Compound for producing sulfonamide or sulfinamide compound having effect of inducing BRD4 protein degradation

Abstract

To provide a compound which is superior in an action inducing degradation of BRD4 protein and useful as a therapeutic agent for cancer, or a pharmaceutically acceptable salt thereof.SOLUTION: Provided is a compound represented by the formula (I) in the figure or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to sulfonamide or sulfinamide compounds or pharmaceutically acceptable salts thereof that have excellent cytotoxic effects on cancer cells, effects of inducing the degradation of BRD4 protein in cancer cells, and effects of inhibiting the binding of BRD4 protein to acetylated histones, and are useful as anticancer agents, BRD4 protein degradation inducers, and BRD4 protein inhibitors, as well as compounds for producing them. [Background technology]

[0002] Eukaryotic DNA is contained within the nucleus as a chromatin structure. Nucleosomes, the building blocks of chromatin, are composed of DNA wrapped around a histone octamer, consisting of two molecules of each of four histones: H2A, H2B, H3, and H4. The several dozen residues at the N-terminus of histones, known as the histone tail, are subject to various post-translational modifications, such as acetylation, methylation, phosphorylation, and ubiquitination. These post-translational modifications, also known as the histone code, are one of the mechanisms responsible for epigenetic regulation of gene expression, determining when and where genetic information on DNA is expressed. Histone modifications are reversible and functionally regulated by histone modification enzymes (writers), which write the modification groups onto histones, histone erasure enzymes (erasers), and histone readers, which specifically read the modified histones. While these regulatory mechanisms significantly contribute to ontogenesis and cell differentiation, epigenetic abnormalities are known to be involved in various diseases.

[0003] Bromodomains are reader proteins consisting of approximately 110 amino acids that recognize acetylated lysines on histones. Approximately 50 types of proteins containing bromodomains have been identified to date. They function as scaffolding proteins for various transcription factors by binding to acetylated lysines on histones, and they exert various functions within cells, such as chromatin remodeling and transcriptional regulation through their own histone acetyltransferase and kinase activities. BRD2, BRD3, BRD4, and BRDT, which belong to the BET (bromodomain and extraterminal) family of bromodomain-containing proteins (sometimes referred to as BET proteins in this specification and claims), possess two N-terminal bromodomains and an extra C-terminal domain that are highly conserved within the family. Each BET protein is known to function independently and cooperatively (Non-Patent Document 1).

[0004] Among the BET family proteins, BRD4 is expected to be a target for drug discovery in cancer treatment because it controls the expression of the proto-oncogene c-MYC (Non-Patent Document 2), and because it has been reported to correlate with prognosis in various carcinomas, such as gastric cancer (Non-Patent Document 3), ovarian cancer (Non-Patent Document 4), lung cancer (Non-Patent Document 5), liver cancer (Non-Patent Document 6), urothelial cancer (Non-Patent Document 7), testicular tumor (Non-Patent Document 8), skin cancer (Non-Patent Document 9), prostate cancer (Non-Patent Document 10), breast cancer (Non-Patent Document 11), colorectal cancer (Non-Patent Document 12), and leukemia (Non-Patent Document 13).

[0005] To date, BRD4 inhibitors that inhibit the binding of BRD4 to histones have been clinically developed as anticancer drugs targeting BRD4 (Non-Patent Document 14). However, BRD4 inhibitors are insufficiently effective because they cause BRD4 accumulation (Non-Patent Document 15). In addition, resistance to these inhibitors is acquired through the expression of proteins that stabilize BRD4 expression or proteins that enhance BRD4-mediated transcriptional activity in a bromodomain-independent manner (Non-Patent Documents 16 and 17). Therefore, there is a need for the development of anticancer drugs that target BRD4 using new methods.

[0006] Recently, ligands for E3 ligases with ubiquitin ligase activity [Von Hippel-Lindau (VHL), Cereblon (CRBN), Cellular Inhibitor of Apoptosis Protein 1 (cIAP1)] have been identified. Chemical knockdown, a technique that uses a compound linked to a binder that binds to a target protein to form an artificial complex between an E3 ligase and the target protein in cells and induces degradation of the target protein by utilizing the ubiquitin-proteasome system, an intracellular protein degradation mechanism, is attracting attention as a new drug discovery technology (Non-Patent Document 18). To date, BRD4 protein degradation inducers that utilize this technology have been reported, such as ARV-771, which utilizes a ligand for VHL, and ARV-825, which utilizes a ligand for CRBN (Non-Patent Documents 15 and 19).

[0007] In cancer chemotherapy, the emergence of spontaneous resistance, in which anticancer drugs are ineffective from the start of treatment, and acquired resistance, in which the efficacy of anticancer drugs decreases with long-term use, are major problems (Non-Patent Document 20). Overcoming this resistance to anticancer drugs is expected to lead to improved cancer chemotherapy outcomes, and various resistance mechanisms have been elucidated (Non-Patent Document 20). It has been reported that acquired resistance to BRD4 proteolysis inducers is induced in cancer cells through dysfunction of the E3 ligase VHL or CRBN complex, which mediates proteolysis (Non-Patent Document 21). Furthermore, tumors such as renal cell carcinoma caused by mutations in the VHL gene (Non-Patent Document 22) are thought to exhibit spontaneous resistance to BRD4 proteolysis inducers that utilize VHL ligands. Therefore, the development of novel BRD4 proteolysis inducers that utilize novel E3 ligase ligands and overcome resistance to existing BRD4 proteolysis inducers is desirable. Recently, many target protein degradation inducers that combine novel E3 ligase ligands with target protein binders have been reported (Non-Patent Document 23). For example, a new BRD4 protein degradation inducer utilizing the E3 ligase DCAF15 has been reported (Non-Patent Document 24). However, its BRD4 protein degradation-inducing activity and cytotoxicity are not sufficient. Currently, there are only a limited number of combinations of ligands for E3 ligase and binders for target proteins (Non-Patent Document 23). Therefore, it is necessary to find an appropriate combination of ligands for E3 ligase and linker structures for BRD4 protein binders that will exhibit sufficient BRD4 protein degradation-inducing activity and cytotoxicity as anticancer agents. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Taniguchi Y., Int J Mol Sci. 2016, 17: E1849 [Non-patent document 2] Kanno T., Nat Struct Mol Biol. 2014, 21: 1047-1057 [Non-licensed document 3] Zhu Y., Oncotarget. 2017, 8: 31092-31100

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

Non-licensed Document 14

[0009] An objective of the present invention is to provide a compound or a pharmaceutically acceptable salt thereof that utilizes a ligand for E3 ligase DCAF15, has excellent BRD4 protein degradation-inducing activity, and is useful as a therapeutic agent for cancer. [Means for solving the problem]

[0010] As a result of intensive research aimed at solving the above problems, the present inventors have discovered compounds that utilize ligands for the E3 ligase DCAF15 and have the effect of inducing BRD4 protein degradation, and have found that these compounds can provide therapeutic agents for cancer. In particular, they have discovered an optimal linker structure for the ligand for DCAF15, thereby completing the present invention. That is, the gist of the present invention is as follows.

[0011] [1] Formula (I):

[0012] [ka]

[0013] [In the formula, A and Q each independently represent a ring selected from an aromatic hydrocarbon ring; an aromatic heterocycle containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen; a cycloalkane ring; and an aliphatic heterocycle containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen; The ring is halogen atoms; hydroxy groups; cyano group; hydroxycarbonyl group; oxo group; Thioxo group; an alkyl group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxy group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; -CO-N(R 7a )(R 7b ); -N(R 7a )(R 7b );and -N(R 7c )-CO-R 7d ; may be substituted with a group selected from Z 1 is a group selected from C and N, Z 2 is a group selected from C and N, Z 3 is =CR Z3 - and ═N—, Z 4 is =CR Z4 - and ═N—, Z 5 is =CR Z5 - and =N-, R Z3 , R Z4 , and R Z5 are independent of each other, a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; a hydroxycarbonyl group; an alkyl group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; a cycloalkyl group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxy group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; -CO-N(R 7a )(R 7b );-N(R 7a )(R 7b );-N(R 7c )-CO-R 7d an aromatic hydrocarbon group; and a 5- to 6-membered aromatic heterocyclic group containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen; Substructure:

[0014] [ka]

[0015] is represented by the following formula (Ea), (Eb) or (Ec):

[0016] [ka]

[0017] indicates one of the following: L, T, and M each independently represent a single bond; -O-;-S-;-NR 7a -;-CO-;-SO-;-SO2-;-CO-NR 7c -;-NR 7c -CO-;-SO2-NR 7c -;-NR 7c -SO2-;-NR 7a -CO-NR 7b -;-(OCH2CH2) m -;-OR 7r -;-R 7r -O-;-SR 7r -;-R 7r -S-;-NR 7a -R 7r -;-R 7r -NR 7a -;-CO-NR 7c -R 7r -;-R 7r -CO-NR 7c -;-SO2-NR 7c -R 7r -; and -R 7r -SO2-NR 7c -; or represents a group selected from a divalent aromatic hydrocarbon group; a divalent aliphatic heterocyclic group; a divalent aromatic heterocyclic group which may be partially hydrogenated; an alkylene group; a cycloalkylene group; an alkenylene group; and an alkynylene group; the group may be optionally substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; an oxo group; a hydroxycarbonyl group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; -LTM- is -OO-, -SS-, or -NR as a whole or a part of the structure. 7a -NR 7a -, -OS-, -SO-, -O-NR 7a -, -NR 7a -O-, -S-NR 7a - and -NR 7a -S- does not represent a group selected from G represents N or C; J represents N or O; Further substructures:

[0018] [ka]

[0019] teeth,

[0020] [ka]

[0021] represents a partial structure selected from n is 1 or 2, m represents an integer from 1 to 6; R 5 is a group selected from a hydrogen atom; and an alkyl group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; R 6a and R 6b are each independently a group selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group, and an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; R 7a and R 7b are each independently a hydrogen atom; or an alkyl group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group, R attached to the same nitrogen atom 7a and R 7b may bond together with the nitrogen atom to form an aliphatic heterocycle containing one nitrogen atom which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group, R 7c and R 7d are each independently a hydrogen atom; or an alkyl group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group, R 7r is a group selected from an alkylene group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkenylene group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; or an alkynylene group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; R 8a and R 8b are each independently a group selected from a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; R 9a and R 9b are, independently of one another, a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; a hydroxycarbonyl group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxy ...carbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and -CO-N(R 7a )(R 7b ); or R 9a and R 9bmay be taken together to form a fused ring with the adjacent ring E; an alkylene group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; or an alkenylene group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; R 10a and R 10b are each independently a hydrogen atom; a hydroxy group; a cyano group; -N(R 7a )(R 7b );-N(R 7c )-CO-OR 7d and alkyl groups; The alkyl group is a halogen atom; a hydroxy group; a cyano group; an alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; a hydroxycarbonyl group; and -CO-N(R 7a )(R 7b or may be substituted with a substituent selected from: R 10a and R 10b represent, together with each other, an alkylene group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group to form a ring, R 11 is a group selected from a hydrogen atom; and an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group. or a pharmaceutically acceptable salt thereof (in this specification, may be abbreviated as "compound (I)").

[0022] [2] Partial structure:

[0023] [ka]

[0024] But the following formula:

[0025] [ka]

[0026] [In the formula, R a represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; R a’ represents a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; or -CO-N(R 7a )(R 7b ) and R a’’ represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; or -CO-N(R 7a )(R 7b ) indicates. Denoted by [1] The compound or a pharmaceutically acceptable salt thereof according to [1].

[0027] [3] A is a ring selected from an aromatic hydrocarbon ring, a 5- to 6-membered aromatic heterocycle containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen, and a cycloalkane ring; R Z3 but, a hydroxy group; a cyano group; a hydroxycarbonyl group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; a cycloalkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; R Z4 and R Z5 each independently represents a group selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group, and an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; Substructure:

[0028] [ka]

[0029] is expressed by the following formula (Ea) or (Ec):

[0030] [ka]

[0031] indicates, Substructure:

[0032] [ka]

[0033] but,

[0034] [ka]

[0035] indicates, Substructure:

[0036] [ka]

[0037] but,

[0038] [ka]

[0039] indicates, L is a group selected from a divalent aromatic hydrocarbon group; a divalent aliphatic heterocyclic group; a divalent aromatic heterocyclic group which may be partially hydrogenated; an alkylene group; a cycloalkylene group; an alkenylene group; and an alkynylene group; the group may be optionally substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; a hydroxycarbonyl group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; T is a single bond, -CO-, or -CO-NR 7c -, -NR 7c -CO- or -O- an alkylene group optionally substituted by a substituent selected from a halogen atom; a hydroxy group; a cyano group; an oxo group; a hydroxycarbonyl group; an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and an alkoxy group optionally substituted by a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; M is a single bond, or -O-;-S-;-NR 7a -;-CO-;-SO-;-SO2-;-CO-NR 7c -;-NR 7c-CO-;-SO2-NR 7c -;-NR 7c -SO2-;-NR 7a -CO-NR 7b -;-(OCH2CH2) m -;-OR 7r -;-R 7r -O-;-SR 7r -;-R 7r -S-;-NR 7a -R 7r -;-R 7r -NR 7a -;-CO-NR 7c -R 7r -;-R 7r -CO-NR 7c -; and an alkylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkynylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and a divalent aliphatic heterocyclic group optionally substituted with a substituent selected from a) a halogen atom, b) a hydroxy group, c) a cyano group, d) an oxo group, e) an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group, and f) an alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; R 5 is a hydrogen atom, R 6a and R 6b are each independently selected from a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; and an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; R 7c is a hydrogen atom, R 8a and R 8b are each independently a group selected from a hydrogen atom; a halogen atom; a hydroxy group; and a cyano group; R 9a and R 9bare each independently selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, and an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; R 10a and R 10b are each independently a hydrogen atom; -N(R 7c )-CO-OR 7d and alkyl groups; The alkyl group is a halogen atom; a hydroxy group; a cyano group; an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; -CO-N(R 7a )(R 7b and a hydroxycarbonyl group; The compound according to [2] or a pharmaceutically acceptable salt thereof.

[0040] [4] A is a ring selected from a benzene ring; a pyridine ring; and a cycloalkane ring; R a represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R a’ represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R a’’ represents a hydrogen atom; a halogen atom; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; or a cyano group, R Z3represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a cycloalkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; or an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; R Z4 and R Z5 each independently represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; Substructure:

[0041] [ka]

[0042] But the following formula (Ea):

[0043] [ka]

[0044] indicates, L is a group selected from an alkynyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a divalent aromatic hydrocarbon group optionally substituted with a substituent selected from a) a halogen atom, b) a hydroxy group, c) a cyano group, d) an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, and e) an alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a divalent aliphatic heterocyclic group containing one nitrogen atom optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, which may be partially hydrogenated; the aromatic heterocyclic group may be substituted with a substituent selected from a halogen atom, a hydroxy group, a cyano group, and an oxo group; T is a single bond; -CO-; -CO-NR 7c -;-NR 7c -CO- or -O-; M is a single bond, or -R 7r -O-;-R 7r -NR 7a -; an alkylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; an alkynylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and a divalent aliphatic heterocyclic group; R 6a and R 6b are each independently a group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; R 7a and R 7b each independently represents a hydrogen atom; or an alkyl group which may be substituted by a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R 7c indicates a hydrogen atom, R 7d represents an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R 7r represents an alkylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; R 8a and R 8b are both hydrogen atoms, R 9a and R 9b are each independently an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R 10a is a hydrogen atom; and halogen atoms, hydroxy groups, cyano groups, -NH-CO-OR 7d , -CO-N(R 7a )(R 7ban alkyl group optionally substituted with a substituent selected from an alkoxycarbonyl group and a hydroxycarbonyl group; R 10b is a hydrogen atom, R 11 is an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; The compound according to [2] or [3], or a pharmaceutically acceptable salt thereof.

[0045] [5]R a represents a hydrogen atom; or an alkyl group, R a’ represents a hydrogen atom; or an alkyl group, R a’’ represents a hydrogen atom; a halogen atom; an alkyl group; or a cyano group, R Z3 represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom and a hydroxy group; a cycloalkyl group; or an alkoxy group; R Z4 and R Z5 each independently represents a hydrogen atom or an alkyl group; Substructure:

[0046] [ka]

[0047] But the following formula (Ea):

[0048] [ka]

[0049] indicates, L is a group selected from an alkynylene group; a divalent aromatic hydrocarbon group optionally substituted with 1 to 2 substituents selected from a halogen atom, a hydroxy group, an alkyl group optionally substituted with 1 to 3 halogen atoms, and an alkoxy group; a divalent aliphatic heterocyclic group containing one nitrogen atom; and a divalent aromatic heterocyclic group optionally partially hydrogenated containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom; When the aromatic heterocyclic group is a partially hydrogenated divalent aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, it may be substituted with an oxo group, T is a single bond, or -CO-;-CO-NR 7c -;-NR 7c -CO- or -O-; M is a single bond, or -R 7r -O-;-R 7r -NR 7a -; an alkylene group optionally substituted with one hydroxy group; an alkynylene group; and a divalent aliphatic heterocyclic group; R 6a and R 6b are each independently a group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group; R 7a and R 7b are each independently a hydrogen atom or an alkyl group, R 7c indicates a hydrogen atom, R 7d represents an alkyl group, R 7r represents an alkylene group, R 8a and R 8b are both hydrogen atoms, R 9a and R 9b are each independently an alkyl group optionally substituted with one hydroxy group. Kill group, R 10a is a hydrogen atom; and -NH-CO-OR7d , -CO-N(R 7a )(R 7b ), one selected from a cyano group, an alkoxycarbonyl group, and a hydroxycarbonyl group an alkyl group optionally substituted by a substituent selected from the group consisting of R 10b is a hydrogen atom, R 11 is an alkyl group; The compound according to any one of [2] to [4] or a pharmaceutically acceptable salt thereof.

[0050] [6] A represents a benzene ring; R a indicates a hydrogen atom, R 10a is an alkyl group optionally substituted with one alkoxycarbonyl group, L is a group selected from a divalent aromatic hydrocarbon group optionally substituted with 1 to 2 substituents selected from a halogen atom, an alkyl group optionally substituted with 1 to 3 halogen atoms, and an alkoxy group; and a divalent aromatic heterocyclic group optionally partially hydrogenated and containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom; M is an alkylene group optionally substituted with one substituent selected from a hydroxy group and a cyano group; The compound according to any one of [2] to [5] or a pharmaceutically acceptable salt thereof.

[0051] [7]R a’ indicates a hydrogen atom, R a’’ represents a cyano group, R Z3 represents an alkyl group or an alkoxy group which may be substituted with 1 to 3 halogen atoms or hydroxy groups, R Z4 indicates a hydrogen atom, R Z5 indicates a hydrogen atom, The compound according to any one of [2] to [6] or a pharmaceutically acceptable salt thereof.

[0052] [8]R 8a and R 8b are both hydrogen atoms, R 9a and R 9b are each independently an alkyl group optionally substituted with one hydroxy group, R 10a is an alkyl group optionally substituted with one alkoxycarbonyl group; , R 10b is a hydrogen atom, R 11 is an alkyl group; The compound according to any one of [2] to [7] or a pharmaceutically acceptable salt thereof.

[0053] [9] L is a phenylene group optionally substituted with 1 to 2 substituents selected from a halogen atom and an alkyl group; or a pyrazinediyl group; T is -CO-NR 7c - and R 7c is a hydrogen atom, M is -CH2- or -CH(CH3)-; The compound according to any one of [2] to [8] or a pharmaceutically acceptable salt thereof.

[0054]

[10] methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methoxy-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-{4'-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2'-fluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]-2'-fluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-{2'-chloro-4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-3'-methyl[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, t-butyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, t-butyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-3'-fluoro[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-(3'-chloro-4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, 5-chloro-N-({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)-2-fluoro-4'-[(6S)-2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl][1,1'-biphenyl]-4-carboxamide, methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2',3'-difluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-2'-fluoro[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl {(6S)-4-[4-(6-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyridin-3-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate, methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-2',5'-difluoro[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-2'-fluoro-5'-methyl[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-2',3'-difluoro[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]-2',3'-difluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazin-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate, methyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazin-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate, methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl {(6S)-4-[4-(6-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyridin-3-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate, methyl [(6S)-4-(4-{6-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-{4'-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2',3'-difluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, Methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, and t-Butyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate or a pharmaceutically acceptable salt thereof.

[0055]

[11] methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-{4'-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-{2'-chloro-4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, t-butyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, t-butyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-3'-fluoro[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, 5-chloro-N-({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)-2-fluoro-4'-[(6S)-2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl][1,1'-biphenyl]-4-carboxamide, methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2',3'-difluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl {(6S)-4-[4-(6-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyridin-3-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate, methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazin-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate, methyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazin-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate, methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, Methyl {(6S)-4-[4-(6-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyridin-3-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate, and Methyl [(6S)-4-(4-{6-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate or a pharmaceutically acceptable salt thereof.

[0056]

[12] A pharmaceutical composition comprising the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof.

[13] The pharmaceutical composition according to

[12] for inducing BRD4 protein degradation.

[14] The pharmaceutical composition according to

[12] or

[13] for treating cancer.

[15] The pharmaceutical composition described in

[14] , wherein the cancer is selected from acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, diffuse large B-cell lymphoma, adult T-cell leukemia / lymphoma, Burkitt's lymphoma, prostate cancer, ovarian cancer, bladder cancer, breast cancer, cervical cancer, uterine sarcoma, gastric cancer, lung cancer, colorectal cancer, glioma, pancreatic cancer, liver cancer, bile duct cancer, renal cell carcinoma, and fibrosarcoma.

[16] The pharmaceutical composition described in

[15] , wherein the cancer is selected from acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, diffuse large B-cell lymphoma, multiple myeloma, Burkitt's lymphoma, glioma, gastric cancer, colorectal cancer, pancreatic cancer, liver cancer, prostate cancer, non-small cell lung cancer, breast cancer, ovarian cancer, and uterine sarcoma.

[17] The pharmaceutical composition according to

[16] , wherein the cancer is selected from acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, prostate cancer, ovarian cancer, and breast cancer.

[18] Use of the pharmaceutical composition according to any one of

[12] to

[17] for treating cancer.

[19] Use of the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating cancer.

[20] A method for treating cancer, comprising administering a compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of

[12] to

[17] . [Effects of the Invention]

[0057] The compounds of the present invention have excellent BRD4 protein degradation-inducing activity and are useful as therapeutic agents for cancer. [Brief explanation of the drawings]

[0058] [Figure 1] 1 shows the results of BRD4 protein degradation induction effect in Test Example 4. [Figure 2] 1 shows the results of the antitumor effect in Test Example 6. DETAILED DESCRIPTION OF THE INVENTION

[0059] The compound of the present invention is a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. In this specification, "a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof" may be collectively referred to as the compound of the present invention. The meanings of the terms used in this specification will be explained below to further explain the present invention. However, the explanations of the terms below do not limit the present invention in any way.

[0060] In the present specification, examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0061] In the present specification, examples of the "alkyl group" include "C butyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc. 1-6 alkyl groups”.

[0062] In the present specification, examples of the "cycloalkyl group" include "C cycloalkyl groups" such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl. 3-10 cycloalkyl groups.

[0063] In the present specification, examples of the "alkoxy group" include "C alkoxy group" such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, etc. 1-6 Alkoxy groups are examples of such groups.

[0064] In the present specification, examples of the "alkylene group" include "C(CH3)-, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH(CH3)-, -C(CH3)2-, -CH(C2H5)-, -CH(C3H7)-, -CH(CH(CH3)2)-, -(CH(CH3))2-, -CH2-CH(CH3)-, -CH(CH3)-CH2-, -CH2-CH2-C(CH3)2-, -C(CH3)2-CH2-CH2-, -CH2-CH2-CH2-C(CH3)2-, and -C(CH3)2-CH2-CH2-CH2-CH2-. 1-6 alkylene groups.

[0065]

[0023] In the present specification, examples of the "alkenylene group" include "C" groups such as -CH=CH-, -CH2-CH=CH-, -CH=CH-CH2-, -CH=CH-CH2-, -C(CH3)2-CH=CH-, -CH=CH-C(CH3)2-, -CH2-CH=CH-CH2-, -CH2-CH2-CH=CH-, -CH=CH-CH2-CH2-, -CH=CH-CH=CH-, -CH=CH-CH2-CH2-CH2-, -CH2-CH2-CH2-CH=CH-, etc. 2-6 alkenylene groups.

[0066]

[0033] In the present specification, examples of the "alkynylene group" include "C" groups such as -C≡C-, -CH2-C≡C-, -C≡C-CH2-, -C(CH3)2-C≡C-, -C≡CC(CH3)2-, -CH2-C≡C-CH2-, -CH2-CH2-C≡C-, -C≡C-CH2-CH2-, -C≡CC≡C-, -C≡C-CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-C≡C-, etc. 2-6 Alkynylene groups are examples of such groups.

[0067] In the present specification, examples of the "cycloalkylene group" include "C cycloalkylene groups" such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, and cyclooctylene. 3-10 cycloalkylene groups.

[0068] As used herein, examples of the "alkoxycarbonyl group" include "C" groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl. 1-6 Alkoxy-carbonyl groups are examples of such groups.

[0069] In the present specification, examples of the "cycloalkane ring" include "C cycloalkane rings" such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. 3-10 Cycloalkane rings are examples.

[0070] In the present specification, the term "aromatic hydrocarbon ring" refers to, for example, "C benzene, naphthalene, anthracene, etc. 6-14 "Aromatic hydrocarbon ring" is an example.

[0071] In the present specification, examples of the "aromatic hydrocarbon group" include C phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, etc. 6-14 An example is an aryl group.

[0072] In the present specification, examples of the "divalent aromatic hydrocarbon group" include C phenylene, naphthylene, anthrylene, etc. 6-14 Examples include an arylene group.

[0073] In the present specification, examples of the "aliphatic heterocycle containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen" include 3- to 14-membered (preferably 4- to 10-membered) aliphatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 3 atoms selected from oxygen, sulfur, and nitrogen. Preferable examples of the "aliphatic heterocycle" include 3- to 8-membered monocyclic aliphatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepanine, diazepane, azepine, azocane, diazocane, and oxepane; Examples thereof include 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) aliphatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, and octahydroisoquinoline.

[0074] In the present specification, examples of the "aliphatic heterocycle containing one nitrogen atom" include, among the above-mentioned "aliphatic heterocycles containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen," an aliphatic heterocycle containing one nitrogen atom.

[0075] In the present specification, examples of the "divalent aliphatic heterocyclic group" include divalent aliphatic heterocyclic groups derived from the above-mentioned "aliphatic heterocycle".

[0076] In the present specification, examples of the "divalent aliphatic heterocyclic group containing one nitrogen atom" include a divalent aliphatic heterocyclic group derived from an aliphatic heterocycle containing one nitrogen atom among the above-mentioned "aliphatic heterocycles".

[0077] In the present specification, examples of the "aromatic heterocycle containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen" include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 3 atoms selected from oxygen, sulfur, and nitrogen. Preferable examples of the "aromatic heterocycle" include 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, and triazine; Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidin and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocycles such as benzophenone, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, and phenoxazine.

[0078] In the present specification, examples of the "5- or 6-membered aromatic heterocyclic group containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen" include 5- or 6-membered aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 3 atoms selected from oxygen, sulfur, and nitrogen. Preferable examples of the "aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl.

[0079] In the present specification, examples of the "divalent aromatic heterocyclic group which may be partially hydrogenated" include divalent ring groups derived from the above-mentioned "aliphatic heterocycle" and "aromatic heterocycle".

[0080] In the present specification, examples of the "divalent aromatic heterocyclic group which may be partially hydrogenated and contains 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom" include divalent ring groups derived from the above-mentioned "aliphatic heterocycle" and the above-mentioned "aromatic heterocycle" which contains 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom. Among "divalent aromatic heterocyclic groups which may be partially hydrogenated and contain 1 to 2 atoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms," a suitable example of the "divalent aromatic heterocyclic group which is partially hydrogenated and contains 1 to 2 atoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms" includes tetrahydroisoquinolinediyl (particularly, 1,2,3,4-tetrahydroisoquinoline-2,6-diyl).

[0081] In the present specification, the number of substituents in the case of "substituted" is 1 or more, unless otherwise specified, and the types of substituents may be the same or different.

[0082] Next, preferred embodiments of the above general formula (I) will be explained. A is preferably a ring selected from an aromatic hydrocarbon ring (e.g., a benzene ring), a 5- or 6-membered aromatic heterocycle containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen, and a cycloalkane ring (e.g., a cyclobutane ring), more preferably a ring selected from a benzene ring; a pyridine ring; and a cycloalkane ring (e.g., a cyclobutane ring), and even more preferably a benzene ring.

[0083] Q is preferably a 5- or 6-membered aromatic heterocycle (eg, a pyrrole ring) containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen.

[0084] Substructure:

[0085] [ka]

[0086] is preferably of the formula:

[0087] [ka]

[0088] That is, Z 1 is preferably C, and Z 2 is preferably C, and Z 3 is preferably =CR Z3 - and Z 4 is preferably =CR Z4 - and Z 5 is preferably =CR Z5 - and Q is preferably a pyrrole ring.

[0089] R Z3is preferably a hydrogen atom; a halogen atom (e.g., chlorine atom, bromine atom); a hydroxy group; a cyano group; a hydroxycarbonyl group; an alkyl group (e.g., methyl, ethyl) optionally substituted with a group selected from a halogen atom (e.g., fluorine atom), a hydroxy group, an alkoxy group, and a cyano group; a cycloalkyl group (e.g., cyclopropyl) optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group (e.g., methoxy) optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group. a cyano group; an alkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxy group, and a cyano group; a cycloalkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxy group, and a cyano group; or an alkoxy group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxy group, and a cyano group, and even more preferably an alkyl group optionally substituted with 1 to 3 halogen atoms or hydroxy groups; or an alkoxy group, and particularly preferably an alkyl group, and even more particularly preferably a methyl group or an ethyl group.

[0090] R Z4 and R Z5 are preferably, each independently, a group selected from a hydrogen atom; a halogen atom; a cyano group; an alkyl group (e.g., methyl) which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; or an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; more preferably, are, each independently, a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and even more preferably, both are hydrogen atoms.

[0091] R ais preferably a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, more preferably a hydrogen atom; or an alkyl group, and even more preferably a hydrogen atom. R a’ is preferably a hydrogen atom; an alkyl group (e.g., methyl) optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, more preferably a hydrogen atom; or an alkyl group, and even more preferably a hydrogen atom. R a’’ is preferably a hydrogen atom; a halogen atom (e.g., a chlorine atom); an alkyl group (e.g., methyl) optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; or a cyano group, more preferably a hydrogen atom; a halogen atom; an alkyl group; or a cyano group, and even more preferably a cyano group.

[0092] Substructure:

[0093] [ka]

[0094] is preferably represented by the following formula (Ea) or (Ec):

[0095] [ka]

[0096] and more preferably,

[0097] [ka]

[0098] is. R 9a and R 9bare, for example, independently of one another, a hydrogen atom; a halogen atom; a cyano group; an alkyl group (e.g., methyl) optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and an alkoxy group (e.g., methoxy) optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, preferably a group selected from independently of one another, a hydrogen atom; a halogen atom; a cyano group; an alkyl group (e.g., methyl) optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, more preferably an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, even more preferably an alkyl group optionally substituted with a hydroxy group, independently of one another, particularly preferably an unsubstituted alkyl group, and even more particularly preferably a methyl group.

[0099] L is preferably a group selected from a divalent aromatic hydrocarbon group (e.g., phenylene); a divalent aliphatic heterocyclic group (e.g., pyrrolidinediyl); a divalent aromatic heterocyclic group which may be partially hydrogenated (e.g., thiophenediyl, pyridinediyl, tetrahydropyridinediyl, pyrazinediyl, benzofurandiyl, benzoxazinediyl, benzothiophenediyl, tetrahydroquinolinediyl); an alkylene group; a cycloalkylene group; an alkenylene group; and an alkynylene group (e.g., -C≡C-, -C≡C-CH2-); and the group is a halogen atom (e.g., a fluorine atom, a chlorine atom); a hydroxy group; a cyano group; a hydroxycarbonyl group; an alkyl group (e.g., methyl) optionally substituted with a group selected from a halogen atom (e.g., a fluorine atom), a hydroxy group, an alkoxy group, and a cyano group; and an alkoxy group (e.g., methoxy) optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; more preferably, a substituent selected from a halogen atom, a hydroxy group, and a cyano group. a divalent aromatic hydrocarbon group optionally substituted with a substituent selected from a) a halogen atom, b) a hydroxy group, c) a cyano group, d) an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, and e) an alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a divalent aliphatic heterocyclic group containing one nitrogen atom optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, which may be partially hydrogenated; wherein the aromatic heterocyclic group may be substituted with a substituent selected from a halogen atom, a hydroxy group, a cyano group, and an oxo group, and more preferably an alkynylene group; a divalent aromatic hydrocarbon group optionally substituted with a substituent selected from a halogen atom, an alkyl group optionally substituted with a halogen atom, and an alkoxy group; a divalent aliphatic heterocyclic group containing one nitrogen atom;and a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, which may be partially hydrogenated; the aromatic heterocyclic group may be substituted with an oxo group, and is particularly preferably an aromatic hydrocarbon group optionally substituted with a substituent selected from a halogen atom, an alkyl group optionally substituted with a halogen atom, and an alkoxy group; and a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, which may be partially hydrogenated; and is particularly preferably a divalent aromatic hydrocarbon group optionally substituted with 1 to 2 halogen atoms; and a divalent aromatic heterocyclic group containing 1 to 2 nitrogen atoms, and is particularly preferably a group selected from phenylene optionally substituted with 1 to 2 halogen atoms; pyridinediyl; and pyrazinediyl, and is even more particularly preferably a group selected from phenylene optionally substituted with 1 to 2 halogen atoms; and pyrazinediyl.

[0100] In another embodiment, L is preferably a divalent aromatic hydrocarbon group (e.g., phenylene), which may be substituted with a substituent selected from a halogen atom (e.g., fluorine atom, chlorine atom); a hydroxy group; a cyano group; a hydroxycarbonyl group; an alkyl group (e.g., methyl) optionally substituted with a group selected from a halogen atom (e.g., fluorine atom), a hydroxy group, an alkoxy group, and a cyano group; and an alkoxy group (e.g., methoxy) optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; more preferably a) a halogen atom, b) a hydroxy group, c) a cyano group, d) a halogen atom, a hydroxy group, and e) a divalent aromatic hydrocarbon group optionally substituted with a substituent selected from a halogen atom, an alkyl group optionally substituted with a substituent selected from a cyano group, and a hydroxy group and a cyano group, particularly preferably a divalent aromatic hydrocarbon group optionally substituted with a substituent selected from a halogen atom, an alkyl group optionally substituted with a halogen atom, and an alkoxy group, even more particularly preferably a divalent aromatic hydrocarbon group optionally substituted with 1 to 2 halogen atoms, and particularly preferably phenylene optionally substituted with 1 to 2 halogen atoms.

[0101] In yet another embodiment, L is preferably an optionally partially hydrogenated divalent aromatic heterocyclic group (e.g., thiophenediyl, pyridinediyl, tetrahydropyridinediyl, pyrazinediyl, benzofurandiyl, benzoxazinediyl, benzothiophenediyl, tetrahydroquinolinediyl); an alkylene group; a cycloalkylene group; an alkenylene group; and an alkynylene group (e.g., -C≡C-, -C≡C-CH2-), which may be optionally substituted with a substituent selected from a halogen atom (e.g., fluorine atom, chlorine atom); a hydroxy group; a cyano group; a hydroxycarbonyl group; an alkyl group (e.g., methyl) optionally substituted with a group selected from a halogen atom (e.g., fluorine atom), a hydroxy group, an alkoxy group, and a cyano group; and an alkoxy group (e.g., methoxy) optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group, more preferably a partially hydrogenated divalent aromatic heterocyclic group (e.g., thiophenediyl, pyridinediyl, tetrahydropyridinediyl, pyrazinediyl, benzofurandiyl, benzoxazinediyl, benzothiophenediyl, tetrahydroquinolinediyl). a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, which may be hydrogenated, and which may be substituted with a substituent selected from a halogen atom, a hydroxy group, a cyano group, and an oxo group; more preferably a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, which may be partially hydrogenated, and which may be substituted with an oxo group; particularly preferably a divalent aromatic hydrocarbon group which may be substituted with a substituent selected from a halogen atom, an alkyl group which may be substituted with a halogen atom, and an alkoxy group; even more particularly preferably a group selected from a divalent aromatic heterocyclic group containing 1 to 2 nitrogen atoms; particularly preferably a group selected from pyridinediyl and pyrazinediyl; and even more particularly preferably pyrazinediyl.

[0102] T is preferably a single bond, —CO—, or —CO—NR 7c -, -NR 7c-CO- or -O-, or an alkylene group (e.g., -CH2-) optionally substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; an oxo group; a hydroxycarbonyl group; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and an alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; more preferably a single bond; -CO-; or -CO-NR 7c -;-NR 7c -CO-; or -O-, particularly preferably -CO-NR 7c -It is.

[0103] M is preferably a single bond or -O-; -S-; -NR 7a -;-CO-;-SO-;-SO2-;-CO-NR 7c -;-NR 7c -CO-;-SO2-NR 7c -;-NR 7c -SO2-;-NR 7a -CO-NR 7b -;-(OCH2CH2) m -;-OR 7r -;-R 7r -O-;-SR 7r -;-R 7r -S-;-NR 7a -R 7r -;-R 7r -NR 7a -;-CO-NR 7c -R 7r -;-R 7r -CO-NR 7c - and alkylene groups (e.g., -CH2-, -(CH2)2-, -(CH2)3-) optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; alkynylene groups (e.g., -CH2-C≡C-) optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and divalent aliphatic heterocyclic groups (e.g., piperidinediyl) optionally substituted with a substituent selected from a) halogen atoms, b) hydroxy groups, c) cyano groups, d) oxo groups, e) alkyl groups optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and f) alkoxy groups optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; more preferably, 7r -O-;-R 7r -NR 7a -; an alkylene group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; an alkynylene group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and a divalent aliphatic heterocyclic group; and more preferably a single bond or -R 7r -O-;-R 7r -NR 7a -; an alkylene group which may be substituted with a substituent selected from a hydroxy group and a cyano group; an alkynylene group; and a divalent aliphatic heterocyclic group; particularly preferably an alkylene group which may be substituted with one substituent selected from a hydroxy group and a cyano group, particularly preferably -CH2- or -CH(CH3)-, and particularly particularly preferably -CH2- or

[0104] [ka]

[0105] is.

[0106] However, -LTM- does not include, as a whole or a part of the structure, -OO-, -SS-, or -NR 7a -NR 7a -, -OS-, -SO-, -O-NR 7a -, -NR 7a -O-, -S-NR 7a - and -NR 7a It does not refer to a group selected from -S-.

[0107] -LTM- is Preferably, L is a group selected from an aromatic hydrocarbon group optionally substituted with 1 to 2 substituents selected from a halogen atom and an alkyl group; and a divalent aromatic heterocyclic group containing 1 to 2 nitrogen atoms, T is -CO-NR 7c - and R 7c is a hydrogen atom, M is -CH2-, -(CH2)2- or -CH(CH3)-; More preferably, L is a group selected from a phenylene group optionally substituted with 1 to 2 substituents selected from a halogen atom and an alkyl group; a pyridinediyl group; and a pyrazinediyl group, T is -CO-NR 7c - and R 7c is a hydrogen atom, M is -CH2-, -(CH2)2- or -CH(CH3)-; More preferably, L is a phenylene group optionally substituted with 1 to 2 halogen atoms; or a pyrazinediyl group; T is -CO-NR 7c - and R 7c is a hydrogen atom, M is -CH2- or -CH(CH3)-; Particularly preferably, L is a phenylene group optionally substituted with 1 to 2 halogen atoms; or a pyrazinediyl group; T is -CO-NR 7c - and R 7c is a hydrogen atom, M is -CH2-, or

[0108] [ka]

[0109] is.

[0110] Substructure:

[0111] [ka]

[0112] is preferably

[0113] [ka]

[0114] is.

[0115] Substructure:

[0116] [ka]

[0117] is preferably

[0118] [ka]

[0119] That is, G is preferably N and J is preferably N.

[0120] R 5 is preferably a hydrogen atom.

[0121] R 6a and R 6bare preferably, each independently selected from a hydrogen atom; a halogen atom (e.g., a fluorine atom); a hydroxy group; a cyano group; and an alkyl group (e.g., methyl) which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; more preferably, each independently selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and even more preferably, selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group.

[0122] R 7a and R 7b are preferably, each independently a hydrogen atom; or an alkyl group (e.g., methyl, ethyl) which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, and more preferably, each independently a hydrogen atom; or an alkyl group which may be substituted with a hydroxy group.

[0123] R 7c is preferably a hydrogen atom. R 7d is preferably an alkyl group (eg, methyl) which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, and more preferably an alkyl group.

[0124] R 7r is preferably an alkylene group (e.g., —CH—, —(CH)—, —(CH)—) optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, and is more preferably an alkylene group.

[0125] R 8a and R 8b are preferably, independently of one another, a group selected from a hydrogen atom; a halogen atom; a hydroxy group; and a cyano group, and more preferably, all are hydrogen atoms.

[0126] R 10a and R 10bare preferably, independently of one another, a hydrogen atom; —N(R 7c )-CO-OR 7d and an alkyl group (e.g., methyl); wherein the alkyl group is a substituent selected from a halogen atom; a hydroxy group; a cyano group; an alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group (e.g., methoxycarbonyl, t-butoxycarbonyl) optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; 7a )(R 7b and a hydroxycarbonyl group; more preferably, R 10a is a hydrogen atom; and halogen atoms, hydroxy groups, cyano groups, -NH-CO-OR 7d , -CO―N(R 7a )(R 7b an alkyl group optionally substituted with a substituent selected from the group consisting of an alkoxycarbonyl group, an alkoxycarbonyl group, and a hydroxycarbonyl group; and R 10b is a hydrogen atom, and more preferably, R 10a is a hydrogen atom; and -NH-CO-OR 7d , -CO―N(R 7a )(R 7b ), an alkyl group optionally substituted with a substituent selected from a cyano group, an alkoxycarbonyl group, and a hydroxycarbonyl group; and R 10b is a hydrogen atom, and particularly preferably, R 10a is an alkyl group optionally substituted with one alkoxycarbonyl group, and R 10b is a hydrogen atom, and more particularly preferably, R 10a is a methyl group optionally substituted with one substituent selected from a tert-butoxycarbonyl group and a methoxycarbonyl group, Also preferred is a methyl group substituted with a methoxycarbonyl group.

[0127] R 11is preferably an alkyl group (e.g., methyl) optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, more preferably an alkyl group, and particularly preferably a methyl group.

[0128] Suitable examples of the compound represented by formula (I) include the following compounds: [Compound IA] A is a ring selected from an aromatic hydrocarbon ring, a 5- to 6-membered aromatic heterocycle containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen, and a cycloalkane ring; Substructure:

[0129] [ka]

[0130] But the following formula:

[0131] [ka]

[0132] indicates, R a represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; R a’ is a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; or -CO-N(R 7a )(R 7b ) and R a’’is a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; or -CO-N(R 7a )(R 7b ) and R Z3 but, a hydroxy group; a cyano group; a hydroxycarbonyl group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; a cycloalkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; R Z4 and R Z5 each independently represents a group selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group, and an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; Substructure:

[0133] [ka]

[0134] is expressed by the following formula (Ea) or (Ec):

[0135] [ka]

[0136] indicates, Substructure:

[0137] [ka]

[0138] but,

[0139] [ka]

[0140] indicates, Substructure:

[0141] [ka]

[0142] but,

[0143] [ka]

[0144] indicates, L is a group selected from a divalent aromatic hydrocarbon group; a divalent aliphatic heterocyclic group; a divalent aromatic heterocyclic group which may be partially hydrogenated; an alkylene group; a cycloalkylene group; an alkenylene group; and an alkynylene group; the group may be optionally substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; a hydroxycarbonyl group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; T is a single bond, -CO-, or -CO-NR 7c -, -NR 7c -CO- or -O- an alkylene group optionally substituted by a substituent selected from a halogen atom; a hydroxy group; a cyano group; an oxo group; a hydroxycarbonyl group; an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and an alkoxy group optionally substituted by a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; M is a single bond, or -O-;-S-;-NR 7a -;-CO-;-SO-;-SO2-;-CO-NR 7c -;-NR 7c -CO-;-SO2-NR 7c -;-NR 7c -SO2-;-NR 7a -CO-NR 7b -;-(OCH2CH2) m -;-OR 7r -;-R 7r -O-;-SR 7r -;-R 7r -S-;-NR 7a -R 7r -;-R 7r -NR 7a -;-CO-NR 7c -R 7r -;-R 7r -CO-NR 7c -; and an alkylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkynylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and a divalent aliphatic heterocyclic group optionally substituted with a substituent selected from a) a halogen atom, b) a hydroxy group, c) a cyano group, d) an oxo group, e) an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group, and f) an alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; R 5 is a hydrogen atom, R 6a and R 6bare each independently selected from a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; and an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; R 7c is a hydrogen atom, R 8a and R 8b are each independently a group selected from a hydrogen atom; a halogen atom; a hydroxy group; and a cyano group; R 9a and R 9b are each independently selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, and an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; R 10a and R 10b are each independently a hydrogen atom; -N(R 7c )-CO-OR 7d and alkyl groups; The alkyl group is a halogen atom; a hydroxy group; a cyano group; an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; -CO-N(R 7a )(R 7b and a hydroxycarbonyl group; Compound (I).

[0145] [Compound IB] A is a ring selected from a benzene ring; a pyridine ring; and a cycloalkane ring; Substructure:

[0146] [ka]

[0147] But the following formula:

[0148] [ka]

[0149] indicates, R a represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R a’ represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R a’’ represents a hydrogen atom; a halogen atom; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; or a cyano group, R Z3 represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a cycloalkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; or an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; R Z4 and R Z5 each independently represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; Substructure:

[0150] [ka]

[0151] But the following formula (Ea):

[0152] [ka]

[0153] indicates, Substructure:

[0154] [ka]

[0155] but,

[0156] [ka]

[0157] indicates, Substructure:

[0158] [ka]

[0159] but,

[0160] [ka]

[0161] indicates, L is a group selected from an alkynyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a divalent aromatic hydrocarbon group optionally substituted with a substituent selected from a) a halogen atom, b) a hydroxy group, c) a cyano group, d) an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, and e) an alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a divalent aliphatic heterocyclic group containing one nitrogen atom optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, which may be partially hydrogenated; the aromatic heterocyclic group may be substituted with a substituent selected from a halogen atom, a hydroxy group, a cyano group, and an oxo group; T is a single bond; -CO-; -CO-NR 7c -;-NR 7c -CO- or -O-; M is a single bond, or -R 7r -O-;-R 7r -NR 7a -; an alkylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; an alkynylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and a divalent aliphatic heterocyclic group; R 6a and R 6b are each independently a group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; R 7a and R 7b each independently represents a hydrogen atom; or an alkyl group which may be substituted by a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R 7c indicates a hydrogen atom, R 7d represents an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R 7r represents an alkylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; R 8a and R 8b are both hydrogen atoms, R 9a and R 9b are each independently an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R 10a is a hydrogen atom; and halogen atoms, hydroxy groups, cyano groups, -NH-CO-OR7d , -CO-N(R 7a )(R 7b an alkyl group optionally substituted with a substituent selected from an alkoxycarbonyl group and a hydroxycarbonyl group; R 10b is a hydrogen atom, R 11 is an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; Compound (I).

[0162] [Compound IC] A is a ring selected from a benzene ring; a pyridine ring; and a cycloalkane ring; Substructure:

[0163] [ka]

[0164] But the following formula:

[0165] [ka]

[0166] indicates, R a represents a hydrogen atom; or an alkyl group, R a’ represents a hydrogen atom; or an alkyl group, R a’’ represents a hydrogen atom; a halogen atom; an alkyl group; or a cyano group, R Z3 represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a halogen atom or a hydroxy group; a cycloalkyl group; or an alkoxy group; R Z4 and R Z5 each independently represents a hydrogen atom or an alkyl group; Substructure:

[0167] [ka]

[0168] But the following formula (Ea):

[0169] [ka]

[0170] indicates, Substructure:

[0171] [ka]

[0172] but,

[0173] [ka]

[0174] indicates, Substructure:

[0175] [ka]

[0176] but,

[0177] [ka]

[0178] indicates, L is a group selected from an alkynyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a divalent aromatic hydrocarbon group optionally substituted with a substituent selected from a) a halogen atom, b) a hydroxy group, c) a cyano group, d) an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, and e) an alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a divalent aliphatic heterocyclic group containing one nitrogen atom optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, which may be partially hydrogenated; the aromatic heterocyclic group may be substituted with a substituent selected from a halogen atom, a hydroxy group, a cyano group, and an oxo group; T is a single bond; -CO-; -CO-NR 7c -;-NR 7c -CO- or -O-; M is a single bond, or -R 7r -O-;-R 7r -NR 7a -; an alkylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; an alkynylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and a divalent aliphatic heterocyclic group; R 6a and R 6b are each independently a group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; R 7a and R 7b each independently represents a hydrogen atom; or an alkyl group which may be substituted by a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R 7c indicates a hydrogen atom, R 7drepresents an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R 7r represents an alkylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; R 8a and R 8b are both hydrogen atoms, R 9a and R 9b are each independently an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R 10a is a hydrogen atom; and halogen atoms, hydroxy groups, cyano groups, -NH-CO-OR 7d , -CO-N(R 7a )(R 7b an alkyl group optionally substituted with a substituent selected from an alkoxycarbonyl group and a hydroxycarbonyl group; R 10b is a hydrogen atom, R 11 is an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; Compound (I).

[0179] [Compound ID] A is a benzene ring, Substructure:

[0180] [ka]

[0181] But the following formula:

[0182] [ka]

[0183] indicates, R a indicates a hydrogen atom, R a’ represents a hydrogen atom; or an alkyl group, R a’’ represents a hydrogen atom; a halogen atom; an alkyl group; or a cyano group, R Z3 represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a halogen atom or a hydroxy group; a cycloalkyl group; or an alkoxy group; R Z4 and R Z5 each independently represents a hydrogen atom or an alkyl group; Substructure:

[0184] [ka]

[0185] But the following formula (Ea):

[0186] [ka]

[0187] indicates, Substructure:

[0188] [ka]

[0189] but,

[0190] [ka]

[0191] indicates, Substructure:

[0192] [ka]

[0193] but,

[0194] [ka]

[0195] indicates, L is a group selected from a divalent aromatic hydrocarbon group which may be substituted with a substituent selected from a halogen atom, an alkyl group which may be substituted with a halogen atom, and an alkoxy group; and a divalent aromatic heterocyclic group which may be partially hydrogenated and contains 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom; T is a single bond; -CO-; -CO-NR 7c -;-NR 7c -CO- or -O-; M is an alkylene group optionally substituted with a hydroxy group and a cyano group, R 6a and R 6b are each independently a group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; R 7a and R 7b each independently represents a hydrogen atom; or an alkyl group which may be substituted by a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R 7c indicates a hydrogen atom, R 7d represents an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R 7r represents an alkylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; R 8a and R 8b are both hydrogen atoms, R 9a and R 9bare each independently an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R 10a is an alkyl group optionally substituted with an alkoxycarbonyl group, R 10b is a hydrogen atom, R 11 is an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; Compound (I).

[0196] [Compound IE] A is a benzene ring, Substructure:

[0197] [ka]

[0198] But the following formula:

[0199] [ka]

[0200] indicates, R a indicates a hydrogen atom, R a’ indicates a hydrogen atom, R a’’ represents a cyano group, R Z3 represents an alkyl group or an alkoxy group which may be substituted with 1 to 3 halogen atoms or hydroxy groups, R Z4 indicates a hydrogen atom, R Z5 indicates a hydrogen atom, Substructure:

[0201] [ka]

[0202] But the following formula (Ea):

[0203] [ka]

[0204] indicates, Substructure:

[0205] [ka]

[0206] but,

[0207] [ka]

[0208] indicates, Substructure:

[0209] [ka]

[0210] but,

[0211] [ka]

[0212] indicates, L is a group selected from a divalent aromatic hydrocarbon group optionally substituted with 1 to 2 substituents selected from a halogen atom, an alkyl group optionally substituted with 1 to 3 halogen atoms, and an alkoxy group; and a divalent aromatic heterocyclic group optionally partially hydrogenated and containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom; T is a single bond; -CO-; -CO-NR 7c -;-NR 7c-CO- or -O-; M is an alkylene group optionally substituted with one substituent selected from a hydroxy group and a cyano group, R 6a and R 6b are each independently a group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxy group, and a cyano group; R 7a and R 7b each independently represents a hydrogen atom; or an alkyl group which may be substituted by 1 to 3 substituents selected from a halogen atom, a hydroxy group, and a cyano group, R 7c indicates a hydrogen atom, R 7d represents an alkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxy group, and a cyano group, R 7r represents an alkylene group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxy group, and a cyano group, R 8a and R 8b are both hydrogen atoms, R 9a and R 9b are each independently an alkyl group optionally substituted with one substituent selected from a halogen atom, a hydroxy group, and a cyano group, R 10a is an alkyl group optionally substituted with one alkoxycarbonyl group, R 10b is a hydrogen atom, R 11 is an alkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxy group, and a cyano group, Compound (I).

[0213] [Compound IF] A is a benzene ring, Substructure:

[0214] [ka]

[0215] But the following formula:

[0216] [ka]

[0217] indicates, R a’ indicates a hydrogen atom, R a’’ represents a cyano group, R Z3 represents an alkyl group or an alkoxy group; R Z4 indicates a hydrogen atom, R Z5 indicates a hydrogen atom, Substructure:

[0218] [ka]

[0219] But the following formula (Ea):

[0220] [ka]

[0221] indicates, Substructure:

[0222] [ka]

[0223] but,

[0224] [ka]

[0225] indicates, Substructure:

[0226] [ka]

[0227] but,

[0228] [ka]

[0229] indicates, L is a group selected from a divalent aromatic hydrocarbon group optionally substituted with 1 to 2 substituents selected from a halogen atom and an alkyl group; and a divalent aromatic heterocyclic group containing 1 to 2 nitrogen atoms; T is -CO-NR 7c - and R 7c is a hydrogen atom, M is —CH—, —(CH)—, or —CH(CH)—; R 8a and R 8b are both hydrogen atoms, R 9a and R 9b are each independently an alkyl group, R 10a is an alkyl group optionally substituted with one alkoxycarbonyl group, R 10b is a hydrogen atom, R 11 is an alkyl group; Compound (I).

[0230] [Compound IG] A is a benzene ring, Substructure:

[0231] [ka]

[0232] But the following formula:

[0233] [ka]

[0234] indicates, R a’ indicates a hydrogen atom, R a’’ represents a cyano group, R Z3 represents an alkyl group or an alkoxy group; R Z4 indicates a hydrogen atom, R Z5 indicates a hydrogen atom, Substructure:

[0235] [ka]

[0236] But the following formula (Ea):

[0237] [ka]

[0238] indicates, Substructure:

[0239] [ka]

[0240] but,

[0241] [ka]

[0242] indicates, Substructure:

[0243] [ka]

[0244] but,

[0245] [ka]

[0246] indicates, L is a group selected from a phenylene group optionally substituted with 1 to 2 substituents selected from a halogen atom and an alkyl group; a pyridinediyl group; and a pyrazinediyl group; T is -CO-NR 7c - and R 7c is a hydrogen atom, M is —CH—, —(CH)—, or —CH(CH)—; R 8a and R 8b are both hydrogen atoms, R 9a and R 9b are each independently an alkyl group, R 10a is an alkyl group optionally substituted with one alkoxycarbonyl group, R 10b is a hydrogen atom, R 11 is an alkyl group; Compound (I).

[0247] [Compound IH] A is a benzene ring, Substructure:

[0248] [ka]

[0249] But the following formula:

[0250] [ka]

[0251] indicates, R a’ indicates a hydrogen atom, R a’’ represents a cyano group, R Z3 represents an alkyl group or an alkoxy group; R Z4 indicates a hydrogen atom, R Z5 indicates a hydrogen atom, Substructure:

[0252] [ka]

[0253] But the following formula (Ea):

[0254] [ka]

[0255] indicates, Substructure:

[0256] [ka]

[0257] but,

[0258] [ka]

[0259] indicates, Substructure:

[0260] [ka]

[0261] but,

[0262] [ka]

[0263] indicates, L is a group selected from a phenylene group optionally substituted with 1 to 2 substituents selected from a halogen atom and an alkyl group; and a pyrazinediyl group; T is -CO-NR 7c - and R 7c is a hydrogen atom, M is -CH2- or -CH(CH3)-, R 8a and R 8b are both hydrogen atoms, R 9a and R 9b are each independently an alkyl group, R 10a is an alkyl group substituted with one alkoxycarbonyl group, R 10b is a hydrogen atom, R 11 is an alkyl group; Compound (I).

[0264] [Compound II] A is a benzene ring, Substructure:

[0265] [ka]

[0266] But the following formula:

[0267] [ka]

[0268] indicates, R aindicates a hydrogen atom, R a’ indicates a hydrogen atom, R a’’ represents a cyano group, R Z3 represents an alkyl group or an alkoxy group which may be substituted with 1 to 3 halogen atoms or hydroxy groups, R Z4 indicates a hydrogen atom, R Z5 indicates a hydrogen atom, Substructure:

[0269] [ka]

[0270] But the following formula (Ea):

[0271] [ka]

[0272] indicates, Substructure:

[0273] [ka]

[0274] but,

[0275] [ka]

[0276] indicates, Substructure:

[0277] [ka]

[0278] but,

[0279] [ka]

[0280] indicates, L is a divalent aromatic hydrocarbon group optionally substituted with 1 to 2 substituents selected from a halogen atom, an alkyl group optionally substituted with 1 to 3 halogen atoms, and an alkoxy group; T is a single bond; -CO-; -CO-NR 7c -;-NR 7c -CO- or -O-; M is an alkylene group optionally substituted with one substituent selected from a hydroxy group and a cyano group, R 6a and R 6b are each independently a group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxy group, and a cyano group; R 7a and R 7b each independently represents a hydrogen atom; or an alkyl group which may be substituted by 1 to 3 substituents selected from a halogen atom, a hydroxy group, and a cyano group, R 7c indicates a hydrogen atom, R 7d represents an alkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxy group, and a cyano group, R 7r represents an alkylene group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxy group, and a cyano group, R 8a and R 8b are both hydrogen atoms, R 9a and R 9b are each independently an alkyl group optionally substituted with one substituent selected from a halogen atom, a hydroxy group, and a cyano group, R 10ais an alkyl group optionally substituted with one alkoxycarbonyl group, R 10b is a hydrogen atom, R 11 is an alkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxy group, and a cyano group, Compound (I).

[0281] [Compound IJ] A is a benzene ring, Substructure:

[0282] [ka]

[0283] But the following formula:

[0284] [ka]

[0285] indicates, R a indicates a hydrogen atom, R a’ indicates a hydrogen atom, R a’’ represents a cyano group, R Z3 represents an alkyl group or an alkoxy group which may be substituted with 1 to 3 halogen atoms or hydroxy groups, R Z4 indicates a hydrogen atom, R Z5 indicates a hydrogen atom, Substructure:

[0286] [ka]

[0287] But the following formula (Ea):

[0288] [ka]

[0289] indicates, Substructure:

[0290] [ka]

[0291] but,

[0292] [ka]

[0293] indicates, Substructure:

[0294] [ka]

[0295] but,

[0296] [ka]

[0297] indicates, L is a divalent aromatic heterocyclic group containing 1 to 2 nitrogen atoms, T is a single bond; -CO-; -CO-NR 7c -;-NR 7c -CO- or -O-; M is an alkylene group optionally substituted with one substituent selected from a hydroxy group and a cyano group, R 6a and R 6b are each independently a group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxy group, and a cyano group; R 7a and R 7b each independently represents a hydrogen atom; or an alkyl group which may be substituted by 1 to 3 substituents selected from a halogen atom, a hydroxy group, and a cyano group, R 7c indicates a hydrogen atom, R 7d represents an alkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxy group, and a cyano group, R 7r represents an alkylene group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxy group, and a cyano group, R 8a and R 8b are both hydrogen atoms, R 9a and R 9b are each independently an alkyl group optionally substituted with one substituent selected from a halogen atom, a hydroxy group, and a cyano group, R 10a is an alkyl group optionally substituted with one alkoxycarbonyl group, R 10b is a hydrogen atom, R 11 is an alkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxy group, and a cyano group, Compound (I).

[0298] Specific examples of the compound represented by formula (I) include the compounds of Examples 1 to 126 described below, preferably the compounds of Examples 1, 11, 15, 26, 43, 45, 46, 47, 50, 53, 63, 64, 65, 69, 70, 71, 74, 85, 92, 97, 98, 99, 100, 102, 103, 105, 106, 107, 108, 109, 110, 118, 127, and 148, more preferably the compounds of Examples 1, 11, 26, 43, 47, 53, 63, 64, 65, 69, 71, 74, 92, 102, 103, 105, 106, 107, 108, 109, and 110, and even more preferably the compounds of Examples 1, 47, 74, and 106.

[0299] In the present invention, the term "pharmaceutically acceptable salt" is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include salts with inorganic acids, salts with organic acids, salts with alkali metals, salts with alkaline earth metals, salts with inorganic bases, and salts with organic bases. Furthermore, hydrates, which are hydrated salts, and solvates, which are solvent-containing salts, are also included in the pharmaceutically acceptable salts of the present invention.

[0300] "Pharmaceutically acceptable," as used herein, means generally safe and non-toxic, biologically undesirable but otherwise desirable, and useful in preparing pharmaceutical compositions, including those useful for veterinary as well as human pharmaceutical use.

[0301] The compounds of the present invention can be produced by the following methods A to F. These methods and steps may be combined with one another, but the production methods are not limited to these.

[0302] Below, R 10 is R 10a or R 10b indicates R 10a or R 10b Here we will explain the case where one of the atoms is a hydrogen atom, but 10a , R 10b Even when both R are optionally substituted alkyl, the following method is followed.10a , R 10b has the same meaning as above.)

[0303] (Method A) (1) The production method described here is suitable for producing an intermediate of a compound represented by general formula (I) in which ring E is represented by the above-mentioned general formula (Ea), G is a nitrogen atom, and J is a nitrogen atom, i.e., compound (A-1) shown below.

[0304] [ka]

[0305] (In the formula, each symbol has the same meaning as defined above.) Process A-1 Compound (1-2) can be derived from compound (1-1) according to known methods (for example, J. Med. Chem. 1973, 16, 214-219). Process A-2 Compound (1-3) can be obtained by acylation of compound (1-2). The reaction proceeds using a base in an appropriate solvent, usually at temperatures between -20°C and the reflux temperature of the solvent. The reaction time varies depending on the starting materials, solvent, and reaction temperature used, but is usually 0.5 to 24 hours. Examples of acylating agents include trifluoroacetic anhydride, acetic anhydride, propanoic acid anhydride, and acetyl chloride. Examples of bases include triethylamine and pyridine. Examples of solvents include tetrahydrofuran, dichloromethane, toluene, and 1,4-dioxane. Process A-3 Compound (1-4) can be obtained by thioamidating compound (1-3). The thioamidation reaction proceeds using a sulfurizing agent in an appropriate solvent, usually at room temperature to the solvent reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature used, but is usually 0.5 to 24 hours. Examples of sulfurizing agents include Lawesson's reagent and diphosphorus pentasulfide. Examples of solvents include 1,2-dichloroethane, tetrahydrofuran, and 1,4-dioxane. Process A-4 Compound (1-5) can be obtained by reacting compound (1-4) with hydrazine. The reaction with hydrazine proceeds using hydrazine monohydrate in an appropriate solvent, usually at room temperature to the solvent reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature used, but is usually 1 to 24 hours. Examples of solvents include tetrahydrofuran, 1,4-dioxane, and N,N-dimethylformamide. Process A-5 Compound (1-6) is R 10 The carboxylic acid (1-10) having the substituent (1-1) is converted to an acid halide using a halogenating agent, and then reacted with compound (1-5). The reaction proceeds using a base in an appropriate solvent, usually at temperatures between 0°C and the solvent's reflux temperature. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually 1 to 24 hours. Examples of halogenating agents include thionyl chloride, oxalyl chloride, and phenylphosphonyl dichloride. Examples of bases include triethylamine and pyridine. Examples of solvents include dichloromethane, 1,2-dichloroethane, chloroform, pyridine, and toluene. Process A-6 Compound (1-7) can be obtained by the cyclization reaction of compound (1-6). The reaction proceeds in an appropriate solvent, usually at room temperature to the solvent reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature used, but is usually 1 to 24 hours. Examples of solvents include 2-propanol, 1-butanol, and tetrahydrofuran. Process A-7 Compound (1-8) can be obtained by deprotection of compound (1-7). The reaction proceeds using an acid in an appropriate solvent, usually at room temperature to the reflux temperature of the solvent. The reaction time varies depending on the starting materials, solvent, and reaction temperature used, but is usually 1 to 24 hours. Examples of the acid include hydrochloric acid and trifluoroacetic acid. Examples of the solvent include ethyl acetate, 1,4-dioxane, tetrahydrofuran, dichloromethane, and chloroform. Process A-8 Compound (1-9) can be obtained by the cyclization reaction of compound (1-8). The reaction proceeds using a condensing agent in the presence of a suitable base in a suitable solvent at temperatures between 0°C and the solvent's reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature used, but is typically 1 to 24 hours. Examples of condensing agents include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC·HCl), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM), and 2-chloro-1-methylpyridinium iodide. Examples of solvents include methanol, N,N-dimethylformamide, chloroform, dichloromethane, and tetrahydrofuran. The reaction may be accelerated by adding 1-hydroxybenzotriazole (HOBt). Examples of bases include triethylamine, N,N-diisopropylethylamine, and pyridine. Process A-9 Compound (A-1) can be obtained by halogenating compound (1-9). The reaction usually proceeds at room temperature to the reflux temperature of the solvent using a halogenating agent. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually 1 to 24 hours. Examples of halogenating agents include phosphoryl chloride.

[0306] (2) The production method described here is suitable for producing an intermediate of a compound represented by general formula (I) in which ring E is represented by the above-mentioned general formula (Ec), G is a nitrogen atom, and J is a nitrogen atom, i.e., compound (A-2) shown below.

[0307] [ka]

[0308] (In the formula, each symbol has the same meaning as defined above.) Compound (A-2) can be derived from compound (2-1) according to a known method (for example, J. Med. Chem. 2016, 59, 1426).

[0309] (3) The production method described here is suitable for producing an intermediate of a compound represented by general formula (I) in which G is a carbon atom and J is an oxygen atom, i.e., compound (A-3) shown below.

[0310] [ka]

[0311] (In the formula, B 1 is a boronic acid or an optionally substituted boronic acid ester, Z A is a halogen atom, P A represents a protecting group, and the other symbols are as defined above. B in the formula 1 The boronic acid ester which may have a substituent of Z represents pinacolatoboron, neopentylglycolateboron, etc. A The halogen atom in the formula refers to a chlorine atom, a bromine atom, or an iodine atom. A The protecting group is one that protects the carboxyl group and is not particularly limited as long as it allows compound (3-7) to be obtained, and examples thereof include alkyl (specifically, methyl, ethyl), etc. Compound (A-3) can be derived from compound (3-1) according to known methods (for example, WO2012 / 075383).

[0312] (Method B) (1) An intermediate for the compound represented by the general formula (I), that is, the following compound (B-1), can be synthesized by the following method.

[0313] [ka]

[0314] (In the formula, Z Brepresents a chlorine atom or a hydroxyl group, and other symbols have the same meanings as above. Process B-1 Compound (B-1) can be obtained by coupling reaction of compound (A-4) with boronic acid derivative (4-1). The reaction proceeds suitably in the presence of a palladium catalyst, a phosphine ligand, and a base in an appropriate solvent at temperatures between 0°C and heating, particularly at room temperature and the boiling point of the solvent. The reaction time varies depending on the starting materials, solvent, and reaction temperature used, but is usually between 1 and 24 hours. Examples of palladium catalysts include palladium(II) acetate, palladium(II) chloride, tris(dibenzylideneacetone)dipalladium(0), and its chloroform adduct. Phosphine ligands include triphenylphosphine, 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, 2-(dicyclohexylphosphino)-2,6-diisopropoxy-1,1'-biphenyl, and 2-di-t-butylphosphino-2',4',6'-triisopropylbiphenyl. , 2-dicyclohexylphosphino-2'-6'-dimethoxybiphenyl, 2-(dicyclohexylphosphino)-2-(N,N-dimethylamino)biphenyl, tri-ortho-tolylphosphine, 2-(dicyclohexylphosphino)biphenyl, 2-(di-t-butylphosphino)biphenyl, 2-(di-t-butylphosphino)-1,1-binaphthyl, tri-t-butylphosphine, tri-t-butylphosphonium tetrafluoroborate, and the like.A reagent in which a palladium catalyst and a phosphine ligand form a complex may also be used, and examples thereof include tetrakis(triphenylphosphine)palladium(0), 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, dichlorobis(triphenylphosphine)palladium(II), dichlorobis(tricyclohexylphosphine)palladium(II), bis(tri-t-butylphosphine)palladium(0), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)palladium(II) methanesulfonate, (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, [(2-di-t-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)palladium(II) methanesulfonate, [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II), and the like. Examples of the base include sodium t-butoxide, potassium acetate, tripotassium phosphate, cesium carbonate, potassium carbonate, sodium hydrogencarbonate, lithium bis(trimethylsilyl)amide, triethylamine, diisopropylethylamine, dicyclohexylethylamine, potassium fluoride, cesium fluoride, etc. Examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane, alcohol solvents such as methanol, ethanol, propanol, and butanol, N,N-dimethylformamide, and mixed solvents of these organic solvents with water.

[0315] (2) The production method described here is suitable for producing an intermediate of a compound represented by general formula (I) in which G is a nitrogen atom and J is a nitrogen atom, i.e., compound (B-2) shown below.

[0316] [ka]

[0317] (wherein each symbol has the same meaning as defined above) Process B-2 Compound (5-2) is R 10 The carboxylic acid (1-10) having the substituent (1-1) is converted to an acid halide using a halogenating agent, followed by reaction with compound (5-1). The reaction proceeds using a base in an appropriate solvent, usually at temperatures between -20°C and the solvent's reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature used, but is usually 0.5 to 24 hours. Examples of halogenating agents include thionyl chloride, oxalyl chloride, and phenylphosphonyl dichloride. Examples of bases include triethylamine and pyridine. Examples of solvents include dichloromethane, 1,2-dichloroethane, chloroform, pyridine, and toluene.

[0318] Process B-3 Compound (5-3) can be obtained by deprotection and cyclization of compound (5-2). The deprotection reaction is carried out using an acid in a suitable solvent, usually at 0°C to the solvent reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature used, but is usually 0.5 to 24 hours. Examples of acids include trifluoroacetic acid and hydrochloric acid. Examples of solvents include dichloromethane, chloroform, and tetrahydrofuran. This reaction can also be carried out using an acid alone. The cyclization reaction is carried out using an acid in a suitable solvent, usually at room temperature to the solvent reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature used, but is usually 0.5 to 24 hours. Examples of acids include trifluoroacetic acid and acetic acid. Examples of solvents include tetrahydrofuran, N,N-dimethylformamide, 1-butanol, and 2-propanol.

[0319] Process B-4 Compound (B-2) can be obtained from compound (5-3) by the following two methods. The first can be obtained by hydrazine addition, acylation, and cyclization. The reaction with hydrazine proceeds using a base and hydrazine in an appropriate solvent, usually at 0°C to room temperature. Examples of bases include sodium hydride, sodium t-butoxide, and potassium t-butoxide. The acylation reaction proceeds using an acylating agent in an appropriate solvent, usually at room temperature to the solvent reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature used, but is usually 0.5 to 24 hours. Examples of acylating agents include trifluoroacetic anhydride, acetic anhydride, and propanoic anhydride. Examples of solvents include tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and dichloromethane. The above reaction can also be carried out using an acylhydrazide instead of hydrazine and an acid chloride or acid anhydride. Examples of acylhydrazides include acetylhydrazine. The cyclization reaction proceeds using an acid in a suitable solvent, usually at room temperature to the solvent reflux temperature. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually 0.5 to 24 hours. Examples of acids include acetic acid and trifluoroacetic acid. Examples of solvents include tetrahydrofuran, N,N-dimethylformamide, 1-butanol, and 2-propanol. This reaction proceeds using the corresponding orthoester after the addition of hydrazine in a suitable solvent, usually at room temperature to the solvent reflux temperature. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually 0.5 to 24 hours. Examples of orthoesters include 1,1,1-triethoxyethane and 1,1,1-trimethoxypentane. Examples of solvents include toluene and tetrahydrofuran.

[0320] The second method involves converting the amide group to a thioamide group, followed by hydrazine addition, acylation, and cyclization. The thioamidation reaction uses a sulfurizing agent in an appropriate solvent, typically at room temperature to the solvent's reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is typically 0.5 to 24 hours. Examples of sulfurizing agents include Lawesson's reagent and diphosphorus pentasulfide. Examples of solvents include 1,2-dichloroethane, tetrahydrofuran, and 1,4-dioxane. The hydrazine addition reaction uses hydrazine in an appropriate solvent, typically at room temperature to the solvent's reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is typically 1 to 24 hours. Examples of solvents include tetrahydrofuran, 1,4-dioxane, and N,N-dimethylformamide. The acylation reaction uses an acylating agent in an appropriate solvent, typically at room temperature to the solvent's reflux temperature. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually 1 to 24 hours. Examples of acylating agents include trifluoroacetic anhydride, acetic anhydride, and propanoic anhydride. Instead of using hydrazine and an acid chloride or acid anhydride, the above reaction can also be carried out using an acyl hydrazide. Examples of acyl hydrazides include acetylhydrazine. Examples of solvents include tetrahydrofuran and N,N-dimethylformamide. The cyclization reaction proceeds using an acid in an appropriate solvent, usually at room temperature to the solvent reflux temperature. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually 0.5 to 24 hours. Examples of acids include acetic acid and trifluoroacetic acid. Examples of solvents include tetrahydrofuran, N,N-dimethylformamide, 1-butanol, and 2-propanol. This reaction proceeds using the corresponding orthoester after the addition of hydrazine in an appropriate solvent, usually at room temperature to the solvent reflux temperature. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually 0.5 to 24 hours. Examples of orthoesters include 1,1,1-triethoxyethane and 1,1,1-trimethoxypentane. Examples of solvents include toluene and tetrahydrofuran.

[0321] (3) Among the compounds represented by the general formula (I), an intermediate of a compound in which G is a nitrogen atom and J is a nitrogen atom, that is, the following compound (B-2), can also be synthesized by the following method.

[0322] [ka]

[0323] (In the formula, P B represents a protecting group, and other symbols are as defined above. P in the formula B is not particularly limited as long as it protects a carboxyl group, and examples thereof include alkyl (specifically, methyl, ethyl, t-butyl, etc.) and aralkyl (benzyl, etc.). Compound (B-2) can also be synthesized from compound (6-1) according to known methods (for example, the methods described in WO1993 / 007129 and WO1998 / 011111).

[0324] (4) The production method described herein is directed to a compound represented by general formula (I) R 10 -N(R 7c )-CO-OR 7d (R 7c and R 7d has the same meaning as above.)

[0325] [ka]

[0326] (In the formula, each symbol has the same meaning as defined above.) Process B-8 Compound (B-3) can be prepared by converting the corresponding acid halide (Cl-CO-OR) from compound (7-1), which is synthesized according to a known method (for example, Japanese Patent Laid-Open Publication No. 7-17941). 7d ) or acid anhydride (R 7d O-CO-O-CO-OR 7d) can be obtained by reacting the compound with the base. The reaction proceeds using a suitable solvent, usually at temperatures between -20°C and the reflux temperature of the solvent. The reaction time varies depending on the raw materials and solvent used, the reaction temperature, etc., but is usually 30 minutes to 24 hours. Examples of the base include triethylamine, N,N-diisopropylethylamine, and pyridine. Examples of the solvent include dichloromethane, 1,2-dichloroethane, chloroform, N-methylpyrrolidone, pyridine, and toluene. The base used in this reaction can also be used as a solvent.

[0327] Process B-9 Compound (B-4) can be obtained by alkylating compound (B-3). The alkylation reaction uses a base and an alkylating agent such as an alkyl halide in an appropriate solvent, and typically proceeds at temperatures between 0°C and the solvent's reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature used, but is typically 10 minutes to 24 hours. Examples of the base include inorganic bases such as sodium hydride, potassium hydroxide, and potassium carbonate, and alkoxides such as potassium t-butoxide. Examples of the solvent include N,N-dimethylformamide, tetrahydrofuran, and dimethyl sulfoxide.

[0328] (5) The production method described herein is directed to a compound represented by general formula (I) R 10 is a hydroxyl group, that is, is suitable for producing the following compound (B-5).

[0329] [ka]

[0330] (In the formula, each symbol has the same meaning as defined above.) Compound (B-5) can be derived from compound (8-1) according to known methods (for example, US Pat. No. 4,959,361).

[0331] (6) The production method described herein is directed to a compound represented by general formula (I) in which R 10 Ga-(CH2)k -CO-N(R 7a )(R 7b ), that is, the following compound (B-6).

[0332] [ka]

[0333] (In the formula, P C represents a hydrogen atom or a protecting group, and k represents an integer of 1 to 6. Each symbol has the same meaning as defined above. P in the formula C The protecting group is not particularly limited as long as it protects the carboxyl group, and examples thereof include alkyl (specifically, methyl, ethyl, t-butyl, etc.) and aralkyl (benzyl, etc.). Process B-13 Compound (9-2) is a compound obtained by removing the protecting group P of compound (9-1). C It is obtained by removing P C When P is a hydrogen atom, this step can be omitted. C There is no particular limitation as long as it can be used for deprotection of P C If P is methyl or ethyl, methods using an inorganic base such as sodium hydroxide in a mixed solvent of an alcoholic solvent and water can be used. If P is t-butyl, methods using an acid such as hydrochloric acid or trifluoroacetic acid can be used. C When is benzyl or substituted benzyl, benzyloxymethyl or the like, a method using catalytic hydrogenation can be mentioned. Process B-14 Compound (B-6) is a compound having the R corresponding to compound (9-2). 7a , R 7b The reaction proceeds using a condensing agent in the presence of a suitable base in a suitable solvent at a temperature between 0°C and the reflux temperature of the solvent. The reaction time, condensing agent, solvent, reaction accelerator, and base used are the same as in Step A-8.

[0334] (7) The production method described here is suitable for producing an intermediate of a compound represented by general formula (I) in which ring E is represented by the above-mentioned general formula (Eb), G is a nitrogen atom, and J is a nitrogen atom, i.e., the following compound (B-7).

[0335] [ka]

[0336] (In the formula, P D represents a protecting group, and each symbol has the same meaning as defined above. P in the formula D The group is not particularly limited as long as it protects the amide group and gives compound (10-9), and examples thereof include a 4-methoxybenzyl group and a 2,4-dimethoxybenzyl group. Compound (B-7) can be synthesized from compound (10-1) according to the methods described in SYNLETT, 2008, 15, 2360-2364 and J. Org. Chem., 2009, 74, 4975-4981.

[0337] (8) Among the compounds represented by the general formula (I), the ring E is represented by the above general formula (Ea), G is a nitrogen atom and J is a nitrogen atom, and R 9a The intermediate of the compound in which R represents cyanomethyl, that is, the following compound (B-8), can be produced, for example, by the following production method.

[0338] [ka]

[0339] (The symbols in the formula are as defined above.) Process B-24 Compound (11-2) can be obtained by reacting compound (11-1) with a mixture of magnesium acetate dihydrate, acetic acid, acetic anhydride and concentrated sulfuric acid at room temperature for an appropriate time. Process B-25 Compound (11-3) can be obtained by reacting compound (11-2) with a base. The reaction usually proceeds in an appropriate solvent at 0°C to room temperature. The reaction time varies depending on the starting materials, solvent, reaction temperature, etc., but is usually 0.5 to 24 hours. Examples of the base include aqueous sodium hydroxide and aqueous potassium hydroxide. Examples of the solvent include methanol, ethanol, tetrahydrofuran, and 1,4-dioxane. Process B-26 Compound (B-8) can be obtained by converting the hydroxyl group of compound (11-3) to a leaving group and then substituting it with a cyano group (cyanation). The conversion to a leaving group is carried out using a protecting agent and a base in an appropriate solvent, usually at 0°C to room temperature. Examples of protecting agents include p-toluenesulfonyl chloride and mesyl chloride. The reaction time varies depending on the raw materials, solvent, reaction temperature, etc., but is usually 1 to 24 hours. Examples of bases include triethylamine and N,N-diisopropylethylamine. Examples of solvents include dichloromethane and tetrahydrofuran. The cyanation reaction is carried out using a cyanating agent in an appropriate solvent, usually at 0°C to the reflux temperature of the solvent. The reaction time varies depending on the raw materials, solvent, reaction temperature, etc., but is usually 1 to 24 hours. Examples of cyanating agents include sodium cyanide and trimethylsilyl cyanide. Examples of the solvent include dimethyl sulfoxide, acetonitrile, tetrahydrofuran, etc. In the case of trimethylsilyl cyanide, tetrabutylammonium fluoride is used.

[0340] (9) Among the compounds represented by the general formula (I), the ring E is represented by the above general formula (Ea), G is a nitrogen atom and J is a nitrogen atom, and R 9a An intermediate of a compound in which represents an alkyl having 1 to 6 carbon atoms substituted with a cyano group, that is, the following compound (B-9), can also be produced, for example, by the following production method.

[0341] [ka]

[0342] (In the formula, k represents an integer of 1 to 6. The other symbols have the same meanings as above.) Process B-27 Compound (B-9) can be obtained by cyanating compound (12-1). The reaction conditions can be the same as those in step B-26.

[0343] (10) Among the compounds represented by the general formula (I), the ring E is represented by the above general formula (Ea), G is a nitrogen atom and J is a nitrogen atom, and R 9a An intermediate of the compound in which represents a cyano group, that is, the following compound (B-10), can be produced, for example, by the following production method.

[0344] [ka]

[0345] (wherein each symbol has the same meaning as defined above) Process B-28 Compound (13-1) can be obtained by oxidizing compound (11-3). The reaction conditions include, for example, reacting a mixture of compound (11-3), manganese dioxide, and dichloromethane at room temperature for an appropriate time. Process B-29 Compound (B-10) can be obtained by cyanating compound (13-1). The reaction conditions include, for example, reacting a mixture of hydroxylamine hydrochloride and dimethyl sulfoxide under heating for an appropriate period of time.

[0346] (11) Among the compounds represented by the general formula (I), the ring E is represented by the above general formula (Ea), G is a nitrogen atom and J is a nitrogen atom, and R 9a An intermediate of the compound in which represents a hydrogen atom, that is, the following compound (B-11), can be produced, for example, by the following production method.

[0347] [ka]

[0348] (wherein each symbol has the same meaning as defined above) Process B-30 Compound (14-1) can be obtained by oxidizing compound (13-1). The reaction proceeds using an oxidizing agent in an appropriate solvent, usually at temperatures between 0°C and the reflux temperature of the solvent. The reaction time varies depending on the starting materials, solvent, and reaction temperature used, but is usually between 0.5 and 24 hours. Examples of oxidizing agents include hydrogen peroxide, t-butyl hydroperoxide, sodium chlorite, and potassium permanganate. Examples of solvents include methanol, acetonitrile, and water. The reaction proceeds, for example, by adding 35% aqueous hydrogen peroxide and aqueous sodium chlorite to a mixture of acetonitrile and aqueous sodium dihydrogen phosphate at 0°C to room temperature. Process B-31 Compound (B-11) can be obtained by decarboxylating compound (14-1). The reaction conditions include, for example, reacting in quinoline in the presence of copper at 150°C.

[0349] (Method C) (1) An intermediate of the compound represented by the general formula (I), that is, the following compound (C-1), can be produced, for example, by the following production method.

[0350] [ka]

[0351] (In the formula, Z A indicates a halogen atom, and Z D indicates the activating group of the hydroxyl group, and B 2 represents a hydrogen atom, an amine, an olefin, an acetylene, a thiol, an alcohol, a boronic acid, or a boronic acid ester which may have a substituent. The other symbols are as defined above. Z in the formula A The halogen atoms in the above list refer to chlorine atoms, bromine atoms, and iodine atoms, and Z DExamples of the activating group for the hydroxyl group represented by the formula (B) include sulfonyl groups such as trifluoromethanesulfonyl and toluenesulfonyl. 2 The optionally substituted boronic acid ester includes pinacolatoboron, neopentylglycolateboron, and the like. Process C-1 The hydroxyl group of compound (16-2) is converted to the activating group OZ. D This is a process for converting the carboxylic acid into the following: The reaction proceeds in the presence of a base in a suitable solvent at a temperature of about -50 to 50°C, particularly at 0°C to room temperature. Activated sulfonic acid derivatives such as trifluoromethanesulfonic anhydride, 1-(trifluoromethanesulfonyl)imidazole, and toluenesulfonyl chloride are used as activating reagents. This reaction can also be carried out by using a sulfonic acid in combination with a condensing agent. Examples of bases include triethylamine, pyridine, and lutidine. Examples of solvents include dichloromethane, 1,2-dichloroethane, chloroform, pyridine, and toluene. Process C-2 Compound (C-1) can be obtained by reacting compound (16-1) or compound (16-3) with compound (16-4). Compound (16-1) or compound (16-3) and P C OC(O)-LB 2 (In the formula, L, P C is as defined above.), an olefin, acetylene, thiol, alcohol, or an arylboronic acid derivative represented by LB(OH)2 or its ester (wherein L is as defined above) to obtain compound (C-1). The palladium catalyst, phosphine ligand, reagent in which the palladium catalyst and phosphine ligand form a complex, base, and solvent used are the same as those in step B-1. Furthermore, when L is an aryl having 6 to 12 carbon atoms, a heteroaryl having 5 to 12 ring atoms, an olefin, or an acetylene, compound (C-1) can also be obtained by a coupling reaction between an organometallic salt of L (e.g., tin, zinc, copper, etc.) or an alkylmetal derivative of L (e.g., alkylaluminum derivative, alkyltin derivative, alkylborane derivative, etc.) and compound (16-1) or compound (16-3).

[0352] (2) The intermediate of the compound represented by the general formula (I), that is, the following compound (C-1), can also be produced, for example, by the following production method.

[0353] [ka]

[0354] (wherein each symbol has the same meaning as defined above) Compound (C-1) can be obtained by coupling reaction of compound (17-1) with boronic acid derivative (17-2). The reaction conditions can be the same as those in step B-1 above.

[0355] (3) The following step is suitable for producing a compound (C-1) in which L can be introduced by a reaction with boronic acid (18-1) (for example, L is an unsubstituted or substituted aryl having 6 to 10 carbon atoms, an unsubstituted or substituted heteroaryl containing 1 to 5 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom and having 3 to 10 ring atoms, an olefin, an acetylene, etc.).

[0356] [ka]

[0357] (wherein each symbol has the same meaning as defined above) Process C-4 The reaction of compound (16-1) with a boronic acid derivative (e.g., bis-pinacolatodiboron, bis-neopentylglycolatodiboron, etc.) yields boronic acid (18-1). The reaction proceeds in the presence of a palladium catalyst, a phosphine ligand, and a base in an appropriate solvent at temperatures between 0°C and heating, particularly at room temperature and the boiling point of the solvent. The palladium catalyst, phosphine ligand, base, and solvent used in Step B-1 can be used. Process C-5 The reaction of boronic acid (18-1) with compound (18-2) yields compound (C-1). The reaction proceeds favorably in the presence of a palladium catalyst, a phosphine ligand, and a base in an appropriate solvent at temperatures between 0°C and heating, particularly at room temperature and the boiling point of the solvent. The palladium catalyst, phosphine ligand, base, and solvent used in step B-1 can be used.

[0358] (4) Among the compounds represented by general formula (I), ring E is represented by the above general formula (Ea), G is a nitrogen atom and J is a nitrogen atom, and R 9a An intermediate compound in which is a halogen atom, that is, the following compound (C-2), can be produced, for example, by the following production method.

[0359] [ka]

[0360] (In the formula, each symbol has the same meaning as defined above.) Process C-6 Compound (19-1) can be obtained by reacting compound (B-11) with compound (16-4). The reaction conditions can be the same as those in step C-2. Process C-7 Compound (19-1) is reacted with sulfuryl chloride, N-bromosuccinimide, or the like in acetic acid or a mixture of acetic acid and chloroform at room temperature to 50° C. to give compound (C- 2) is obtained.

[0361] (Method D) (1) Among the compounds represented by general formula (I), a compound in which T is -CO-NH- and n is 2, i.e., the following compound (D-1), can be produced, for example, by the following production method.

[0362] [ka]

[0363] (wherein each symbol has the same meaning as defined above) Process D-1 Compound (20-1) is a compound obtained by removing the protecting group P of compound (C-1). C It is obtained by removing P C If is a hydrogen atom, this step can be omitted. C The deprotection conditions of P C There is no particular limitation as long as it can be used for deprotection of P C If P is methyl, methods using a Lewis acid such as boron tribromide in a methylene chloride solvent or a method using an inorganic base such as sodium hydroxide in a mixed solvent of an alcoholic solvent and water can be used. If P is ethyl, methods using an inorganic base such as sodium hydroxide in a mixed solvent of an alcoholic solvent and water can be used. If P is t-butyl, methods using an acid such as hydrochloric acid or trifluoroacetic acid can be used. C When is benzyl or substituted benzyl, benzyloxymethyl or the like, a method using catalytic hydrogenation can be mentioned. Process D-2 Compound (D-1) can be obtained by condensation reaction of carboxylic acid derivative (20-1) with amine derivative (20-2). The reaction conditions can be the same as those in step B-14.

[0364] (2) Among the compounds represented by general formula (I), a compound in which T is -CO-NH- and n is 2, i.e., the following compound (D-1), can be produced, for example, by the following production method.

[0365] [ka]

[0366] (In the formula, Z F represents a chlorine atom or a bromine atom, and other symbols have the same meanings as above.) Process D-3 This is a process for converting compound (20-1) to acid halide (21-1). The reaction proceeds in an appropriate solvent, usually at 0°C to the solvent reflux temperature, usually for 1 to 24 hours. Examples of halogenating agents include thionyl chloride, oxalyl chloride, and phenylphosphonyl dichloride. Examples of bases include triethylamine and pyridine. Examples of solvents include dichloromethane, 1,2-dichloroethane, chloroform, pyridine, and toluene. Process D-4 Compound (D-1) can be obtained by reacting acid halide (21-1) with amine derivative (20-2). The reaction proceeds using a base in an appropriate solvent, usually at temperatures between 0°C and the reflux temperature of the solvent. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually 30 minutes to 12 hours. Examples of the base include triethylamine and pyridine. Examples of the solvent include dichloromethane, dichloroethane, chloroform, N-methylpyrrolidone, pyridine, and toluene.

[0367] (Method E) (1) Among the compounds represented by general formula (I), a compound in which T is -CO-NH- and n is 2, i.e., the following compound (D-1), can be produced, for example, by the following production method.

[0368] [ka]

[0369] (In the formula, each symbol has the same meaning as defined above.) Process E-1 Compound (22-2) was synthesized by the reaction of amine (20-2) with HOC(O)-LZ A (In the formula, Z Ais as defined above) with a carboxylic acid (22-1) represented by the formula (22-1). The reaction conditions may be the same as those in the above-mentioned step B-14. Process E-2 In this step, compound (22-2) is reacted with boronic acid or its ester derivative (18-1) to give compound (D-1). The reaction conditions can be the same as those in step B-1.

[0370] (2) Among the compounds represented by general formula (I), a compound in which T is -CO-NH- and n is 2, i.e., the following compound (D-1), can be produced, for example, by the following production method.

[0371] [ka]

[0372] (The symbols in the formula are as defined above.) Process E-3 Compound (23-2) can be obtained by reacting amine derivative (20-2) with carboxylic acid derivative (23-1). The reaction conditions can be the same as those in step B-14. 2 When there is a possibility of self-condensation, such as when the group is an amine, appropriate steps of protection and deprotection can be inserted. Process E-4 The hydroxyl group of compound (16-2) is converted to the activating group OZ. D The reaction conditions may be the same as those in the above-mentioned step C-1. Process E-5 In this step, compound (16-1) or compound (16-3) obtained in step E-4 is reacted with compound (23-2) to obtain compound (D-1). The reaction conditions may be the same as those in step C-2.

[0373] (3) Among the compounds represented by general formula (I), a compound in which T is -CO-NH- and n is 2, i.e., the following compound (D-1), can be produced, for example, by the following production method.

[0374] [ka]

[0375] (The symbols in the formula are as defined above.) In the above-mentioned method E(2), compound (24-1) is used instead of compound (23-1) to obtain boronic acid derivative (24-2), which is then reacted with iminochloride (A-4) to obtain compound (D-1). The reaction conditions for step E-6 may be the same as those for step B-14. The reaction conditions for step E-7 may be the same as those for step B-1.

[0376] (Method F) (1) Among the compounds represented by general formula (I), a compound in which T is -CO-NH- and n is 2, i.e., the following compound (D-1), can be produced, for example, by the following production method.

[0377] [ka]

[0378] (In the formula, P E represents a protecting group, and the other symbols are as defined above. P in the formula E The group is not particularly limited as long as it protects the thiol group and gives compound (25-5). For example, a benzyl group can be mentioned. Process F-1 Compound (25-2) can be obtained by reacting carboxylic acid derivative (20-1) with amine derivative (25-1). The reaction conditions can be the same as those in step B-14. Process F-2 Compound (25-2) and P E This is a step of obtaining compound (25-4) by reaction with SH (25-3). The reaction conditions can be the same as those in the above step C-2. Process F-3 Compound (25-5) can be obtained by reacting compound (25-4) with N-chlorosuccinimide or the like in a mixed solution of acetonitrile-hydrochloric acid or in acetic acid at 0°C to 50°C. Process F-4 Compound (D-1) can be obtained by reacting sulfonyl chloride derivative (25-5) with amine derivative (25-6). The reaction proceeds using a base in an appropriate solvent, usually at temperatures between 0°C and the solvent's reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature used, but is usually between 0.5 and 24 hours. Examples of the base include triethylamine and pyridine. Examples of the solvent include tetrahydrofuran, dichloromethane, and acetonitrile.

[0379] (2) Among the compounds represented by the above formula (20-2), the fused ring moiety is 3-cyano-1H-isocyano. The compound which is an indole, that is, the following compound (F-1), can be produced, for example, by the following production method.

[0380] [ka]

[0381] (In the formula, P F represents a protecting group for an amino group, and the other symbols are as defined above. P in the formula F The group is not particularly limited as long as it protects the amino group and gives compound (26-6), and examples thereof include a t-butyloxycarbonyl group and a benzyloxycarbonyl group. Process F-5 Compound (26-3) can be obtained by the reaction of nitro compound (26-1) with vinylmagnesium bromide (26-2). The reaction usually proceeds in an appropriate solvent at temperatures between -78°C and room temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually between 0.5 and 24 hours. Examples of solvents include tetrahydrofuran. Process F-6 Compound (26-4) can be obtained, for example, by formylation of indole derivative (26-3), followed by oxime formation and dehydration. The formylation reaction uses a halogenating agent and DMF and typically proceeds at room temperature to the solvent reflux temperature. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is typically 1 to 24 hours. Examples of halogenating agents include phosphoryl chloride and phenylphosphonyl dichloride. Examples of solvents include DMF and a dichlorobenzene-DMF mixed solution. Compound (26-4) can be obtained by adding hydroxylamine hydrochloride to the above reaction solution and heating. The reaction typically proceeds at 40°C to the solvent reflux temperature. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is typically 0.5 to 24 hours. Process F-7 Compound (26-5) can be obtained by coupling compound (26-4) with benzophenone imine, followed by a deprotection reaction. The conditions for the coupling reaction are the same as those for step C-2. The deprotection reaction involves the use of an acid such as hydrochloric acid, or hydroxylamine. The reaction typically proceeds at room temperature to the reflux temperature of the solvent. The reaction time varies depending on the starting materials, solvent, and reaction temperature used, but is typically between 1 and 24 hours. Examples of suitable solvents include methanol, tetrahydrofuran, 1,4-dioxane, or a mixture thereof. Process F-8 Compound (26-7) can be obtained by reacting sulfonyl chloride derivative (26-6) with amine derivative (26-5). The reaction conditions for step F-8 are the same as those for step F-4. Process F-9 Compound (F-1) is a compound obtained by removing the protecting group P of compound (26-7). F The deprotection conditions are as follows: F There is no particular limitation as long as it can be used for deprotection of P FWhen P is a t-butyloxycarbonyl group, it can be deprotected with an acid. Examples of the acid include inorganic acids such as hydrochloric acid and trifluoroacetic acid. The reaction conditions include an alcoholic solvent such as ethanol, an ethereal solvent such as tetrahydrofuran, water, or a mixture thereof, at ice-cooling to 80°C for about 10 minutes to 12 hours. F is a benzyloxycarbonyl group, it can be deprotected by reduction through catalytic hydrogenation. Examples of catalysts include palladium on carbon, and the reaction temperature is usually room temperature to the reflux temperature of the solvent, the hydrogen pressure is 1 to 20 atmospheres, and the reaction time varies depending on the starting material, solvent, reaction temperature, etc., but is usually 1 to 48 hours.

[0382] The compound represented by general formula (I) produced by the above-mentioned method can be purified to any desired purity by applying conventional purification means, such as concentration, extraction, chromatography, reprecipitation, recrystallization, etc. Furthermore, if necessary, it can be converted into a pharmaceutically acceptable salt by treating it with an acid or base in an appropriate solvent (water, alcohol, ether, etc.). Furthermore, the obtained compound of the present invention or a pharmaceutically acceptable salt thereof can be converted into a hydrate or solvate by treating it with water, a water-containing solvent, or other solvent.

[0383] The compounds of the present invention, or pharmaceutically acceptable salts thereof, include racemates, stereoisomers, and mixtures of these compounds, including isotopically and radiolabeled compounds. Such isomers can be isolated by standard separation techniques, including fractional crystallization and chiral column chromatography. The compounds of the present invention also contain asymmetric carbon atoms and therefore include enantiomers or diastereomers. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical / chemical differences by methods well known in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by chiral column chromatography or by reacting the enantiomeric compound with a suitable optically active compound to convert it into a diastereomeric mixture, separating the diastereomers, and then converting the individual diastereomers into their corresponding enantiomers. The compounds of the present invention may be any isomer, including diastereomers, enantiomers, and mixtures thereof.

[0384] The compounds of the present invention or pharmaceutically acceptable salts thereof have cytotoxic activity against cancer cells. Furthermore, they also have the activity of inducing the degradation of BET proteins in cancer cells and inhibiting the binding of BET proteins to acetylated histones. Therefore, the compounds of the present invention or pharmaceutically acceptable salts thereof can be used as anticancer agents, and can also be used as BET protein degradation inducers or BET protein inhibitors. Furthermore, the present invention can provide methods for treating cancer, methods for inducing BET protein degradation, and methods for inhibiting BET proteins using the compounds of the present invention or pharmaceutically acceptable salts thereof.

[0385] Furthermore, the compounds of the present invention or pharmaceutically acceptable salts thereof have the effect of inducing degradation of BRD4 protein in cancer cells and inhibiting the binding of BRD4 protein to acetylated histones. Therefore, the compounds of the present invention or pharmaceutically acceptable salts thereof can also be used as BRD4 protein degradation inducers or BRD4 protein inhibitors. The present invention also provides methods for treating cancer, methods for inducing BRD4 protein degradation, and methods for inhibiting BRD4 protein using the compounds of the present invention or pharmaceutically acceptable salts thereof.

[0386] In the present invention, cancer refers to any type of cancer, and specific examples include oral cancer, pharyngeal cancer, laryngeal cancer, thyroid cancer, esophageal cancer, gastric cancer, duodenal cancer, small intestine cancer, colon cancer, anal cancer, liver cancer, biliary tract cancer, pancreatic cancer, gastrointestinal stromal tumor, lung cancer, skin cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, testicular tumor, bladder cancer, kidney cancer, urothelial cancer, brain tumor, bone and soft tissue tumor, leukemia, malignant lymphoma, multiple myeloma, and sarcoma (e.g., Ewing's sarcoma, rhabdomyosarcoma, and bone and soft tissue sarcoma).

[0387] In the medical field, colorectal cancer is sometimes called colon cancer or rectal cancer, liver cancer is sometimes called hepatocellular carcinoma, biliary tract cancer is sometimes called bile duct cancer or gallbladder cancer, pancreatic cancer is sometimes called pancreatic ductal carcinoma or pancreatic endocrine tumor, lung cancer is sometimes called non-small cell lung cancer, small cell lung cancer, large cell lung cancer, malignant pleural mesothelioma or thymic tumor, skin cancer is sometimes called cutaneous malignant tumor or cutaneous lymphoma, uterine cancer is sometimes called cervical cancer, uterine corpus cancer or uterine sarcoma, kidney cancer is sometimes called renal cell carcinoma, urothelial cancer is sometimes called renal pelvis cancer or ureter cancer, and brain tumors are sometimes called gliomas. In addition, breast cancer has subtypes such as triple-negative breast cancer, HER2-positive breast cancer, luminal A type breast cancer, and luminal B type breast cancer; prostate cancer has subtypes such as hormone-dependent prostate cancer, hormone-independent prostate cancer, and castration-resistant prostate cancer; leukemia has subtypes such as acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LBL), chronic myeloid leukemia (CML), myeloproliferative neoplasm (MPN), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), There are subtypes of malignant lymphomas called myelodysplastic syndromes (MDS), and subtypes of malignant lymphomas called follicular lymphoma (FL), MALT lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma (LPL), Waldenström's macroglobulinemia (WM), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL, NOS), Burkitt's lymphoma (BL), peripheral T-cell lymphoma (PTCL), adult T-cell leukemia-lymphoma (ATL), extranodal NK / T-cell lymphoma, nasal type (ENKL), and Hodgkin's lymphoma (HL).

[0388] In one embodiment, the compounds of the invention, or pharmaceutically acceptable salts thereof, may be useful in the treatment of acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, diffuse large B-cell lymphoma, adult T-cell leukemia / lymphoma, Burkitt's lymphoma, prostate cancer, ovarian cancer, bladder cancer, breast cancer, cervical cancer, uterine sarcoma, gastric cancer, lung cancer, colorectal cancer, glioma, pancreatic cancer, liver cancer, bile duct cancer, renal cell carcinoma, and fibrosarcoma. In another embodiment, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may be useful in the treatment of acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, diffuse large B-cell lymphoma, multiple myeloma, Burkitt's lymphoma, glioma, gastric cancer, colon cancer, pancreatic cancer, liver cancer, prostate cancer, non-small cell lung cancer, breast cancer, ovarian cancer, and uterine sarcoma. In yet another embodiment, the compounds of the invention, or pharmaceutically acceptable salts thereof, may be useful in the treatment of acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, prostate cancer, non-small cell lung cancer, ovarian cancer, and breast cancer. In still further embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, may be useful in the treatment of acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, prostate cancer, ovarian cancer, and breast cancer.

[0389] As used herein, the term "anticancer agent" encompasses anticancer agents, antitumor agents, and the like, and is intended to treat cancer by damaging and killing or weakening cancer cells or tumor cells, thereby reducing, eliminating, or preventing the growth of abnormally proliferating cell masses. Furthermore, "treatment" refers to the administration of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, to an individual who has already developed a disease, disorder, or symptom. Therefore, administering the compound or a pharmaceutically acceptable salt thereof to an individual who has already developed a disease, disorder, or symptom in order to prevent the worsening or recurrence of symptoms is one aspect of treatment.

[0390] When the compound of the present invention is used as a medicine, it can be administered orally or parenterally as a pharmaceutical composition obtained by mixing the compound of the present invention with pharmaceutically acceptable additives (excipients, binders, disintegrants, flavoring agents, odorants, emulsifiers, diluents, solubilizing agents, etc.). Pharmaceutical compositions can be formulated according to conventional methods.

[0391] The subject to which the compound or pharmaceutical composition of the present invention is administered is not particularly limited, but is preferably a mammal. Examples of mammals include primates (e.g., humans, monkeys, chimpanzees), rodents (e.g., mice, rats, guinea pigs), pets (e.g., dogs, cats, rabbits), working animals or livestock (e.g., cows, horses, pigs, sheep, goats), with humans being preferred.

[0392] As used herein, parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion, or local administration (intra-articular administration, transdermal administration, ocular administration, pulmonary / bronchial administration, nasal administration, rectal administration, etc.).

[0393] The dosage of the compound of the present invention is determined taking into consideration age, body weight, general health condition, sex, diet, administration time, administration method, excretion rate, and the severity of the patient's condition currently being treated, as well as other factors. The daily dosage of the compound of the present invention varies depending on the patient's condition and body weight, the type of compound, the administration route, etc., but is, for example, about 0.001 to 100 mg / person / day administered parenterally subcutaneously, intravenously, intramuscularly, intraarticularly, transdermally, ocularly, pulmonary / bronchially, nasally, or rectally, and about 0.01 to 1000 mg / person / day administered orally. [Example]

[0394] The present invention will be explained in detail below with reference to Reference Examples, Examples and Test Examples, but the present invention is not limited to these examples in any way.

[0395] Reference example 1 (1-1) Methyl [(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Reference Example Compound 1)

[0396] [ka]

[0397] To a suspension of (6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (300 g) in methanol (1.5 L), thionyl chloride (320 g) was added dropwise over 1 hour (10-25°C) under ice cooling, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and chloroform (1.5 L) and water (1 L) were added. The mixture was separated and further extracted with chloroform (500 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (500 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure (azeotropically twice with methanol). The residue was washed with methanol / water (300 mL / 300 mL) to obtain the title compound (250 g). MS(ESI)m / z:415.2[M+H] +

[0398] Reference example 2 (2-1) 3-(4-bromophenyl)-3-oxopropanenitrile (Reference Example Compound 2-1)

[0399] [ka]

[0400] Acetonitrile (12.3 g) was added to a suspension of sodium methoxide (12.4 g) in dimethyl sulfoxide (23 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. After that, a solution of ethyl 4-bromobenzoate (22.9 g) in dimethyl sulfoxide (23 mL) was slowly added, and the mixture was stirred at 45°C for 3 hours. The reaction solution was cooled on ice, and water and concentrated hydrochloric acid were added. The mixture was stirred for 0.5 hours, and the precipitate was collected by filtration. The resulting residue was dried to obtain the title compound (22.4 g) as a light brown solid. 1 H NMR(400MHz,DMSO-d6)δ4.75(brs,2H),7.87-7.70(m,4H)

[0401] (2-2) (2-amino-4,5-dimethylthiophen-3-yl)(4-bromophenyl)methanone (Reference Example Compound 2-2)

[0402] [ka]

[0403] A mixture of Reference Example Compound 2-1 (25.0 g), ethyl methyl ketone (8.0 g), sulfur (3.6 g), morpholine (9.7 mL), and ethanol (325 mL) was stirred at 70°C for 7 hours. After the solvent was distilled off, ethyl acetate was added. The organic layer was washed with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution, and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Ethanol was added to the resulting solid, and the mixture was stirred at room temperature for 2 hours. The precipitate was then collected by filtration to obtain the title compound (13.5 g) as a yellow solid. MS (ESI) m / z: 310.2, 312.1 [M+H] +

[0404] (2-3) (3S)-5-(4-bromophenyl)-3,6,7-trimethyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one (Reference Example Compound 2-3)

[0405] [ka]

[0406] (2S)-2-(t-butoxycarbonylamino)propanoic acid (27.6 g) and pyridine (200 mL) were added to Reference Example Compound 2-2 (43.0 g) under ice-cooling, followed by slow dropwise addition of phenylphosphonyl dichloride (29.7 g) and stirring for 1 hour under ice-cooling. After distilling off the solvent, ethyl acetate was added. The organic layer was washed with saturated aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Trifluoroacetic acid (53 mL) was added to a solution of the resulting residue in dichloromethane (70 mL) and stirred at room temperature for 2 hours. Trifluoroacetic acid (53 mL) was then added and stirred at room temperature for 2 hours. The reaction solution was concentrated and azeotroped with toluene. Saturated aqueous sodium bicarbonate was added to the resulting mixture, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Acetic acid (12 mL) was added to a suspension of the resulting residue in 2-propanol (200 mL), and the mixture was stirred at 90°C for 1 hour. Saturated aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture, and the mixture was extracted. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate (43 mL) was added to the resulting residue, and the mixture was stirred at 45°C for 1 hour, after which the insoluble matter was filtered off. The resulting solid was dried under reduced pressure to give the title compound (25.7 g) as a yellow solid. MS (ESI) m / z: 363.2, 365.2 [M+H] +

[0407] (2-4) (6S)-4-(4-bromophenyl)-2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (Reference Example Compound 2)

[0408] [ka]

[0409] Sodium hydride (60%, 1.1 g) was added to a solution of Reference Example Compound 2-3 (9.6 g) in tetrahydrofuran (65 mL) under ice cooling and stirred for 0.5 hours. Diethylphosphonyl chloride (5.5 g) was then added and stirred at room temperature for 0.25 hours. Acetohydrazide (2.9 g) and n-butanol (10 mL) were added and stirred at 70°C for 0.5 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate) to give the title compound (8.9 g) as a yellow powder. MS (ESI) m / z: 401.1, 403.1 [M+H] +

[0410] Reference example 3 (3-1) Methyl {(6S)-2,3,9-trimethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboronane-2-yl)phenyl]-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate (Reference Example Compound 3)

[0411] [ka]

[0412] Under an argon atmosphere, Reference Example Compound 1 (5.00 g), bis(pinacolato)diboron (4.59 g), potassium acetate (2.37 g), and dichlorobis(tricyclohexylphosphine)palladium (445 mg) were heated to reflux in tetrahydrofuran for 25 hours. Dichlorobis(tricyclohexylphosphine)palladium (445 mg) and bis(pinacolato)diboron (1.53 g) were added and the mixture was heated to reflux for 7 hours. After that, bis(pinacolato)diboron (1.53 g), potassium acetate (1.18 g), and dichlorobis(tricyclohexylphosphine)palladium (445 mg) were added and the mixture was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature and filtered through Celite pad using ethyl acetate. The filtrate was washed twice with saturated brine, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 100:0 to 97:3) followed by silica gel column chromatography (ethyl acetate / methanol = 100:0 to 95:5) to give the title compound (5.27 g) as a pale yellow solid. MS (ESI) m / z: 507.2 [M+H] +

[0413] Reference example 4 (4-1) t-Butyl 4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl][1,1'-biphenyl]-4-carboxylate (Reference Example Compound 4-1)

[0414] [ka]

[0415] A mixture of Reference Example Compound 1 (5.00 g), t-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (4.03 g), potassium fluoride (2.10 g), 2-dicyclohexylphosphino-2'-6'-dimethoxybiphenyl (hereinafter referred to as S-phos, 495 mg), palladium acetate (271 mg), tetrahydrofuran (40.2 mL), and water (0.78 mL) was stirred under reflux for 40 hours. (4-t-Butoxycarbonylphenyl)boronic acid (803 mg), S-phos (247 mg), palladium acetate (135 mg), and water (0.78 mL) were added and stirred for 20 hours. Ethyl acetate was added to the reaction mixture, and the insoluble matter was removed by filtration through diatomaceous earth. The filtrate was then concentrated under reduced pressure. Chloroform and water were added to the residue to extract the organic layer, and the aqueous layer was re-extracted with chloroform. The organic layer was collected and dried over anhydrous sodium sulfate, after which the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 95:5). Further purification by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) afforded the title compound (6.55 g) as a crude yellow solid. MS (ESI) m / z: 557.3 [M+H] +

[0416] (4-2) 4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl][1,1'-biphenyl]-4-carboxylic acid (Reference Example Compound 4)

[0417] [ka]

[0418] Reference Example Compound 4-1 (7.05 g) was dissolved in chloroform (8.0 mL), and trifluoroacetic acid (8.0 mL) was added at room temperature. The mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, and azeotroped twice with toluene. The mixture was dissolved in ethyl acetate, cooled to 0°C, and saturated aqueous sodium bicarbonate was added little by little to adjust the pH to 8. The organic layer was separated and washed with ethyl acetate. 1N hydrochloric acid was slowly added to the aqueous layer to adjust the pH to 5, and the mixture was extracted twice with chloroform. The organic layer was concentrated under reduced pressure to give a pale yellow solid (6.29 g). MS (ESI) m / z: 501.2 [M+H] +

[0419] Reference example 5 (5-1) N-(3-cyano-4-methyl-1H-indol-7-yl)-4-formylbenzene-1-sulfonamide (Reference Example Compound 5-1)

[0420] [ka]

[0421] To a solution of Reference Example Compound 9 (100 mg) and 4-formylbenzenesulfonyl chloride (132 mg) in tetrahydrofuran (6.0 mL) was added pyridine (0.29 mL) at room temperature and stirred at the same temperature for 16 hours. 4-Formylbenzenesulfonyl chloride (48 mg) was added and stirred at room temperature for 1 hour. The reaction mixture was acidified with 1N hydrochloric acid and then extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0 to 40:60). Chloroform was added to the resulting purified product to solidify it, and the mixture was concentrated under reduced pressure to give the title compound (126 mg) as a yellow powder. MS (ESI) m / z: 340.1 [M+H] +

[0422] (5-2) 4-(azidomethyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide (Reference Example Compound 5-2)

[0423] [ka]

[0424] To a solution of Reference Example Compound 5-1 (730 mg) in methanol (21.0 mL) was added sodium borohydride (163 mg) at room temperature and stirred at the same temperature for 20 minutes. 1N hydrochloric acid-water-saturated brine and ethyl acetate-acetone were added to the reaction solution and the layers were separated. The aqueous layer was extracted once with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then distilled off under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (30.0 mL), and 1,8-diazabicyclo[5.4.0]-7-undecene (0.49 mL) and 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (736 mg) were added at room temperature, followed by stirring at the same temperature for 15 hours. 1,8-Diazabicyclo[5.4.0]-7-undecene (0.486 mL) and 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (736 mg) were added at room temperature and stirred at the same temperature for 4 hours. 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0 to 60:40). Chloroform was added to the resulting product to solidify it, and the mixture was concentrated under reduced pressure to give the title compound (355 mg) as a pale yellow powder. MS (ESI) m / z: 365.3 [MH] -

[0425] (5-3) 4-(aminomethyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide (Reference Example Compound 5)

[0426] [ka]

[0427] To a mixture of Reference Example Compound 5-2 (350 mg) and triphenylphosphine (326 mg), tetrahydrofuran (10.0 mL) and water (1.0 mL) were added, and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and chloroform was added to the resulting residue. The precipitate was collected by filtration to give the title compound (300 mg) as a white powder. MS (ESI) m / z: 341.1 [M+H] +

[0428] Reference example 6 (6-1) 4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]benzoic acid (Reference Example Compound 6)

[0429] [ka]

[0430] To a mixture of Reference Example Compound 9 (1.00 g) and tetrahydrofuran (30.0 mL), 4-chlorosulfonylbenzoic acid (1.42 g) was added under ice cooling, and the mixture was stirred at room temperature for 24 hours. 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. Diethyl ether was added to the resulting residue, and the precipitate was collected by filtration to obtain the title compound (1.81 g) as a brown solid. MS (ESI) m / z: 354.1 [MH] -

[0431] Reference example 7 (7-1) 7-Bromo-4-methyl-1H-indole (Reference Example Compound 7)

[0432] [ka]

[0433] To a solution of 1-bromo-4-methyl-2-nitrobenzene (1.08 g) in tetrahydrofuran (35.0 mL), a 1 M vinylmagnesium bromide / tetrahydrofuran solution (15.0 mL) was added at -40°C. After stirring at the same temperature for 40 minutes, saturated aqueous ammonium chloride and water were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 98:2 to 95:5) to give the title compound (600 mg) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm 2.52(3H,d,J=0.77Hz),6.63(1H,dd,J=3.28,2.25Hz),6.80(1H,dq,J=7.71,0.81Hz),7.22-7.27(2H,m),8.32(1H,brs)

[0434] Reference example 8 (8-1) 7-Bromo-4-methyl-1H-indole-3-carbonitrile (Reference Example Compound 8)

[0435] [ka]

[0436] To a solution of Reference Example compound 7 (284 mg) in N,N-dimethylformamide (1.35 mL) was added phenylphosphonyl dichloride (0.23 mL) at room temperature. After stirring at room temperature for 0.5 hours, additional phenylphosphonyl dichloride (0.04 mL) was added and the mixture was stirred at the same temperature for an additional 0.5 hours. Hydroxylamine hydrochloride (188 mg) was added to the reaction mixture at room temperature, and the mixture was heated and stirred at 60°C for 1 hour and at 100°C for 2 hours. The reaction mixture was diluted with ethyl acetate, washed twice with saturated aqueous sodium bicarbonate and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2) to give the title compound (220 mg) as a pale brown solid. 1H NMR(400MHz,CDCl3)δ ppm 2.75(3H,d,J=0.6Hz),6.92(1H,dq,J=7.6,1.8Hz),7.36(1H,d,J=7.7Hz),7.78(1H,d,J=2.8Hz),8.73(1H,brs)

[0437] Reference example 9 (9-1) 7-Amino-4-methyl-1H-indole-3-carbonitrile (Reference Example Compound 9)

[0438] [ka]

[0439] To a mixture of Reference Example Compound 8 (215 mg), benzophenone imine (240 mg), [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II) (Pd-PEPPSI-IPent catalyst, 22 mg), and tetrahydrofuran (2.3 mL) was added 1.3 M lithium bis(trimethylsilyl)amide / tetrahydrofuran solution (2.5 mL) at room temperature, and the mixture was stirred at 120°C under a nitrogen atmosphere and microwave irradiation for 0.5 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (2.3 mL) and methanol (2.3 mL), and hydroxylamine hydrochloride (159 mg) and sodium acetate (225 mg) were added at room temperature, followed by stirring at the same temperature for 4 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2) to give the title compound (139 mg) as a pale brown solid. MS (ESI) m / z: 172.1 [M+H] +

[0440] Reference example 10 (10-1) Methyl [(6S)-4-(4'-{[(4-bromophenyl)methyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Reference Example Compound 10-1)

[0441] [ka]

[0442] To a solution of Reference Example compound 4 (500 mg) and 4-bromobenzylamine (223 mg) in N,N-dimethylformamide (5.0 mL) was added N,N-diisopropylethylamine (0.52 mL) and HATU (456 mg) at room temperature, followed by stirring at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed three times with saturated brine-water (1:1) and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 90:10) to give the title compound (643 mg) as a pale yellow powder. MS (ESI) m / z: 668.3, 670.3 [M+H] +

[0443] (10-2) Methyl {(6S)-4-[4'-({[4-(benzylsulfanyl)phenyl]methyl}carbamoyl)[1,1'-biphenyl]-4-yl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate (Reference Example Compound 10-2)

[0444] [ka]

[0445] A mixture of Reference Example Compound 10-1 (635 mg), benzyl mercaptan (0.14 mL), N,N-diisopropylethylamine (0.50 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 110 mg), tris(dibenzylideneacetone)dipalladium (87 mg), toluene (9.0 mL), and tetrahydrofuran (3.0 mL) was stirred at 150°C for 0.5 hours under nitrogen atmosphere and microwave irradiation. After cooling to room temperature, the reaction mixture was directly purified by NH silica gel column chromatography (hexane:ethyl acetate = 50:50 to 0:100) to obtain the title compound (613 mg) as a pale yellow powder. MS (ESI) m / z: 712.4 [M+H] +

[0446] (10-3) Methyl {(6S)-4-[4'-({[4-(chlorosulfonyl)phenyl]methyl}carbamoyl)[1,1'-biphenyl]-4-yl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate (Reference Example Compound 10)

[0447] [ka]

[0448] To a solution of Reference Example compound 10-2 (594 mg) in acetonitrile (12.0 mL) and 2N hydrochloric acid (2.4 mL), N-chlorosuccinimide (390 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 1.5 hours. N-chlorosuccinimide (23 mg) was added to the reaction mixture, and the mixture was stirred at the same temperature for 0.5 hours. Saturated saline-water (1:1) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2) to give the title compound (570 mg) as a pale yellow powder. MS (ESI) m / z: 670.4 [M-Cl + HO] + ; 1H NMR(400MHz,CDCl3) δ ppm 1.75(3H,d,J=0.64Hz),2.41-2.46(3H,m),2.70(3H,s),3.66(2H,dd,J=7.06,3.72Hz),3.79(3H,s),4.44(1H,d,J=5.65Hz),4.67(1H, dd,J=7.77,6.36Hz),4.80(2H,d,J=6.04Hz),7.55-7.63(6H,m),7.68(2H,m,J=8.61Hz),7.90(2H,m,J=8.61Hz),8.02(2H,d,J=7.74Hz)

[0449] Reference example 11 (11-1) t-Butyl (2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamate (Reference Example Compound 11-1)

[0450] [ka]

[0451] A mixed solution of Reference Example Compound 9 (120 mg), t-butyl N-2-[4-(chlorosulfonyl)phenyl]ethylcarbamate (250 mg), pyridine (0.28 mL), and tetrahydrofuran (5.0 mL) was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed twice with 1N hydrochloric acid and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was then distilled off under reduced pressure. The resulting residue was suspended and washed in hexane, and then collected by filtration to give the title compound (301 mg) as a pale yellow solid. MS (ESI) m / z: 455.4 [M+H] +

[0452] (11-2) 4-(2-aminoethyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide hydrochloride (Reference Example Compound 11)

[0453] [ka]

[0454] To Example Compound 11-1 (301 mg), a 4M solution of hydrogen chloride in 1,4-dioxane (3.0 mL) was added at room temperature. After stirring at the same temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. The residue was suspended and washed with diethyl ether, and then collected by filtration to obtain the title compound (260 mg) as a milky white solid. MS (ESI) m / z: 355.1 [M+H] +

[0455] Reference example 12 (12-1) t-Butyl 3-fluoro-4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl][1,1'-biphenyl]-4-carboxylate (Reference Example Compound 12-1)

[0456] [ka]

[0457] Reference Example Compound 3 (300 mg) was dissolved in tetrahydrofuran (3.0 mL), and t-butyl 4-bromo-2-fluorobenzoate (196 mg), tetrakis(triphenylphosphine)palladium(0) (69 mg), potassium phosphate (377 mg), and water (0.038 mL) were added. The mixture was stirred at 90°C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate, and insoluble matter was removed by filtration through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 98:2, precolumn: NH silica gel) to give the title compound (346 mg) as a crude white powder. MS (ESI) m / z: 575.4 [M+H] +

[0458] (12-2) 3-Fluoro-4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl][1,1'-biphenyl]-4-carboxylic acid (Reference Example Compound 12)

[0459] [ka]

[0460] Reference Example Compound 12-1 (240 mg) was dissolved in dichloromethane (2.0 mL), and trifluoroacetic acid (2.0 mL) was added at room temperature. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and extracted twice with saturated aqueous sodium bicarbonate. The aqueous layers were combined, and 2N hydrochloric acid was added in small portions under ice-cooling to adjust the pH to 4. The combined organic layer was extracted twice with chloroform, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the title compound (205 mg) as a white powder. MS (ESI) m / z: 519.1 [M+H] +

[0461] Reference example 13 (13-1) 3-chloro-4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl][1,1'-biphenyl]-4-carboxylic acid (Reference Example Compound 13)

[0462] [ka]

[0463] Reference Example Compound 3 (117 mg) was dissolved in tetrahydrofuran (1.0 mL), and 4-bromo-2-chlorobenzoic acid (48 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 10 mg), X-Phos aminobiphenyl palladium chloride precatalyst (16 mg), cesium fluoride (93 mg), and water (0.25 mL) were added. The mixture was stirred at 120°C for 1 hour under a nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate and extracted twice with saturated aqueous sodium bicarbonate. The aqueous layers were combined, and 2N hydrochloric acid was added portionwise under ice cooling to adjust the pH to 1. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was then removed under reduced pressure to give the title compound (73 mg) as a white powder. MS(ESI)m / z:535.1,537.1[M+H] +

[0464] Reference example 14 (14-1) 4-Bromo-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide (Reference Example Compound 14)

[0465] [ka]

[0466] To a solution (12.0 mL) of Reference Example compound 9 (622 mg) and pyridine (2.92 mL) in tetrahydrofuran, 4-bromobenzenesulfonyl chloride (929 mg) was added at room temperature, followed by stirring at the same temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed once with saturated brine-water (1:1) and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was suspended and washed in chloroform, and then filtered to give the title compound (1061 mg) as a beige powder. MS (ESI) m / z: 390.2, 392.1 [M+H] +

[0467] Reference example 15 (15-1) 7-Amino-4-bromo-1H-indole-3-carbonitrile (Reference Example Compound 15)

[0468] [ka]

[0469] Phenylphosphonyl dichloride (1.27 mL) was added to N,N-dimethylformamide (11.0 mL) and stirred at 70°C for 10 minutes. N-(4-bromo-1H-indol-7-yl)-2,2,2-trifluoroacetamide (929 mg) and N,N-dimethylformamide (11.0 mL) were then added and stirred at 70°C for 1 hour. Hydroxylamine hydrochloride (2.42 g) was then added and stirred at 100°C for 2 hours. Ethylenediamine (2.02 mL) and methanol (22.0 mL) were then added and stirred at 70°C for 1 hour. After cooling to room temperature, the methanol was evaporated under reduced pressure. Ethyl acetate, saturated aqueous sodium bicarbonate, and saturated brine were added to the resulting residue and the layers were separated. The organic layer was washed twice with a mixture of saturated aqueous sodium bicarbonate and saturated brine, once with water, and once with saturated brine. After drying over anhydrous sodium sulfate and filtration, the solvent was evaporated under reduced pressure. The resulting residue was suspended and washed with ethyl acetate, filtered, and dried under reduced pressure to obtain the title compound (260 mg) as a brown powder. The filtrate was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 50:50 to 75:25) to obtain the target compound (104 mg) as a brown solid. MS (ESI) m / z: 236.0, 237.9 [M+H] +

[0470] Reference example 16 (16-1) 7-Bromo-4-ethyl-1H-indole-3-carbonitrile (Reference Example Compound 16-1)

[0471] [ka]

[0472] Phenylphosphonyl dichloride (3.64 mL) was added to a solution of 7-bromo-4-ethyl-1H-indole (3.90 g) in N,N-dimethylformamide (17.4 mL) under ice cooling, and the mixture was stirred at room temperature for 30 minutes and at 70°C for 40 minutes. Hydroxylamine hydrochloride (2.42 g) was added, and the mixture was stirred at 70°C for 30 minutes and at 80°C for 30 minutes. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and then ice-cooled. Saturated aqueous sodium bicarbonate was added while stirring. The mixture was extracted twice with ethyl acetate, and the combined extracts were washed twice with a mixture of saturated brine and saturated aqueous sodium bicarbonate and once with saturated brine. After drying over anhydrous sodium sulfate and filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10 to 70:30), and toluene was added to the residue, followed by concentration under reduced pressure twice. The title compound (3.12 g) was obtained as a pale yellow solid. MS (ESI) m / z: 246.9, 248.9 [M−H] -

[0473] (16-2) 7-Amino-4-ethyl-1H-indole-3-carbonitrile (Reference Example Compound 16)

[0474] [ka]

[0475] To a mixture of Reference Example compound 16-1 (2.12 g), benzophenone imine (2.16 g), and [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II) (Pd-PEPPSI-IPent catalyst, 202 mg), 1.3 M lithium bis(trimethylsilyl)amide / tetrahydrofuran solution (23.0 mL) was added at room temperature, and the mixture was stirred at 120°C under a nitrogen atmosphere and microwave irradiation for 1 hour. After cooling to room temperature, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (11.0 mL)-methanol (11.0 mL), and hydroxylamine hydrochloride (1.48 g) and sodium acetate (2.09 g) were added at room temperature, followed by stirring at the same temperature for 16 hours. Saturated sodium bicarbonate water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The organic layers were combined, washed once with a mixture of saturated brine and water, and once with saturated brine, then dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 98:2) to give the title compound (954 mg) as a pale brown solid. MS (ESI) m / z: 186.1 [M+H] +

[0476] Reference example 17 (17-1) t-Butyl [(1R)-1-(4-bromophenyl)ethyl]carbamate (Reference Example Compound 17-1)

[0477] [ka]

[0478] Di-t-butyl carbonate (3.60 g) was added to a dichloromethane solution (45.0 mL) of (R)-1-(4-bromophenyl)ethanamine (3.00 g) and triethylamine (2.50 mL) at room temperature, and the mixture was stirred at room temperature for 14 hours. 1N hydrochloric acid was added to the reaction mixture, and the layers were separated. The aqueous layer was extracted once with chloroform, and the combined organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was suspended and washed with hexane, and then collected by filtration to give the title compound (4.36 g) as a white solid. MS (ESI) m / z: 300.2, 302.1 [M+H] +

[0479] (17-2) t-Butyl {(1R)-1-[4-(benzylsulfanyl)phenyl]ethyl}carbamate (Reference Example Compound 17-2)

[0480] [ka]

[0481] A mixture of Reference Example Compound 17-1 (4.34 g), benzyl mercaptan (2.04 mL), N,N-diisopropylethylamine (3.75 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 1.67 g), tris(dibenzylideneacetone)dipalladium (1.32 g), and toluene (10.0 mL) was stirred at 150°C for 0.5 hours under nitrogen atmosphere and microwave irradiation. Ethyl acetate was added to the reaction mixture, and insoluble matter was removed by filtration through diatomaceous earth. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10 to 80:20) to obtain the title compound (4.91 g) as a pale yellow solid. MS (ESI) m / z: 344.3 [M+H] +

[0482] (17-3) t-Butyl {(1R)-1-[4-(chlorosulfonyl)phenyl]ethyl}carbamate (Reference Example Compound 17-3)

[0483] [ka]

[0484] To a solution of Reference Example compound 17-2 (2.72 g) in acetonitrile (50.0 mL)-2N hydrochloric acid (10.0 mL), N-chlorosuccinimide (4.30 g) was added under ice cooling and stirred at the same temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10 to 75:25) to give the title compound (2.21 g) as a white solid. 1 H NMR(400MHz,CDCl3) δ ppm 1.32-1.51(12H,m),4.87(2H,brs),7.48-7.60(2H,m),7.93-8.06(2H,m)

[0485] (17-4) t-Butyl [(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamate (Reference Example Compound 17-4)

[0486] [ka]

[0487] To a solution of Reference Example Compound 17-3 (2.20 g) in tetrahydrofuran (66.0 mL) was added Reference Example Compound 9 (1.18 g) and pyridine (2.77 mL) at room temperature, followed by stirring at the same temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed twice with 1N hydrochloric acid and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was then distilled off under reduced pressure. The residue was suspended in chloroform, washed, and filtered to give the title compound (1.67 g) as a pale brown solid. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=98:2) to give the title compound (0.84 g) as a pale brown solid. MS (ESI) m / z: 455.3 [M+H] +

[0488] (17-5) 4-[(1R)-1-aminoethyl]-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide hydrochloride (Reference Example Compound 17)

[0489] [ka]

[0490] To Example Compound 17-4 (2.47 g), 4M hydrogen chloride / 1,4-dioxane solution (25.0 mL) was added at room temperature. After stirring at the same temperature for 3 hours, the reaction mixture was diluted with diethyl ether, and the solid was suspended and washed, then filtered to obtain the title compound (2.27 g) as a milky white solid. MS (ESI) m / z: 355.2 [M+H] +

[0491] Reference example 18 (18-1) t-Butyl 2-fluoro-4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl][1,1'-biphenyl]-4-carboxylate (Reference Example Compound 18-1)

[0492] [ka]

[0493] Reference Example Compound 3 (300 mg) was dissolved in tetrahydrofuran (3.0 mL), and t-butyl 4-bromo-3-fluorobenzoate (180 mg), tetrakis(triphenylphosphine)palladium(0) (69 mg), potassium phosphate (378 mg), and water (0.039 mL) were added. The mixture was stirred at 90°C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate, and insoluble matter was removed by filtration through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate = 50:50 to 0:100) to obtain the title compound (300 mg) as a white powder. MS (ESI) m / z: 575.3 [M+H] +

[0494] (18-2) 2-Fluoro-4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl][1,1'-biphenyl]-4-carboxylic acid (Reference Example Compound 18)

[0495] [ka]

[0496] Reference Example Compound 18-1 (290 mg) was dissolved in dichloromethane (2.0 mL), and trifluoroacetic acid (2.0 mL) was added at room temperature. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and extracted twice with saturated aqueous sodium bicarbonate. The aqueous layers were combined, and 2N hydrochloric acid was added in small portions under ice-cooling to adjust the pH to 4. The organic layer was extracted twice with chloroform, and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was then evaporated under reduced pressure to give the title compound (246 mg) as a white powder. MS (ESI) m / z: 519.3 [M+H] +

[0497] Reference example 19 (19-1) 2-chloro-4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl][1,1'-biphenyl]-4-carboxylic acid (Reference Example Compound 19)

[0498] [ka]

[0499] Reference Example Compound 3 (364 mg) was dissolved in tetrahydrofuran (3.2 mL), and 4-bromo-3-chlorobenzoic acid (150 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 30 mg), X-Phos aminobiphenyl palladium chloride precatalyst (50 mg), cesium fluoride (290 mg), and water (0.80 mL) were added. The mixture was stirred at 120°C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate and extracted twice with saturated aqueous sodium bicarbonate. The aqueous layers were combined, and 2N hydrochloric acid was added portionwise under ice cooling to adjust the pH to 1. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was then evaporated under reduced pressure to give the title compound (247 mg) as a pale yellow powder. MS(ESI)m / z:535.3,537.3[M+H] +

[0500] Reference example 20 (20-1) 4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl]-3-methyl[1,1'-biphenyl]-4-carboxylic acid (Reference Example Compound 20)

[0501] [ka]

[0502] Reference Example Compound 3 (231 mg) was dissolved in tetrahydrofuran (2.0 mL), and 4-bromo-2-methylbenzoic acid (87 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 19 mg), X-Phos aminobiphenyl palladium chloride precatalyst (32 mg), cesium fluoride (185 mg), and water (0.50 mL) were added. The mixture was stirred at 120°C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate and extracted twice with saturated aqueous sodium bicarbonate. The aqueous layers were combined, and 2N hydrochloric acid was added portionwise under ice cooling to adjust the pH to 1. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was then evaporated under reduced pressure to give the title compound (229 mg) as a crude white powder. MS(ESI)m / z:515.3[M+H] +

[0503] Reference example 21 (21-1) t-Butyl ({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamate (Reference Example Compound 21-1)

[0504] [ka]

[0505] To a solution of Reference Example Compound 16 (347 mg) in tetrahydrofuran (9.4 mL) was added t-butyl N-[(4-chlorosulfonylphenyl)methyl]carbamate (630 mg) and pyridine (0.76 mL) at room temperature, followed by stirring at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed twice with 1N hydrochloric acid and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was suspended and washed in diethyl ether-hexane (1:1), and then filtered to obtain the title compound (730 mg) as a beige solid. MS (ESI) m / z: 453.3 [MH] -

[0506] (21-2) 4-(aminomethyl)-N-(3-cyano-4-ethyl-1H-indol-7-yl)benzene-1-sulfonamide hydrochloride (Reference Example Compound 21)

[0507] [ka]

[0508] To Reference Example Compound 21-1 (720 mg) was added 4 M hydrogen chloride / 1,4-dioxane solution (7.2 mL) at room temperature. After stirring at the same temperature for 16 hours, the reaction mixture was diluted with diethyl ether, and the solid was suspended and washed, then collected by filtration to obtain the title compound (653 mg) as a beige solid. MS (ESI) m / z: 355.0 [M+H] +

[0509] Reference example 22 (22-1) t-Butyl [(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamate (Reference Example Compound 22-1)

[0510] [ka]

[0511] To a solution of Reference Example Compound 16 (300 mg) in tetrahydrofuran (8.0 mL) was added Reference Example Compound 17-3 (570 mg) and pyridine (0.65 mL) at room temperature, followed by stirring at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed twice with 1N hydrochloric acid and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was suspended and washed in hexane-chloroform (15:1), and then collected by filtration to give the title compound (710 mg) as a pale brown solid. MS (ESI) m / z: 467.3 [MH] -

[0512] (22-2) 4-[(1R)-1-aminoethyl]-N-(3-cyano-4-ethyl-1H-indol-7-yl)benzene-1-sulfonamide hydrochloride (Reference Example Compound 22)

[0513] [ka]

[0514] To Reference Example Compound 22-1 (701 mg) was added 4 M hydrogen chloride / 1,4-dioxane solution (7.0 mL) at room temperature. After stirring at the same temperature for 16 hours, the reaction mixture was diluted with diethyl ether, and the solid was collected by filtration to obtain the title compound (653 mg) as a beige solid. MS (ESI) m / z: 369.1 [M+H] +

[0515] Reference example 23 (23-1) t-Butyl (2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamate (Reference Example Compound 23-1)

[0516] [ka]

[0517] To a solution of Reference Example compound 16 (300 mg) in tetrahydrofuran (8.0 mL) was added t-butyl N-2-[4-(chlorosulfonyl)phenyl]ethylcarbamate (570 mg) and pyridine (0.65 mL) at room temperature, followed by stirring at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed twice with 1N hydrochloric acid and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was suspended and washed in diethyl ether-hexane (1:1), and then collected by filtration to give the title compound (710 mg) as a beige solid. MS (ESI) m / z: 467.3 [MH] -

[0518] (23-2) 4-(2-aminoethyl)-N-(3-cyano-4-ethyl-1H-indol-7-yl)benzene-1-sulfonamide hydrochloride (Reference Example Compound 23)

[0519] [ka]

[0520] To Reference Example Compound 23-1 (702 mg) was added 4 M hydrogen chloride / 1,4-dioxane solution (7.0 mL) at room temperature. After stirring at the same temperature for 16 hours, the reaction mixture was diluted with diethyl ether, and the solid was suspended and washed, then filtered to obtain the title compound (610 mg) as a beige solid. MS (ESI) m / z: 369.1 [M+H] +

[0521] Example 1 (1-1) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 1)

[0522] [ka]

[0523] To a solution of Reference Example Compound 4 (50 mg), Reference Example Compound 5 (38 mg), and triethylamine (0.042 mL) in N,N-dimethylformamide (2.0 mL) was added HATU (46 mg) at room temperature, and the mixture was stirred at the same temperature for 5 hours. Water was added to the reaction mixture under ice-cooling, and the mixture was extracted twice with chloroform. The combined organic layer was washed twice with water, dried over anhydrous sodium sulfate, and filtered. The solvent was then distilled off under reduced pressure. The resulting residue was purified by preparative HPLC (10 mM aqueous ammonium carbonate solution-acetonitrile) to give the title compound (49 mg) as a pale yellow powder. MS (ESI) m / z: 823.5 [M+H]+

[0524] Example 2 (2-1) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-3'-fluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 2)

[0525] [ka]

[0526] A mixture of Reference Example Compound 12 (78 mg), Reference Example Compound 5 (56 mg), N,N-diisopropylethylamine (0.052 mL), and HATU (86 mg) was stirred in N,N-dimethylformamide (3.0 mL) at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was stirred. The resulting solid was filtered off. The product was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) to give the title compound (86 mg) as a white solid. MS (ESI) m / z: 841.6 [M+H] +

[0527] Example 3 (3-1) Methyl [(6S)-4-{3'-chloro-4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 3)

[0528] [ka]

[0529] A mixture of Reference Example Compound 13 (80 mg), Reference Example Compound 5 (56 mg), N,N-diisopropylethylamine (0.052 mL), and HATU (86 mg) was stirred in N,N-dimethylformamide (3 mL) at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was stirred. The resulting solid was filtered off. The product was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) to give the title compound (115 mg) as a pale yellow solid. MS (ESI) m / z: 857.6, 859.6 [M+H] +

[0530] Example 4 (4-1) t-Butyl (3R)-1-{4-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl]phenyl}pyrrolidine-3-carboxylate (Example Compound 4-1)

[0531] [ka]

[0532] Under a nitrogen stream, Reference Example Compound 1 (200 mg), t-butyl pyrrolidine-3-carboxylate (99 mg), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (40 mg), potassium phosphate (256 mg), and water (0.043 mL) were heated under reflux in tetrahydrofuran (1.0 mL) for 100 minutes. The reaction mixture was allowed to cool, diluted with ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the mixture was filtered through activated carbon, washed with methanol and tetrahydrofuran, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) to give the title compound (266 mg) as a pale yellow powder. MS(ESI)m / z:550.3[M+H] +

[0533] (4-2) (3R)-1-{4-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl]phenyl}pyrrolidine-3-carboxylic acid (Example Compound 4-2)

[0534] [ka]

[0535] Trifluoroacetic acid (1.0 mL) was added to a solution of Example Compound 4-1 (266 mg) in dichloromethane (1.0 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was azeotroped three times with chloroform-toluene. The residue was dissolved in ethyl acetate, and N,N-diisopropylethylamine (0.30 mL) was added portionwise with stirring. Hexane (2.5 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The resulting solid was filtered and washed with a 2:1 ethyl acetate-hexane mixture to obtain the title compound (181 mg) as a yellow powder. MS (ESI) m / z: 494.3 [M+H] +

[0536] (4-3) Methyl [(6S)-4-(4-{(3R)-3-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrrolidin-1-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 4)

[0537] [ka]

[0538] The title compound (111 mg) was obtained as a yellow powder by the same reaction and treatment as in (2-1) except that Example Compound 4-2 (74 mg) was used instead of Reference Example Compound 12 in Example 2. MS (ESI) m / z: 816.3 [M+H] +

[0539] Example 5 (5-1) Methyl {(6S)-4-[4-(3-hydroxyprop-1-yn-1-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate (Example Compound 5-1)

[0540] [ka]

[0541] Reference Example: A mixture of compound 1 (100 mg), propargyl alcohol (27 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 12 mg), X-Phos aminobiphenyl palladium chloride precatalyst (21 mg), potassium phosphate (102 mg), and tetrahydrofuran (1.2 mL) was The mixture was stirred at 90°C for 1 hour under a nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate, washed twice with saturated brine-water (1:1) and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 90:10, precolumn: NH silica gel) to give the title compound (63 mg) as a pale yellow viscous substance. MS (ESI) m / z: 435.3 [M+H] +

[0542] (5-2) Methyl {(6S)-2,3,9-trimethyl-4-[4-(3-oxoprop-1-yn-1-yl)phenyl]-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate (Example Compound 5-2)

[0543] [ka]

[0544] 1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin reagent, 71 mg) was added to Example Compound 5-1 (60 mg) in dichloromethane (1.2 mL) and stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate and saturated aqueous sodium thiosulfate were added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layer was washed twice with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 90:10) to give the title compound (59 mg) as a pale yellow viscous material. MS (ESI) m / z: 433.3 [M+H] +

[0545] (5-3) Methyl [(6S)-4-(4-{3-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)amino]-3-oxoprop-1-yn-1-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 5)

[0546] [ka]

[0547] To a solution of Example Compound 5-2 (57 mg) and 2-methyl-but-2-ene (0.021 mL) in acetonitrile (3.0 mL), a solution of 80% sodium chlorite (18 mg) and sodium dihydrogen phosphate (19 mg) in water (1.0 mL) was added and stirred at room temperature for 30 minutes. 2-Methyl-but-2-ene (0.021 mL), 80% sodium chlorite (18 mg), and sodium dihydrogen phosphate (19 mg) were added to the reaction solution at room temperature and stirred for an additional 30 minutes at the same temperature. The reaction solution was concentrated under reduced pressure, and then ethanol was added and the mixture was concentrated under reduced pressure again. To the resulting residue, Reference Example Compound 5 (47 mg), N,N-diisopropylethylamine (0.11 mL), and N,N-dimethylformamide (2.0 mL) were added at room temperature, and finally HATU (57 mg) was added. The mixture was stirred at the same temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed three times with saturated brine-water (1:1) and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 90:10) to give the title compound (17 mg) as a beige powder. MS (ESI) m / z: 771.4 [M+H] +

[0548] Example 6 (6-1) Methyl {(6S)-4-[4-(3-aminoprop-1-yn-1-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate (Example Compound 6-1)

[0549] [ka]

[0550] A mixture of Reference Example Compound 1 (25 mg), propargylamine (0.019 mL), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 3 mg), X-Phos aminobiphenyl palladium chloride precatalyst (5 mg), potassium phosphate (64 mg), and tetrahydrofuran (0.3 mL) was stirred at 90°C for 2 hours under nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 95:5 to 90:10) to give the title compound (15 mg) as a beige powder. MS (ESI) m / z: 434.3 [M+H] +

[0551] (6-2) Methyl {(6S)-4-[4-(3-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]benzamido}prop-1-yn-1-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate (Example Compound 6)

[0552] [ka]

[0553] To a solution of Example Compound 6-1 (14 mg) and Reference Example Compound 6 (13 mg) in N,N-dimethylformamide (0.4 mL) was added N,N-diisopropylethylamine (0.11 mL) and HATU (15 mg) at room temperature, followed by stirring at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed three times with saturated brine-water (1:1) and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 90:10) to give the title compound (20 mg) as a white powder. MS (ESI) m / z: 771.4 [M+H] +

[0554] Example 7 (7-1) 7-Bromo-3-chloro-1H-indole (Example Compound 7-1)

[0555] [ka]

[0556] N-Chlorosuccinimide (358 mg) was added to a solution of 7-bromo-1H-indole (500 mg) in N,N-dimethylformamide (5.0 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours. Saturated aqueous sodium bicarbonate and saturated aqueous sodium thiosulfate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5 to 90:10) to give the title compound (577 mg) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm 7.09(1H,t,J=7.77Hz),7.24-7.27(1H,m),7.41(1H,dd,J=7.71,0.64Hz),7.59(1H,dt,J=7.96,0.77Hz),8.25(1H,brs)

[0557] (7-2) 3-chloro-1H-indol-7-amine (Example Compound 7-2)

[0558] [ka]

[0559] In Reference Example 9, Example Compound 7-1 (570 mg) was used instead of Reference Example Compound 8, and the same reaction and treatment were carried out to obtain the title compound (163 mg) as a pale brown solid. MS (ESI) m / z: 167.0, 169.0 [M+H] +

[0560] (7-3) Methyl [(6S)-4-{4'-[({4-[(3-chloro-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 7)

[0561] [ka]

[0562] To a solution of Example Compound 7-2 (18 mg) and Reference Example Compound 10 (50 mg) in tetrahydrofuran (2.0 mL), pyridine (0.060 mL) was added at room temperature and stirred at the same temperature for 16 hours. The reaction solution was diluted with ethyl acetate, washed once with 1N hydrochloric acid and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 90:10) to obtain the title compound (37 mg) as a white solid. MS (ESI) m / z: 818.4, 820.4 [M+H] +

[0563] Example 8 (8-1) 7-Bromo-3-chloro-4-methyl-1H-indole (Example Compound 8-1)

[0564] [ka]

[0565] In Example 7, 7-bromo-4-methyl-1H-indole (200 mg) was used instead of 7-bromo-1H-indole, and the reaction and treatment were carried out in the same manner as in (7-1) to obtain the title compound (212 mg) as a yellow oil. 1H NMR(400MHz,CDCl3)δ ppm 2.75(3H,d,J=0.64Hz),6.77(1H,d,J=7.87Hz),7.20(1H,d,J=2.70Hz),7.24(1H,d,J=7.71Hz),8.22(1H,brd,J=1.67Hz)

[0566] (8-2) 3-chloro-4-methyl-1H-indol-7-amine (Example Compound 8-2)

[0567] [ka]

[0568] In Reference Example 9, Example Compound 8-1 (205 mg) was used instead of Reference Example Compound 8, and the same reaction and treatment were carried out to obtain the title compound (56 mg) as a light brown solid. MS (ESI) m / z: 181.0, 183.0 [M+H] +

[0569] (8-3) Methyl [(6S)-4-{4'-[({4-[(3-chloro-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 8)

[0570] [ka]

[0571] In Example 7, Example Compound 8-2 (20 mg) was used instead of Example Compound 7-2, and Reference Example Compound 10 (50 mg) was used, and the reaction and treatment were carried out in the same manner as in (7-3), to obtain the title compound (44 mg) as a gray powder. MS (ESI) m / z: 832.4, 834.4 [M+H] +

[0572] Example 9 (9-1) 7-Bromo-1H-indole-3-carbonitrile (Example Compound 9-1)

[0573] [ka]

[0574] In Reference Example 8, 7-bromo-1H-indole (500 mg) was used instead of Reference Example Compound 7, and the same reaction and treatment were carried out to give the title compound (548 mg) as a pale brown solid. 1 H NMR(400MHz,CDCl3)δ ppm 7.20(1H,t,J=7.83Hz),7.50(1H,dd,J=7.71,0.77Hz),7.73(1H,d,J=7.96Hz),7.80(1H,d,J=2.95Hz),8.84(1H,brs)

[0575] (9-2) 7-Amino-1H-indole-3-carbonitrile (Example Compound 9-2)

[0576] [ka]

[0577] In Reference Example 9, Example Compound 9-1 (542 mg) was used instead of Reference Example Compound 8, and the same reaction and treatment were carried out as in Reference Example 9 to give the title compound (322 mg) as a pale brown solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 5.33(2H,s),6.47(1H,dd,J=7.58,0.90Hz),6.81(1H,dd,J=7.96,0.90Hz),6.94(1H,t,J=7.77Hz),8.13(1H,s),11.73(1H,brs)

[0578] (9-3) Methyl [(6S)-4-{4'-[({4-[(3-cyano-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 9)

[0579] [ka]

[0580] In Example 7, Example Compound 9-2 (15 mg) was used instead of Example Compound 7-2, and Reference Example Compound 10 (44 mg) was used, and the reaction and treatment were carried out in the same manner as in (7-3), to obtain the title compound (40 mg) as a beige powder. MS (ESI) m / z: 809.4 [M+H] +

[0581] Example 10 (10-1) 4-methyl-1H-indol-7-amine (Example Compound 10-1)

[0582] [ka]

[0583] The same reaction and treatment as in Reference Example 9 was carried out using Reference Example Compound 7 (92 mg) instead of Reference Example Compound 8 to give the title compound (29 mg) as a pale brown solid. MS (ESI) m / z: 147.1 [M+H] +

[0584] (10-2) Methyl [(6S)-2,3,9-trimethyl-4-{4'-[({4-[(4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 10)

[0585] [ka]

[0586] In Example 7, Example Compound 10-1 (28 mg) was used instead of Example Compound 7-2, and Reference Example Compound 10 (120 mg) was used, and the reaction and treatment were carried out in the same manner as in (7-3), to obtain the title compound (107 mg) as a beige powder. MS (ESI) m / z: 798.5 [M+H] +

[0587] Example 11 (11-1) Methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 11)

[0588] [ka]

[0589] A mixture of Reference Example Compound 4 (75 mg), Reference Example Compound 11 (65 mg), N,N-diisopropylethylamine (0.078 mL), and HATU (86 mg) was stirred in N,N-dimethylformamide (3.0 mL) at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was stirred. The resulting solid was filtered off. The product was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) to give the title compound (115 mg) as a pale yellow solid. MS (ESI) m / z: 837.4 [M+H] +

[0590] Example 12 (12-1) Methyl 3-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]benzoate (Example Compound 12-1)

[0591] [ka]

[0592] Reference Example Compound 9 (200 mg), methyl 3-(chlorosulfonyl)benzoate (302 mg), and triethylamine (0.33 mL) were stirred in chloroform (5.0 mL) at room temperature for 7 hours. Water was added to the reaction mixture and stirred. The aqueous layer was removed using a phase separator, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 70:30 to 30:70) and silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) to obtain the title compound (190 mg) as a pale yellow solid. MS (ESI) m / z: 370.3 [M+H] +

[0593] (12-2) N-(3-cyano-4-methyl-1H-indol-7-yl)-3-(hydroxymethyl)benzene-1-sulfonamide (Example Compound 12-2)

[0594] [ka]

[0595] A solution of Example Compound 12-1 (190 mg) in tetrahydrofuran (5.0 mL) was cooled to 0°C, and 2 M lithium borohydride / tetrahydrofuran solution (0.77 mL) and methanol (0.063 mL) were added. The mixture was stirred for 4 hours while naturally warming to room temperature. 2 M lithium borohydride / tetrahydrofuran solution (0.77 mL) was added, and the mixture was stirred at room temperature for 3 hours. 1 N hydrochloric acid was added portionwise to the reaction mixture and stirred, followed by addition of chloroform and stirring. The aqueous layer was removed using a phase separator, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) to obtain the title compound (124 mg) as a white solid. MS (ESI) m / z: 342.1 [M+H]+

[0596] (12-3) 3-(azidomethyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide (Example Compound 12-3)

[0597] [ka]

[0598] To a solution of Example Compound 12-2 (124 mg) in tetrahydrofuran (5.0 mL), 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (207 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (111 mg) were added and stirred at room temperature for 4 hours. 1N hydrochloric acid and ethyl acetate were added to the reaction solution and stirred. The organic layer was separated, washed twice with brine, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 80:20 to 50:50) to obtain the title compound (69 mg) as a white solid. MS (ESI) m / z: 367.1 [M+H] +

[0599] (12-4) 3-(aminomethyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide (Example Compound 12-4)

[0600] [ka]

[0601] Example compound 12-3 (69 mg), triphenylphosphine (64 mg), and water (0.5 mL) were stirred in tetrahydrofuran (5.0 mL) at 50° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and the resulting solid was suspended and washed in chloroform, then filtered and dried to obtain the title compound (60 mg) as a white solid. MS (ESI) m / z: 341.1 [M+H] +

[0602] (12-5) Methyl [(6S)-4-{4'-[({3-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 12)

[0603] [ka]

[0604] The title compound was obtained as a white solid by the same reaction and treatment as in (11-1) except that Example Compound 12-4 was used instead of Reference Example Compound 11 in Example 11. MS (ESI) m / z: 823.4 [M+H] +

[0605] Example 13 (13-1) 7-Bromo-6-methyl-1H-indole (Example Compound 13-1)

[0606] [ka]

[0607] The same reaction and treatment as in Reference Example 7 was carried out using 2-bromo-3-nitrotoluene (2160 mg) instead of 1-bromo-4-methyl-2-nitrobenzene to give the title compound (1108 mg) as a white solid. 1 H NMR(400MHz,CDCl3)δ ppm 2.52(3H,s),6.58(1H,dd,J=3.21,2.18Hz),7.00(1H,d,J=7.96Hz),7.19(1H,dd,J=3.08,2.44Hz),7.46(1H,d,J=7.96Hz),8.27(1H,brs)

[0608] (13-2) 7-Bromo-6-methyl-1H-indole-3-carbonitrile (Example Compound 13-2)

[0609] [ka]

[0610] In Reference Example 8, Example Compound 13-1 (500 mg) was used instead of Reference Example Compound 7, and the same reaction and treatment were carried out to give the title compound (461 mg) as a beige solid. 1 H NMR(400MHz,CDCl3)δ ppm 2.54(3H,s),7.19(1H,d,J=8.1Hz),7.61(1H,d,J=8.1Hz),7.72(1H,d,J=2.8Hz),8.72(1H,brs)

[0611] (13-3) 7-Amino-6-methyl-1H-indole-3-carbonitrile (Example compound 13-3)

[0612] [ka]

[0613] In Reference Example 9, Example Compound 13-2 (455 mg) was used instead of Reference Example Compound 8, and the same reaction and treatment were carried out to obtain the title compound (146 mg) as a white solid. MS (ESI) m / z: 172.1 [M+H] +

[0614] (13-4) Methyl [(6S)-4-{4'-[({4-[(3-cyano-6-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 13)

[0615] [ka]

[0616] In Example 7, Example Compound 13-3 (17 mg) was used instead of Example Compound 7-2, and Reference Example Compound 10 (60 mg) was used, and the reaction and treatment were carried out in the same manner as in (7-3), to obtain the title compound (34 mg) as a white powder. MS (ESI) m / z: 823.5 [M+H] +

[0617] Example 14 (14-1) Methyl [(6S)-4-{4'-[({4-[(4-chloro-3-cyano-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 14)

[0618] [ka]

[0619] The title compound was obtained as a white solid by the same reaction and treatment as in (13-1)-(13-4) using 1-bromo-4-chloro-2-nitrobenzene instead of 2-bromo-3-nitrotoluene in Example 13. MS (ESI) m / z: 843.4, 845.5 [M+H] +

[0620] Example 15 (15-1) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methoxy-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 15)

[0621] [ka]

[0622] The title compound was obtained as a purple solid by the same reaction and treatment as in (13-1)-(13-4) using 4-bromo-3-nitroanisole instead of 2-bromo-3-nitrotoluene in Example 13. MS (ESI) m / z: 839.5 [M+H] +

[0623] Example 16 (16-1) Methyl [(6S)-4-{4'-[({4-[(2,3-dimethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 16)

[0624] [ka]

[0625] In Example 7, 2,3-dimethyl-1H-indol-7-amine (17 mg) was used instead of Example Compound 7-2, and Reference Example Compound 10 (50 mg) was used, and the reaction and treatment were carried out in the same manner as in (7-3), to obtain the title compound (22 mg) as a brown solid. MS (ESI) m / z: 812.5 [M+H] +

[0626] Example 17 (17-1) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-fluoro-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 17)

[0627] [ka]

[0628] The title compound was obtained as a beige powder by the same reaction and treatment as in Example 13 (13-1)-(13-4), except that 1-bromo-4-fluoro-2-nitrobenzene was used instead of 2-bromo-3-nitrotoluene. MS (ESI) m / z: 827.5 [M+H] +

[0629] Example 18 (18-1) Methyl [(6S)-4-(4'-{[(4-{[3-cyano-4-(trifluoromethyl)-1H-indol-7-yl]sulfamoyl}phenyl)methyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 18)

[0630] [ka]

[0631] The title compound was obtained as a white powder by the same reaction and treatment as in (13-1)-(13-4) using 1-bromo-2-nitro-4-trifluoromethylbenzene instead of 2-bromo-3-nitrotoluene in Example 13. MS (ESI) m / z: 877.5 [M+H] +

[0632] Example 19 (19-1) Methyl [(6S)-4-{4'-[({4-[(3-cyano-5-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 19)

[0633] [ka]

[0634] The title compound was obtained as a white powder by the same reaction and treatment as in (13-1)-(13-4) using 3-bromo-4-nitrotoluene instead of 2-bromo-3-nitrotoluene in Example 13. MS (ESI) m / z: 823.5 [M+H] +

[0635] Example 20 (20-1) Methyl 5-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]pyridine-2-carboxylate (Example Compound 20-1)

[0636] [ka]

[0637] Reference Example Compound 9 (300 mg), methyl 5-(chlorosulfonyl)pyridine-2-carboxylate (454 mg), and pyridine (0.71 mL) were stirred in tetrahydrofuran (5.0 mL) at room temperature for 4 hours. Ethyl acetate and 1N hydrochloric acid were added to the reaction solution and stirred, and the resulting solid was filtered off. Saturated aqueous sodium bicarbonate and tetrahydrofuran were added to the solid and stirred, followed by addition of chloroform. The aqueous layer was removed using a phase separator, and the organic layer was concentrated under reduced pressure. The residue was suspended and washed in diethyl ether, and then collected by filtration to obtain the title compound (210 mg) as a yellow solid. MS (ESI) m / z: 371.1 [M+H] +

[0638] (20-2) 6-(azidomethyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)pyridine-3-sulfonamide (Example Compound 20-2)

[0639] [ka]

[0640] Under a nitrogen stream, a 2M lithium borohydride / tetrahydrofuran solution (1.14 mL) was added to a suspension of Example Compound 20-1 (210 mg) in tetrahydrofuran (5.0 mL) and stirred at room temperature for 5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and stirred, followed by the addition of chloroform and stirring. The aqueous layer was removed using a phase separator, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) to obtain a white solid (75 mg). This solid, 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (125 mg), and 1,8-diazabicyclo[5.4.0]-7-undecene (0.066 mL) were added to tetrahydrofuran (5.0 mL) and stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride and chloroform were added to the reaction mixture and stirred. The aqueous layer was removed using a phase separator, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30 to 30:70) to give the title compound (63 mg) as a white solid. MS(ESI) m / z: 368.2 [M+H] +

[0641] (20-3) 6-(aminomethyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)pyridine-3-sulfonamide (Example Compound 20-3)

[0642] [ka]

[0643] In Example 12, Example Compound 20-2 (63 mg) was used instead of Example Compound 12-3, and the same reaction and treatment as in (12-4) was carried out to obtain the title compound (24 mg) as a white solid. MS (ESI) m / z: 342.1 [M+H] +

[0644] (20-4) Methyl [(6S)-4-{4'-[({5-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]pyridin-2-yl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 20)

[0645] [ka]

[0646] In Example 11, Example Compound 20-3 was used instead of Reference Example Compound 11, and the reaction and treatment were carried out in the same manner as in (11-1) to obtain the title compound as a pale yellow solid. MS (ESI) m / z: 824.3 [M+H] +

[0647] Example 21 (21-1) t-Butyl 4-{4-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate (Example Compound 21-1)

[0648] [ka]

[0649] Under an argon atmosphere, Reference Example Compound 1 (500 mg), N-(t-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (447 mg), palladium acetate (7 mg), S-phos (99 mg), potassium fluoride (210 mg), and water (0.078 mL) were heated under reflux in tetrahydrofuran (5.0 mL) for 7 hours. The reaction mixture was filtered through diatomaceous earth using ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate = 70:30 to 20:80) to obtain the title compound (680 mg) as a pale yellow solid. MS (ESI) m / z: 562.5 [M+H] +

[0650] (21-2) Methyl {(6S)-2,3,9-trimethyl-4-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate hydrochloride (Example Compound 21-2)

[0651] [ka]

[0652] To a solution of Example Compound 21-1 (217 mg) in methanol (0.5 mL), 4 M hydrogen chloride / 1,4-dioxane solution (2.0 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was suspended and washed with diisopropyl ether, filtered, and dried to obtain the title compound (198 mg) as a yellow solid. MS (ESI) m / z: 462.2 [M+H] +

[0653] (21-3) Methyl [(6S)-4-(4-{1-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 21)

[0654] [ka]

[0655] To a solution of triphosgene (22 mg) in tetrahydrofuran (3.0 mL), Reference Example Compound 5 (68 mg) and N,N-diisopropylethylamine (0.11 mL) were added and stirred at room temperature for 15 minutes. Subsequently, Example Compound 21-2 (100 mg) and N,N-dimethylformamide (0.5 mL) were added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by stirring. The mixture was extracted three times with ethyl acetate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5), suspended and washed with diethyl ether, filtered, and dried to give the title compound (60 mg) as a milky white powder. MS (ESI) m / z: 828.4 [M+H] +

[0656] Example 22 (22-1) 7-Bromo-1H-indole-4-carbonitrile (Example Compound 22-1)

[0657] [ka]

[0658] The same reaction and treatment as in Reference Example 7 was carried out using 4-bromo-3-benzonitrile (2270 mg) instead of 1-bromo-4-methyl-2-nitrobenzene to give the title compound (540 mg) as a pale yellow solid. 1H NMR(400MHz,CDCl3)δ ppm 6.86(1H,dd,J=3.21,2.18Hz),7.36(1H,d,J=8.35Hz),7.41(1H,d,J=7.83Hz),7.46(1H,t,J=3.21Hz),8.65(1H,brs)

[0659] (22-2) 7-Amino-1H-indole-4-carbonitrile (Example Compound 22-2)

[0660] [ka]

[0661] In Reference Example 9, Example Compound 22-1 (100 mg) was used instead of Reference Example Compound 8, and the same reaction and treatment were carried out to give the title compound (53 mg) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 6.06(2H,s),6.34-6.41(2H,m),7.22(1H,d,J=7.96Hz),7.49(1H,t,J=2.83Hz),11.15(1H,brs)

[0662] (22-3) Methyl [(6S)-4-{4'-[({4-[(4-cyano-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 22)

[0663] [ka]

[0664] In Example 7, Example Compound 22-2 (29 mg) was used instead of Example Compound 7-2, and Reference Example Compound 10 (80 mg) was used, and the reaction and treatment were carried out in the same manner as in (7-3), to obtain the title compound (26 mg) as a white powder. MS (ESI) m / z: 809.4 [M+H] +

[0665] Example 23 (23-1) 7-Bromo-1H-indole-3,4-dicarbonitrile (Example Compound 23-1)

[0666] [ka]

[0667] In Reference Example 8, Example Compound 22-1 (100 mg) was used instead of Reference Example Compound 7, and the same reaction and treatment were carried out to obtain the title compound (48 mg) as a pale yellow solid. MS (ESI) m / z: 246.0, 248.0 [M+H] +

[0668] (23-2) 7-Amino-1H-indole-3,4-dicarbonitrile (Example Compound 23-2)

[0669] [ka]

[0670] In Reference Example 9, Example Compound 23-1 (45 mg) was used instead of Reference Example Compound 8, and the same reaction and treatment were carried out to obtain the title compound (10 mg) as a pale yellow solid. MS (ESI) m / z: 183.1 [M+H] +

[0671] (23-3) Methyl [(6S)-4-{4'-[({4-[(3,4-dicyano-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 23)

[0672] [ka]

[0673] In Example 7, Example Compound 23-2 (9.4 mg) was used instead of Example Compound 7-2, and Reference Example Compound 10 (72 mg) was used, and the reaction and treatment were carried out in the same manner as in (7-3), to obtain the title compound (15 mg) as a pale yellow powder. MS (ESI) m / z: 834.5 [M+H] +

[0674] Example 24 (24-1) N-(3-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}propyl)-2,2,2-trifluoroacetamide (Example Compound 24-1)

[0675] [ka]

[0676] The title compound was obtained as a brown powder by the same reaction and treatment as in Example 20-1, except that 4-[3-(trifluoroacetamido)propyl]benzenesulfonyl chloride was used instead of methyl 5-(chlorosulfonyl)pyridine-2-carboxylate. MS (ESI) m / z: 465.2 [M+H] +

[0677] (24-2) 4-(3-aminopropyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide (Example Compound 24-2)

[0678] [ka]

[0679] Example compound 24-1 (610 mg), potassium carbonate (545 mg), and water (0.8 mL) were stirred in methanol (8.0 mL) at room temperature for 2 hours. Methanol was evaporated under reduced pressure, and water was added and the mixture was stirred. 1N hydrochloric acid (5 mL) was added and the mixture was stirred, and the resulting solid was filtered off. The resulting solid was suspended and washed with water and dried to obtain a gray solid. Potassium carbonate (273 mg), water (0.5 mL), and methanol (5.0 mL) were added to the solid, and the mixture was heated to reflux for 6 hours. Methanol was evaporated under reduced pressure, and water was added and the mixture was stirred. 1N hydrochloric acid was added and the resulting solid was filtered off. The resulting solid was suspended and washed with water, filtered, and dried to obtain the title compound (453 mg) as a gray solid. MS (ESI) m / z: 369.2 [M+H] +

[0680] (24-3) Methyl [(6S)-4-{4'-[(3-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}propyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 24)

[0681] [ka]

[0682] The title compound was obtained as a beige solid by the same reaction and treatment as in (11-1) except that Example Compound 24-2 was used instead of Reference Example Compound 11 in Example 11. MS (ESI) m / z: 851.7 [M+H] +

[0683] Example 25 (25-1) Methyl {(6S)-4-[4'-({[4-(chlorosulfonyl)-3-fluorophenyl]methyl}carbamoyl)[1,1'-biphenyl]-4-yl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate (Example Compound 25-1)

[0684] [ka]

[0685] In Reference Example 10, 4-bromo-3-fluorophenylmethanamine hydrochloride was used instead of 4-bromobenzylamine, and the reaction and treatment were carried out in the same manner as in (10-1)-(10-3), to obtain the title compound as a pale yellow powder. MS (ESI) m / z: 688.4 [M-Cl + HO] +

[0686] (25-2) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]-3-fluorophenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 25)

[0687] [ka]

[0688] In Example 7, Reference Example Compound 9 (26 mg) was used instead of Example Compound 7-2, and Example Compound 25-1 (97 mg) was used instead of Example Compound 10, and the reaction and treatment were carried out in the same manner as in (7-3), to obtain the title compound (69 mg) as a beige powder. MS (ESI) m / z: 841.5 [M+H] +

[0689] Example 26 (26-1) Methyl [(6S)-4-(4'-{[(1R)-1-(4-bromophenyl)ethyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 26-1)

[0690] [ka]

[0691] A mixture of Reference Example Compound 4 (100 mg), (1R)-1-(4-bromophenyl)ethanamine (48 mg), N,N-diisopropylethylamine (0.10 mL), HATU (91 mg) and N,N-dimethylformamide (2.0 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed three times with saturated brine-water (1:1) and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 90:10) to give the title compound (156 mg) as a crude pale yellow powder. MS (ESI) m / z: 682.4, 684.4 [M+H] +

[0692] (26-2) Methyl {(6S)-4-[4'-({(1R)-1-[4-(benzylsulfanyl)phenyl]ethyl}carbamoyl)[1,1'-biphenyl]-4-yl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate (Example Compound 26-2)

[0693] [ka]

[0694] A mixture of Example Compound 26-1 (133 mg), benzyl mercaptan (0.028 mL), N,N-diisopropylethylamine (0.10 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 23 mg), tris(dibenzylideneacetone)dipalladium (18 mg), toluene (2.0 mL), and tetrahydrofuran (0.70 mL) was stirred at 150 °C for 0.5 hours under nitrogen atmosphere and microwave irradiation. After cooling to room temperature, the reaction mixture was directly purified by NH silica gel column chromatography (hexane:ethyl acetate = 50:50 to 0:100) to obtain the title compound (126 mg) as a pale yellow powder. MS (ESI) m / z: 726.5 [M+H] +

[0695] (26-3) Methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 26)

[0696] [ka]

[0697] To a solution of Example Compound 26-2 (124 mg) in acetonitrile (2.5 mL) and 2N hydrochloric acid (0.50 mL), N-chlorosuccinimide (80 mg) was added under ice-cooling, and the mixture was stirred at the same temperature for 2 hours. Saturated saline-water (1:1) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Pyridine (0.14 mL) was added to a solution of the resulting residue and Reference Example Compound 9 (33 mg) in tetrahydrofuran (5.0 mL) at room temperature, and the mixture was stirred at the same temperature for 16 hours. Saturated saline-water (1:1) was added to the reaction solution, and the mixture was extracted once with chloroform-methanol and twice with chloroform. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (chloroform:methanol = 90:10 to 50:50), and then again by silica gel column chromatography (chloroform:methanol = 98:2 to 90:10) to obtain a crude product of the title compound. The entire crude product was purified by preparative HPLC (10 mM aqueous ammonium carbonate-acetonitrile) to obtain the title compound (16 mg) as a white powder. MS (ESI) m / z: 837.5 [M+H] +

[0698] Example 27 (27-1) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]-2-fluorophenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 27)

[0699] [ka]

[0700] The title compound was obtained as a beige powder by the same reaction and treatment as in (25-1)-(25-2) except that 4-bromo-2-fluorophenylmethanamine hydrochloride was used instead of 4-bromo-3-fluorophenylmethanamine hydrochloride in Example 25. MS (ESI) m / z: 841.5 [M+H] +

[0701] Example 28 (28-1) Methyl [(6S)-4-{4'-[(1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}-2-hydroxyethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 28)

[0702] [ka]

[0703] The title compound was obtained as a white powder by the same reaction and treatment as in (25-1)-(25-2) using 2-amino-2-(4-bromophenyl)ethanol instead of 4-bromo-3-fluorophenylmethanamine hydrochloride in Example 25. MS (ESI) m / z: 853.5 [M+H] +

[0704] Example 29 (29-1) 3,4-dimethyl-1H-indol-7-amine (Example Compound 29-1)

[0705] [ka]

[0706] Under a nitrogen stream, 7-bromo-3,4-dimethyl-1H-indole (443 mg), benzophenone imine (501 mg), 1.3 M lithium bis(trimethylsilyl)amide / tetrahydrofuran solution (5.3 mL), and [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II) (Pd-PEPPSI-IPent catalyst, 47 mg) were heated to reflux in tetrahydrofuran (3.0 mL) for 7 hours. Saturated aqueous ammonium chloride and chloroform were added to the reaction mixture and stirred. The aqueous layer was removed using a phase separator, and the organic layer was concentrated under reduced pressure. The residue, hydroxylamine hydrochloride (344 mg), and sodium acetate (487 mg) were stirred in a methanol (3.0 mL)-tetrahydrofuran (3.0 mL) mixed solvent at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and saturated sodium bicarbonate water and chloroform were added and stirred. The aqueous layer was removed using a phase separator, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) to obtain the title compound (279 mg) as a gray solid. MS (ESI) m / z: 161.2 [M+H] +

[0707] (29-2) Methyl [(6S)-4-{4'-[({4-[(3,4-dimethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 29)

[0708] [ka]

[0709] Example compound 29-1 (19 mg), Reference Example compound 10 (70 mg), and pyridine (0.041 mL) were stirred in tetrahydrofuran (3.0 mL) at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) and silica gel column chromatography (ethyl acetate:methanol = 100:0 to 95:5) to obtain the title compound (57 mg) as a pale yellow solid. MS (ESI) m / z: 812.7 [M+H] +

[0710] Example 30 (30-1) Methyl {(6S)-4-[4'-(4-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}piperidine-1-carbonyl)[1,1'-biphenyl]-4-yl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate (Example Compound 30)

[0711] [ka]

[0712] In Example 25, 4-(4-bromophenyl)piperidine hydrochloride was used instead of 4-bromo-3-fluorophenylmethanamine hydrochloride, and the reaction and treatment were carried out in the same manner as in (25-1)-(25-2), to obtain the title compound as a white powder. MS (ESI) m / z: 877.6 [M+H] +

[0713] Example 31 (31-1) t-Butyl (3-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}prop-2-yn-1-yl)carbamate (Example Compound 31-1)

[0714] [ka]

[0715] A mixture of Reference Example compound 14 (300 mg), N-(t-butoxycarbonyl)propargylamine (239 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 37 mg), X-Phos aminobiphenyl palladium chloride precatalyst (61 mg), potassium phosphate (490 mg), and tetrahydrofuran (4.0 mL) was stirred at 120°C for 1 hour under nitrogen atmosphere and microwave irradiation. Saturated saline-water (1:1) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 95:5) and then purified again by NH silica gel column chromatography (chloroform:methanol = 95:5 to 50:50) to give the title compound (209 mg) as a pale yellow powder. MS(ESI) m / z: 465.3 [M+H] +

[0716] (31-2) 4-(3-aminoprop-1-yn-1-yl)-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide hydrochloride (Example compound 31-2)

[0717] [ka]

[0718] To Example Compound 31-1 (205 mg) was added 4M hydrogen chloride / 1,4-dioxane solution (6.0 mL) at room temperature. After stirring at the same temperature for 1.5 hours, the reaction mixture was concentrated under reduced pressure. The residue was suspended and washed with diethyl ether and collected by filtration to obtain the title compound (150 mg) as a brown solid. MS (ESI) m / z: 365.2 [M+H] +

[0719] (31-3) Methyl [(6S)-4-{4'-[(3-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}prop-2-yn-1-yl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 31)

[0720] [ka]

[0721] To a solution of Example Compound 31-2 (65 mg) and Reference Example Compound 4 (80 mg) in N,N-dimethylformamide (1.6 mL) was added N,N-diisopropylethylamine (0.083 mL) and HATU (73 mg) at room temperature, followed by stirring at the same temperature for 1 hour. The reaction mixture was diluted with methanol and added to ethyl acetate and saturated brine-water (1:1). After removing a small amount of insoluble material by filtration, the filtrate was separated. The organic layer was washed twice with saturated brine-water (1:1) and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (chloroform:methanol = 95:5 to 50:50, precolumn: silica gel) to give the title compound (103 mg) as a white powder. MS (ESI) m / z: 847.5 [M+H] +

[0722] Example 31 (32-1) Methyl 4'-[(6S)-2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl][1,1'-biphenyl]-4-carboxylate (Example Compound 32-1)

[0723] [ka]

[0724] Reference Example Compound 2 (150 mg), 4-(methoxycarbonyl)phenylboronic acid (81 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenylaminobiphenyl palladium chloride precatalyst (15 mg), sodium carbonate (79 mg), 1,4-dioxane (3.0 mL), and water (1.0 mL) were mixed and stirred at 100°C for 20 minutes under microwave irradiation. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate = 80:20 to 0:100) to give the title compound (161 mg) as a white powder. MS (ESI) m / z: 457.3 [M+H] +

[0725] (32-2) N-({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)-4'-[(6S)-2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl][1,1'-biphenyl]-4-carboxamide (Example Compound 32)

[0726] [ka]

[0727] To a solution of Example Compound 32-1 (73 mg) in methanol (3.0 mL), 1N aqueous sodium hydroxide solution (0.32 mL) was added and stirred at room temperature for 9 hours. 1N hydrochloric acid was added to the reaction solution, which was then stirred and concentrated under reduced pressure. The resulting solid, Reference Example Compound 5 (60 mg), N,N-diisopropylethylamine (0.082 mL), and HATU (72 mg) were stirred in N,N-dimethylformamide (3.0 mL) at room temperature for 1 hour. Water was added to the reaction solution, which was then stirred, and the resulting solid was filtered off. The title compound (100 mg) was obtained as a white solid by purification using silica gel column chromatography (chloroform:methanol = 100:0 to 95:5). MS (ESI) m / z: 765.6 [M+H]+

[0728] Example 33 (33-1) Methyl 7-bromo-1H-indole-4-carboxylate (Example compound 33-1)

[0729] [ka]

[0730] To a tetrahydrofuran solution (30.0 mL) of methyl 4-bromo-3-nitrobenzoate (2600 mg), a 1 M vinylmagnesium bromide / tetrahydrofuran solution (25.0 mL) was added over 5 minutes at -78°C. After stirring at the same temperature for 1 hour, saturated aqueous ammonium chloride and water were added to the reaction mixture, and the mixture was warmed to room temperature. After separation, the aqueous layer was extracted once with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10) to give the title compound (1223 mg) as a white solid. MS (ESI) m / z: 254.1, 256.0 [M+H] +

[0731] (33-2) Methyl 7-bromo-3-cyano-1H-indole-4-carboxylate (Example compound 33-2)

[0732] [ka]

[0733] To a solution of Example Compound 33-1 (1,000 mg) in N,N-dimethylformamide (4.0 mL) was added phenylphosphonyl dichloride (1.0 mL) at room temperature. After stirring at 100°C for 20 minutes, N,N-dimethylformamide (4.0 mL) was added and the mixture was stirred at 100°C for an additional 40 minutes. Hydroxylamine hydrochloride (547 mg) was added, and the mixture was heated and stirred at 100°C for 2 hours and at 140°C for 0.5 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed three times with saturated aqueous sodium bicarbonate and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 95:5) to give the title compound (703 mg) as a crude brown solid. MS (ESI) m / z: 279.2, 281.2 [M+H] +

[0734] (33-3) 7-Bromo-4-(hydroxymethyl)-1H-indole-3-carbonitrile (Example compound 33-3)

[0735] [ka]

[0736] To a suspension of Example Compound 33-2 (391 mg) in tetrahydrofuran (16.0 mL), 2.5 M lithium aluminum hydride / tetrahydrofuran solution (1.70 mL) was added dropwise under ice cooling. After stirring at the same temperature for 10 minutes, 1 N hydrochloric acid was added and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was then distilled off under reduced pressure. The resulting residue was suspended in chloroform, washed, and collected by filtration to give the title compound (221 mg) as a gray solid. MS (ESI) m / z: 233.0, 235.0 [M-OH] + ; 1H NMR(400MHz,DMSO-d6)δ ppm 4.94(2H,d,J=5.27Hz),5.33(1H,t,J=5.33Hz),7.10-7.27(1H,m),7.48(1H,d,J=7.83Hz),8.31(1H,s),12.44(1H,brs)

[0737] (33-4) 7-[(diphenylmethylidene)amino]-4-(hydroxymethyl)-1H-indole-3-carbonitrile (Example compound 33-4)

[0738] [ka]

[0739] To a mixture of Example compound 33-3 (267 mg), benzophenone imine (270 mg), [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II) (Pd-PEPPSI-IPent catalyst, 26 mg), and tetrahydrofuran (7.0 mL), 1.3 M lithium bis(trimethylsilyl)amide / tetrahydrofuran solution (2.9 mL) was added at room temperature, and the mixture was stirred at 140 ° C. under microwave irradiation in a nitrogen atmosphere for 0.5 hours. Pd-PEPPSI-IPent catalyst (85 mg) and 1.3 M lithium bis(trimethylsilyl)amide / tetrahydrofuran solution (2.9 mL) were added, and the mixture was stirred at 160 ° C. under microwave irradiation in a nitrogen atmosphere for 0.5 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2) and then purified again by NH silica gel column chromatography (chloroform:methanol=98:2) to give the title compound (59 mg) as a pale yellow solid. MS (ESI) m / z: 352.2 [M+H] +

[0740] (33-5) 7-Amino-4-(hydroxymethyl)-1H-indole-3-carbonitrile (Example compound 33-5)

[0741] [ka]

[0742] Example compound 33-4 (57 mg) was dissolved in tetrahydrofuran (1.0 mL)-methanol (1.0 mL), and hydroxylamine hydrochloride (28 mg) and sodium acetate (40 mg) were added at room temperature. The mixture was stirred at the same temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (chloroform:methanol = 98:2 to 80:20) to obtain the title compound (14 mg) as a pale brown solid. MS (ESI) m / z: 170.1 [M-OH] + , 1 H NMR(400MHz,DMSO-d6)δ ppm 4.74-4.83(3H,m),5.22(2H,s),6.42(1H,d,J=7.7Hz),6.91(1H,d,J=7.7Hz),8.12(1H,s),11.75(1H,brs)

[0743] (33-6) Methyl [(6S)-4-(4'-{[(4-{[3-cyano-4-(hydroxymethyl)-1H-indol-7-yl]sulfamoyl}phenyl)methyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 33)

[0744] [ka]

[0745] To a solution of Example Compound 33-5 (13 mg) and Reference Example Compound 10 (73 mg) in tetrahydrofuran (1.0 mL), pyridine (0.17 mL) was added at room temperature and stirred at the same temperature for 14 hours. The reaction solution was diluted with ethyl acetate-methanol, washed once with saturated brine-water (1:1) and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified twice by silica gel column chromatography (chloroform:methanol = 98:2 to 90:10) to give the title compound (29 mg) as a beige powder. MS (ESI) m / z: 839.5 [M+H] +

[0746] Example 34 (34-1) [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetic acid (Example Compound 34)

[0747] [ka]

[0748] To a solution of Example Compound 1 (295 mg) in tetrahydrofuran (2.0 mL) and methanol (2.0 mL), 2N aqueous lithium hydroxide solution (0.72 mL) was added and stirred at room temperature for 2 hours. 1N hydrochloric acid was added, and the mixture was stirred and concentrated under reduced pressure. The residue was suspended and washed with water, filtered, and dried to obtain the title compound (258 mg) as a yellow powder. MS (ESI) m / z: 809.4 [M+H] +

[0749] Example 35 (35-1) t-Butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboronane-2-yl)-1-benzofuran-2-carboxylate (Example Compound 35-1)

[0750] [ka]

[0751] A mixture of t-butyl 5-bromo-1-benzofuran-2-carboxylate (1.50 g), bis(pinacolato)diboron (1.41 g), 1,1'-(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (206 mg), and potassium acetate (991 mg) was added to 1,4-dioxane (17 mL) and purged with nitrogen. The mixture was heated and stirred at 130°C for 30 minutes under microwave irradiation. Water, ethyl acetate, and activated carbon were added to the reaction mixture. Insoluble material was removed by filtration through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was separated, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0 to 90:10) to give the title compound (1.38 g) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δppm 1.37(12H,s),1.63(9H,s),7.40(1H,d,J=1.0Hz),7.56(1H,d,J=8.7Hz),7.87(1H,dd,J=1.3,8.5Hz),8.15(1H,s)

[0752] (35-2) t-Butyl 5-{4-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl]phenyl}-1-benzofuran-2-carboxylate (Example Compound 35-2)

[0753] [ka]

[0754] A mixture of Reference Example Compound 1 (80 mg), Example Compound 35-1 (73 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 9 mg), X-Phos aminobiphenyl palladium chloride precatalyst (15 mg), potassium phosphate (123 mg), water (0.013 mL), and tetrahydrofuran (1.0 mL) was stirred at 90°C for 0.5 hours under nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate = 50:50 to 0:100) to give the title compound (115 mg) as a white powder. MS (ESI) m / z: 597.5 [M+H] +

[0755] (35-3) Methyl [(6S)-4-(4-{2-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-1-benzofuran-5-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 35)

[0756] [ka]

[0757] Trifluoroacetic acid (1.0 mL) was added to a solution of Example Compound 35-2 (111 mg) in dichloromethane (1.0 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated, and toluene was added to the mixture to remove the solvent. The resulting residue was dissolved in N,N-dimethylformamide (2.0 mL). Reference Example Compound 5 (64 mg), N,N-diisopropylethylamine (0.32 mL), and HATU (85 mg) were added at room temperature and stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate and then added to saturated aqueous sodium bicarbonate solution. The resulting precipitate (A) was collected by filtration. The filtrate was separated, and the aqueous layer was extracted once with ethyl acetate. The combined organic layer (B) was washed twice with saturated brine-water (1:1) and once with saturated brine. The residue (A) was dissolved in chloroform and combined with the organic layer (B). The mixture was dried over anhydrous sodium sulfate and filtered, and the solvent was removed by filtration under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 95:5) to give the title compound (104 mg) as a white powder. MS (ESI) m / z: 863.5 [M+H] +

[0758] Example 36 (36-1) Methyl [4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]carbamate (Example Compound 36-1)

[0759] [ka]

[0760] To a solution of 6-amino-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (200 mg) described in Japanese Patent Publication No. 7-17941, Raw Material Preparation Example 1, in dichloromethane (6.0 mL), methyl chloroformate (0.048 mL) and N,N-diisopropylethylamine (0.15 mL) were added under ice cooling and stirred at the same temperature for 0.5 hours. Water was added to the reaction solution, which was then extracted twice with chloroform, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 97:3) to give the title compound (233 mg) as a pale orange powder. MS (ESI) m / z: 416.3 [M+H] +

[0761] (36-2) t-Butyl 4'-{6-[(methoxycarbonyl)amino]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl}[1,1'-biphenyl]-4-carboxylate (Example Compound 36-2)

[0762] [ka]

[0763] A mixture of Example Compound 36-1 (30 mg), t-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (25 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 4 mg), X-Phos aminobiphenyl palladium chloride precatalyst (6 mg), potassium phosphate (46 mg), water (0.005 mL), and tetrahydrofuran (0.36 mL) was stirred at 90 °C for 0.5 hours under nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate = 50:50 to 0:100) to obtain the title compound (39 mg) as a white powder. MS(ESI)m / z:558.4[M+H] +

[0764] (36-3) Methyl (4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)carbamate (Example Compound 36)

[0765] [ka]

[0766] To a solution of Example Compound 36-2 (37 mg) in dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and toluene was added to distill off the solvent. The resulting residue was dissolved in N,N-dimethylformamide (0.67 mL). Reference Example Compound 5 (25 mg), N,N-diisopropylethylamine (0.12 mL), and HATU (31 mg) were added at room temperature, and the mixture was stirred at the same temperature for 15 hours. The reaction mixture was diluted with ethyl acetate and washed once with saturated sodium bicarbonate water, twice with saturated brine-water (1:1), and once with saturated brine. After drying over anhydrous sodium sulfate and filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 95:5) to give the title compound (43 mg) as a white powder. MS (ESI) m / z: 824.5 [M+H] +

[0767] Example 37 (37-1) N-({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)-4'-[(6S)-6-{2-[(2-hydroxyethyl)amino]-2-oxoethyl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl][1,1'-biphenyl]-4-carboxamide (Example Compound 37)

[0768] [ka]

[0769] Example compound 34 (100 mg), 2-aminoethanol (12 mg), N,N-diisopropylethylamine (0.064 mL), and HATU (56 mg) were stirred in N,N-dimethylformamide (3.0 mL) at room temperature for 2 hours. Water was added to the reaction mixture, which was then stirred and extracted twice with ethyl acetate. The combined organic layer was washed twice with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 80:20) to give the title compound (97 mg) as a white solid. MS (ESI) m / z: 852.5 [M+H] +

[0770] Example 38 (38-1) N-({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)-4'-{(6S)-6-[2-(dimethylamino)-2-oxoethyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl}[1,1'-biphenyl]-4-carboxamide (Example Compound 38)

[0771] [ka]

[0772] The title compound was obtained as a milky white solid by the same reaction and treatment as in Example 37-1, except that dimethylamine hydrochloride was used instead of 2-aminoethanol. MS (ESI) m / z: 836.5 [M+H] +

[0773] Example 39 (39-1) Methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenoxy}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 39)

[0774] [ka]

[0775] The title compound was obtained as a beige powder by the same reaction and treatment as in (25-1)-(25-2) using 2-(4-bromophenoxy)ethanamine instead of 4-bromo-3-fluorophenylmethanamine hydrochloride in Example 25. MS (ESI) m / z: 853.5 [M+H] +

[0776] Example 40 (40-1) Methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]-3'-fluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 40)

[0777] [ka]

[0778] To a solution of Reference Example Compound 12 (63 mg) and Reference Example Compound 11 (53 mg) in N,N-dimethylformamide (1.3 mL) were added N,N-diisopropylethylamine (0.063 mL) and HATU (56 mg) at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. Water was added to the reaction solution, and the precipitate was collected by filtration and washed with water. The residue was dissolved in chloroform, dried over anhydrous sodium sulfate, and filtered. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 95:5) to give the title compound (61 mg) as a pale yellow powder. MS (ESI) m / z: 855.5 [M+H] +

[0779] Example 41 (41-1) Methyl [(6S)-4-{3'-chloro-4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 41)

[0780] [ka]

[0781] In Example 40, Reference Example Compound 13 (80 mg) was used instead of Reference Example Compound 12, and the same reaction and treatment were carried out to obtain the title compound (115 mg) as a white powder. MS (ESI) m / z: 871.5 [M+H] +

[0782] Example 42 (42-1) Methyl [(6S)-4-{4'-[({4-[(4-bromo-3-cyano-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 42)

[0783] [ka]

[0784] In Example 7, Reference Example Compound 15 (24 mg) was used instead of Example Compound 7-2, and the reaction and treatment were carried out in the same manner as in (7-3) to obtain the title compound (56 mg) as a pale yellow solid. MS (ESI) m / z: 887.3, 889.3 [M+H] +

[0785] Example 43 (43-1) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 43)

[0786] [ka]

[0787] A mixture of Reference Example Compound 16 (14 mg), pyridine (0.059 mL), tetrahydrofuran (2.0 mL), and Reference Example Compound 10 (50 mg) was stirred at room temperature for 24 hours. The reaction mixture was diluted and dissolved with a mixture of tetrahydrofuran and ethyl acetate (1:1) and a small amount of methanol. The organic layer was washed once with a mixture of saturated saline and 1N aqueous hydrochloric acid, once with saturated saline, and The residue was purified by preparative HPLC (10 mM aqueous ammonium carbonate solution - acetonitrile) to give the title compound (42 mg) as a pale yellow solid. MS (ESI) m / z: 837.5 [M+H] +

[0788] Example 44 (44-1) 7-Amino-4-cyclopropyl-1H-indole-3-carbonitrile (Example compound 44-1)

[0789] [ka]

[0790] To a solution of Reference Example Compound 15 (90 mg) and mesyl[(tri-t-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) in tetrahydrofuran (1.9 mL), 0.5 M cyclopropylzinc bromide / tetrahydrofuran solution (4.6 mL) was added under a nitrogen atmosphere and ice-cooled, and the mixture was stirred at room temperature for 50 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After stirring, ethyl acetate and water were added and the mixture was separated. The organic layer was washed once with saturated aqueous sodium bicarbonate and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 50:50 to 20:80) and then by preparative HPLC (10 mM aqueous ammonium carbonate-acetonitrile) to give the title compound (26 mg) as a white solid. MS (ESI) m / z: 198.1 [M+H] +

[0791] (44-2) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-cyclopropyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 44)

[0792] [ka]

[0793] In Example 7, Example compound 44-1 (18 mg) was used instead of Example compound 7-2, and the reaction and treatment were carried out in the same manner as in (7-3) to obtain the title compound (47 mg) as a pale yellow solid. MS (ESI) m / z: 849.5 [M+H] +

[0794] Example 45 (45-1) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2'-fluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 45)

[0795] [ka]

[0796] Trifluoroacetic acid (1.0 mL) was added to a solution of Reference Example Compound 18-1 (85 mg) in dichloromethane (1.0 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and toluene was added to distill off the solvent. The resulting residue was dissolved in N,N-dimethylformamide (1.5 mL), and Reference Example Compound 5 (56 mg), N,N-diisopropylethylamine (0.26 mL), and HATU (68 mg) were added at room temperature and stirred for 16 hours at the same temperature. Water was added to the reaction mixture, and the precipitate was collected by filtration and washed with water. The residue was dissolved in chloroform, dried over anhydrous sodium sulfate, and filtered. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 95:5) to give the title compound (87 mg) as a white powder. MS (ESI) m / z: 841.5 [M+H] +

[0797] Example 46 (46-1) Methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]-2'-fluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 46)

[0798] [ka]

[0799] Trifluoroacetic acid (1.0 mL) was added to a solution of Reference Example Compound 18-1 (85 mg) in dichloromethane (1.0 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and toluene was added to distill off the solvent. The resulting residue was dissolved in N,N-dimethylformamide (1.5 mL), and Reference Example Compound 11 (64 mg), N,N-diisopropylethylamine (0.26 mL), and HATU (68 mg) were added at room temperature and stirred for 16 hours at the same temperature. Water was added to the reaction mixture, and the precipitate was collected by filtration and washed with water. The residue was dissolved in chloroform, dried over anhydrous sodium sulfate, and filtered. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 95:5) to give the title compound (65 mg) as a white powder. MS (ESI) m / z: 855.5 [M+H] +

[0800] Example 47 (47-1) t-Butyl 2-chloro-4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl][1,1'-biphenyl]-4-carboxylate (Example Compound 47-1)

[0801] [ka]

[0802] The title compound (374 mg) was obtained as a crude white powder by the same reaction and treatment as in Reference Example 18, except that Reference Example Compound 3 (300 mg) and 4-bromo-3-chlorobenzoic acid t-butyl (207 mg) were used instead of 4-bromo-3-fluorobenzoic acid t-butyl. MS (ESI) m / z: 591.4, 593.4 [M+H] +

[0803] (47-2) Methyl [(6S)-4-{2'-chloro-4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 47)

[0804] [ka]

[0805] In Example 45, Example Compound 47-1 (180 mg) was used instead of Reference Example Compound 18-1, and the same reaction and treatment were carried out to obtain the title compound (221 mg) as a beige powder. MS (ESI) m / z: 857.5, 859.5 [M+H] +

[0806] Example 48 (48-1) Methyl [(6S)-4-{2'-chloro-4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 48)

[0807] [ka]

[0808] In Example 46, Example Compound 47-1 (180 mg) was used instead of Reference Example Compound 18-1, and the same reaction and treatment were carried out to obtain the title compound (189 mg) as a beige powder. MS (ESI) m / z: 871.5, 873.5 [M+H] +

[0809] Example 49 (49-1) Methyl [(6S)-4-(4-{2-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-1,3-benzoxazol-5-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 49)

[0810] [ka]

[0811] Reference Example Compound 3 (200 mg), methyl 5-bromobenzoxazole-2-carboxylate (121 mg), palladium acetate (9 mg), S-phos (32 mg), potassium fluoride (69 mg), and water (0.026 mL) were stirred in tetrahydrofuran (5.0 mL) under a nitrogen atmosphere and microwave irradiation at 100°C for 1 hour. The mixture was filtered using ethyl acetate, and the filtrate was concentrated under reduced pressure to give an orange viscous substance. The resulting viscous substance, Reference Example Compound 5 (134 mg), 1H-1,2,4-triazole (6 mg), and triethylamine (0.055 mL) were heated to reflux in tetrahydrofuran (5.0 mL) for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) to give the title compound (190 mg) as a milky-white solid. MS(ESI)m / z:864.4[M+H] +

[0812] Example 50 (50-1) t-Butyl 4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl]-3-methyl[1,1'-biphenyl]-4-carboxylate (Example Compound 50-1)

[0813] [ka]

[0814] Reference Example Compound 3 (100 mg) was dissolved in tetrahydrofuran (2.0 mL), and t-butyl 4-bromo-2-methylbenzoate (65 mg), tetrakis(triphenylphosphine)palladium(0) (23 mg), potassium phosphate (126 mg), and water (0.013 mL) were added. The mixture was stirred at 90°C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate, and insoluble matter was removed by filtration through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate = 50:50 to 0:100) to obtain the title compound (117 mg) as a crude white powder. MS (ESI) m / z: 571.3 [M+H] +

[0815] (50-2) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-3'-methyl[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 50)

[0816] [ka]

[0817] To a solution of Example Compound 50-1 (113 mg) in dichloromethane (2.0 mL), trifluoroacetic acid (2.0 mL) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated, and toluene was added to distill off the solvent. The resulting residue was dissolved in N,N-dimethylformamide (2.0 mL), and Reference Example Compound 5 (74 mg), N,N-diisopropylethylamine (0.34 mL), and HATU (90 mg) were added at room temperature and stirred at the same temperature for 1 hour. Water was added to the reaction solution, and the precipitate was collected by filtration and washed with water. The residue was dissolved in chloroform, dried over anhydrous sodium sulfate, and filtered. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 95:5) to give the title compound (121 mg) as a white powder. MS (ESI) m / z: 837.5 [M+H] +

[0818] Example 51 (51-1) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-3'-(trifluoromethyl)[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 51)

[0819] [ka]

[0820] In Example 50, t-butyl 4-bromo-2-trifluoromethylbenzoate was used instead of t-butyl 4-bromo-2-methylbenzoate, and the reaction and treatment were carried out in the same manner as in (50-1)-(50-2), to obtain the title compound as a white powder. MS (ESI) m / z: 891.5 [M+H] +

[0821] Example 52 (52-1) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-3'-methoxy[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 52)

[0822] [ka]

[0823] In Example 50, t-butyl 4-bromo-2-methoxybenzoate was used instead of t-butyl 4-bromo-2-methylbenzoate, and the reaction and treatment were carried out in the same manner as in (50-1)-(50-2), to obtain the title compound as a white powder. MS (ESI) m / z: 853.5 [M+H] +

[0824] Example 53 (53-1) t-Butyl 5-{4-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl]phenyl}pyridine-2-carboxylate (Example Compound 53-1)

[0825] [ka]

[0826] Example compound 3 (100 mg), t-butyl 5-bromopyridine-2-carboxylate (77 mg), tetrakis(triphenylphosphine)palladium(0) (23 mg), potassium phosphate (126 mg), and water (0.014 mL) were stirred in tetrahydrofuran (4.0 mL) under a nitrogen atmosphere and microwave irradiation at 100°C for 0.5 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) to obtain the title compound (109 mg) as a colorless viscous substance. MS (ESI) m / z: 558.5 [M+H] +

[0827] (53-2) Methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 53)

[0828] [ka]

[0829] Trifluoroacetic acid (1.0 mL) was added to a solution of Example Compound 53-1 (109 mg) in chloroform (1.0 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and azeotroped twice with toluene. The residue, Reference Example Compound 5 (73 mg), N,N-diisopropylethylamine (0.17 mL), and HATU (89 mg) were stirred in N,N-dimethylformamide (3.0 mL) at room temperature for 2 hours. Water was added to the reaction mixture, which was then stirred and extracted twice with ethyl acetate. The combined organic layer was washed twice with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) to give the title compound (104 mg) as a milky white solid. MS (ESI) m / z: 824.7 [M+H] +

[0830] Example 54 (54-1) Methyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 54)

[0831] [ka]

[0832] The title compound was obtained as a milky white solid by the same reaction and treatment as in Example 53 (53-1)-(53-2) using t-butyl 6-bromopyridine-3-carboxylate instead of t-butyl 5-bromopyridine-2-carboxylate. MS (ESI) m / z: 824.7 [M+H] +

[0833] Example 55 (55-1) t-Butyl 4'-[(6S)-2-(hydroxymethyl)-6-(2-methoxy-2-oxoethyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl][1,1'-biphenyl]-4-carboxylate (Example Compound 55-1)

[0834] [ka]

[0835] A mixture of methyl [(6S)-4-(4-chlorophenyl)-2-(hydroxymethyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (500 mg), (4-t-butoxycarbonylphenyl)boronic acid (386 mg), potassium phosphate (616 mg), tetrahydrofuran (5.0 mL), water (0.52 mL), 2-dicyclohexylphosphino-2'-6'-dimethoxybiphenyl aminobiphenyl palladium chloride precatalyst (42 mg), and S-phos (24 mg) was heated under reflux and stirred for 3 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=99:1 to 90:10) to give the title compound (610 mg) as a milky white solid. MS(ESI) m / z: 573.2 [M+H] +

[0836] (55-2) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2-(hydroxymethyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 55)

[0837] [ka]

[0838] To a solution of Example Compound 55-1 (80 mg) in dichloromethane (1.0 mL) was added trifluoroacetic acid (1.0 mL), and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure. The resulting residue and Reference Example Compound 5 (57 mg) were dissolved in N,N-dimethylformamide (3.0 mL), and N,N-diisopropylethylamine (0.073 mL) was added at room temperature. HATU (69 mg) was added under ice cooling, and the mixture was stirred at room temperature for 7 hours. The reaction solution was diluted with a mixture of ethyl acetate and tetrahydrofuran (1:1), and 1N hydrochloric acid and saturated saline were added, followed by separation. The organic layer was washed once with saturated saline, once with saturated sodium bicarbonate water, and once with saturated saline. After drying over anhydrous sodium sulfate and filtering, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0 to 85:15) to obtain the title compound (51 mg) as a pale yellow solid. MS (ESI) m / z: 839.4 [M+H] +

[0839] Example 56 (56-1) Methyl {(6S)-2,3,9-trimethyl-4-[4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl]-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate (Example Compound 56-1)

[0840] [ka]

[0841] A mixture of Reference Example Compound 1 (200 mg), t-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (208 mg), X-Phos aminobiphenylpalladium chloride precatalyst (38 mg), X-Phos (23 mg), potassium phosphate (307 mg), water (0.031 mL), and tetrahydrofuran (2.4 mL) was stirred at 90°C for 0.5 hours under microwave irradiation. Ethyl acetate and saturated brine were added to the reaction solution, insoluble matter was filtered off, and the filtrate was separated. The organic layer was washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was dissolved in chloroform (1.0 mL), trifluoroacetic acid (1.0 mL) was added at room temperature, and the mixture was stirred at the same temperature for 6 hours. The solvent was removed under reduced pressure, and the residue was azeotropically concentrated with toluene. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=100:0 to 96:4) to give the title compound (244 mg) as a pale yellow powder. MS(ESI) m / z: 512.3 [M+H] +

[0842] (56-2) Methyl [(6S)-4-{4-[2-({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]phenyl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 56)

[0843] [ka]

[0844] To a mixture of Example Compound 56-1 (60 mg), Reference Example Compound 5-1 (44 mg), and chloroform (2.0 mL), sodium triacetoxyborohydride (50 mg) was added at room temperature, and the mixture was stirred at the same temperature for 22 hours. Further, sodium triacetoxyborohydride (50 mg) was added at room temperature, and the mixture was stirred at the same temperature for 8 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Saturated brine was added, and the mixture was extracted three times with chloroform. The extract was dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (10 mM aqueous ammonium carbonate solution-acetonitrile) to obtain the title compound (74 mg) as a pale yellow solid. MS (ESI) m / z: 835.5 [M+H] +

[0845] Example 57 (57-1) N-(3-cyano-4-methyl-1H-indol-7-yl)-4-fluorobenzene-1-sulfonamide (Example compound 57-1)

[0846] [ka]

[0847] To a mixture of Reference Example Compound 9 (300 mg), pyridine (0.71 mL), and tetrahydrofuran (3.0 mL), 4-fluorobenzenesulfonyl chloride (375 mg) was added at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate, and saturated saline and 1N hydrochloric acid were added, followed by separation. The organic layer was washed twice with saturated saline, dried over anhydrous sodium sulfate, and filtered. The solvent was then evaporated under reduced pressure to give the title compound (580 mg) as a brown solid. MS (ESI) m / z: 328.1 [MH] -

[0848] (57-2) 4-[(2-aminoethyl)amino]-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide (Example compound 57-2)

[0849] [ka]

[0850] A mixture of Example Compound 57-1 (200 mg), ethylenediamine (0.61 mL), and tetrahydrofuran (1.0 mL) was heated and stirred at 150°C for 0.5 hours under microwave irradiation. Saturated saline was added to the reaction mixture, and the mixture was extracted three times with a mixture of ethyl acetate and tetrahydrofuran (1:1). The extracts were combined, washed once with a small amount of saturated saline, dried over anhydrous sodium sulfate, and filtered. The solvent was then distilled off under reduced pressure. The resulting residue was suspended and washed with ethyl acetate, and then collected by filtration to give the title compound (180 mg) as a brown powder. MS (ESI) m / z: 370.2 [M+H] +

[0851] (57-3) Methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]anilino}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 57)

[0852] [ka]

[0853] To a mixture of Example Compound 57-2 (41 mg), Reference Example Compound 4 (50 mg), N,N-diisopropylethylamine (0.043 mL), and N,N-dimethylformamide (1.0 mL), HATU (49 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 5 minutes and at room temperature for 3 hours. The reaction mixture was diluted with a mixture of ethyl acetate and tetrahydrofuran (1:1), washed once with saturated aqueous sodium bicarbonate and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was suspended and washed in acetonitrile-water, filtered, and washed with water to give the title compound (45 mg) as a pink powder. MS (ESI) m / z: 852.5 [M+H] +

[0854] Example 58 (58-1) 3-[4-(benzylsulfanyl)phenyl]propan-1-ol (Example compound 58-1)

[0855] [ka]

[0856] A mixture of 3-(4-bromophenyl)propan-1-ol (1000 mg), benzyl mercaptan (0.55 mL), N,N-diisopropylethylamine (2.41 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 269 mg), tris(dibenzylideneacetone)dipalladium (213 mg), and toluene (15.0 mL) was stirred at 100°C for 5 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was directly purified by silica gel column chromatography (hexane:ethyl acetate = 60:40 to 20:80, precolumn: NH silica gel) to give the title compound (681 mg) as a red solid. 1 H NMR (400 MHz, CDCl3) δ ppm 1.23(1H,t,J=5.3Hz),1.81-1.91(2H,m),2.62-2.71(2H,m),3.61-3.70(2H,m),4.08(2H,s),7.05-7.11(2H,m),7.19-7.31(7H,m)

[0857] (58-2) 2-(4-{3-[4-(benzylsulfanyl)phenyl]propoxy}phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Example Compound 58-2)

[0858] [ka]

[0859] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (200 mg) and Example Compound 58-1 (281 mg) in toluene (3.0 mL), cyanomethylenetrimethylphosphorane (157 mg) was added at room temperature and stirred at 150°C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, washed once with saturated brine-water (1:1) and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5) to give the title compound (338 mg) as a colorless viscous liquid. 1 H NMR(400MHz,CDCl3)δ ppm 1.33(12H,s),2.00-2.12(2H,m),2.76(2H,t,J=7.6Hz),3.96(2H,t,J=6.2Hz),4.08(2H,s),6.87(2H ,d,J=8.7Hz),7.09(2H,d,J=8.3Hz),7.22(3H,d,J=8.3Hz),7.25-7.28(4H,m),7.74(2H,d,J=8.7Hz)

[0860] (58-3) Methyl [(6S)-4-(4'-{3-[4-(benzylsulfanyl)phenyl]propoxy}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 58-3)

[0861] [ka]

[0862] A mixture of Reference Example Compound 1 (100 mg), Example Compound 58-2 (122 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 12 mg), X-Phos aminobiphenyl palladium(II) methanesulfonate precatalyst (21 mg), potassium phosphate (154 mg), water (0.016 mL), and tetrahydrofuran (1.2 mL) was stirred at 90°C under nitrogen atmosphere and microwave irradiation for 0.5 hours. Example Compound 58-2 (67 mg), X-Phos (12 mg), and X-Phos aminobiphenyl palladium(II) methanesulfonate precatalyst (21 mg) were added, and the mixture was stirred at 90°C under nitrogen atmosphere and microwave irradiation for 1 hour. The reaction mixture was diluted with ethyl acetate, and insoluble matter was removed by filtration through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=50:50 to 0:100) to give the title compound (147 mg) as a pale yellow powder. MS(ESI) m / z: 713.5 [M+H] +

[0863] (58-4) Methyl [(6S)-4-(4'-{3-[4-(chlorosulfonyl)phenyl]propoxy}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example Compound 58-4)

[0864] [ka]

[0865] To a solution of Example Compound 58-3 (141 mg) in acetonitrile (3.0 mL) and 2N hydrochloric acid (0.60 mL), N-chlorosuccinimide (93 mg) was added under ice cooling and stirred at the same temperature for 1.5 hours. N-chlorosuccinimide (6 mg) was added and stirred at the same temperature for 0.5 hours. The reaction solution was diluted with ethyl acetate, washed sequentially with saturated brine-water (1:1) and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2) to give the title compound (134 mg) as a pale yellow powder. MS (ESI) m / z: 671.4 [M-Cl + HO] +

[0866] (58-5) Methyl {(6S)-4-[4'-(3-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}propoxy)[1,1'-biphenyl]-4-yl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate (Example Compound 58)

[0867] [ka]

[0868] To a solution of Example Compound 58-4 (130 mg) and Reference Example Compound 9 (39 mg) in tetrahydrofuran (2.6 mL), pyridine (0.15 mL) was added at room temperature and stirred at the same temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in chloroform. The mixture was washed once with 1N hydrochloric acid and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (chloroform:methanol = 95:5 to 50:50) and then purified again by silica gel column chromatography (chloroform:methanol = 98:2 to 95:5) to give the title compound (52 mg) as a pale brown powder. MS (ESI) m / z: 824.5 [M+H] +

[0869] Example 59 (59-1) t-Butyl 5-{4-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl]phenyl}thiophene-2-carboxylate (Example Compound 59-1)

[0870] [ka]

[0871] Example compound 3 (100 mg), t-butyl 5-bromothiophene-2-carboxylate (78 mg), tetrakis(triphenylphosphine)palladium(0) (23 mg), potassium phosphate (126 mg), and water (0.014 mL) were stirred in tetrahydrofuran (4.0 mL) under a nitrogen atmospher...

Claims

1. Formula (20-1): 【Chemical 1】 in the presence of a condensing agent and a base, a compound represented by the formula (20-2): 【Chemistry 2】 or its hydrochloride salt to obtain a compound represented by formula (I): 【Chemistry 3】 or a pharmaceutically acceptable salt thereof, In the above formula, A represents a ring selected from an aromatic hydrocarbon ring, a 5- to 6-membered aromatic heterocycle containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen, and a cycloalkane ring; The ring is halogen atoms; hydroxy group; cyano group; hydroxycarbonyl group; oxo group; Thioxo group; an alkyl group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxy group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; ----N(R ７ａ )(R ７ｂ ); -N(R ７ａ ) (R ７ｂ );and -N(R ７ｃ )----R ７ｄ ; may be substituted with a group selected from Substructure: 【Chemistry 4】 is expressed by the following formula: 【Chemistry 5】 [In the formula, R ａ represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; R ａ’ represents a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; or —CO—N(R ７ａ ) (R ７ｂ ) and R ａ’’ represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; or —CO—N(R ７ａ ) (R ７ｂ ) is shown.] is shown by R Ｚ３ represents a group selected from a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; a hydroxycarbonyl group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; a cycloalkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxy ...carbonyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; R Ｚ４ and R Ｚ５ each independently represents a group selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group, and an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group, Substructure: 【Chemistry 6】 is represented by the following formula (Ea) or (Ec): 【Chemistry 7】 indicates, Substructure: 【Chemistry 8】 teeth, 【Chemistry 9】 indicates, L represents a group selected from a divalent aromatic hydrocarbon group; a divalent aliphatic heterocyclic group; a divalent aromatic heterocyclic group which may be partially hydrogenated; an alkylene group; a cycloalkylene group; an alkenylene group; and an alkynylene group; the group may be optionally substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; a hydroxycarbonyl group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; T is —CO—NR ７ｃ - indicates M represents a single bond, or -O-;-S-;-NR ７ａ -;-CO-;-SO-;-SO ２ -;-CO-NR ７ｃ -;-NR ７ｃ -CO-; -SO ２ -NR ７ｃ -;-NR ７ｃ -SO ２ -;-NR ７ａ -CO-NR ７ｂ -;-(OCH ２ CH ２ ) ｍ -;-O-R ７ｒ -;-R ７ｒ -O-; -S-R ７ｒ -;-R ７ｒ -S-; -NR ７ａ -R ７ｒ -;-R ７ｒ -NR ７ａ -;-CO-NR ７ｃ -R ７ｒ -;-R ７ｒ -CO-NR ７ｃ -; an alkylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkynylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and a divalent aliphatic heterocyclic group optionally substituted with a substituent selected from a) a halogen atom, b) a hydroxy group, c) a cyano group, d) an oxo group, e) an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group, and f) an alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group, -L-T-M- represents, in whole or in part, -O-O-, -S-S-, or -NR ７ａ -NR ７ａ -, -O-S-, -S-O-, -O-NR ７ａ -, -NR ７ａ —O—, —S—NR ７ａ - and -NR ７ａ does not represent a group selected from -S-, Further substructure: 【Chemistry 10】 teeth, 【Chemistry 11】 indicates, n represents 2; m represents an integer from 1 to 6; R ５ indicates a hydrogen atom, R ６ａ and R ６ｂ each independently represents a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; or an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, and a cyano group, R ７ａ and R ７ｂ each independently represents a hydrogen atom; or an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group, R bonded to the same nitrogen atom ７ａ and R ７ｂ may bond together with the nitrogen atom to form an aliphatic heterocycle containing one nitrogen atom which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group, R ７ｃ indicates a hydrogen atom, R ７ｄ represents a hydrogen atom; or an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group, R ７ｒ represents a group selected from an alkylene group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkenylene group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; or an alkynylene group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; R ８ａ and R ８ｂ represent, independently of one another, a group selected from a hydrogen atom; a halogen atom; a hydroxy group; and a cyano group; R ９ａ and R ９ｂ each independently represents a group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group optionally substituted with a group selected from a halogen atom, a hydroxy group, and a cyano group; R １０ａ and R １０ｂ are each independently a hydrogen atom; ７ｃ )-CO-OR ７ｄ and alkyl groups; The alkyl group is a halogen atom; a hydroxy group; a cyano group; an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; a hydroxycarbonyl group; and —CO—N(R ７ａ ) (R ７ｂ ) optionally substituted with a substituent selected from: R １１ is a group selected from a hydrogen atom; and an alkyl group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; use.

2. In the above formula, A is a ring selected from a benzene ring; a pyridine ring; and a cycloalkane ring; R ａ is a hydrogen atom; or an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R ａ’ is a hydrogen atom; or an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R ａ’’ is a hydrogen atom; a halogen atom; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; or a cyano group, R Ｚ３ is a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a cycloalkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; or an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; R Ｚ４ and R Ｚ５ are each independently a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; Substructure: 【Chemistry 12】 is expressed by the following formula (Ea): 【Chemistry 13】 and L is a group selected from an alkynylene group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a divalent aromatic hydrocarbon group which may be substituted with a substituent selected from a) a halogen atom, b) a hydroxy group, c) a cyano group, d) an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, and e) an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a divalent aliphatic heterocyclic group containing one nitrogen atom which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and a divalent aromatic heterocyclic group which may be partially hydrogenated and contains 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, the aromatic heterocyclic group may be substituted with a substituent selected from a halogen atom, a hydroxy group, a cyano group, and an oxo group; T is —CO—NR ７ｃ - indicates M is a single bond, or -R ７ｒ -O-; -R ７ｒ -NR ７ａ an alkylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; an alkynylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and a divalent aliphatic heterocyclic group; R ６ａ and R ６ｂ are each independently a group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; R ７ａ and R ７ｂ are each independently a hydrogen atom; or an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R ７ｃ is a hydrogen atom, R ７ｄ is an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R ７ｒ is an alkylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R ８ａ and R ８ｂ are both hydrogen atoms, R ９ａ and R ９ｂ are each independently an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, R １０ａ is a hydrogen atom; and halogen atoms, hydroxy groups, cyano groups, -NH-CO-OR ７ｄ , —CO—N(R ７ａ ) (R ７ｂ an alkyl group optionally substituted with a substituent selected from an alkoxycarbonyl group and a hydroxycarbonyl group; R １０ｂ is a hydrogen atom, R １１ is an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; 2. The use according to claim 1.

3. In the above formula, R ａ is a hydrogen atom; or an alkyl group, R ａ’ is a hydrogen atom; or an alkyl group, R ａ’’ is a hydrogen atom; a halogen atom; an alkyl group; or a cyano group, R Ｚ３ is a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom and a hydroxy group; a cycloalkyl group; or an alkoxy group; R Ｚ４ and R Ｚ５ are each independently a hydrogen atom; or an alkyl group; Substructure: 【Chemistry 14】 is expressed by the following formula (Ea): 【Chemistry 15】 and L is a group selected from an alkynylene group; a divalent aromatic hydrocarbon group optionally substituted with 1 to 2 substituents selected from a halogen atom, a hydroxy group, an alkyl group optionally substituted with 1 to 3 halogen atoms, and an alkoxy group; a divalent aliphatic heterocyclic group containing one nitrogen atom; and a divalent aromatic heterocyclic group optionally partially hydrogenated containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom; When the aromatic heterocyclic group is a partially hydrogenated divalent aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, it may be substituted with an oxo group; T is —CO—NR ７ｃ - and M is a single bond, or -R ７ｒ -O-; -R ７ｒ -NR ７ａ an alkylene group optionally substituted with one hydroxy group; an alkynylene group; and a divalent aliphatic heterocyclic group; R ６ａ and R ６ｂ are each independently a group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group; R ７ａ and R ７ｂ are each independently a hydrogen atom; or an alkyl group, R ７ｃ is a hydrogen atom, R ７ｄ is an alkyl group, R ７ｒ is an alkylene group, R ８ａ and R ８ｂ are both hydrogen atoms, R ９ａ and R ９ｂ are each independently an alkyl group optionally substituted with one hydroxy group, R １０ａ is a hydrogen atom; and —NH—CO—OR ７ｄ , —CO—N(R ７ａ ) (R ７ｂ an alkyl group optionally substituted with one substituent selected from a cyano group, an alkoxycarbonyl group, and a hydroxycarbonyl group; R １０ｂ is a hydrogen atom, R １１ is an alkyl group; 2. The use according to claim 1.

4. In the above formula, A is a benzene ring; R ａ is a hydrogen atom, R １０ａ is an alkyl group optionally substituted with one alkoxycarbonyl group, L is a group selected from a divalent aromatic hydrocarbon group optionally substituted with 1 to 2 substituents selected from a halogen atom, an alkyl group optionally substituted with 1 to 3 halogen atoms, and an alkoxy group; and a divalent aromatic heterocyclic group optionally partially hydrogenated and containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom; M is an alkylene group optionally substituted with one substituent selected from a hydroxy group and a cyano group; 2. The use according to claim 1.

5. In the above formula, R ａ’ is a hydrogen atom, R ａ’’ is a cyano group, R Ｚ３ is an alkyl group optionally substituted with 1 to 3 halogen atoms or hydroxy groups; or an alkoxy group; R Ｚ４ is a hydrogen atom, R Ｚ５ is a hydrogen atom, 2. The use according to claim 1.

6. In the above formula, R ８ａ and R ８ｂ are both hydrogen atoms, R ９ａ and R ９ｂ are each independently an alkyl group optionally substituted with one hydroxy group, R １０ａ is an alkyl group optionally substituted with one alkoxycarbonyl group, R １０ｂ is a hydrogen atom, R １１ is an alkyl group; 2. The use according to claim 1.

7. In the above formula, L is a phenylene group optionally substituted with 1 to 2 substituents selected from a halogen atom and an alkyl group; or a pyrazinediyl group; T is -CO-NR ７ｃ - and R ７ｃ is a hydrogen atom, M is -CH ２ - or -CH(CH ３ ) - is, 2. The use according to claim 1.

8. The compound represented by formula (20-1) is a compound represented by formula (C-1): 【Chemistry 16】 [In the formula, P Ｃ is a protecting group for a carboxylic acid, and the other symbols are as defined above. The protecting group P of the compound represented by Ｃ is obtained by removing 2. The use according to claim 1.

9. The compound represented by formula (20-1) or formula (C-1) is a compound represented by the formula: 【Chemistry 17】 A compound represented by the formula: 【Chemistry 18】 A compound represented by the formula: 【Chemistry 19】 and compounds represented by the formula: 【Chemistry 20】 The use according to claim 1 or 8, wherein the compound is selected from the group consisting of compounds represented by the formula:

10. The compound represented by formula (20-2) or its hydrochloride salt is a compound represented by the formula: ​ A compound represented by the formula: 【Chemical 22】 and compounds represented by the formula: 【Chemical 23】 The use according to claim 1, wherein the compound is selected from the group consisting of compounds represented by the formula:

11. formula: 【Chemistry 24】 A compound represented by the formula: 【Chemistry 25】 and compounds represented by the formula: 【Chemical Formula 26】 A compound selected from the group consisting of compounds represented by:

12. formula: 【Chemical 27】 A compound represented by the formula: 【Chemical 28】 and compounds represented by the formula: 【Chemical formula 29】 A compound selected from the group consisting of compounds represented by:

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