JP7614145B2 - Medicine containing BRD4 protein degradation inducer - Google Patents

Description

The present invention relates to a pharmaceutical composition that contains a sulfonamide or sulfinamide compound or a pharma- ceutical acceptable salt thereof that has excellent cytotoxicity against cancer cells, an effect of inducing the degradation of BRD4 protein in cancer cells, and an effect of inhibiting the binding of BRD4 protein to acetylated histones, 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 the form of chromatin. The building block of the nucleosome is a histone octamer consisting of two molecules of each of four types of histones, H2A, H2B, H3, and H4, with DNA wrapped around it. The several dozen residues on the N-terminal side of the histone are called the histone tail, and various post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination are present. Post-translational modifications, also called the histone code, are one of the mechanisms responsible for epigenetic gene expression control, which determines when and where the genetic information on DNA is expressed. Histone modifications are reversible and are functionally controlled by modification enzymes (writers) that write modification groups on histones, de-modification enzymes (erasers) that remove modification groups, and histone readers that specifically read modified histones. These control mechanisms contribute greatly to individual development and cell differentiation, and epigenetic abnormalities are known to be involved in various diseases.

Bromodomains are reader proteins consisting of about 110 amino acids that recognize acetylated lysines on histones. Approximately 50 types of proteins containing bromodomains are known to date. They function as scaffolding proteins for various transcription factors by binding to acetylated lysines on histones, and exert various functions within cells, such as reconstructing chromatin and regulating transcription through their own histone acetyltransferase activity and kinase activity. BRD2, BRD3, BRD4, and BRDT, which are included in the BET (bromodomain and extraterminal) family proteins (sometimes referred to as BET proteins in this specification and claims), which are bromodomain-containing proteins, have two bromodomains on the N-terminus and an extra C-terminal domain on the C-terminus that are highly conserved within the family, and each BET protein is known to function both independently and cooperatively (Non-Patent Document 1).

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

To date, BRD4 inhibitors that inhibit the binding of BRD4 to histones have been clinically developed as anticancer drugs targeting BRD4 (Non-Patent Document 14). However, BRD4 inhibitors are not sufficiently effective in causing BRD4 accumulation (Non-Patent Document 15), and resistance is acquired through the expression of proteins that stabilize BRD4 expression or proteins that enhance BRD4-mediated transcriptional activity in a bromodomain-independent manner (Non-Patent Documents 16, 17). Therefore, there is a need to develop anticancer drugs that target BRD4 by new means.

In recent years, a new drug discovery technology (chemical knockdown) has been attracting attention. The technology uses a compound that combines a ligand for E3 ligase with ubiquitin ligase activity [Von Hippel-Lindau (VHL), Cereblon (CRBN), Cellular Inhibitor of Apoptosis Protein 1 (cIAP1)] with a binder that binds to the target protein to form an artificial complex between E3 ligase and the target protein in cells, and induces the degradation of the target protein by utilizing the ubiquitin-proteasome system, which is an intracellular protein degradation mechanism (Non-Patent Document 18). To date, BRD4 protein degradation inducers that use this technology include ARV-771, which uses a ligand for VHL, and ARV-825, which uses a ligand for CRBN (Non-Patent Documents 15, 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 when used for a long period of time, is a major problem (Non-Patent Document 20). Overcoming this resistance to anticancer drugs is expected to lead to improved treatment outcomes in cancer chemotherapy, and the existence of various resistance mechanisms has been revealed so far (Non-Patent Document 20). It has been reported that acquired resistance to BRD4 protein degradation inducers is induced in cancer cells due to functional abnormalities of the complex of E3 ligase VHL or CRBN, which causes protein degradation (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 show natural resistance to BRD4 protein degradation inducers that utilize ligands for VHL, and it is hoped that new BRD4 protein degradation inducers that utilize ligands for new E3 ligases and overcome the resistance of conventional BRD4 protein degradation inducers will be developed. In recent years, many target protein degradation inducer compounds that combine a ligand for a new E3 ligase with a binder for the target protein have been reported (Non-Patent Document 23). For example, a new BRD4 protein degradation inducer that utilizes the E3 ligase DCAF15 has been reported (Non-Patent Document 24). However, its BRD4 protein degradation induction and cytotoxicity are not sufficient. Currently, there are only a limited number of combinations of ligands for E3 ligase and binders for target proteins (Non-Patent Document 23), and it is necessary to find a combination of an appropriate E3 ligase ligand and linker structure for a binder for BRD4 protein that will exhibit sufficient BRD4 protein degradation induction and cytotoxicity as an anticancer drug.

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 that is useful as a cancer therapeutic agent, comprising a compound or a pharma- ceutical acceptable salt thereof that has excellent BRD4 protein degradation-inducing activity by utilizing a ligand for E3 ligase DCAF15.

As a result of intensive research aimed at solving the above problems, the present inventors have discovered a compound that utilizes a ligand for E3 ligase DCAF15 and has the effect of inducing the degradation of BRD4 protein, and have found that a pharmaceutical composition containing said compound that is useful as a cancer treatment agent can be provided. In particular, the present invention has been completed by finding an optimal linker structure for the ligand for DCAF15. That is, the gist of the present invention is as follows.

[1] Formula (I):

[Wherein,
A and Q each independently represent a ring selected from an aromatic hydrocarbon ring; an aromatic heterocycle containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen; a cycloalkane ring; and an aliphatic heterocycle containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen;
The ring is
Halogen atoms;
Hydroxy group;
Cyano group;
Hydroxycarbonyl group;
oxo group;
Thioxo group;
an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
an alkoxy group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
an alkoxycarbonyl group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
-CO-N(R ^7a )(R ^7b );
-N(R ^7a )(R ^7b ); and -N(R ^7c )-CO-R ^7d ;
may be substituted with a group selected from
^Z1 is a group selected from C and N;
^Z2 is a group selected from C and N;
^Z3 is a group selected from ═CR ^Z3 — and ═N—;
^Z4 is a group selected from ═CR ^Z4 — and ═N—;
^Z5 is a group selected from = ^CRZ5- and =N-;
R ^Z3 , R ^Z4 , and R ^Z5 are each independently
a group selected from a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; a hydroxycarbonyl group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; a cycloalkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; -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,
Partial structure:

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

Indicates either
L, T, and M each independently represent a single bond;
-O-;-S-;-NR ^7a -;-CO-;-SO-;-SO ₂ -;-CO-NR ^7c -;-NR ^7c -CO-;-SO ₂ -NR ^7c -;-NR ^7c -SO ₂ -;-NR ^7a -CO-NR ^7b -;-(OCH ₂ CH ₂ ) _m -;-O-R ^7r -;-R ^7r -O-;-S-R ^7r -;-R ^7r -S-;-NR ^7a -R ^7r -;-R ^7r -NR ^7a -;-CO-NR ^7c -R ^7r -;-R ^7r -CO-NR ^7c -;-SO ₂ -NR ^7c -R ^7r -; and -R ^7r -SO ₂ -NR ^7c -; or
represents a group selected from a divalent aromatic hydrocarbon group; a divalent aliphatic heterocyclic group; a divalent aromatic heterocyclic group which may be partially hydrogenated; an alkylene group; a cycloalkylene group; an alkenylene group; and an alkynylene group;
the group may be substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; an oxo group; a hydroxycarbonyl group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
-L-T-M- does not represent, as the whole or a part of the structure, a group selected from -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-,
G represents N or C;
J represents N or O;
Further substructure:

teeth,

represents a partial structure selected from
n is 1 or 2;
m represents an integer from 1 to 6;
^R5 is a group selected from a hydrogen atom; and an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
R ^6a and R ^6b are each independently a group selected from a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
R ^7a and R ^7b each independently represent a hydrogen atom; or an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
R ^7a and R ^7b bonded to the same nitrogen atom may be bonded to form, together with the nitrogen atom, an aliphatic heterocycle containing one nitrogen atom which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group;
R ^7c and R ^7d are each independently a hydrogen atom; or an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group;
^R7r is a group selected from an alkylene group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkenylene group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; or an alkynylene group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
R ^8a and R ^8b are each independently a group selected from a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
R ^9a and R ^9b are each independently a group selected from a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; a hydroxycarbonyl group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and -CO-N(R ^7a )(R ^7b );
R ^9a and R ^9b together may represent an alkylene group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; or an alkenylene group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and may form a condensed ring with the adjacent ring E;
R ^10a and R ^10b each independently represent a substituent selected from a hydrogen atom; a hydroxy group; a cyano group; -N(R ^7a )(R ^7b ); -N(R ^7c )-CO-OR ^7d ; and an alkyl group;
The alkyl group is
a halogen atom; a hydroxy group; a cyano group; an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; a hydroxycarbonyl group; and -CO-N(R ^7a )(R ^7b );
R ^10a and R ^10b together form a ring and represent an alkylene group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
R ¹¹ is a group selected from a hydrogen atom; and an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group.
or a pharma- ceutical acceptable salt thereof (in the present specification, may be abbreviated as "compound (I)").

[2] Substructure:

But the formula is:

[Wherein,
R ^a represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
R ^a′ represents a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; or —CO—N(R ^7a )(R ^7b ),
R ^a″ represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; or —CO—N(R ^7a )(R ^7b ).
Denoted by
The pharmaceutical composition described in [1].

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

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

indicates,
Partial structure:

but,

indicates,
Partial structure:

but,

indicates,
L is a group selected from a divalent aromatic hydrocarbon group; a divalent aliphatic heterocyclic group; a divalent aromatic heterocyclic group which may be partially hydrogenated; an alkylene group; a cycloalkylene group; an alkenylene group; and an alkynylene group;
the group is optionally substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; a hydroxycarbonyl group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
T represents a single bond, —CO—, —CO—NR ^7c —, —NR ^7c —CO—, or —O—;
an alkylene group optionally substituted by a substituent selected from a halogen atom; a hydroxy group; a cyano group; an oxo group; a hydroxycarbonyl group; an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and an alkoxy group optionally substituted by a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
M is a single bond,
-O-;-S-;-NR ^7a -;-CO-;-SO-;-SO ₂ -;-CO-NR ^7c -;-NR ^7c -CO-;-SO ₂ -NR ^7c -;-NR ^7c -SO ₂ -;-NR ^7a -CO-NR ^7b -;-(OCH ₂ CH ₂ ) _m -;-O-R ^7r -;-R ^7r -O-;-S-R ^7r -;-R ^7r -S-;-NR ^7a -R ^7r -;-R ^7r -NR ^7a -;-CO-NR ^7c -R ^7r -;-R ^7r -CO-NR ^7c -; and an alkylene group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkynylene group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and a divalent aliphatic heterocyclic group which may be substituted with a substituent selected from a) a halogen atom, b) a hydroxy group, c) a cyano group, d) an oxo group, e) an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group, and f) an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
^R5 is a hydrogen atom;
R ^6a and R ^6b are each independently a group selected from a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; and an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group;
R ^7c is a hydrogen atom;
R ^8a and R ^8b are each independently a group selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, and a cyano group;
R ^9a and R ^9b are each independently a group selected from a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
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
optionally substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; -CO-N(R ^7a )(R ^7b ); and a hydroxycarbonyl group,
The pharmaceutical composition described in [2].

[4] A is a ring selected from a benzene ring; a pyridine ring; and a cycloalkane ring,
R ^a represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^a′ represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^a″ represents a hydrogen atom; a halogen atom; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; or a cyano group;
R ^Z3 represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a cycloalkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; or an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group;
R ^Z4 and R ^Z5 each independently represent a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
Partial structure:

is expressed by the following formula (Ea):

indicates,
L is a group selected from an alkynyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a divalent aromatic hydrocarbon group which may be substituted with a substituent selected from a) a halogen atom, b) a hydroxy group, c) a cyano group, d) an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, and e) an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a divalent aliphatic heterocyclic group containing one nitrogen atom which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and a divalent aromatic heterocyclic group which may be partially hydrogenated and contains 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom;
the aromatic heterocyclic group may be substituted with a substituent selected from a halogen atom, a hydroxy group, a cyano group, and an oxo group;
T represents a single bond; -CO-; -CO-NR ^7c -; -NR ^7c -CO-; or -O-;
M is a single bond,
a group selected from -R ^7r -O-; -R ^7r -NR ^7a -; an alkylene group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; an alkynylene group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and a divalent aliphatic heterocyclic group;
R ^6a and R ^6b are each independently a group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^7a and R ^7b each independently represent a hydrogen atom; or an alkyl group which may be substituted by a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^7c represents a hydrogen atom;
R ^7d represents an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group;
R ^7r represents an alkylene group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^8a and R ^8b are both hydrogen atoms;
R ^9a and R ^9b each independently represent an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^10a is a group selected from a hydrogen atom; and an alkyl group which may be substituted with 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;
R ^10b is a hydrogen atom;
R ¹¹ is an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
The compound according to [2] or [3], or a pharma- ceutically 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 represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom and a hydroxy group; a cycloalkyl group; or an alkoxy group;
^R and ^R each independently represent a hydrogen atom or an alkyl group;
Partial structure:

is expressed by the following formula (Ea):

indicates,
L is a group selected from an alkynylene group; a divalent aromatic hydrocarbon group which may be substituted with 1 to 2 substituents selected from a halogen atom, a hydroxy group, an alkyl group which may be substituted with 1 to 3 halogen atoms, and an alkoxy group; a divalent aliphatic heterocyclic group containing one nitrogen atom; and a divalent aromatic heterocyclic group which may be partially hydrogenated and contains 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom;
When the aromatic heterocyclic group is a partially hydrogenated divalent aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, it may be substituted with an oxo group.
T is a single bond or
-CO-; -CO-NR ^7c -; -NR ^7c -CO-; or -O-;
M is a single bond,
a group selected from ^-R7r -O-; ^-R7r - ^NR7a- ; an alkylene group which may be substituted with one hydroxy group; an alkynylene group; and a divalent aliphatic heterocyclic group;
R ^6a and R ^6b are each independently a group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group;
R ^7a and R ^7b each 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;
R ^8a and R ^8b are both hydrogen atoms;
R ^9a and R ^9b each independently represent an alkyl group optionally substituted with one hydroxy group;
R ^10a is a group selected from a hydrogen atom; and an alkyl group optionally 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;
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 group selected from a divalent aromatic hydrocarbon group which may be substituted with 1 to 2 substituents selected from a halogen atom, an alkyl group which may be substituted with 1 to 3 halogen atoms, and an alkoxy group; and a divalent aromatic heterocyclic group which may be partially hydrogenated and contains 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom;
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 which may be 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] R ^8a and R ^8b are both hydrogen atoms;
R ^9a and R ^9b each independently represent 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 which may be 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]diazepin-6-yl]acetate,
methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methoxy-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-{4'-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2'-fluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]-2'-fluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-{2'-chloro-4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-3'-methyl[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
t-butyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
t-butyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-3'-fluoro[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(3'-chloro-4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
5-chloro-N-({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)-2-fluoro-4'-[(6S)-2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl][1,1'-biphenyl]-4-carboxamide,
methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2',3'-difluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-2'-fluoro[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl {(6S)-4-[4-(6-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyridin-3-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate,
methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-2',5'-difluoro[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-2'-fluoro-5'-methyl[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-2',3'-difluoro[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]-2',3'-difluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazin-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate,
methyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazin-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate,
methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl {(6S)-4-[4-(6-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyridin-3-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate,
methyl [(6S)-4-(4-{6-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-{4'-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2',3'-difluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
Methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, and t-butyl 2. A pharmaceutical composition comprising a compound selected from [(6S)-4-(4-{5-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, or a pharma- ceutically 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]diazepin-6-yl]acetate,
methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-{4'-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-{2'-chloro-4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
t-butyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
t-butyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-3'-fluoro[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
5-chloro-N-({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)-2-fluoro-4'-[(6S)-2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl][1,1'-biphenyl]-4-carboxamide,
methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2',3'-difluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl {(6S)-4-[4-(6-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyridin-3-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate,
methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazin-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate,
methyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazin-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate,
methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl {(6S)-4-[4-(6-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyridin-3-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate, and methyl A pharmaceutical composition comprising a compound selected from [(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 pharma- ceutical composition comprising a pharma-ceutical acceptable salt thereof.

[12] The pharmaceutical composition according to any one of [1] to [11], for inducing degradation of BRD4 protein.
[13] The pharmaceutical composition according to any one of [1] to [12] for treating cancer.
[14] The pharmaceutical composition described in [13], wherein the cancer is selected from acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, diffuse large B-cell lymphoma, adult T-cell leukemia/lymphoma, Burkitt's lymphoma, prostate cancer, ovarian cancer, bladder cancer, breast cancer, cervical cancer, uterine sarcoma, gastric cancer, lung cancer, colorectal cancer, glioma, pancreatic cancer, liver cancer, bile duct cancer, renal cell carcinoma, and fibrosarcoma.
[15] The pharmaceutical composition according to [14], wherein the cancer is selected from acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, diffuse large B-cell lymphoma, multiple myeloma, Burkitt's lymphoma, glioma, gastric cancer, colorectal cancer, pancreatic cancer, liver cancer, prostate cancer, non-small cell lung cancer, breast cancer, ovarian cancer, and uterine sarcoma.
[16] The pharmaceutical composition according to [15], wherein the cancer is selected from acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, prostate cancer, ovarian cancer, and breast cancer.

The compound of the present invention has excellent BRD4 protein degradation inducing activity, and a pharmaceutical composition containing the compound is useful as a cancer treatment agent.

1 shows the results of BRD4 protein degradation-inducing effect in Test Example 4. 1 shows the results of the antitumor effect in Test Example 6.

The compound of the present invention is a compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof. In this specification, the "compound represented by general formula (I) or a pharma- ceutically acceptable salt thereof" may be collectively referred to as the compound of the present invention.
The meanings of the terms used in this specification will be explained below, and the present invention will be described in more detail. Note that the explanations of the terms below do not limit the present invention in any way.

In this specification, examples of "halogen atom" include fluorine atom, chlorine atom, bromine atom, and iodine atom.

In the present specification, examples of the "alkyl group" include "C 1-6 alkyl groups" such as 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, and 2-ethylbutyl.

In the present specification, examples of the "cycloalkyl group" include "C 3-10 cycloalkyl groups" such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[ _3.2.1 ]octyl, adamantyl, etc.

In the present specification, examples of the "alkoxy group" include "C _1-6 alkoxy groups" such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the "alkylene group" include, for example, _-CH2- , _- ( _{CH2 ) 2-} , -( _CH2 ) _3- , -(CH2)4- _, -( _CH2 ) _5- , -( _CH2 ) _6- , -CH( _CH3 )- _, -C(CH3)2-, -CH(C2H5)-, _-CH (C3H7)- _, -CH(CH( _CH3 ) ₂ )-, -(CH( _CH3 )) _2- , _-CH2 - _CH ( _CH3 )-, _-CH ( _CH3 ) _-CH2- , _-CH2 -CH2-C(CH3) _2- , -C( _CH3 ) _{2 - CH2 -CH2- , -CH2} -CH Examples of such a group include "C _1-6 alkylene groups" such as _{-CH 2} -C(CH ₃ ) ₂ - and -C(CH ₃ ) ₂ -CH ₂ -CH ₂ -CH ₂ -.

In the present specification, examples of the "alkenylene group" include "C 2-6 alkenylene groups" such as -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 -, -CH=CH-CH=CH-, -CH=CH-CH _{2 -CH 2 -CH 2 -, -CH=CH-CH=CH-, -CH=CH-CH 2 -CH 2} -CH ₂ -, and -CH ₂ -CH ₂ -CH ₂ -CH=CH-.

[0046] In the present specification, examples of the "alkynylene group" include "C 2-6 alkynylene groups" such as -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≡C-C≡C-, -C≡C-CH 2 -CH 2 -CH 2 - ,} and -CH _{2 -CH 2} -CH ₂ -C≡C-.

In the present specification, examples of the "cycloalkylene group" include "C _3-10 cycloalkylene groups" such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, etc.

In the present specification, examples of the "alkoxycarbonyl group" include "C 1-6 alkoxy-carbonyl groups" such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert- _{butoxycarbonyl} , pentyloxycarbonyl and hexyloxycarbonyl.

In the present specification, examples of the "cycloalkane ring" include "C _3-10 cycloalkane rings" such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

In the present specification, examples of the "aromatic hydrocarbon ring" include "C _6-14 aromatic hydrocarbon rings" such as benzene, naphthalene, anthracene, etc.

In the present specification, examples of the "aromatic hydrocarbon group" include C _6-14 aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.

In the present specification, examples of the "divalent aromatic hydrocarbon group" include C _6-14 arylene groups such as phenylene, naphthylene, and anthrylene.

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

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

In this specification, examples of the "divalent aliphatic heterocyclic group" include divalent aliphatic heterocyclic groups derived from the above-mentioned "aliphatic heterocycles."

In this specification, examples of "divalent aliphatic heterocyclic groups containing one nitrogen atom" include divalent aliphatic heterocyclic groups derived from the aliphatic heterocyclic rings containing one nitrogen atom among the above-mentioned "aliphatic heterocycles."

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

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

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

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

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

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

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

Substructure:

is preferably the following formula:

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

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

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

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

Substructure:

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

and more preferably,

It 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 (e.g., methyl) which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and an alkoxy group (e.g., methoxy) which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group. Preferably, each independently of each other, a hydrogen atom; a halogen atom; a cyano group; an alkyl group (e.g., methyl) which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; More preferably, each independently of each other, an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; Even more preferably, each independently of each other, an alkyl group which may be substituted with a hydroxy group; Particularly preferably, an unsubstituted alkyl group; and Even more particularly preferably, a methyl group.

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

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

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

T preferably represents a single bond, -CO-, -CO-NR ^7c -, -NR ^7c -CO- or -O-, or an alkylene group (e.g., -CH 2 -) optionally substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; an oxo group; a hydroxycarbonyl group; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; and an alkoxy group optionally substituted with a substituent selected from a halogen atom, a _hydroxy group, an alkoxy group and a cyano group; more preferably a single bond; -CO-; -CO-NR ^7c -; -NR ^7c -CO-; or -O-, and particularly preferably -CO-NR ^7c -.

M is preferably a single bond or -O-;-S-;- ^NR7a -;-CO-;-SO-;- _SO2 -;-CO- ^NR7c -;- ^NR7c -CO -;-SO ₂ -NR ^7c -;-NR ^7c -SO ₂ -;-NR ^7a -CO-NR ^7b -;-(OCH ₂ CH ₂ ) _m -;-O-R ^7r -;-R ^7r -O-;-S-R ^7r -;-R ^7r -S-;-NR ^7a -R ^7r -;-R ^7r -NR ^7a -;-CO-NR ^7c -R ^7r -;-R ^7r -CO-NR ^7c -; and an alkylene group which may be substituted by 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 (e.g., -CH ₂ -C≡C-) which may be 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 cyclic alkyl group, a hydroxy group, c) a cyano group, d) an oxo group, e) an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and f) a halogen atom, a hydroxy group, an alkoxy group which may be substituted by a substituent selected from the group consisting of a cyclic group, an alkoxy group, and a cyano group; a divalent aliphatic heterocyclic group which may be substituted by a substituent selected from the group consisting of a piperidinediyl group, ), and more preferably a single bond, —R ^7r —O—, —R ^7r —NR ^7a -; an alkylene group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; an alkynylene group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group. group; and a divalent aliphatic heterocyclic group; and more preferably, it is a single bond, -R ^7r -O-; -R ^7r -NR ^7a -; a hydroxy group, and an alkylene group which may be substituted with a substituent selected from a cyano group; an alkynylene group; and a divalent aliphatic heterocyclic group; and particularly preferably a hydroxy group and a cyano group. An alkylene group which may be substituted by one selected substituent is particularly preferably -CH ₂ - or -CH(CH ₃ )-, and particularly preferably -CH ₂ - or ,

It is.

However, -L-T-M- does not represent, as all or a part of the structure, a group selected from -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-.

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

It is.

Substructure:

is preferably,

It is.

Substructure:

is preferably,

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

^R5 is preferably a hydrogen atom.

R ^6a and R ^6b are preferably, independently of each other, a group selected from a hydrogen atom; a halogen atom (e.g., a fluorine atom); a hydroxy group; a cyano group; and an alkyl group (e.g., methyl) which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; more preferably, independently of each other, a group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and even more preferably, a group selected from 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 (e.g., methyl, ethyl) which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, and more preferably each independently a hydrogen atom; or an alkyl group which may be substituted with a hydroxy group.

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

R ^7r is preferably an alkylene group (e.g., —CH ₂ —, —(CH ₂ ) ₂ —, —(CH ₂ ) ₃ —) optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, and is more preferably an alkylene group.

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

R ^10a and R ^10b preferably each independently represent a substituent selected from a hydrogen atom; -N(R ^7c )-CO-OR ^7d ; and an alkyl group (e.g., methyl); the alkyl group may be substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group (e.g., methoxycarbonyl, t-butoxycarbonyl) which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; -CO-N(R ^7a )(R ^7b ); and a hydroxycarbonyl group; more preferably, R ^10a represents a hydrogen atom; and a halogen atom, a hydroxy group, a cyano group, -NH-CO-OR ^7d , -CO-N(R ^7a )(R ^7b and R 10b is a hydrogen atom, more preferably R ^10a is a hydrogen atom; and an alkyl group which may be 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 which may be substituted with one alkoxycarbonyl group, and R ^10b is a hydrogen atom, even more particularly preferably R ^10a is a methyl group ^which may be substituted with one substituent selected from a tert-butoxycarbonyl group and a methoxycarbonyl group, and most preferably a methyl group substituted with a methoxycarbonyl group.

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

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

But the formula is:

indicates,
R ^a represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
R ^a' represents a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; or -CO-N(R ^7a )(R ^7b ),
R ^a″ represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; or —CO—N(R ^7a )(R ^7b ),
R ^Z3 ,
a hydroxy group; a cyano group; a hydroxycarbonyl group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; a cycloalkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
R ^Z4 and R ^Z5 each independently represent a group selected from a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
Partial structure:

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

indicates,
Partial structure:

but,

indicates,
Partial structure:

but,

indicates,
L is a group selected from a divalent aromatic hydrocarbon group; a divalent aliphatic heterocyclic group; a divalent aromatic heterocyclic group which may be partially hydrogenated; an alkylene group; a cycloalkylene group; an alkenylene group; and an alkynylene group;
the group is optionally substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; a hydroxycarbonyl group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
T represents a single bond, —CO—, —CO—NR ^7c —, —NR ^7c —CO—, or —O—;
an alkylene group optionally substituted by a substituent selected from a halogen atom; a hydroxy group; a cyano group; an oxo group; a hydroxycarbonyl group; an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and an alkoxy group optionally substituted by a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
M is a single bond,
-O-;-S-;-NR ^7a -;-CO-;-SO-;-SO ₂ -;-CO-NR ^7c -;-NR ^7c -CO-;-SO ₂ -NR ^7c -;-NR ^7c -SO ₂ -;-NR ^7a -CO-NR ^7b -;-(OCH ₂ CH ₂ ) _m -;-O-R ^7r -;-R ^7r -O-;-S-R ^7r -;-R ^7r -S-;-NR ^7a -R ^7r -;-R ^7r -NR ^7a -;-CO-NR ^7c -R ^7r -;-R ^7r -CO-NR ^7c -; and an alkylene group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkynylene group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and a divalent aliphatic heterocyclic group which may be substituted with a substituent selected from a) a halogen atom, b) a hydroxy group, c) a cyano group, d) an oxo group, e) an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group, and f) an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
^R5 is a hydrogen atom;
R ^6a and R ^6b are each independently a group selected from a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; and an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group;
R ^7c is a hydrogen atom;
R ^8a and R ^8b are each independently a group selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, and a cyano group;
R ^9a and R ^9b are each independently a group selected from a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
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
optionally substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; -CO-N(R ^7a )(R ^7b ); and a hydroxycarbonyl group,
Compound (I).

[Compound I-B]
A is a ring selected from a benzene ring; a pyridine ring; and a cycloalkane ring;
Partial structure:

But the formula is:

indicates,
R ^a represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^a′ represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^a″ represents a hydrogen atom; a halogen atom; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; or a cyano group;
R ^Z3 represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a cycloalkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; or an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group;
R ^Z4 and R ^Z5 each independently represent a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
Partial structure:

is expressed by the following formula (Ea):

indicates,
Partial structure:

but,

indicates,
Partial structure:

but,

indicates,
L is a group selected from an alkynyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a divalent aromatic hydrocarbon group which may be substituted with a substituent selected from a) a halogen atom, b) a hydroxy group, c) a cyano group, d) an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, and e) an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a divalent aliphatic heterocyclic group containing one nitrogen atom which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and a divalent aromatic heterocyclic group which may be partially hydrogenated and contains 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom;
the aromatic heterocyclic group may be substituted with a substituent selected from a halogen atom, a hydroxy group, a cyano group, and an oxo group;
T represents a single bond; -CO-; -CO-NR ^7c -; -NR ^7c -CO-; or -O-;
M is a single bond,
a group selected from -R ^7r -O-; -R ^7r -NR ^7a -; an alkylene group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; an alkynylene group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and a divalent aliphatic heterocyclic group;
R ^6a and R ^6b are each independently a group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^7a and R ^7b each independently represent a hydrogen atom; or an alkyl group which may be substituted by a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^7c represents a hydrogen atom;
R ^7d represents an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group;
R ^7r represents an alkylene group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^8a and R ^8b are both hydrogen atoms;
R ^9a and R ^9b each independently represent an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^10a is a group selected from a hydrogen atom; and an alkyl group which may be substituted with 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;
R ^10b is a hydrogen atom;
R ¹¹ is an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl 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;
Partial structure:

But the formula is:

indicates,
R ^a represents a hydrogen atom or an alkyl group;
R ^a' represents a hydrogen atom or an alkyl group;
R ^a″ represents a hydrogen atom; a halogen atom; an alkyl group; or a cyano group;
R ^Z3 represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a halogen atom or a hydroxy group; a cycloalkyl group; or an alkoxy group;
^R and ^R each independently represent a hydrogen atom or an alkyl group;
Partial structure:

is expressed by the following formula (Ea):

indicates,
Partial structure:

but,

indicates,
Partial structure:

but,

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

[Compound ID]
A is a benzene ring;
Partial structure:

But the formula is:

indicates,
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 represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a halogen atom or a hydroxy group; a cycloalkyl group; or an alkoxy group;
^R and ^R each independently represent a hydrogen atom or an alkyl group;
Partial structure:

is expressed by the following formula (Ea):

indicates,
Partial structure:

but,

indicates,
Partial structure:

but,

indicates,
L is a group selected from a divalent aromatic hydrocarbon group which may be substituted with a substituent selected from a halogen atom, an alkyl group which may be substituted with a halogen atom, and an alkoxy group; and a divalent aromatic heterocyclic group which may be partially hydrogenated and contains 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom;
T 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 group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^7a and R ^7b each independently represent a hydrogen atom; or an alkyl group which may be substituted by a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^7c represents a hydrogen atom;
R ^7d represents an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group;
R ^7r represents an alkylene group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^8a and R ^8b are both hydrogen atoms;
R ^9a and R ^9b each independently represent an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^10a is an alkyl group which may be substituted with an alkoxycarbonyl group;
R ^10b is a hydrogen atom;
R ¹¹ is an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
Compound (I).

[Compound I-E]
A is a benzene ring;
Partial structure:

But the formula is:

indicates,
R ^a represents a hydrogen atom;
R ^a′ represents a hydrogen atom;
R ^a″ represents a cyano group;
R ^Z3 represents an alkyl group which may be 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;
Partial structure:

is expressed by the following formula (Ea):

indicates,
Partial structure:

but,

indicates,
Partial structure:

but,

indicates,
L is a group selected from a divalent aromatic hydrocarbon group which may be substituted with 1 to 2 substituents selected from a halogen atom, an alkyl group which may be substituted with 1 to 3 halogen atoms, and an alkoxy group; and a divalent aromatic heterocyclic group which may be partially hydrogenated and contains 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom;
T 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 group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^7a and R ^7b each independently represent a hydrogen atom; or an alkyl group which may be substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^7c represents a hydrogen atom;
R ^7d represents an alkyl group which may be substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^7r represents an alkylene group which may be substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^8a and R ^8b are both hydrogen atoms;
R ^9a and R ^9b each independently represent an alkyl group optionally substituted with one substituent selected from a halogen atom, a hydroxyl 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 which may be substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group;
Compound (I).

[Compound I-F]
A is a benzene ring;
Partial structure:

But the formula is:

indicates,
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;
Partial structure:

is expressed by the following formula (Ea):

indicates,
Partial structure:

but,

indicates,
Partial structure:

but,

indicates,
L is a group selected from a divalent aromatic hydrocarbon group which may be substituted with 1 to 2 substituents selected from a halogen atom and an alkyl group; and a divalent aromatic heterocyclic group containing 1 to 2 nitrogen atoms;
T is -CO-NR ^7c -, R ^7c is a hydrogen atom,
M is —CH ₂ —, —(CH ₂ ) ₂ —, or —CH(CH ₃ )—;
R ^8a and R ^8b are both hydrogen atoms;
R ^9a and R ^9b are each independently an alkyl group;
R ^10a is an alkyl group which may be substituted with one alkoxycarbonyl group;
R ^10b is a hydrogen atom;
R ¹¹ is an alkyl group;
Compound (I).

[Compound I-G]
A is a benzene ring;
Partial structure:

But the formula is:

indicates,
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;
Partial structure:

is expressed by the following formula (Ea):

indicates,
Partial structure:

but,

indicates,
Partial structure:

but,

indicates,
L is a group selected from a phenylene group optionally substituted with 1 to 2 substituents selected from a halogen atom and an alkyl group; a pyridinediyl group; and a pyrazinediyl group;
T is -CO-NR ^7c -, R ^7c is a hydrogen atom,
M is —CH ₂ —, —(CH ₂ ) ₂ —, or —CH(CH ₃ )—;
R ^8a and R ^8b are both hydrogen atoms;
R ^9a and R ^9b are each independently an alkyl group;
R ^10a is an alkyl group which may be substituted with one alkoxycarbonyl group;
R ^10b is a hydrogen atom;
R ¹¹ is an alkyl group;
Compound (I).

[Compound I-H]
A is a benzene ring;
Partial structure:

But the formula is:

indicates,
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;
Partial structure:

is expressed by the following formula (Ea):

indicates,
Partial structure:

but,

indicates,
Partial structure:

but,

indicates,
L is a group selected from a phenylene group which may be 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 )—;
R ^8a and R ^8b are both hydrogen atoms;
R ^9a and R ^9b are each independently an alkyl group;
R ^10a is an alkyl group substituted with one alkoxycarbonyl group;
R ^10b is a hydrogen atom;
R ¹¹ is an alkyl group;
Compound (I).

[Compound I-I]
A is a benzene ring;
Partial structure:

But the formula is:

indicates,
R ^a represents a hydrogen atom;
R ^a′ represents a hydrogen atom;
R ^a″ represents a cyano group;
R ^Z3 represents an alkyl group which may be 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;
Partial structure:

is expressed by the following formula (Ea):

indicates,
Partial structure:

but,

indicates,
Partial structure:

but,

indicates,
L is a divalent aromatic hydrocarbon group which may be substituted by 1 to 2 substituents selected from a halogen atom, an alkyl group which may be substituted by 1 to 3 halogen atoms, and an alkoxy 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 group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^7a and R ^7b each independently represent a hydrogen atom; or an alkyl group which may be substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^7c represents a hydrogen atom;
R ^7d represents an alkyl group which may be substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^7r represents an alkylene group which may be substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^8a and R ^8b are both hydrogen atoms;
R ^9a and R ^9b each independently represent an alkyl group optionally substituted with one substituent selected from a halogen atom, a hydroxyl 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 which may be substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group;
Compound (I).

[Compound I-J]
A is a benzene ring;
Partial structure:

But the formula is:

indicates,
R ^a represents a hydrogen atom;
R ^a′ represents a hydrogen atom;
R ^a″ represents a cyano group;
R ^Z3 represents an alkyl group which may be 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;
Partial structure:

is expressed by the following formula (Ea):

indicates,
Partial structure:

but,

indicates,
Partial structure:

but,

indicates,
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 group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^7a and R ^7b each independently represent a hydrogen atom; or an alkyl group which may be substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^7c represents a hydrogen atom;
R ^7d represents an alkyl group which may be substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^7r represents an alkylene group which may be substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^8a and R ^8b are both hydrogen atoms;
R ^9a and R ^9b each independently represent an alkyl group optionally substituted with one substituent selected from a halogen atom, a hydroxyl 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 which may be substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl 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 below, preferably the compounds of Examples 1, 11, 15, 26, 43, 45, 46, 47, 50, 53, 63, 64, 65, 69, 70, 71, 74, 85, 92, 97, 98, 99, 100, 102, 103, 105, 106, 107, 108, 109, 110, 118, 127, and 148, more preferably the compounds of Examples 1, 11, 26, 43, 47, 53, 63, 64, 65, 69, 71, 74, 92, 102, 103, 105, 106, 107, 108, 109, and 110, and even more preferably the compounds of Examples 1, 47, 74, and 106.

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

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

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

Hereinafter, R ¹⁰ represents R ^10a or R ^10b , and one of R ^10a or R ^10b is a hydrogen atom. However, even when R ^10a and R ^10b are both optionally substituted alkyl, the following method is applicable. (R ^10a and R ^10b are the same as defined above.)

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

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

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

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

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

(In the formula, ^B1 represents a boronic acid or a boronic acid ester which may have a substituent, ^Z1 represents a halogen atom, ^P1 represents a protecting group, and the other symbols are as defined above.)
In the formula, the boronic acid ester which may have a substituent represented by ^B1 is pinacolato boron, neopentyl glycolato boron, etc., and the halogen atom represented by ^ZA is a chlorine atom, a bromine atom, or an iodine atom. The protecting group represented by ^PA in the formula is one which protects a carboxyl group, and is not particularly limited as long as it can give compound (3-7). Examples of the protecting group include alkyl (specifically, methyl, ethyl), etc.
Compound (A-3) can be derived from compound (3-1) in accordance with a known method (for example, 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 the 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 proceeds suitably in the presence of a palladium catalyst, a phosphine ligand and a base, in a suitable solvent, at 0° C. to heating, particularly at room temperature to the boiling point of the solvent. The reaction time varies depending on the raw materials and solvent used, and the reaction temperature, but is usually 1 hour to 24 hours. Examples of the palladium catalyst include palladium acetate (II), palladium chloride (II), tris(dibenzylideneacetone)dipalladium (0) and its chloroform adduct. Phosphine ligands include triphenylphosphine, 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, 2-(dicyclohexylphosphino)-2,6-diisopropoxy-1,1'-biphenyl, and 2-di-t-butylphosphino-2'-4'-6'-triisopropylbiphenyl. , 2-dicyclohexylphosphino-2'-6'-dimethoxybiphenyl, 2-(dicyclohexylphosphino)-2-(N,N-dimethylamino)biphenyl, tri-ortho-tolylphosphine, 2-(dicyclohexylphosphino)biphenyl, 2-(di-t-butylphosphino)biphenyl, 2-(di-t-butylphosphino)-1,1-binaphthyl, tri-t-butylphosphine, tri-t-butylphosphonium tetrafluoroborate, and the like. A reagent in which a palladium catalyst and a phosphine ligand form a complex may be used, and examples of such a reagent include tetrakis(triphenylphosphine)palladium(0), 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, dichlorobis(triphenylphosphine)palladium(II), dichlorobis(tricyclohexylphosphine)palladium(II), bis(tri-t-butylphosphine)palladium(0), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)palladium(II) methanesulfonate, (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, [(2-di-t-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)palladium(II) methanesulfonate, [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II), and the like. Examples of the base include sodium t-butoxide, potassium acetate, tripotassium phosphate, cesium carbonate, potassium carbonate, sodium hydrogencarbonate, lithium bis(trimethylsilyl)amide, triethylamine, diisopropylethylamine, dicyclohexylethylamine, potassium fluoride, cesium fluoride, etc. Examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, etc., alcohol solvents such as methanol, ethanol, propanol, butanol, etc., N,N-dimethylformamide, or a mixed solvent of these organic solvents with water, etc.

(2) The manufacturing method described here is suitable for manufacturing 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, compound (B-2) shown below.

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

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

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

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

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

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

(4) The production method described here is suitable for producing intermediates of the compounds represented by formula (I) in which R ¹⁰ is -N(R ^7c )-CO-OR ^7d , i.e., the following compounds (B-3) and (B-4). (R ^7c and R ^7d have the same meanings as above.)

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

Step B-9
Compound (B-4) can be 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 between 0° C. and the reflux temperature of the solvent. The reaction time varies depending on the raw materials and solvent used, and the reaction temperature, but is usually 10 minutes to 24 hours. Examples of the base include inorganic bases such as sodium hydride, potassium hydroxide, and potassium carbonate, and alkoxides such as potassium t-butoxide. Examples of the solvent include N,N-dimethylformamide, tetrahydrofuran, and dimethyl sulfoxide.

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

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

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

(In the formula, P ^C represents a hydrogen atom or a protecting group, and k represents an integer of 1 to 6. Each symbol has the same meaning as defined above.)
The protecting group for P ^C in the formula is not particularly limited as long as it protects a carboxyl group, and examples thereof include alkyl (specifically, methyl, ethyl, t-butyl, etc.) and aralkyl (benzyl, etc.).
Step B-13
Compound (9-2) can be obtained by removing the protecting group P ^C of compound (9-1). When P ^C is a hydrogen atom, this step can be omitted. The deprotection conditions are not particularly limited as long as they are those used for deprotection of P ^C. For example, when P ^C is methyl or ethyl, a method using an inorganic base such as sodium hydroxide in a mixed solvent of an alcoholic solvent and water, and when P C is t-butyl, a method using an acid such as hydrochloric acid or trifluoroacetic acid, etc. can be mentioned. Note that when P ^C is benzyl or substituted benzyl, benzyloxymethyl, etc., a method using catalytic hydrogenation can be mentioned.
Step B-14
Compound (B-6) can be obtained by condensing compound (9-2) with an amine having the corresponding 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 between 0° C. and the solvent reflux temperature. The reaction time and the condensing agent, solvent, reaction promoter and base used are the same as those in Step A-8.

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

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

(8) Among the compounds represented by general formula (I), an intermediate of the compound in which ring E is represented by the above-mentioned general formula (Ea), G is a nitrogen atom, J is a nitrogen atom, and R ^9a is cyanomethyl, i.e., the following compound (B-8), can be produced, for example, by the following production method.

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

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

(In the formula, k is an integer of 1 to 6. The other symbols are as defined above.)
Step B-27
Compound (B-9) can be obtained by cyanating compound (12-1) under the same reaction conditions as those in the above-mentioned step B-26.

(10) Among the compounds represented by general formula (I), an intermediate of the compound in which ring E is represented by the above-mentioned general formula (Ea), G is a nitrogen atom, J is a nitrogen atom, and R ^9a is a cyano group, i.e., 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 defined above.)
Step B-28
Compound (13-1) can be obtained by oxidizing compound (11-3). The reaction conditions include, for example, reacting a mixture of compound (11-3), manganese dioxide and dichloromethane at room temperature for an appropriate period of time.
Step B-29
Compound (B-10) can be obtained by cyanating compound (13-1). The reaction conditions include, for example, reacting a mixture of hydroxylamine hydrochloride and dimethyl sulfoxide under heating for an appropriate period of time.

(11) Among the compounds represented by general formula (I), an intermediate of the compound in which ring E is represented by the above-mentioned general formula (Ea), G is a nitrogen atom, J is a nitrogen atom, and R ^9a is a hydrogen atom, i.e., 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 defined above.)
Step B-30
Compound (14-1) can be obtained by oxidizing compound (13-1). The reaction proceeds using an oxidizing agent in a suitable solvent, usually at 0° C. to the reflux temperature of the solvent. The reaction time varies depending on the raw materials and solvent used, and the reaction temperature, but is usually 0.5 to 24 hours. Examples of the oxidizing agent include hydrogen peroxide, t-butyl hydroperoxide, sodium chlorite, potassium permanganate, etc. Examples of the solvent include methanol, acetonitrile, water, etc. The reaction proceeds, for example, by adding 35% hydrogen peroxide water and sodium chlorite aqueous solution to a mixture of acetonitrile and an aqueous solution of sodium dihydrogen phosphate at 0° C. to room temperature.
Step B-31
Compound (B-11) can be obtained by decarboxylating compound (14-1). The reaction conditions include, for example, reacting in quinoline in the presence of copper at 150° C.

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

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

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

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

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

(In the formula, each symbol has the same meaning as defined above.)
Step C-4
The reaction of compound (16-1) with a boronic acid derivative (e.g., bis-pinacolatodiboron, bis-neopentylglycolatodiboron, etc.) gives boronic acid (18-1). The reaction proceeds suitably in the presence of a palladium catalyst, a phosphine ligand, and a base, in a suitable solvent, at 0° C. to heating, particularly at room temperature to the boiling point of the solvent. The palladium catalyst, phosphine ligand, base, and solvent used in step B-1 can be used.
Step C-5
Compound (C-1) is obtained by reacting boronic acid (18-1) with compound (18-2). The reaction proceeds suitably in the presence of a palladium catalyst, a phosphine ligand, and a base in a suitable solvent at a temperature of 0° C. to heating, particularly at room temperature to the boiling point of the solvent. The palladium catalyst, phosphine ligand, base, and solvent used in step B-1 can be used.

(4) Among the compounds represented by general formula (I), an intermediate of the compound in which ring E is represented by the above-mentioned general formula (Ea), G is a nitrogen atom, J is a nitrogen atom, and R ^9a is a halogen atom, i.e., the following compound (C-2), can be produced, for example, by the following production method.

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

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

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

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

(In the formula, ^ZF represents a chlorine atom or a bromine atom, and the 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 an appropriate solvent, usually at a temperature between 0° C. and the solvent reflux temperature, usually for 1 hour to 24 hours. Examples of halogenating agents include thionyl chloride, oxalyl chloride, phenylphosphonyl dichloride, etc. Examples of bases include triethylamine, pyridine, etc. Examples of solvents include dichloromethane, 1,2-dichloroethane, chloroform, pyridine, toluene, etc.
Process D-4
Compound (D-1) is obtained by the reaction of acid halide (21-1) with amine derivative (20-2). The reaction proceeds using a base in an appropriate solvent, usually at 0° C. to the solvent reflux temperature. The reaction time varies depending on the raw materials and solvent used, reaction temperature, etc., but is usually 30 minutes to 12 hours. Examples of the base include triethylamine and pyridine. Examples of the solvent include dichloromethane, dichloroethane, chloroform, N-methylpyrrolidone, pyridine, toluene, etc.

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

(In the formula, each symbol has the same meaning as defined above.)
Step E-1
Compound (22-2) can be obtained by reacting amine (20-2) with carboxylic acid (22-1) represented by HOC(O)-L-Z ^A (wherein Z ^A has the same meaning as defined above). The reaction conditions can be the same as those in the above-mentioned step B-14.
Step E-2
In this step, compound (22-2) is reacted with boronic acid or its ester derivative (18-1) to obtain compound (D-1). The reaction conditions may be the same as those in step B-1.

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

(The symbols in the formula are as defined above.)
Step E-3
Compound (23-2) is obtained by reacting amine derivative (20-2) with carboxylic acid derivative (23-1). The reaction conditions may be the same as those in step B-14 above. When ^B2 is an amine and there is a possibility of self-condensation, steps of protection and deprotection may be appropriately inserted.
Step E-4
This is a step of converting the hydroxyl group of compound (16-2) into an activating group OZ ^D. The reaction conditions can be the same as those in the above-mentioned step C-1.
Step E-5
This is a step of reacting compound (16-1) or compound (16-3) obtained in step E-4 with compound (23-2) to obtain compound (D-1). The reaction conditions may be the same as those in step C-2 above.

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

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

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

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

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

(In the formula, P ^F represents an amino-protecting group, and the other symbols are as defined above.)
In the formula, P ^F is not particularly limited as long as it protects the amino group and gives compound (26-6), and examples thereof include a t-butyloxycarbonyl group and a benzyloxycarbonyl group.
Step F-5
Compound (26-3) can be obtained by reacting nitro compound (26-1) with vinylmagnesium bromide (26-2). The reaction usually proceeds in a suitable solvent at a temperature between −78° C. and room temperature. The reaction time varies depending on the raw materials and solvent used, and the reaction temperature, but is usually 0.5 to 24 hours. An example of the solvent is tetrahydrofuran.
Step F-6
Compound (26-4) can be obtained, for example, by formylation of indole derivative (26-3), followed by generation of oxime, and dehydration reaction. The formylation reaction proceeds using a halogenating agent and DMF, usually at room temperature to solvent reflux temperature. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually 1 hour to 24 hours. Examples of halogenating agents include phosphoryl chloride and phenylphosphonyl dichloride. Examples of solvents include DMF, or a dichlorobenzene-DMF mixed solution. Compound (26-4) can be obtained by adding hydroxylamine hydrochloride to the above reaction solution and heating. The reaction proceeds usually at 40° C. to solvent reflux temperature. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually 0.5 hours to 24 hours.
Step F-7
Compound (26-5) is obtained by a coupling reaction between compound (26-4) and benzophenone imine, followed by a deprotection reaction. The reaction conditions for the coupling reaction include the same conditions as those for step C-2. The reaction conditions for the deprotection include the reaction with an acid such as hydrochloric acid, or with hydroxylamine or the like. The reaction usually proceeds at room temperature to the reflux temperature of the solvent. The reaction time varies depending on the raw materials and solvent used, and the reaction temperature, but is usually 1 hour to 24 hours. Examples of the solvent include methanol, tetrahydrofuran, 1,4-dioxane, a mixed solution thereof, and the like.
Step F-8
The compound (26-7) can be obtained by reacting the sulfonyl chloride derivative (26-6) with the amine derivative (26-5). The reaction conditions in step F-8 are the same as those in step F-4.
Step F-9
Compound (F-1) can be obtained by removing the protecting group P ^F of compound (26-7). The deprotection conditions are not particularly limited as long as they are used for deprotection of P ^F. For example, when P ^F is a t-butyloxycarbonyl group, deprotection can be performed with an acid. Examples of the acid include inorganic acids such as hydrochloric acid and trifluoroacetic acid. Examples of reaction conditions include an alcoholic solvent such as ethanol, an ether solvent such as tetrahydrofuran, water, or a mixed solvent thereof, at ice-cooling to 80° C. for about 10 minutes to 12 hours. When ^{P F} is a benzyloxycarbonyl group, deprotection can be performed by reduction by catalytic hydrogenation. Examples of the catalyst include palladium on carbon, and the reaction temperature is usually room temperature to the reflux temperature of the solvent, the hydrogen pressure is 1 to 20 atm, and the reaction time is usually 1 hour to 48 hours, although it varies depending on the raw material, solvent, reaction temperature, etc. used.

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

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

The compound of the present invention or a pharma- ceutical acceptable salt thereof has a cytotoxic effect on cancer cells. Furthermore, it also has an effect of inducing the degradation of BET protein in cancer cells and an effect of inhibiting the binding of BET protein to acetylated histones. Therefore, a pharmaceutical composition containing the compound of the present invention or a pharma-ceutical acceptable salt thereof can be used as an anticancer agent, and can also be used as a BET protein degradation inducer or a BET protein inhibitor. Furthermore, according to the present invention, it is possible to provide a method for treating cancer, a method for inducing the degradation of BET protein, and a method for inhibiting BET protein using a pharmaceutical composition containing the compound of the present invention or a pharma-ceutical acceptable salt thereof.

Furthermore, the compound of the present invention or a pharma- ceutical acceptable salt thereof has an effect of inducing the degradation of BRD4 protein in cancer cells and an effect of inhibiting the binding of BRD4 protein to acetylated histones. Therefore, a pharmaceutical composition containing the compound of the present invention or a pharma-ceutical acceptable salt thereof can also be used as a BRD4 protein degradation inducer or a BRD4 protein inhibitor. Furthermore, according to the present invention, it is possible to provide a method for treating cancer, a method for inducing the degradation of BRD4 protein, and a method for inhibiting BRD4 protein using a pharmaceutical composition containing the compound of the present invention or a pharma-ceutical acceptable salt thereof.

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

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

In one embodiment, a pharmaceutical composition comprising a compound of the invention or a pharma- ceutically acceptable salt thereof may be useful for the treatment of acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, diffuse large B-cell lymphoma, adult T-cell leukemia/lymphoma, Burkitt's lymphoma, prostate cancer, ovarian cancer, bladder cancer, breast cancer, cervical cancer, uterine sarcoma, gastric cancer, lung cancer, colon cancer, glioma, pancreatic cancer, liver cancer, bile duct cancer, renal cell carcinoma, and fibrosarcoma.
In another embodiment, a pharmaceutical composition comprising a compound of the present invention or a pharma- ceutically acceptable salt thereof may be useful for the treatment of acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, diffuse large B-cell lymphoma, multiple myeloma, Burkitt's lymphoma, glioma, gastric cancer, colon cancer, pancreatic cancer, liver cancer, prostate cancer, non-small cell lung cancer, breast cancer, ovarian cancer, and uterine sarcoma.
In yet another embodiment, pharmaceutical compositions comprising a compound of the invention or a pharma- ceutically acceptable salt thereof may be useful in the treatment of acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, prostate cancer, non-small cell lung cancer, ovarian cancer, and breast cancer.
In yet another embodiment, pharmaceutical compositions comprising a compound of the invention or a pharma- ceutically acceptable salt thereof may be useful in the treatment of acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, prostate cancer, ovarian cancer, and breast cancer.

In this specification, the term "anticancer agent" refers to a concept that includes anticancer agents, antitumor agents, etc., and has the effect of damaging and killing or weakening cancer cells or tumor cells, and shrinking or eliminating abnormal cell proliferation and clumping, or preventing proliferation, for the purpose of treating cancer. Furthermore, "treatment" refers to the act of administering the compound of the present invention or a pharma- ceutical composition containing the compound or a pharma- ceutical salt thereof to an individual who has already developed a disease, disorder, or symptom. Therefore, administering to an individual who has already developed a disease, disorder, or symptom in order to prevent the worsening or recurrence of symptoms, etc., is one aspect of treatment.

A pharmaceutical composition containing the compound of the present invention or a pharma- ceutical acceptable salt thereof can be obtained by mixing the compound of the present invention or a pharma- ceutical acceptable salt thereof with pharma- ceutical acceptable additives (such as excipients, binders, disintegrants, flavorings, odorants, emulsifiers, diluents, and solubilizing agents), and can be administered orally or parenterally. The pharmaceutical composition can be formulated according to conventional methods. Alternatively, the compound of the present invention or a pharma- ceutical acceptable salt thereof can be administered orally or parenterally as it is.

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

In this specification, parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion, or local administration (intra-articular administration, transdermal administration, ocular administration, pulmonary/bronchial administration, nasal administration, rectal administration, etc.).

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

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

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)

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

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 the mixture was stirred at room temperature for 2 hours. Then, a solution of ethyl 4-bromobenzoate (22.9 g) in dimethyl sulfoxide (23 mL) was slowly added, and the mixture was stirred at 45° C. for 3 hours. The reaction solution was cooled on ice, and water and concentrated hydrochloric acid were added. The mixture was stirred for 0.5 hours, and the precipitate was collected by filtration. The residue obtained was dried to obtain the title compound (22.4 g) as a light 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 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 the solvent was distilled off, ethyl acetate was added. The organic layer was washed with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution, and saturated saline, dried over anhydrous sodium sulfate, 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. The precipitate was then filtered 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]diazepin-2-one (Reference 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 stirred under ice cooling for 1 hour. After the solvent was distilled off, ethyl acetate was added, and the organic layer was washed with saturated sodium bicarbonate water and water, dried over anhydrous sodium sulfate, 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, and then trifluoroacetic acid (53 mL) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated and azeotroped with toluene. Saturated sodium bicarbonate water was added to the obtained mixture, and the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Acetic acid (12 mL) was added to a suspension of the obtained residue in 2-propanol (200 mL), and the mixture was stirred at 90° C. for 1 hour. Saturated aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture, and the mixture was extracted. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate (43 mL) was added to the obtained residue, and the mixture was stirred at 45° C. for 1 hour, and the insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain 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 compound 2)

Sodium hydride (60%, 1.1 g) was added to a solution of Reference Example Compound 2-3 (9.6 g) in tetrahydrofuran (65 mL) under ice cooling, and the mixture was stirred for 0.5 hours. Then, diethylphosphonyl chloride (5.5 g) was added and the mixture was stirred at room temperature for 0.25 hours. Acetohydrazide (2.9 g) and n-butanol (10 mL) were added and the mixture was stirred at 70° C. for 0.5 hours. 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 saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate) to obtain 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-dioxaboronane-2-yl)phenyl]-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate (Reference Example Compound 3)

Under an argon atmosphere, Reference Example Compound 1 (5.00 g), bis(pinacolato)diboron (4.59 g), potassium acetate (2.37 g), and dichlorobis(tricyclohexylphosphine)palladium (445 mg) were heated and refluxed in tetrahydrofuran solvent for 25 hours. Dichlorobis(tricyclohexylphosphine)palladium (445 mg) and bis(pinacolato)diboron (1.53 g) were further added and the mixture was heated and refluxed for 7 hours, and then bis(pinacolato)diboron (1.53 g), potassium acetate (1.18 g), and dichlorobis(tricyclohexylphosphine)palladium (445 mg) were added and the mixture was heated and refluxed for 16 hours. The mixture was cooled to room temperature, and the reaction solution was filtered through Celite using ethyl acetate. The filtrate was washed twice with saturated saline, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol = 100:0 to 97:3), and then purified by silica gel column chromatography (ethyl acetate/methanol = 100:0 to 95:5) to obtain the title compound (5.27 g) 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)

A mixture of Reference Example Compound 1 (5.00 g), t-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (4.03 g), potassium fluoride (2.10 g), 2-dicyclohexylphosphino-2'-6'-dimethoxybiphenyl (hereinafter referred to as S-phos, 495 mg), palladium acetate (271 mg), tetrahydrofuran (40.2 mL), and water (0.78 mL) was stirred under heating and reflux 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, and 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, after which the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5). It was further purified by silica gel column chromatography (chloroform:methanol=100:0-95:5) to obtain the title compound (6.55 g) as a crude product in the form of a 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 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 azeotropic distillation with toluene was performed twice. The mixture was dissolved in ethyl acetate, cooled to 0° C., and saturated sodium bicarbonate water was added little by little to adjust the pH to 8. The organic layer was separated and washed with ethyl acetate. 1N hydrochloric acid was slowly added to the aqueous layer to adjust the pH to 5, and the mixture was extracted twice with chloroform. The organic layer was concentrated under reduced pressure to obtain a pale yellow solid (6.29 g). 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)

Reference Example Compound 9 (100 mg) and 4-formylbenzenesulfonyl chloride (132 mg) were added to a solution of tetrahydrofuran (6.0 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. The reaction mixture was acidified with 1N hydrochloric acid, and then extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-40:60), and the resulting purified product was solidified with chloroform, and then concentrated under reduced pressure to obtain the title compound (126 mg) 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 compound 5-2)

Sodium borohydride (163 mg) was added to a solution of Reference Example Compound 5-1 (730 mg) in methanol (21.0 mL) 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 solution, and the layers were separated. The aqueous layer was extracted once with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (30.0 mL), and 1,8-diazabicyclo[5.4.0]-7-undecene (0.49 mL) and 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (736 mg) were added at room temperature, and the mixture was 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 the mixture was stirred at the same temperature for 4 hours. 1N hydrochloric acid was added to the reaction solution, 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 resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 60:40), and the resulting purified product was solidified by adding chloroform, and then concentrated under reduced pressure to obtain the title compound (355 mg) as a pale yellow powder. MS (ESI) m/z: 365.3 [M-H] ^-

(5-3) 4-(aminomethyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide (Reference 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, and chloroform was added to the resulting residue. The precipitate was collected by filtration to obtain 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 solution, 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 obtain the title compound (1.81 g) as a brown solid. MS (ESI) m/z: 354.1 [M-H] ^-

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

To a solution of 1-bromo-4-methyl-2-nitrobenzene (1.08 g) in tetrahydrofuran (35.0 mL), 1M vinylmagnesium bromide/tetrahydrofuran solution (15.0 mL) was added 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 solution to separate the layers. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-95:5) to obtain the title compound (600 mg) as a yellow oil. ^1H NMR (400MHz, _CDCl3 ) δ ppm 2.52 (3H, d, J = 0.77Hz), 6.63 (1H, dd, J = 3.28, 2.25Hz), 6.80 (1H, dq, J = 7.71, 0.81Hz), 7.22-7.27 (2H, m), 8.32 (1H, brs)

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 a solution of Reference Example Compound 7 (284 mg) in N,N-dimethylformamide (1.35 mL) at room temperature. After stirring at room temperature for 0.5 hours, phenylphosphonyl dichloride (0.04 mL) was added and stirred at the same temperature for another 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 solution with ethyl acetate, the mixture was washed twice with saturated sodium bicarbonate water and once with saturated saline, dried over anhydrous sodium sulfate, 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 obtain the title compound (220 mg) as a light brown solid. ^1H NMR (400MHz, _CDCl3 ) δ ppm 2.75 (3H, d, J = 0.6Hz), 6.92 (1H, dq, J = 7.6, 1.8Hz), 7.36 (1H, d, J = 7.7Hz), 7.78 (1H, d, J = 2.8Hz), 8.73 (1H, brs)

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

Reference Example Compound 8 (215 mg), benzophenone imine (240 mg), [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II) (Pd-PEPPSI-IPent catalyst, 22 mg), and tetrahydrofuran (2.3 mL) were mixed at room temperature with 1.3 M lithium bis(trimethylsilyl)amide/tetrahydrofuran solution (2.5 mL), and stirred at 120° C. for 0.5 hours under nitrogen atmosphere and microwave irradiation. After cooling to room temperature, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (2.3 mL)-methanol (2.3 mL), and hydroxylamine hydrochloride (159 mg) and sodium acetate (225 mg) were added at room temperature, followed by stirring at the same temperature for 4 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, 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 obtain the title compound (139 mg) as a light 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) was added with N,N-diisopropylethylamine (0.52 mL) and HATU (456 mg) at room temperature, and stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed three times with saturated saline-water (1:1) and once with saturated saline, dried over anhydrous sodium sulfate, 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 90:10) to obtain 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 compound 10-2)

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

(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 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. N-chlorosuccinimide (23 mg) was added to the reaction solution, and the mixture was stirred at the same temperature for 0.5 hours. Saturated saline-water (1:1) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2) to obtain 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 = 0.64Hz), 2.41-2.46 (3H, m), 2.70 (3H, s), 3.66 (2H, d d, J = 7.06, 3.72Hz), 3.79 (3H, s), 4.44 (1H, d, J = 5.65Hz), 4.67 (1H, dd, J=7.77, 6.36Hz), 4.80 (2H, d, J=6.04Hz), 7.55-7.63 (6H, m), 7. 68 (2H, m, J = 8.61Hz), 7.90 (2H, m, J = 8.61Hz), 8.02 (2H, d, J = 7.74Hz)

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 stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed twice with 1N hydrochloric acid and once with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was suspended and washed with hexane, and then filtered to obtain 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 compound 11)

To Example Compound 11-1 (301 mg), 4M hydrogen chloride/1,4-dioxane solution (3.0 mL) was added 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 obtain 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), and t-butyl 4-bromo-2-fluorobenzoate (196 mg), tetrakis(triphenylphosphine)palladium(0) (69 mg), potassium phosphate (377 mg) and water (0.038 mL) were added, and the mixture was stirred at 90° C. for 0.5 hours under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, and insoluble matter was removed by filtration with 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 crude product of white powder. 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 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 solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and extracted twice with saturated aqueous sodium bicarbonate. The aqueous layers were combined, and 2N hydrochloric acid was added little by little under ice cooling to adjust the pH to 4. The organic layer was extracted twice with chloroform, and the combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain 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 precatalyst (16 mg), cesium fluoride (93 mg) and water (0.25 mL) were added, and the mixture was stirred at 120°C for 1 hour under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate and then extracted twice with saturated sodium bicarbonate water. 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, and the combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the title compound (73 mg) as a white powder. 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)

4-Bromobenzenesulfonyl chloride (929 mg) was added to a solution (12.0 mL) of Reference Example Compound 9 (622 mg) and pyridine (2.92 mL) in tetrahydrofuran at room temperature, and the mixture was stirred at the same temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed once with saturated saline-water (1:1) and once with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was suspended and washed in chloroform, and then filtered to obtain 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 the mixture was stirred at 70° C. for 10 minutes. N-(4-bromo-1H-indol-7-yl)-2,2,2-trifluoroacetamide (929 mg) and N,N-dimethylformamide (11.0 mL) were then added, and the mixture was stirred at 70° C. for 1 hour. Hydroxylamine hydrochloride (2.42 g) was then added, and the mixture was stirred at 100° C. for 2 hours. Ethylenediamine (2.02 mL) and methanol (22.0 mL) were further 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 saline were added to the obtained residue, and the mixture was separated. The organic layer was washed twice with a mixture of saturated aqueous sodium bicarbonate and saturated saline, once with water, and once with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was suspended and washed in ethyl acetate, filtered, and dried under reduced pressure to obtain the title compound (260 mg) as a brown powder. The filtrate was distilled under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50 to 75:25) to obtain the target compound (104 mg) as a brown solid. MS (ESI) m/z: 236.0, 237.9 [M+H] ⁺

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 a solution (17.4 mL) of 7-bromo-4-ethyl-1H-indole (3.90 g) in N,N-dimethylformamide under ice cooling, and the mixture was stirred at room temperature for 30 minutes and at 70°C for 40 minutes. Hydroxylamine hydrochloride (2.42 g) was added, and the mixture was stirred at 70°C for 30 minutes and at 80°C for 30 minutes. After cooling to room temperature, ethyl acetate was added to the reaction solution to dilute it, and the mixture was cooled on ice, and saturated sodium bicarbonate water was added while stirring. The mixture was extracted twice with ethyl acetate, and the extracts were combined, washed twice with a mixture of saturated saline and saturated sodium bicarbonate water, and once with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10-70:30), and toluene was added to the residue and concentrated under reduced pressure twice to obtain 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 compound 16)

A mixture of Reference Example Compound 16-1 (2.12 g), benzophenone imine (2.16 g), and [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II) (Pd-PEPPSI-IPent catalyst, 202 mg) was added with 1.3 M lithium bis(trimethylsilyl)amide/tetrahydrofuran solution (23.0 mL) at room temperature, and stirred at 120° C. for 1 hour under nitrogen atmosphere and microwave irradiation. After cooling to room temperature, water was added to the reaction solution and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (11.0 mL)-methanol (11.0 mL), and hydroxylamine hydrochloride (1.48 g) and sodium acetate (2.09 g) were added at room temperature, followed by stirring at the same temperature for 16 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, 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, then dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0-98:2) to obtain the title compound (954 mg) as a light 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 the mixture was stirred at room temperature for 14 hours. 1N hydrochloric acid was added to the reaction solution, and the layers were separated. The aqueous layer was extracted once with chloroform, and the combined organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was suspended and washed with hexane, and then filtered to obtain 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 compound 17-2)

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

(17-3) t-Butyl {(1R)-1-[4-(chlorosulfonyl)phenyl]ethyl}carbamate (Reference 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), N-chlorosuccinimide (4.30 g) was added under ice cooling, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated 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 (hexane:ethyl acetate=90:10 to 75:25) to obtain 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 compound 17-4)

To a solution of Reference Example Compound 17-3 (2.20 g) in tetrahydrofuran (66.0 mL), Reference Example Compound 9 (1.18 g) and pyridine (2.77 mL) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed twice with 1N hydrochloric acid and once with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was suspended and washed in chloroform, and filtered to obtain the title compound (1.67 g) as a light brown solid. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=98:2) to obtain the title compound (0.84 g) as a light 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 compound 17)

To Example Compound 17-4 (2.47 g), 4M hydrogen chloride/1,4-dioxane solution (25.0 mL) was added at room temperature. After stirring at the same temperature for 3 hours, the reaction solution was diluted with diethyl ether, and the solid was suspended and washed, and then collected by filtration to obtain 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), and t-butyl 4-bromo-3-fluorobenzoate (180 mg), tetrakis(triphenylphosphine)palladium(0) (69 mg), potassium phosphate (378 mg) and water (0.039 mL) were added, and the mixture was stirred at 90° C. for 0.5 hours under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, and insoluble matter was removed by filtration with diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=50:50 to 0:100) to obtain the title compound (300 mg) as a white powder. MS (ESI) m/z: 575.3 [M+H] ⁺

(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 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 solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and extracted twice with saturated aqueous sodium bicarbonate. The aqueous layers were combined, and 2N hydrochloric acid was added little by little under ice cooling to adjust the pH to 4. The organic layer was extracted twice with chloroform, and the combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain 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 precatalyst (50 mg), cesium fluoride (290 mg) and water (0.80 mL) were added, and the mixture was stirred at 120°C for 0.5 hours under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate and then extracted twice with saturated sodium bicarbonate water. 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, and the combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the title compound (247 mg) as a pale yellow powder. 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 aminobiphenyl palladium chloride precatalyst (32 mg), cesium fluoride (185 mg) and water (0.50 mL) were added, and the mixture was stirred at 120°C for 0.5 hours under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate and then extracted twice with saturated sodium bicarbonate water. 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, and the combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the title compound (229 mg) as a crude product of white powder. 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), t-butyl N-[(4-chlorosulfonylphenyl)methyl]carbamate (630 mg) and pyridine (0.76 mL) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed twice with 1N hydrochloric acid and once with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was suspended and washed in diethyl ether-hexane (1:1), and then filtered to obtain the title compound (730 mg) as a beige solid. MS (ESI) m/z: 453.3 [M-H] ^-

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

To Reference Example Compound 21-1 (720 mg), 4M hydrogen chloride/1,4-dioxane solution (7.2 mL) was added at room temperature. After stirring at the same temperature for 16 hours, the reaction solution was diluted with diethyl ether, and the solid was suspended and washed, and then collected by filtration to obtain 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)

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

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

To Reference Example Compound 22-1 (701 mg), 4M hydrogen chloride/1,4-dioxane solution (7.0 mL) was added 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 obtain 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), t-butyl N-2-[4-(chlorosulfonyl)phenyl]ethylcarbamate (570 mg) and pyridine (0.65 mL) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed twice with 1N hydrochloric acid and once with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was suspended and washed in diethyl ether-hexane (1:1), and then filtered to obtain the title compound (710 mg) as a beige solid. MS (ESI) m/z: 467.3 [M-H] ^-

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

To Reference Example Compound 23-1 (702 mg), 4M hydrogen chloride/1,4-dioxane solution (7.0 mL) was added at room temperature. After stirring at the same temperature for 16 hours, the reaction solution was diluted with diethyl ether, and the solid was suspended and washed, and then collected by filtration to obtain 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, and the mixture was stirred at the same temperature for 5 hours. Water was added to the reaction solution 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, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative HPLC (10 mM aqueous ammonium carbonate solution-acetonitrile) to obtain 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 stirred in N,N-dimethylformamide (3.0 mL) at room temperature for 2 hours. Water was added to the reaction solution, which was then stirred, and the resulting solid was filtered off. The title compound (86 mg) was obtained as a white solid by purification using silica gel column chromatography (chloroform:methanol=100:0 to 95:5). MS (ESI) m/z: 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), and HATU (86 mg) was stirred in N,N-dimethylformamide (3 mL) at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was stirred, and the resulting solid was filtered off. The product was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain 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)

Under a nitrogen stream, Reference Example Compound 1 (200 mg), t-butyl pyrrolidine-3-carboxylate (99 mg), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium (II) methanesulfonate (40 mg), potassium phosphate (256 mg), and water (0.043 mL) were heated under reflux for 100 minutes in tetrahydrofuran (1.0 mL) solvent. The reaction solution was allowed to cool, diluted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solution was filtered through activated charcoal, washed with methanol and tetrahydrofuran, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) to obtain 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 azeotroped three times with chloroform-toluene. The residue was dissolved in ethyl acetate, and N,N-diisopropylethylamine (0.30 mL) was added little by little while stirring. Hexane (2.5 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The resulting solid was filtered and washed with a mixture of ethyl acetate and hexane (2:1) to obtain 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)

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

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)

A mixture of 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 hour under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, washed twice with saturated saline-water (1:1) and once with saturated saline, 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 = 98:2 to 90:10, precolumn: NH silica gel) to obtain the title compound (63 mg) as a pale yellow viscous material. 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)

1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one (Dess-Martin reagent, 71 mg) was added to Example Compound 5-1 (60 mg) in dichloromethane (1.2 mL), and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate and saturated aqueous sodium thiosulfate 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, 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 90:10) to obtain the title compound (59 mg) as a pale yellow viscous material. 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)

To a solution of Example Compound 5-2 (57 mg) and 2-methyl-but-2-ene (0.021 mL) in acetonitrile (3.0 mL), a solution of 80% sodium chlorite (18 mg) and sodium dihydrogen phosphate (19 mg) in water (1.0 mL) was added and stirred at room temperature for 30 minutes. 2-Methyl-but-2-ene (0.021 mL), 80% sodium chlorite (18 mg) and sodium dihydrogen phosphate (19 mg) were added to the reaction solution at room temperature and stirred at the same temperature for another 30 minutes. After concentrating the reaction solution under reduced pressure, ethanol was added and the mixture was concentrated under reduced pressure again. To the obtained residue, Reference Example Compound 5 (47 mg), N,N-diisopropylethylamine (0.11 mL), and N,N-dimethylformamide (2.0 mL) were added at room temperature, and finally HATU (57 mg) was added. The mixture was stirred at the same temperature for 16 hours. The reaction solution was diluted with ethyl acetate, washed three times with saturated saline-water (1:1) and once with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2 to 90:10) to obtain 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)

A mixture of Reference Example Compound 1 (25 mg), propargylamine (0.019 mL), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 3 mg), X-Phos aminobiphenyl palladium chloride precatalyst (5 mg), potassium phosphate (64 mg) and tetrahydrofuran (0.3 mL) was stirred at 90°C for 2 hours under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, washed twice with water and once with saturated saline, 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 = 95:5 to 90:10) to obtain 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]benzamido}prop-1-yn-1-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate (Example compound 6)

To a solution of Example Compound 6-1 (14 mg) and Reference Example Compound 6 (13 mg) in N,N-dimethylformamide (0.4 mL), N,N-diisopropylethylamine (0.11 mL) and HATU (15 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed three times with saturated saline-water (1:1) and once with saturated saline, dried over anhydrous sodium sulfate, 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 90:10) to obtain 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)

N-Chlorosuccinimide (358 mg) was added to a solution of 7-bromo-1H-indole (500 mg) in N,N-dimethylformamide (5.0 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours. Saturated aqueous sodium bicarbonate and saturated aqueous sodium thiosulfate were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed 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 (hexane:ethyl acetate=95:5 to 90:10) to obtain the title compound (577 mg) as a pale yellow solid. ^1H NMR (400MHz, _CDCl3 ) δ ppm 7.09 (1H, t, J = 7.77Hz), 7.24-7.27 (1H, m), 7.41 (1H, dd, J = 7.71, 0.64Hz), 7.59 (1H, dt, J = 7.96, 0.77Hz), 8.25 (1H, brs)

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

In Reference Example 9, Example Compound 7-1 (570 mg) was used instead of Reference Example Compound 8, and the same reaction and treatment were carried out to give the title compound (163 mg) as a light 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]diazepin-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 solution was diluted with ethyl acetate, washed once with 1N hydrochloric acid and once with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2 to 90:10) to obtain 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, 7-bromo-4-methyl-1H-indole (200 mg) was used instead of 7-bromo-1H-indole, and the reaction and treatment were carried out in the same manner as in (7-1) to obtain the title compound (212 mg) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.75 (3H, d, J = 0.64 Hz), 6.77 (1H, d, J = 7.87 Hz), 7.20 (1H, 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)

In Reference Example 9, Example Compound 8-1 (205 mg) was used instead of Reference Example Compound 8, and the same reaction and treatment were carried out to give the title compound (56 mg) as a light 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, Example compound 8-2 (20 mg) was used instead of Example compound 7-2, and Reference Example compound 10 (50 mg) was used, and the reaction and treatment were carried out in the same manner as in (7-3), to obtain the title compound (44 mg) as a gray powder. MS (ESI) m/z: 832.4, 834.4 [M+H] ⁺

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 instead of Reference Example Compound 7, and the same reaction and treatment were carried out to give the title compound (548 mg) as a light brown solid. 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)

In Reference Example 9, Example Compound 9-1 (542 mg) was used instead of Reference Example Compound 8, and the same reaction and treatment were carried out to obtain the title compound (322 mg) as a light 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, 0.90 Hz), 6.94 (1H, t, J = 7.77 Hz), 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]diazepin-6-yl]acetate (Example compound 9)

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

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 instead of Reference Example Compound 8, and the same reaction and treatment were carried out to give the title compound (29 mg) as a light 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]diazepin-6-yl]acetate (Example compound 10)

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

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 stirred in N,N-dimethylformamide (3.0 mL) at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was stirred, and the resulting solid was filtered off. The product was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain 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 using a phase separator, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30-30:70) and silica gel column chromatography (chloroform:methanol=100:0-95:5) to obtain the title compound (190 mg) 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., and 2M lithium borohydride/tetrahydrofuran solution (0.77 mL) and methanol (0.063 mL) were added, followed by stirring for 4 hours while naturally raising the temperature to room temperature. 2M lithium borohydride/tetrahydrofuran solution (0.77 mL) was added, followed by stirring at room temperature for 3 hours. 1N hydrochloric acid was gradually added to the reaction solution, followed by stirring after adding chloroform. The aqueous layer was removed using a Phase Separator, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain the title compound (124 mg) as a white solid. MS (ESI) m/z: 342.1 [M+H] ⁺

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

(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 solution was concentrated under reduced pressure, and the resulting solid was suspended and washed in chloroform, filtered, and dried to obtain 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)

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

Example 13
(13-1) 7-Bromo-6-methyl-1H-indole (Example compound 13-1)

In Reference Example 7, 2-bromo-3-nitrotoluene (2160 mg) was used instead of 1-bromo-4-methyl-2-nitrobenzene, and the same reaction and treatment were carried out to give the title compound (1108 mg) as a white 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 = 7.96 Hz), 7.19 (1H, dd, J = 3.08, 2.44 Hz), 7.46 (1H, d, J = 7.96 Hz), 8.27 (1H, brs).

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

In Reference Example 8, Example Compound 13-1 (500 mg) was used instead of Reference Example Compound 7, and the same reaction and treatment were carried out to obtain 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 = 2.8 Hz), 8.72 (1H, brs).

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

In Reference Example 9, Example Compound 13-2 (455 mg) was used instead of Reference Example Compound 8, and the same reaction and treatment were carried out to 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, Example compound 13-3 (17 mg) was used instead of Example compound 7-2, and Reference Example compound 10 (60 mg) was used, and the reaction and treatment were carried out in the same manner as in (7-3), to obtain the title compound (34 mg) as a white powder. MS (ESI) m/z: 823.5 [M+H] ⁺

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, 1-bromo-4-chloro-2-nitrobenzene was used instead of 2-bromo-3-nitrotoluene, and the reaction and treatment were carried out in the same manner as in (13-1)-(13-4), to obtain 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, 4-bromo-3-nitroanisole was used instead of 2-bromo-3-nitrotoluene, and the reaction and treatment were carried out in the same manner as in (13-1)-(13-4), to obtain the title compound 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]diazepin-6-yl]acetate (Example compound 16)

In Example 7, 2,3-dimethyl-1H-indol-7-amine (17 mg) was used instead of Example compound 7-2, and Reference Example compound 10 (50 mg) was used in the same reaction and treatment as in (7-3) to obtain the title compound (22 mg) 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, 1-bromo-4-fluoro-2-nitrobenzene was used instead of 2-bromo-3-nitrotoluene, and the reaction and treatment were carried out in the same manner as in (13-1)-(13-4), to obtain 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, 1-bromo-2-nitro-4-trifluoromethylbenzene was used instead of 2-bromo-3-nitrotoluene, and the reaction and treatment were carried out in the same manner as in (13-1)-(13-4), to obtain the title compound 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, 3-bromo-4-nitrotoluene was used instead of 2-bromo-3-nitrotoluene, and the reaction and treatment were carried out in the same manner as in (13-1)-(13-4), to obtain the title compound 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 stirred, and the resulting solid was filtered off. Saturated aqueous sodium bicarbonate and tetrahydrofuran were added to the solid and stirred, and then chloroform was added, the aqueous layer was removed using a phase separator, and the organic layer was concentrated under reduced pressure. The residue was suspended and washed in diethyl ether, and then filtered to obtain 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 aqueous solution of ammonium chloride was added to the reaction solution and the mixture was stirred, and then chloroform was added and the mixture was stirred. The aqueous layer was removed using a phase separator, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) to obtain 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 stirred in tetrahydrofuran (5.0 mL) at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride and chloroform were added to the reaction solution and stirred, the aqueous layer was removed using a phase separator, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30 to 30:70) to obtain 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 instead of Example compound 12-3, and the reaction and treatment were carried out in the same manner as in (12-4) to obtain the title compound (24 mg) as a white solid. 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)

The title compound was obtained as a pale yellow solid by carrying out the same reaction and treatment as in (11-1) except that Example Compound 20-3 was used instead of Reference Example Compound 11 in Example 11. 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 atmosphere, Reference Example Compound 1 (500 mg), N-(t-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (447 mg), palladium acetate (7 mg), S-phos (99 mg), potassium fluoride (210 mg), and water (0.078 mL) were heated under reflux in tetrahydrofuran (5.0 mL) for 7 hours. The reaction 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 to 20:80) to obtain 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)

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

(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)

To a solution of triphosgene (22 mg) in tetrahydrofuran (3.0 mL), Reference Example Compound 5 (68 mg) and N,N-diisopropylethylamine (0.11 mL) were added and stirred at room temperature for 15 minutes, followed by addition of Example Compound 21-2 (100 mg) and N,N-dimethylformamide (0.5 mL) and stirring at room temperature for 2 hours. Water was added to the reaction solution, followed by stirring, extraction 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, filtered, and dried to obtain the title compound (60 mg) as a milky white powder. MS (ESI) m/z: 828.4 [M+H] ⁺

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

The title compound (540 mg) was obtained as a pale yellow solid by carrying out the same reaction and treatment as in Reference Example 7 using 4-bromo-3-benzonitrile (2270 mg) instead of 1-bromo-4-methyl-2-nitrobenzene. 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)

In Reference Example 9, Example Compound 22-1 (100 mg) was used instead of Reference Example Compound 8, and the same reaction and treatment were carried out to obtain 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 = 2.83 Hz), 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]diazepin-6-yl]acetate (Example compound 22)

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

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

In Reference Example 8, Example Compound 22-1 (100 mg) was used instead of Reference Example Compound 7, and the same reaction and treatment were carried out to 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)

In Reference Example 9, Example Compound 23-1 (45 mg) was used instead of Reference Example Compound 8, and the same reaction and treatment were carried out to 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]diazepin-6-yl]acetate (Example compound 23)

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

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

In Example 20, 4-[3-(trifluoroacetamido)propyl]benzenesulfonyl chloride was used instead of methyl 5-(chlorosulfonyl)pyridine-2-carboxylate, and the same reaction and treatment as in (20-1) were carried out to obtain the title compound 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 removed by distillation 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. The mixture was suspended and washed with water, and dried to obtain a gray solid. Potassium carbonate (273 mg), water (0.5 mL), and methanol (5.0 mL) were added to the solid, and the mixture was heated to reflux for 6 hours. Methanol was removed by distillation under reduced pressure, and water was added and stirred. 1N hydrochloric acid was added and stirred, and the resulting solid was filtered off. The mixture was suspended and washed with water, and filtered, and dried to obtain 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)

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

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, 4-bromo-3-fluorophenylmethanamine hydrochloride was used instead of 4-bromobenzylamine, and the same reaction and treatment as in (10-1)-(10-3) were carried out to obtain the title compound as a pale yellow powder. MS (ESI) m/z: 688.4 [M-Cl+H ₂ O] ⁺

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

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)

A mixed solution of Reference Example Compound 4 (100 mg), (1R)-1-(4-bromophenyl)ethanamine (48 mg), N,N-diisopropylethylamine (0.10 mL), and HATU (91 mg) in N,N-dimethylformamide (2.0 mL) was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate, washed three times with saturated saline-water (1:1) and once with saturated saline, dried over anhydrous sodium sulfate, 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 obtain the title compound (156 mg) as a crude product of 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)

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

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

In Example 25, 4-bromo-2-fluorophenylmethanamine hydrochloride was used instead of 4-bromo-3-fluorophenylmethanamine hydrochloride, and the reaction and treatment were carried out in the same manner as in (25-1)-(25-2), to obtain the title compound as a beige powder. 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-hydroxyethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example compound 28)

In Example 25, 2-amino-2-(4-bromophenyl)ethanol was used instead of 4-bromo-3-fluorophenylmethanamine hydrochloride, and the reaction and treatment were carried out in the same manner as in (25-1)-(25-2), to obtain the title compound as a white powder. MS (ESI) m/z: 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), benzophenone imine (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) were heated under reflux in tetrahydrofuran (3.0 mL) for 7 hours. A saturated aqueous ammonium chloride solution and chloroform were added to the reaction solution and stirred, the aqueous layer was removed using a PhaseSeparator, and the organic layer was concentrated under reduced pressure. The residue, hydroxylamine hydrochloride (344 mg), and sodium acetate (487 mg) were stirred in a methanol (3.0 mL)-tetrahydrofuran (3.0 mL) mixed solvent at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and saturated sodium bicarbonate water and chloroform were added and stirred, the aqueous layer was removed using a phase separator, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain the title compound (279 mg) as a gray solid. MS (ESI) m/z: 161.2 [M+H] ⁺

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

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 obtain the title compound (57 mg) 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)

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

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

A mixture of Reference Example Compound 14 (300 mg), N-(t-butoxycarbonyl)propargylamine (239 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 37 mg), X-Phos aminobiphenyl palladium chloride precatalyst (61 mg), potassium phosphate (490 mg) and tetrahydrofuran (4.0 mL) was stirred at 120°C for 1 hour under nitrogen atmosphere and microwave irradiation. Saturated saline-water (1:1) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=98:2 to 95:5), and then purified again by NH silica gel column chromatography (chloroform:methanol=95:5 to 50:50) to obtain 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 (Example compound 31-2)

To Example Compound 31-1 (205 mg), 4M hydrogen chloride/1,4-dioxane solution (6.0 mL) was added 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 obtain 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}prop-2-yn-1-yl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (Example compound 31)

To a solution of Example Compound 31-2 (65 mg) and Reference Example Compound 4 (80 mg) in N,N-dimethylformamide (1.6 mL), N,N-diisopropylethylamine (0.083 mL) and HATU (73 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with methanol, and added to ethyl acetate and saturated saline-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 saline-water (1:1) and once with saturated saline, dried over anhydrous sodium sulfate, 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 to 50:50, precolumn: silica gel) to obtain 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), sodium carbonate (79 mg), 1,4-dioxane (3.0 mL), and water (1.0 mL) were mixed and stirred at 100°C for 20 minutes under microwave irradiation. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate = 80:20 to 0:100) to obtain 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 solution, which was then stirred and concentrated under reduced pressure. The resulting solid, Reference Example Compound 5 (60 mg), N,N-diisopropylethylamine (0.082 mL), and HATU (72 mg) were stirred in N,N-dimethylformamide (3.0 mL) at room temperature for 1 hour. Water was added to the reaction solution, which was then stirred, and the resulting solid was filtered off. The product was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain 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), 1M vinylmagnesium bromide/tetrahydrofuran solution (25.0 mL) was added at −78° C. over 5 minutes. After stirring at the same temperature for 1 hour, a saturated aqueous ammonium chloride solution and water were added to the reaction solution, and the temperature was raised to room temperature. After separation, the aqueous layer was extracted once with ethyl acetate. The combined organic layer was washed 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 (hexane:ethyl acetate=90:10) to obtain 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)

To a solution (4.0 mL) of Example Compound 33-1 (1000 mg) in N,N-dimethylformamide, phenylphosphonyl dichloride (1.0 mL) was added at room temperature. After stirring at 100° C. for 20 minutes, N,N-dimethylformamide (4.0 mL) was added and the mixture was stirred at 100° C. for another 40 minutes. Hydroxylamine hydrochloride (547 mg) was added, and the mixture was heated and stirred at 100° C. for 2 hours and at 140° C. for 0.5 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed three times with saturated aqueous sodium bicarbonate and once with saturated saline, dried over anhydrous sodium sulfate, 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 obtain the title compound (703 mg) as a crude product in the form of a 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), 2.5 M lithium aluminum hydride/tetrahydrofuran solution (1.70 mL) was added dropwise under ice cooling. After stirring at the same temperature for 10 minutes, 1N hydrochloric acid was added and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was suspended and washed in chloroform and collected by filtration to obtain 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 = 5.27Hz), 5.33 (1H, t, J = 5.33Hz), 7.10-7.27 (1H, m), 7.48 (1H, d, J = 7.83Hz), 8.31 (1H, s), 12.44 (1H, brs)

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

Example compound 33-3 (267 mg), benzophenone imine (270 mg), [1,3-bis (2,6-di-3-pentylphenyl) imidazol-2-ylidene] (3-chloropyridyl) dichloropalladium (II) (Pd-PEPPSI-IPent catalyst, 26 mg), tetrahydrofuran (7.0 mL) mixture was added with 1.3 M lithium bis (trimethylsilyl) amide / tetrahydrofuran solution (2.9 mL) at room temperature, and stirred at 140 ° C. for 0.5 hours under nitrogen atmosphere and microwave irradiation. Pd-PEPPSI-IPent catalyst (85 mg), 1.3 M lithium bis (trimethylsilyl) amide / tetrahydrofuran solution (2.9 mL) were added, and stirred at 160 ° C. for 0.5 hours under nitrogen atmosphere and microwave irradiation. After cooling to room temperature, water was added to the reaction solution and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2) and then purified again by NH silica gel column chromatography (chloroform:methanol=98:2) to obtain the title compound (59 mg) 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), and hydroxylamine hydrochloride (28 mg) and sodium acetate (40 mg) were added at room temperature, followed by stirring at the same temperature for 2 hours. Saturated aqueous 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 saline, dried over anhydrous sodium sulfate, 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 obtain the title compound (14 mg) as a light 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 = 7.7Hz), 6.91 (1H, d, J = 7.7Hz), 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)

Pyridine (0.17 mL) was added to a solution of Example Compound 33-5 (13 mg) and Reference Example Compound 10 (73 mg) in tetrahydrofuran (1.0 mL) at room temperature, and the mixture was stirred at the same temperature for 14 hours. The reaction solution was diluted with ethyl acetate-methanol, washed once with saturated saline-water (1:1) and once with saturated saline, dried over anhydrous sodium sulfate, 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 obtain 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]diazepin-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), 2N aqueous lithium hydroxide solution (0.72 mL) was added and stirred at room temperature for 2 hours. 1N hydrochloric acid was added, stirred, and concentrated under reduced pressure. The residue was suspended and washed with water, filtered, and dried to obtain the title compound (258 mg) as a yellow powder. MS (ESI) m/z: 809.4 [M+H] ⁺

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

1,4-dioxane (17 mL) was added to a mixture of t-butyl 5-bromo-1-benzofuran-2-carboxylate (1.50 g), bis(pinacolato)diboron (1.41 g), 1,1'-(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (206 mg), and potassium acetate (991 mg), and the mixture was substituted with nitrogen, and then heated and stirred at 130°C for 30 minutes under microwave irradiation. Water, ethyl acetate, and activated carbon were added to the reaction solution, and the insoluble matter was removed by filtration using diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was separated, and the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and filtered, after which the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 90:10) to obtain the title compound (1.38 g) as a pale yellow solid. ^1H NMR (400MHz, _CDCl3 ) δppm 1.37 (12H, s), 1.63 (9H, s), 7.40 (1H, d, J = 1.0Hz), 7.56 (1H, d, J = 8.7Hz), 7.87 (1H, dd, J = 1.3, 8.5Hz), 8.15 (1H, s)

(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)

A mixture of Reference Example Compound 1 (80 mg), Example Compound 35-1 (73 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 9 mg), X-Phos aminobiphenyl palladium chloride precatalyst (15 mg), potassium phosphate (123 mg), water (0.013 mL) and tetrahydrofuran (1.0 mL) was stirred at 90°C for 0.5 hours under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, washed once with water and once with saturated saline, dried over anhydrous sodium sulfate, 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 to 0:100) to obtain 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), and Reference Example Compound 5 (64 mg), N,N-diisopropylethylamine (0.32 mL), and HATU (85 mg) were added at room temperature and stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate, and then added to saturated sodium bicarbonate water, 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, 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 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)

Methyl chloroformate (0.048 mL) and N,N-diisopropylethylamine (0.15 mL) were added to a dichloromethane (6.0 mL) solution of 6-amino-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (200 mg) described in Japanese Patent Publication (JP Patent Publication No. 7-17941, Raw Material Preparation Example 1) under ice cooling, and the mixture was stirred at the same temperature for 0.5 hours. Water was added to the reaction solution, which was then extracted twice with chloroform, dried over anhydrous sodium sulfate, and filtered, after which the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 97:3) to obtain 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)

A mixture of Example Compound 36-1 (30 mg), t-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (25 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 4 mg), X-Phos aminobiphenyl palladium chloride precatalyst (6 mg), potassium phosphate (46 mg), water (0.005 mL) and tetrahydrofuran (0.36 mL) was stirred at 90°C for 0.5 hours under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, washed once with water and once with saturated saline, dried over anhydrous sodium sulfate, 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 to 0:100) to obtain 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]diazepin-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), and Reference Example Compound 5 (25 mg), N,N-diisopropylethylamine (0.12 mL), and HATU (31 mg) were added at room temperature, and the mixture was stirred at the same temperature for 15 hours. The reaction solution was diluted with ethyl acetate, and washed once with saturated sodium bicarbonate water, twice with saturated saline-water (1:1), and once with saturated saline. After drying and filtration with 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 obtain 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), and HATU (56 mg) were stirred in N,N-dimethylformamide (3.0 mL) at room temperature for 2 hours. Water was added to the reaction solution, which was then stirred and extracted twice with ethyl acetate. The combined organic layer was washed twice with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 80:20) to obtain 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]diazepin-4-yl}[1,1'-biphenyl]-4-carboxamide (Example compound 38)

In Example 37, dimethylamine hydrochloride was used instead of 2-aminoethanol, and the reaction and treatment were carried out in the same manner as in (37-1) to obtain 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, 2-(4-bromophenoxy)ethanamine was used instead of 4-bromo-3-fluorophenylmethanamine hydrochloride, and the reaction and treatment were carried out in the same manner as in (25-1)-(25-2), to obtain the title compound as a 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)

To a solution of Reference Example Compound 12 (63 mg) and Reference Example Compound 11 (53 mg) in N,N-dimethylformamide (1.3 mL), N,N-diisopropylethylamine (0.063 mL) and HATU (56 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. Water was added to the reaction solution, and the precipitate was collected by filtration and washed with water. The residue was dissolved in chloroform, dried over anhydrous sodium sulfate, and then 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 95:5) to obtain 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, the same reaction and treatment were carried out using Reference Example Compound 13 (80 mg) instead of Reference Example Compound 12 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 instead of Example Compound 7-2, and the reaction and treatment were carried out in the same manner as in (7-3) to obtain the title compound (56 mg) as a pale yellow solid. MS (ESI) m/z: 887.3, 889.3 [M+H] ⁺

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 mixture of tetrahydrofuran-ethyl acetate (1:1) and a small amount of methanol. The organic layer was washed once with a mixture of saturated saline and 1N hydrochloric acid water, once with saturated saline, once with saturated sodium bicarbonate water, and once with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative HPLC (10 mM ammonium carbonate aqueous solution-acetonitrile) to obtain 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)

To a solution of Reference Example Compound 15 (90 mg) and mesyl[(tri-t-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) in tetrahydrofuran (1.9 mL), 0.5M cyclopropylzinc bromide/tetrahydrofuran solution (4.6 mL) was added under ice cooling in a nitrogen atmosphere, 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 the mixture was stirred at room temperature for 1 hour, and then ethyl acetate and water were added to separate the mixture. The organic layer was washed once with a saturated aqueous sodium bicarbonate solution and once with saturated saline, dried over anhydrous sodium sulfate, 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 purified by preparative HPLC (10 mM aqueous ammonium carbonate solution-acetonitrile) to obtain 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 instead of Example compound 7-2, and the reaction and treatment were carried out in the same manner as in (7-3) to obtain the title compound (47 mg) as a pale yellow solid. MS (ESI) m/z: 849.5 [M+H] ⁺

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 resulting residue was dissolved in N,N-dimethylformamide (1.5 mL), and Reference Example Compound 5 (56 mg), N,N-diisopropylethylamine (0.26 mL), and HATU (68 mg) were added at room temperature, and 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 residue was dissolved in chloroform, dried over anhydrous sodium sulfate, 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 95:5) to obtain 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 resulting residue was dissolved in N,N-dimethylformamide (1.5 mL), and Reference Example Compound 11 (64 mg), N,N-diisopropylethylamine (0.26 mL), and HATU (68 mg) were added at room temperature, and 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 residue was dissolved in chloroform, dried over anhydrous sodium sulfate, 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 95:5) to obtain 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 reaction and treatment were carried out using Reference Example Compound 3 (300 mg) and 4-bromo-3-chlorobenzoic acid t-butyl (207 mg) instead of 4-bromo-3-fluorobenzoic acid t-butyl to obtain the title compound (374 mg) as a crude product of 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)

The title compound (221 mg) was obtained as a beige powder by carrying out the same reaction and treatment as in Example 45, except that Example compound 47-1 (180 mg) was used instead of Reference Example compound 18-1. 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)

The title compound (189 mg) was obtained as a beige powder by carrying out the same reaction and treatment as in Example 46, except that Example compound 47-1 (180 mg) was used instead of Reference Example compound 18-1. 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), and water (0.026 mL) were stirred in tetrahydrofuran (5.0 mL) under nitrogen atmosphere and microwave irradiation at 100° C. for 1 hour. The mixture was filtered using ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain an orange viscous material. The obtained viscous material, 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 to 95:5) to obtain 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), and t-butyl 4-bromo-2-methylbenzoate (65 mg), tetrakis(triphenylphosphine)palladium(0) (23 mg), potassium phosphate (126 mg) and water (0.013 mL) were added, and the mixture was stirred at 90° C. for 0.5 hours under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, and insoluble matter was removed by filtration through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=50:50 to 0:100) to obtain the title compound (117 mg) as a crude product in the form of a white powder. 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), and Reference Example Compound 5 (74 mg), N,N-diisopropylethylamine (0.34 mL), and HATU (90 mg) were added at room temperature, and 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 residue was dissolved in chloroform, dried over anhydrous sodium sulfate, 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 95:5) to obtain 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, t-butyl 4-bromo-2-trifluoromethylbenzoate was used instead of t-butyl 4-bromo-2-methylbenzoate, and the reaction and treatment were carried out in the same manner as in (50-1)-(50-2), to obtain the title compound as a white powder. MS (ESI) m/z: 891.5 [M+H] ⁺

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)

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

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), and water (0.014 mL) were stirred in tetrahydrofuran (4.0 mL) under a nitrogen atmosphere and microwave irradiation at 100° C. for 0.5 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain the title compound (109 mg) as a colorless viscous material. 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]diazepin-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 azeotropic distillation was performed 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 solution, 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 to 95:5) to obtain 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]diazepin-6-yl]acetate (Example compound 54)

The title compound was obtained as a milky white solid by carrying out the same reaction and treatment as in (53-1)-(53-2) using t-butyl 6-bromopyridine-3-carboxylate instead of t-butyl 5-bromopyridine-2-carboxylate in Example 53. 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)

A mixture of methyl [(6S)-4-(4-chlorophenyl)-2-(hydroxymethyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (500 mg), (4-t-butoxycarbonylphenyl)boronic acid (386 mg), potassium phosphate (616 mg), tetrahydrofuran (5.0 mL), water (0.52 mL), 2-dicyclohexylphosphino-2'-6'-dimethoxybiphenyl aminobiphenyl palladium chloride precatalyst (42 mg), and S-phos (24 mg) described in WO2006/129623 was stirred under heating and reflux for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=99:1 to 90:10) to give the title compound (610 mg) as a milky white solid. MS (ESI) m/z: 573.2 [M+H] ⁺

(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 obtained 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, HATU (69 mg) was added under ice cooling, and the mixture was stirred at room temperature for 7 hours. The reaction solution was diluted with a mixture of ethyl acetate-tetrahydrofuran (1:1), 1N hydrochloric acid and saturated saline were added, and the layers were separated. The organic layer was washed once with saturated saline, once with saturated sodium bicarbonate water, and once with saturated saline, dried over anhydrous sodium sulfate, 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 to 85:15) to obtain 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)

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

(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)

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

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

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

(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 hours under microwave irradiation. Saturated saline was added to the reaction solution, and the mixture was extracted three times with a mixture of ethyl acetate and tetrahydrofuran (1:1). The extracts were combined, washed once with a small amount of saturated saline, dried over anhydrous sodium sulfate, and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was suspended and washed in ethyl acetate, and then collected by filtration to obtain 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)

To a mixture of Example Compound 57-2 (41 mg), Reference Example Compound 4 (50 mg), N,N-diisopropylethylamine (0.043 mL), and N,N-dimethylformamide (1.0 mL), HATU (49 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 5 minutes and at room temperature for 3 hours. The reaction solution was diluted with a mixture of ethyl acetate-tetrahydrofuran (1:1), washed once with saturated sodium bicarbonate water and once with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was suspended and washed in acetonitrile-water, filtered, and washed with water to obtain 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)

A mixture of 3-(4-bromophenyl)propan-1-ol (1000 mg), benzyl mercaptan (0.55 mL), N,N-diisopropylethylamine (2.41 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 269 mg), tris(dibenzylideneacetone)dipalladium (213 mg), and toluene (15.0 mL) was stirred for 5 hours at 100° C. under a nitrogen atmosphere. After cooling to room temperature, the reaction solution was directly purified by silica gel column chromatography (hexane:ethyl acetate=60:40 to 20:80, precolumn: NH silica gel) to obtain the title compound (681 mg) as a red solid. ^1H NMR (400MHz, _CDCl3 ) δ ppm 1.23 (1H, t, J = 5.3Hz), 1.81-1.91 (2H, m), 2.62-2.71 (2H, m), 3.61-3.70 (2H, m), 4.08 (2H, s), 7.05-7.11 (2H, m), 7.19-7.31 (7H, m)

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

To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (200 mg) and Example Compound 58-1 (281 mg) in toluene (3.0 mL), cyanomethylenetrimethylphosphorane (157 mg) was added at room temperature, and the mixture was stirred at 150° C. for 0.5 hours under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, washed once with saturated saline-water (1:1) and once with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to obtain the title compound (338 mg) as a colorless viscous substance. ^1H NMR (400MHz, _CDCl3 ) δ ppm 1.33 (12H, s), 2.00-2.12 (2H, m), 2.76 (2H, t, J = 7.6Hz), 3.96 (2H, t, J = 6.2Hz), 4.08 (2H, s), 6.87 (2H , d, J=8.7Hz), 7.09 (2H, d, J=8.3Hz), 7.22 (3H, d, J=8.3Hz), 7.25-7.28 (4H, m), 7.74 (2H, d, J=8.7Hz)

(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)

A mixture of Reference Example Compound 1 (100 mg), Example Compound 58-2 (122 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 12 mg), X-Phos aminobiphenyl palladium (II) methanesulfonate precatalyst (21 mg), potassium phosphate (154 mg), water (0.016 mL) and tetrahydrofuran (1.2 mL) was stirred at 90°C for 0.5 hours under nitrogen atmosphere and microwave irradiation. Example Compound 58-2 (67 mg), X-Phos (12 mg), and X-Phos aminobiphenyl palladium (II) methanesulfonate precatalyst (21 mg) were added and stirred at 90°C for 1 hour under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, and insoluble matter was removed by filtration with diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=50:50 to 0:100) to obtain the title compound (147 mg) as a 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), N-chlorosuccinimide (93 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 1.5 hours. N-chlorosuccinimide (6 mg) was added, and the mixture was stirred at the same temperature for 0.5 hours. The reaction solution was diluted with ethyl acetate, washed with saturated saline-water (1:1) and saturated saline in that order, dried over anhydrous sodium sulfate, 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 obtain the title compound (134 mg) as a pale yellow powder. MS (ESI) m/z: 671.4 [M-Cl+H ₂ O] ⁺

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

Pyridine (0.15 mL) was added to a solution of Example Compound 58-4 (130 mg) and Reference Example Compound 9 (39 mg) in tetrahydrofuran (2.6 mL) at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform, washed once with 1N hydrochloric acid and once with saturated saline, dried over anhydrous sodium sulfate, 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 obtain the title compound (52 mg) as a light 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), and water (0.014 mL) were stirred in tetrahydrofuran (4.0 mL) under a nitrogen atmosphere and microwave irradiation at 100° C. for 0.5 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain the title compound (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]diazepin-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 azeotropic distillation was performed 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 solution, 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 to 95:5) to obtain 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)

The title compound was obtained as a beige solid by carrying out the same reaction and treatment as in (20-1)-(20-4) using methyl trans-3-(chlorosulfonyl)cyclobutane-1-carboxylate instead of methyl 5-(chlorosulfonyl)pyridine-2-carboxylate in Example 20. 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)

In Example 50, t-butyl 5-bromobenzothiophene-2-carboxylate was used instead of t-butyl 4-bromo-2-methylbenzoate, and the reaction and treatment were carried out in the same manner as in (50-1)-(50-2), to obtain the title compound as a white powder. MS (ESI) m/z: 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)

In Example 50, t-butyl 6-bromobenzothiophene-2-carboxylate was used instead of t-butyl 4-bromo-2-methylbenzoate, and the reaction and treatment were carried out in the same manner as in (50-1)-(50-2), to obtain the title compound as a white powder. MS (ESI) m/z: 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)

A mixture of 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 aminobiphenyl palladium chloride precatalyst (18 mg), potassium phosphate (140 mg), water (0.015 mL) and tetrahydrofuran (1.5 mL) was stirred under a nitrogen atmosphere and microwave irradiation at 90°C for 0.5 hours. The reaction solution was diluted with ethyl acetate, and insoluble matter was removed by filtration with diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=98:2) to obtain the title compound (107 mg) as a 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 carbon (46 mg) was added, the reaction vessel was replaced with hydrogen, and the mixture was stirred at room temperature for 1 hour. After replacing the reaction vessel with nitrogen, the reaction solution was filtered, and the solvent was concentrated under reduced pressure to obtain a crude product of the 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)

To a solution of Example Compound 63-2 (43 mg) and Reference Example Compound 5 (30 mg) in N,N-dimethylformamide (1.0 mL), N,N-diisopropylethylamine (0.027 mL) and HATU (37 mg) were added at room temperature, and the mixture was stirred at the same temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed three times with saturated saline-water (1:1) and once with saturated saline, dried over anhydrous sodium sulfate, 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 obtain 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)

To a solution of Example Compound 63-2 (43 mg) and Reference Example Compound 11 (34 mg) in N,N-dimethylformamide (1.0 mL), N,N-diisopropylethylamine (0.041 mL) and HATU (37 mg) were added at room temperature, and the mixture was stirred at the same temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed three times with saturated saline-water (1:1) and once with saturated saline, dried over anhydrous sodium sulfate, 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 obtain 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), and water (0.014 mL) were stirred in tetrahydrofuran (4.0 mL) under a nitrogen atmosphere and microwave irradiation at 100° C. for 0.5 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain the title compound (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]diazepin-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 azeotropic distillation was performed 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 solution, 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 to 95:5) to obtain 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)

In Example 50, t-butyl 6-bromobenzofuran-2-carboxylate was used instead of t-butyl 4-bromo-2-methylbenzoate, and the reaction and treatment were carried out in the same manner as in (50-1)-(50-2), to obtain the title compound as a white powder. MS (ESI) m/z: 863.5 [M+H] ⁺

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

A mixture of (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 hours under a nitrogen atmosphere and microwave irradiation. After cooling to room temperature, insoluble matter was removed by filtration, and the residue 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 to 50:50, precolumn: NH silica gel) to obtain the title compound (2141 mg) as a pale yellow solid. ^1H NMR (400MHz, _CDCl3 ) δ ppm 1.61 (1H, t, J = 5.91Hz), 4.11 (2H, s), 4.65 (2H, d, J = 5.91Hz), 7.17-7.35 (9H, m)

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

To a suspension of Example Compound 67-1 (556 mg) in toluene (5.6 mL), thionyl chloride (0.21 mL) was added at room temperature, and the mixture was stirred at the same temperature for 0.5 hours. The reaction solution was diluted with ethyl acetate, washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure to obtain the title compound (592 mg) as a crude product in the form of a light brown solid. 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)

Sodium hydride (115 mg, 60%, dispersed in liquid paraffin) was added to a solution of 6-bromo-3,4-dihydro-2H-isoquinolin-1-one (500 mg) in N,N-dimethylformamide (5.0 mL) at room temperature and stirred for 10 minutes, and then a solution of Example Compound 67-2 (585 mg) in N,N-dimethylformamide (5.0 mL) was added and stirred at the same temperature for 2 hours. 1N hydrochloric acid and ethyl acetate were added to the reaction solution and the mixture was separated. The organic layer was washed twice with saturated saline-water (1:1) and once with saturated saline, 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=90:10-80:20) to obtain 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) were added, and the mixture was stirred at 90° C. for 0.5 hours under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, and insoluble matter was removed by filtration through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=50:50 to 0:100) to obtain the title compound (151 mg) as a crude product of white powder. 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), N-chlorosuccinimide (92 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 1.5 hours. N-chlorosuccinimide (8 mg) was added, and the mixture was stirred at the same temperature for 0.5 hours. The reaction solution was diluted with ethyl acetate, washed with saturated saline-water (1:1) and saturated saline in that order, dried over anhydrous sodium sulfate, 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 obtain 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 = 0.6Hz), 2.43 (3H, d, J = 0.6Hz), 2.69 (3H, s), 3.08 (2H , t, J=6.7Hz), 3.59 (2H, t, J=6.6Hz), 3.67 (2H, dd, J=7.1, 4.1Hz), 3. 79 (3H, s), 4.66 (1H, dd, J = 7.8, 6.4Hz), 4.91 (2H, s), 7.41 (1H, d, J = 1.3Hz), 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)

Pyridine (0.085 mL) was added to a solution of Example Compound 67-5 (77 mg) and Reference Example Compound 9 (22 mg) in tetrahydrofuran (1.5 mL) at room temperature, and the mixture was stirred at the same temperature for 16 hours. Chloroform was added to the reaction solution, and the mixture was washed once with 1N hydrochloric acid and once with saturated saline. 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 resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 95:5) to obtain 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)

In Example 11, 3-bromophenethylamine was used instead of Reference Example Compound 11, and the reaction and treatment were carried out in the same manner as in (11-1) to obtain the title compound as a 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)

Under a nitrogen stream, Example Compound 68-1 (183 mg), benzyl mercaptan (0.038 mL), tris(dibenzylideneacetone)dipalladium (25 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (31 mg), and N,N-diisopropylethylamine (0.070 mL) were stirred in a toluene (3.0 mL)-tetrahydrofuran (1.5 mL) mixed solvent under microwave irradiation at 150° C. for 0.5 hours. The mixture was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain 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)

A mixed solution of Example Compound 68-2 (193 mg) in acetonitrile (5.0 mL)-2N hydrochloric acid (1.0 mL) was cooled to 0° C., N-chlorosuccinimide (124 mg) was added, and the mixture was stirred at the same temperature for 3 hours. Water was added to the reaction solution, which was then 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 obtain the title compound (183 mg) as a yellow solid. MS (ESI) m/z: 684.3 [M-Cl+H ₂ O] ⁺

(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, Example compound 68-3 was used instead of Reference Example compound 10, and Example compound 9 was used instead of Example compound 29-1, and the reaction and treatment were carried out in the same manner as in (29-2), to obtain 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), and Reference Example Compound 17 (63 mg), N,N-diisopropylethylamine (0.25 mL), and HATU (67 mg) were added at room temperature, and the mixture was stirred at the same temperature for 16 hours. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, and washed three times with saturated saline-water (1:1) and once with saturated saline. After drying and filtration with 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 to 95:5) to obtain 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)

To a solution of Reference Example Compound 13 (80 mg) in N,N-dimethylformamide (1.6 mL), Reference Example Compound 17 (65 mg), N,N-diisopropylethylamine (0.078 mL), and HATU (69 mg) were added at room temperature, and the mixture was stirred at the same temperature for 16 hours. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed three times with saturated saline-water (1:1) and once with saturated saline. After drying over anhydrous sodium sulfate and filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to obtain the title compound (53 mg) as a light 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)

A mixture of Reference Example Compound 2 (370 mg), 2-chloro-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid t-butyl (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), and 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 saline, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=85:15 to 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. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 1M aqueous sodium carbonate solution and washed with toluene. The aqueous layer was acidified with 2N hydrochloric acid, and the resulting precipitate was collected by filtration to obtain 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)

To a solution of Example Compound 71-1 (50 mg) in N,N-dimethylformamide (1.0 mL), Reference Example Compound 5 (38 mg), N,N-diisopropylethylamine (0.054 mL), and HATU (46 mg) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed three times with saturated saline-water (1:1) and once with saturated saline. After drying over anhydrous sodium sulfate and filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to obtain 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, 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate t-butyl was used instead of 2-chloro-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate t-butyl, and the reaction and treatment were carried out in the same manner as in (71-1)-(71-2), 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]diazepine-6-acetic acid (500 mg) in N,N-dimethylformamide (6.0 mL) was added with 28% aqueous ammonia (0.30 mL), and then 1-hydroxy-7-azabenzotriazole (HOAt) (170 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSCI) (311 mg) were added and stirred at room temperature for 5 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, 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), and then trifluoroacetic anhydride (0.34 mL) was added and stirred at room temperature for 3 hours. N,N-diisopropylethylamine (0.43 mL) and trifluoroacetic anhydride (0.17 mL) were further added and stirred at room temperature for 16 hours. Water was added to the reaction solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain 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)

A mixture of Example Compound 73-1 (114 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate t-butyl (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), and S-phos (12 mg) was stirred under heating and reflux for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 99:1 to 90:10) to obtain 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), and Reference Example Compound 5 (36 mg), N,N-diisopropylethylamine (0.17 mL), and HATU (44 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, and washed three times with saturated saline-water (1:1) and once with saturated saline. After drying and filtration with 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 obtain 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), and 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 the mixture was stirred at 90° C. for 0.5 hours under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, and insoluble matter was removed by filtration with 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) to obtain the title compound (125 mg) as a crude product in the form of a 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), and Reference Example Compound 5 (74 mg), N,N-diisopropylethylamine (0.34 mL), and HATU (90 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, and washed three times with saturated saline-water (1:1) and once with saturated saline. After drying and filtration with 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 obtain 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 aminobiphenyl palladium chloride precatalyst (8 mg), cesium fluoride (46 mg) and water (0.2 mL) were added, and the mixture was stirred at 120°C for 0.5 hours under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate and then extracted twice with saturated sodium bicarbonate water. 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, and the combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the title compound (52 mg) as a white powder. 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)

To a solution of Example Compound 75-1 (50 mg) and Reference Example Compound 5 (37 mg) in N,N-dimethylformamide (1.0 mL), N,N-diisopropylethylamine (0.050 mL) and HATU (45 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed three times with saturated saline-water (1:1) and once with saturated saline. After drying and filtration with 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 obtain 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)

To a solution of 4-bromo-2-cyanobenzoic acid (100 mg) and Reference Example Compound 5 (158 mg) in N,N-dimethylformamide (2.2 mL), N,N-diisopropylethylamine (0.23 mL) and HATU (202 mg) were added at room temperature, and the mixture was stirred at the same temperature for 2 days. The reaction solution was diluted with ethyl acetate, washed twice with saturated sodium bicarbonate water, once with saturated saline-water (1:1), and once with saturated saline. After drying over anhydrous sodium sulfate and filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified twice by silica gel column chromatography (chloroform:methanol=98:2) to obtain 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 aminobiphenyl palladium chloride precatalyst (4 mg), cesium fluoride (20 mg) and water (0.2 mL) were added, and the mixture was stirred at 120°C for 0.5 hours under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, washed twice with saturated sodium bicarbonate water and once with saturated saline, dried over anhydrous sodium sulfate, 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 to 95:5) to obtain 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)

The title compound was obtained as a milky white solid by carrying out the same reaction and treatment as in (53-1)-(53-2) using t-butyl 5-bromopyridine-2-carboxylate instead of t-butyl 5-bromopyridine-2-carboxylate in Example 53. 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 to 70:30) to obtain 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)

The title compound was obtained as a milky white solid by carrying out the same reaction and treatment as in (53-1)-(53-2) using Example compound 78-1 instead of t-butyl 5-bromopyridine-2-carboxylate in Example 53. 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)

In Example 75, 4-bromo-3-(trifluoromethyl)benzoic acid was used instead of 4-bromo-3-methylbenzoic acid, and the reaction and treatment were carried out in the same manner as in (75-1)-(75-2), to obtain 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, 4-bromo-3-methoxybenzoic acid was used instead of 4-bromo-3-methylbenzoic acid, and the reaction and treatment were carried out in the same manner as in (75-1)-(75-2), to obtain 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, 4-bromo-3-cyanobenzoic acid was used instead of 4-bromo-3-methylbenzoic acid, and the reaction and treatment were carried out in the same manner as in (75-1)-(75-2), to obtain 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, 4-bromo-2,5-difluorobenzoic acid (48 mg) was used instead of 4-bromo-3-methylbenzoic acid, and the reaction and treatment were carried out in the same manner as in (75-1) to obtain the title compound (116 mg) as a crude product of 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 reaction and treatment were carried out in the same manner as in (75-2) to obtain the title compound (39 mg) as a beige 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, 4-bromo-5-fluoro-2-methylbenzoic acid (47 mg) was used instead of 4-bromo-3-methylbenzoic acid, and the reaction and treatment were carried out in the same manner as in (75-1) to obtain the title compound (96 mg) 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 reaction and treatment were carried out in the same manner as in (75-2) to obtain the title compound (45 mg) as a beige 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)

To a solution of Reference Example Compound 19 (85 mg) and Reference Example Compound 17 (68 mg) in N,N-dimethylformamide (1.7 mL), N,N-diisopropylethylamine (0.083 mL) and HATU (73 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed three times with saturated saline-water (1:1) and once with saturated saline. After drying and filtration with 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 obtain 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)

To a solution of Reference Example Compound 18 (50 mg) and Reference Example Compound 17 (42 mg) in N,N-dimethylformamide (1.0 mL), N,N-diisopropylethylamine (0.050 mL) and HATU (44 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed three times with saturated saline-water (1:1) and once with saturated saline. After drying and filtration with 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 obtain 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)

To a solution of Reference Example Compound 20 (50 mg) and Reference Example Compound 17 (42 mg) in N,N-dimethylformamide (1.0 mL), N,N-diisopropylethylamine (0.050 mL) and HATU (45 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed three times with saturated saline-water (1:1) and once with saturated saline. After drying and filtration with 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 obtain 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)

To a solution of Reference Example Compound 20 (50 mg) and Reference Example Compound 11 (42 mg) in N,N-dimethylformamide (1.0 mL), N,N-diisopropylethylamine (0.050 mL) and HATU (45 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed three times with saturated saline-water (1:1) and once with saturated saline. After drying and filtration with 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 obtain 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)

In Example 86, Example compound 75-1 (50 mg) was used instead of Reference Example compound 20, and the same reaction and treatment were carried out to obtain 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)

In Example 87, Example compound 75-1 (50 mg) was used instead of Reference Example compound 20, and the same reaction and treatment were carried out to obtain 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]diazepin-6-yl]acetate (Example compound 90)

The title compound was obtained as a beige solid by carrying out the same reaction and treatment as in (53-2) using Reference Example Compound 11 instead of Reference Example Compound 5 in Example 53. 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)

The title compound was obtained as a milky white solid by carrying out the same reaction and treatment as in (53-1)-(53-2) using t-butyl 5-bromopyridine-2-carboxylate instead of t-butyl 5-bromopyridine-2-carboxylate in Example 53. 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)

The title compound was obtained as a milky white solid by carrying out the same reaction and treatment as in (53-2) using Reference Example Compound 17 instead of Reference Example Compound 5 in Example 53. 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), and 4-bromo-3-methylbenzoic acid (83 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 18 mg), X-Phos aminobiphenyl palladium chloride precatalyst (30 mg), cesium fluoride (175 mg) and water (0.5 mL) were added, and the mixture was stirred under a nitrogen atmosphere and microwave irradiation at 120°C for 0.5 hours and then at 160°C for 0.5 hours. The reaction solution was diluted with ethyl acetate and extracted twice with saturated sodium bicarbonate water. 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 layer was dried over anhydrous sodium sulfate and filtered, and the solvent was removed under reduced pressure to obtain 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)

1-Hydroxy-7-azabenzotriazole (HOAt, 22 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSCI, 31 mg) were added to a solution of Example Compound 93-1 (68 mg) and Reference Example Compound 5 (54 mg) in N,N-dimethylformamide (2.0 mL) at room temperature, and the mixture was stirred at the same temperature for 3 hours. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed three times with saturated saline-water (1:1) and once with saturated saline. After drying and filtration with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2-90:10) to obtain 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)

In Example 25, (4-bromo-2-methyl-phenyl)methanamine was used instead of 4-bromo-3-fluorophenylmethanamine hydrochloride, and the reaction and treatment were carried out in the same manner as in (25-1)-(25-2), to obtain the title compound as a gray powder. 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, (1R)-1-(4-bromophenyl)propan-1-amine was used instead of 4-bromo-3-fluorophenylmethanamine hydrochloride, and the reaction and treatment were carried out in the same manner as in (25-1)-(25-2), to obtain the title compound as a gray powder. 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)

In Example 25, (4-bromo-3-methyl-phenyl)methanamine hydrochloride was used instead of 4-bromo-3-fluorophenylmethanamine hydrochloride, and the reaction and treatment were carried out in the same manner as in (25-1)-(25-2), to obtain the title compound as a beige powder. 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)

In Example 86, Example Compound 82-1 (40 mg) was used instead of Reference Example Compound 20, and the same reaction and treatment were carried out to obtain 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)

In Example 86, Example Compound 83-1 (30 mg) was used instead of Reference Example Compound 20, and the same reaction and treatment were carried out to obtain 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), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (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 mixture was stirred at 120°C for 0.5 hours under nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate and then extracted twice with saturated sodium bicarbonate water. 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 layer was dried over anhydrous sodium sulfate and filtered, and the solvent was removed under reduced pressure to obtain the title compound (365 mg) as a crude product of 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)

To a solution of Example Compound 99-1 (50 mg) and Reference Example Compound 17 (40 mg) in N,N-dimethylformamide (2.0 mL), N,N-diisopropylethylamine (0.49 mL) and HATU (43 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate-tetrahydrofuran, washed three times with saturated saline-water (1:1) and once with saturated saline. After drying over anhydrous sodium sulfate and filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to obtain 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)

In Example 87, Example compound 99-1 (50 mg) was used instead of Reference Example compound 20, and the same reaction and treatment were carried out to obtain 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 (Example compound 101-1)

The title compound was obtained as a white solid by carrying out the same reaction and treatment as in (2-1) using 5-bromo-4-methylpyridine-2-carboxylic acid instead of Reference Example Compound 12 in Example 2. MS (ESI) m/z: 536.1, 538.2 [M−H] ⁻

(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)

Under a nitrogen stream, Example Compound 101-1 (134 mg), Reference Example Compound 3 (126 mg), XPhos aminobiphenylpalladium chloride precatalyst (20 mg), XPhos (12 mg), and cesium fluoride (113 mg) were stirred in a water (1.0 mL)-tetrahydrofuran (4.0 mL) mixed solvent under microwave irradiation at 120° C. for 0.5 hours. The reaction solution was directly purified by silica gel column chromatography (chloroform:methanol=100:0-95:5). The obtained solid was purified again by silica gel column chromatography (ethyl acetate:methanol=100:0-95:5) to obtain 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]diazepin-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 azeotropic distillation was performed twice with toluene. The residue, 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 solution, and the mixture was stirred. The resulting solid was filtered off and washed by suspending it in water. The title compound (79 mg) was obtained as a pale yellow solid by purifying it by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5). 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 azeotropic distillation was performed twice with toluene. The residue, 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 solution, and the mixture was stirred. The resulting solid was filtered off and washed by suspending it in water. The title compound (74 mg) was obtained as a beige solid by purification using silica gel column chromatography (chloroform:methanol = 100:0 to 95:5). 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)

Cesium carbonate (1778 mg) was added to a solution of 5-bromo-2-(bromomethyl)benzonitrile (500 mg) and di-t-butyl iminodicarboxylate (396 mg) in N,N-dimethylformamide (5.0 mL) at room temperature, and the mixture was stirred at 60° C. for 0.5 hours. The reaction solution was diluted with ethyl acetate, washed three times with saturated saline-water (1:1) and once with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-90:10) to obtain 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)

To the example compound 104-1 (400 mg), 4M hydrogen chloride/1,4-dioxane solution (4.0 mL) was added 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 mixture was suspended and washed, and then filtered to obtain 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, Example compound 104-2 was used instead of 4-bromo-3-fluorophenylmethanamine hydrochloride, and the reaction and treatment were carried out in the same manner as in (25-1)-(25-2), to obtain the title compound as a 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 azeotropic distillation with toluene was performed twice. Ethyl acetate and water were added and the mixture was 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 mixture was extracted three times with chloroform. The organic layer was concentrated under reduced pressure to obtain 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]diazepin-6-yl]acetate (Example compound 105)

Example compound 105-1 (53 mg), Reference Example compound 21 (45 mg), N,N-diisopropylethylamine (0.055 mL), and HATU (48 mg) were stirred in N,N-dimethylformamide (2.0 mL) at room temperature for 2 hours. Water was added to the reaction solution and stirred, and the resulting solid was filtered off and washed by suspending it in water. The title compound (65 mg) was obtained as a pale yellow solid by purifying it with silica gel column chromatography (chloroform:methanol=100:0 to 95:5). 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), and HATU (48 mg) were stirred in N,N-dimethylformamide (2.0 mL) at room temperature for 2 hours. Water was added to the reaction solution and stirred, and the resulting solid was filtered off and washed by suspending it in water. The title compound (70 mg) was obtained as a pale yellow solid by purifying it with silica gel column chromatography (chloroform:methanol=100:0 to 95:5). 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]diazepin-6-yl]acetate (Example compound 107)

Example compound 105-1 (53 mg), Reference Example compound 23 (47 mg), N,N-diisopropylethylamine (0.055 mL), and HATU (48 mg) were stirred in N,N-dimethylformamide (2.0 mL) at room temperature for 2 hours. Water was added to the reaction solution and stirred, and the resulting solid was filtered off and washed by suspending it in water. The title compound (73 mg) was obtained as a pale yellow solid by purifying it with silica gel column chromatography (chloroform:methanol=100:0 to 95:5). 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 instead of Example compound 65-1, and the reaction and treatment were carried out in the same manner as in (105-1) to obtain the title compound (150 mg) as a pale yellow solid. 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]diazepin-6-yl]acetate (Example compound 108)

In Example 105, Example compound 108-1 (50 mg) was used instead of Example compound 105-1, and the reaction and treatment were carried out in the same manner as in (105-2) to obtain the title compound (51 mg) as a beige 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 instead of Example compound 105-1, and the reaction and treatment were carried out in the same manner as in (106-1) to obtain the title compound (68 mg) as a beige 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]diazepin-6-yl]acetate (Example compound 110)

In Example 107, Example compound 108-1 (50 mg) was used instead of Example compound 105-1, and the reaction and treatment were carried out in the same manner as in (107-1) to obtain the title compound (63 mg) as a beige 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)

In Example 25, 2-amino-2-(4-bromophenyl)acetonitrile was used instead of 4-bromo-3-fluorophenylmethanamine hydrochloride, and the reaction and treatment were carried out in the same manner as in (25-1)-(25-2), to obtain the title compound as a light 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)

To a solution of Reference Example Compound 12 (60 mg) and Reference Example Compound 21 (50 mg) in N,N-dimethylformamide (1.0 mL), N,N-diisopropylethylamine (0.060 mL) and HATU (53 mg) were added at room temperature, and the mixture was 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 obtain 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, the same reaction and treatment were carried out using Reference Example Compound 13 (68 mg) instead of Reference Example Compound 12 to obtain 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, the same reaction and treatment were carried out using Reference Example Compound 20 (50 mg) instead of Reference Example Compound 12 to obtain 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, the same reaction and treatment were carried out using Reference Example Compound 18 (50 mg) instead of Reference Example Compound 12 to obtain 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, the same reaction and treatment were carried out using Reference Example Compound 19 (50 mg) instead of Reference Example Compound 12 to obtain 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)

In Example 112, Example compound 75-1 (50 mg) was used instead of Reference Example compound 12, and the same reaction and treatment were carried out to obtain 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)

In Example 112, Example compound 99-1 (50 mg) was used instead of Reference Example compound 12, and the same reaction and treatment were carried out to obtain 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)

In Example 112, Example compound 82-1 (26 mg) was used instead of Reference Example compound 12, and the same reaction and treatment were carried out to obtain 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)

In Example 112, Example compound 83-1 (19 mg) was used instead of Reference Example compound 12, and the same reaction and treatment were carried out to obtain 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)

To a solution of Reference Example Compound 18 (50 mg) and Reference Example Compound 22 (43 mg) in N,N-dimethylformamide (1.0 mL), N,N-diisopropylethylamine (0.050 mL) and HATU (44 mg) were added at room temperature, and the mixture was 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 obtain 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)

In Example 121, Example compound 99-1 (50 mg) was used instead of Reference Example compound 18, and the same reaction and treatment were carried out to obtain 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, the same reaction and treatment were carried out using Reference Example Compound 20 (30 mg) instead of Reference Example Compound 18 to obtain 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)

To a solution of Reference Example Compound 18 (50 mg) and Reference Example Compound 23 (43 mg) in N,N-dimethylformamide (1.0 mL), N,N-diisopropylethylamine (0.050 mL) and HATU (44 mg) were added at room temperature, and the mixture was 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 obtain 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)

In Example 124, Example compound 99-1 (50 mg) was used instead of Reference Example compound 18, and the same reaction and treatment were carried out to obtain 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, the same reaction and treatment were carried out using Reference Example Compound 20 (32 mg) instead of Reference Example Compound 18 to obtain 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 reaction and treatment were carried out in the same manner as in (1-1) to obtain the title compound (58 mg) as a pale yellow solid. 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)

The same reaction and treatment as in Example 1 was carried out using Reference Example Compound 23 (39 mg) instead of Reference Example Compound 5 to give the title compound (56 mg) 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-dioxaboronane-2-yl)benzamide (Example compound 129-1)

Under a nitrogen stream, N,N-diisopropylethylamine (0.41 mL) and HATU (363 mg) were added to a solution of Reference Example Compound 5 (300 mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (198 mg) in N,N-dimethylformamide (6.0 mL), and the mixture was stirred at the same temperature for 1 hour, after which Reference Example Compound 5 (45 mg) was added and the mixture was further stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate, water, and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (499 mg) as a crude 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)

To a solution of (S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (70 g) in ethanol (500 mL), concentrated sulfuric acid (4 mL) was added 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 saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was recrystallized with 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=7.0Hz), 7.47 (2H, d, J=7.0Hz)
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, a mixture of 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 at 130° C. for 90 minutes under microwave irradiation. The reaction solution was diluted with ethyl acetate-tetrahydrofuran (1:1), washed twice with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (chloroform:methanol=90:10 to 0:100) to obtain 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, n-propyl alcohol was used instead of isopropyl alcohol, and the reaction and treatment were carried out in the same manner as in (131-1)-(131-2) to obtain the title compound (80 mg) as a pale yellow solid. 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)

Pivaloyl chloride (0.53 mL) was added to a solution of (S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (1.44 g) and triethylamine (0.75 mL) in tetrahydrofuran (14 mL) at -10°C to -20°C, and the mixture was stirred at -10°C for 2 hours. Sodium isopropoxide prepared from isopropyl alcohol (5 mL) and a suspension of sodium hydride (60%, 430 mg) in tetrahydrofuran (20 mL) was added to the reaction solution at -10°C, and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to water (100 mL), extracted three times with ethyl acetate (100 mL), washed twice with saturated saline, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to obtain 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 reaction and treatment were carried out in the same manner as in (129-3), to obtain the title compound (31 mg) as a pale 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]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetate (43 mg) was used instead of Example compound 129-2, and the reaction and treatment were carried out in the same manner as in (129-3), to obtain the title compound (49 mg) as a pale 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[4,3-a][1,4]benzodiazepin-4-yl]acetate (40 mg) was used instead of Example compound 129-2, and the reaction and treatment were carried out in the same manner as in (129-3) to obtain the title compound (41 mg) as a pale yellow solid. 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 reaction and treatment were carried out in the same manner as in (63-3) to give the title compound (21 mg) as a light brown solid. 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 reaction and treatment were carried out in the same manner as in (63-3) to obtain the title compound (26 mg) as a light brown solid. 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 reaction and treatment were carried out in the same manner as in (63-3) to obtain the title compound (52 mg) as a light brown solid. 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 reaction and treatment were carried out in the same manner as in (63-3) to obtain the title compound (36 mg) as a light brown solid. 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-dioxaboronane-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][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (1.47 g) was used instead of Reference Example Compound 1, and the reaction and treatment were carried out in the same manner as in (3-1) to obtain the title compound (1.73 g) 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)

To 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), N,N-diisopropylethylamine (0.061 mL) and HATU (54 mg) were added and stirred at room temperature for 0.5 hours. The reaction solution was diluted with ethyl acetate (30 mL)-tetrahydrofuran (5 mL), washed three times with half-saturated saline and once with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure.
To the obtained residue, a mixture of Example Compound 138-1 (71 mg), cesium fluoride (54 mg), water (0.5 mL), tetrahydrofuran (2.0 mL), X-Phos (6 mg), and X-Phos aminobiphenylpalladium chloride precatalyst (10 mg) was added, and the mixture was stirred at 120° C. for 30 minutes under microwave irradiation. The reaction solution was diluted with ethyl acetate (40 mL)-tetrahydrofuran (10 mL) and washed with semi-saturated saline. The aqueous layer was extracted with ethyl acetate-tetrahydrofuran (10 mL-2 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The obtained residue was purified twice by silica gel column chromatography (chloroform:methanol=98:2-95:5) to obtain 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)

A mixture of 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), and 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, extracted twice with chloroform, and the organic layers were combined, dried over anhydrous sodium sulfate, and filtered, and the solvent was removed 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 stirred at room temperature for 1 hour. The reaction solution was purified by preparative HPLC (10 mM aqueous ammonium carbonate solution-acetonitrile) to obtain 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, 4-bromo-2-chlorobenzoic acid (30 mg) was used instead of 4-bromo-2-fluorobenzoic acid, and the reaction and treatment were carried out in the same manner as in (139-1) to obtain the title compound (24 mg) 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, 4-bromo-2-methylbenzoic acid (30 mg) was used instead of 4-bromo-2-fluorobenzoic acid, and the reaction and treatment were carried out in the same manner as in (139-1) to obtain the title compound (39 mg) 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, 4-bromo-3-fluorobenzoic acid (30 mg) was used instead of 4-bromo-2-fluorobenzoic acid, and the reaction and treatment were carried out in the same manner as in (139-1) to obtain the title compound (13 mg) 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, 4-bromo-3-chlorobenzoic acid (30 mg) was used instead of 4-bromo-2-fluorobenzoic acid, and the reaction and treatment were carried out in the same manner as in (139-1) to obtain the title compound (23 mg) 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, 4-bromo-3-methylbenzoic acid (30 mg) was used instead of 4-bromo-2-fluorobenzoic acid, and the reaction and treatment were carried out in the same manner as in (139-1) to obtain the title compound (24 mg) 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]diazepin-6-yl]acetate (Example compound 145)

In Example 138, 5-bromopyridine-2-carboxylic acid (65 mg) was used instead of 4-bromo-2,3-fluorobenzoic acid, and the reaction and treatment were carried out in the same manner as in (138-2) to obtain 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]diazepin-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, and the reaction and treatment were carried out in the same manner as in (138-2), to obtain the title compound (4.2 mg) as a pale yellow solid. 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]diazepin-6-yl]acetate (Example compound 147)

In Example 138, 5-bromopyrimidine-2-carboxylic acid (80 mg) was used instead of 4-bromo-2,3-fluorobenzoic acid, and the reaction and treatment were carried out in the same manner as in (138-2) to obtain 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), and water (0.011 mL) were stirred in tetrahydrofuran (1.0 mL) under a nitrogen atmosphere and microwave irradiation at 100° C. for 0.5 hours. The reaction solution was diluted with ethyl acetate, and 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 to 0:100) to obtain 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 carbon (15 mg) was added, the reaction vessel was replaced with hydrogen, and the mixture was stirred at room temperature for 3 hours. Further, 20% palladium hydroxide 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 obtain a crude product of the 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]diazepin-6-yl]acetate (Example compound 148)

In Example 63, Example compound 148-2 (20 mg) was used instead of Example compound 63-2, and the reaction and treatment were carried out in the same manner as in (63-3) to obtain the title compound (8.7 mg) 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]diazepin-6-yl]acetate (Example compound 149)

In Example 65, t-butyl 6-bromopyridazine-3-carboxylate (283 mg) was used instead of t-butyl 5-bromopyrazine-2-carboxylate, and the reaction and treatment were carried out in the same manner as in (65-1)-(65-2) to obtain the title compound (81 mg) 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)

A mixture of 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-Phos (18 mg), and X-Phos aminobiphenylpalladium chloride precatalyst (29 mg) was heated and refluxed for 3 hours under nitrogen flow. Methyl 6-chloropyridazine-3-carboxylate (95 mg), cesium fluoride (139 mg), water (0.02 mL), X-Phos (18 mg), and X-Phos aminobiphenylpalladium chloride precatalyst (29 mg) were added to the reaction solution, and the mixture was further stirred under reflux for 2 hours. The reaction solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate water, and 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 to 95:5) and NH silica gel column chromatography (hexane:ethyl acetate=50:50 to 0:100) to give the title compound (52 mg) 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]diazepin-6-yl]acetate (Example compound 150)

To a solution of Example Compound 150-1 (50 mg) in tetrahydrofuran (1 mL) and methanol (1 mL), an aqueous solution (0.25 mL) of lithium hydroxide (7.5 mg) was added under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate, and then washed twice with saturated aqueous sodium bicarbonate. The aqueous layer was adjusted to pH 3 by adding 2N hydrochloric acid under ice-cooling, and then extracted three times with chloroform. 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 stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate (30 mL)-tetrahydrofuran (5 mL), washed three times with half-saturated saline and once with saturated saline, dried over anhydrous sodium sulfate, 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 against Cancer Cells The compounds of the present invention were evaluated in vitro for their cytotoxicity against human cancer cells. In this experiment, (+)-JQ1 (Nature volume 468, pages 1067-1073 (23 December 2010)), known to have binding inhibitory activity between BRD4 protein and its ligand, was used as a positive control. Each cell was suspended in 10% FBS/RPMI1640, seeded on a 96-well plate, and cultured overnight at 5% CO ₂ and 37° C., after which a test compound dissolved in DMSO was diluted with 10% FBS/RPMI1640 and added, followed by further culture for 96 hours. After culture, the number of viable cells was measured using a WST-8 kit for cell count measurement (Kishida Chemical). The control was measured under conditions that did not contain the test compound. Table 1 shows the cytotoxicity of the compounds of the present invention against human prostate cancer LNCaP cells as IC ₅₀ values. The _IC50 value is the compound concentration at which the cell viability is 50% when the cell viability under the compound untreated condition is taken as 100%, and was calculated from a straight line connecting the cell viability and compound concentration at two points on either side of the cell viability of 50%. Table 2 also shows the results of human acute myeloid leukemia MV-4-11 cells, human chronic myeloid 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 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 The cytotoxic activity against each cancer cell of 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-O cells, and human fibrosarcoma HT1080 cells was expressed as IC ₅₀ value. The compound of the present invention showed a strong cytotoxic effect against cancer cells.

Test Example 2
BRD4 protein degradation-inducing effect in cancer cells The degradation-inducing effect of the compound of the present invention on BRD4 protein in cancer cells was evaluated in vitro using human prostate cancer LNCaP cells. LNCaP cells were suspended in 10% FBS/RPMI1640, seeded on a 96-well Cell carrier plate (Perkin Elmer), and cultured overnight at 5% CO ₂ and 37°C, after which a test compound dissolved in DMSO was diluted with 10% FBS/RPMI1640 and added, followed by further culture for 6 hours. After culture, the cells were fixed with 4% paraformaldehyde/PBS, and further permeabilized with 0.25% Triton X-100/PBS. Thereafter, the cells were blocked with 10% BSA/PBS, and Anti-BRD4 (Sigma-Aldrich) solution was added and incubated overnight at 4°C. Further, 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) were added and incubated for 1 hour, after which 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 of the compounds of the present invention in LNCaP cells as DC ₅₀ values. The DC ₅₀ value is the compound concentration at which the fluorescence intensity is 50% when the fluorescence intensity under compound-untreated conditions is taken as 100%, and was calculated from the straight line connecting the fluorescence intensity and compound concentration at two points on either side of the 50% fluorescence intensity. The compounds of the present invention induced degradation of BRD4 protein in cancer cells at concentrations that exhibited cytostatic activity.

Test Example 3
Cytotoxicity against cancer cells that have acquired resistance to conventional BRD4 protein degradation inducers The cytotoxicity against cancer cells that have acquired resistance to conventional BRD4 protein degradation inducers was evaluated in vitro for the compounds of the present invention. 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)), which are VHL ligands linked to BRD4 protein inhibitors, were used as control conventional BRD4 protein degradation inducers. Human breast cancer MDA-MB-436 cells and MDA-MB-436 cells that have acquired resistance to conventional BRD4 protein degradation inducers (MDA-MB-436 w/o2 cells) were suspended in 10% FBS/RPMI1640, seeded on a 96-well plate, and cultured overnight at 5% CO ₂ and 37° C., after which a test compound dissolved in DMSO was diluted with 10% FBS/RPMI1640 and added, and cultured for another 96 hours. After culture, the number of live cells was measured using a WST-8 kit for cell count measurement (Kishida Chemical). Note that the control was measured under conditions that did not contain the test compound. Table 4 shows the cytotoxic activity of the compounds of the present invention against each cell type as IC ₅₀ values. Note that the IC ₅₀ value is the compound concentration at which the cell viability becomes 50% when the cell viability under compound-untreated conditions is taken as 100%, and was calculated from the straight line connecting the cell viability and compound concentration at two points on either side of the cell viability of 50%. The resistance fold was calculated 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 showed resistance to ARV-771 and MZ1, but did not show resistance to the compounds of the present invention.

Test Example 4
BRD4 protein degradation induction effect on cancer cells that have acquired resistance to conventional BRD4 protein degradation inducers The compound of the present invention was evaluated in vitro for its BRD4 protein degradation induction effect on cancer cells that have acquired resistance to conventional BRD4 protein degradation inducers. In this experiment, ARV-771 and MZ1, which are VHL ligands linked to BRD4 protein inhibitors, were used as conventional BRD4 protein degradation inducers for comparison. Human breast cancer MDA-MB-436 cells and MDA-MB-436 cells that have acquired resistance to conventional BRD4 protein degradation inducers (MDA-MB-436 w/o2 cells) were suspended in 10% FBS/RPMI1640, seeded on a 6-well plate, and cultured overnight at 5% CO ₂ and 37°C, after which a test compound dissolved in DMSO was diluted with 10% FBS/RPMI1640 and added, followed by further culture for 6 hours. After incubation, the cells were dissolved in a solubilizing solution (10 mM Tris-HCl, pH 7.4, 0.1% NP-40, 0.1% sodium deoxycholate, 0.1% SDS, 0.15 M NaCl, 1 mM EDTA, 10 μg/mL aprotinin). Electrophoresis was performed on the lysate, and the proteins in the acrylamide gel were transferred to an Immobilon PVDF membrane using a semi-dry transfer device. After transfer, the membrane was blocked and immersed in a primary antibody solution (Anti-BRD4: Sigma-Aldrich, Anti-β-Actin antibody: Sigma-Aldrich) overnight at 4°C. After immersion in a secondary antibody solution for 1 hour, the target protein on the membrane was detected using the 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
Inhibitory effect of the binding of BRD4 protein to its ligand acetylated histone H4 The inhibitory effect of the compound of the present invention on the binding of BRD4 protein to its ligand acetylated histone H4 was evaluated by time-resolved fluorescence resonance energy transfer (TR-FRET) using EPIgeneous ^TM Binding Domain Kit A (Cisbio), BRD4-1(GST) (Reaction Biology Corp) and [Lys(Ac)5/8/12/16]-Histone H4(1-21)-GGK(Biotin) (Eurogentec). In this experiment, (+)-JQ1 (Nature volume 468, pages 1067-1073 (23 December 2010)), which is known to have inhibitory activity on the binding of BRD4 protein to its acetylated histone H4, was used as a positive control. The test compound dissolved in DMSO was diluted with the attached Diluent Buffer and added to a 384-well white plate, and BRD4-1 (GST) and [Lys (Ac) 5/8/12/16]-Histone H4 (1-21)-GGK (Biotin) were further added. Then, Streptavidin-d2 conjugate and Anti-GST-Eu ³⁺ Cryptate Conjugate were added and incubated at room temperature for 3 hours, and the binding amount of BRD4 protein and acetylated histone H4 was measured as fluorescence intensity (excitation: 314 nm/emission: 620 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 (the concentration of the compound that inhibits the binding of BRD4 protein and acetylated histone H4 by 50%). The _IC50 value is the compound concentration at which the fluorescence intensity is 50% when the fluorescence intensity without the compound is taken as 100%, and was calculated from the straight line connecting the decomposition rate and compound concentration at two points on either side of the 50% fluorescence intensity. The compound of the present invention showed a strong inhibitory effect on the binding of BRD4 protein to the ligand.

Test Example 6
Antitumor effect in mice transplanted with human acute myeloid leukemia MV-4-11 cells The in vivo antitumor effect of the compound of the present invention was examined using mice transplanted with human acute myeloid leukemia MV-4-11 cells. After transplanting MV-4-11 cells subcutaneously in the inguinal region of 6-week-old male BALB/c nude mice (5 x 10 ⁶ cells/mouse), the compound of the present invention was administered into the tail vein on days 1, 5, 9, and 13 from the time when the estimated tumor volume calculated from 1/2ab ² (a is the long axis of the tumor, b is the short axis) reached about 100 mm ³ (day 1). The control group was administered a 20% hydroxypropyl-β-cyclodextrin solution as a solvent. On day 15, 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 treated group/average tumor weight of untreated control group)} x 100 (%)
As a result, as shown in Table 6 and FIG. 2, it was demonstrated that the compound of the present invention exhibits an antitumor effect in mice transplanted with human acute myeloid leukemia MV-4-11 cells.

Test Example 7
Antitumor effect of one week intermittent administration in mice transplanted with human acute myeloid leukemia MV-4-11 cells The in vivo antitumor effect of the compound of the present invention was examined using mice transplanted with human acute myeloid leukemia MV-4-11 cells. After MV-4-11 cells were transplanted subcutaneously in the inguinal region of 6-week-old male BALB/c nude mice (5 x 10 ⁶ cells/mouse), the compound of the present invention was administered into the tail vein on days 1 and 8 from the time when the estimated tumor volume calculated from 1/2ab ² (a is the long axis of the tumor, b is the short axis) reached about 200 mm ³ (day 1). The control group was administered a solvent solution of 10% Kolliphor ELP/5% ethanol/85% saline. On day 15, 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 treated group/average tumor weight of untreated control group)} x 100 (%)
As a result, as shown in Table 7, it was demonstrated that the compound of the present invention exhibited an antitumor effect even when administered intermittently for one week in mice implanted with human acute myeloid leukemia MV-4-11 cells.

Test Example 8
Maximum Tolerated Dose The maximum tolerated dose (MTD) of the compound of the present invention in rats was determined. In this experiment, a control compound 157 (PCT/JP2019/026553) in which a VHL ligand and a BRD4 protein inhibitor are linked was used as a conventional BRD4 protein degradation inducer for comparison. The compound of the present invention or compound 157 was administered once via the tail vein to male, 6-week-old CD (SD) rats, and the general condition was observed to determine the MTD.
As a result, as shown in Table 8, the compounds of the present invention showed improved MTD compared to BRD4 protein degradation inducers that utilize VHL ligands.

The compound of the present invention has excellent BRD4 protein degradation inducing activity, and therefore a pharmaceutical composition containing the compound is useful as a cancer treatment agent.

Claims (17)

Formula (I):

[Wherein,
A represents a ring selected from an aromatic hydrocarbon ring , a 5- to 6-membered aromatic heterocycle containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen, and a cycloalkane ring ;
The ring is
Halogen atoms;
Hydroxy group;
Cyano group;
Hydroxycarbonyl group;
oxo group;
Thioxo group;
an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
an alkoxy group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
an alkoxycarbonyl group optionally substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
-CO-N(R ^7a )(R ^7b );
-N(R ^7a )(R ^7b ); and -N(R ^7c )-CO-R ^7d ;
may be substituted with a group selected from
Partial structure:

is expressed by the following formula:

[Wherein,
R ^a represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
R ^a′ represents a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; or —CO—N(R ^7a )(R ^7b ),
R ^a″ represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; or —CO—N(R ^7a )(R ^7b ).
is shown in
R ^Z3 represents a group selected from a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; a hydroxycarbonyl group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; a cycloalkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxy ...carbonyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
R ^Z4 and R ^Z5 each independently represent a group selected from a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
Partial structure:

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

indicates ,
Partial structure:

teeth,

indicates,
L represents a group selected from a divalent aromatic hydrocarbon group; a divalent aliphatic heterocyclic group; a divalent aromatic heterocyclic group which may be partially hydrogenated; an alkylene group; a cycloalkylene group; an alkenylene group; and an alkynylene group;
the group is optionally substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; a hydroxycarbonyl group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
T represents a single bond, —CO—, —CO—NR ^7c —, —NR ^7c —CO—, or —O—;
an alkylene group optionally substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; an oxo group; a hydroxycarbonyl group; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and an alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
M represents a single bond;
-O-;-S-;-NR ^7a -;-CO-;-SO-;-SO ₂ -;-CO-NR ^7c -;-NR ^7c -CO-;-SO ₂ -NR ^7c -;-NR ^7c -SO ₂ -;-NR ^7a -CO-NR ^7b -;-(OCH ₂ CH ₂ ) _m -;-O-R ^7r -;-R ^7r -O-;-S-R ^7r -;-R ^7r -S-;-NR ^7a -R ^7r -;-R ^7r -NR ^7a -;-CO-NR ^7c -R ^7r -;-R ^7r -CO-NR ^7c -; an alkylene group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkynylene group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and a divalent aliphatic heterocyclic group which may be substituted with a substituent selected from a) a halogen atom, b) a hydroxy group, c) a cyano group, d) an oxo group, e) an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group, and f) an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
- L-T-M- does not represent, as the whole or a part of the structure, a group selected from -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- ,
Further substructure:

teeth,

indicates ,
n represents 1 or 2;
m represents an integer from 1 to 6;
^R5 represents a hydrogen atom;
R ^6a and R ^6b each independently represent a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; or an alkyl group which may be substituted by a group selected from a halogen atom, a hydroxy group, and a cyano group;
R ^7a and R ^7b each independently represent a hydrogen atom; or an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
R ^7a and R ^7b bonded to the same nitrogen atom may be bonded to form, together with the nitrogen atom, an aliphatic heterocycle containing one nitrogen atom which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group;
R ^7c represents a hydrogen atom;
R ^7d represents a hydrogen atom; or an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
^R7r represents a group selected from an alkylene group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkenylene group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; or an alkynylene group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group;
R ^8a and R ^8b each independently represent a group selected from a hydrogen atom; a halogen atom; a hydroxy group; and a cyano group;
R ^9a and R ^9b each independently represent a group selected from a hydrogen atom; a halogen atom ; a cyano group ; and an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxyl group, and a cyano group ;
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
optionally substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; a hydroxycarbonyl group ; and -CO-N(R ^7a )(R ^7b );
R ¹¹ represents a group selected from a hydrogen atom; and an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group.
A pharmaceutical composition comprising a compound represented by the formula: or a pharma- ceutically acceptable salt thereof. A is a ring selected from a benzene ring; a pyridine ring; and a cycloalkane ring;
R ^a represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^a′ represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^a″ represents a hydrogen atom; a halogen atom; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; or a cyano group;
R ^Z3 represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a cycloalkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; or an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group;
R ^Z4 and R ^Z5 each independently represent a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
Partial structure:

is expressed by the following formula (Ea):

indicates,
L is a group selected from an alkynylene group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a divalent aromatic hydrocarbon group which may be substituted with a substituent selected from a) a halogen atom, b) a hydroxy group, c) a cyano group, d) an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, and e) an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a divalent aliphatic heterocyclic group containing one nitrogen atom which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and a divalent aromatic heterocyclic group which may be partially hydrogenated and contains 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom;
the aromatic heterocyclic group may be substituted with a substituent selected from a halogen atom, a hydroxy group, a cyano group, and an oxo group;
T represents a single bond; -CO-; -CO-NR ^7c -; -NR ^7c -CO-; or -O-;
M is a single bond,
a group selected from -R ^7r -O-; -R ^7r -NR ^7a -; an alkylene group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; an alkynylene group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and a divalent aliphatic heterocyclic group;
R ^6a and R ^6b are each independently a group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^7a and R ^7b each independently represent a hydrogen atom; or an alkyl group which may be substituted by a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^7c represents a hydrogen atom;
R ^7d represents an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group;
R ^7r represents an alkylene group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^8a and R ^8b are both hydrogen atoms;
R ^9a and R ^9b each independently represent an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
R ^10a is a group selected from a hydrogen atom; and an alkyl group which may be substituted with 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;
R ^10b is a hydrogen atom;
R ¹¹ is an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group;
The pharmaceutical composition of claim 1 . R ^a represents a hydrogen atom or an alkyl group;
R ^a' represents a hydrogen atom or an alkyl group;
R ^a″ represents a hydrogen atom; a halogen atom; an alkyl group; or a cyano group;
R ^Z3 represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom and a hydroxy group; a cycloalkyl group; or an alkoxy group;
^R and ^R each independently represent a hydrogen atom or an alkyl group;
Partial structure:

is expressed by the following formula (Ea):

indicates,
L is a group selected from an alkynylene group; a divalent aromatic hydrocarbon group which may be substituted with 1 to 2 substituents selected from a halogen atom, a hydroxy group, an alkyl group which may be substituted with 1 to 3 halogen atoms, and an alkoxy group; a divalent aliphatic heterocyclic group containing one nitrogen atom; and a divalent aromatic heterocyclic group which may be partially hydrogenated and contains 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom;
When the aromatic heterocyclic group is a partially hydrogenated divalent aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, it may be substituted with an oxo group.
T is a single bond or
-CO-; -CO-NR ^7c -; -NR ^7c -CO-; or -O-;
M is a single bond,
a group selected from ^-R7r -O-; ^-R7r - ^NR7a- ; an alkylene group which may be substituted with one hydroxy group; an alkynylene group; and a divalent aliphatic heterocyclic group;
R ^6a and R ^6b are each independently a group selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group;
R ^7a and R ^7b are each independently a hydrogen atom; or an alkyl group;
R ^7c is a hydrogen atom;
R ^7d is an alkyl group;
R ^7r is an alkylene group;
R ^8a and R ^8b are both hydrogen atoms;
R ^9a and R ^9b each independently represent an alkyl group optionally substituted with one hydroxy group;
R ^10a is a group selected from a hydrogen atom; and an alkyl group optionally 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;
R ^10b is a hydrogen atom;
R ¹¹ is an alkyl group;
The pharmaceutical composition of claim 1 . 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 group selected from a divalent aromatic hydrocarbon group which may be substituted with 1 to 2 substituents selected from a halogen atom, an alkyl group which may be substituted with 1 to 3 halogen atoms, and an alkoxy group; and a divalent aromatic heterocyclic group which may be partially hydrogenated and contains 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom;
M is an alkylene group optionally substituted with one substituent selected from a hydroxy group and a cyano group;
The pharmaceutical composition of claim 1 . R ^a′ represents a hydrogen atom;
R ^a″ represents a cyano group;
R ^Z3 represents an alkyl group which may be 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 of claim 1 . R ^8a and R ^8b are both hydrogen atoms;
R ^9a and R ^9b each independently represent 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 of claim 1 . 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 of claim 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,
methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methoxy-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-{4'-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2'-fluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]-2'-fluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-{2'-chloro-4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-3'-methyl[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
t-butyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
t-butyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-3'-fluoro[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(3'-chloro-4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
5-chloro-N-({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)-2-fluoro-4'-[(6S)-2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl][1,1'-biphenyl]-4-carboxamide,
methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2',3'-difluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-2'-fluoro[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl {(6S)-4-[4-(6-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyridin-3-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate,
methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-2',5'-difluoro[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-2'-fluoro-5'-methyl[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-2',3'-difluoro[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]-2',3'-difluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazin-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate,
methyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazin-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate,
methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl {(6S)-4-[4-(6-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyridin-3-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate,
methyl [(6S)-4-(4-{6-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-{4'-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2',3'-difluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
Methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, and t-butyl 2. A pharmaceutical composition comprising a compound selected from [(6S)-4-(4-{5-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate, or a pharma- ceutically 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]diazepin-6-yl]acetate,
methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-{4'-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-{2'-chloro-4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
t-butyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
t-butyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-3'-fluoro[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
5-chloro-N-({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)-2-fluoro-4'-[(6S)-2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl][1,1'-biphenyl]-4-carboxamide,
methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2',3'-difluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl {(6S)-4-[4-(6-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyridin-3-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate,
methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazin-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate,
methyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazin-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate,
methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate,
methyl {(6S)-4-[4-(6-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyridin-3-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate, and methyl A pharmaceutical composition comprising a compound selected from [(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 pharma- ceutical composition comprising a pharma-ceutical acceptable salt thereof. 2. A pharmaceutical composition comprising 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, or a pharma- ceutical composition comprising a pharma-ceutical acceptable salt thereof. 2. A pharmaceutical composition comprising 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, or a pharma- ceutical composition comprising a pharma-ceutical acceptable salt thereof. A pharmaceutical composition comprising 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, or a pharma- ceutical composition comprising a pharma-ceutical acceptable salt thereof. The pharmaceutical composition according to any one of claims 1 to 12 , for inducing degradation of BRD4 protein. The pharmaceutical composition according to any one of claims 1 to 12 for treating cancer. The pharmaceutical composition according to claim 14, wherein the cancer is selected from acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, diffuse large B-cell lymphoma, adult T-cell leukemia/lymphoma, Burkitt's lymphoma, prostate cancer, ovarian cancer, bladder cancer, breast cancer, cervical cancer, uterine sarcoma, gastric cancer, lung cancer, colorectal cancer, glioma, pancreatic cancer, liver cancer, bile duct cancer, renal cell carcinoma, and fibrosarcoma . The pharmaceutical composition according to claim 14, wherein the cancer is selected from acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, diffuse large B-cell lymphoma, multiple myeloma, Burkitt's lymphoma, glioma, gastric cancer, colon cancer, pancreatic cancer, liver cancer, prostate cancer, non-small cell lung cancer, breast cancer, ovarian cancer and uterine sarcoma. The pharmaceutical composition according to claim 14 , wherein the cancer is selected from acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, prostate cancer, ovarian cancer and breast cancer.