropriate amount of DMA, Solutol HS 15, and 20% HP-β-CD were added sequentially, and the mixture was mixed by sonication and vortexing to prepare a 20 mg / mL dosage formulation, wherein the ratio of DMA, Solutol HS 15, and 20% HP-β-CD was 10:10:80 (v / v / v).

[1245] Compound 68: After weighing an appropriate amount of Compound 68, an appropriate amount of DMA, Solutol HS 15, and 20% HP-β-CD were added sequentially, and the mixture was mixed by sonication and vortexing to prepare a 10 mg / mL dosage formulation, wherein the ratio of DMA, Solutol HS 15, and 20% HP-β-CD was 10:10:80 (v / v / v).

[1246] Compound 73: After weighing an appropriate amount of Compound 73, an appropriate amount of DMA, Solutol HS 15, and 20% HP-β-CD were added sequentially, and the mixture was mixed by sonication and vortexing to prepare a 10 mg / mL dosage formulation, wherein the ratio of DMA, Solutol HS 15, and 20% HP-β-CD was 10:10:80 (v / v / v).

[1247] 4. LS411N cell culture medium

[1248] LS411N human appendiceal cancer cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin-amphotericin B solution. LS411N cells in the exponential growth phase were collected and resuspended in a mixture of PBS and Matrigel (1:1). The concentration of the cell suspension was adjusted to a concentration suitable for subcutaneous tumor inoculation on the right dorsal side of BALB / c nude mice.

[1249] 5. Animal Vaccination and Group Assignment

[1250] Approximately 4.0 x 10⁶ 6 100 LS411N cells were inoculated. The average tumor volume was approximately 100–250 mm³ 3 When the time was reached, mice were randomly assigned to groups based on tumor size, with 6 mice assigned to each group.

[1251] 6. Animal Administration and Observation

[1252] Animals in each group were orally administered the test compound twice a day at a fixed time each day according to their body weight, and administration of the test compound to the animals was started for 21 consecutive days starting from the day of group assignment, and the animals' body weight was recorded daily.

[1253] Group 1 (G1): Vehicle control group

[1254] Group 2 (G2): ATX-968, dose 200 mg / kg, orally administered twice daily (BID).

[1255] Group 3 (G3): Compound 68, dose 100 mg / kg, administered orally twice daily (BID).

[1256] Group 4 (G4): Compound 73, dose 100 mg / kg, administered orally twice daily (BID).

[1257] Tumor formation at the tumor inoculation sites of each animal in each group was observed, and tumor volume was measured twice weekly. The formulas for Tumor Volume (TV), Relative Tumor Volume (RTV), Relative Tumor Growth Rate (T / C), and Relative Tumor Growth Inhibition Rate (TGI) are as follows:

[1258] (1) TV (tumor volume)

[1259] TV = 1 / 2 xaxb 2 (Here, a is the length of the tumor and b is the width of the tumor)

[1260] (2) RTV (Relative Tumor Volume)

[1261] RTV = V t / V0(where V0 is the tumor volume measured at the time of group assignment, V t is the tumor volume at each measurement)

[1262] (3) T / C(%)

[1263] T / C(%) = (T RTV / C RTV ) x 100% (where T RTV is the RTV, C of the treatment group RTV is the RTV of the solvent control group)

[1264] (4) TGI (%)

[1265] TGI(%) = (1 - T / C) x 100% (where T and C are the relative tumor volume of the treatment group and the relative tumor volume of the solvent control group at a specific time point, respectively)

[1266] 7. Results

[1267] The results can be seen in Table 5.

[1268]

[1269] Conclusion: In the LS411N human appendicitis subcutaneous xenograft-carrying mouse model under the conditions set in this experiment, when compared to the vehicle control group and the group administered ATX-968 at a dose of 200 mg / kg, the groups administered compounds 68 and 73 of the present invention exhibited a more significant tumor growth inhibitory effect at a lower dose (100 mg / kg).

Claims

Claim 1 Chemical formula I, that is, [Chemical formula I] A compound as shown in or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from a tricyclic heteroaryl or tricyclic fused ring; X is selected from a halogen; and R 1 C 1-6 Selected from alkyl or ternary to pentary cycloalkyl, wherein the alkyl or cycloalkyl is a halogen, hydroxyl, cyano, C 1-6 alkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from alkoxy; each R 2 is independently a hydrogen atom, cyano, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclil, 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 Selected from, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclil, aryl, or heteroaryl is a deuterium atom, halogen, nitro, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclil, 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 Optionally additionally substituted with one or more substituents selected from; or two R 2 forms -C(O) or cyclopropyl with the same carbon to which these groups are attached; and each R 3 is independently selected from hydrogen atoms, alkyl, cycloalkyl, heterocyclil, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclil, aryl, or heteroaryl is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclil, 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 Optionally additionally substituting with one or more substituents selected from;R A is selected from hydrogen atoms, alkyl, cycloalkyl, heterocyclil, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclil, aryl, or heteroaryl is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclil, 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 Optionally additionally substituting with one or more substituents selected from;R 4 and R 5 Each is independently selected from hydrogen atoms, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclil, aryl, or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclil, aryl, or heteroaryl is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclil, 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 Optionally additionally substituted with one or more substituents selected from; or R 4 and R 5 ... forms a 4- to 8-membered heterocyclile together with atoms to which these groups are attached, wherein the 4- to 8-membered heterocyclile comprises one or more N, O, or S(O) r Containing, wherein the 4- to 8-membered heterocyclile is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclile, 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 Optionally additionally substituting with one or more substituents selected from;R 6 , R 7 and R 8 A compound or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein each is independently selected from a hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxylate groups; t is selected from 0 or 1; n is selected from 0, 1, 2, 3, 4, 5, 6, 7, or 8; and each r is independently 0, 1, or 2. Claim 2 In claim 1, the ring A is a compound or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, selected from a 12- to 18-membered tricyclic fusion ring or a 12- to 18-membered tricyclic heteroaryl, preferably a 12- to 16-membered tricyclic fusion ring or a 12- to 14-membered tricyclic heteroaryl. Claim 3 In paragraph 1 or 2, the above R 2 is a 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 Selected from, but the above C 1-6 Alkyl groups consist of deuterium atoms, halogens, cyanos, and C 1-6 Alkyl, -C(O)OR 6 or -OR A Optionally additionally substituted with one or more substituents selected from, or two R 2 is formed with the same carbon atom to which these groups are attached to form -C(O) or cyclopropyl; and the R A is a hydrogen atom, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Selected from aryl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclil, wherein C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 6-membered heteroaryls, or 5- to 6-membered heterocyclils are hydroxyl, halogen, cyano, -NR 7 R 8 , C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from alkoxy; and the R 3 Silver is a hydrogen atom, C 3-8 Cycloalkyl, C 6-10 Aryl or C 1-6 Selected from alkyl, wherein C 3-8 Cycloalkyl, C 6-10 Aryl or C 1-6 Alkyl groups are halogens, hydroxyl groups, cyano groups, C 1-6 alkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from alkoxy; and the R 6 It is a hydrogen atom or C 1-6 Selected from alkyls; said R 7 and R 8 Each independently consists of a hydrogen atom or C 1-6 A compound or its stereoisomer, its tautomer, or its pharmaceutically acceptable salt, selected from alkyl; wherein t is selected from 0 or 1. Claim 4 In any one of paragraphs 1 to 3, the above R 2 is a hydrogen atom, halogen, C 1-6 Alkyl, hydroxyl, cyano, C 1-6 Alkoxy, SF5, C 1-6 Haloalkyl or C 1-6 Selected from haloalkoxy; or 2 R 2 is a compound or its stereoisomer, its tautomer, or its pharmaceutically acceptable salt that forms a -C(O) group with the same carbon atom to which these groups are attached. Claim 5 In any one of paragraphs 1 to 4, the chemical formula IIA, i.e., [chemical formula IIA] A compound as shown in, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein is a 5-membered heteroaryl; X1 and X2 are each independently selected from CH, S, or N, and X1 and X2 are not simultaneously S; X3 is selected from C or N, wherein when X3 is C, X1 and X2 are not simultaneously CH; ring B is selected from a 5- to 8-membered heterocyclil, a 6- to 10-membered aryl, or a 5- to 6-membered heteroaryl, wherein the heterocyclil contains one or two double bonds; is selected from single or double bonds as needed, each of which exists in a normal valence state; Y and Z are each independently CR a , CHR a , O, N, or NR b Selected from;R 2a is a hydrogen atom, C 3-8 Cycloalkyl, C 1-6 Alkyl or -C(O)R 3 Selected from, but the above C 1-6 Alkyl atoms are deuterium atoms, halogens, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 6 Optionally additionally substituted with one or more substituents selected from; or two R 2a These groups form -C(O) or cyclopropyl with the same carbon atom to which they are attached; and each R 2b is independently a hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 3 Selected from, but the above C 1-6 alkyl or C 1-6 The alkoxy is optionally additionally substituted with one or more substituents selected from hydroxyl, halogen, or cyano;R a and R b Each independently consists of a hydrogen atom, halogen, cyano, and C 1-6 Alkyl, amino, -NHC(O)R 3 or -O(CH2) t R A Selected from, but the above C 1-6 Alkyl groups are halogens, cyanos, C 1-6 alkyl or -OR A Optionally additionally substituted with one or more substituents selected from; each R A is independently a hydrogen atom, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Selected from aryl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclil, wherein C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 6-membered heteroaryls, or 5- to 6-membered heterocyclils are hydroxyl, halogen, cyano, -NR 7 R 8 , C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from the alkoxy;R 3 is a hydrogen atom, C 6-10 Aril, C 3-8 Cycloalkyl or C 1-6 Selected from alkyl, wherein C 6-10 Aril, C 3-8 Cycloalkyl or C 1-6 Alkyl groups are halogens, hydroxyl groups, cyano groups, C 1-6 alkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from the alkoxy;R 6 It is a hydrogen atom or C 1-6 Selected from alkyl; R 7 and R 8 Each independently consists of a hydrogen atom or C 1-6 Selected from alkyl; t is selected from 0 or 1; each p is independently selected from 0, 1, 2, 3, 4 or 5; each q is independently selected from 0, 1 or 2; R 1 and X is a compound or its stereoisomer, its tautomer, or its pharmaceutically acceptable salt as defined in claim 1. Claim 6 In paragraph 5, chemical formula IIIA or IIIB, i.e., [chemical formula IIIA] [Chemical Formula IIIB] A compound as shown in, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from 5- to 8-membered heterocyclies, said heterocyclies containing one or two double bonds; and Y and Z are each independently CR a or selected from N; R 2a is a hydrogen atom, C 1-6 Alkyl or -C(O)R 3 Selected from, but the above C 1-6 Alkyl groups are halogens, hydroxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 6 Optionally additionally substituted with one or more substituents selected from; or two R 2a These groups form -C(O) or cyclopropyl with the same carbon atom to which they are attached; and each R 2b is independently a hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 3 Selected from; each R a is independently a hydrogen atom, halogen, cyano, C 1-6 Alkyl, amino, -NHC(O)R 3 or -O(CH2) t R A Selected from, but the above C 1-6 Alkyl groups are halogens, cyanos, C 1-6 alkyl or -OR A Optionally additionally substituted with one or more substituents selected from; each R A is independently a hydrogen atom, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Selected from aryl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclil, wherein C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 6-membered heteroaryls, or 5- to 6-membered heterocyclils are hydroxyl, halogen, cyano, -NR 7 R 8 , C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from the alkoxy;R 3 is a hydrogen atom, C 6-10 Aryl or C 1-6 Selected from alkyl, wherein C 6-10 Aryl or C 1-6 Alkyl groups are halogens, hydroxyl groups, cyano groups, C 1-6 alkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from the alkoxy;R 6 It is a hydrogen atom or C 1-6 Selected from alkyl; R 7 and R 8 Each independently consists of a hydrogen atom or C 1-6 Selected from alkyl; t is selected from 0 or 1; each p is independently selected from 0, 1, 2, 3, 4 or 5; R 1 and X is a compound, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof as defined in paragraph 5. Claim 7 In paragraph 5, chemical formula IIIC, i.e., [chemical formula IIIC] A compound as shown in, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y and Z are each independently CHR a , O or NR b Selected from;R 2a is a hydrogen atom or C 1-6 Selected from alkyl, wherein C 1-6 Alkyl groups are halogens, hydroxyl groups, cyano groups, C 1-6 alkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from alkoxy; each R 2b is independently a hydrogen atom or C 1-6 Selected from alkyl; R a and R b Each is independently a hydrogen atom, halogen, hydroxyl, cyano, or C 1-6 Selected from alkyl, wherein C 1-6 Alkyl groups are halogens, hydroxyl groups, cyano groups, C 1-6 alkyl or C 1-6 Optionally additionally substituent with one or more substituents selected from alkoxy; each p is independently selected from 0, 1, or 2; each q is independently selected from 0, 1, or 2; R 1 and X is a compound, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof as defined in paragraph 5. Claim 8 In any one of paragraphs 1 to 4, Chemical Formula II, i.e., [Chemical Formula II] A compound as shown in, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein is a 5-membered heteroaryl; X1 and X2 are each independently selected from CH, S, or N, and X1 and X2 are not simultaneously S; X3 is selected from C or N, where X3 is C, X1 and X2 are not simultaneously CH; ring B is selected from a 5- to 8-membered heterocyclil, a 6- to 10-membered aryl, or a 5- to 6-membered heteroaryl, wherein the heterocyclil contains one or two double bonds; is a 6-membered heteroaryl or a 6-membered heterocyclil; is selected from single or double bonds as needed, each of which exists in a normal valence state; Y and Z are each independently CR a , O or NR b Selected from;R a is a hydrogen atom, halogen, hydroxyl, cyano, C 1-6 alkyl or C 1-6 Selected from alkoxy, wherein the alkyl or alkoxy is a halogen, hydroxyl, cyano, C 1-6 alkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from the alkoxy;R b is a hydrogen atom or C 1-6 Selected from alkyl, wherein the alkyl is a halogen, hydroxyl, cyano, C 1-6 alkyl or C 1-6 Optionally additionally substituent with one or more substituents selected from alkoxy; m is selected from 0, 1, 2 or 3; R 1 , R 2 and X is a compound, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof as defined in claim 1. Claim 9 In any one of paragraphs 1 to 4, chemical formula III, i.e., [chemical formula III] Provides a compound as shown in, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from a 5- to 8-membered heterocyclile or a 5- to 6-membered heteroaryl, said heterocyclile containing one or two double bonds; and Y and Z are each independently CR a or selected from N; R a is a hydrogen atom, halogen, hydroxyl, cyano, C 1-6 alkyl or C 1-6 Selected from alkoxy, wherein the above C 1-6 alkyl or C 1-6 Alkoxy is a halogen, hydroxyl, cyano, C 1-6 alkyl or C 1-6 Optionally additionally substituent with one or more substituents selected from alkoxy; p is selected from 0, 1, 2 or 3; R 1 , R 2 and X is a compound, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof as defined in claim 1. Claim 10 In any one of paragraphs 1 through 4, is the following elements, that is Selected from, R 2 and n is a compound, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof as defined in claim 1. Claim 11 In Paragraph 10, is the following elements, that is A compound selected from, or its stereoisomer, its tautomer, or its pharmaceutically acceptable salt. Claim 12 In paragraph 5, is the following elements, that is Selected from, R 2a is a hydrogen atom, C 1-6 Alkyl, C 3-8 Cycloalkyl or -C(O)R 3 Selected from, but the above C 1-6 Alkyl atoms are deuterium atoms, halogens, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 6 Optionally additionally substituted with one or more substituents selected from; or two R 2a These groups form -C(O) or cyclopropyl with the same carbon atom to which they are attached; and each R 2b is independently a hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or -C(O)OR 3 Selected from; each R a is independently a hydrogen atom, halogen, cyano, C 1-6 Alkyl, amino, -NHC(O)R 3 or -O(CH2) t R A Selected from, but the above C 1-6 Alkyl groups are halogens, cyanos, C 1-6 alkyl or -OR A Optionally additionally substituting with one or more substituents selected from;R b is a hydrogen atom or C 1-6 Selected from alkyl, wherein C 1-6 The alkyl group is optionally additionally substituted with one or more halogens; R A is a hydrogen atom, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Selected from aryl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclil, wherein C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 6-membered heteroaryls, or 5- to 6-membered heterocyclils are hydroxyl, halogen, cyano, -NR 7 R 8 , C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from the alkoxy;R 3 is a hydrogen atom, C 6-10 Aril, C 3-8 Cycloalkyl or C 1-6 Selected from alkyl, wherein C 6-10 Aril, C 3-8 Cycloalkyl or C 1-6 Alkyl groups are halogens, hydroxyl groups, cyano groups, C 1-6 alkyl or C 1-6 Optionally additionally substituted with one or more substituents selected from the alkoxy;R 6 It is a hydrogen atom or C 1-6 Selected from alkyl; R 7 and R 8 Each independently consists of a hydrogen atom or C 1-6 A compound, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, selected from alkyl; t is selected from 0 or 1; each p is independently selected from 0, 1, 2, 3, 4 or 5; each p' is independently selected from 0, 1, 2, 3 or 4; and each q is independently selected from 0, 1 or 2. Claim 13 In Clause 12, the above R 2a is a hydrogen atom, methyl, ethyl, isopropyl, Selected from; or 2 R 2a A compound, or its stereoisomer, its tautomer, or its pharmaceutically acceptable salt, which forms -C(O) or cyclopropyl with the same carbon atom to which these groups are attached. Claim 14 In Clause 12, the above R a is a hydrogen atom, hydroxyl, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, amino, A compound selected from, or its stereoisomer, its tautomer, or its pharmaceutically acceptable salt. Claim 15 In paragraph 12, the compound, or its stereoisomer, its tautomer, or its pharmaceutically acceptable salt, wherein q is 0. Claim 16 In any one of paragraphs 12 through 15, is the following elements, that is A compound selected from, or its stereoisomer, its tautomer, or its pharmaceutically acceptable salt. Claim 17 In any one of claims 1 to 16, X is a compound selected from Cl or Br, preferably Cl, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof. Claim 18 In any one of claims 1 to 17, the above R 1 A compound selected from methyl or ethyl, or its stereoisomer, its tautomer, or its pharmaceutically acceptable salt. Claim 19 In any one of claims 1 to 18, the compound is Phosphorus, a compound, or its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof. Claim 20 A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof. Claim 21 The use of a compound according to any one of claims 1 to 19, or its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20 in the manufacture of a DHX9 inhibitor. Claim 22 A use of a compound according to any one of claims 1 to 19, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, wherein the DHX9-mediated disease is preferably cancer, a viral infection, or an autoimmune disease, more preferably cancer, and more preferably the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic cancer, breast cancer, brain cancer, skin cancer, lung cancer, blood cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft tissue cancer, kidney cancer, and liver cancer, and preferably selected from colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic cancer, and gastric cancer. Claim 23 In paragraph 22, the above cancer is a microsatellite unstable cancer, preferably a microsatellite high-stable cancer, more preferably a microsatellite high-stable colorectal cancer. Claim 24 A use of a compound according to any one of claims 1 to 19, or a stereoisomer thereof, a tautomeric isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, in the manufacture of a medicine for treating cancer, viral infection or autoimmune disease, preferably said cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic cancer, breast cancer, brain cancer, skin cancer, lung cancer, blood cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft tissue cancer, kidney cancer, and liver cancer, more preferably said cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic cancer, and gastric cancer. Claim 25 In paragraph 24, the above cancer is a microsatellite unstable cancer, preferably a microsatellite high-stable cancer, more preferably a microsatellite high-stable colorectal cancer.

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