JP2023024381A - Drug containing brd4 protein degradation inducer - Google Patents

Abstract

To provide a pharmaceutical composition which contains a compound excellent in BRD4 protein degradation inducing effect and is useful as a cancer therapeutic agent.SOLUTION: A pharmaceutical composition contains a compound represented by a formula (I) in the figure or a pharmaceutically acceptable salt thereof. {In the formula, each symbol is as defined in the specification.}SELECTED DRAWING: None

Description

The present invention provides a sulfonamide or sulfinamide compound having excellent cytotoxic activity against cancer cells, activity of inducing degradation of BRD4 protein in cancer cells, and activity of inhibiting the binding between BRD4 protein and acetylated histones, or its pharmaceutical properties. and is useful as an anticancer agent, a BRD4 protein degradation inducer, and a BRD4 protein inhibitor.

Eukaryotic DNA is stored in the nucleus in a chromatin structure. Its constituent unit, the nucleosome, has a structure in which DNA is wrapped around a histone octamer formed from two molecules each of four types of histones, H2A, H2B, H3, and H4. Several dozen residues on the N-terminal side of histones are called histone tails, and various post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination are present. Post-translational modifications, also called histone codes, are one of the mechanisms responsible for the epigenetic control of gene expression that determines "when" or "where" genetic information on DNA is expressed. Histone modifications are reversible and functionally activated by modifying enzymes (writers) that write modification groups into histones, demodification enzymes (erasers) that remove modification groups, and histone readers that specifically read modified histones. controlled. It is known that such control mechanisms greatly contribute to ontogeny and cell differentiation, and at the same time, epigenetic abnormalities are involved in various diseases.

A bromodomain is a reader protein consisting of about 110 amino acids that recognizes acetylated lysines of histones. Approximately 50 types of proteins possessing bromodomains have been known so far, and by binding to histone acetylated lysines, they function as scaffold proteins for various transcription factors, and their own histone acetylation. It exerts various functions in the cell, such as chromatin remodeling and transcription regulation through transferase activity and kinase activity. BRD2, BRD3, BRD4 and BRDT contained in BET (bromodomain and extraterminal) family proteins of bromodomain-bearing proteins (sometimes referred to as BET proteins in the specification and claims) are conserved within the family It possesses two bromodomains on the N-terminal side and an Extra C-Terminal domain on the C-terminal side, and each BET protein is known to function both independently and cooperatively. (Non-Patent Document 1).

Among the BET family proteins, BRD4 regulates the expression of the proto-oncogene c-MYC (Non-Patent Document 2), 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 There is a correlation with prognosis in 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). It is expected to be a target for drug discovery in cancer treatment.

BRD4 inhibitors that inhibit the binding of BRD4 to histones have been clinically developed as anticancer agents targeting BRD4 (Non-Patent Document 14). However, BRD4 inhibitors do not show sufficient effects to cause BRD4 accumulation (Non-Patent Document 15), and proteins that stabilize BRD4 expression and BRD4-mediated transcriptional activity are bromodomain-independent. Since resistance is acquired by the expression of a protein that improves the resistance to cancer (Non-Patent Documents 16 and 17), development of an anticancer agent targeting BRD4 by a new means is desired.

In recent years, we have used compounds that link ligands for E3 ligases [Von Hippel-Lindau (VHL), Cereblon (CRBN), Cellular Inhibitor of Apoptosis Protein 1 (cIAP1)] with ubiquitin ligase activity and binders that bind to target proteins. A new technology (chemical knockdown) is to form an artificial complex between E3 ligase and the target protein in the cell, and to induce the degradation of the target protein by using the ubiquitin-proteasome system, which is the intracellular protein degradation mechanism. It is attracting attention as an effective drug discovery technology (Non-Patent Document 18). So far, ARV-771 using a VHL ligand and ARV-825 using a CRBN ligand have been reported as BRD4 protein degradation inducers using this technology (Non-Patent Documents 15 and 19). .

In cancer chemotherapy, the emergence of natural resistance, which is ineffective against anticancer drugs from the start of treatment, and acquired resistance, which reduces the effectiveness of anticancer drugs after long-term use, is a major problem (non-patent literature). 20). Overcoming resistance to this anticancer drug is expected to lead to improved treatment outcomes of cancer chemotherapy, and the existence of various resistance mechanisms has been clarified so far (Non-Patent Document 20). Regarding BRD4 proteolytic inducers, it has been reported that acquired resistance is induced in cancer cells by the dysfunction of the complex of E3 ligase VHL or CRBN that induces proteolytic activity (Non-Patent Document 21). In addition, tumors such as renal cell carcinoma caused by mutations in the VHL gene (Non-Patent Document 22) are thought to exhibit natural resistance to BRD4 protein degradation inducers using ligands for VHL. It is desired to develop a novel BRD4 proteolysis inducer using a new ligand for E3 ligase that overcomes the resistance of the inducer. In recent years, there have been many reports of target proteolysis-inducing compounds in which a new ligand for E3 ligase and a binder for target protein are combined (Non-Patent Document 23). For example, a new BRD4 protein degradation inducer using E3 ligase DCAF15 has been reported (Non-Patent Document 24). However, its BRD4 proteolysis-inducing action and cytotoxic action cannot be said to be sufficient. Combinations of ligands for E3 ligase and binders for target proteins are currently limited (Non-Patent Document 23). It is required to find a combination of ligands and linker structures for the E3 ligase that are suitable for exhibiting .

Taniguchi Y., Int J Mol Sci. 2016, 17: E1849 Kanno T., Nat Struct Mol Biol. 2014, 21: 1047-1057 Zhu Y., Oncotarget. 2017, 8: 31092-31100 Ucar D., Mol Clin Oncol. 2015, 3: 1291-1294 Liao YF., Oncotarget. 2016, 7: 9491-9500 Zhang P., Int J Immunopathol Pharmacol. 2015, 28: 36-44 Yan Y., Int J Clin Exp Pathol. 2014, 7: 4231-4238 Stathis A., Cancer Discov. 2016, 6: 492-500 Segura MF., Cancer Res. 2013, 73: 6264-6276 Dai X., Nat Med. 2017, 23: 1063-1071 Crawford NP., Proc Natl Acad Sci U S A. 2008, 105: 6380-6385 Hu Y., Int J Mol Sci. 2015, 16: 1928-1948 Herrmann H., Oncotarget. 2012, 3: 1588-1599 Liu Z., J Med Chem. 2017, 60: 4533-4558 Lu J., Chem Biol. 2015, 22: 755-763 Dai X., Nat Med. 2017, 23: 1063-1071 Shu S., Nature. 2016, 529: 413-417 Toure M., Angew Chem Int Ed Engl. 2016, 55: 1966-1973 Raina K., Proc Natl Acad Sci U S A. 2016, 113: 7124-7129 Neil V., Nature. 2019, 575: 299-309 Zhang L., Mol Cancer Ther. 2019, 18: 1302-1311. Iliopoulos O., Nat Med. 1995, 1: 822-826. Schapira M., Nat Rev Drug Discov. 2019, 18: 949-963. Li L., Signal Transduct Target Ther. 2020, 5: 129.

The present invention aims to provide a pharmaceutical composition useful as a therapeutic agent for cancer, comprising a compound or a pharmaceutically acceptable salt thereof that is excellent in inducing BRD4 proteolysis using a ligand for E3 ligase DCAF15. Make it an issue.

As a result of intensive research to solve the above problems, the present inventors found a compound having a BRD4 proteolysis-inducing action using a ligand for the E3 ligase DCAF15, and a drug containing the compound useful as a therapeutic agent for cancer. The present invention has been completed by discovering that a composition can be provided, and in particular by discovering an optimum linker structure for a ligand for DCAF15. That is, the gist of the present invention is as follows.

[1] Formula (I):

[In the formula,
A and Q are independently selected from an aromatic hydrocarbon ring; an aromatic heterocyclic ring containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen; a cycloalkane ring; and oxygen, sulfur and nitrogen. an aliphatic heterocyclic ring containing 1 to 3 atoms;
The ring is
halogen atom;
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;
—CO—N(R ^7a )(R ^7b );
—N(R ^7a )(R ^7b ); and —N(R ^7c )—CO—R ^7d ;
It 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 a group selected from =CR ^Z3 - and =N-;
Z ⁴ is a group selected from =CR ^Z4 - and =N-;
Z ⁵ is a group selected from =CR ^Z5 - and =N-;
R ^Z3 , R ^Z4 and R ^Z5 are each independently
hydrogen atom; halogen atom; hydroxy group; cyano group; hydroxycarbonyl group; alkyl group optionally substituted by a group selected from halogen atom, hydroxy group, alkoxy group and cyano group; and a cycloalkyl group optionally substituted with a group selected from a cyano group; a halogen atom, a hydroxy group, an alkoxy group optionally substituted with a group selected from an alkoxy group and a cyano group; a halogen atom, a hydroxy group , an alkoxycarbonyl group optionally substituted with a group selected from 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:

is the following formula (Ea), (Eb) or (Ec):

indicates either
L, T, and M each independently represent a single bond, or
-O-; -S-; -NR ^7a -; -CO-; -SO-; -SO ₂ -; -CO-NR ^7c -; -NR ^7c -CO-; -SO ₂ -NR ^7c -; ^7c —SO ₂ —; —NR ^7a —CO—NR ^7b —; —(OCH ₂ CH ₂ ) _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 -; -SO ₂ -NR ^7c -R ^7r - and —R ^7r —SO ₂ —NR ^7c —; or
bivalent aromatic hydrocarbon group; bivalent aliphatic heterocyclic group; bivalent aromatic heterocyclic group which may be partially hydrogenated; alkylene group; cycloalkylene group; alkenylene group; ; represents a group selected from
a hydroxy group; a cyano group; an oxo group; a hydroxycarbonyl group; an alkyl group optionally substituted by 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 hydroxy group, an alkoxy group and a cyano group;
-LTM- is -O-O-, -S-S-, -NR ^7a -NR ^7a -, -OS-, -S-O-, - as a whole or a part of the structure without indicating a group selected from O—NR ^7a —, —NR ^7a —O—, —S—NR ^7a — and —NR ^7a —S—,
G represents N or C,
J represents N or O,
Further substructure:

teeth,

Denotes a substructure selected from
n is 1 or 2,
m represents an integer from 1 to 6,
R ⁵ is 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 hydrogen atom; a halogen atom; a hydroxy group; a cyano group; an alkyl group optionally substituted by 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;
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 ^7a and R ^7b bonded to the same nitrogen atom are bonded and together with the nitrogen atom may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; may form an aliphatic heterocyclic ring containing
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 an alkylene group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; 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; 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 are each independently a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; and an alkoxy group optionally 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 each independently substituted with a group selected from a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; a hydroxycarbonyl group; 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; a substituent selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; an alkoxycarbonyl group which may be present; and —CO—N(R ^7a )(R ^7b ); or
R ^9a and R ^9b together are an alkylene group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; or a halogen atom, a hydroxy group, an alkoxy group and a cyano group an alkenylene group optionally substituted with a group selected from; may form a condensed ring with the adjacent ring E,
hydroxy group; cyano group; —N( ^{R 7a )} (R ^7b ); —N(R ^7c )—CO—OR ^{7d ;} and alkyl group; indicates a substituent that is
The alkyl group is
Halogen atom; hydroxy group; cyano group; alkoxy group optionally substituted with a substituent selected from halogen atom, hydroxy group, alkoxy group and cyano group; selected from halogen atom, hydroxy group, alkoxy group and cyano group an alkoxycarbonyl group optionally substituted with a substituent; a hydroxycarbonyl group; and —CO—N(R ^7a )(R ^7b );
R ^10a and R ^10b together form a ring representing an alkylene group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group,
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. ]
A pharmaceutical composition comprising a compound represented by or a pharmaceutically acceptable salt thereof (herein sometimes abbreviated as "compound (I)").

[2] partial structure:

is the following formula:

[In the formula,
R ^a is a hydrogen atom; or an alkyl group optionally 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 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 an alkoxy group and a cyano group; or —CO—N(R ^7a )(R ^7b ),
R ^a'' is a hydrogen atom; a halogen atom; a cyano 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 alkoxycarbonyl group optionally substituted with a substituent selected from a cyano group; or —CO—N(R ^7a )(R ^7b ). ]
indicated by
The pharmaceutical composition according to [1].

[3] A is a ring selected from an aromatic hydrocarbon ring, a 5- to 6-membered aromatic heterocyclic ring containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen, and a cycloalkane ring;
^RZ3 is
hydrogen atom; halogen atom; hydroxy group; cyano group; hydroxycarbonyl group; alkyl group optionally substituted by a group selected from halogen atom, hydroxy group, alkoxy group and cyano group; and a cycloalkyl group optionally substituted with a group selected from a cyano group; a halogen atom, a hydroxy group, an alkoxy group optionally substituted with a group selected from an alkoxy group and a cyano group; a halogen atom, a hydroxy group , an alkoxycarbonyl group optionally substituted with a group selected from an alkoxy group and a cyano group;
R ^Z4 and R ^Z5 are each independently a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted with a substituent 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 hydroxy group, an alkoxy group and a cyano group;
Substructure:

is the following formula (Ea) or (Ec):

shows
Substructure:

but,

indicates
Substructure:

but,

shows
L is a divalent aromatic hydrocarbon group; a divalent aliphatic heterocyclic group; a partially hydrogenated bivalent aromatic heterocyclic group; an alkylene group; a cycloalkylene group; an alkenylene group; , an alkynylene group;
cyano group; hydroxycarbonyl group; alkyl group optionally substituted with a group selected from halogen atom, hydroxy group, alkoxy group and cyano group; and halogen atom, hydroxy group, an alkoxy group optionally substituted with a group selected from an alkoxy group and a cyano group;
T represents a single bond, —CO—, —CO—NR ^7c —, —NR ^7c —CO—, or —O—;
hydroxycarbonyl group; halogen atom, hydroxy group, alkoxy group and alkyl group optionally substituted with a substituent selected from cyano group; and halogen atom, hydroxy group, an alkoxy group optionally substituted with a substituent selected from an alkoxy group and a cyano group; an alkylene group optionally substituted with a substituent selected from
M is a single bond;
-O-; -S-; -NR ^7a -; -CO-; -SO-; -SO ₂ -; -CO-NR ^7c -; -NR ^7c -CO-; -SO ₂ -NR ^7c -; ^7c —SO ₂ —; —NR ^7a —CO—NR ^7b —; —(OCH ₂ CH ₂ ) _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 -; an alkylene group optionally substituted with a substituent selected from 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) 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) a halogen atom , an alkoxy group optionally substituted with a substituent selected from a hydroxy group, an alkoxy group and a cyano group; a divalent aliphatic heterocyclic group optionally substituted with a substituent selected from; is a group that
^R5 is a hydrogen atom,
R ^6a and R ^6b are independently selected from a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; is a group that is
R ^7c is a hydrogen atom,
R ^8a and R ^8b are each independently a hydrogen atom; a halogen atom; a hydroxy group; and a cyano group;
R ^9a and R ^9b are each independently a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group; can be,
R ^10a and R ^10b each independently represent a substituent selected from a hydrogen atom; —N(R ^7c )—CO—OR ^7d ; and an alkyl group;
The alkyl group is
Halogen atom; hydroxy group; cyano group; alkoxy group optionally substituted with a substituent selected from halogen atom, hydroxy group, alkoxy group and cyano group; selected from halogen atom, hydroxy group, alkoxy group and cyano group an alkoxycarbonyl group optionally substituted with a substituent; —CO—N(R ^7a ) (R ^7b ); and a hydroxycarbonyl group; optionally substituted with a substituent selected from
The pharmaceutical composition according to [2].

[4] 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 ″} represents a hydrogen atom; a halogen atom; an alkyl group optionally 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 optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group; a substitution selected from a halogen atom, a hydroxy group and a cyano group a cycloalkyl group optionally substituted with a group; or an alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group;
R ^Z4 and R ^Z5 independently represent a hydrogen atom; or an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group;
Substructure:

is the following formula (Ea):

shows
L is an alkynyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group; a) a halogen atom, b) a hydroxy group, c) a cyano group, d) a halogen atom, a hydroxy group and Substitution selected from an alkyl group optionally substituted with a substituent selected from 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 aromatic hydrocarbon group optionally substituted with a group; a divalent aliphatic containing one nitrogen atom, optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group heterocyclic 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; and
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 represents a single bond; -CO-; -CO-NR ^7c -; -NR ^7c -CO-; or -O-;
M is a single bond;
—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; from a halogen atom, a hydroxy group, and a cyano group an alkynylene group optionally substituted with a selected substituent; and a divalent aliphatic heterocyclic group;
R ^6a and R ^6b are each independently 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; and
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 represents a hydrogen atom,
R ^7d represents an alkyl group optionally 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,
both R ^8a and R ^8b are 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 a substituent selected from a halogen atom, a hydroxy group, a cyano group, —NH—CO—OR ^7d , —CO—N(R ^7a )(R ^7b ), an alkoxycarbonyl group and a hydroxycarbonyl group. A group selected from an optionally substituted alkyl 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 of [2] or [3] or a pharmaceutically acceptable salt thereof.

[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 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 independently represent a hydrogen atom; or an alkyl group;
Substructure:

is the following formula (Ea):

shows
L is an alkynylene group; a halogen atom, a hydroxy group, an alkyl group optionally substituted with 1 to 3 halogen atoms, and an alkoxy group. A good divalent aromatic hydrocarbon group; a divalent aliphatic heterocyclic group containing one nitrogen atom; and an atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may be partially hydrogenated is a group selected from a divalent aromatic heterocyclic group containing 1 to 2
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 is an oxo group. may be replaced,
T is a single bond;
-CO-; -CO-NR ^7c -; -NR ^7c -CO-; or -O-;
M is a single bond;
—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; can be,
R ^6a and R ^6b are each independently a hydrogen atom; a halogen atom; a cyano group; and an alkyl group;
R ^7a and R ^7b independently represent a hydrogen atom; or an alkyl group;
R ^7c represents a hydrogen atom,
R ^7d represents an alkyl group,
R ^7r represents an alkylene group,
both R ^8a and R ^8b are hydrogen atoms,
R ^9a and R ^9b are each independently an alkyl group optionally substituted with one hydroxy group,
R ^10a is substituted with a hydrogen atom; and one substituent selected from —NH—CO—OR ^7d , —CO—N(R ^7a )(R ^7b ), a cyano group, an alkoxycarbonyl group and a hydroxycarbonyl group; A group selected from an optionally alkyl group;
R ^10b is a hydrogen atom,
R ¹¹ is an alkyl group,
The pharmaceutical composition according to any one of [2] to [4].

[6] A represents a benzene ring,
R ^a represents a hydrogen atom,
R ^10a is an alkyl group optionally substituted with one alkoxycarbonyl group,
L is a divalent aromatic optionally substituted by 1 to 2 substituents selected from a halogen atom, an alkyl group optionally substituted by 1 to 3 halogen atoms, and an alkoxy group a hydrocarbon 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; can be,
M is an alkylene group optionally substituted with one substituent selected from a hydroxy group and a cyano group;
The pharmaceutical composition according to any one of [2] to [5].

[7] R ^{a '} represents a hydrogen atom,
R ^a'' represents a cyano group,
R ^Z3 represents an alkyl group optionally substituted with 1 to 3 halogen atoms or hydroxy groups; or an alkoxy group;
R ^Z4 represents a hydrogen atom,
R ^Z5 represents a hydrogen atom,
The pharmaceutical composition according to any one of [2] to [6].

[8] both R ^8a and R ^8b are 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 pharmaceutical composition according to any one of [2] to [7].

[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 -, R ^7c is a hydrogen atom,
M is -CH ₂ - or -CH(CH ₃ )-,
The pharmaceutical composition according to any one of [2] to [8].

[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]diazepine- 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]diazepine-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]diazepine-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]diazepine -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]diazepine- 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]pyrazine-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]diazepine- 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]diazepine- 6-yl} acetate,
methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazine-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]diazepine- 6-yl} acetate,
methyl [(6S)-4-(4-{6-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyridine-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][ A pharmaceutical composition comprising a compound selected from 1,4]diazepin-6-yl]acetate, or a pharmaceutically acceptable salt thereof.

[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]diazepine- 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]diazepine-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]diazepine-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]diazepine -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]diazepine- 6-yl} acetate,
methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazine-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]diazepine- 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]diazepine- 6-yl} acetate,
methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazine-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]diazepine- 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.

[12] The pharmaceutical composition of any one of [1] to [11] for inducing BRD4 proteolysis.
[13] The pharmaceutical composition of any one of [1] to [12] for treating cancer.
[14] The cancer is acute myelogenous leukemia, chronic myelogenous 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, colon cancer, glioma, pancreatic cancer, liver cancer, bile duct cancer, renal cell carcinoma, and fibrosarcoma The pharmaceutical composition of [13], which is cancer.
[15] The cancer is acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, diffuse large B-cell lymphoma, multiple myeloma, Burkitt's lymphoma, glioma, gastric cancer, colorectal cancer, pancreatic cancer The pharmaceutical composition of [14], wherein the cancer is selected from cancer, liver cancer, prostate cancer, non-small cell lung cancer, breast cancer, ovarian cancer and uterine sarcoma.
[16] according to [15], wherein the cancer is selected from acute myelogenous leukemia, diffuse large B-cell lymphoma, multiple myeloma, prostate cancer, ovarian cancer and breast cancer pharmaceutical composition.

The compounds of the present invention are excellent in BRD4 proteolysis-inducing action, and pharmaceutical compositions containing the compounds are useful as therapeutic agents for cancer.

The results of the BRD4 proteolysis-inducing action in Test Example 4 are shown. The results of the antitumor effect of Test Example 6 are shown.

The compound in the present invention is a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. In the present specification, "compounds represented by formula (I) or pharmaceutically acceptable salts thereof" may be collectively referred to as compounds of the present invention.
The meanings of the terms used in this specification are described below, and the present invention will be explained in more detail. It should be noted that the following explanation of terms does not limit the present invention in any way.

As used herein, the "halogen atom" includes, for example, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

As used herein, the "alkyl group" includes, for example, methyl, 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 and other “C _1-6 alkyl groups”.

As used herein, the "cycloalkyl group" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, “C _3-10 cycloalkyl group” such as bicyclo[3.2.1]octyl and adamantyl.

As used herein, the "alkoxy group" includes, for example, "C _1-6 alkoxy group" such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, etc. are mentioned.

In the present specification, the "alkylene group" includes, for example, -CH ₂ -, -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -, -(CH ₂ ) ₄ -, -(CH ₂ ) ₅ - , -(CH ₂ ) ₆ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -CH(C ₂ H ₅ )-, -CH(C ₃ H ₇ )-, -CH(CH (CH ₃ ) ₂ )-, -(CH(CH ₃ )) ₂ -, -CH ₂ -CH(CH ₃ )-, -CH(CH ₃ )-CH ₂ -, -CH ₂ -CH ₂ -C( CH ₃ ) ₂ -, -C(CH ₃ ) ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -C(CH ₃ ) ₂ -, -C(CH ₃ ) ₂ -CH ₂ - “C _1-6 alkylene groups” such as CH ₂ —CH ₂ — are included.

In the present specification, the "alkenylene group" includes, for example, -CH=CH-, -CH ₂ -CH=CH-, -CH=CH-CH ₂ -, -C(CH ₃ ) ₂ -CH=CH- , -CH=CH-C(CH ₃ ) ₂ -, -CH ₂ -CH=CH-CH ₂ -, -CH ₂ -CH ₂ -CH=CH-, -CH=CH-CH ₂ -CH ₂ -, "C _2-6 alkenylene group" such as -CH=CH-CH=CH-, -CH=CH-CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -CH=CH- mentioned.

In the present specification, the "alkynylene group" includes, for example, -C≡C-, -CH ₂ -C≡C-, -C≡C-CH ₂ -, -C(CH ₃ ) ₂ -C≡C- , -C≡C-C(CH ₃ ) ₂ -, -CH ₂ -C≡C-CH ₂ -, -CH ₂ -CH ₂ -C≡C-, -C≡C-CH ₂ -CH ₂ -, "C _2-6 alkynylene group" such as -C≡C-C≡C-, -C≡C-CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -C≡C- mentioned.

As used herein, the “cycloalkylene group” includes, for example, “C _3-10 cycloalkylene groups” such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene and the like.

As used herein, the "alkoxycarbonyl group" includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyl and "C _1-6 alkoxy-carbonyl group" such as oxycarbonyl.

As used herein, "cycloalkane ring" includes, for example, "C _3-10 cycloalkane ring" such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like.

As used herein, the “aromatic hydrocarbon ring” includes, for example, “C _6-14 aromatic hydrocarbon ring” such as benzene, naphthalene, anthracene and the like.

As used herein, the “aromatic hydrocarbon group” includes, for example, C _6-14 aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

As used herein, the “divalent aromatic hydrocarbon group” includes, for example, C _6-14 arylene groups such as phenylene, naphthylene and anthrylene.

In the present specification, the "aliphatic heterocyclic ring containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen" includes, for example, atoms selected from oxygen, sulfur and nitrogen in addition to carbon atoms as ring-constituting atoms 3- to 14-membered (preferably 4- to 10-membered) aliphatic heterocycles containing 1 to 3 of Suitable examples of the "aliphatic heterocycle" include 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 3- to 8-membered monocyclic aliphatic heterocycles such as , azepine, azocane, diazocane, oxepane;
Dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolidine, indoline, isoindoline, tetrahydrothieno[2 ,3-c]pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline , tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, octahydroisoquinoline, and other 9- to 14-membered condensed polycyclic (preferably bi- or tricyclic) aliphatic heterocycles.

In the present specification, the "aliphatic heterocyclic ring containing one nitrogen atom" includes, for example, the above "aliphatic heterocyclic ring containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen", the nitrogen atom and an aliphatic heterocycle containing one.

As used herein, the "divalent aliphatic heterocyclic group" includes, for example, a divalent aliphatic heterocyclic group derived from the above "aliphatic heterocyclic group".

In the present specification, the "divalent aliphatic heterocyclic group containing one nitrogen atom" includes, for example, the above "aliphatic heterocycle" derived from an aliphatic heterocyclic ring containing one nitrogen atom and a divalent aliphatic heterocyclic group.

In the present specification, the "aromatic heterocyclic ring containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen" includes, for example, atoms selected from oxygen, sulfur and nitrogen in addition to carbon atoms as ring-constituting atoms 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic ring containing 1 to 3 of Preferable examples of the "aromatic heterocycle" include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxazide 5- to 6-membered monocyclic aromatic heterocycles such as azoles, 1,3,4-oxadiazoles, 1,2,4-thiadiazoles, 1,3,4-thiadiazoles, triazoles, tetrazoles, triazines;
Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, 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, phenoxazine, and the like. Bi- or tricyclic) aromatic heterocycles are preferred.

In the present specification, the "5- to 6-membered aromatic heterocyclic group containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen" includes, for example, oxygen, sulfur and 5- to 6-membered aromatic heterocyclic groups containing 1 to 3 atoms selected from nitrogen are included.
Preferable examples of the "aromatic heterocyclic group" include 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, triazinyl, and other 5- to 6-membered monocyclic aromatic heterocyclic groups.

In the present specification, the "optionally partially hydrogenated divalent aromatic heterocyclic group" includes, for example, the above "aliphatic heterocycle" and the above "aromatic heterocycle" bivalent and a ring group of

As used herein, "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" includes, for example, Divalent ring groups derived from rings containing 1 to 2 atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms among the above "aliphatic heterocycles" and "aromatic heterocycles". .
Of the "partially hydrogenated, divalent aromatic heterocyclic group containing 1 to 2 atoms selected from nitrogen, oxygen and sulfur atoms", "partially hydrogenated , a nitrogen atom, an oxygen atom and a sulfur atom,” preferred examples of the divalent aromatic heterocyclic group” include tetrahydroisoquinolinediyl (especially 1,2,3,4 -tetrahydroisoquinoline-2,6-diyl).

In this specification, the number of substituents in the case of "substituted" is 1 or 2 or more, and the types of substituents may be the same or different, unless otherwise specified.

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

Q is preferably a 5-6 membered aromatic heterocyclic ring (eg, pyrrole ring) containing 1-3 atoms selected from oxygen, sulfur and nitrogen.

Substructure:

is preferably of the formula:

is. That is, Z ¹ is preferably C, Z ² is preferably C, Z ³ is preferably ═CR ^Z3 —, Z ⁴ is preferably ═CR ^Z4 — and Z ⁵ is preferably ═CR ^Z5 — and Q is preferably a pyrrole ring.

R ^Z3 is preferably hydrogen atom; halogen atom (e.g., chlorine atom, bromine atom); hydroxy group; cyano group; hydroxycarbonyl group; halogen atom (e.g., fluorine atom), hydroxy group, alkoxy group and cyano group Alkyl groups optionally substituted by selected groups (e.g., methyl, ethyl); Halogen atoms, hydroxy groups, alkoxy groups and cycloalkyl groups optionally substituted by groups selected from cyano groups (e.g., cyclopropyl); an alkoxy group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group (e.g., methoxy); a halogen atom, a hydroxy group, an alkoxy group and a cyano group an alkoxycarbonyl group optionally substituted with a group; more preferably a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted by a substituent; a cycloalkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxy group and a cyano group; or a halogen atom, a hydroxy group and a cyano an alkoxy group optionally substituted by 1 to 3 substituents selected from groups, more preferably an alkyl group optionally substituted by 1 to 3 halogen atoms or hydroxy groups; or alkoxy groups, particularly preferably alkyl groups, very particularly preferably methyl or ethyl groups.

R ^Z4 and R ^Z5 are preferably, independently of each other, an optionally substituted alkyl group selected from a hydrogen atom; a halogen atom; a cyano group; a halogen atom, a hydroxy group, an alkoxy group and a cyano group; (e.g., methyl); an alkoxy group optionally substituted by a group selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; Atom: an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group, more preferably a hydrogen atom.

R ^a is preferably a hydrogen atom; or an alkyl group 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 more preferably a hydrogen atom.
R ^{a '} is preferably a hydrogen atom; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group (e.g., methyl), more preferably a hydrogen atom; or an alkyl group, more preferably a hydrogen atom.
R ^a'' is preferably a hydrogen atom; a halogen atom (e.g., chlorine atom); an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group (e.g., methyl) or a cyano group, more preferably a hydrogen atom; a halogen atom; an alkyl group; or a cyano group, more preferably a cyano group.

Substructure:

is preferably the following formula (Ea) or (Ec):

and more preferably

is.
R ^9a and R ^9b are, for example, independently of each other a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group (e.g., methyl) and an alkoxy group (e.g., methoxy) optionally substituted by a substituent selected from a halogen atom, a hydroxy group and a cyano group, preferably independently of each other, a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted by a substituent selected from an atom, a hydroxy group and a cyano group (e.g., methyl); more preferably a halogen atom, a hydroxy group and a an alkyl group which may be substituted with a substituent selected from a cyano group, more preferably an alkyl group which may be independently substituted with a hydroxy group, and particularly preferably an unsubstituted alkyl group and most preferably a methyl group.

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

In another aspect, L is preferably a divalent aromatic hydrocarbon group (e.g., phenylene), the group being a halogen atom (e.g., fluorine atom, chlorine atom); hydroxy group; cyano group; a carbonyl group; a halogen atom (e.g., a fluorine atom), an alkyl group (e.g., methyl) optionally substituted with a group selected from a hydroxy group, an alkoxy group and a cyano group; and a halogen atom, a hydroxy group, an alkoxy group, and an alkoxy group optionally substituted with a group selected from a cyano group (e.g., methoxy); 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) 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 an alkoxy group which may be substituted, particularly preferably a halogen atom, an alkyl group which may be substituted with a halogen atom , and an alkoxy group, a divalent aromatic hydrocarbon group optionally substituted with a substituent selected from, more preferably divalent optionally substituted with 1 to 2 halogen atoms and particularly preferably phenylene optionally substituted with 1 to 2 halogen atoms.

In another aspect, 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; Atom (e.g. fluorine atom, chlorine atom); hydroxy group; cyano group; hydroxycarbonyl group; halogen atom (e.g. fluorine atom), hydroxy group, alkoxy group and cyano group. an alkyl group (e.g., methyl); 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 containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, The group may be substituted with a substituent selected from halogen atoms, hydroxy groups, cyano groups and oxo groups, more preferably from nitrogen, oxygen and sulfur atoms, which may be partially hydrogenated. divalent aromatic heterocyclic group containing 1 to 2 selected atoms; the aromatic heterocyclic group may be substituted with an oxo group, particularly preferably halogen A divalent aromatic hydrocarbon group which may be substituted with a substituent selected from an atom, an alkyl group which may be substituted with a halogen atom, and an alkoxy group, and more particularly preferably a nitrogen atom. It is a group selected from 1-2 divalent aromatic heterocyclic groups, particularly preferably pyridinediyl; and pyrazinediyl, and most preferably pyrazinediyl.

T preferably represents a single bond, —CO—, —CO—NR ^7c —, —NR ^7c —CO—, or —O—, halogen atom; hydroxy group; cyano group; oxo group; 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 a substituent selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group an alkoxy group which may be optionally substituted; an alkylene group (eg, —CH ₂ —) which may be substituted with a substituent selected from; more preferably a single bond; ^—CO— ; —NR ^7c —CO—; or —O—, particularly preferably —CO—NR ^7c —.

M is preferably 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 -;-OR ^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 -; and an alkylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group (e.g., -CH ₂ -, -(CH ₂ ) ₂ -, -(CH ₂ ) _3- ); an alkynylene group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group (e.g., —CH ₂ —C≡C—); and 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) a halogen atom, hydroxy A divalent aliphatic heterocyclic group (e.g., piperidinediyl ); more preferably a single bond or a substituent selected from —R ^7r —O—; —R ^7r —NR ^7a —; a halogen atom, a hydroxy group, and a cyano group an alkylene group optionally substituted with; 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; more preferably a single bond or an alkylene group optionally substituted with a substituent selected from —R ^7r —O—; —R ^7r —NR ^7a —; a hydroxy group and a cyano group an alkynylene group; and a divalent aliphatic heterocyclic group; a group selected from, particularly preferably an alkylene group optionally substituted with one substituent selected from a hydroxy group and a cyano group and particularly preferably —CH ₂ — or —CH(CH ₃ )—, particularly particularly preferably or -CH ₂ - or

is.

provided that -LTM- is, as a whole or a part of the structure, -O-O-, -S-S-, -NR ^7a -NR ^7a -, -O-S-, -S-O- , —O—NR ^7a —, —NR ^7a —O—, —S—NR ^7a — and —NR ^7a —S— are not indicated.

-LTM- is
Preferably,
an aromatic hydrocarbon group optionally substituted with 1 to 2 substituents in which L is selected from a halogen atom and an alkyl group; and a divalent aromatic heterocyclic group containing 1 to 2 nitrogen atoms is a selected group;
T is -CO-NR ^7c -, R ^7c is a hydrogen atom,
M is -CH ₂ -, -(CH ₂ ) ₂ - or -CH(CH ₃ )-,
More preferably
L is a phenylene group optionally substituted with 1 to 2 substituents selected from a halogen atom and an alkyl group; pyridinediyl; and a pyrazinediyl group,
T is -CO-NR ^7c -, R ^7c is a hydrogen atom,
M is -CH ₂ -, -(CH ₂ ) ₂ - or -CH(CH ₃ )-,
More preferably
L is a phenylene group optionally substituted with 1 to 2 halogen atoms; and a pyrazinediyl group,
T is -CO-NR ^7c -, R ^7c is a hydrogen atom,
M is -CH ₂ - or -CH(CH ₃ )-,
Especially preferably
L is a phenylene group optionally substituted with 1 to 2 halogen atoms; and a pyrazinediyl group,
T is -CO-NR ^7c -, R ^7c is a hydrogen atom,
M is -CH ₂ -, or

is.

Substructure:

is preferably

is.

Substructure:

is preferably

is. That is, G is preferably N and J is preferably N.

^R5 is preferably a hydrogen atom.

R ^6a and R ^6b are preferably substituted independently of each other with a hydrogen atom; a halogen atom (e.g. a fluorine atom); a hydroxy group; a cyano group; and a substituent selected from a halogen atom, a hydroxy group and a cyano group more preferably, independently of each other, hydrogen atoms; halogen atoms; cyano groups; and halogen atoms, hydroxy groups and cyano groups. an alkyl group optionally substituted with a substituent group selected from; more preferably a hydrogen atom; a halogen atom; a cyano group; and an alkyl group;

R ^7a and R ^7b are preferably 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 (e.g., methyl, ethyl). , more preferably, independently of each other, a hydrogen atom; or an alkyl group optionally substituted by a hydroxy group.

^R7c is preferably a hydrogen atom.
^R7d is preferably an alkyl group (eg, methyl) optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group, more preferably an alkyl group.

R ^7r is preferably an alkylene group (eg, —CH ₂ —, —(CH ₂ ) ₂ —, —(CH ₂ ) _3- ), more preferably an alkylene group.

R ^8a and R ^8b are preferably groups independently selected from a hydrogen atom; a halogen atom; a hydroxy group; and a cyano group; and more preferably both are hydrogen atoms.

R ^10a and R ^10b preferably represent, independently of each other, a substituent selected from a hydrogen atom; —N(R ^7c )—CO—OR ^7d ; and an alkyl group (eg, methyl); The 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; a halogen atom, a hydroxy group, an alkoxy group and a cyano group. an alkoxycarbonyl group optionally substituted with a substituent selected from (e.g., methoxycarbonyl, t-butoxycarbonyl); —CO—N(R ^7a )(R ^7b ); and a hydroxycarbonyl group; optionally substituted with a substituent, more preferably R ^10a is a hydrogen atom; and a halogen atom, a hydroxy group, a cyano group, —NH—CO—OR ^7d , —CO—N(R ^7a )(R ^7b ) , an alkoxycarbonyl group, and an alkyl group optionally substituted with a substituent selected from a hydroxycarbonyl group; and R ^10b is a hydrogen atom, more preferably R ^10a is hydrogen atom; and an alkyl group optionally substituted with a substituent selected from —NH—CO—OR ^7d , —CO—N(R ^7a )(R ^7b ), a cyano group, an alkoxycarbonyl group, and a hydroxycarbonyl group. and R 10b is a hydrogen atom, 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 by one substituent selected from a tert-butoxycarbonyl group and a methoxycarbonyl group, most preferably substituted by a methoxycarbonyl group is a methyl group.

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

Preferred 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 heterocyclic ring containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen, and a cycloalkane ring;
Substructure:

is the following formula:

indicates
R ^a is a hydrogen atom; or an alkyl group optionally 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 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 an alkoxy group and a cyano group; or —CO—N(R ^7a )(R ^7b );
R ^a″ is a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; a halogen atom, a hydroxy group, an alkoxy group and an alkoxycarbonyl group optionally substituted with a substituent selected from a cyano group; or —CO—N(R ^7a )(R ^7b ),
^RZ3 is
hydrogen atom; halogen atom; hydroxy group; cyano group; hydroxycarbonyl group; alkyl group optionally substituted by a group selected from halogen atom, hydroxy group, alkoxy group and cyano group; and a cycloalkyl group optionally substituted with a group selected from a cyano group; a halogen atom, a hydroxy group, an alkoxy group optionally substituted with a group selected from an alkoxy group and a cyano group; a halogen atom, a hydroxy group , an alkoxycarbonyl group optionally substituted with a group selected from an alkoxy group and a cyano group;
R ^Z4 and R ^Z5 are each independently a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted with a substituent 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 hydroxy group, an alkoxy group and a cyano group;
Substructure:

is the following formula (Ea) or (Ec):

shows
Substructure:

but,

shows
Substructure:

but,

shows
L is a divalent aromatic hydrocarbon group; a divalent aliphatic heterocyclic group; a partially hydrogenated bivalent aromatic heterocyclic group; an alkylene group; a cycloalkylene group; an alkenylene group; , an alkynylene group;
cyano group; hydroxycarbonyl group; alkyl group optionally substituted with a group selected from halogen atom, hydroxy group, alkoxy group and cyano group; and halogen atom, hydroxy group, an alkoxy group optionally substituted with a group selected from an alkoxy group and a cyano group;
T represents a single bond, —CO—, —CO—NR ^7c —, —NR ^7c —CO—, or —O—;
hydroxycarbonyl group; halogen atom, hydroxy group, alkoxy group and alkyl group optionally substituted with a substituent selected from cyano group; and halogen atom, hydroxy group, an alkoxy group optionally substituted with a substituent selected from an alkoxy group and a cyano group; an alkylene group optionally substituted with a substituent selected from
M is a single bond;
-O-; -S-; -NR ^7a -; -CO-; -SO-; -SO ₂ -; -CO-NR ^7c -; -NR ^7c -CO-; -SO ₂ -NR ^7c -; ^7c —SO ₂ —; —NR ^7a —CO—NR ^7b —; —(OCH ₂ CH ₂ ) _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 -; an alkylene group optionally substituted with a substituent selected from 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) 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) a halogen atom , an alkoxy group optionally substituted with a substituent selected from a hydroxy group, an alkoxy group and a cyano group; a divalent aliphatic heterocyclic group optionally substituted with a substituent selected from; is a group that
^R5 is a hydrogen atom,
R ^6a and R ^6b are independently selected from a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; is a group that is
R ^7c is a hydrogen atom,
R ^8a and R ^8b are each independently a hydrogen atom; a halogen atom; a hydroxy group; and a cyano group;
R ^9a and R ^9b are each independently a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group; can be,
R ^10a and R ^10b each independently represent a substituent selected from a hydrogen atom; —N(R ^7c )—CO—OR ^7d ; and an alkyl group;
The alkyl group is
Halogen atom; hydroxy group; cyano group; alkoxy group optionally substituted with a substituent selected from halogen atom, hydroxy group, alkoxy group and cyano group; selected from halogen atom, hydroxy group, alkoxy group and cyano group an alkoxycarbonyl group optionally substituted with a substituent; —CO—N(R ^7a ) (R ^7b ); and a hydroxycarbonyl group; optionally substituted with a substituent selected from
Compound (I).

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

is the following formula:

indicates
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 ″} represents a hydrogen atom; a halogen atom; an alkyl group optionally 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 optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group; a substitution selected from a halogen atom, a hydroxy group and a cyano group a cycloalkyl group optionally substituted with a group; or an alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group;
R ^Z4 and R ^Z5 independently represent a hydrogen atom; or an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group;
Substructure:

is the following formula (Ea):

indicates
Substructure:

but,

shows
Substructure:

but,

indicates
L is an alkynyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group; a) a halogen atom, b) a hydroxy group, c) a cyano group, d) a halogen atom, a hydroxy group and Substitution selected from an alkyl group optionally substituted with a substituent selected from 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 aromatic hydrocarbon group optionally substituted with a group; a divalent aliphatic containing one nitrogen atom, optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group heterocyclic 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; and
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 represents a single bond; -CO-; -CO-NR ^7c -; -NR ^7c -CO-; or -O-;
M is a single bond;
—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; from a halogen atom, a hydroxy group, and a cyano group an alkynylene group optionally substituted with a selected substituent; and a divalent aliphatic heterocyclic group;
R ^6a and R ^6b are each independently 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; and
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 represents a hydrogen atom,
R ^7d represents an alkyl group optionally 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,
both R ^8a and R ^8b are 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 a substituent selected from a halogen atom, a hydroxy group, a cyano group, —NH—CO—OR ^7d , —CO—N(R ^7a )(R ^7b ), an alkoxycarbonyl group and a hydroxycarbonyl group. A group selected from an optionally substituted alkyl 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).

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

is the following formula:

indicates
R ^a is 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 is a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted with a halogen atom or a hydroxy group; a cycloalkyl group; or an alkoxy group;
R ^Z4 and R ^Z5 independently represent a hydrogen atom; or an alkyl group;
Substructure:

is the following formula (Ea):

shows
Substructure:

but,

shows
Substructure:

but,

shows
L is an alkynyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group; a) a halogen atom, b) a hydroxy group, c) a cyano group, d) a halogen atom, a hydroxy group and Substitution selected from an alkyl group optionally substituted with a substituent selected from 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 aromatic hydrocarbon group optionally substituted with a group; a divalent aliphatic containing one nitrogen atom, optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group heterocyclic 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; and
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 represents a single bond; -CO-; -CO-NR ^7c -; -NR ^7c -CO-; or -O-;
M is a single bond;
—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; from a halogen atom, a hydroxy group, and a cyano group an alkynylene group optionally substituted with a selected substituent; and a divalent aliphatic heterocyclic group;
R ^6a and R ^6b are each independently 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; and
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 represents a hydrogen atom,
R ^7d represents an alkyl group optionally 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,
Both R ^8a and R ^8b are 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 a substituent selected from a halogen atom, a hydroxy group, a cyano group, —NH—CO—OR ^7d , —CO—N(R ^7a )(R ^7b ), an alkoxycarbonyl group and a hydroxycarbonyl group. A group selected from an alkyl group optionally substituted with
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).

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

is the following formula:

shows
R ^a represents 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 is a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted with a halogen atom or a hydroxy group; a cycloalkyl group; or an alkoxy group;
R ^Z4 and R ^Z5 independently represent a hydrogen atom; or an alkyl group;
Substructure:

is the following formula (Ea):

shows
Substructure:

but,

shows
Substructure:

but,

shows
L is 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 aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;
T represents 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 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; and
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 represents a hydrogen atom,
R ^7d represents an alkyl group optionally 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,
both R ^8a and R ^8b are 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 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).

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

is the following formula:

shows
R ^a represents a hydrogen atom,
R ^{a '} represents a hydrogen atom,
R ^a'' represents a cyano group,
R ^Z3 represents an alkyl group optionally substituted with 1 to 3 halogen atoms or hydroxy groups; or an alkoxy group;
R ^Z4 represents a hydrogen atom,
R ^Z5 represents a hydrogen atom,
Substructure:

is the following formula (Ea):

shows
Substructure:

but,

shows
Substructure:

but,

shows
L is a divalent aromatic optionally substituted by 1 to 2 substituents selected from a halogen atom, an alkyl group optionally substituted by 1 to 3 halogen atoms, and an alkoxy group a hydrocarbon 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; can be,
T represents 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 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; is a group selected from
R ^7a and R ^7b are each independently a hydrogen atom; or an alkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxy group and a cyano group,
R ^7c represents 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;
both R ^8a and R ^8b are 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).

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

is the following formula:

shows
R ^{a '} represents a hydrogen atom,
R ^a'' represents a cyano group,
R ^Z3 represents an alkyl group; or an alkoxy group;
R ^Z4 represents a hydrogen atom,
R ^Z5 represents a hydrogen atom,
Substructure:

is the following formula (Ea):

shows
Substructure:

but,

shows
Substructure:

but,

shows
L is a divalent aromatic hydrocarbon group optionally substituted with 1 to 2 substituents selected from halogen atoms and alkyl groups; and a divalent aromatic heteroaromatic group containing 1 to 2 nitrogen atoms a group selected from a ring group;
T is -CO-NR ^7c -, R ^7c is a hydrogen atom,
M is —CH ₂ —, —(CH ₂ ) ₂ —, or —CH(CH ₃ )—;
both R ^8a and R ^8b are 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).

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

is the following formula:

shows
R ^{a '} represents a hydrogen atom,
R ^a'' represents a cyano group,
R ^Z3 represents an alkyl group; or an alkoxy group;
R ^Z4 represents a hydrogen atom,
R ^Z5 represents a hydrogen atom,
Substructure:

is the following formula (Ea):

shows
Substructure:

but,

shows
Substructure:

but,

shows
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 -, R ^7c is a hydrogen atom,
M is —CH ₂ —, —(CH ₂ ) ₂ —, or —CH(CH ₃ )—;
both R ^8a and R ^8b are 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).

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

is the following formula:

shows
R ^{a '} represents a hydrogen atom,
R ^a'' represents a cyano group,
R ^Z3 represents an alkyl group; or an alkoxy group;
R ^Z4 represents a hydrogen atom,
R ^Z5 represents a hydrogen atom,
Substructure:

is the following formula (Ea):

shows
Substructure:

but,

shows
Substructure:

but,

shows
L is 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 -, R ^7c is a hydrogen atom,
M is -CH ₂ - or -CH(CH ₃ )-,
both R ^8a and R ^8b are 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).

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

is the following formula:

shows
R ^a represents a hydrogen atom,
R ^{a '} represents a hydrogen atom,
R ^a'' represents a cyano group,
R ^Z3 represents an alkyl group optionally substituted with 1 to 3 halogen atoms or hydroxy groups; or an alkoxy group;
R ^Z4 represents a hydrogen atom,
R ^Z5 represents a hydrogen atom,
Substructure:

is the following formula (Ea):

shows
Substructure:

but,

shows
Substructure:

but,

shows
L is a divalent aromatic optionally substituted by 1 to 2 substituents selected from a halogen atom, an alkyl group optionally substituted by 1 to 3 halogen atoms, and an alkoxy group is a hydrocarbon group,
T represents 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 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; is a group selected from
R ^7a and R ^7b are each independently a hydrogen atom; or an alkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxy group and a cyano group,
R ^7c represents 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;
both R ^8a and R ^8b are 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).

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

is the following formula:

shows
R ^a represents a hydrogen atom,
R ^{a '} represents a hydrogen atom,
R ^a'' represents a cyano group,
R ^Z3 represents an alkyl group optionally substituted with 1 to 3 halogen atoms or hydroxy groups; or an alkoxy group;
R ^Z4 represents a hydrogen atom,
R ^Z5 represents a hydrogen atom,
Substructure:

is the following formula (Ea):

shows
Substructure:

but,

shows
Substructure:

but,

shows
L is a divalent aromatic heterocyclic group containing 1 to 2 nitrogen atoms,
T represents 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 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; is a group selected from
R ^7a and R ^7b are each independently a hydrogen atom; or an alkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxy group and a cyano group,
R ^7c represents 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;
both R ^8a and R ^8b are 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).

Specific examples of the compound represented by formula (I) include the compounds of Examples 1 to 126 described later, preferably 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 Examples 1, 11, 26, 43, 47, 53, 63, 64, 65, 69, 71, 74, 92, 102, 103, 105, 106, 107, 108, 109 and 110, more preferably Examples 1, 47, 74 and 106.

In the present invention, "pharmaceutically acceptable salt" is not particularly limited as long as it is a pharmaceutically acceptable salt, salts with inorganic acids, salts with organic acids, salts with alkali metals, alkali Examples include salts with earth metals, salts with inorganic bases, and salts with organic bases. Furthermore, hydrates that are hydrates and solvates that are solvates are also included in the pharmaceutically acceptable salts of the present invention.

"Pharmaceutically acceptable" as used herein means generally safe and non-toxic, biologically undesirable but otherwise preferable, as human pharmaceuticals. It is meant to be useful in preparing pharmaceutical compositions, including those useful for veterinary use as well as for use in medicine.

Compounds of the invention can be prepared by Methods AF below. These methods and steps may be combined with each other, but the manufacturing method is not limited to these.

Hereinafter, the case where R ¹⁰ represents R ^10a or R ^10b and one of R ^10a or R ^10b is a hydrogen atom is described as an example, but the case where both R ^10a and R ^10b are optionally substituted alkyl is described. However, the following method shall be followed. (R ^10a and R ^10b are as defined above.)

(Method A)
(1) The production method described here is an intermediate of compounds represented by the general formula (I) in which the ring E is represented by the above general formula (Ea), G is a nitrogen atom, and J is a nitrogen atom compound (A-1) below.

(In the formula, each symbol has the same meaning as above.)
Step A-1
Compound (1-2) can be derived from compound (1-1) according to known methods (eg, J. Med. Chem. 1973, 16, 214-219).
Step A-2
Compound (1-3) is obtained by acylating compound (1-2). The reaction proceeds with a base in an appropriate solvent, usually at -20°C to the reflux temperature of the solvent. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 0.5 to 24 hours. Acylating agents include trifluoroacetic anhydride, acetic anhydride, propanoic anhydride, acetyl chloride and the like. Examples of bases include triethylamine and pyridine. Examples of solvents include tetrahydrofuran, dichloromethane, toluene, 1,4-dioxane and the like.
Step A-3
Compound (1-4) is obtained by thioamidating compound (1-3). The thioamidation reaction proceeds with a sulfurizing agent in a suitable solvent, usually at room temperature to solvent reflux temperature. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 0.5 to 24 hours. Examples of the sulfurizing agent include Lawesson's reagent and phosphorus pentasulfide. Examples of solvents include 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane and the like.
Step A-4
Compound (1-5) is obtained by reacting compound (1-4) with hydrazine. The reaction with hydrazine proceeds with hydrazine monohydrate in a suitable solvent, usually from room temperature to solvent reflux temperature. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 1 to 24 hours. Solvents include tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide and the like.
Step A-5
Compound (1-6) is obtained by converting carboxylic acid form (1-10) having a substituent of R ¹⁰ into an acid halide using a halogenating agent and then reacting it with compound (1-5). be done. The reaction proceeds with a base in a suitable solvent, usually at temperatures from 0° C. to the reflux temperature of the solvent. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 1 to 24 hours. Halogenating agents include, for example, thionyl chloride, oxalyl chloride, phenylphosphonyl dichloride and the like. Examples of the base include triethylamine, pyridine and the like. Examples of solvents include dichloromethane, 1,2-dichloroethane, chloroform, pyridine and toluene.
Process A-6
Compound (1-7) is obtained by cyclization reaction of compound (1-6). Proceeding in a suitable solvent, usually from room temperature to the reflux temperature of the solvent. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 1 to 24 hours. Examples of solvents include 2-propanol, 1-butanol, tetrahydrofuran and the like.
Step A-7
Compound (1-8) is obtained by deprotection reaction of compound (1-7). The reaction proceeds with an acid in a suitable solvent, usually from room temperature to the reflux temperature of the solvent. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 1 to 24 hours. Acids include, for example, hydrochloric acid and trifluoroacetic acid. Examples of solvents include ethyl acetate, 1,4-dioxane, tetrahydrofuran, dichloromethane, chloroform and the like.
Step A-8
Compound (1-9) is obtained by 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 a temperature from 0° C. to the reflux temperature of the solvent. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 1 to 24 hours. Condensing agents include, for example, 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), 2-chloro-1-methylpyridinium iodide and the like. Solvents include methanol, N,N-dimethylformamide, chloroform, dichloromethane, tetrahydrofuran and the like. Also, the addition of 1-hydroxybenzotriazole (HOBt) may accelerate the reaction. Examples of bases include triethylamine, N,N-diisopropylethylamine, pyridine and the like.
Process A-9
Compound (A-1) is obtained by halogenating compound (1-9). The reaction generally proceeds at room temperature to the reflux temperature of the solvent using a halogenating agent. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 1 to 24 hours. Halogenating agents include, for example, phosphoryl chloride.

(2) The production method described here is an intermediate of compounds represented by general formula (I) in which ring E is represented by general formula (Ec) above, G is a nitrogen atom, and J is a nitrogen atom. compound (A-2) below.

(In the formula, each symbol has the same meaning as above.)
Compound (A-2) can be derived from compound (2-1) according to known methods (eg, J. Med. Chem. 2016, 59, 1426).

(3) The production method described here is an intermediate of a compound represented by general formula (I) in which G is a carbon atom and J is an oxygen atom, that is, the following compound (A-3). Suitable for

(In the formula, B ¹ is a boronic acid or an optionally substituted boronic acid ester, Z ^A is a halogen atom, ^PA is a protecting group, and other symbols are as defined above.)
In the formula, the optionally substituted boronic acid ester of B ¹ indicates pinacolato boron, neopentyl glycolato boron, etc., and the halogen atom of Z ^A is a chlorine atom, a bromine atom, an iodine atom. indicates The protecting group of P ^{1 A} in the formula protects the carboxyl group, and is not particularly limited as long as the compound (3-7) can be obtained. Examples thereof include alkyl (specifically methyl, ethyl) and the like.
Compound (A-3) can be derived from compound (3-1) according to known methods (eg WO2012/075383).

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

(In the formula, ^ZB represents a chlorine atom or a hydroxyl group, and other symbols are as defined above.)
Step B-1
Compound (B-1) is obtained by a coupling reaction between compound (A-4) and boronic acid derivative (4-1). The reaction preferably proceeds in the presence of a palladium catalyst, a phosphine ligand and a base in a suitable solvent at a temperature from 0° C. to heating, especially from room temperature to the boiling point of the solvent. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 1 to 24 hours. Palladium catalysts include, for example, palladium(II) acetate, palladium(II) chloride, tris(dibenzylideneacetone)dipalladium(0), and chloroform adducts thereof. 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, 2-di-t-butylphosph Phino-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. Reagents in which a palladium catalyst and a phosphine ligand are complexed may also be used, such as tetrakis(triphenylphosphine)palladium(0), 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, dichlorobis(tri phenylphosphine)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-di isopropoxy-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. Bases include t-butoxysodium, potassium acetate, tripotassium phosphate, cesium carbonate, potassium carbonate, sodium hydrogen carbonate, lithium bis(trimethylsilyl)amide, triethylamine, diisopropylethylamine, dicyclohexylethylamine, potassium fluoride, cesium fluoride, and the like. is mentioned. Examples of solvents 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 organic solvents thereof. and water.

(2) The production method described here is an intermediate of a compound represented by general formula (I) in which G is a nitrogen atom and J is a nitrogen atom, that is, the following compound (B-2). Suitable for

(In the formula, each symbol has the same meaning as above.)
Step B-2
Compound (5-2) can be obtained by converting carboxylic acid form (1-10) having a substituent of R ¹⁰ into an acid halide with a halogenating agent and then reacting it with compound (5-1). The reaction proceeds with a base in an appropriate solvent, usually at -20°C to the reflux temperature of the solvent. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 0.5 to 24 hours. Halogenating agents include, for example, thionyl chloride, oxalyl chloride, phenylphosphonyl dichloride and the like. Examples of bases include triethylamine and pyridine. Examples of solvents include dichloromethane, 1,2-dichloroethane, chloroform, pyridine and toluene.

Step B-3
Compound (5-3) is obtained by deprotection and cyclization of compound (5-2). The deprotection reaction proceeds with an acid in a suitable solvent, usually from 0° C. to the reflux temperature of the solvent. The reaction time varies depending on the starting material, 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, tetrahydrofuran and the like. In addition, this reaction can also be performed only with an acid. The cyclization reaction proceeds with an acid in a suitable solvent, usually from room temperature to the reflux temperature of the solvent. The reaction time varies depending on the starting material, 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, 2-propanol and the like.

Step 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 reactions. The reaction with hydrazine proceeds using a base and hydrazine in an appropriate solvent, usually at 0°C to room temperature. Examples of the base include sodium hydride, sodium t-butoxy, potassium t-butoxy and the like. The acylation reaction proceeds with an acylating agent in a suitable solvent, usually at room temperature to the reflux temperature of the solvent. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 0.5 to 24 hours. Examples of the acylating agent include trifluoroacetic anhydride, acetic anhydride, propanoic anhydride and the like. Examples of solvents include tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dichloromethane and the like. The above reaction can also be carried out using an acylhydrazide instead of using hydrazine and acid chloride or acid anhydride. Acylhydrazides include, for example, acetylhydrazine. The cyclization reaction proceeds with an acid in a suitable solvent, usually from room temperature to the reflux temperature of the solvent. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 0.5 to 24 hours. Examples of acids include acetic acid and trifluoroacetic acid. Solvents include tetrahydrofuran, N,N-dimethylformamide, 1-butanol, 2-propanol and the like. This reaction is carried out using the corresponding orthoester after addition of hydrazine in an appropriate solvent, usually at room temperature to solvent reflux temperature. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 0.5 to 24 hours. Orthoesters include, for example, 1,1,1-triethoxyethane and 1,1,1-trimethoxypentane. Examples of solvents include toluene and tetrahydrofuran.

The second one can be obtained by converting the amide group to a thioamide group, followed by hydrazine addition, acylation and cyclization. The thioamidation reaction proceeds with a sulfurizing agent in a suitable solvent, usually at room temperature to solvent reflux temperature. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 0.5 to 24 hours. Examples of the sulfurizing agent include Lawesson's reagent and phosphorus pentasulfide. Examples of solvents include 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane and the like. The hydrazine addition reaction proceeds with hydrazine in a suitable solvent, usually at room temperature to solvent reflux temperature. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 1 to 24 hours. Solvents include tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide and the like. The acylation reaction, using an acylating agent, proceeds in a suitable solvent, usually at room temperature to the reflux temperature of the solvent. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 1 to 24 hours. Acylating agents include trifluoroacetic anhydride, acetic anhydride, propanoic anhydride and the like. Instead of using hydrazine and acid chloride or acid anhydride, the above reaction can also be carried out using an acylhydrazide. Acylhydrazides include, for example, acetylhydrazine. Solvents include tetrahydrofuran, N,N-dimethylformamide and the like. The cyclization reaction proceeds with an acid in a suitable solvent, usually from room temperature to the reflux temperature of the solvent. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 0.5 to 24 hours. Examples of acids include acetic acid and trifluoroacetic acid. Solvents include tetrahydrofuran, N,N-dimethylformamide, 1-butanol, 2-propanol and the like. This reaction is carried out using the corresponding orthoester after addition of hydrazine in an appropriate solvent, usually at room temperature to solvent reflux temperature. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 0.5 to 24 hours. Orthoesters include, for example, 1,1,1-triethoxyethane and 1,1,1-trimethoxypentane. Examples of solvents include toluene and tetrahydrofuran.

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

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

(4) The production method described here is an intermediate of a compound represented by general formula (I) in which R ¹⁰ is —N(R ^7c )—CO—OR ^7d , namely the following compound (B-3 ), suitable for producing compound (B-4). ( ^R7c and ^R7d are as defined above.)

(In the formula, each symbol has the same meaning as above.)
Step B-8
Compound (B-3) is synthesized from compound (7-1) according to a known method (for example, JP-A-7-17941) to the corresponding acid halide (Cl—CO—OR ^7d ) or Obtained by reacting with an acid anhydride (R ^7d O—CO—O—CO—OR ^7d ). The reaction proceeds with a base in an appropriate solvent, usually at -20°C to the reflux temperature of the solvent. The reaction time varies depending on the starting material, solvent, reaction temperature, etc. used, but is usually 30 minutes to 24 hours. Examples of bases include triethylamine, N,N-diisopropylethylamine, pyridine and the like. Examples of solvents include dichloromethane, 1,2-dichloroethane, chloroform, N-methylpyrrolidone, pyridine and toluene. In addition, the base used in this reaction can also be used as a solvent.

Process B-9
Compound (B-4) is obtained by alkylating compound (B-3). The alkylation reaction proceeds using a base and an alkylating agent such as an alkyl halide in an appropriate solvent, usually at a temperature from 0°C to the reflux temperature of the solvent. The reaction time is usually 10 minutes to 24 hours, although it varies depending on the starting material, solvent and reaction temperature used. 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 solvents include N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide and the like.

(5) The production method described here is suitable for producing intermediates of compounds represented by general formula (I) in which R ¹⁰ is a hydroxyl group, namely the following compound (B-5).

(In the formula, each symbol has the same meaning as above.)
Compound (B-5) can be derived from compound (8-1) according to a known method (eg US4959361).

(6) The production method described here is an intermediate of a compound represented by general formula (I) in which R ¹⁰ is —(CH ₂ ) _k —CO—N(R ^7a )(R ^7b ), namely It is suitable for producing compound (B-6) below.

(Wherein, P ^C represents a hydrogen atom or a protecting group, k represents an integer of 1 to 6. Each symbol has the same meaning as above.)
The protective group for P 2 ^C in the formula is not particularly limited as long as it protects the carboxyl group. Examples include alkyl (specifically, methyl, ethyl, t-butyl, etc.), aralkyl (benzyl, etc.), and the like.
Step B-13
Compound (9-2) is obtained by removing the protecting group P 2 ^C from compound (9-1). This step can be omitted when P 2 ^C is a hydrogen atom. Deprotection conditions are not particularly limited as long as they ^are used for deprotection of PC ^. In the case of t-butyl, a method using an acid such as hydrochloric acid or trifluoroacetic acid can be used. If P 2 ^C is benzyl, substituted benzyl, benzyloxymethyl or the like, a method using catalytic hydrogenation reaction can be used.
Step B-14
Compound (B-6) is obtained by condensing compound (9-2) with the corresponding amine having R ^7a and R ^7b . The reaction proceeds using a condensing agent in the presence of a suitable base in a suitable solvent at a temperature from 0° C. to the reflux temperature of the solvent. The reaction time and the condensing agent, solvent, reaction accelerator and base used are the same as in step A-8.

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

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

(8) Among the compounds represented by general formula (I), ring E is represented by the above general formula (Ea), G is a nitrogen atom, J is a nitrogen atom, and ^R9a is an intermediate of a compound in which R9a is cyanomethyl; That is, the following compound (B-8) can also be produced, for example, by the following production method.

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

(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, J is a nitrogen atom, and R ^9a is the number of carbon atoms substituted with a cyano group. An intermediate of a compound having 1 to 6 alkyl, ie, the following compound (B-9) can be produced, for example, by the following production method.

(Wherein, k represents an integer of 1 to 6. Other symbols are as defined above.)
Process B-27
Compound (B-9) is obtained by cyanating compound (12-1). Examples of the reaction conditions include the same conditions as in step B-26 described above.

(10) Among the compounds represented by the general formula (I), ring E is represented by the above general formula (Ea), G is a nitrogen atom, J is a nitrogen atom, and ^R9a is an intermediate of a compound having a cyano group. , that is, the following compound (B-10) can be produced, for example, by the following production method.

(In the formula, each symbol has the same meaning as above.)
Process B-28
Compound (13-1) is obtained by oxidizing compound (11-3). The reaction conditions include, for example, conditions for reacting a mixture of compound (11-3), manganese dioxide and dichloromethane for an appropriate time at room temperature.
Process B-29
Compound (B-10) is obtained by cyanating compound (13-1). The reaction conditions include, for example, conditions for reacting a mixture of hydroxylamine hydrochloride and dimethylsulfoxide for an appropriate time under heating.

(11) Among the compounds represented by general formula (I), ring E is represented by the above general formula (Ea), G is a nitrogen atom, J is a nitrogen atom, and ^R9a is a hydrogen atom. , that is, the following compound (B-11) can be produced, for example, by the following production method.

(In the formula, each symbol has the same meaning as above.)
Process B-30
Compound (14-1) is obtained by oxidizing compound (13-1). The reaction is carried out with an oxidizing agent in a suitable solvent, usually at temperatures from 0° C. to the reflux temperature of the solvent. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 0.5 to 24 hours. Examples of the oxidizing agent include hydrogen peroxide, t-butyl hydroperoxide, sodium chlorite, potassium permanganate and the like. Solvents include, for example, methanol, acetonitrile, and water. The reaction proceeds, for example, by adding a 35% hydrogen peroxide solution and a sodium chlorite solution to a mixed solution of acetonitrile and a sodium dihydrogen phosphate solution at 0° C. to room temperature.
Process B-31
Compound (B-11) is obtained by decarboxylating compound (14-1). The reaction conditions include, for example, conditions for reacting at 150° C. in copper-containing quinoline.

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

(In the formula, Z ^A represents a halogen atom, Z ^D represents a hydroxyl group activating group, and ^B2 represents a hydrogen atom, amine, olefin, acetylene, thiol, alcohol, boronic acid, or a substituent. indicates a good boronate ester. Other symbols are as defined above.)
In the formula, the halogen atom of Z ^A represents a chlorine atom, a bromine atom or an iodine atom, and the activating group for the hydroxyl group represented by Z ^D includes sulfonyl groups such as trifluoromethanesulfonyl and toluenesulfonyl. In the formula, the optionally substituted boronic acid ester of ^B2 includes pinacolatoboron, neopentylglycolatoboron and the like.
Step C-1
This is the step of converting the hydroxyl group of the compound (16-2) to the activating group ^OZD . The reaction preferably proceeds at about -50 to 50°C, especially from 0°C to room temperature in the presence of a base in a suitable solvent. Activated sulfonic acid derivatives such as trifluoromethanesulfonic anhydride, 1-(trifluoromethanesulfonyl)imidazole, and toluenesulfonyl chloride are used as the activating reagent. This reaction can also be carried out by using a combination of sulfonic acid and a condensing agent. Bases include triethylamine, pyridine, lutidine and the like. Examples of solvents include dichloromethane, 1,2-dichloroethane, chloroform, pyridine and toluene.
Step C-2
Compound (C-1) is obtained by reacting compound (16-1) or compound (16-3) with compound (16-4).
compound (16-1) or compound ( ^{16-3 )} and an amine, olefin, ^acetylene , A compound (C-1) is obtained by a coupling reaction with an arylboronic acid derivative represented by a thiol, an alcohol, LB(OH) ₂ or an ester thereof (wherein L is as defined above). The palladium catalyst, the phosphine ligand, the reagent formed by forming a complex of the palladium catalyst and the phosphine ligand, the base and the solvent to be used are the same as in step B-1.
In addition, when L is aryl having 6 to 12 carbon atoms, heteroaryl having 5 to 12 ring atoms, olefin or acetylene, an organometallic salt of L (for example, tin, zinc, copper, etc.), or an alkyl of L Compound (C-1) can also be obtained by coupling reaction of compound (16-1) or compound (16-3) with a metal derivative (eg, alkylaluminum derivative, alkyltin derivative, alkylborane derivative, etc.). can.

(2) The intermediate of the compound represented by general formula (I), ie the compound (C-1) below, can be produced, for example, by the following production method.

(In the formula, each symbol has the same meaning as above.)
A compound (C-1) is obtained by a coupling reaction between a compound (17-1) and a boronic acid derivative (17-2). As the reaction conditions, the same conditions as in the above step B-1 can be mentioned.

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

(In the formula, each symbol has the same meaning as above.)
Step C-4
Boronic acid (18-1) is obtained by reaction of compound (16-1) with a boronic acid derivative (eg, bispinacolatodiboron, bisneopentyl glycolatodiboron, etc.). The reaction preferably proceeds in the presence of a palladium catalyst, a phosphine ligand and a base in a suitable solvent at a temperature from 0° C. to heating, especially from room temperature to the boiling point of the solvent. Palladium catalysts, phosphine ligands, bases and solvents that can be used are those listed in step B-1.
Step C-5
Compound (C-1) is obtained by reacting boronic acid (18-1) with compound (18-2). The reaction preferably proceeds in the presence of a palladium catalyst, a phosphine ligand and a base in a suitable solvent at a temperature from 0° C. to heating, especially from room temperature to the boiling point of the solvent. Palladium catalysts, phosphine ligands, bases and solvents that can be used are those listed in step B-1.

(4) Among the compounds represented by general formula (I), ring E is represented by the above general formula (Ea), G is a nitrogen atom, J is a nitrogen atom, and ^R9a is a halogen atom. , that is, the following compound (C-2) can also be produced, for example, by the following production method.

(In the formula, each symbol has the same meaning as above.)
Process C-6
Compound (19-1) is obtained by reacting compound (B-11) with compound (16-4). As the reaction conditions, the same conditions as in step C-2 can be mentioned.
Step C-7
Compound (C-2) is obtained by reacting compound (19-1) 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.

(Method D)
(1) Among the compounds represented by the general formula (I), the compound in which T is -CO-NH- and n is 2, that is, the following compound (D-1) is produced, for example, by the following production method. can do

(In the formula, each symbol has the same meaning as above.)
Process D-1
Compound (20-1) is obtained by removing the protecting group P 2 ^C from compound (C-1). This step can be omitted when P 2 ^C is a hydrogen atom. The deprotection conditions for the protecting group P 2 ^C are not particularly limited as long as they are used for the deprotection of P 2 ^C. For example, when P 2 ^C is methyl, Lewis A method using an acid, a method using an inorganic base such as sodium hydroxide in a mixed solvent of an alcoholic solvent and water, and an inorganic base such as sodium hydroxide in a mixed solvent of an alcoholic solvent and water for ethyl. Examples thereof include a method using a base and, in the case of t-butyl, a method using an acid such as hydrochloric acid or trifluoroacetic acid. If P 2 ^C is benzyl, substituted benzyl, benzyloxymethyl or the like, a method using catalytic hydrogenation reaction can be used.
Process D-2
A compound (D-1) is obtained by a condensation reaction between a carboxylic acid derivative (20-1) and an amine derivative (20-2). Examples of the reaction conditions include the same conditions as in step B-14 described above.

(2) Among the compounds represented by the general formula (I), the compound in which T is —CO—NH— and n is 2, that is, the following compound (D-1) can also be produced, for example, by the following production method. can do

(In the formula, ^ZF represents a chlorine atom or a bromine atom, and other symbols are as defined above.)
Process D-3
This is a step of converting compound (20-1) to acid halide (21-1). The reaction proceeds in a suitable solvent, usually at a temperature from 0° C. to the reflux temperature of the solvent, usually for 1 hour to 24 hours. Halogenating agents include, for example, thionyl chloride, oxalyl chloride, phenylphosphonyl dichloride and the like. Examples of the base include triethylamine, pyridine and the like. Examples of solvents include dichloromethane, 1,2-dichloroethane, chloroform, pyridine and toluene.
Process D-4
A compound (D-1) is obtained by reacting an acid halide (21-1) with an amine derivative (20-2). The reaction is carried out using a base in a suitable solvent, usually at a temperature from 0°C to the reflux temperature of the solvent. The reaction time varies depending on the starting material, solvent, reaction temperature, etc. used, but is usually 30 minutes to 12 hours. Examples of bases include triethylamine and pyridine. Examples of solvents include dichloromethane, dichloroethane, chloroform, N-methylpyrrolidone, pyridine and toluene.

(Method E)
(1) Among the compounds represented by the general formula (I), the compound in which T is -CO-NH- and n is 2, that is, the following compound (D-1) can also be produced, for example, by the following production method. can do

(In the formula, each symbol has the same meaning as above.)
Step E-1
Compound (22-2) is a compound of amine (20-2) and carboxylic acid (22-1) represented by HOC(O)-LZ ^A (where Z ^A is as defined above). Obtained by reaction. Examples of the reaction conditions include the same conditions as in step B-14 described above.
Process E-2
This step is a step of obtaining compound (D-1) by reacting compound (22-2) with boronic acid or its ester derivative (18-1). Examples of the reaction conditions include the same conditions as in step B-1.

(2) Among the compounds represented by the general formula (I), the compound in which T is —CO—NH— and n is 2, that is, the following compound (D-1) can also be produced, for example, by the following production method. can do

(The symbols in the formula are as defined above.)
Step E-3
A compound (23-2) is obtained by reacting an amine derivative (20-2) with a carboxylic acid derivative (23-1). Examples of the reaction conditions include the same conditions as in step B-14 described above. When there is a possibility of self-condensation, such as when ^B2 is an amine, steps of protection and deprotection can be included as appropriate.
Step E-4
This is the step of converting the hydroxyl group of the compound (16-2) to the activating group ^OZD . As the reaction conditions, the same conditions as in the above step C-1 can be mentioned.
Step E-5
In this step, compound (D-1) is obtained by reacting compound (16-1) or compound (16-3) obtained in step E-4 with compound (23-2). As the reaction conditions, the same conditions as in the above step C-2 can be mentioned.

(3) Among the compounds represented by the general formula (I), the compound in which T is -CO-NH- and n is 2, that is, the following compound (D-1) can also be produced, for example, by the following production method. can do

(The symbols in the formula are as defined above.)
In (2) of Method E above, compound (24-1) is used in place of compound (23-1) to obtain boronic acid derivative (24-2), followed by reaction with imino chloride (A-4). is a method for obtaining compound (D-1).
The reaction conditions for step E-6 include the same conditions as for step B-14.
The reaction conditions for step E-7 include the same conditions as for step B-1.

(Method F)
(1) Among the compounds represented by the general formula (I), the compound in which T is -CO-NH- and n is 2, that is, the following compound (D-1) can also be produced, for example, by the following production method. can do

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

(2) Among the compounds represented by (20-2) above, the compound in which the fused ring moiety is 3-cyano-1H-indole, that is, the following compound (F-1) is produced, for example, by the following production method. can do

(In the formula, ^PF represents an amino-protecting group, and other symbols are as defined above.)
P 1 ^F in the formula is not particularly limited as long as it protects the amino group and gives compound (26-6). Examples thereof include a t-butyloxycarbonyl group and a benzyloxycarbonyl group.
Process F-5
Compound (26-3) is obtained by reacting nitro compound (26-1) with vinylmagnesium bromide (26-2). The reaction proceeds in a suitable solvent, usually at -78°C to room temperature. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 0.5 to 24 hours. Solvents include, for example, tetrahydrofuran.
Process F-6
Compound (26-4) can be obtained, for example, by formylation of indole derivative (26-3), subsequent formation of oxime, and dehydration reaction. The formylation reaction usually proceeds at room temperature to solvent reflux temperature using a halogenating agent and DMF. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 1 to 24 hours. Halogenating agents include, for example, phosphoryl chloride and phenylphosphonyl dichloride. Examples of the solvent include DMF, dichlorobenzene-DMF mixed solution, and the like. Compound (26-4) is obtained by adding hydroxylamine hydrochloride to the above reaction solution and heating. The reaction usually proceeds at a temperature from 40° C. to the reflux temperature of the solvent. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
Process F-7
Compound (26-5) is obtained by coupling reaction of compound (26-4) with benzophenoneimine, followed by deprotection reaction. The reaction conditions for the coupling reaction include the same conditions as in step C-2. As the deprotection reaction conditions, an acid such as hydrochloric acid is allowed to act, or hydroxylamine or the like is allowed to act. The reaction usually proceeds at room temperature to the reflux temperature of the solvent. The reaction time varies depending on the starting material, solvent and reaction temperature used, but is usually 1 to 24 hours. Examples of solvents include methanol, tetrahydrofuran, 1,4-dioxane, and mixed solutions thereof.
Process F-8
A compound (26-7) is obtained by reacting a sulfonyl chloride derivative (26-6) with an amine derivative (26-5). The reaction conditions for step F-8 include the same conditions as for step F-4.
Process F-9
Compound (F-1) is obtained by removing the protecting group P 2 ^F from compound (26-7). Deprotection conditions are not particularly limited as long as they are used for deprotection of P ^{5 F.} For example, when P 5 ^F is a t-butyloxycarbonyl group, it can be deprotected with an acid. Examples of the acid at this time include inorganic acids such as hydrochloric acid, trifluoroacetic acid, and the like. Reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof, at a temperature of up to 80° C. under ice cooling, for about 10 minutes to 12 hours. When ^PF is a benzyloxycarbonyl group, it can be deprotected by reduction by catalytic hydrogenation. Examples of the catalyst include palladium carbon, etc. 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 raw materials and solvents used, the reaction temperature, and the like. is usually 1 hour to 48 hours.

The compound represented by the general formula (I) produced by the method described above can be purified to any degree of purity by subjecting it to conventional purification means such as concentration, extraction, chromatography, reprecipitation, recrystallization, and the like. can do. If necessary, it can be converted to a pharmaceutically acceptable salt by treating with an acid or base in a suitable solvent (water, alcohol, ether, etc.). Furthermore, the obtained compound of the present invention or a pharmaceutically acceptable salt thereof can be converted to a hydrate or solvate by treating it with water, a water-containing solvent or other solvent.

A compound of the present invention, or a pharmaceutically acceptable salt thereof, includes racemates, stereoisomers, and mixtures of these compounds, including isotopically-labeled and radio-labeled compounds. Such isomers can be isolated by standard separation techniques, including fractional crystallization and chiral column chromatography. Also, the compounds of the present invention have an asymmetric carbon atom. It therefore includes enantiomers or diastereomers. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical/chemical differences by methods well known in the art, eg by chromatography and/or fractional crystallization. Enantiomers can be separated by chiral column chromatography or by reacting an enantiomeric compound with a suitable optically active compound to convert it into a diastereomeric mixture, separate each diastereomer and then convert the individual diastereomers to their corresponding enantiomers. can be separated by The compounds of the present invention can be any isomers including diastereomers, enantiomers and mixtures thereof.

The compound of the present invention or a pharmaceutically acceptable salt thereof has a cytotoxic effect on cancer cells. Furthermore, it also has an action of inducing degradation of BET protein in cancer cells and an action of inhibiting binding between BET protein and acetylated histone. Therefore, a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof can be used as an anticancer agent, and can also be used as a BET protein degradation inducer or BET protein inhibitor. Further, according to the present invention, a method for treating cancer, a method for inducing degradation of BET protein, and a method for inhibiting BET protein using a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof can be provided. be.

Furthermore, the compound of the present invention or a pharmaceutically acceptable salt thereof also has an action of inducing degradation of BRD4 protein in cancer cells and an action of inhibiting binding between BRD4 protein and acetylated histone. Therefore, a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof can be used as a BRD4 protein degradation inducer or BRD4 protein inhibitor. Further, according to the present invention, a method for treating cancer, a method for inducing degradation of BRD4 protein, and a method for inhibiting BRD4 protein using a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof can be provided. be.

In the present invention, cancer is of any type, but specific examples include oral cavity cancer, pharyngeal cancer, laryngeal cancer, thyroid cancer, esophageal cancer, gastric cancer, duodenal cancer, and small intestine cancer. , colorectal 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 cancer, Bladder cancer, kidney cancer, urothelial cancer, brain tumor, bone and soft tissue tumor, leukemia, malignant lymphoma, multiple myeloma, sarcoma (e.g., Ewing's sarcoma, rhabdomyosarcoma, bone and soft tissue sarcoma), etc. can be mentioned.

In the medical field, colorectal cancer is classified as colon cancer or rectal cancer, liver cancer as hepatocellular carcinoma, biliary tract cancer as bile duct cancer or gallbladder cancer, pancreatic cancer as pancreatic duct cancer or pancreatic cancer. Endocrine tumors, lung cancers such as non-small cell lung cancer, small cell lung cancer, large cell lung cancer, malignant pleural mesothelioma or thymic tumors, skin cancers such as cutaneous malignant tumors or cutaneous lymphomas, uterine cancers such as 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 ureteral cancer, and brain tumor is called glioma. Breast cancer has subtypes called triple-negative breast cancer, HER2-positive breast cancer, luminal A-type breast cancer, and luminal B-type breast cancer. Leukemia includes acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), acute lymphoblastic leukemia (ALL), and lymphoblastic lymphoma (LBL). ), chronic myelogenous leukemia (CML), myeloproliferative neoplasm (MPN), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), etc. Lymphomas include follicular lymphoma (FL), MALT lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma (LPL), Waldenstrom's macroglobulinemia (WM), mantle cell lymphoma (MCL), diffuse large cell Type 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 subtypes called Hodgkin's lymphoma (HL).

In one embodiment, a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof is used for acute myelogenous leukemia, chronic myelogenous 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 It may be useful in treating cancer, cholangiocarcinoma, renal cell carcinoma and fibrosarcoma.
In another embodiment, a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, is used to treat acute myelogenous leukemia, chronic myelogenous 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, a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, is used for acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, prostate cancer. , non-small cell lung cancer, ovarian cancer and breast cancer.
In still yet another embodiment, a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, is used for acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, prostate cancer. It may be useful in the treatment of cancer, ovarian cancer and breast cancer.

As used herein, the term "anticancer agent" is a concept that includes anticancer agents, antitumor agents, and the like. It has the effect of shrinking or extinguishing abnormally proliferating cells, or preventing them from increasing. In addition, treatment means the act of administering a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing these to an individual who has already developed a disease, disease or symptom. Therefore, the act of administering to an individual who has already developed a disease, disease, or symptom in order to prevent exacerbation or recurrence of symptoms, etc., is one mode of treatment.

A pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof may contain the compound of the present invention or a pharmaceutically acceptable salt thereof with pharmaceutically acceptable additives (excipients, binders, disintegrants). agents, flavoring agents, flavoring agents, emulsifiers, diluents, solubilizers, etc.), and can be administered orally or parenterally. Pharmaceutical compositions can be formulated according to conventional methods. Alternatively, a compound of the present invention or a pharmaceutically acceptable salt thereof can be directly administered orally or parenterally.

Subjects to which the compounds or pharmaceutical compositions of the present invention are administered are not particularly limited, but mammals are preferred. Mammals include, for example, 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. cattle, horses, pigs, sheep, goats), but humans are preferred.

Parenteral as used herein means subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion method or local administration (intraarticular administration, transdermal administration, transocular administration, transpulmonary/bronchial administration). , nasal or rectal administration, etc.).

The dosage of the compounds of the present invention may vary depending on age, body weight, general health, sex, diet, time of administration, method of administration, rate of excretion, severity of the patient's condition being treated at the time, or other factors. can be determined in consideration of the factors of The daily dose of the compound of the present invention varies depending on the patient's condition and body weight, type of compound, route of administration, etc. For example, parenterally, subcutaneously, intravenously, intramuscularly, intraarticularly, percutaneously, About 0.001 to 100 mg/person/day is administered intraocularly, transpulmonary/bronchially, nasally or intrarectally, and about 0.01 to 1000 mg/person/day is administered orally.

Hereinafter, the present invention will be described in detail with reference examples, examples and test examples, but the present invention is not limited to these.

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)

(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4] To a suspension of 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 distilled off under reduced pressure, chloroform (1.5 L) and water (1 L) were added to separate the layers, and the mixture was extracted with chloroform (500 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (500 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure (azeotropic distillation with methanol twice). The residue was washed with methanol/water (300 mL/300 mL) to give the title compound (250 g). MS (ESI) m/z: 415.2 [M+H] ⁺

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

Acetonitrile (12.3 g) was added to a suspension of sodium methoxide (12.4 g) in dimethyl sulfoxide (23 mL) at room temperature, and after stirring at room temperature for 2 hours, ethyl 4-bromobenzoate (22.9 g) was added. was slowly added to the solution in dimethyl sulfoxide (23 mL), and the mixture was stirred at 45° C. for 3 hours. The reaction solution was cooled with ice, water and concentrated hydrochloric acid were added, and the mixture was stirred for 0.5 hours, and the precipitate was collected by filtration. The resulting residue was dried to give the title compound (22.4 g) as a pale brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 4.75 (brs, 2H), 7.87-7.70 (m, 4H)

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

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 distilling off the solvent, 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 and filtered, and the filtrate was concentrated under reduced pressure. Ethanol was added to the obtained solid, and the mixture was stirred at room temperature for 2 hours, and the precipitate was 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] ⁺

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

(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, and then phenylphosphonyl Dichloride (29.7 g) was slowly added dropwise, and the mixture was stirred under ice cooling for 1 hour. 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 and filtered, and the filtrate was concentrated under reduced pressure. Trifluoroacetic acid (53 mL) was added to a dichloromethane (70 mL) solution of the obtained residue, and the mixture was stirred at room temperature for 2 hours, then trifluoroacetic acid (53 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and azeotroped with toluene. A saturated aqueous solution of sodium bicarbonate was added to the resulting mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. Acetic acid (12 mL) was added to a 2-propanol (200 mL) suspension of the resulting residue, and the mixture was stirred at 90° C. for 1 hour. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction mixture for extraction. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate (43 mL) was added to the obtained residue, and the mixture was stirred at 45° C. for 1 hour, and the insoluble matter was collected by filtration. The obtained 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] ⁺

(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)

Under ice cooling, sodium hydride (60%, 1.1 g) was added to a solution of Reference Example compound 2-3 (9.6 g) in tetrahydrofuran (65 mL) and stirred for 0.5 hours. .5 g) was 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 hour. Saturated sodium bicarbonate water was 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, and the filtrate was concentrated under reduced pressure. The obtained 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] ⁺

Reference example 3
(3-1) methyl {(6S)-2,3,9-trimethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboronan-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)

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 in a tetrahydrofuran solvent for 25 hours under an argon stream. Heated to reflux. Furthermore, dichlorobis(tricyclohexylphosphine)palladium (445 mg) and bis(pinacolato)diboron (1.53 g) were added and heated under reflux for 7 hours, followed by bis(pinacolato)diboron (1.53 g), potassium acetate (1.18 g), Dichlorobis(tricyclohexylphosphine)palladium (445 mg) was added and the mixture was heated under reflux for 16 hours. After cooling to room temperature, the reaction solution was filtered through celite 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=100:0-97:3), followed by silica gel column chromatography (ethyl acetate/methanol=100:0-95:5). The title compound (5.27 g) was obtained as a pale yellow solid. MS (ESI) m/z: 507.2 [M+H] ⁺

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)

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), water (0.78 mL) ) was heated under reflux and stirred for 40 hours. Further, (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 solution, the insoluble matter in the reaction solution was removed by filtration through diatomaceous earth, and the filtrate was 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, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5). Further purification by silica gel column chromatography (chloroform:methanol=100:0-95:5) gave the title compound (6.55 g) as a crude yellow solid. MS (ESI) m/z: 557.3 [M+H] ⁺

(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)

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

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

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 the mixture was stirred at the same temperature for 16 hours. 4-Formylbenzenesulfonyl chloride (48 mg) was added, and the mixture was stirred at room temperature for 1 hour. 1N Hydrochloric acid was added to the reaction mixture to make it acidic, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-40:60), chloroform was added to the obtained purified product to solidify, and then concentrated under reduced pressure to give the title compound (126 mg). ) was obtained as a yellow powder. MS (ESI) m/z: 340.1 [M+H] ⁺

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

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 the mixture was stirred at the same temperature for 20 minutes. 1N Hydrochloric acid-water-saturated saline and ethyl acetate-acetone were added to the reaction mixture to separate the layers. The aqueous layer was extracted once with ethyl acetate, the combined organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (30.0 mL), 1,8-diazabicyclo[5.4.0]-7-undecene (0.49 mL) and 2-azido-1,3-dimethylimidazolinium hexa Fluorophosphate (736 mg) was added at room temperature and stirred 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 and stirred 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 and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-60:40), chloroform was added to the obtained purified product to solidify, and then concentrated under reduced pressure to give the title compound (355 mg). ) was obtained as a pale yellow powder. MS (ESI) m/z: 365.3 [MH] ^-

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

Tetrahydrofuran (10.0 mL) and water (1.0 mL) were added to a mixture of Reference Example compound 5-2 (350 mg) and triphenylphosphine (326 mg), and the mixture was stirred at 50° C. for 3 hours. The reaction solution was concentrated under reduced pressure, chloroform was added to the resulting residue, and 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] ⁺

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

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 distilled off under reduced pressure. Diethyl ether was added to the resulting residue, and the precipitate was collected by filtration to give the title compound (1.81 g) as a brown solid. MS (ESI) m/z: 354.1 [MH] ^-

Reference example 7
(7-1) 7-bromo-4-methyl-1H-indole (Reference Example Compound 7)

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

Reference example 8
(8-1) 7-bromo-4-methyl-1H-indole-3-carbonitrile (Reference Example Compound 8)

Phenylphosphonyl dichloride (0.23 mL) was added to an N,N-dimethylformamide solution (1.35 mL) of Reference Example compound 7 (284 mg) at room temperature. After stirring at room temperature for 0.5 hours, phenylphosphonyl dichloride (0.04 mL) was added, and the mixture was further stirred at the same temperature for 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. After diluting the reaction mixture with ethyl acetate, the mixture was washed twice with saturated aqueous sodium bicarbonate and once with saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was 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. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.75 (3H, d, J = 0.6 Hz), 6.92 (1H, dq, J = 7.6, 1.8 Hz), 7.36 (1H , d, J = 7.7 Hz), 7.78 (1H, d, J = 2.8 Hz), 8.73 (1H, brs)

Reference example 9
(9-1) 7-amino-4-methyl-1H-indole-3-carbonitrile (Reference Example Compound 9)

Reference Example Compound 8 (215 mg), benzophenoneimine (240 mg), [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium (II) ( Pd-PEPPSI-IPent catalyst, 22 mg), to a mixture of tetrahydrofuran (2.3 mL) at room temperature, 1.3 M lithium bis (trimethylsilyl) amide / tetrahydrofuran solution (2.5 mL) was added, nitrogen atmosphere, under microwave irradiation at 120° C. for 0.5 hours. After allowing to cool 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 and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (2.3 mL)-methanol (2.3 mL), hydroxylamine hydrochloride (159 mg) and sodium acetate (225 mg) were added at room temperature, and the mixture was stirred at the same temperature for 4 hours. A saturated aqueous solution of sodium bicarbonate 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 and filtered, and the solvent was distilled off under reduced pressure. The obtained 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] ⁺

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)

Reference Example Compound 4 (500 mg), 4-bromobenzylamine (223 mg) in N,N-dimethylformamide (5.0 mL) solution at room temperature, N,N-diisopropylethylamine (0.52 mL), HATU (456 mg) was added, and the mixture was stirred 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 and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2-90:10) to give the title compound (643 mg) as a pale yellow powder. MS (ESI) m/z: 668.3, 670.3 [M+H] ⁺

(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)

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 hour under microwave irradiation in a nitrogen atmosphere. After allowing to cool to room temperature, the reaction mixture was directly purified by NH silica gel column chromatography (hexane:ethyl acetate=50:50-0:100) to give the title compound (613 mg) as a pale yellow powder. . MS (ESI) m/z: 712.4 [M+H] ⁺

(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)

To a solution of Reference Example compound 10-2 (594 mg) in acetonitrile (12.0 mL)-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. bottom. N-Chlorosuccinimide (23 mg) was added to the reaction mixture, and the mixture was stirred at the same temperature for 0.5 hour. 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 brine, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained 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+H ₂ O] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.75 (3H, d, J=0.64 Hz), 2.41- 2.46 (3H, m), 2.70 (3H, s), 3.66 (2H, dd, J = 7.06, 3.72 Hz), 3.79 (3H, s), 4.44 ( 1H, d, J = 5.65 Hz), 4.67 (1H, dd, J = 7.77, 6.36 Hz), 4.80 (2H, d, J = 6.04 Hz), 7.55-7 .63 (6H, m), 7.68 (2H, m, J = 8.61 Hz), 7.90 (2H, m, J = 8.61 Hz), 8.02 (2H, d, J = 7.61 Hz). 74Hz)

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)

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 heated to room temperature. and stirred for 3 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, and the solvent was distilled off under reduced pressure. The obtained residue was suspended and washed with 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] ⁺

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

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

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)

Reference Example compound 3 (300 mg) was dissolved in tetrahydrofuran (3.0 mL), t-butyl 4-bromo-2-fluorobenzoate (196 mg), tetrakis(triphenylphosphine) palladium (0) (69 mg), phosphoric acid Potassium (377 mg) and water (0.038 mL) were added and stirred at 90° C. for 0.5 hours under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, and the 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 obtain the title compound (346 mg) as a white powder. obtained as an object. MS (ESI) m/z: 575.4 [M+H] ⁺

(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)

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

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)

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

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

To a tetrahydrofuran solution (12.0 mL) of Reference Example compound 9 (622 mg) and pyridine (2.92 mL) was added 4-bromobenzenesulfonyl chloride (929 mg) at room temperature, and the mixture was stirred 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 and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was suspended and washed with chloroform, and then collected by filtration to give the title compound (1061 mg) as a beige powder. MS (ESI) m/z: 390.2, 392.1 [M+H] ⁺

Reference example 15
(15-1) 7-amino-4-bromo-1H-indole-3-carbonitrile (Reference Example Compound 15)

Phenylphosphonyl dichloride (1.27 mL) was added to N,N-dimethylformamide (11.0 mL), and after stirring 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 added, and the mixture was stirred at 70° C. for 1 hour. Then hydroxylamine hydrochloride (2.42 g) was added and stirred at 100° C. for 2 hours. Furthermore, ethylenediamine (2.02 mL) and methanol (22.0 mL) were added, and the mixture was stirred at 70°C for 1 hour. After cooling to room temperature, methanol was distilled off under reduced pressure, and 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, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was suspended and washed with ethyl acetate, collected by filtration and dried under reduced pressure to give 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=50:50-75:25) to give the target compound (104 mg) as a brown solid. Obtained. MS (ESI) m/z: 236.0, 237.9 [M+H] ⁺

Reference example 16
(16-1) 7-bromo-4-ethyl-1H-indole-3-carbonitrile (Reference Example Compound 16-1)

Phenylphosphonyl dichloride (3.64 mL) was added to N,N-dimethylformamide solution (17.4 mL) of 7-bromo-4-ethyl-1H-indole (3.90 g) under ice cooling, and the mixture was stirred at room temperature. Stirred for 30 minutes and 40 minutes at 70°C. Hydroxylamine hydrochloride (2.42 g) was added and 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, cooled with ice, and saturated aqueous sodium bicarbonate was added with stirring. Extract twice with ethyl acetate, combine the extracts, wash twice with a mixture of saturated brine and saturated aqueous sodium bicarbonate, wash once with saturated brine, dry and filter over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure. bottom. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10-70:30), toluene was added to the residue, and concentration under reduced pressure was repeated twice to give the title compound (3.12 g). ) as a pale yellow solid. MS (ESI) m/z: 246.9, 248.9 [MH] ^-

(16-2) 7-amino-4-ethyl-1H-indole-3-carbonitrile (Reference Example Compound 16)

Reference Example Compound 16-1 (2.12 g), benzophenoneimine (2.16 g), [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl) To a mixture of 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, nitrogen atmosphere, under microwave irradiation, Stir at 120° C. for 1 hour. After allowing to cool 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 and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (11.0 mL)-methanol (11.0 mL), hydroxylamine hydrochloride (1.48 g) and sodium acetate (2.09 g) were added at room temperature, and the mixture was stirred at the same temperature for 16 minutes. Stirred for an hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed once with a mixture of saturated saline and water and once with saturated saline, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0-98:2) to give the title compound (954 mg) as a pale brown solid. MS (ESI) m/z: 186.1 [M+H] ⁺

Reference example 17
(17-1) t-butyl [(1R)-1-(4-bromophenyl)ethyl]carbamate (Reference Example compound 17-1)

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 stirred at room temperature for 14 hours. 1N Hydrochloric acid was added to the reaction mixture and the mixture was separated. The aqueous layer was extracted once with chloroform, and the combined organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained 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] ⁺

(17-2) t-butyl {(1R)-1-[4-(benzylsulfanyl)phenyl]ethyl}carbamate (Reference Example compound 17-2)

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), toluene (10.0 mL) was stirred at 150° C. under microwave irradiation for 0.5 h under a nitrogen atmosphere. Ethyl acetate was added to the reaction solution, the insoluble matter was filtered off through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10-80:20) to give the title compound (4.91 g) as a pale yellow solid. MS (ESI) m/z: 344.3 [M+H] ⁺

(17-3) t-butyl {(1R)-1-[4-(chlorosulfonyl)phenyl]ethyl}carbamate (Reference Example compound 17-3)

To a solution of Reference Example Compound 17-2 (2.72 g) in acetonitrile (50.0 mL)-2N hydrochloric acid (10.0 mL) was added N-chlorosuccinimide (4.30 g) under ice-cooling. Stirred for an hour. 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, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10-75:25) to give the title compound (2.21 g) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.32-1.51 (12H, m), 4.87 (2H, brs), 7.48-7.60 (2H, m), 7.93- 8.06 (2H, m)

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

Reference Example Compound 9 (1.18 g) and pyridine (2.77 mL) were added to a solution of Reference Example Compound 17-3 (2.20 g) in tetrahydrofuran (66.0 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours. bottom. 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, and the solvent was distilled off under reduced pressure. The residue was suspended and washed with chloroform 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] ⁺

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

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

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)

Reference Example compound 3 (300 mg) was dissolved in tetrahydrofuran (3.0 mL), t-butyl 4-bromo-3-fluorobenzoate (180 mg), tetrakis(triphenylphosphine) palladium (0) (69 mg), phosphoric acid Potassium (378 mg) and water (0.039 mL) were added and stirred at 90° C. for 0.5 hours under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, and the 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=50:50-0:100) to give the title compound (300 mg) as a white powder. MS (ESI) m/z: 575.3 [M+H] ⁺

(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)

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

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)

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

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)

Reference Example Compound 3 (231 mg) was dissolved in tetrahydrofuran (2.0 mL), 4-bromo-2-methylbenzoic acid (87 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl ( X-Phos, 19 mg), X-Phos aminobiphenylpalladium chloride pre-catalyst (32 mg), cesium fluoride (185 mg) and water (0.50 mL) were added, and the reaction was carried out in a nitrogen atmosphere under microwave irradiation at 120° C. for 0.5 Stirred for an hour. After diluting the reaction solution with ethyl acetate, it was extracted twice with saturated aqueous sodium bicarbonate solution. The aqueous layers were combined, and 2N hydrochloric acid was added little by little under ice-cooling to adjust the pH to 1. The aqueous layer was extracted twice with ethyl acetate, the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to give the title compound (229 mg) as a white powder. obtained as a crude product of MS (ESI) m/z: 515.3 [M+H] ⁺

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)

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. The mixture was stirred at warm 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 and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was suspended in diethyl ether-hexane (1:1), washed, and collected by filtration to give the title compound (730 mg) as a beige solid. MS (ESI) m/z: 453.3 [MH] ^-

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

A 4M hydrogen chloride/1,4-dioxane solution (7.2 mL) was added to Reference Example compound 21-1 (720 mg) 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, followed by filtration to give the title compound (653 mg) as a beige solid. MS (ESI) m/z: 355.0 [M+H] ⁺

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 )

Reference Example Compound 17-3 (570 mg) and pyridine (0.65 mL) were added to a solution of Reference Example Compound 16 (300 mg) in tetrahydrofuran (8.0 mL) at room temperature, and the mixture was stirred 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 and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was suspended and washed with hexane-chloroform (15:1) and collected by filtration to give the title compound (710 mg) as a pale brown solid. MS (ESI) m/z: 467.3 [MH] ^-

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

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

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)

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. , and stirred 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 and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was suspended and washed with diethyl ether-hexane (1:1) and collected by filtration to give the title compound (710 mg) as a beige solid. MS (ESI) m/z: 467.3 [MH] ^-

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

A 4M hydrogen chloride/1,4-dioxane solution (7.0 mL) was added to Reference Example compound 23-1 (702 mg) 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, followed by filtration to give the title compound (610 mg) as a beige solid. MS (ESI) m/z: 369.1 [M+H] ⁺

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)

HATU (46 mg) was added 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) at room temperature. Stirred 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, and the solvent was distilled off under reduced pressure. The obtained 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] ⁺

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)

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 added in N,N-dimethylformamide (3.0 mL) at room temperature. Stirred for 2 hours. Water was added to the reaction solution, the mixture was stirred, and the resulting solid was separated by filtration. Purification by silica gel column chromatography (chloroform:methanol=100:0-95:5) gave the title compound (86 mg) as a white solid. MS (ESI) m/z: 841.6 [M+H] ⁺

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)

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

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)

Reference Example compound 1 (200 mg), t-butylpyrrolidine-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), water (0.043 mL) in tetrahydrofuran (1.0 mL) solvent, 100 Heated to reflux for a minute. The reaction solution was allowed to cool, diluted with ethyl acetate, and washed with water and saturated brine. After drying with anhydrous sodium sulfate, the extract was filtered with 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=100:0-95:5) to give the title compound (266 mg) as a pale yellow powder. MS (ESI) m/z: 550.3 [M+H] ⁺

(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)

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 solution was concentrated under reduced pressure, and the residue was subjected to azeotropic distillation with chloroform-toluene three times. The residue was dissolved in ethyl acetate and N,N-diisopropylethylamine (0.30 mL) was added portionwise while stirring. Hexane (2.5 mL) was added dropwise and stirred at room temperature for 1 hour. The resulting solid was filtered and washed with an ethyl acetate-hexane mixture (2:1) to give the title compound (181 mg) as a yellow powder. MS (ESI) m/z: 494.3 [M+H] ⁺

(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)

Example compound 4-2 (74 mg) was used in place of Reference example compound 12 in Example 2, and the same reaction and treatment as in (2-1) were carried out to obtain the title compound (111 mg) as a yellow powder. . MS (ESI) m/z: 816.3 [M+H] ⁺

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)

Reference Example 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 stirred at 90° C. for 1 h under 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 and filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=98:2-90:10, precolumn: NH silica gel) to give the title compound (63 mg) as a pale yellow viscous. MS (ESI) m/z: 435.3 [M+H] ⁺

(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)

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

(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)

Example compound 5-2 (57 mg), 2-methyl-but-2-ene (0.021 mL) in acetonitrile (3.0 mL) solution, 80% sodium chlorite (18 mg) and sodium dihydrogen phosphate ( 19 mg) in water (1.0 mL) was added, and the mixture was 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 the mixture was allowed to stand at the same temperature for another 30 minutes. Stirred. After the reaction mixture was concentrated under reduced pressure, ethanol was added and the mixture was concentrated again under reduced pressure. Reference example compound 5 (47 mg), N,N-diisopropylethylamine (0.11 mL) and N,N-dimethylformamide (2.0 mL) were added to the resulting residue at room temperature, and finally HATU (57 mg) was added. 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 and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2-90:10) to give the title compound (17 mg) as a beige powder. MS (ESI) m/z: 771.4 [M+H] ⁺

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)

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 A mixture of catalyst (5 mg), potassium phosphate (64 mg) and tetrahydrofuran (0.3 mL) was stirred at 90° C. for 2 hours under microwave irradiation under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=95:5-90:10) to give the title compound (15 mg) as a beige powder. MS (ESI) m/z: 434.3 [M+H] ⁺

(6-2) methyl {(6S)-4-[4-(3-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]benzamide}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)

Example Compound 6-1 (14 mg), Reference Example Compound 6 (13 mg) in N,N-dimethylformamide (0.4 mL) solution at room temperature N,N-diisopropylethylamine (0.11 mL) and HATU (15 mg ) was added, and the mixture was stirred 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 and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=98:2-90:10) to give the title compound (20 mg) as a white powder. MS (ESI) m/z: 771.4 [M+H] ⁺

Example 7
(7-1) 7-bromo-3-chloro-1H-indole (Example compound 7-1)

To a solution of 7-bromo-1H-indole (500 mg) in N,N-dimethylformamide (5.0 mL) was added N-chlorosuccinimide (358 mg) at room temperature, and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium thiosulfate were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-90:10) to give the title compound (577 mg) as a pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.09 (1H, t, J=7.77 Hz), 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)

(7-2) 3-chloro-1H-indol-7-amine (Example compound 7-2)

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

(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]diazepine-6- yl]acetate (Example Compound 7)

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

Example 8
(8-1) 7-bromo-3-chloro-4-methyl-1H-indole (Example Compound 8-1)

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

(8-2) 3-chloro-4-methyl-1H-indol-7-amine (Example compound 8-2)

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

(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)

In Example 7, using Example Compound 8-2 (20 mg) and Reference Example Compound 10 (50 mg) instead of Example Compound 7-2, and performing the same reaction and treatment as in (7-3). afforded the title compound (44 mg) as a gray powder. MS (ESI) m/z: 832.4, 834.4 [M+H] ⁺

Example 9
(9-1) 7-bromo-1H-indole-3-carbonitrile (Example compound 9-1)

In Reference Example 8, 7-bromo-1H-indole (500 mg) was used in place of Reference Example Compound 7, and the title compound (548 mg) was obtained as a pale brown solid by the same reaction and treatment. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.20 (1H, t, J = 7.83 Hz), 7.50 (1H, dd, J = 7.71, 0.77 Hz), 7.73 (1H , d, J = 7.96 Hz), 7.80 (1H, d, J = 2.95 Hz), 8.84 (1H, brs)

(9-2) 7-amino-1H-indole-3-carbonitrile (Example compound 9-2)

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

(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]diazepine-6- yl]acetate (Example Compound 9)

In Example 7, using Example Compound 9-2 (15 mg) and Reference Example Compound 10 (44 mg) instead of Example Compound 7-2, and performing the same reaction and treatment as in (7-3). afforded the title compound (40 mg) as a beige powder. MS (ESI) m/z: 809.4 [M+H] ⁺

Example 10
(10-1) 4-methyl-1H-indol-7-amine (Example compound 10-1)

In Reference Example 9, Reference Example Compound 7 (92 mg) was used in place of Reference Example Compound 8, and the same reaction and treatment were performed to give the title compound (29 mg) as a pale brown solid. MS (ESI) m/z: 147.1 [M+H] ⁺

(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]diazepine-6- yl]acetate (Example compound 10)

In Example 7, using Example Compound 10-1 (28 mg) and Reference Example Compound 10 (120 mg) instead of Example Compound 7-2, and performing the same reaction and treatment as in (7-3). afforded the title compound (107 mg) as a beige powder. MS (ESI) m/z: 798.5 [M+H] ⁺

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)

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 added in N,N-dimethylformamide (3.0 mL) at room temperature. Stirred for 2 hours. Water was added to the reaction solution, the mixture was stirred, and the resulting solid was separated by filtration. Purification by silica gel column chromatography (chloroform:methanol=100:0-95:5) gave the title compound (115 mg) as a pale yellow solid. MS (ESI) m/z: 837.4 [M+H] ⁺

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

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 solution and stirred, the aqueous layer was removed with a Phase Separator, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30-30:70) and silica gel column chromatography (chloroform:methanol=100:0-95:5) to give the title compound (190 mg). Obtained as a pale yellow solid. MS (ESI) m/z: 370.3 [M+H] ⁺

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

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

(12-3) 3-(azidomethyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide (Example compound 12-3)

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

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

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 with chloroform, collected by filtration and dried to give the title compound (60 mg) as a white solid. MS (ESI) m/z: 341.1 [M+H] ⁺

(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)

Example compound 12-4 was used in place of Reference example compound 11 in Example 11 and the same reaction and treatment as in (11-1) were carried out to obtain the title compound as a white solid. MS (ESI) m/z: 823.4 [M+H] ⁺

Example 13
(13-1) 7-bromo-6-methyl-1H-indole (Example Compound 13-1)

By performing the same reaction and treatment using 2-bromo-3-nitrotoluene (2160 mg) instead of 1-bromo-4-methyl-2-nitrobenzene in Reference Example 7, the title compound (1108 mg) was obtained as a white Obtained as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.52 (3H, s), 6.58 (1H, dd, J=3.21, 2.18 Hz), 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)

(13-2) 7-bromo-6-methyl-1H-indole-3-carbonitrile (Example compound 13-2)

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

(13-3) 7-amino-6-methyl-1H-indole-3-carbonitrile (Example compound 13-3)

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

(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)

In Example 7, using Example Compound 13-3 (17 mg) and Reference Example Compound 10 (60 mg) instead of Example Compound 7-2, and performing the same reaction and treatment as in (7-3). gave the title compound (34 mg) as a white powder. MS (ESI) m/z: 823.5 [M+H] ⁺

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)

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

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)

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

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]diazepine- 6-yl]acetate (Example compound 16)

In Example 7, using 2,3-dimethyl-1H-indol-7-amine (17 mg) and Reference Example Compound 10 (50 mg) instead of Example Compound 7-2, the same procedure as in (7-3) By reacting and working up, the title compound (22 mg) was obtained as a brown solid. MS (ESI) m/z: 812.5 [M+H] ⁺

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)

In Example 13, using 1-bromo-4-fluoro-2-nitrobenzene instead of 2-bromo-3-nitrotoluene, and performing the same reaction and treatment as (13-1)-(13-4) gave the title compound as a beige powder. MS (ESI) m/z: 827.5 [M+H] ⁺

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)

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

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)

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

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

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 the mixture was stirred, and the resulting solid was separated by filtration. Saturated sodium bicarbonate water and tetrahydrofuran were added to the solid and stirred, then chloroform was added, the aqueous layer was removed with a Phase Separator, and the organic layer was concentrated under reduced pressure. The residue was suspended and washed with diethyl ether, and then collected by filtration to give the title compound (210 mg) as a yellow solid. MS (ESI) m/z: 371.1 [M+H] ⁺

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

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 the mixture was stirred at room temperature for 5 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution and stirred, then chloroform was added and stirred, the aqueous layer was removed with a Phase Separator, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0-95:5) to give 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 dissolved in tetrahydrofuran (5.4 mL). 0 mL) and stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution and chloroform were added to the reaction mixture and the mixture was stirred, the aqueous layer was removed with a Phase Separator, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30-30:70) to give the title compound (63 mg) as a white solid. MS (ESI) m/z: 368.2 [M+H] ⁺

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

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

(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)

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

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)

Under an argon stream, 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 solution 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=70:30-20:80) to give the title compound (680 mg) as a pale yellow solid. MS (ESI) m/z: 562.5 [M+H] ⁺

(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)

A 4M hydrogen chloride/1,4-dioxane solution (2.0 mL) was added to a solution of Example Compound 21-1 (217 mg) in methanol (0.5 mL), and the mixture was 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, collected by filtration and dried to give the title compound (198 mg) as a yellow solid. MS (ESI) m/z: 462.2 [M+H] ⁺

(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)

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

Example 22
(22-1) 7-bromo-1H-indole-4-carbonitrile (Example compound 22-1)

In Reference Example 7, using 4-bromo-3-benzonitrile (2270 mg) instead of 1-bromo-4-methyl-2-nitrobenzene, the title compound (540 mg) was obtained by the same reaction and treatment. Obtained as a pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 6.86 (1H, dd, J = 3.21, 2.18 Hz), 7.36 (1H, d, J = 8.35 Hz), 7.41 (1H , d, J = 7.83 Hz), 7.46 (1H, t, J = 3.21 Hz), 8.65 (1H, brs)

(22-2) 7-amino-1H-indole-4-carbonitrile (Example compound 22-2)

Example compound 22-1 (100 mg) was used in place of Reference example compound 8 in Reference example 9, and the same reaction and treatment were carried out to give the title compound (53 mg) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 6.06 (2H, s), 6.34-6.41 (2H, m), 7.22 (1H, d, J = 7.96 Hz), 7 .49 (1H, t, J=2.83Hz), 11.15 (1H, brs)

(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]diazepine-6- yl]acetate (Example Compound 22)

In Example 7, using Example Compound 22-2 (29 mg) and Reference Example Compound 10 (80 mg) instead of Example Compound 7-2, and performing the same reaction and treatment as in (7-3). gave the title compound (26 mg) as a white powder. MS (ESI) m/z: 809.4 [M+H] ⁺

Example 23
(23-1) 7-bromo-1H-indole-3,4-dicarbonitrile (Example compound 23-1)

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

(23-2) 7-amino-1H-indole-3,4-dicarbonitrile (Example Compound 23-2)

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

(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]diazepine- 6-yl]acetate (Example Compound 23)

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

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

Using 4-[3-(trifluoroacetamido)propyl]benzenesulfonyl chloride in place of methyl 5-(chlorosulfonyl)pyridine-2-carboxylate in Example 20, react and treat in the same manner as in (20-1). Thus, the title compound was obtained as a brown powder. MS (ESI) m/z: 465.2 [M+H] ⁺

(24-2) 4-(3-aminopropyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide (Example compound 24-2)

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 distilled off under reduced pressure, and water was added and stirred. 1N Hydrochloric acid (5 mL) was added and stirred, and the resulting solid was filtered off. A gray solid was obtained by suspension washing with water and drying. Potassium carbonate (273 mg), water (0.5 mL) and methanol (5.0 mL) were added to this solid, and the mixture was heated under reflux for 6 hours. Methanol was distilled off under reduced pressure, and water was added and stirred. 1N Hydrochloric acid was added and the mixture was stirred, and the resulting solid was separated by filtration. The suspension was washed with water, collected by filtration and dried to give the title compound (453 mg) as a gray solid. MS (ESI) m/z: 369.2 [M+H] ⁺

(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)

Example compound 24-2 was used in place of Reference example compound 11 in Example 11 and the same reaction and treatment as in (11-1) were carried out to obtain the title compound as a beige solid. MS (ESI) m/z: 851.7 [M+H] ⁺

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)

In Reference Example 10, by using 4-bromo-3-fluorophenylmethanamine hydrochloride instead of 4-bromobenzylamine and performing the same reaction and treatment as for (10-1)-(10-3) , to obtain the title compound as a pale yellow powder. MS (ESI) m/z: 688.4 [M-Cl + _H2O ] ⁺

(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)

In Example 7, using Reference Example Compound 9 (26 mg) instead of Example Compound 7-2, and Example Compound 25-1 (97 mg) instead of Example Compound 10, the same as in (7-3) The title compound (69 mg) was obtained as a beige powder by the reaction and treatment of . MS (ESI) m/z: 841.5 [M+H] ⁺

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)

Reference Example Compound 4 (100 mg), (1R)-1-(4-bromophenyl)ethanamine (48 mg), N,N-diisopropylethylamine (0.10 mL), HATU (91 mg) of 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 and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2-90:10) to give the title compound (156 mg) as a crude pale-yellow powder. MS (ESI) m/z: 682.4, 684.4 [M+H] ⁺

(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)

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 hour under microwave irradiation under nitrogen atmosphere. After allowing to cool to room temperature, the reaction mixture was directly purified by NH silica gel column chromatography (hexane:ethyl acetate=50:50-0:100) to give the title compound (126 mg) as a pale yellow powder. MS (ESI) m/z: 726.5 [M+H] ⁺

(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)

To a solution of Example Compound 26-2 (124 mg) in acetonitrile (2.5 mL)-2N hydrochloric acid (0.50 mL) was added N-chlorosuccinimide (80 mg) 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 mixture, 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, and the solvent was distilled off under reduced pressure. To a solution of the obtained residue and Reference Example compound 9 (33 mg) in tetrahydrofuran (5.0 mL) was added pyridine (0.14 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 mixture, and the mixture was extracted once with chloroform-methanol and twice with chloroform. The combined organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (chloroform:methanol=90:10-50:50) and then purified again by silica gel column chromatography (chloroform:methanol=98:2-90:10). , to obtain the crude product of the title compound. The entire crude product was purified by preparative HPLC (10 mM aqueous ammonium carbonate solution-acetonitrile) to give the title compound (16 mg) as a white powder. MS (ESI) m/z: 837.5 [M+H] ⁺

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)

Similar to (25-1)-(25-2) using 4-bromo-2-fluorophenylmethanamine hydrochloride instead of 4-bromo-3-fluorophenylmethanamine hydrochloride in Example 25. The title compound was obtained as a beige powder by reaction and work-up. MS (ESI) m/z: 841.5 [M+H] ⁺

Example 28
(28-1) methyl [(6S)-4-{4′-[(1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}-2-hydroxy 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 28)

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

Example 29
(29-1) 3,4-dimethyl-1H-indol-7-amine (Example compound 29-1)

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

(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]diazepine- 6-yl]acetate (Example compound 29)

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 solution was concentrated under reduced pressure and azeotroped with toluene. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0-95:5) and silica gel column chromatography (ethyl acetate:methanol=100:0-95:5) to give the title compound (57 mg). Obtained as a pale yellow solid. MS (ESI) m/z: 812.7 [M+H] ⁺

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)

Similar reaction to (25-1)-(25-2) using 4-(4-bromophenyl)piperidine hydrochloride instead of 4-bromo-3-fluorophenylmethanamine hydrochloride in Example 25 , to obtain the title compound as a white powder. MS (ESI) m/z: 877.6 [M+H] ⁺

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

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

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

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

(31-3) methyl [(6S)-4-{4′-[(3-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}propa-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)

Example Compound 31-2 (65 mg), Reference Example Compound 4 (80 mg) in N,N-dimethylformamide (1.6 mL) solution, N,N-diisopropylethylamine (0.083 mL) and HATU (73 mg) at room temperature ) was added, and the mixture was stirred 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 matter 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, and the solvent was distilled off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (chloroform:methanol=95:5-50:50, pre-column: silica gel) to give the title compound (103 mg) as a white powder. MS (ESI) m/z: 847.5 [M+H] ⁺

Example 32
(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)

Reference Example compound 2 (150 mg), 4-(methoxycarbonyl)phenylboronic acid (81 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl aminobiphenyl palladium chloride precatalyst (15 mg), carbonic acid Sodium (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 and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=80:20-0:100) to give the title compound (161 mg) as a white powder. MS (ESI) m/z: 457.3 [M+H] ⁺

(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)

A 1N aqueous sodium hydroxide solution (0.32 mL) was added to a solution of Example Compound 32-1 (73 mg) in methanol (3.0 mL), and the mixture was stirred at room temperature for 9 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was 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, the mixture was stirred, and the resulting solid was separated by filtration. Purification by silica gel column chromatography (chloroform:methanol=100:0-95:5) gave the title compound (100 mg) as a white solid. MS (ESI) m/z: 765.6 [M+H] ⁺

Example 33
(33-1) Methyl 7-bromo-1H-indole-4-carboxylate (Example Compound 33-1)

To a tetrahydrofuran solution (30.0 mL) of methyl 4-bromo-3-nitrobenzoate (2600 mg) was added a 1M vinylmagnesium bromide/tetrahydrofuran solution (25.0 mL) at -78°C over 5 minutes. After stirring at the same temperature for 1 hour, saturated aqueous ammonium chloride solution and water were added to the reaction solution, and the temperature was raised to room temperature. After liquid separation, the aqueous layer was extracted once with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained 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] ⁺

(33-2) Methyl 7-bromo-3-cyano-1H-indole-4-carboxylate (Example Compound 33-2)

Phenylphosphonyl dichloride (1.0 mL) was added to an N,N-dimethylformamide solution (4.0 mL) of Example Compound 33-1 (1000 mg) at room temperature. After stirring at 100°C for 20 minutes, N,N-dimethylformamide (4.0 mL) was added, and the mixture was further stirred at 100°C for 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 allowing to cool 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 and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (703 mg) as a crude brown solid. MS (ESI) m/z: 279.2, 281.2 [M+H] ⁺

(33-3) 7-bromo-4-(hydroxymethyl)-1H-indole-3-carbonitrile (Example compound 33-3)

To a suspension of Example Compound 33-2 (391 mg) in tetrahydrofuran (16.0 mL) was added dropwise a 2.5 M lithium aluminum hydride/tetrahydrofuran solution (1.70 mL) under ice cooling. After stirring at the same temperature for 10 minutes, 1N 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, and the solvent was distilled off under reduced pressure. The obtained residue was suspended and washed with chloroform 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] ⁺ ; ¹ H NMR (400 MHz, DMSO-d6) δ ppm 4.94 (2H, d, J = 5.27 Hz), 5 .33 (1H, t, J = 5.33 Hz), 7.10-7.27 (1 H, m), 7.48 (1 H, d, J = 7.83 Hz), 8.31 (1 H, s) , 12.44 (1H, brs)

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

Example compound 33-3 (267 mg), benzophenoneimine (270 mg), [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium (II ) (Pd-PEPPSI-IPent catalyst, 26 mg), to a mixture of tetrahydrofuran (7.0 mL), 1.3 M lithium bis (trimethylsilyl) amide / tetrahydrofuran solution (2.9 mL) was added at room temperature, nitrogen atmosphere, microwave Stir at 140° C. for 0.5 hours under irradiation. 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 under microwave irradiation at 160° C. for 0.5 hour under nitrogen atmosphere. After allowing to cool 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 and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2) and purified again by NH silica gel column chromatography (chloroform:methanol=98:2) to give the title compound (59 mg). was obtained as a pale yellow solid. MS (ESI) m/z: 352.2 [M+H] ⁺

(33-5) 7-amino-4-(hydroxymethyl)-1H-indole-3-carbonitrile (Example compound 33-5)

Example compound 33-4 (57 mg) was dissolved in tetrahydrofuran (1.0 mL)-methanol (1.0 mL), hydroxylamine hydrochloride (28 mg) and sodium acetate (40 mg) were added at room temperature, and the mixture was stirred at the same temperature. Stirred for 2 hours. A saturated aqueous solution of 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 and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (chloroform:methanol=98:2-80:20) to give the title compound (14 mg) as a pale brown solid. MS (ESI) m/z: 170.1 [M-OH] ⁺ , ¹ H NMR (400 MHz, DMSO-d6) δ ppm 4.74-4.83 (3H, m), 5.22 (2H, s ), 6.42 (1H, d, J = 7.7 Hz), 6.91 (1H, d, J = 7.7 Hz), 8.12 (1H, s), 11.75 (1H, brs)

(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)

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 the mixture was stirred at the same temperature for 14 hours. The reaction mixture was diluted with ethyl acetate-methanol, washed once with saturated brine-water (1:1) and once with saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified twice by silica gel column chromatography (chloroform:methanol=98:2-90:10) to give the title compound (29 mg) as a beige powder. MS (ESI) m/z: 839.5 [M+H] ⁺

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]diazepine -6-yl]acetic acid (Example compound 34)

To a mixed solution of example compound 1 (295 mg) in tetrahydrofuran (2.0 mL)-methanol (2.0 mL) was added 2N lithium hydroxide aqueous solution (0.72 mL), and the mixture was 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, collected by filtration and dried to give the title compound (258 mg) as a yellow powder. MS (ESI) m/z: 809.4 [M+H] ⁺

Example 35
(35-1) t-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboronan-2-yl)-1-benzofuran-2-carboxylate (Example compound 35-1 )

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 1,4-dioxane (17 mL) was added to a mixture of (206 mg) and potassium acetate (991 mg), and after purging with nitrogen, the mixture was heated and stirred at 130° C. for 30 minutes under microwave irradiation. Water, ethyl acetate and activated charcoal were added to the reaction solution, insoluble matter was removed by filtration through diatomaceous earth, and the filtrate was washed with ethyl acetate. The filtrate was separated, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-90:10) to give the title compound (1.38 g) as a pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.37 (12 H, s), 1.63 (9 H, s), 7.40 (1 H, d, J = 1.0 Hz), 7.56 (1 H, d , J = 8.7 Hz), 7.87 (1H, dd, J = 1.3, 8.5 Hz), 8.15 (1H, s)

(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)

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 A mixture of chloride precatalyst (15 mg), potassium phosphate (123 mg), water (0.013 mL) and tetrahydrofuran (1.0 mL) was stirred at 90° C. under microwave irradiation for 0.5 h under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=50:50-0:100) to give the title compound (115 mg) as a white powder. MS (ESI) m/z: 597.5 [M+H] ⁺

(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)

Trifluoroacetic acid (1.0 mL) was added to a solution of Example Compound 35-2 (111 mg) in dichloromethane (1.0 mL), and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction solution, toluene was added and the solvent was distilled off. 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, The mixture was stirred at the same temperature for 1 hour. After diluting the reaction solution with ethyl acetate, it was added to saturated aqueous sodium bicarbonate solution, and 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 saline-water (1:1) and once with saturated saline. The filtrate (A) was dissolved in chloroform, combined with the organic layer (B), dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (104 mg) as a white powder. MS (ESI) m/z: 863.5 [M+H] ⁺

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)

6-Amino-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1 described in Japanese Patent Publication (JP-A-7-17941, Raw Material Preparation Example 1) ,2,4]triazolo[4,3-a][1,4]diazepine (200 mg) in dichloromethane (6.0 mL) was added with methyl chloroformate (0.048 mL) and N,N- Diisopropylethylamine (0.15 mL) was added, and the mixture was stirred at the same temperature for 0.5 hours. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0-97:3) to give the title compound (233 mg) as a pale orange powder. MS (ESI) m/z: 416.3 [M+H] ⁺

(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)

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) of the mixture was stirred at 90° C. for 0.5 h 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, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=50:50-0:100) to give the title compound (39 mg) as a white powder. MS (ESI) m/z: 558.4 [M+H] ⁺

(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]diazepine-6- yl) carbamate (Example compound 36)

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

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)

Example compound 34 (100 mg), 2-aminoethanol (12 mg), N,N-diisopropylethylamine (0.064 mL), HATU (56 mg) in N,N-dimethylformamide (3.0 mL) at room temperature for 2 hours Stirred. Water was added to the reaction mixture, and the mixture was 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=100:0-80:20) to give the title compound (97 mg) as a white solid. MS (ESI) m/z: 852.5 [M+H] ⁺

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]diazepine-4 -yl}[1,1′-biphenyl]-4-carboxamide (Example Compound 38)

In Example 37, dimethylamine hydrochloride was used instead of 2-aminoethanol and the same reaction and treatment as in (37-1) were carried out to give the title compound as a milky white solid. MS (ESI) m/z: 836.5 [M+H] ⁺

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)

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

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)

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

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)

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] ⁺

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)

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

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)

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 solution was diluted and dissolved with a mixed solution of tetrahydrofuran-ethyl acetate (1:1) and a small amount of methanol. The organic layer was washed once with a mixture of saturated brine and 1N hydrochloric acid, once with saturated brine, once with saturated aqueous sodium bicarbonate, and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and filtered under reduced pressure. The solvent was distilled off. The resulting 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] ⁺

Example 44
(44-1) 7-amino-4-cyclopropyl-1H-indole-3-carbonitrile (Example Compound 44-1)

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

(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)

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

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)

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

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)

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

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)

In Reference Example 18, the same procedure was performed using Reference Example Compound 3 (300 mg) and 4-bromo-3-fluorobenzoate t-butyl 4-bromo-3-chlorobenzoate (207 mg) instead of 4-bromo-3-fluorobenzoate t-butyl. By reaction and work-up, the title compound (374 mg) was obtained as a crude white powder. MS (ESI) m/z: 591.4, 593.4 [M+H] ⁺

(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)

Example compound 47-1 (180 mg) was used in place of Reference example compound 18-1 in Example 45, and the same reaction and treatment were performed to give the title compound (221 mg) as a beige powder. . MS (ESI) m/z: 857.5, 859.5 [M+H] ⁺

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)

Example compound 47-1 (180 mg) was used in place of Reference example compound 18-1 in Example 46, and the same reaction and treatment were performed to give the title compound (189 mg) as a beige powder. . MS (ESI) m/z: 871.5, 873.5 [M+H] ⁺

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)

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

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)

Reference Example compound 3 (100 mg) was dissolved in tetrahydrofuran (2.0 mL), t-butyl 4-bromo-2-methylbenzoate (65 mg), tetrakis(triphenylphosphine) palladium (0) (23 mg), phosphoric acid Potassium (126 mg) and water (0.013 mL) were added and stirred at 90° C. for 0.5 hours under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, and the 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=50:50-0:100) to give the title compound (117 mg) as a crude white powder. rice field. MS (ESI) m/z: 571.3 [M+H] ⁺

(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)

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

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)

In Example 50, using t-butyl 4-bromo-2-trifluoromethylbenzoate instead of t-butyl 4-bromo-2-methylbenzoate, (50-1)-(50-2) The title compound was obtained as a white powder by the same reaction and treatment. MS (ESI) m/z: 891.5 [M+H] ⁺

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)

Similar to (50-1)-(50-2) in Example 50 using t-butyl 4-bromo-2-methoxybenzoate instead of t-butyl 4-bromo-2-methylbenzoate. The title compound was obtained as a white powder by the reaction and treatment. MS (ESI) m/z: 853.5 [M+H] ⁺

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)

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

(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]diazepine-6 -yl]acetate (Example Compound 53)

Trifluoroacetic acid (1.0 mL) was added to a solution of Example Compound 53-1 (109 mg) in chloroform (1.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution 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, and the mixture was 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=100:0-95:5) to give the title compound (104 mg) as a milky white solid. MS (ESI) m/z: 824.7 [M+H] ⁺

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]diazepine-6 -yl]acetate (Example Compound 54)

Similar reactions to (53-1)-(53-2) using t-butyl 6-bromopyridine-3-carboxylate instead of t-butyl 5-bromopyridine-2-carboxylate in Example 53, Work-up gave the title compound as an off-white solid. MS (ESI) m/z: 824.7 [M+H] ⁺

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)

methyl [(6S)-4-(4-chlorophenyl)-2-(hydroxymethyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2, as described in WO2006/129623; 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), S-phos (24 mg) was heated under reflux for 3 Stirred for an hour. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=99:1-90:10) to give the title compound (610 mg) as a milky white solid. MS (ESI) m/z: 573.2 [M+H] ⁺

(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)

Trifluoroacetic acid (1.0 mL) was added to a solution of Example Compound 55-1 (80 mg) in dichloromethane (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), N,N-diisopropylethylamine (0.073 mL) was added at room temperature, and HATU was stirred under ice cooling. (69 mg) was added and stirred at room temperature for 7 hours. A mixture of ethyl acetate-tetrahydrofuran (1:1) was added to dilute the reaction solution, 1N hydrochloric acid and saturated brine were added, and the layers were separated. The organic layer was washed once with saturated aqueous sodium chloride solution, once with saturated aqueous sodium bicarbonate solution and once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0-85:15) to give the title compound (51 mg) as a pale yellow solid. MS (ESI) m/z: 839.4 [M+H] ⁺

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)

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)- A mixture of carboxylate (208 mg), X-Phos aminobiphenyl palladium chloride pre-catalyst (38 mg), X-Phos (23 mg), potassium phosphate (307 mg), water (0.031 mL) and tetrahydrofuran (2.4 mL) was prepared in a microscope. Stir at 90° C. for 0.5 hours under wave 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, and the solvent was distilled off 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 distilled off under reduced pressure, followed by azeotropic concentration with toluene, and the resulting 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] ⁺

(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)

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

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

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 stirred at the same temperature for 1.5 hours. bottom. The reaction mixture was diluted with ethyl acetate, saturated brine and 1N hydrochloric acid were added, and the mixture was partitioned. The organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to give the title compound (580 mg) as a brown solid. MS (ESI) m/z: 328.1 [MH] ^-

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

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 hour under microwave irradiation. Saturated brine was added to the reaction solution, and the mixture was extracted three times with a mixed solution of ethyl acetate-tetrahydrofuran (1:1). The extracts were combined, washed once with a small amount of saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained 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] ⁺

(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)

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) in a mixture, HATU under ice cooling (49 mg) was added, 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 and filtered, and the solvent was distilled off under reduced pressure. . The residue was suspended and washed with acetonitrile-water, collected by filtration, and washed with water to give the title compound (45 mg) as a pink powder. MS (ESI) m/z: 852.5 [M+H] ⁺

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

3-(4-bromophenyl)propan-1-ol (1000 mg), benzyl mercaptan (0.55 mL), N,N-diisopropylethylamine (2.41 mL), 4,5-bis(diphenylphosphino)-9, A mixture of 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=60:40-20:80, precolumn: NH silica gel) to give the title compound (681 mg) as a red solid. rice field. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.23 (1H, t, J=5.3 Hz), 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)

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

In a toluene (3.0 mL) solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (200 mg) and Example compound 58-1 (281 mg), Cyanomethylenetrimethylphosphorane (157 mg) was added at room temperature and stirred at 150° C. for 0.5 hour under nitrogen atmosphere and microwave irradiation. 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 and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to give the title compound (338 mg) as a colorless viscous. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.33 (12 H, s), 2.00-2.12 (2 H, m), 2.76 (2 H, t, J=7.6 Hz), 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 = 8.3 Hz), 7.25-7.28 (4H, m), 7.74 (2H, d, J = 8.7 Hz)

(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)

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) A mixture of methanesulfonate precatalyst (21 mg), potassium phosphate (154 mg), water (0.016 mL) and tetrahydrofuran (1.2 mL) was heated at 90° C. under microwave irradiation to 0.5 Stirred for an hour. Example compound 58-2 (67 mg), X-Phos (12 mg), X-Phos aminobiphenyl palladium(II) methanesulfonate precatalyst (21 mg) were added, and the reaction was carried out for 1 at 90° C. under microwave irradiation in a nitrogen atmosphere. Stirred for an hour. The reaction solution was diluted with ethyl acetate, and the 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=50:50-0:100) to give the title compound (147 mg) as pale yellow powder. MS (ESI) m/z: 713.5 [M+H] ⁺

(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)

To a solution of Example Compound 58-3 (141 mg) in acetonitrile (3.0 mL)-2N hydrochloric acid (0.60 mL) was added N-chlorosuccinimide (93 mg) under ice cooling, and the mixture was stirred at the same temperature for 1.5 hours. bottom. Additional N-chlorosuccinimide (6 mg) was added, and the mixture was stirred at the same temperature for 0.5 hour. The reaction mixture was diluted with ethyl acetate, washed successively with saturated brine-water (1:1) and saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained 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 + _H2O ] ⁺

(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]diazepine -6-yl}acetate (Example Compound 58)

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 the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in chloroform, washed once with 1N hydrochloric acid and once with saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (chloroform:methanol=95:5-50:50) and then purified again by silica gel column chromatography (chloroform:methanol=98:2-95:5). , to give the title compound (52 mg) as a pale brown powder. MS (ESI) m/z: 824.5 [M+H] ⁺

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)

Example compound 3 (100 mg), t-butyl 5-bromothiophene-2-carboxylate (78 mg), tetrakis(triphenylphosphine) palladium (0) (23 mg), potassium phosphate (126 mg), water (0.014 mL ) was stirred in tetrahydrofuran (4.0 mL) at 100° C. for 0.5 h under nitrogen atmosphere and microwave irradiation. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0-95:5) to give the title compound (89 mg) as a pale yellow solid. MS (ESI) m/z: 563.2 [M+H] ⁺

(59-2) methyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl] thiophen-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6 -yl]acetate (Example Compound 59)

Trifluoroacetic acid (1.0 mL) was added to a solution of Example Compound 59-1 (89 mg) in chloroform (1.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and azeotroped twice with toluene. The residue, Reference Example compound 5 (59 mg), N,N-diisopropylethylamine (0.14 mL) and HATU (72 mg) were 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 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=100:0-95:5) to give the title compound (117 mg) as a beige solid. MS (ESI) m/z: 829.6 [M+H] ⁺

Example 60
(60-1) methyl [(6S)-4-{4′-[({trans-3-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]cyclobutyl}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 60)

(20-1)-(20-4) using methyl trans-3-(chlorosulfonyl)cyclobutane-1-carboxylate instead of methyl 5-(chlorosulfonyl)pyridine-2-carboxylate in Example 20 The title compound was obtained as a beige solid by the same reaction and treatment as above. MS (ESI) m/z: 801.7 [M+H] ⁺

Example 61
(61-1) methyl [(6S)-4-(4-{2-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl] -1-benzothiophen-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 61)

As for (50-1)-(50-2) in Example 50 using t-butyl 5-bromobenzothiophene-2-carboxylate instead of t-butyl 4-bromo-2-methylbenzoate The title compound was obtained as a white powder by the reaction and treatment of . MS (ESI) m/z: 879.5 [M+H] ⁺

Example 62
(62-1) methyl [(6S)-4-(4-{2-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl] -1-benzothiophen-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 62)

As for (50-1)-(50-2) in Example 50 using t-butyl 6-bromobenzothiophene-2-carboxylate instead of t-butyl 4-bromo-2-methylbenzoate The title compound was obtained as a white powder by the reaction and treatment of . MS (ESI) m/z: 879.5 [M+H] ⁺

Example 63
(63-1) benzyl 4′-[(6S)-6-(2-t-butoxy-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 63-1)

t-butyl [(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 (100 mg), (4-benzyloxycarbonylphenyl)boronic acid (68 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X- Phos, 11 mg), X-Phos aminobiphenylpalladium chloride precatalyst (18 mg), potassium phosphate (140 mg), water (0.015 mL) and tetrahydrofuran (1.5 mL) was treated under microwave irradiation under nitrogen atmosphere. Stir at 90° C. for 0.5 hours. The reaction solution was diluted with ethyl acetate, and the 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=98:2) to give the title compound (107 mg) as pale yellow powder. MS (ESI) m/z: 633.5 [M+H] ⁺

(63-2) 4′-[(6S)-6-(2-t-butoxy-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 (Example compound 63-2)

Example compound 63-1 (103 mg) was dissolved in methanol (5.0 mL), 10% palladium hydroxide on carbon (46 mg) was added, the reaction vessel was purged with hydrogen, and the mixture was stirred at room temperature for 1 hour. After purging the reaction vessel with nitrogen, the reaction solution was filtered, and the solvent was concentrated under reduced pressure to obtain the crude title compound (89 mg) as a pale yellow powder. MS (ESI) m/z: 543.4 [M+H] ⁺

(63-3) 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 (Example compound 63)

Example Compound 63-2 (43 mg), Reference Example Compound 5 (30 mg) in N,N-dimethylformamide (1.0 mL) solution, N,N-diisopropylethylamine (0.027 mL) and HATU (37 mg) at room temperature ) was added, and the mixture was stirred at the same temperature for 3 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 and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (38 mg) as a beige powder. MS (ESI) m/z: 865.5 [M+H] ⁺

Example 64
(64-1) 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 (Example Compound 64)

Example Compound 63-2 (43 mg), Reference Example Compound 11 (34 mg) in N,N-dimethylformamide (1.0 mL) solution, at room temperature N,N-diisopropylethylamine (0.041 mL) and HATU (37 mg ) was added, and the mixture was stirred at the same temperature for 3 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 and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (49 mg) as a white powder. MS (ESI) m/z: 879.6 [M+H] ⁺

Example 65
(65-1) 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}pyrazine-2-carboxylate (Example Compound 65-1)

Example compound 3 (100 mg), t-butyl 5-bromopyrazine-2-carboxylate (77 mg), tetrakis(triphenylphosphine) palladium (0) (23 mg), potassium phosphate (126 mg), water (0.014 mL ) was stirred in tetrahydrofuran (4.0 mL) at 100° C. for 0.5 h under nitrogen atmosphere and microwave irradiation. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0-95:5) to give the title compound (97 mg) as a pale yellow solid. MS (ESI) m/z: 559.3 [M+H] ⁺

(65-2) 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]diazepine-6 -yl]acetate (Example compound 65)

Trifluoroacetic acid (1.0 mL) was added to a solution of Example Compound 65-1 (97 mg) in chloroform (1.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and azeotroped twice with toluene. The residue, Reference Example compound 5 (65 mg), N,N-diisopropylethylamine (0.15 mL) and HATU (79 mg) were stirred in N,N-dimethylformamide (3.0 mL) at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was 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=100:0-95:5) to give the title compound (111 mg) as a beige solid. MS (ESI) m/z: 825.4 [M+H] ⁺

Example 66
(66-1) methyl [(6S)-4-(4-{2-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl] -1-benzofuran-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 66)

Similar to (50-1)-(50-2) in Example 50 using t-butyl 6-bromobenzofuran-2-carboxylate instead of t-butyl 4-bromo-2-methylbenzoate. The title compound was obtained as a white powder by the reaction and treatment. MS (ESI) m/z: 863.5 [M+H] ⁺

Example 67
(67-1) [4-(benzylsulfanyl)phenyl]methanol (Example compound 67-1)

(4-bromophenyl)methanol (2000 mg), benzyl mercaptan (1.51 mL), N,N-diisopropylethylamine (2.78 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos , 1237 mg), tris(dibenzylideneacetone)dipalladium (980 mg), and toluene (10.0 mL) was stirred at 150° C. for 0.5 hour under microwave irradiation in a nitrogen atmosphere. After allowing to cool to room temperature, insoluble matter was removed by filtration, and the filtered matter was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=90:10-50:50, precolumn: NH silica gel) to give the title compound (2141 mg) as a pale yellow solid. rice field. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.61 (1H, t, J = 5.91 Hz), 4.11 (2H, s), 4.65 (2H, d, J = 5.91 Hz), 7.17-7.35 (9H, m)

(67-2) 1-(benzylsulfanyl)-4-(chloromethyl)benzene (Example compound 67-2)

Thionyl chloride (0.21 mL) was added to a toluene (5.6 mL) suspension of Example Compound 67-1 (556 mg) at room temperature, and the mixture was stirred at the same temperature for 0.5 hour. The reaction mixture was diluted with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to give the title compound (592 mg) as a crude pale brown solid. Obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.13 (2H, s), 4.54 (2H, s), 7.18-7.35 (9H, m)

(67-3) 2-{[4-(benzylsulfanyl)phenyl]methyl}-6-bromo-3,4-dihydroisoquinolin-1(2H)-one (Example compound 67-3)

To a solution of 6-bromo-3,4-dihydro-2H-isoquinolin-1-one (500 mg) in N,N-dimethylformamide (5.0 mL) was added sodium hydride (115 mg, 60%, in liquid paraffin) at room temperature. dispersion) was added and stirred for 10 minutes, a solution of example compound 67-2 (585 mg) in N,N-dimethylformamide (5.0 mL) was added, and the mixture was stirred at the same temperature for 2 hours. 1N Hydrochloric acid and ethyl acetate were added to the reaction mixture to separate the layers. The organic layer was washed twice with saturated brine-water (1:1) and once with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10-80:20) to give the title compound (717 mg) as a pale yellow solid. MS (ESI) m/z: 438.2, 440.2 [M+H] ⁺

(67-4) methyl {(6S)-4-[4-(2-{[4-(benzylsulfanyl)phenyl]methyl}-1-oxo-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 67-4)

Reference Example Compound 3 (100 mg) was dissolved in tetrahydrofuran (1.3 mL), Example Compound 67-3 (104 mg), tetrakis(triphenylphosphine)palladium (0) (23 mg), potassium phosphate (126 mg) and water. (0.013 mL) was added and stirred at 90° C. for 0.5 hour under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, and the 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=50:50-0:100) to give the title compound (151 mg) as a crude white powder. rice field. MS (ESI) m/z: 738.5 [M+H] ⁺

(67-5) methyl [(6S)-4-{4′-[{[4-(chlorosulfinyl)phenyl]methyl}(ethyl)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 67-5)

To a suspension of Example Compound 67-4 (145 mg) in acetonitrile (3.0 mL)-2N hydrochloric acid (0.60 mL) was added N-chlorosuccinimide (92 mg) under ice-cooling, and the mixture was heated to 1.5 at the same temperature. Stirred for an hour. Additional N-chlorosuccinimide (8 mg) was added, and the mixture was stirred at the same temperature for 0.5 hour. The reaction mixture was diluted with ethyl acetate, washed successively with saturated brine-water (1:1) and saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=98:2) to give the title compound (80 mg) as a white powder. MS (ESI) m/z: 696.4 [M—Cl+H ₂ O] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.74 (3H, d, J=0.6 Hz), 2.43 ( 3H, d, J = 0.6 Hz), 2.69 (3H, s), 3.08 (2H, t, J = 6.7 Hz), 3.59 (2H, t, J = 6.6 Hz), 3.67 (2H, dd, J = 7.1, 4.1 Hz), 3.79 (3H, s), 4.66 (1H, dd, J = 7.8, 6.4 Hz), 4.91 (2H, s), 7.41 (1H, d, J=1.3 Hz), 7.51-7.64 (7H, m), 7.96-8.07 (2H, m), 8.20 (1H, d, J=8.2Hz)

(67-6) methyl [(6S)-4-(4′-{[(4-{[(3-cyano-4-methyl-1H-indol-7-yl)amino]sulfinyl}phenyl)methyl]( Ethyl)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 67)

To a solution of Example compound 67-5 (77 mg) and Reference example compound 9 (22 mg) in tetrahydrofuran (1.5 mL), pyridine (0.085 mL) was added at room temperature and the mixture was stirred at the same temperature for 16 hours. Chloroform was added to the reaction mixture, and the mixture was washed once with 1N hydrochloric acid and once with saturated brine. The aqueous layer was extracted once with chloroform, and the combined organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (70 mg) as a beige solid. MS (ESI) m/z: 849.5 [M+H] ⁺

Example 68
(68-1) methyl [(6S)-4-(4′-{[2-(3-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 68-1)

By using 3-bromophenethylamine in place of Reference Example Compound 11 in Example 11 and performing the same reaction and treatment as in (11-1), the title compound was obtained as a white solid. MS (ESI) m/z: 682.2, 684.2 [M+H] ⁺

(68-2) methyl {(6S)-4-[4′-({2-[3-(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 68-2 )

Example compound 68-1 (183 mg), benzyl mercaptan (0.038 mL), tris(dibenzylideneacetone) dipalladium (25 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyl under nitrogen stream Xanthene (31 mg) and N,N-diisopropylethylamine (0.070 mL) were stirred in a toluene (3.0 mL)-tetrahydrofuran (1.5 mL) mixed solvent at 150° C. for 0.5 hour under microwave irradiation. Purification by silica gel column chromatography (chloroform:methanol=100:0-95:5) gave the title compound (193 mg) as a yellow solid. MS (ESI) m/z: 726.4 [M+H] ⁺

(68-3) methyl {(6S)-4-[4′-({2-[3-(chlorosulfonyl)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 68-3 )

Acetonitrile (5.0 mL)-2N hydrochloric acid (1.0 mL) mixed solution of Example compound 68-2 (193 mg) was cooled to 0° C., N-chlorosuccinimide (124 mg) was added, and the mixture was stirred at the same temperature for 3 hours. bottom. Water was added to the reaction mixture, and the mixture was stirred and extracted twice with ethyl acetate. The combined organic layer was washed with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0-95:5) to give the title compound (183 mg) as a yellow solid. MS (ESI) m/z: 684.3 [M-Cl + _H2O ] ⁺

(68-4) methyl [(6S)-4-{4′-[(2-{3-[(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 68)

In Example 29, by using Example Compound 68-3 instead of Reference Example Compound 10 and Reference Example Compound 9 instead of Example Compound 29-1 and performing the same reaction and treatment as in (29-2) , to give the title compound as a beige solid. MS (ESI) m/z: 837.6 [M+H] ⁺

Example 69
(69-1) 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 (Example compound 69)

Trifluoroacetic acid (2.0 mL) was added to a solution of Reference Example compound 12-1 (84 mg) in dichloromethane (2.0 mL), and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution, toluene was added and the solvent was distilled off. The resulting residue was dissolved in N,N-dimethylformamide (1.5 mL), Reference Example compound 17 (63 mg), N,N-diisopropylethylamine (0.25 mL) and HATU (67 mg) were added at room temperature, The mixture was stirred at the same temperature for 16 hours. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed with saturated brine-water (1:1) three times and saturated brine once. After drying and filtering over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (77 mg) as a white powder. MS (ESI) m/z: 855.5 [M+H] ⁺

Example 70
(70-1) 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 (Example Compound 70)

Reference Example Compound 17 (65 mg), N,N-diisopropylethylamine (0.078 mL) and HATU (69 mg) were added to a solution of Reference Example Compound 13 (80 mg) in N,N-dimethylformamide (1.6 mL) at room temperature. The mixture was added and stirred at the same temperature for 16 hours. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed with saturated brine-water (1:1) three times and saturated brine once. After drying and filtering over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (53 mg) as a pale brown powder. MS (ESI) m/z: 871.5, 873.5 [M+H] ⁺

Example 71
(71-1) 5-chloro-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-carboxylic acid (Example compound 71-1)

Reference Example Compound 2 (370 mg), t-butyl 2-chloro-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (330 mg) , potassium phosphate (587 mg), 1,4-dioxane (5.0 mL), water (1.1 mL), 2-dicyclohexylphosphino-2′-6′-dimethoxybiphenyl aminobiphenyl palladium chloride precatalyst (66 mg), A mixture of S-phos (38 mg) was heated and stirred at 75° C. for 4 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=85:15-45:55). The obtained compound was dissolved in dichloromethane (4.0 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at room temperature for 2.5 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in a 1M sodium carbonate aqueous solution and washed with toluene. The aqueous layer was acidified with 2N hydrochloric acid, and the resulting precipitate was collected by filtration to give the title compound (310 mg) as a white solid. MS (ESI) m/z: 495.3, 497.3 [M+H] ⁺

(71-2) 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 (Example compound 71)

Example compound 71-1 (50 mg) in N,N-dimethylformamide (1.0 mL) solution at room temperature, reference compound 5 (38 mg), N,N-diisopropylethylamine (0.054 mL), HATU (46 mg ) was added, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed with saturated brine-water (1:1) three times and saturated brine once. After drying and filtering over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (31 mg) as a white powder. MS (ESI) m/z: 817.3, 819.3 [M+H] ⁺

Example 72
(72-1) 3-chloro-N-({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)-5-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 (Example compound 72)

In Example 71, t-butyl 2-chloro-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate was replaced with 2-chloro (71-1)-(71-2) using t-butyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate ) to obtain the title compound as a white powder. MS (ESI) m/z: 817.3, 819.3 [M+H] ⁺

Example 73
(73-1) [(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]acetonitrile (Example Compound 73-1)

(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4] After adding 28% aqueous ammonia (0.30 mL) to a solution of diazepine-6-acetic acid (500 mg) in N,N-dimethylformamide (6.0 mL), 1-hydroxy-7-azabenzotriazole (HOAt) (170 mg) ), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSCI) (311 mg) was added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (18.0 mL) and N,N-diisopropylethylamine (0.85 mL), trifluoroacetic anhydride (0.34 mL) was added, and the mixture was stirred at room temperature for 3 hours. Furthermore, N,N-diisopropylethylamine (0.43 mL) and trifluoroacetic anhydride (0.17 mL) were added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to give the title compound (255 mg) as a milky white powder. MS (ESI) m/z: 382.2, 384.2 [M+H] ⁺

(73-2) t-butyl 4′-[(6S)-6-(cyanomethyl)-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 73-2)

Example compound 73-1 (114 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) t-butyl benzoate (227 mg), potassium carbonate (124 mg) , tetrahydrofuran (3.0 mL), water (0.80 mL), 2-dicyclohexylphosphino-2′-6′-dimethoxybiphenyl aminobiphenyl palladium chloride precatalyst (22 mg), S-phos (12 mg) was heated to reflux. Stirred for 3 hours under. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=99:1-90:10) to give the title compound (165 mg) as a gray powder. MS (ESI) m/z: 524.4 [M+H] ⁺

(73-3) N-({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)-4′-[(6S)-6-(cyanomethyl)- 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 73)

Trifluoroacetic acid (1.0 mL) was added to a solution of Example Compound 73-2 (50 mg) in dichloromethane (1.0 mL), and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction solution, toluene was added and the solvent was distilled off. The resulting residue was dissolved in N,N-dimethylformamide (1.0 mL), Reference Example compound 5 (36 mg), N,N-diisopropylethylamine (0.17 mL) and HATU (44 mg) were added at room temperature, The mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed with saturated brine-water (1:1) three times and saturated brine once. After drying and filtering over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (51 mg) as a white powder. MS (ESI) m/z: 790.3 [M+H] ⁺

Example 74
(74-1) t-butyl 2,3-difluoro-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 74-1)

Reference Example compound 3 (100 mg) was dissolved in tetrahydrofuran (2.0 mL), t-butyl 4-bromo-2,3-difluorobenzoate (70 mg), tetrakis(triphenylphosphine) palladium (0) (23 mg), Potassium phosphate (126 mg) and water (0.013 mL) were added and stirred at 90° C. for 0.5 hour under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, and the 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=100:0-98:2) to give the title compound (125 mg) as a crude white powder. MS (ESI) m/z: 593.4 [M+H] ⁺

(74-2) 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 (Example Compound 74)

Trifluoroacetic acid (2.0 mL) was added to a solution of Example Compound 74-1 (117 mg) in dichloromethane (2.0 mL), and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction solution, toluene was added and the solvent was distilled off. The resulting residue was dissolved in N,N-dimethylformamide (2.0 mL), Reference Example compound 5 (74 mg), N,N-diisopropylethylamine (0.34 mL) and HATU (90 mg) were added at room temperature, The mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed with saturated brine-water (1:1) three times and saturated brine once. After drying and filtering over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (108 mg) as a beige powder. MS (ESI) m/z: 859.5 [M+H] ⁺

Example 75
(75-1) 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]-2-methyl[1,1′-biphenyl]-4-carboxylic acid (Example compound 75-1)

Reference Example Compound 3 (55 mg) was dissolved in tetrahydrofuran (0.8 mL), 4-bromo-3-methylbenzoic acid (22 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl ( X-Phos, 5 mg), X-Phos aminobiphenylpalladium chloride pre-catalyst (8 mg), cesium fluoride (46 mg) and water (0.2 mL) were added, and the reaction was carried out at 120° C. under microwave irradiation in a nitrogen atmosphere for 0.5 Stirred for an hour. After diluting the reaction solution with ethyl acetate, it was extracted twice with saturated aqueous sodium bicarbonate solution. The aqueous layers were combined, and 2N hydrochloric acid was added little by little under ice-cooling to adjust the pH to 1. The aqueous layer was extracted twice with ethyl acetate, the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to give the title compound (52 mg) as a white powder. obtained as MS (ESI) m/z: 515.3 [M+H] ⁺

(75-2) methyl [(6S)-4-{4′-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2 '-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 75)

Example compound 75-1 (50 mg) and Reference example compound 5 (37 mg) in N,N-dimethylformamide (1.0 mL) solution at room temperature N,N-diisopropylethylamine (0.050 mL), HATU (45 mg ) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed with saturated brine-water (1:1) three times and saturated brine once. After drying and filtering over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (59 mg) as a beige powder. MS (ESI) m/z: 837.4 [M+H] ⁺

Example 76
(76-1) 4-bromo-2-cyano-N-({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)benzamide (Example compound 76- 1)

4-bromo-2-cyanobenzoic acid (100 mg) and Reference Example compound 5 (158 mg) in N,N-dimethylformamide (2.2 mL) was added at room temperature with N,N-diisopropylethylamine (0.23 mL), HATU (202 mg) was added and stirred at the same temperature for 2 days. The reaction mixture was diluted with ethyl acetate, washed twice with saturated aqueous sodium bicarbonate, once with saturated brine-water (1:1), and once with saturated brine. After drying and filtering over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified twice by silica gel column chromatography (chloroform:methanol=98:2) to give the title compound (29 mg) as a white solid. MS (ESI) m/z: 548.1, 550.1 [M+H] ⁺

(76-2) methyl [(6S)-4-{3′-cyano-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 76)

Reference Example Compound 3 (25 mg) was dissolved in tetrahydrofuran (0.8 mL), Example Compound 76-1 (24 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos , 2 mg), X-Phos aminobiphenylpalladium chloride pre-catalyst (4 mg), cesium fluoride (20 mg) and water (0.2 mL) were added and stirred at 120° C. for 0.5 h under nitrogen atmosphere and microwave irradiation. . 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, and the solvent was distilled off under reduced pressure. The resulting residue was purified twice by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (13 mg) as a white powder. MS (ESI) m/z: 848.4 [M+H] ⁺

Example 77
(77-1) methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl] -5-fluoropyridin-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 77)

(53-1)-(53-2) using t-butyl 5-bromo-3-fluoropyridine-2-carboxylate instead of t-butyl 5-bromopyridine-2-carboxylate in Example 53 The title compound was obtained as a milky white solid by the same reaction and treatment. MS (ESI) m/z: 842.3 [M+H] ⁺

Example 78
(78-1) t-butyl 5-bromo-6-methylpyridine-2-carboxylate (Example Compound 78-1)

5-bromo-6-methylpyridine-2-carboxylic acid (500 mg), di-t-butyl dicarbonate (1010 mg) and 4-dimethylaminopyridine (28 mg) were stirred in tetrahydrofuran (5.0 mL) at room temperature for 3 hours. . The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-70:30) to give the title compound (572 mg) as a colorless oil. MS (ESI) m/z: 215.9, 217.9 [M-tBu+2H] ⁺

(78-2) methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl] -2-methylpyridin-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 78)

By using Example Compound 78-1 in place of t-butyl 5-bromopyridine-2-carboxylate in Example 53 and performing the same reaction and treatment as in (53-1)-(53-2), The title compound was obtained as an off-white solid. MS (ESI) m/z: 838.4 [M+H] ⁺

Example 79
(79-1) methyl [(6S)-4-{4′-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2 '-(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 79)

Similar reactions to (75-1)-(75-2) using 4-bromo-3-(trifluoromethyl)benzoic acid instead of 4-bromo-3-methylbenzoic acid in Example 75, Work-up gave the title compound as a white powder. MS (ESI) m/z: 891.4 [M+H] ⁺

Example 80
(80-1) methyl [(6S)-4-{4′-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2 '-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 80)

In Example 75, using 4-bromo-3-methoxybenzoic acid instead of 4-bromo-3-methylbenzoic acid, (75-1) - (75-2) the same reaction and treatment gave the title compound as a beige powder. MS (ESI) m/z: 853.4 [M+H] ⁺

Example 81
(81-1) methyl [(6S)-4-{2′-cyano-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 81)

In Example 75, using 4-bromo-3-cyanobenzoic acid instead of 4-bromo-3-methylbenzoic acid, (75-1) - (75-2) the same reaction and treatment gave the title compound as a beige powder. MS (ESI) m/z: 848.4 [M+H] ⁺

Example 82
(82-1) 2,5-difluoro-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 (Example compound 82-1)

In Example 75, using 4-bromo-2,5-difluorobenzoic acid (48 mg) instead of 4-bromo-3-methylbenzoic acid, by the same reaction and treatment as in (75-1) , to obtain the title compound (116 mg) as a crude white powder. MS (ESI) m/z: 537.3 [M+H] ⁺

(82-2) methyl [(6S)-4-{4′-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)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 (Example Compound 82)

In Example 75, Example Compound 82-1 (40 mg) was used instead of Example Compound 75-1, and the same reaction and treatment as in (75-2) were carried out to give the title compound (39 mg) as beige. Obtained as a colored powder. MS (ESI) m/z: 859.4 [M+H] ⁺

Example 83
(83-1) 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]-5-methyl[1,1′-biphenyl]-4-carboxylic acid (Example Compound 83-1)

In Example 75, using 4-bromo-5-fluoro-2-methylbenzoic acid (47 mg) instead of 4-bromo-3-methylbenzoic acid, react and treat in the same manner as in (75-1) Thus, the title compound (96 mg) was obtained as a white powder. MS (ESI) m/z: 533.3 [M+H] ⁺

(83-2) methyl [(6S)-4-{4′-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)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 (Example Compound 83)

In Example 75, Example Compound 83-1 (40 mg) was used instead of Example Compound 75-1, and the same reaction and treatment as in (75-2) were carried out to obtain the title compound (45 mg) as beige. Obtained as a colored powder. MS (ESI) m/z: 855.4 [M+H] ⁺

Example 84
(84-1) methyl [(6S)-4-(2′-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 (Example Compound 84)

A solution of Reference Example Compound 19 (85 mg) and Reference Example Compound 17 (68 mg) in N,N-dimethylformamide (1.7 mL) was added with N,N-diisopropylethylamine (0.083 mL) and HATU (73 mg) at room temperature. The mixture was added and stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed with saturated brine-water (1:1) three times and saturated brine once. After drying and filtering over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (42 mg) as a beige powder. MS (ESI) m/z: 871.4 [M+H] ⁺

Example 85
(85-1) 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 (Example Compound 85)

A solution of Reference Example Compound 18 (50 mg) and Reference Example Compound 17 (42 mg) in N,N-dimethylformamide (1.0 mL) was added with N,N-diisopropylethylamine (0.050 mL) and HATU (44 mg) at room temperature. The mixture was added and stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed with saturated brine-water (1:1) three times and saturated brine once. After drying and filtering over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (70 mg) as a beige powder. MS (ESI) m/z: 855.5 [M+H] ⁺

Example 86
(86-1) methyl [(6S)-4-(4′-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl} Ethyl]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 86)

N,N-diisopropylethylamine (0.050 mL) and HATU (45 mg) were added to a solution of Reference Example Compound 20 (50 mg) and Reference Example Compound 17 (42 mg) in N,N-dimethylformamide (1.0 mL) at room temperature. The mixture was added and stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed with saturated brine-water (1:1) three times and saturated brine once. After drying and filtering over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (62 mg) as a beige powder. MS (ESI) m/z: 851.4 [M+H] ⁺

Example 87
(87-1) methyl [(6S)-4-{4′-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)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 87)

N,N-Diisopropylethylamine (0.050 mL) and HATU (45 mg) were added to a solution of Reference Example Compound 20 (50 mg) and Reference Example Compound 11 (42 mg) in N,N-dimethylformamide (1.0 mL) at room temperature. The mixture was added and stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed with saturated brine-water (1:1) three times and saturated brine once. After drying and filtering over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (60 mg) as a white powder. MS (ESI) m/z: 851.5 [M+H] ⁺

Example 88
(88-1) methyl [(6S)-4-(4′-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl} Ethyl]carbamoyl}-2′-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 88)

Example compound 75-1 (50 mg) was used in place of Reference example compound 20 in Example 86, and the same reaction and treatment were carried out to give the title compound (63 mg) as a beige powder. MS (ESI) m/z: 851.5 [M+H] ⁺

Example 89
(89-1) methyl [(6S)-4-{4′-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl] -2'-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 89)

Example compound 75-1 (50 mg) was used in place of Reference example compound 20 in Example 87, and the same reaction and treatment were carried out to give the title compound (53 mg) as a white powder. MS (ESI) m/z: 851.4 [M+H] ⁺

Example 90
(90-1) methyl [(6S)-4-(4-{6-[(2-{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]diazepine -6-yl]acetate (Example compound 90)

By using Reference Example Compound 11 instead of Reference Example Compound 5 in Example 53 and performing the same reaction and treatment as in (53-2), the title compound was obtained as a beige solid. MS (ESI) m/z: 838.4 [M+H] ⁺

Example 91
(91-1) methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl] -5-methylpyridin-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 91)

(53-1)-(53-2) using t-butyl 5-bromo-3-methylpyridine-2-carboxylate instead of t-butyl 5-bromopyridine-2-carboxylate in Example 53 The title compound was obtained as a milky white solid by the same reaction and treatment. MS (ESI) m/z: 838.4 [M+H] ⁺

Example 92
(92-1) 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 (Example compound 92)

By using Reference Example Compound 17 instead of Reference Example Compound 5 in Example 53 and performing the same reaction and treatment as in (53-2), the title compound was obtained as a milky white solid. MS (ESI) m/z: 838.4 [M+H] ⁺

Example 93
(93-1) 3-hydroxy-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 (Example compound 93-1)

Reference Example Compound 3 (204 mg) was dissolved in tetrahydrofuran (2.0 mL), 4-bromo-3-methylbenzoic acid (83 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl ( X-Phos, 18 mg), X-Phos aminobiphenylpalladium chloride pre-catalyst (30 mg), cesium fluoride (175 mg) and water (0.5 mL) were added, and the reaction was carried out at 120° C. under nitrogen atmosphere and microwave irradiation for 0.5 hour, and further stirred at 160° C. for 0.5 hour. After diluting the reaction solution with ethyl acetate, it was extracted twice with saturated aqueous sodium bicarbonate solution. The aqueous layers were combined, and 2N hydrochloric acid was added little by little under ice-cooling to adjust the pH to 1. The aqueous layer was extracted twice with chloroform, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to give the title compound (130 mg) as a pale yellow powder. MS (ESI) m/z: 517.3 [M+H] ⁺

(93-2) methyl [(6S)-4-{4′-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-3 '-Hydroxy[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 93)

Example Compound 93-1 (68 mg) and Reference Example Compound 5 (54 mg) were dissolved in N,N-dimethylformamide (2.0 mL) at room temperature with 1-hydroxy-7-azabenzotriazole (HOAt, 22 mg), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSCI, 31 mg) was added, and the mixture was stirred at the same temperature for 3 hours. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed with saturated brine-water (1:1) three times and saturated brine once. After drying and filtering over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=98:2-90:10) to give the title compound (72 mg) as a beige powder. MS (ESI) m/z: 839.4 [M+H] ⁺

Example 94
(94-1) methyl [(6S)-4-{4′-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]-2-methylphenyl}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 94)

Similar to (25-1)-(25-2) using (4-bromo-2-methyl-phenyl)methanamine in place of 4-bromo-3-fluorophenylmethanamine hydrochloride in Example 25. The title compound was obtained as a gray powder by reaction and treatment. MS (ESI) m/z: 837.4 [M+H] ⁺

Example 95
(95-1) methyl [(6S)-4-(4′-{[(1R)-1-{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 95)

In Example 25, (25-1)-(25- The title compound was obtained as a gray powder by the same reaction and treatment as in 2). MS (ESI) m/z: 851.4 [M+H] ⁺

Example 96
(96-1) methyl [(6S)-4-{4′-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]-3-methylphenyl}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 96)

(25-1)-(25-2) with (4-bromo-3-methyl-phenyl)methanamine hydrochloride in place of 4-bromo-3-fluorophenylmethanamine hydrochloride in Example 25 The title compound was obtained as a beige powder by the same reaction and treatment. MS (ESI) m/z: 837.7 [M+H] ⁺

Example 97
(97-1) 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 (Example Compound 97)

Example compound 82-1 (40 mg) was used in place of Reference example compound 20 in Example 86, and the same reaction and treatment were carried out to give the title compound (48 mg) as a milky white powder. MS (ESI) m/z: 873.7 [M+H] ⁺

Example 98
(98-1) 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 (Example Compound 98)

Example compound 83-1 (30 mg) was used in place of Reference example compound 20 in Example 86, and the same reaction and treatment were carried out to give the title compound (34 mg) as a milky white powder. MS (ESI) m/z: 869.7 [M+H] ⁺

Example 99
(99-1) 2,3-difluoro-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 (Example compound 99-1)

Reference Example compound 3 (362 mg) was dissolved in tetrahydrofuran (3.0 mL), 4-bromo-2,3-difluorobenzoic acid (150 mg) and 2-dicyclohexylphosphino-2',4',6'-triisopropyl Biphenyl (X-Phos, 30 mg), X-Phos aminobiphenyl palladium chloride precatalyst (50 mg), cesium fluoride (289 mg) and water (0.75 mL) were added and the temperature was adjusted to 0 at 120°C under microwave irradiation in a nitrogen atmosphere. Stirred for .5 hours. After diluting the reaction solution with ethyl acetate, it was extracted twice with saturated aqueous sodium bicarbonate solution. The aqueous layers were combined, and 2N hydrochloric acid was added little by little under ice-cooling to adjust the pH to 1. The aqueous layer was extracted twice with chloroform, and the combined organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure to give the title compound (365 mg) as a crude pale yellow powder. . MS (ESI) m/z: 537.2 [M+H] ⁺

(99-2) 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 (Example Compound 99)

Example compound 99-1 (50 mg) and Reference example compound 17 (40 mg) in N,N-dimethylformamide (2.0 mL) solution at room temperature N,N-diisopropylethylamine (0.49 mL), HATU (43 mg ) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed with saturated brine-water (1:1) three times and saturated brine once. After drying and filtering over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (60 mg) as a beige powder. MS (ESI) m/z: 873.7 [M+H] ⁺

Example 100
(100-1) 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 (Example compound 100)

Example compound 99-1 (50 mg) was used in place of Reference example compound 20 in Example 87, and the same reaction and treatment were carried out to give the title compound (60 mg) as a milky white powder. MS (ESI) m/z: 873.4 [M+H] ⁺

Example 101
(101-1) 5-bromo-N-({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)-4-methylpyridine-2-carboxamide (performed Example compound 101-1)

In Example 2, 5-bromo-4-methylpyridine-2-carboxylic acid was used in place of Reference Example compound 12 and the same reaction and treatment as in (2-1) were carried out to obtain the title compound as a white solid. rice field. MS (ESI) m/z: 536.1, 538.2 [MH] ^-

(101-2) methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl] -4-methylpyridin-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 101)

Example Compound 101-1 (134 mg), Reference Example Compound 3 (126 mg), XPhos aminobiphenylpalladium chloride precatalyst (20 mg), XPhos (12 mg), cesium fluoride (113 mg) and water (1.0 mL) were added under a nitrogen stream. )-tetrahydrofuran (4.0 mL) and stirred at 120° C. for 0.5 hours under microwave irradiation. The reaction solution was directly purified by silica gel column chromatography (chloroform:methanol=100:0-95:5). The resulting solid was purified again by silica gel column chromatography (ethyl acetate:methanol=100:0-95:5) to give the title compound (114 mg) as a white solid. MS (ESI) m/z: 838.7 [M+H] ⁺

Example 102
(102-1) 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]diazepine -6-yl]acetate (Example compound 102)

Trifluoroacetic acid (1.0 mL) was added to a solution of Example Compound 65-1 (68 mg) in chloroform (1.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and azeotroped twice with toluene. The residue and Reference Example compound 11 (47 mg), N,N-diisopropylethylamine (0.11 mL) and HATU (55 mg) were 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, and the resulting solid was separated by filtration and suspended and washed with water. Purification by silica gel column chromatography (chloroform:methanol=100:0-95:5) gave the title compound (79 mg) as a pale yellow solid. MS (ESI) m/z: 839.2 [M+H] ⁺

Example 103
(103-1) 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 (Example compound 103)

Trifluoroacetic acid (1.0 mL) was added to a solution of Example Compound 65-1 (68 mg) in chloroform (1.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and azeotroped twice with toluene. The residue and Reference Example compound 17 (47 mg), N,N-diisopropylethylamine (0.11 mL) and HATU (55 mg) were 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, and the resulting solid was separated by filtration and suspended and washed with water. Purification by silica gel column chromatography (chloroform:methanol=100:0-95:5) gave the title compound (74 mg) as a beige solid. MS (ESI) m/z: 839.2 [M+H] ⁺

Example 104
(104-1) Di-t-butyl [(4-bromo-2-cyanophenyl)methyl]-2-imidodicarbonate (Example compound 104-1)

A solution of 5-bromo-2-(bromomethyl)benzonitrile (500 mg) and di-t-butyl iminodicarboxylate (396 mg) in N,N-dimethylformamide (5.0 mL) was added at room temperature with cesium carbonate (1778 mg). was added and stirred at 60° C. for 0.5 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, and evaporated under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-90:10) to give the title compound (703 mg) as a colorless oil. MS (ESI) m/z: 311.1, 313.2 [M-Boc+2H] ⁺

(104-2) 2-(aminomethyl)-5-bromobenzonitrile hydrochloride (Example compound 104-2)

A 4M hydrogen chloride/1,4-dioxane solution (4.0 mL) was added to Example Compound 104-1 (400 mg) at room temperature. After stirring at the same temperature for 1 hour, the reaction solution was concentrated under reduced pressure. Diethyl ether was added to the residue, and the suspension was washed and collected by filtration to give the title compound (233 mg) as a white solid. MS (ESI) m/z: 211.1, 213.1 [M+H] ⁺

(104-3) methyl [(6S)-4-{4′-[({2-cyano-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 104)

In Example 25, using Example Compound 104-2 instead of 4-bromo-3-fluorophenylmethanamine hydrochloride, reacting and treating in the same manner as in (25-1)-(25-2) afforded the title compound as a brown powder. MS (ESI) m/z: 848.3 [M+H] ⁺

Example 105
(105-1) 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}pyrazine-2-carboxylic acid (Example compound 105-1)

Trifluoroacetic acid (1.0 mL) was added to a solution of Example Compound 65-1 (218 mg) in chloroform (1.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and azeotroped with toluene twice. Ethyl acetate and water were added and stirred, and saturated aqueous sodium bicarbonate was added little by little to adjust the pH to 8. The organic layer was removed and the aqueous layer was washed with ethyl acetate. 1N Hydrochloric acid was slowly added to the aqueous layer to adjust the pH to 5, and the aqueous layer was extracted three times with chloroform. The organic layer was concentrated under reduced pressure to give the title compound (161 mg) as a pale yellow solid. MS (ESI) m/z: 503.1 [M+H] ⁺

(105-2) 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]diazepine-6 -yl]acetate (Example compound 105)

Example compound 105-1 (53 mg), Reference example compound 21 (45 mg), N,N-diisopropylethylamine (0.055 mL), HATU (48 mg) in N,N-dimethylformamide (2.0 mL) at room temperature and stirred for 2 hours. Water was added to the reaction mixture and the mixture was stirred, and the resulting solid was separated by filtration and suspended and washed with water. Purification by silica gel column chromatography (chloroform:methanol=100:0-95:5) gave the title compound (65 mg) as a pale yellow solid. MS (ESI) m/z: 839.2 [M+H] ⁺

Example 106
(106-1) 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 (Example compound 106)

Example compound 105-1 (53 mg), Reference example compound 22 (47 mg), N,N-diisopropylethylamine (0.055 mL), HATU (48 mg) in N,N-dimethylformamide (2.0 mL) at room temperature and stirred for 2 hours. Water was added to the reaction mixture and the mixture was stirred, and the resulting solid was separated by filtration and suspended and washed with water. Purification by silica gel column chromatography (chloroform:methanol=100:0-95:5) gave the title compound (70 mg) as a pale yellow solid. MS (ESI) m/z: 853.2 [M+H] ⁺

Example 107
(107-1) 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]diazepine -6-yl]acetate (Example compound 107)

Example compound 105-1 (53 mg), Reference example compound 23 (47 mg), N,N-diisopropylethylamine (0.055 mL), HATU (48 mg) in N,N-dimethylformamide (2.0 mL) at room temperature and stirred for 2 hours. Water was added to the reaction mixture and the mixture was stirred, and the resulting solid was separated by filtration and suspended and washed with water. Purification by silica gel column chromatography (chloroform:methanol=100:0-95:5) gave the title compound (73 mg) as a pale yellow solid. MS (ESI) m/z: 853.2 [M+H] ⁺

Example 108
(108-1) 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-carboxylic acid (Example compound 108-1)

In Example 105, Example Compound 53-1 (219 mg) was used in place of Example Compound 65-1 and the same reaction and treatment as in (105-1) were carried out to give the title compound (150 mg) as a pale yellow solid. obtained as MS (ESI) m/z: 502.1 [M+H] ⁺

(108-2) 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]diazepine-6 -yl]acetate (Example compound 108)

In Example 105, Example Compound 108-1 (50 mg) was used in place of Example Compound 105-1, and the same reaction and treatment as in (105-2) were carried out to give the title compound (51 mg) as a beige color. Obtained as a solid. MS (ESI) m/z: 838.2 [M+H] ⁺

Example 109
(109-1) 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 (Example compound 109)

In Example 106, Example Compound 108-1 (50 mg) was used in place of Example Compound 105-1 and the same reaction and treatment as in (106-1) were carried out to give the title compound (68 mg) as a beige color. Obtained as a solid. MS (ESI) m/z: 852.2 [M+H] ⁺

Example 110
(110-1) 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]diazepine -6-yl]acetate (Example Compound 110)

In Example 107, Example Compound 108-1 (50 mg) was used in place of Example Compound 105-1 and the same reaction and treatment as in (107-1) were carried out to give the title compound (63 mg) as a beige color. Obtained as a solid. MS (ESI) m/z: 852.2 [M+H] ⁺

Example 111
(111-1) methyl [(6S)-4-{4′-[(cyano{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 111)

Same as (25-1)-(25-2) using 2-amino-2-(4-bromophenyl)acetonitrile in place of 4-bromo-3-fluorophenylmethanamine hydrochloride in Example 25 The title compound was obtained as a pale brown powder. MS (ESI) m/z: 848.3 [M+H] ⁺

Example 112
(112-1) methyl [(6S)-4-{4′-[({4-[(3-cyano-4-ethyl-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 112)

N,N-diisopropylethylamine (0.060 mL) and HATU (53 mg) were added to a solution of Reference Example Compound 12 (60 mg) and Reference Example Compound 21 (50 mg) in N,N-dimethylformamide (1.0 mL) at room temperature. The mixture was added and stirred at the same temperature for 1 hour. The reaction solution was directly purified by preparative HPLC (10 mM aqueous ammonium carbonate solution-acetonitrile) to give the title compound (78 mg) as a beige powder. MS (ESI) m/z: 855.2 [M+H] ⁺

Example 113
(113-1) methyl [(6S)-4-{3′-chloro-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 113)

In Example 112, Reference Example Compound 13 (68 mg) was used in place of Reference Example Compound 12, and the same reaction and treatment were carried out to give the title compound (88 mg) as a white powder. MS (ESI) m/z: 871.2, 873.1 [M+H] ⁺

Example 114
(114-1) methyl [(6S)-4-{4′-[({4-[(3-cyano-4-ethyl-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 114)

In Example 112, Reference Example Compound 20 (50 mg) was used in place of Reference Example Compound 12, and the same reaction and treatment were performed to give the title compound (39 mg) as a beige powder. MS (ESI) m/z: 851.3 [M+H] ⁺

Example 115
(115-1) methyl [(6S)-4-{4′-[({4-[(3-cyano-4-ethyl-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 115)

In Example 112, Reference Example Compound 18 (50 mg) was used in place of Reference Example Compound 12, and the same reaction and treatment were carried out to give the title compound (56 mg) as a beige powder. MS (ESI) m/z: 855.3 [M+H] ⁺

Example 116
(116-1) methyl [(6S)-4-{2′-chloro-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 116)

In Example 112, Reference Example Compound 19 (50 mg) was used in place of Reference Example Compound 12, and the same reaction and treatment were performed to give the title compound (33 mg) as a white powder. MS (ESI) m/z: 871.2, 873.2 [M+H] ⁺

Example 117
(117-1) methyl [(6S)-4-{4′-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2 '-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 117)

Example compound 75-1 (50 mg) was used in place of Reference example compound 12 in Example 112, and the same reaction and treatment were carried out to give the title compound (39 mg) as a white powder. MS (ESI) m/z: 851.3 [M+H] ⁺

Example 118
(118-1) 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 (Example Compound 118)

Example compound 99-1 (50 mg) was used in place of Reference example compound 12 in Example 112, and the same reaction and treatment were carried out to give the title compound (47 mg) as a white powder. MS (ESI) m/z: 873.2 [M+H] ⁺

Example 119
(119-1) methyl [(6S)-4-{4′-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)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 (Example Compound 119)

Example compound 82-1 (26 mg) was used in place of Reference example compound 12 in Example 112, and the same reaction and treatment were carried out to give the title compound (29 mg) as a white powder. MS (ESI) m/z: 873.2 [M+H] ⁺

Example 120
(120-1) methyl [(6S)-4-{4′-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)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 (Example compound 120)

Example compound 83-1 (19 mg) was used in place of Reference example compound 12 in Example 112, and the same reaction and treatment were carried out to give the title compound (22 mg) as a white powder. MS (ESI) m/z: 869.2 [M+H] ⁺

Example 121
(121-1) methyl [(6S)-4-(4′-{[(1R)-1-{4-[(3-cyano-4-ethyl-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 121)

A solution of Reference Example Compound 18 (50 mg) and Reference Example Compound 22 (43 mg) in N,N-dimethylformamide (1.0 mL) was added with N,N-diisopropylethylamine (0.050 mL) and HATU (44 mg) at room temperature. The mixture was added and stirred at the same temperature for 1 hour. The reaction mixture was directly purified by preparative HPLC (10 mM aqueous ammonium carbonate solution-acetonitrile) to give the title compound (35 mg) as a white powder. MS (ESI) m/z: 869.2 [M+H] ⁺

Example 122
(122-1) methyl [(6S)-4-(4′-{[(1R)-1-{4-[(3-cyano-4-ethyl-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 (Example compound 122)

Example compound 99-1 (50 mg) was used in place of Reference example compound 18 in Example 121 and the same reaction and treatment were carried out to give the title compound (39 mg) as a white powder. MS (ESI) m/z: 887.2 [M+H] ⁺

Example 123
(123-1) methyl [(6S)-4-(4′-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl} Ethyl]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 123)

In Example 121, Reference Example Compound 20 (30 mg) was used instead of Reference Example Compound 18, and the same reaction and treatment were carried out to give the title compound (30 mg) as a beige powder. MS (ESI) m/z: 865.3 [M+H] ⁺

Example 124
(124-1) methyl [(6S)-4-{4′-[(2-{4-[(3-cyano-4-ethyl-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 124)

A solution of Reference Example Compound 18 (50 mg) and Reference Example Compound 23 (43 mg) in N,N-dimethylformamide (1.0 mL) was added with N,N-diisopropylethylamine (0.050 mL) and HATU (44 mg) at room temperature. The mixture was added and stirred at the same temperature for 1 hour. The reaction mixture was directly purified by preparative HPLC (10 mM aqueous ammonium carbonate solution-acetonitrile) to give the title compound (42 mg) as a beige powder. MS (ESI) m/z: 869.3 [M+H] ⁺

Example 125
(125-1) methyl [(6S)-4-{4′-[(2-{4-[(3-cyano-4-ethyl-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 (Example Compound 125)

Example compound 99-1 (50 mg) was used in place of Reference example compound 18 in Example 124, and the same reaction and treatment were carried out to give the title compound (48 mg) as a white powder. MS (ESI) m/z: 887.2 [M+H] ⁺

Example 126
(126-1) methyl [(6S)-4-{4′-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)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 126)

In Example 124, Reference Example Compound 20 (32 mg) was used instead of Reference Example Compound 18, and the same reaction and treatment were carried out to give the title compound (28 mg) as a white powder. MS (ESI) m/z: 865.3 [M+H] ⁺

Example 127
(127-1) 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 (Example compound 127)

In Example 1, Reference Example Compound 22 (39 mg) was used instead of Reference Example Compound 5, and the same reaction and treatment as in (1-1) were performed to obtain the title compound (58 mg) as a pale yellow solid. rice field. MS (ESI) m/z: 851.3 [M+H] ⁺

Example 128
(128-1) methyl [(6S)-4-{4′-[(2-{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 (Example compound 128)

By using Reference Example Compound 23 (39 mg) instead of Reference Example Compound 5 in Example 1 and performing the same reaction and treatment, the title compound (56 mg) was obtained as a pale yellow solid. MS (ESI) m/z: 851.2 [M+H] ⁺

Example 129
(129-1) N-({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaboronan-2-yl)benzamide (Example Compound 129-1)

N,N-dimethylformamide of Reference Example compound 5 (300 mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (198 mg) under a nitrogen stream (6.0 mL), N,N-diisopropylethylamine (0.41 mL) and HATU (363 mg) were added and stirred at the same temperature for 1 hour. and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give crude title compound (499 mg). was obtained as a gray solid. MS (ESI) m/z: 571.0 [M+H] ⁺

(129-2) ethyl [(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 (Example compound 129-2)

(S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4] Concentrated sulfuric acid (4 mL) was added to an ethanol (500 mL) solution of diazepine-6-acetic acid (70 g), and the mixture was heated under reflux for 9 hours. After cooling, the solvent was distilled off under reduced pressure, an aqueous potassium carbonate solution was added, the mixture was extracted with chloroform, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was recrystallized from ethyl acetate to obtain the title compound (45 g).
¹ H NMR (300 MHz, DMSO-d6) δ ppm 1.19 (3H, t, J = 7.1H), 1.60 (3H, s), 2.39 (3H, s), 2.58 ( 3H, s), 3.3-3.5 (2H, m), 4.0-4.3 (2H, m), 4.47 (1H, dd, J = 7.8, 6.8 Hz) , 7.41 (2H, d, J=7.0 Hz), 7.47 (2H, d, J=7.0 Hz)
MS (ESI) m/z: 429 (M+H) ⁺

(129-3) ethyl [(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 129)

Under a nitrogen stream, Example Compound 129-1 (73 mg), Example Compound 129-2 (50 mg), cesium fluoride (53 mg), water (0.2 mL), tetrahydrofuran (0.8 mL), X-Phos (5 .6 mg) and X-Phos aminobiphenylpalladium chloride precatalyst (9.2 mg) was stirred under microwave irradiation at 130° C. for 90 minutes. The reaction mixture was diluted with ethyl acetate-tetrahydrofuran (1:1), washed twice with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue was purified by NH silica gel column chromatography (chloroform:methanol=90:10-0:100) to give the title compound (14 mg) as a pale yellow solid. MS (ESI) m/z: 837.3 [M+H] ⁺

Example 130
(130-1) n-propyl [(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 130)

In Example 131, using n-propyl alcohol instead of isopropyl alcohol, the same reaction and treatment as for (131-1)-(131-2) gave the title compound (80 mg) as a pale yellow solid. Obtained. MS (ESI) m/z: 851.3 [M+H] ⁺

Example 131
(131-1) isopropyl [(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 (Example Compound 131-1)

(S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4] Pivaloyl chloride (0.53 mL) was added to a solution of diazepine-6-acetic acid (1.44 g) and triethylamine (0.75 mL) in tetrahydrofuran (14 mL) at -10°C to -20°C, followed by Stirred for an hour. To the reaction solution, sodium isopropoxide prepared from isopropyl alcohol (5 mL) and a suspension of sodium hydride (60%, 430 mg) in tetrahydrofuran (20 mL) was added at -10°C and stirred at room temperature for 1 hour. The reaction mixture was added to water (100 mL), extracted three times with ethyl acetate (100 mL), washed twice with saturated brine, and evaporated under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=19:1) to give the title compound (0.45 g) as a pale yellow solid.

(131-2) isopropyl [(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 131)

In Example 129, Example Compound 131-1 (50 mg) was used instead of Example Compound 129-2, and the same reaction and treatment as in (129-3) were carried out to obtain the title compound (31 mg). Obtained as a yellow solid. MS (ESI) m/z: 851.3 [M+H] ⁺

Example 132
(132-1) t-butyl [(4S)-6-{4′-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl] [1,1′-biphenyl]-4-yl}-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl] Acetate (Example Compound 132)

In Example 129, t-butyl [(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4] instead of Example Compound 129-2 Using triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetate (43 mg), the title compound (49 mg) was obtained by the same reaction and treatment as in (129-3). Obtained as a yellow solid. MS (ESI) m/z: 861.4 [M+H] ⁺

Example 133
(133-1) methyl [(4S)-6-{4′-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1 ,1′-biphenyl]-4-yl}-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetate ( Example compound 133)

In Example 129, methyl [(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[ Using 4,3-a][1,4]benzodiazepin-4-yl]acetate (40mg), the same reaction and treatment as in (129-3) gave the title compound (41mg) as a pale yellow solid. obtained as MS (ESI) m/z: 819.4 [M+H] ⁺

Example 134
(134-1) t-butyl [(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 134)

In Example 63, Reference Example Compound 17 (40 mg) was used instead of Reference Example Compound 5, and the same reaction and treatment as in (63-3) were performed to give the title compound (21 mg) as a pale brown solid. rice field. MS (ESI) m/z: 879.3 [M+H] ⁺

Example 135
(135-1) t-butyl [(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 135)

In Example 63, Reference Example Compound 21 (40 mg) was used instead of Reference Example Compound 5, and the same reaction and treatment as in (63-3) were performed to give the title compound (26 mg) as a pale brown solid. rice field. MS (ESI) m/z: 879.2 [M+H] ⁺

Example 136
(136-1) t-butyl [(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 (Example Compound 136)

In Example 63, Reference Example Compound 22 (41 mg) was used instead of Reference Example Compound 5, and the same reaction and treatment as in (63-3) were performed to give the title compound (52 mg) as a pale brown solid. rice field. MS (ESI) m/z: 893.2 [M+H] ⁺

Example 137
(137-1) t-butyl [(6S)-4-{4′-[(2-{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 (Example Compound 137)

In Example 63, Reference Example Compound 23 (41 mg) was used instead of Reference Example Compound 5, and the same reaction and treatment as in (63-3) were performed to give the title compound (36 mg) as a pale brown solid. rice field. MS (ESI) m/z: 893.2 [M+H] ⁺

Example 138
(138-1) t-butyl {(6S)-2,3,9-trimethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboronan-2-yl) Phenyl]-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate (Example compound 138-1)

In Reference Example 3, t-butyl [(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2 instead of Reference Example Compound 1 ,4]Triazolo[4,3-a][1,4]diazepin-6-yl]acetate (1.47 g) was used to react and treat in the same manner as in (3-1) to obtain the title compound. (1.73 g) was obtained as a pale yellow solid. MS (ESI) m/z: 549.4 [M+H] ⁺

(138-2) t-butyl [(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 (Example compound 138)

A solution of 4-bromo-2,3-fluorobenzoic acid (28 mg) and Reference Example compound 5 (40 mg) in N,N-dimethylformamide (2.0 mL) was added with N,N-diisopropylethylamine (0.061 mL) and HATU. (54 mg) was added and stirred at room temperature for 0.5 hours. The reaction mixture was diluted with ethyl acetate (30 mL)-tetrahydrofuran (5 mL), washed three times with half-saturated brine and once with saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure.
To the obtained residue, Example compound 138-1 (71 mg), cesium fluoride (54 mg), water (0.5 mL), tetrahydrofuran (2.0 mL), X-Phos (6 mg), X-Phos aminobiphenyl palladium A mixture of chloride precatalyst (10 mg) was added and stirred at 120° C. for 30 minutes under microwave irradiation. The reaction mixture was diluted with ethyl acetate (40 mL)-tetrahydrofuran (10 mL) and washed with half-saturated brine. The aqueous layer was extracted with ethyl acetate-tetrahydrofuran (10 mL-2 mL), the organic layers were combined, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified twice by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (23 mg) as a pale yellow solid. MS (ESI) m/z: 901.5 [M+H] ⁺

Example 139
(139-1) t-butyl [(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 139)

Example compound 138-1 (83 mg), 4-bromo-2-fluorobenzoic acid (30 mg), cesium fluoride (63 mg), water (0.25 mL), tetrahydrofuran (1.0 mL), X-Phos (7 mg) , X-Phos aminobiphenylpalladium chloride precatalyst (11 mg) was stirred at 120° C. for 30 minutes under microwave irradiation. A solution of ethyl acetate-water (1:1) was added to the reaction solution, and the organic layer was washed with saturated aqueous sodium bicarbonate. The aqueous layer was adjusted to pH 1 with 2N hydrochloric acid and extracted twice with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure.
To the resulting residue, a solution of Reference Example compound 5 (47 mg) in N,N-dimethylformamide (1.0 mL), N,N-diisopropylethylamine (0.071 mL) and HATU (63 mg) were added, and the mixture was stirred at room temperature for 1 hour. Stirred for an hour. The reaction mixture was purified by preparative HPLC (10 mM aqueous ammonium carbonate solution-acetonitrile) to give the title compound (43 mg) as a white solid. MS (ESI) m/z: 883.2 [M+H] ⁺

Example 140
(140-1) t-butyl [(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 140)

In Example 139, using 4-bromo-2-chlorobenzoic acid (30 mg) instead of 4-bromo-2-fluorobenzoic acid, the same reaction and treatment as in (139-1) yielded the title The compound (24 mg) was obtained as a white solid. MS (ESI) m/z: 899.2 [M+H] ⁺

Example 141
(141-1) t-butyl [(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 141)

In Example 139, using 4-bromo-2-methylbenzoic acid (30 mg) instead of 4-bromo-2-fluorobenzoic acid, the same reaction and treatment as in (139-1) yielded the title The compound (39 mg) was obtained as a white solid. MS (ESI) m/z: 879.3 [M+H] ⁺

Example 142
(142-1) t-butyl [(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 142)

In Example 139, using 4-bromo-3-fluorobenzoic acid (30 mg) instead of 4-bromo-2-fluorobenzoic acid, the same reaction and treatment as in (139-1) were performed to obtain the title The compound (13 mg) was obtained as a white solid. MS (ESI) m/z: 883.2 [M+H] ⁺

Example 143
(143-1) t-butyl [(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 143)

In Example 139, using 4-bromo-3-chlorobenzoic acid (30 mg) instead of 4-bromo-2-fluorobenzoic acid, the same reaction and treatment as in (139-1) yielded the title The compound (23 mg) was obtained as a white solid. MS (ESI) m/z: 899.2 [M+H] ⁺

Example 144
(144-1) t-butyl [(6S)-4-{4′-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl] -2'-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 144)

In Example 139, using 4-bromo-3-methylbenzoic acid (30 mg) instead of 4-bromo-2-fluorobenzoic acid, the same reaction and treatment as in (139-1) were performed to obtain the title The compound (24 mg) was obtained as a white solid. MS (ESI) m/z: 879.3 [M+H] ⁺

Example 145
(145-1) t-butyl [(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]diazepine -6-yl]acetate (Example Compound 145)

In Example 138, using 5-bromopyridine-2-carboxylic acid (65 mg) instead of 4-bromo-2,3-fluorobenzoic acid, by the same reaction and treatment as in (138-2) , to give the title compound (67 mg) as a white solid. MS (ESI) m/z: 866.2 [M+H] ⁺

Example 146
(146-1) methyl [(6S)-4-(4-{2-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl] pyrimidin-5-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6 -yl]acetate (Example compound 146)

In Example 138, 5-bromopyrimidine-2-carboxylic acid (100 mg) was used instead of 4-bromo-2,3-fluorobenzoic acid, and Reference Example Compound 3 (114 mg) was used instead of Example Compound 138-1. The title compound (4.2 mg) was obtained as a pale yellow solid by reacting and treating in the same manner as for (138-2). MS (ESI) m/z: 825.3 [M+H] ⁺

Example 147
(147-1) t-butyl [(6S)-4-(4-{2-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl) Carbamoyl]pyrimidin-5-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl]acetate (Example Compound 147)

In Example 138, using 5-bromopyrimidine-2-carboxylic acid (80 mg) instead of 4-bromo-2,3-fluorobenzoic acid, by the same reaction and treatment as in (138-2) , to give the title compound (10 mg) as a white solid. MS (ESI) m/z: 867.2 [M+H] ⁺

Example 148
(148-1) benzyl 5-{4-[(6S)-6-(2-t-butoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1 ,2,4]triazolo[4,3-a][1,4]diazepin-4-yl]phenyl}pyrazine-2-carboxylate (Example compound 148-1)

Example compound 138-1 (89 mg), benzyl 5-bromopyrazine-2-carboxylate (71 mg), tetrakis(triphenylphosphine) palladium (0) (19 mg), potassium phosphate (103 mg), water (0.011 mL ) was stirred in tetrahydrofuran (1.0 mL) at 100° C. for 0.5 h under nitrogen atmosphere and microwave irradiation. After diluting the reaction solution with ethyl acetate, the insoluble matter was filtered through celite. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50-0:100) to give the title compound (97 mg) as a pale yellow solid. MS (ESI) m/z: 635.4 [M+H] ⁺

(148-2) 5-{4-[(6S)-6-(2-t-butoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1, 2,4]triazolo[4,3-a][1,4]diazepin-4-yl]phenyl}pyrazine-2-carboxylic acid (Example compound 148-2)

Example compound 148-1 (33 mg) was dissolved in tetrahydrofuran (3.0 mL), 20% palladium hydroxide on carbon (15 mg) was added, the reaction vessel was purged with hydrogen, and the mixture was stirred at room temperature for 3 hours. Further, 20% palladium hydroxide on carbon (15 mg) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, and the solvent was concentrated under reduced pressure to give the crude title compound (24 mg) as a pale yellow solid. MS (ESI) m/z: 545.3 [M+H] ⁺

(148-3) 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]diazepine -6-yl]acetate (Example compound 148)

In Example 63, using Example Compound 148-2 (20 mg) instead of Example Compound 63-2, the same reaction and treatment as in (63-3) gave the title compound (8.7 mg). was obtained as a yellow solid. MS (ESI) m/z: 867.5 [M+H] ⁺

Example 149
(149-1) methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl] pyridazin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6 -yl]acetate (Example Compound 149)

Using t-butyl 6-bromopyridazine-3-carboxylate (283 mg) instead of t-butyl 5-bromopyrazine-2-carboxylate in Example 65, (65-1)-(65-2) By the same reaction and treatment as above, the title compound (81 mg) was obtained as a pale yellow solid. MS (ESI) m/z: 825.5 [M+H] ⁺

Example 150
(150-1) methyl 6-{4-[(6S)-6-(2-t-butoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1 ,2,4]triazolo[4,3-a][1,4]diazepin-4-yl]phenyl}pyridazine-3-carboxylate (Example Compound 150)

Example compound 138-1 (100 mg), methyl 6-chloropyridazine-3-carboxylate (95 mg), cesium fluoride (139 mg), water (0.02 mL), tetrahydrofuran (2.0 mL), X under nitrogen stream A mixture of -Phos (18 mg) and X-Phos aminobiphenylpalladium chloride precatalyst (29 mg) was stirred under reflux for 3 hours. Methyl 6-chloropyridazine-3-carboxylate (95 mg), cesium fluoride (139 mg), water (0.02 mL), X-Phos (18 mg), X-Phos aminobiphenyl palladium chloride precatalyst (29 mg) were added to the reaction mixture. was added, and the mixture was further stirred under reflux with heating for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) and NH silica gel column chromatography (hexane:ethyl acetate=50:50-0:100) to obtain the title compound. The compound (52 mg) was obtained as a pale yellow oil. MS (ESI) m/z: 559.3 [M+H] ⁺

(150-2) t-butyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl) Carbamoyl]pyridazin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl]acetate (Example compound 150)

To a solution of example compound 150-1 (50 mg) in tetrahydrofuran (1 mL) and methanol (1 mL) was added an aqueous solution (0.25 mL) of lithium hydroxide (7.5 mg) under ice cooling, and the mixture was stirred at the same temperature for 1 hour. . After diluting the reaction solution with ethyl acetate, it was washed twice with saturated aqueous sodium bicarbonate solution. 2N Hydrochloric acid was added to the aqueous layer under ice-cooling to adjust the pH to 3, followed by extraction with chloroform three times. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
To the resulting residue, a solution of Reference Example compound 5 (21 mg) in N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (0.021 mL) and HATU (19 mg) were added, and the mixture was stirred at room temperature for 1 hour. bottom. The reaction mixture was diluted with ethyl acetate (30 mL)-tetrahydrofuran (5 mL), washed three times with half-saturated brine and once with saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (29 mg) as a white solid. MS (ESI) m/z: 867.4 [M+H] ⁺

Test example 1
Cytotoxicity to Cancer Cells Cytotoxicity to human cancer cells was evaluated in vitro for the compounds of the present invention. In this experiment, (+)-JQ1 (Nature volume 468, pages 1067-1073 (23 December 2010)), which is known to have binding inhibitory activity between BRD4 protein and its ligand, was used as a positive control drug. board. Each cell was suspended in 10% FBS/RPMI1640, seeded in a 96-well plate, and cultured overnight at 37°C in 5% CO ₂ , after which the test compound dissolved in DMSO was diluted with 10% FBS/RPMI1640 and added. , and cultured for an additional 96 hours. After culturing, the number of viable cells was measured using a WST-8 kit for measuring cell count (Kishida Chemical). In addition, the control was measured under conditions not containing the test compound. Table 1 shows the cytotoxic activity of the compounds of the present invention against human prostate cancer LNCaP cells as IC ₅₀ values. The IC ₅₀ value is the compound concentration when the cell viability in the compound-untreated condition is 100%, and the compound concentration is 50%. Calculated from a straight line. In addition, Table 2 shows human acute myelogenous leukemia MV-4-11 cells, human chronic myelogenous leukemia K562 cells, human multiple myeloma MM.1S cells, human diffuse large B-cell lymphoma SU-DHL- 6 cells, human T-cell leukemia Jurkat cells, human Burkitt's lymphoma Raji cells, human castration-resistant prostate cancer PC-3 cells, human AR-V7-positive castration-resistant prostate cancer 22Rv1 cells, human ovarian cancer A2780 cells , human cisplatin-resistant ovarian cancer SK-OV-03 cells, human bladder cancer 5637 cells, human breast cancer ZR-75-1 cells, human triple-negative breast cancer MDA-MB-231 cells, human cervical cancer HeLa cells, Human uterine sarcoma MES-SA cells, human gastric cancer SNU-16 cells, human non-small cell lung cancer NCI-H2126 cells, human EGFRT790M mutation-positive non-small cell lung cancer NCI-H1975 cells, human small cell lung cancer NCI-H82 cells, human large cell Lung cancer NCI-H460 cells, human colon cancer HCT116 cells, human glioma U-87 MG cells, human pancreatic cancer BxPC-3 cells, human liver cancer HLF cells, human cholangiocarcinoma HuCCT1 cells, human renal cell carcinoma 786 The cytotoxic activity against cancer cells of -O cells and human fibrosarcoma HT1080 cells was expressed as an _IC50 value. The compounds of the present invention exhibited potent cytotoxicity against cancer cells.

Test example 2
Effect of Inducing BRD4 Protein Degradation in Cancer Cells The effect of the compound of the present invention on inducing degradation of BRD4 protein in cancer cells was evaluated in vitro using human prostate cancer LNCaP cells. LNCaP cells were suspended in 10% FBS/RPMI1640, seeded in a 96-well cell carrier plate (Perkin Elmer), and cultured overnight at 37°C in 5% _CO2 . It was diluted with RPMI1640 and added, and cultured for an additional 6 hours. After culture, the cells were fixed with 4% paraformaldehyde/PBS and permeabilized with 0.25% Triton X-100/PBS. Then, the cells were blocked with 10% BSA/PBS, added with Anti-BRD4 (Sigma-Aldrich) solution, and incubated overnight at 4°C. Additionally Goat anti-Rabbit IgG(H+L) Cross-Adsorbed Secondary Antibody, Alexa Fluor 546 (Thermo Fisher Scientific) solution, 0.5 μg/mL Hoechst 33342 (Sigma-Aldrich), and 14 μM Acti-Stain 555 Fluorescent Phalloidin (Cytoskeleton) was added and incubated for 1 hour, the amount of BRD4 protein was measured as fluorescence intensity (excitation: 560 nm, emission: 572 nm) using Operetta (Perkin Elmer). Table 3 shows the BRD4 protein degradation-inducing activity in LNCaP cells of the compounds of the present invention as DC ₅₀ values. The DC ₅₀ value is the compound concentration at which the fluorescence intensity becomes 50% when the fluorescence intensity under the compound untreated condition is 100%, and is calculated from the straight line connecting the fluorescence intensity and the compound concentration at two points between the fluorescence intensity of 50%. bottom. The compounds of the present invention induced degradation of BRD4 protein in cancer cells at concentrations exhibiting cell growth inhibitory activity.

Test example 3
Cytotoxic effect on cancer cells that have acquired resistance to conventional BRD4 proteolytic inducers. evaluated in vitro. In this experiment, ARV-771 (Proc Natl Acad Sci USA. volume 113, pages 7124-7129 (28 Jun 2016)) and MZ1 (ACS Chem Biol. Volume 10, pages 1770-1777 (21 Aug 2015)). Human breast cancer MDA-MB-436 cells and MDA-MB-436 cells (MDA-MB-436 w/o2 cells) that acquired resistance to conventional BRD4 protein degradation inducers were suspended in 10% FBS/RPMI1640, After seeding in a 96-well plate and culturing overnight at 37° C. in 5% CO ₂ , a test compound dissolved in DMSO diluted with 10% FBS/RPMI1640 was added and cultured for an additional 96 hours. After culturing, the number of viable cells was measured using a WST-8 kit for measuring cell count (Kishida Chemical). In addition, the control was measured under conditions not containing the test compound. Table 4 shows the cytotoxic activity of the compounds of the present invention against each cell in terms of _IC50 values. The IC ₅₀ value is the compound concentration when the cell viability in the compound-untreated condition is 100%, and the compound concentration is 50%. Calculated from a straight line. In addition, resistance (fold) was calculated as a value obtained by dividing the _IC50 value in MDA-MB-436 w/o2 cells by the _IC50 value in MDA-MB-436 cells. MDA-MB-436 w/o2 cells were resistant to ARV-771 and MZ1, but not to compounds of the invention.

Test example 4
BRD4 proteolysis-inducing effect on cancer cells that have acquired resistance to conventional BRD4 proteolysis inducers BRD4 proteolysis of the compounds of the present invention on cancer cells that have acquired resistance to conventional BRD4 proteolysis inducers The inductive effect was evaluated in vitro. In this experiment, ARV-771 and MZ1, in which a VHL ligand and a BRD4 protein inhibitor were linked, were used as conventional BRD4 proteolytic inducers for comparison. Human breast cancer MDA-MB-436 cells and MDA-MB-436 cells (MDA-MB-436 w/o2 cells) that acquired resistance to conventional BRD4 protein degradation inducers were suspended in 10% FBS/RPMI1640, After seeding in a 6-well plate and culturing overnight at 37° C. in 5% CO ₂ , a test compound dissolved in DMSO diluted with 10% FBS/RPMI1640 was added and cultured for an additional 6 hours. After incubation, cells were lysed with a lysate solution (10 mM Tris-HCl, pH7.4, 0.1% NP-40, 0.1% sodium deoxycholate, 0.1% SDS, 0.15 M NaCl, 1 mM EDTA, 10 μg/mL aprotinin). Dissolved. Electrophoresis was performed on this lysate, and proteins in the acrylamide gel were transferred to an Immobilon PVDF membrane using a semi-dry transfer apparatus. After transfer, the membrane was blocked and immersed in a primary antibody (Anti-BRD4: Sigma-Aldrich, Anti-β-Actin antibody: Sigma-Aldrich) solution at 4°C overnight. Furthermore, after soaking in the secondary antibody solution for 1 hour, the target protein on the membrane was detected using ECL Prime Western Blotting Detection System or ECL Select Western Blotting Detection System (GE Healthcare). As a result, as shown in Figure 1, ARV-771 and MZ1 induced degradation of BRD4 protein in MDA-MB-436 cells, but not in MDA-MB-436 w/o2 cells. . On the other hand, the compounds of the present invention induced degradation of BRD4 protein equally in both cell lines.

Test example 5
The inhibitory effect of the compound of the present invention on the binding between the BRD4 protein and its ligand, acetylated histone H4, was evaluated using EPIgeneous ^TM Binding Domain Kit A (Cisbio), BRD4-1 (GST) ( by time-resolved fluorescence resonance energy transfer (TR-FRET) using [Lys(Ac)5/8/12/16]-Histone H4(1-21)-GGK(Biotin) (Eurogentec). evaluated. In this experiment, (+)-JQ1 (Nature volume 468, pages 1067-1073 (23 December 2010)), which is known to have binding inhibitory activity between BRD4 protein and its acetylated histone H4, was used as a positive control drug. Using. Test compounds dissolved in DMSO were diluted with the provided Diluent Buffer and added to 384-well white plates. )-GGK (Biotin) was added. Then, add Streptavidin-d2 conjugate and Anti-GST-Eu ³⁺ Cryptate conjugate and incubate at room temperature for 3 hours. nm and excitation: 314 nm/emission: 665 nm). Table 5 shows the BRD4 protein inhibitory activity of the compounds of the present invention as IC ₅₀ values (concentration of compound that inhibits binding of BRD4 protein to acetylated histone H4 by 50%). The _IC50 value is the compound concentration at which the fluorescence intensity becomes 50% when the fluorescence intensity under the compound untreated condition is 100%, and is calculated from the straight line connecting the decomposition rate and the compound concentration at two points between the fluorescence intensity of 50%. bottom. The compounds of the present invention exhibited a strong inhibitory effect on the binding between BRD4 protein and ligand.

Test example 6
Antitumor Effects in Human Acute Myeloid Leukemia MV-4-11 Cell-Transplanted Mice The in vivo antitumor effects of the compounds of the present invention were examined using human acute myeloid leukemia MV-4-11 cell-transplanted mice. Male, 6-week-old BALB/c nude mice were subcutaneously implanted with MV-4-11 cells (5 x 10 ⁶ cells/mouse) in the inguinal region, followed by 1/2ab ² (a is the major axis of the tumor, b is the minor axis of the tumor). ), the compound of the present invention was administered into the tail vein on days 1, 5, 9 and 13 after the estimated tumor volume reached about 100 mm ³ (day 1). A 20% hydroxypropyl-β-cyclodextrin solution as a solvent was administered to the control group. On the 15th day, the tumor was excised and weighed, and the tumor growth inhibition rate IR (%) was calculated by the following formula.
Tumor growth inhibition rate IR (%) =
{1-(average tumor weight of administration group/average tumor weight of non-administration control group)} x 100 (%)
As a result, as shown in Table 6 and FIG. 2, the compounds of the present invention were shown to exhibit antitumor effects in human acute myeloid leukemia MV-4-11 cell-transplanted mice.

Test example 7
Antitumor effect by one-week intermittent administration in human acute myeloid leukemia MV-4-11 cell-transplanted mice Antitumor effect of the compound of the present invention in vivo using human acute myeloid leukemia MV-4-11 cell-transplanted mice investigated. Male, 6-week-old BALB/c nude mice were subcutaneously implanted with MV-4-11 cells (5 x 10 ⁶ cells/mouse) in the inguinal region, followed by 1/2ab ² (a is the major axis of the tumor, b is the minor axis of the tumor). ), the compound of the present invention was administered into the tail vein on days 1 and 8 after the estimated tumor volume reached about 200 mm ³ (day 1). A 10% Kolliphor ELP/5% ethanol/85% saline solution as a solvent was administered to the control group. On the 15th day, the tumor was excised and weighed, and the tumor growth inhibition rate IR (%) was calculated by the following formula.
Tumor growth inhibition rate IR (%) =
{1-(average tumor weight of administration group/average tumor weight of non-administration control group)} x 100 (%)
As a result, as shown in Table 7, it was shown that the compound of the present invention exerts an antitumor effect even in intermittent administration for 1 week in human acute myeloid leukemia MV-4-11 cell-transplanted mice.

Test example 8
Maximum Tolerated Dose The Maximum Tolerated Dose (MTD) in rats was determined for the compounds of the present invention. In this experiment, a control compound 157 (PCT/JP2019/026553) in which a VHL ligand and a BRD4 protein inhibitor were linked was used as a conventional BRD4 proteolytic inducer for comparison. After a single dose of the compound of the present invention or compound 157 was administered to male CD (SD) rats aged 6 weeks through the tail vein, the general condition was observed and the MTD was determined.
As a result, as shown in Table 8, the compounds of the present invention were found to have an improved MTD compared to the BRD4 proteolytic inducer using the VHL ligand.

The compounds of the present invention are excellent in BRD4 proteolysis-inducing action, and therefore pharmaceutical compositions containing the compounds are useful as therapeutic agents for cancer.

Claims (16)

Formula (I):

[In the formula,
A and Q are independently selected from an aromatic hydrocarbon ring; an aromatic heterocyclic ring containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen; a cycloalkane ring; and oxygen, sulfur and nitrogen. an aliphatic heterocyclic ring containing 1 to 3 atoms;
The ring is
halogen atom;
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;
—CO—N(R ^7a )(R ^7b );
—N(R ^7a )(R ^7b ); and —N(R ^7c )—CO—R ^7d ;
It 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 a group selected from =CR ^Z3 - and =N-;
Z ⁴ is a group selected from =CR ^Z4 - and =N-;
Z ⁵ is a group selected from =CR ^Z5 - and =N-;
R ^Z3 , R ^Z4 and R ^Z5 are each independently
hydrogen atom; halogen atom; hydroxy group; cyano group; hydroxycarbonyl group; alkyl group optionally substituted by a group selected from halogen atom, hydroxy group, alkoxy group and cyano group; and a cycloalkyl group optionally substituted with a group selected from a cyano group; a halogen atom, a hydroxy group, an alkoxy group optionally substituted with a group selected from an alkoxy group and a cyano group; a halogen atom, a hydroxy group , an alkoxycarbonyl group optionally substituted with a group selected from 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:

is the following formula (Ea), (Eb) or (Ec):

indicates either
L, T, and M each independently represent a single bond, or
-O-; -S-; -NR ^7a -; -CO-; -SO-; -SO ₂ -; -CO-NR ^7c -; -NR ^7c -CO-; -SO ₂ -NR ^7c -; ^7c —SO ₂ —; —NR ^7a —CO—NR ^7b —; —(OCH ₂ CH ₂ ) _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 -; -SO ₂ -NR ^7c -R ^7r - and —R ^7r —SO ₂ —NR ^7c —; or
bivalent aromatic hydrocarbon group; bivalent aliphatic heterocyclic group; bivalent aromatic heterocyclic group which may be partially hydrogenated; alkylene group; cycloalkylene group; alkenylene group; ; represents a group selected from
a hydroxy group; a cyano group; an oxo group; a hydroxycarbonyl group; an alkyl group optionally substituted by 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 hydroxy group, an alkoxy group and a cyano group;
-LTM- is -O-O-, -S-S-, -NR ^7a -NR ^7a -, -OS-, -S-O-, - as a whole or a part of the structure without indicating a group selected from O—NR ^7a —, —NR ^7a —O—, —S—NR ^7a — and —NR ^7a —S—,
G represents N or C,
J represents N or O,
Further substructure:

teeth,

Denotes a substructure selected from
n is 1 or 2,
m represents an integer from 1 to 6,
R ⁵ is 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 hydrogen atom; a halogen atom; a hydroxy group; a cyano group; an alkyl group optionally substituted by 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;
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 ^7a and R ^7b bonded to the same nitrogen atom are bonded and together with the nitrogen atom may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; may form an aliphatic heterocyclic ring containing
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 an alkylene group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; 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; 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 are each independently a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; and an alkoxy group optionally 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 each independently substituted with a group selected from a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; a hydroxycarbonyl group; 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; a substituent selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; an alkoxycarbonyl group which may be present; and —CO—N(R ^7a )(R ^7b ); or
R ^9a and R ^9b together are an alkylene group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; or a halogen atom, a hydroxy group, an alkoxy group and a cyano group an alkenylene group optionally substituted with a group selected from; may form a condensed ring with the adjacent ring E,
hydroxy group; cyano group; —N( ^{R 7a )} (R ^7b ); —N(R ^7c )—CO—OR ^{7d ;} and alkyl group; indicates a substituent that is
The alkyl group is
Halogen atom; hydroxy group; cyano group; alkoxy group optionally substituted with a substituent selected from halogen atom, hydroxy group, alkoxy group and cyano group; selected from halogen atom, hydroxy group, alkoxy group and cyano group an alkoxycarbonyl group optionally substituted with a substituent; a hydroxycarbonyl group; and —CO—N(R ^7a )(R ^7b );
R ^10a and R ^10b together form a ring representing an alkylene group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group,
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. ]
A pharmaceutical composition comprising a compound represented by or a pharmaceutically acceptable salt thereof. Substructure:

is the following formula:

[In the formula,
R ^a is a hydrogen atom; or an alkyl group optionally 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 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 an alkoxy group and a cyano group; or —CO—N(R ^7a )(R ^7b );
R ^a'' is a hydrogen atom; a halogen atom; a cyano 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 alkoxycarbonyl group optionally substituted with a substituent selected from a cyano group; or —CO—N(R ^7a )(R ^7b ). ]
indicated by
A pharmaceutical composition according to claim 1 . A is a ring selected from an aromatic hydrocarbon ring, a 5- to 6-membered aromatic heterocyclic ring containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen, and a cycloalkane ring;
^RZ3 is
hydrogen atom; halogen atom; hydroxy group; cyano group; hydroxycarbonyl group; alkyl group optionally substituted by a group selected from halogen atom, hydroxy group, alkoxy group and cyano group; and a cycloalkyl group optionally substituted with a group selected from a cyano group; a halogen atom, a hydroxy group, an alkoxy group optionally substituted with a group selected from an alkoxy group and a cyano group; a halogen atom, a hydroxy group , an alkoxycarbonyl group optionally substituted with a group selected from an alkoxy group and a cyano group;
R ^Z4 and R ^Z5 are each independently a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted with a substituent 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 hydroxy group, an alkoxy group and a cyano group;
Substructure:

is the following formula (Ea) or (Ec):

shows
Substructure:

but,

shows
Substructure:

but,

shows
L is a divalent aromatic hydrocarbon group; a divalent aliphatic heterocyclic group; a partially hydrogenated bivalent aromatic heterocyclic group; an alkylene group; a cycloalkylene group; an alkenylene group; , an alkynylene group;
cyano group; hydroxycarbonyl group; alkyl group optionally substituted with a group selected from halogen atom, hydroxy group, alkoxy group and cyano group; and halogen atom, hydroxy group, an alkoxy group optionally substituted with a group selected from an alkoxy group and a cyano group;
T represents a single bond, —CO—, —CO—NR ^7c —, —NR ^7c —CO—, or —O—;
hydroxycarbonyl group; halogen atom, hydroxy group, alkoxy group and alkyl group optionally substituted with a substituent selected from cyano group; and halogen atom, hydroxy group, an alkoxy group optionally substituted with a substituent selected from an alkoxy group and a cyano group; an alkylene group optionally substituted with a substituent selected from
M is a single bond;
-O-; -S-; -NR ^7a -; -CO-; -SO-; -SO ₂ -; -CO-NR ^7c -; -NR ^7c -CO-; -SO ₂ -NR ^7c -; ^7c —SO ₂ —; —NR ^7a —CO—NR ^7b —; —(OCH ₂ CH ₂ ) _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 -; an alkylene group optionally substituted with a substituent selected from 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) 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) a halogen atom , an alkoxy group optionally substituted with a substituent selected from a hydroxy group, an alkoxy group and a cyano group; a divalent aliphatic heterocyclic group optionally substituted with a substituent selected from; is a group that
^R5 is a hydrogen atom,
R ^6a and R ^6b are independently selected from a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; is a group that is
R ^7c is a hydrogen atom,
R ^8a and R ^8b are each independently a hydrogen atom; a halogen atom; a hydroxy group; and a cyano group;
R ^9a and R ^9b are each independently a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group; can be,
R ^10a and R ^10b each independently represent a substituent selected from a hydrogen atom; —N(R ^7c )—CO—OR ^7d ; and an alkyl group;
The alkyl group is
Halogen atom; hydroxy group; cyano group; alkoxy group optionally substituted with a substituent selected from halogen atom, hydroxy group, alkoxy group and cyano group; selected from halogen atom, hydroxy group, alkoxy group and cyano group an alkoxycarbonyl group optionally substituted with a substituent; —CO—N(R ^7a ) (R ^7b ); and a hydroxycarbonyl group; optionally substituted with a substituent selected from
3. A pharmaceutical composition according to claim 2. 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 ″} represents a hydrogen atom; a halogen atom; an alkyl group optionally 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 optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group; a substitution selected from a halogen atom, a hydroxy group and a cyano group a cycloalkyl group optionally substituted with a group; or an alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group;
R ^Z4 and R ^Z5 independently represent a hydrogen atom; or an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group;
Substructure:

is the following formula (Ea):

shows
L is an alkynyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group; a) a halogen atom, b) a hydroxy group, c) a cyano group, d) a halogen atom, a hydroxy group and Substitution selected from an alkyl group optionally substituted with a substituent selected from 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 aromatic hydrocarbon group optionally substituted with a group; a divalent aliphatic containing one nitrogen atom, optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group heterocyclic 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; and
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 represents a single bond; -CO-; -CO-NR ^7c -; -NR ^7c -CO-; or -O-;
M is a single bond;
—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; from a halogen atom, a hydroxy group, and a cyano group an alkynylene group optionally substituted with a selected substituent; and a divalent aliphatic heterocyclic group;
R ^6a and R ^6b are each independently 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; and
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 represents a hydrogen atom,
R ^7d represents an alkyl group optionally 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,
both R ^8a and R ^8b are 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 a substituent selected from a halogen atom, a hydroxy group, a cyano group, —NH—CO—OR ^7d , —CO—N(R ^7a )(R ^7b ), an alkoxycarbonyl group and a hydroxycarbonyl group. A group selected from an optionally substituted alkyl 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;
4. The pharmaceutical composition according to claim 2 or 3. R ^a is 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 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 independently represent a hydrogen atom; or an alkyl group;
Substructure:

is the following formula (Ea):

shows
L is an alkynylene group; a halogen atom, a hydroxy group, an alkyl group optionally substituted with 1 to 3 halogen atoms, and an alkoxy group. A good divalent aromatic hydrocarbon group; a divalent aliphatic heterocyclic group containing one nitrogen atom; and an atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may be partially hydrogenated is a group selected from a divalent aromatic heterocyclic group containing 1 to 2
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 is an oxo group. may be replaced,
T is a single bond;
-CO-; -CO-NR ^7c -; -NR ^7c -CO-; or -O-;
M is a single bond;
-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; can be,
R ^6a and R ^6b are each independently a hydrogen atom; a halogen atom; a cyano group; and an alkyl group;
R ^7a and R ^7b independently represent a hydrogen atom; or an alkyl group;
R ^7c represents a hydrogen atom,
R ^7d represents an alkyl group,
R ^7r represents an alkylene group,
both R ^8a and R ^8b are 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 substituted with one substituent selected from —NH—CO—OR ^7d , —CO—N(R ^7a )(R ^7b ), a cyano group, an alkoxycarbonyl group and a hydroxycarbonyl group; A group selected from an optionally alkyl group;
R ^10b is a hydrogen atom,
R ¹¹ is an alkyl group,
The pharmaceutical composition according to any one of claims 2-4. A represents a benzene ring,
R ^a represents a hydrogen atom,
R ^10a is an alkyl group optionally substituted with one alkoxycarbonyl group,
L is a divalent aromatic optionally substituted by 1 to 2 substituents selected from a halogen atom, an alkyl group optionally substituted by 1 to 3 halogen atoms, and an alkoxy group a hydrocarbon 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; can be,
M is an alkylene group optionally substituted with one substituent selected from a hydroxy group and a cyano group;
The pharmaceutical composition according to any one of claims 2-5. R ^{a '} represents a hydrogen atom,
R ^a'' represents a cyano group,
R ^Z3 represents an alkyl group optionally substituted with 1 to 3 halogen atoms or hydroxy groups; or an alkoxy group;
R ^Z4 represents a hydrogen atom,
R ^Z5 represents a hydrogen atom,
The pharmaceutical composition according to any one of claims 2-6. both R ^8a and R ^8b are 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 pharmaceutical composition according to any one of claims 2-7. 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 -, R ^7c is a hydrogen atom,
M is -CH ₂ - or -CH(CH ₃ )-,
The pharmaceutical composition according to any one of claims 2-8. 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]diazepine-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]diazepine-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]diazepine -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]diazepine- 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]pyrazine-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]diazepine- 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]diazepine- 6-yl} acetate,
methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazine-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]diazepine- 6-yl} acetate,
methyl [(6S)-4-(4-{6-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyridine-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][ A pharmaceutical composition comprising a compound selected from 1,4]diazepin-6-yl]acetate, or a pharmaceutically acceptable salt thereof. 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]diazepine-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]diazepine-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]diazepine -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]diazepine- 6-yl} acetate,
methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazine-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]diazepine- 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]diazepine- 6-yl} acetate,
methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazine-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]diazepine- 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. The pharmaceutical composition according to any one of claims 1 to 11 for inducing BRD4 proteolysis. A pharmaceutical composition according to any one of claims 1 to 12 for treating cancer. Cancer is acute myelogenous leukemia, chronic myelogenous 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 14. The pharmaceutical composition of claim 13. Cancer is acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, diffuse large B-cell lymphoma, multiple myeloma, Burkitt's lymphoma, glioma, gastric cancer, colorectal cancer, pancreatic cancer, 15. The pharmaceutical composition according to claim 14, which is a cancer selected from liver cancer, prostate cancer, non-small cell lung cancer, breast cancer, ovarian cancer and uterine sarcoma. 16. The pharmaceutical composition according to claim 15, wherein the cancer is a cancer selected from acute myelogenous leukemia, diffuse large B-cell lymphoma, multiple myeloma, prostate cancer, ovarian cancer and breast cancer. .

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