Sulfonamide or sulfenamide compound having the effect of inducing BRD4 protein degradation and its pharmaceutical use

Abstract

The present invention provides a compound or a pharmaceutically acceptable salt thereof, which is excellent in inducing BRD4 protein degradation and is useful as a therapeutic agent for cancer: A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, wherein each symbol is as defined in the specification.

Description

Technical Field

[0001] The present invention relates to a sulfonamide or sulfenamide compound or a pharmaceutically acceptable salt thereof, which is excellent in cytotoxic effect on cancer cells, effect of inducing BRD4 protein decomposition in cancer cells, and inhibitory effect on the binding of BRD4 protein to acetylated histones, and can be used as an anticancer drug, BRD4 protein decomposition inducer or BRD4 protein inhibitor. Background Art

[0002] Eukaryotic DNA forms a chromatin structure and is stored in the cell nucleus. The nucleosome, which is its structural unit, has the following structure, wherein DNA is wrapped around a histone octamer formed by two molecules of each of the four histones (H2A, H2B, H3, H4). Many residues on the N-terminal side of the histone are called histone tails, in which there are various post-translational modifications, such as acetylation, methylation, phosphorylation, and ubiquitination. Post-translational modification, also known as histone coding, is one of the mechanisms responsible for controlling epigenetic gene expression, which determines when or where the genetic information on the DNA is expressed. Histone modification is reversible and functional control is performed by modifying enzymes (writers) that write modifying groups into histones, removing demodifying enzymes (erasers) that remove modifying groups, and histone readers (readers) that specifically read the modified histones. This control mechanism is known to contribute greatly to individual development and cell differentiation, and epigenetic abnormalities are associated with various diseases.

[0003] Bromodomain is a reader protein consisting of about 110 amino acids that recognize the acetylated lysine of histones. So far, about 50 kinds of proteins with bromodomains are known, which are used as scaffold proteins for various transcription factors by binding to the acetylated lysine of histones, and also show various functions in cells, such as being responsible for chromatin remodeling and transcriptional regulation by their own histone acetyltransferase activity and kinase activity. BRD2, BRD3, BRD4 and BRDT included in the BET (bromodomain and terminal) family proteins (sometimes referred to as "BET proteins" in this specification and claims) of proteins containing bromodomains have two highly conserved bromodomains on the N-terminal side in the family and have additional C-terminal domains on the C-terminal side, and each BET protein is known to function independently and synergistically (non-patent literature 1).

[0004] Among the BET family proteins, BRD4 is expected to be a target for drug discovery in cancer treatment because it regulates the expression of c-MYC, a proto-oncogene (Non-Patent Document 2), and has been reported to be correlated with the prognosis of various cancers, 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 cancer (Non-Patent Document 8), skin cancer (Non-Patent Document 9), prostate cancer (Non-Patent Document 10), breast cancer (Non-Patent Document 11), colorectal cancer (Non-Patent Document 12), and leukemia (Non-Patent Document 13).

[0005] So far, clinically, BRD4 inhibitors that inhibit BRD4 from being bound to histones have been developed as anticancer drugs targeting BRD4 (non-patent literature 14). However, BRD4 inhibitors do not show sufficient effects because they cause the accumulation of BRD4 (non-patent literature 15), and resistance is obtained by expressing proteins that stabilize BRD4 expression and by enhancing the transcriptional activity of BRD4 mediation in a bromodomain-independent manner (bromodomain-independent). Therefore, it is necessary to develop a kind of anticancer drug targeting BRD4 by a new method.

[0006] In recent years, a technique has been used in which an artificial complex of an E3 ligase and a target protein is formed in a cell by using a compound (a compound that connects a ligand of an E3 ligase having ubiquitin ligase activity [Von Hippel-Lindau (VHL), Cereblon (CRBN), inhibitor of apoptosis 1 (cIAP1)] to a binder that binds to a target protein) and inducing the degradation of the target protein (which is an intracellular protein degradation mechanism) by using the ubiquitin-proteasome system (chemical knockdown) has attracted attention as a drug discovery technique (non-patent document 18). To date, as BRD4 protein degradation inducers using this technology, ARV-771 using a ligand for VHL, ARV-825 using a ligand for CRBN, etc. have been reported (non-patent documents 15, 19).

[0007] In cancer chemotherapy, when long-term continuous use of anticancer drugs, the emergence of acquired resistance that makes anticancer drugs invalid from the beginning of treatment and reduces anticancer drug effect becomes a major problem (non-patent literature 20). By overcoming the resistance of anticancer drugs, it is expected that the treatment result of cancer chemotherapy will be improved, and the existence of various resistance mechanisms has been elucidated so far (non-patent literature 20). About BRD4 protein decomposition inducer, it has been reported that the protein decomposition effect is caused by the abnormal function of the complex of E3 ligase VHL or CRBN, thereby inducing acquired resistance (non-patent literature 21) in cancer cells. In the tumor such as renal cell carcinoma etc. caused by VHL gene mutation (non-patent literature 22), it is believed that the natural resistance to the BRD4 protein decomposition inducer using the part of VHL occurs, and it is necessary to develop a new part for E3 ligase and overcome the novel BRD4 protein degradation inducer of the resistance to conventional BRD4 protein degradation inducer. In recent years, a lot of compounds that induce the decomposition of target proteins have been reported, in which new ligands for E3 ligases and binding substances for target proteins are combined (non-patent literature 23). For example, a BRD4 protein decomposition inducer using the new E3 ligase DCAF15 has been reported (non-patent literature 24). However, it is difficult to say that its BRD4 protein decomposition induction and cytotoxicity are sufficient. At present, the combination of the ligand of the E3 ligase and the binding substance of the target protein is limited (non-patent literature 23), and it is expected to find a combination of a suitable ligand and a linker structure of the E3 ligase, which combination needs to show a BRD4 protein decomposition induction and cytotoxicity sufficient as an anticancer drug for the binding substance of the BRD4 protein.

[0008] Prior art literature

[0009] Non-patent literature

[0010] Non-patent document 1: Taniguchi Y., Int J Mol Sci. 2016, 17: E1849 Non-patent document 2: Kanno T., Nat Struct Mol Biol. 2014, 21: 1047-1057

[0011] Non-patent literature 3: Zhu Y., Oncotarget. 2017, 8: 31092-31100

[0012] Non-patent literature 4: Ucar D., Mol Clin Oncol. 2015, 3: 1291-1294

[0013] Non-patent literature 5: Liao YF., Oncotarget. 2016, 7: 9491-9500

[0014] Non-patent document 6: Zhang P., Int J Immunopathol Pharmacol. 2015, 28: 36-44

[0015] Non-patent document 7: Yan Y., Int J Clin Exp Pathol. 2014, 7: 4231-4238

[0016] Non-patent literature 8: Stathis A., Cancer Discov. 2016, 6: 492-500

[0017] Non-patent document 9: Segura MF., Cancer Res. 2013, 73: 6264-6276

[0018] Non-patent literature 10: Dai X., Nat Med. 2017, 23: 1063-1071

[0019] Non-Patent Document 11: Crawford NP., Proc Natl Acad Sci US A. 2008, 105: 6380-6385

[0020] Non-Patent Literature 12: Hu Y., Int J Mol Sci. 2015, 16: 1928-1948

[0021] Non-Patent Literature 13: Herrmann H., Oncotarget. 2012, 3: 1588-1599

[0022] Non-patent literature 14: Liu Z., J Med Chem. 2017, 60: 4533-4558

[0023] Non-patent literature 15: Lu J., Chem Biol. 2015, 22: 755-763

[0024] Non-patent literature 16: Dai X., Nat Med. 2017, 23: 1063-1071

[0025] Non-Patent Literature 17: Shu S., Nature. 2016, 529: 413-417

[0026] Non-Patent Literature 18: Toure M., Angew Chem Int Ed Engl. 2016, 55: 1966-1973

[0027] Non-Patent Literature 19: Raina K., Proc Natl Acad Sci US A. 2016, 113: 7124-7129

[0028] Non-Patent Literature 20: Neil V., Nature. 2019, 575: 299-309

[0029] Non-Patent Literature 21: Zhang L., Mol Cancer Ther. 2019, 18: 1302-1311.

[0030] Non-patent document 22: Iliopoulos O., Nat Med. 1995, 1: 822-826.

[0031] Non-Patent Literature 23: Schapira M., Nat Rev Drug Discov. 2019, 18: 949-963.

[0032] Non-Patent Literature 24: Li L., Signal Transduct Target Ther. 2020, 5:129. Summary of the Invention

[0033] Technical issues

[0034] An object of the present invention is to provide a compound or a pharmaceutically acceptable salt thereof which is a ligand for the E3 ligase DCAF15, has an excellent effect of inducing BRD4 protein degradation, and is useful as a therapeutic agent for cancer.

[0035] Technical solutions to the problem

[0036] The inventors of the present application conducted intensive research in an effort to address the aforementioned issues and discovered a compound that acts as a ligand for the E3 ligase DCAF15 and induces BRD4 protein degradation, potentially providing a therapeutic agent for cancer. The inventors of the present application discovered a linker structure that is particularly preferred for DCAF15 ligands and completed the present invention. The summary of the present invention is as follows.

[0037] [1] a compound represented by formula (I) or a pharmaceutically acceptable salt thereof (sometimes abbreviated as "Compound (I)" in this specification),

[0038]

[0039] in,

[0040] A and Q are each independently a ring selected from the group consisting of: an aromatic hydrocarbon ring; an aromatic heterocyclic ring containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen; a cycloalkane ring; and an aliphatic heterocyclic ring containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen;

[0041] The ring is optionally substituted with a group selected from:

[0042] halogen atoms;

[0043] hydroxyl group;

[0044] cyano group;

[0045] Hydroxycarbonyl;

[0046] Oxo group;

[0047] thio group;

[0048] an alkyl group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group;

[0049] an alkoxy group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group;

[0050] an alkoxycarbonyl group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group;

[0051] -CO-N(R 7a )(R 7b );

[0052] -N(R 7a )(R 7b );and

[0053] -N(R 7c )-CO-R 7d ;

[0054] Z 1 is a group selected from C and N,

[0055] Z 2 is a group selected from C and N,

[0056] Z 3 =CR Z3 - and =N-,

[0057] Z 4 =CR Z4 - and =N-,

[0058] Z 5 =CR Z5 - and =N-,

[0059] R Z3 、RZ4 and R Z5 are each independently a group selected from the following:

[0060] a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; a hydroxycarbonyl group; an alkyl group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; a cycloalkyl group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; an alkoxycarbonyl group optionally substituted by a group selected from a halogen atom, a hydroxyl 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-membered or 6-membered aromatic heterocyclic group containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen;

[0061] Partial structure:

[0062]

[0063] is any one of the following formulas (Ea), (Eb) and (Ec):

[0064]

[0065] L, T and M are each independently:

[0066] single bond,

[0067] A group selected from the following: -O-, -S-, -NR 7a -, -CO-, -SO-, -SO2-, -CO-NR 7c -、-NR 7c -CO-, -SO2-NR 7c -、-NR 7c -SO2-、-NR 7a -CO-NR 7b -、-(OCH2CH2) m -、-OR 7r -、-R 7r -O-, -SR 7r -、-R 7r -S-, -NR 7a -R 7r -、-R 7r -NR 7a -、-CO-NR 7c -R 7r -、-R 7r -CO-NR7c -、-SO2-NR 7c -R 7r -and-R 7r -SO2-NR 7c -;or

[0068] a group selected from the group consisting of a divalent aromatic hydrocarbon group, a divalent aliphatic heterocyclic group, an optionally partially hydrogenated divalent aromatic heterocyclic group, an alkylene group, a cycloalkylene group, an alkenylene group, and an alkynylene group;

[0069] The group is optionally substituted with a substituent selected from the group consisting of: a halogen atom; a hydroxyl group; a cyano group; an oxo group; a hydroxycarbonyl group; an alkyl group optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; and an alkoxy group optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group;

[0070] As a whole or part of the structure, -LTM- does not represent a structure selected from -OO-, -SS-, -NR 7a -NR 7a -、-OS-、-SO-、-O-NR 7a -、-NR 7a -O-、-S-NR 7a -and-NR 7a -S- group,

[0071] G is N or C,

[0072] J is N or O,

[0073] Partial structure

[0074]

[0075] is a partial structure selected from the following:

[0076]

[0077] n is 1 or 2,

[0078] m is an integer from 1 to 6,

[0079] R 5 is a group selected from the following: a hydrogen atom; and an alkyl group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group;

[0080] R 6a and R 6b are each independently a group selected from the following: a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; an alkyl group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; and an alkoxy group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group;

[0081] R 7a and R 7b are each independently a hydrogen atom; or an alkyl group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group, or,

[0082] Optionally, R bonded to the same nitrogen atom 7a and R 7b is bonded to form, together with the nitrogen atom, an aliphatic heterocyclic ring having 1 nitrogen atom and optionally substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group,

[0083] R 7c and R 7d are each independently a hydrogen atom; or an alkyl group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group,

[0084] R 7r is a group selected from the following: an alkylene group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; an alkenylene group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; or an alkynylene group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group,

[0085] R 8a and R 8b are each independently a group selected from the following: a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; an alkyl group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; and an alkoxy group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group;

[0086] R 9a and R 9b are each independently a group selected from the following: a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; a hydroxycarbonyl group; an alkyl group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; an alkoxy group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; an alkoxycarbonyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; and -CO-N(R 7a )(R 7b ),or,

[0087] R 9a and R 9b is optionally connected to represent an alkylene group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; or an alkenylene group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group, and optionally forms a condensed ring with the adjacent ring E,

[0088] R10a and R 10b Each is independently a substituent selected from the following: hydrogen atom, hydroxyl group, cyano group, -N(R 7a )(R 7b )、-N(R 7c )-CO-OR 7d and alkyl;

[0089] The alkyl group is optionally substituted with a substituent selected from the group consisting of: a halogen atom; a hydroxyl group; a cyano group; an alkoxy group optionally substituted with a substituent selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; an alkoxycarbonyl group optionally substituted with a substituent selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; a hydroxycarbonyl group; and -CO-N(R 7a )(R 7b );or,

[0090] R 10a and R 10b are optionally linked to represent an alkylene group optionally substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group, and form a ring,

[0091] R 11 is a group selected from the group consisting of a hydrogen atom; and an alkyl group optionally substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group.

[0092] [2] [1] The compound or a pharmaceutically acceptable salt thereof, wherein:

[0093] Partial structure

[0094]

[0095] It is expressed by the following formula:

[0096]

[0097] in,

[0098] R a is a hydrogen atom; or an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group;

[0099] R a’ is a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; an alkoxycarbonyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; or -CO-N(R 7a )(R 7b ),

[0100] R a”is a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; an alkoxycarbonyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; or -CO-N(R 7a )(R 7b ).

[0101] [3] [2] or a pharmaceutically acceptable salt thereof, wherein:

[0102] A is a ring selected from the group consisting of an aromatic hydrocarbon ring, a 5-membered or 6-membered aromatic heterocyclic ring containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen, and a cycloalkane ring,

[0103] R Z3 is a group selected from the following: a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; a hydroxycarbonyl group; an alkyl group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; a cycloalkyl group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; an alkoxy group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; an alkoxycarbonyl group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group;

[0104] R Z4 and R Z5 are each independently a group selected from the following: a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; an alkoxy group optionally substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group;

[0105] Partial structure:

[0106]

[0107] It is represented by the following formula (Ea) or (Ec):

[0108]

[0109] Partial structure

[0110]

[0111] It is expressed by the following formula:

[0112]

[0113] Partial structure

[0114]

[0115] It is expressed by the following formula:

[0116]

[0117] L is a group selected from the group consisting of a divalent aromatic hydrocarbon group, a divalent aliphatic heterocyclic group, an optionally partially hydrogenated divalent aromatic heterocyclic group, an alkylene group, a cycloalkylene group, an alkenylene group, and an alkynylene group;

[0118] The group is optionally substituted with a substituent selected from the group consisting of: a halogen atom; a hydroxyl group; a cyano group; a hydroxycarbonyl group; an alkyl group optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; and an alkoxy group optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group.

[0119] T is a single bond, -CO-, or -CO-NR 7c -、-NR 7c -CO- or -O- or an alkylene group optionally substituted by a substituent selected from the group consisting of: a halogen atom; a hydroxyl group; a cyano group; an oxo group; a hydroxycarbonyl group; an alkyl group optionally substituted by a substituent selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; and an alkoxy group optionally substituted by a substituent selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group and a cyano group;

[0120] M is a single bond, or

[0121] A group selected from the following: -O-; -S-; -NR 7a -;-CO-;-SO-;-SO2-;-CO-NR 7c -;-NR 7c -CO-;-SO2-NR 7c -;-NR 7c -SO2-;-NR 7a -CO-NR 7b -;-(OCH2CH2) m -;-OR 7r -;-R 7r -O-;-SR 7r -;-R 7r -S-;-NR 7a -R 7r -;-R 7r -NR 7a -;-CO-NR 7c -R 7r -;-R 7r -CO-NR 7c-; an alkylene group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; an alkynylene group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; and a divalent aliphatic heterocyclic group optionally substituted by a substituent selected from a) a halogen atom, b) a hydroxyl group, c) a cyano group, d) an oxo group, e) an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group, and f) an alkoxy group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group,

[0122] R 5 is a hydrogen atom,

[0123] R 6a and R 6b are each independently a group selected from the following: a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; and an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group;

[0124] R 7c is a hydrogen atom,

[0125] 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;

[0126] R 9a and R 9b are each independently a group selected from the following: a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group;

[0127] R 10a and R 10b are each independently a substituent selected from the following: a hydrogen atom, -N(R 7c )-CO-OR 7d and alkyl;

[0128] The alkyl group is optionally substituted by a substituent selected from the group consisting of: a halogen atom; a hydroxyl group; a cyano group; an alkoxy group optionally substituted by a substituent selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; an alkoxycarbonyl group optionally substituted by a substituent selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; -CO-N(R 7a )(R 7b ); and hydroxycarbonyl.

[0129] [4] The compound of [2] or [3] or a pharmaceutically acceptable salt thereof, wherein A is a ring selected from the group consisting of a benzene ring; a pyridine ring; and a cycloalkane ring,

[0130] R ais a hydrogen atom; or an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0131] R a’ is a hydrogen atom; or an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0132] R a” is a hydrogen atom; a halogen atom; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group; or a cyano group,

[0133] R Z3 is a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group; a cycloalkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group; or an alkoxy group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0134] R Z4 and R Z5 are each independently a hydrogen atom; or an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0135] Partial structure

[0136]

[0137] It is represented by the following formula (Ea):

[0138]

[0139] L is a group selected from the group consisting of an alkynylene group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; a divalent aromatic hydrocarbon group optionally substituted with a substituent selected from the group consisting of a) a halogen atom, b) a hydroxyl group, c) a cyano group, d) an alkyl group optionally substituted with a substituent selected from the group consisting of a halogen atom, a hydroxyl group, and a cyano group, and e) an alkoxy group optionally substituted with a substituent selected from the group consisting of a halogen atom, a hydroxyl group, and a cyano group;

[0140] a divalent aliphatic heterocyclic group containing one nitrogen atom, which is optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group; and

[0141] a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms and optionally partially hydrogenated,

[0142] The aromatic heterocyclic group is optionally substituted by a substituent selected from a halogen atom, a hydroxyl group, a cyano group and an oxo group,

[0143] T is a single bond, -CO-, or -CO-NR 7c -、-NR 7c -CO- or -O-,

[0144] M is a single bond, or a group selected from the following: -R 7r -O-;-R 7r -NR 7a -; an alkylene group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group; an alkynylene group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group; and a divalent aliphatic heterocyclic group,

[0145] R 6a and R 6b are each independently a group selected from the group consisting of a hydrogen atom; a halogen atom; a cyano group; and an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0146] R 7a and R 7b are each independently a hydrogen atom; or an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0147] R 7c is a hydrogen atom,

[0148] R 7d is an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0149] R 7r is an alkylene group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group, R 8a and R 8b are hydrogen atoms,

[0150] R 9a and R 9b are each independently an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0151] R 10a is a group selected from the following: a hydrogen atom; and optionally selected from a halogen atom, a hydroxyl group, a cyano group, a -NH-CO-OR 7d 、-CO-N(R 7a )(R 7b ), an alkyl group substituted with a substituent of an alkoxycarbonyl group and a hydroxycarbonyl group,

[0152] R 10b is a hydrogen atom,

[0153] R 11 is an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group.

[0154] [5] The compound or pharmaceutically acceptable salt thereof according to any one of [2] to [4], wherein

[0155] R a is a hydrogen atom or an alkyl group,

[0156] R a’ is a hydrogen atom or an alkyl group,

[0157] R a” is a hydrogen atom, a halogen atom, an alkyl group or a cyano group,

[0158] R Z3 is a hydrogen atom, a halogen atom, a cyano group, an alkyl group, a cycloalkyl group or an alkoxy group optionally substituted with 1 to 3 substituents selected from halogen atoms and hydroxyl groups,

[0159] R Z4 and R Z5 are each independently a hydrogen atom; or an alkyl group,

[0160] Partial structure:

[0161]

[0162] It is represented by the following formula (Ea):

[0163]

[0164] L is a group selected from the following: an alkynylene group; a divalent aromatic hydrocarbon group optionally substituted by 1 to 2 substituents selected from a halogen atom, a hydroxyl group, an alkyl group optionally substituted by 1 to 3 halogen atoms, and an alkoxy group; a divalent aliphatic heterocyclic group containing 1 nitrogen atom; and a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and optionally partially hydrogenated,

[0165] When the aromatic heterocyclic group is a partially hydrogenated divalent aromatic heterocyclic group containing 1 to 2 atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, it is optionally substituted with an oxo group.

[0166] T is a single bond or -CO-, -CO-NR 7c -、-NR 7c -CO-, or -O-,

[0167] M is a single bond, or a group selected from the following: -R 7r -O-、-R 7r -NR 7a -, an alkylene group, an alkynylene group and a divalent aliphatic heterocyclic group optionally substituted by 1 hydroxyl group,

[0168] R 6a and R 6b are each independently a group selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, and an alkyl group,

[0169] R 7aand R 7b are each independently a hydrogen atom or an alkyl group,

[0170] R 7c is a hydrogen atom,

[0171] R 7d is an alkyl group,

[0172] R 7r is an alkylene group,

[0173] R 8a and R 8b are hydrogen atoms,

[0174] R 9a and R 9b are each independently an alkyl group optionally substituted with 1 hydroxy group,

[0175] R 10a is a group selected from the following: a hydrogen atom; and optionally substituted by 1 group selected from -NH-CO-OR 7d 、-CO-N(R 7a )(R 7b ), an alkyl group substituted with a substituent of a cyano group, an alkoxycarbonyl group, and a hydroxycarbonyl group,

[0176] R 10b is a hydrogen atom,

[0177] R 11 It is an alkyl group.

[0178] [6] The compound or pharmaceutically acceptable salt thereof according to any one of [2] to [5], wherein

[0179] A is a benzene ring,

[0180] R a is a hydrogen atom,

[0181] R 10a is an alkyl group optionally substituted by 1 alkoxycarbonyl group,

[0182] L is a group selected from the following: a divalent aromatic hydrocarbon group optionally substituted by 1 to 2 substituents selected from a halogen atom, an alkyl group optionally substituted by 1 to 3 halogen atoms, and an alkoxy group; and a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and optionally partially hydrogenated,

[0183] M is an alkylene group optionally substituted with one substituent selected from the group consisting of a hydroxy group and a cyano group.

[0184] [7] The compound or pharmaceutically acceptable salt thereof according to any one of [2] to [6], wherein

[0185] Ra’ is a hydrogen atom,

[0186] R a” is cyano,

[0187] R Z3 is an alkyl group optionally substituted by 1 to 3 halogen atoms or a hydroxyl group; or an alkoxy group,

[0188] R Z4 is a hydrogen atom,

[0189] R Z5 A hydrogen atom.

[0190] [8] The compound or pharmaceutically acceptable salt thereof according to any one of [2] to [7], wherein

[0191] R 8a and R 8b are hydrogen atoms,

[0192] R 9a and R 9b are each independently an alkyl group optionally substituted with 1 hydroxy group,

[0193] R 10a is an alkyl group optionally substituted by 1 alkoxycarbonyl group,

[0194] R 10b is a hydrogen atom,

[0195] R 11 It is an alkyl group.

[0196] [9] The compound or pharmaceutically acceptable salt thereof according to any one of [2] to [8], wherein

[0197] L is a phenylene group optionally substituted by 1 to 2 substituents selected from halogen atoms and alkyl groups; or a pyrazinediyl group,

[0198] T is -CO-NR 7c -, R 7c is a hydrogen atom,

[0199] M is -CH2- or -CH(CH3)-.

[0200]

[10] A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0201] [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate,

[0202] [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate,

[0203] [(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]diazepine -6-yl] methyl acetate,

[0204] [(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]diazepine -6-yl] methyl acetate,

[0205] [(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]diazepine -6-yl] methyl acetate,

[0206] [(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]diazepine -6-yl] methyl acetate,

[0207] [(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]diazepine -6-yl] methyl acetate,

[0208] [(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]diazepine -6-yl] methyl acetate,

[0209] [(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]diazepine -6-yl] methyl acetate,

[0210] [(6S)-4-(4-{6-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate,

[0211] [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] tert-butyl acetate,

[0212] [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] tert-butyl acetate,

[0213] [(6S)-4-(4-{5-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate,

[0214] [(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]diazepine -6-yl] methyl acetate,

[0215] [(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]diazepine -6-yl] methyl acetate,

[0216] 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]diazepine -4-yl][1,1'-biphenyl]-4-carboxamide,

[0217] [(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]diazepine -6-yl] methyl acetate,

[0218] [(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]diazepine -6-yl] methyl acetate,

[0219] {(6S)-4-[4-(6-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyridin-3-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl} methyl acetate,

[0220] [(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]diazepine -6-yl] methyl acetate,

[0221] [(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]diazepine -6-yl] methyl acetate,

[0222] [(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]diazepine -6-yl] methyl acetate,

[0223] [(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]diazepine -6-yl] methyl acetate,

[0224] [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate,

[0225] {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazin-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl} methyl acetate,

[0226] [(6S)-4-(4-{5-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate,

[0227] {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazin-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl} methyl acetate,

[0228] [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate,

[0229] [(6S)-4-(4-{6-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate,

[0230] {(6S)-4-[4-(6-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyridin-3-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl} methyl acetate,

[0231] [(6S)-4-(4-{6-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate,

[0232] [(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]diazepine -6-yl] methyl acetate,

[0233] [(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]diazepine -6-yl] methyl acetate, and

[0234] [(6S)-4-(4-{5-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] tert-butyl acetate.

[0235]

[11] A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0236] [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate,

[0237] [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate,

[0238] [(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]diazepine -6-yl] methyl acetate,

[0239] [(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]diazepine -6-yl] methyl acetate,

[0240] [(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]diazepine -6-yl] methyl acetate,

[0241] [(6S)-4-(4-{6-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate,

[0242] [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] tert-butyl acetate,

[0243] [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] tert-butyl acetate,

[0244] [(6S)-4-(4-{5-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate,

[0245] [(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]diazepine -6-yl] methyl acetate,

[0246] 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]diazepine -4-yl][1,1'-biphenyl]-4-carboxamide,

[0247] [(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]diazepine -6-yl] methyl acetate,

[0248] {(6S)-4-[4-(6-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyridin-3-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl} methyl acetate,

[0249] [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate,

[0250] {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazin-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl} methyl acetate,

[0251] [(6S)-4-(4-{5-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate,

[0252] {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazin-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl} methyl acetate,

[0253] [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate,

[0254] [(6S)-4-(4-{6-[({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate,

[0255] {(6S)-4-[4-(6-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyridin-3-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl} methyl acetate, and

[0256] [(6S)-4-(4-{6-[(2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate.

[0257]

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

[11] or a pharmaceutically acceptable salt thereof.

[0258]

[13] The pharmaceutical composition described in

[12] is used to induce the degradation of BRD4 protein.

[0259]

[14] The pharmaceutical composition described in

[12] or

[13] , which is used for treating cancer.

[0260]

[15]

[14] The pharmaceutical composition described in claim 1, 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.

[0261]

[16] The pharmaceutical composition described in

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

[0262]

[17] The pharmaceutical composition described in

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

[0263]

[18] Use of the pharmaceutical composition described in any one of

[12] to

[17] in the treatment of cancer.

[0264]

[19] Use of the compound or pharmaceutically acceptable salt thereof according to any one of [1] to

[11] in the preparation of a pharmaceutical composition for treating cancer.

[0265]

[20] A method for treating cancer, comprising administering the compound or pharmaceutically acceptable salt thereof according to any one of [1] to

[11] , or the pharmaceutical composition according to any one of

[12] to

[17] .

[0266] Effects of the Invention

[0267] The compound of the present invention has an excellent BRD4 protein degradation inducing effect and can be used as a therapeutic agent for cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0268] Figure 1 The results of the induction of BRD4 protein degradation in Test Example 4 are shown.

[0269] Figure 2 The results of the antitumor effect of Test Example 6 are shown. DETAILED DESCRIPTION

[0270] The compound of the present invention is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. In this specification, "a compound represented by formula (I) or a pharmaceutically acceptable salt thereof" may be collectively referred to as the compound of the present invention.

[0271] Hereinafter, the meanings of the terms used in this specification will be explained, and the present invention will be further described in detail. The following explanations of the terms do not limit the present invention in any way.

[0272] In the present specification, examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0273] In this specification, examples of “alkyl” include “C 1-6 alkyl” 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, 2-ethylbutyl, and the like.

[0274] In the present specification, examples of the "cycloalkyl group" include "C 3-10 "cycloalkyl" such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, adamantyl, and the like.

[0275] In this specification, examples of the "alkoxy group" include "C 1-6 "alkoxy" such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0276] In this specification, examples of “alkylene” include “C 1-6 "Alkylene" such as -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH(CH3)-, -C(CH3)2-, -CH(C2H5)-, -CH(C3H7)-, -CH(CH(CH3)2)-, -(CH(CH3))2-, -CH2-CH(CH3)-, -CH(CH3)-CH2-, -CH2-CH2-C(CH3)2-, -C(CH3)2-CH2-CH2-, -CH2-CH2-CH2-C(CH3)2-, -C(CH3)2-CH2-CH2-CH2-, etc.

[0277] In the present specification, examples of "alkenylene" include "C 2-6Alkenylene", such as -CH=CH-, -CH2-CH=CH-, -CH=CH-CH2-, -C(CH3)2-CH=CH-, -CH=CH-C(CH3)2-, -CH2-CH=CH-CH2-, -CH2-CH2-CH=CH-, -CH=CH-CH2-CH2-, -CH=CH-CH=CH-, -CH=CH-CH2-CH2-CH2-, -CH2-CH2-CH2-CH=CH-, etc.

[0278] In the present specification, examples of the "alkynylene group" include "C 2-6 "alkynylene" such as -C≡C-, -CH2-C≡C-, -C≡C-CH2-, -C(CH3)2-C≡C-, -C≡CC(CH3)2-, -CH2-C≡C-CH2-, -CH2-CH2-C≡C-, -C≡C-CH2-CH2-, -C≡CC≡C-, -C≡C-CH2-CH2-, -C≡CC≡C-, -C≡C-CH2-CH2-CH2-, -CH2-CH2-CH2-C≡C-, etc.

[0279] In the present specification, examples of the “cycloalkylene group” include “C 3-10 "cycloalkylene", such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, etc.

[0280] In the present specification, examples of the "alkoxycarbonyl group" include "C 1-6 "alkoxycarbonyl" such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.

[0281] In this specification, examples of the "cycloalkane ring" include "C 3-10 Cycloalkane rings”, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.

[0282] In this specification, examples of the "aromatic hydrocarbon ring" include "C 6-14 Aromatic hydrocarbon rings", such as benzene, naphthalene, anthracene, etc.

[0283] In this specification, examples of the "aromatic hydrocarbon group" include C 6-14 Aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl and the like.

[0284] In this specification, examples of the "divalent aromatic hydrocarbon group" include C 6-14 Arylene groups such as phenylene, naphthylene, anthracene and the like.

[0285] In the present specification, examples of the “aliphatic heterocycle containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen” include 3-membered to 14-membered (preferably 4-membered to 10-membered) aliphatic heterocycles containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen as ring-constituting atoms other than carbon atoms. Preferred 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, azepane, diazepane, azepane, Azocyclooctane, diazacyclooctane, oxepane, etc.;

[0286] 9- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) aliphatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, dihydroindoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxathiine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, octahydroisoquinoline, and the like.

[0287] In the present specification, examples of the "aliphatic heterocycle containing one nitrogen atom" include the aliphatic heterocycle containing one nitrogen atom among the above-mentioned "aliphatic heterocycle containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen".

[0288] In the present specification, examples of the "divalent aliphatic heterocyclic group" include divalent aliphatic heterocyclic groups induced by the above-mentioned "aliphatic heterocycle".

[0289] In the present specification, examples of the "divalent aliphatic heterocyclic group containing one nitrogen atom" include divalent aliphatic heterocyclic groups induced by the aliphatic heterocyclic group containing one nitrogen atom among the above-mentioned "aliphatic heterocycles".

[0290] 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 1 to 3 atoms selected from oxygen, sulfur and nitrogen as ring atoms other than carbon atoms. Preferred 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, triazine and the like;

[0291] 8- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocycles such as benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine pyrimidine, furanopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiazole, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, phenoxathiazole, etc.

[0292] In the present specification, examples of the “5-membered or 6-membered aromatic heterocyclic group containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen” include a 5-membered or 6-membered aromatic heterocyclic group containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen as ring-constituting atoms other than carbon atoms.

[0293] Preferred examples of the “aromatic heterocyclic group” include a 5-membered or 6-membered monocyclic aromatic heterocyclic group such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like.

[0294] In the present specification, examples of the "optionally partially hydrogenated divalent aromatic heterocyclic group" include divalent ring groups induced by the above-mentioned "aliphatic heterocyclic ring" and the above-mentioned "aromatic heterocyclic ring".

[0295] In the present specification, examples of the “divalent aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and optionally partially hydrogenated” include divalent cyclic groups induced by the above-mentioned “aliphatic heterocyclic ring” containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and the above-mentioned “aromatic heterocyclic ring”.

[0296] Among the “divalent aromatic heterocyclic group containing 1 to 2 atoms selected from nitrogen, oxygen and sulfur atoms and optionally partially hydrogenated”, preferred examples of the “divalent aromatic heterocyclic group containing 1 to 2 atoms selected from nitrogen, oxygen and sulfur atoms and partially hydrogenated” include a tetrahydroisoquinolinyl group (particularly 1,2,3,4-tetrahydroisoquinolin-2,6-diyl group).

[0297] In the present specification, unless otherwise specified, the number of substituents when “substituted” is one or two or more, and the types of substituents may be the same or different.

[0298] Preferred embodiments of the above-mentioned formula (I) will be described below.

[0299] A is preferably a ring selected from an aromatic hydrocarbon ring (e.g., a benzene ring), a 5-membered or 6-membered aromatic heterocyclic ring 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 further preferably a benzene ring.

[0300] Q is preferably a 5- or 6-membered aromatic heterocyclic ring (eg, a pyrrole ring) containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen.

[0301] Partial structure

[0302]

[0303] Preferably the following formula:

[0304]

[0305] That is, Z 1 Preferably C, Z 2 Preferably C, Z 3 Preferably =CR Z3 -、Z 4 Preferably =CR Z4 -、Z 5 Preferably =CR Z5 - and Q is preferably a pyrrole ring.

[0306] R Z3Preferably, it is a group selected from the following: a hydrogen atom; a halogen atom (e.g., a chlorine atom, a bromine atom); a hydroxyl group; a cyano group; a hydroxycarbonyl group; an alkyl group (e.g., a methyl group, an ethyl group) optionally substituted by a group selected from a halogen atom (e.g., a fluorine atom), a hydroxyl group, an alkoxy group, and a cyano group; a cycloalkyl group (e.g., a cyclopropyl group) optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; an alkoxy group (e.g., a methoxy group) optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; and cyano groups, more preferably, a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl group and a cyano group; a cycloalkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl group and a cyano group; or an alkoxy group optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl group and a cyano group, further preferably an alkyl group or a hydroxyl group optionally substituted by 1 to 3 halogen atoms; or an alkoxy group, particularly preferably an alkyl group, further more preferably a methyl group or an ethyl group.

[0307] Preferably, R Z4 and R Z5 Each is independently a group selected from the following: a hydrogen atom; a halogen atom; a cyano group; an alkyl group (e.g., a methyl group) optionally substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; an alkoxy group optionally substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; more preferably, each is independently a hydrogen atom; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group, and further preferably, both are hydrogen atoms.

[0308] R a It is preferably a hydrogen atom; or an alkyl group 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, further preferably a hydrogen atom.

[0309] R a’ It is preferably a hydrogen atom; an alkyl group (eg, methyl group) 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, further preferably a hydrogen atom.

[0310] R a” Preferably it is a hydrogen atom; a halogen atom (such as a chlorine atom); an alkyl group (such as a methyl group) optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group; or a cyano group, more preferably a hydrogen atom; a halogen atom; an alkyl group; or a cyano group, further preferably a cyano group.

[0311] Partial structure

[0312]

[0313] Preferably, it is the following formula (Ea) or (Ec):

[0314]

[0315] More preferably:

[0316]

[0317] R 9a and R 9b For example, each is independently a group selected from the following: a hydrogen atom; a halogen atom; a cyano group; an alkyl group (such as a methyl group) optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group; and a substituted alkoxy group (such as a methoxy group) optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group. Preferably, each is independently a hydrogen atom; a halogen atom; a cyano group; an alkyl group (such as a methyl group) optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group; more preferably, each is independently an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group, further preferably, each is independently an alkyl group optionally substituted with a hydroxyl group, particularly preferably an unsubstituted alkyl group, and further more preferably a methyl group.

[0318] L is preferably a group selected from the following: a divalent aromatic hydrocarbon group (for example, a phenylene group); a divalent aliphatic heterocyclic group (for example, a pyrrolidinediyl group); an optionally partially hydrogenated divalent aromatic heterocyclic group (for example, a thiophenediyl group, a pyridinediyl group, a tetrahydropyridinediyl group, a pyrazinediyl group, a benzofurandiyl group, a benzoxazinediyl group, a benzothiophenediyl group, a tetrahydroquinolindiyl group); an alkylene group; a cycloalkylene group; an alkenylene group; and an alkynylene group (for example, -C≡C-, -C≡C-CH2-); said group is optionally substituted with a substituent selected from the group consisting of: a halogen atom (for example, a fluorine atom, a chlorine atom); a hydroxyl group; a cyano group; a hydroxycarbonyl group; a hydroxyl group optionally selected from the group consisting of: a halogen atom (for example, a fluorine atom), a hydroxyl group, an alkoxy group and a cyano group. an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group (e.g., a methoxy group); and an alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group (e.g., a methoxy group); more preferably, a group selected from the following: an alkynylene group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group; a divalent aromatic hydrocarbon group optionally substituted with a substituent selected from a) a halogen atom, b) a hydroxyl group, c) a cyano group, d) an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group, e) an alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group; a divalent aliphatic hydrocarbon group containing one nitrogen atom optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group heterocyclic group; and a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms and optionally partially hydrogenated; the aromatic heterocyclic group is optionally substituted by a substituent selected from a halogen atom, a hydroxyl group, a cyano group and an oxo group, and is further preferably a group selected from the following: an alkynylene group; a divalent aromatic hydrocarbon group optionally substituted by a substituent selected from a halogen atom, an alkyl group optionally substituted by a halogen atom, and an alkoxy group; a divalent aliphatic heterocyclic group containing 1 nitrogen atom; and a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms and optionally partially hydrogenated; the aromatic heterocyclic group is optionally substituted by an oxo group, and is particularly preferably selected from the following Group: an aromatic hydrocarbon group optionally substituted by a substituent selected from the group consisting of a halogen atom, an alkyl group optionally substituted by a halogen atom, and an alkoxy group; and a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and optionally partially hydrogenated; further preferably, a group selected from the group consisting of a divalent aromatic hydrocarbon group optionally substituted by 1 to 2 halogen atoms; and a divalent aromatic heterocyclic group containing 1 to 2 nitrogen atoms, particularly preferably a group selected from the group consisting of a phenylene group optionally substituted by 1 to 2 halogen atoms; a pyridinediyl group; and a pyrazinediyl group, more preferably a group selected from the group consisting of a phenylene group optionally substituted by 1 to 2 halogen atoms; and a pyrazinediyl group.

[0319] In another embodiment, L is preferably a divalent aromatic hydrocarbon group (e.g., a phenylene group), which is optionally substituted with a substituent selected from the group consisting of: a halogen atom (e.g., a fluorine atom, a chlorine atom); a hydroxyl group; a cyano group; a hydroxycarbonyl group; an alkyl group (e.g., a methyl group) optionally substituted with a group selected from a halogen atom (e.g., a fluorine atom), a hydroxyl group, an alkoxy group, and a cyano group; and an alkoxy group (e.g., a methoxy group) optionally substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; more preferably a divalent aromatic hydrocarbon group optionally substituted with a substituent The present invention is preferably selected from the group consisting of a) a halogen atom, b) a hydroxyl group, c) a cyano group, d) an alkyl group optionally substituted with a substituent selected from the group consisting of a halogen atom, a hydroxyl group and a cyano group, and e) a substituted alkoxy group optionally substituted with a substituent selected from the group consisting of a halogen atom, a hydroxyl group and a cyano group, particularly preferably a divalent aromatic hydrocarbon group optionally substituted with a substituent selected from the group consisting of a halogen atom, an alkyl group optionally substituted with a halogen atom, and an alkoxy group, further particularly preferably a divalent aromatic hydrocarbon group optionally substituted with 1 to 2 halogen atoms, and particularly preferably a phenylene group optionally substituted with 1 to 2 halogen atoms.

[0320] In another embodiment, L is preferably an optionally partially hydrogenated divalent aromatic heterocyclic group (e.g., thiophenediyl, pyridinediyl, tetrahydropyridinediyl, pyrazinediyl, benzofurandiyl, benzoxazinediyl, benzothiophenediyl, tetrahydroquinolindiyl), an alkylene group, a cycloalkylene group, an alkenylene group, or an alkynylene group (e.g., -C≡C-, -C≡C-CH2-), which is optionally substituted with a substituent selected from the group consisting of: a halogen atom (e.g., a fluorine atom, a chlorine atom); a hydroxyl group; a cyano group; a hydroxycarbonyl group; an alkyl group (e.g., a methyl group) optionally substituted with a group selected from a halogen atom (e.g., a fluorine atom), a hydroxyl group, an alkoxy group, and a cyano group; and an alkoxy group (e.g., a methoxy group) optionally substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group, more preferably a 1-2-group substituted alkyl group. A divalent aromatic heterocyclic group containing an atom selected from a nitrogen atom, an oxygen atom and a sulfur atom and optionally partially hydrogenated, which group is optionally substituted by a substituent selected from a halogen atom, a hydroxyl group, a cyano group and an oxo group, further preferably a group selected from a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and optionally partially hydrogenated, the aromatic heterocyclic group optionally substituted by an oxo group, particularly preferably a divalent aromatic hydrocarbon group optionally substituted by a substituent selected from a halogen atom, an alkyl group optionally substituted by a halogen atom, and an alkoxy group, further particularly preferably a group selected from a divalent aromatic heterocyclic group containing 1 to 2 nitrogen atoms, particularly preferably a group selected from a pyridinediyl group and a pyrazinediyl group, and further more preferably a pyrazinediyl group.

[0321] T is preferably a single bond, -CO-, or -CO-NR 7c -、-NR 7c-CO- or -O-, or an alkylene group optionally substituted with a substituent selected from the group consisting of: a halogen atom; a hydroxyl group; a cyano group; an oxo group; a hydroxycarbonyl group; an alkyl group optionally substituted with a substituent selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; and an alkoxy group optionally substituted with a substituent selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group, more preferably a single bond; -CO-; -CO-NR 7c -;-NR 7c -CO-; or -O-, particularly preferably -CO-NR 7c -.

[0322] M is preferably a single bond, or a group selected from the following: -O-; -S-; -NR 7a -;-CO-;-SO-;-SO2-;-CO-NR 7c -;-NR 7c -CO-;-SO2-NR 7c -;-NR 7c -SO2-;-NR 7a -CO-NR 7b -;-(OCH2CH2) m -;-OR 7r -;-R 7r -O-;-SR 7r -;-R 7r -S-;-NR 7a -R 7r -;-R 7r -NR 7a -;-CO-NR 7c -R 7r -;-R 7r -CO-NR 7c -; and alkylene optionally substituted by a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group (e.g., -CH2-, -(CH2)2-, -(CH2)3-); alkynylene optionally substituted by a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group (e.g., -CH2-C≡C-); and a divalent aliphatic heterocyclic group (e.g., piperidinediyl) optionally substituted by a substituent selected from a) a halogen atom, b) a hydroxyl group, c) a cyano group, d) an oxo group, e) an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; and f) an alkoxy group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; more preferably a single bond, or a group selected from the following: -R 7r -O-;-R 7r -NR 7a-; an alkylene group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group; an alkynylene group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group; and a divalent aliphatic heterocyclic group, further preferably a single bond, or a group selected from the following: -R 7r -O-;-R 7r -NR 7a -; an alkylene group optionally substituted by a substituent selected from a hydroxyl group and a cyano group; an alkynylene group; and a divalent aliphatic heterocyclic group, particularly preferably an alkylene group optionally substituted by a substituent selected from a hydroxyl group and a cyano group, particularly preferably -CH2- or -CH(CH3)-, more particularly preferably -CH2-,

[0323] or

[0324]

[0325] As a whole or part of the structure, -LTM- does not represent a structure selected from -OO-, -SS-, -NR 7a -NR 7a -、-OS-、-SO-、-O-NR 7a -、-NR 7a -O-、-S-NR 7a -and-NR 7a -S- group,

[0326] -LTM-, preferably,

[0327] L is a group selected from the following: an aromatic hydrocarbon group optionally substituted with 1 to 2 substituents selected from halogen atoms and alkyl groups; and a divalent aromatic heterocyclic group containing 1 to 2 nitrogen atoms,

[0328] T is -CO-NR 7c -, R 7c is a hydrogen atom,

[0329] M is -CH2-, -(CH2)2- or -CH(CH3)-,

[0330] More preferably,

[0331] L is a group selected from the following: 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,

[0332] T is -CO-NR 7c -, R 7c is a hydrogen atom,

[0333] M is -CH2-, -(CH2)2- or -CH(CH3)-,

[0334] More preferably,

[0335] L is a phenylene group optionally substituted by 1 to 2 halogen atoms; or a pyrazinediyl group,

[0336] T is -CO-NR 7c -, R 7c is a hydrogen atom,

[0337] M is -CH2- or -CH(CH3)-,

[0338] Particularly preferably,

[0339] L is a phenylene group optionally substituted by 1 to 2 halogen atoms; or a pyrazinediyl group,

[0340] T is -CO-NR 7c -, R 7c is a hydrogen atom,

[0341] M is -CH2-, or

[0342]

[0343] Partial structure

[0344]

[0345] Preferably:

[0346]

[0347] Partial structure

[0348]

[0349] Preferably:

[0350]

[0351] That is, G is preferably N, and J is preferably N.

[0352] R 5 Preferred is a hydrogen atom.

[0353] R 6a and R 6b Preferably, each is independently a group selected from the following: a hydrogen atom; a halogen atom (e.g., a fluorine atom); a hydroxyl group; a cyano group; and an alkyl group (e.g., a methyl group) optionally substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; more preferably, each is independently a group selected from the following: a hydrogen atom; a halogen atom; a cyano group; and an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; further preferably, it is a group selected from the following: a hydrogen atom; a halogen atom; a cyano group; and an alkyl group.

[0354] R 7a and R7b Preferably, they are each independently a hydrogen atom; or a substituted alkyl group (eg, methyl, ethyl) optionally substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group, and more preferably, they are each independently a hydrogen atom; or an alkyl group optionally substituted with a hydroxyl group.

[0355] R 7c Preferred is a hydrogen atom.

[0356] R 7d It is preferably a substituted alkyl group (eg, methyl group) optionally substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group, and more preferably an alkyl group.

[0357] R 7r An alkylene group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group (e.g., -CH2-, -(CH2)2-, -(CH2)3-) is preferred, and an alkylene group is more preferred.

[0358] R 8a and R 8b Each is preferably independently selected from the group consisting of a hydrogen atom; a halogen atom; a hydroxyl group; and a cyano group; more preferably, both are hydrogen atoms.

[0359] R 10a and R 10b Each substituent is preferably independently selected from the following: hydrogen atom; -N(R 7c )-CO-OR 7d ; and an alkyl group (e.g., methyl); the alkyl group is optionally substituted with a substituent selected from the group consisting of: a halogen atom; a hydroxyl group; a cyano group; an alkoxy group optionally substituted with a substituent selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; an alkoxycarbonyl group (e.g., a methoxycarbonyl group, a tert-butoxycarbonyl group) optionally substituted with a substituent selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; -CO-N(R 7a )(R 7b ); and hydroxycarbonyl; more preferably, R 10a is a group selected from the following: a hydrogen atom; and optionally selected from a halogen atom, a hydroxyl group, a cyano group, a -NH-CO-OR 7d 、-CO-N(R 7a )(R 7b ), alkyl substituted with alkoxycarbonyl, and hydroxycarbonyl, and R 10b is a hydrogen atom, more preferably, R 10a is a group selected from the following: a hydrogen atom; and optionally selected from -NH-CO-OR 7d 、-CO-N(R 7a )(R 7b ), alkyl substituted with a cyano group, an alkoxycarbonyl group, and a hydroxycarbonyl group, and R 10bis a hydrogen atom, particularly preferably, R 10a is an alkyl group optionally substituted with one alkoxycarbonyl group, and R 10b is a hydrogen atom, and more preferably, R 10a It is methyl optionally substituted by one substituent selected from tert-butoxycarbonyl and methoxycarbonyl, and most preferably methyl substituted by methoxycarbonyl.

[0360] R 11 It is preferably a substituted alkyl group (eg, methyl group) optionally substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group, more preferably an alkyl group, and particularly preferably a methyl group.

[0361] Preferred examples of the compound represented by formula (I) include the following compounds.

[0362] [Compound IA]

[0363] Compound (I) wherein A is a ring selected from an aromatic hydrocarbon ring, a 5-membered or 6-membered aromatic heterocyclic ring containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen, and a cycloalkane ring,

[0364] Partial structure

[0365]

[0366] is the following formula:

[0367]

[0368] R a is a hydrogen atom; or an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group,

[0369] R a’ is a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; an alkoxycarbonyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; or -CO-N(R 7a )(R 7b ),

[0370] R a” is a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; an alkoxycarbonyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; or -CO-N(R 7a )(R 7b ),

[0371] R Z3 A group selected from the following:

[0372] a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; a hydroxycarbonyl group; an alkyl group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; a cycloalkyl group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; an alkoxy group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; an alkoxycarbonyl group optionally substituted by a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group;

[0373] R Z4 and R Z5 are each independently a group selected from the following: a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; an alkoxy group optionally substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group;

[0374] Partial structure

[0375]

[0376] It is the following formula (Ea) or (Ec):

[0377]

[0378] Partial structure:

[0379]

[0380] for

[0381]

[0382] Partial structure

[0383]

[0384] for

[0385]

[0386] L is a group selected from the group consisting of a divalent aromatic hydrocarbon group; a divalent aliphatic heterocyclic group; an optionally partially hydrogenated divalent aromatic heterocyclic group; an alkylene group; a cycloalkylene group; an alkenylene group; and an alkynylene group;

[0387] The group is optionally substituted with a substituent selected from the group consisting of: a halogen atom; a hydroxyl group; a cyano group; a hydroxycarbonyl group; an alkyl group optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; and an alkoxy group optionally substituted with a group selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group;

[0388] T is a single bond, -CO-, -CO-NR 7c -、-NR 7c -CO- or -O-, or

[0389] an alkylene group optionally substituted with a substituent selected from the group consisting of a halogen atom; a hydroxyl group; a cyano group; an oxo group; a hydroxycarbonyl group; an alkyl group optionally substituted with a substituent selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; and an alkoxy group optionally substituted with a substituent selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group;

[0390] M is a single bond, or a group selected from the following:

[0391] -O-;-S-;-NR 7a -;-CO-;-SO-;-SO2-;-CO-NR 7c -;-NR 7c -CO-;-SO2-NR 7c -;-NR 7c -SO2-;-NR 7a -CO-NR 7b -;-(OCH2CH2) m -;-OR 7r -;-R 7r -O-;-SR 7r -;-R 7r -S-;-NR 7a -R 7r -;-R 7r -NR 7a -;-CO-NR 7c -R 7r -;-R 7r -CO-NR 7c -; an alkylene group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; an alkynylene group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; and a divalent aliphatic heterocyclic group optionally substituted by a substituent selected from a) a halogen atom, b) a hydroxyl group, c) a cyano group, d) an oxo group, e) an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group, and f) an alkoxy group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group,

[0392] R 5 is a hydrogen atom,

[0393] R 6a and R 6b are each independently a group selected from the following: a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; and an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group;

[0394] R 7c is a hydrogen atom,

[0395] 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;

[0396] R 9a and R 9b are each independently a group selected from the following: a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group;

[0397] R 10a and R 10b are each independently a substituent selected from the following: a hydrogen atom, -N(R 7c )-CO-OR 7d ; and alkyl; and

[0398] The alkyl group is optionally substituted by a substituent selected from the group consisting of: a halogen atom; a hydroxyl group; a cyano group; an alkoxy group optionally substituted by a substituent selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; an alkoxycarbonyl group optionally substituted by a substituent selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; -CO-N(R 7a )(R 7b ); and hydroxycarbonyl.

[0399] [Compound IB]

[0400] Compound (I) wherein A is a ring selected from the group consisting of a benzene ring; a pyridine ring; and a cycloalkane ring,

[0401] Partial structure:

[0402]

[0403] is the following formula:

[0404]

[0405] R a is a hydrogen atom; or an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0406] R a’ is a hydrogen atom; or an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0407] R a” is a hydrogen atom; a halogen atom; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group; or a cyano group,

[0408] R Z3is a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group; a cycloalkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group; or an alkoxy group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group;

[0409] R Z4 and R Z5 are each independently a hydrogen atom; or an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0410] Partial structure:

[0411]

[0412] is the following formula (Ea):

[0413]

[0414] Partial structure

[0415]

[0416] for:

[0417]

[0418] Partial structure

[0419]

[0420] for:

[0421]

[0422] L is a group selected from the group consisting of an alkynylene group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group; a divalent aromatic hydrocarbon group optionally substituted by a substituent selected from the group consisting of a) a halogen atom, b) a hydroxyl group, c) a cyano group, d) an alkyl group optionally substituted by a substituent selected from the group consisting of a halogen atom, a hydroxyl group and a cyano group, and e) an alkoxy group optionally substituted by a substituent selected from the group consisting of a halogen atom, a hydroxyl group and a cyano group; a divalent aliphatic heterocyclic group containing a nitrogen atom optionally substituted by a substituent selected from the group consisting of a halogen atom, a hydroxyl group and a cyano group; and a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and optionally partially hydrogenated,

[0423] The aromatic heterocyclic group is optionally substituted by a substituent selected from a halogen atom, a hydroxyl group, a cyano group and an oxo group,

[0424] T is a single bond, -CO-, or -CO-NR 7c -、-NR 7c -CO- or -O-,

[0425] M is a single bond, followed by a group selected from the following:

[0426] -R 7r -O-;-R 7r -NR 7a -; an alkylene group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group; an alkynylene group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group; and a divalent aliphatic heterocyclic group,

[0427] R 6a and R 6b are each independently a group selected from the group consisting of a hydrogen atom; a halogen atom; a cyano group; and an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0428] R 7a and R 7b are each independently a hydrogen atom; or an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0429] R 7c is a hydrogen atom,

[0430] R 7d is an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0431] R 7r is an alkylene group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0432] R 8a and R 8b are hydrogen atoms,

[0433] R 9a and R 9b are each independently an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0434] R 10a is a group selected from the following: a hydrogen atom; and optionally selected from a halogen atom, a hydroxyl group, a cyano group, a -NH-CO-OR 7d 、-CO-N(R 7a )(R 7b ), an alkyl group substituted with a substituent of an alkoxycarbonyl group and a hydroxycarbonyl group,

[0435] R 10b is a hydrogen atom, and

[0436] R 11 is an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group.

[0437] [Compound IC]

[0438] Compound (I), wherein A is a ring selected from the group consisting of a benzene ring; a pyridine ring; and a cycloalkane ring,

[0439] Partial structure

[0440]

[0441] is the following formula:

[0442]

[0443] R a is a hydrogen atom; or an alkyl group,

[0444] R a’ is a hydrogen atom; or an alkyl group,

[0445] R a” is a hydrogen atom; a halogen atom; an alkyl group; or a cyano group,

[0446] R Z3 is a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted by a halogen atom or a hydroxyl group; a cycloalkyl group; or an alkoxy group,

[0447] R Z4 and R Z5 are each independently a hydrogen atom or an alkyl group,

[0448] Partial structure

[0449]

[0450] is the following formula (Ea):

[0451]

[0452] Partial structure

[0453]

[0454] for

[0455]

[0456] Partial structure

[0457]

[0458] for

[0459]

[0460] L is a group selected from the group consisting of an alkynylene group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group; a divalent aromatic hydrocarbon group optionally substituted by a substituent selected from a) a halogen atom, b) a hydroxyl group, c) a cyano group, d) an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group, and e) an alkoxy group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group; a divalent aliphatic heterocyclic group containing one nitrogen atom which is optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group; and a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and which is optionally partially hydrogenated,

[0461] The aromatic heterocyclic group is optionally substituted by a substituent selected from a halogen atom, a hydroxyl group, a cyano group and an oxo group,

[0462] T is a single bond, -CO-, or -CO-NR 7c -、-NR 7c -CO- or -O-,

[0463] M is a single bond, or a group selected from the following:

[0464] -R 7r -O-;-R 7r -NR 7a -; an alkylene group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group; an alkynylene group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group; and a divalent aliphatic heterocyclic group,

[0465] R 6a and R 6b are each independently a group selected from the group consisting of a hydrogen atom; a halogen atom; a cyano group; and an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0466] R 7a and R 7b are each independently a hydrogen atom; or an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0467] R 7c is a hydrogen atom,

[0468] R 7d is an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0469] R 7r is an alkylene group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0470] R 8a and R 8b are hydrogen atoms,

[0471] R 9a and R 9b are each independently an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0472] R 10a is a group selected from the following: a hydrogen atom; and optionally selected from a halogen atom, a hydroxyl group, a cyano group, a -NH-CO-OR 7d 、-CO-N(R 7a )(R 7b ), an alkyl group substituted with a substituent of an alkoxycarbonyl group and a hydroxycarbonyl group,

[0473] R 10b is a hydrogen atom, and

[0474] R 11 is an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group.

[0475] [Compound ID]

[0476] Compound (I), wherein A is a benzene ring,

[0477] Partial structure

[0478]

[0479] is the following formula:

[0480]

[0481] R a is a hydrogen atom,

[0482] R a’ is a hydrogen atom; or an alkyl group,

[0483] R a” is a hydrogen atom; a halogen atom; an alkyl group; or a cyano group,

[0484] R Z3 is a hydrogen atom; a halogen atom; a cyano group; an alkyl group optionally substituted by a halogen atom or a hydroxyl group; a cycloalkyl group; or an alkoxy group,

[0485] R Z4 and R Z5 are each independently a hydrogen atom or an alkyl group,

[0486] Partial structure:

[0487]

[0488] is the following formula (Ea):

[0489]

[0490] Partial structure:

[0491]

[0492] for

[0493]

[0494] Partial structure:

[0495]

[0496] for

[0497]

[0498] L is a group selected from the following: a divalent aromatic hydrocarbon group optionally substituted by a substituent selected from the group consisting of a halogen atom, an alkyl group optionally substituted by a halogen atom, and an alkoxy group; and a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom and optionally partially hydrogenated,

[0499] T is a single bond, -CO-, or -CO-NR 7c -、-NR 7c -CO- or -O-,

[0500] M is an alkylene group optionally substituted by a hydroxyl group and a cyano group,

[0501] R 6a and R 6b are each independently a group selected from the group consisting of a hydrogen atom; a halogen atom; a cyano group; and an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0502] R 7a and R 7b are each independently a hydrogen atom; or an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0503] R 7c is a hydrogen atom,

[0504] R 7d is an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0505] R 7r is an alkylene group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0506] R 8a and R 8b are hydrogen atoms,

[0507] R9a and R 9b are each independently an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0508] R 10a is an alkyl group optionally substituted by an alkoxycarbonyl group,

[0509] R 10b is a hydrogen atom, and

[0510] R 11 is an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group.

[0511] [Compound IE]

[0512] Compound (I), wherein A is a benzene ring,

[0513] Partial structure:

[0514]

[0515] is the following formula:

[0516]

[0517] R a is a hydrogen atom,

[0518] R a’ is a hydrogen atom,

[0519] R a” is cyano,

[0520] R Z3 is an alkyl group optionally substituted by 1 to 3 halogen atoms or hydroxyl groups; or an alkoxy group, R Z4 is a hydrogen atom,

[0521] R Z5 is a hydrogen atom,

[0522] Partial structure:

[0523]

[0524] is the following formula (Ea):

[0525]

[0526] Partial structure:

[0527]

[0528] for

[0529]

[0530] Partial structure:

[0531]

[0532] for

[0533]

[0534] L is a group selected from the following: a divalent aromatic hydrocarbon group optionally substituted by 1 to 2 substituents selected from a halogen atom, an alkyl group optionally substituted by 1 to 3 halogen atoms, and an alkoxy group; and a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and optionally partially hydrogenated,

[0535] T is a single bond, -CO-, or -CO-NR 7c -、-NR 7c -CO- or -O-,

[0536] M is an alkylene group optionally substituted with one substituent selected from hydroxyl and cyano,

[0537] R 6a and R 6b are each independently a group selected from the group consisting of a hydrogen atom; a halogen atom; a cyano group; and an alkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group and a cyano group,

[0538] R 7a and R 7b are each independently a hydrogen atom; or an alkyl group optionally substituted by 1 to 3 substituents selected from halogen atoms, hydroxyl groups and cyano groups,

[0539] R 7c is a hydrogen atom,

[0540] R 7d is an alkyl group optionally substituted by 1 to 3 substituents selected from halogen atoms, hydroxyl groups and cyano groups,

[0541] R 7r is an alkylene group optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group,

[0542] R 8a and R 8b are hydrogen atoms,

[0543] R 9a and R 9b are each independently an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0544] R 10a is an alkyl group optionally substituted by 1 alkoxycarbonyl group,

[0545] R 10b is a hydrogen atom, and

[0546] R 11 is an alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl group and a cyano group.

[0547] [Compound IF]

[0548] Compound (I), wherein A is a benzene ring,

[0549] Partial structure:

[0550]

[0551] is the following formula:

[0552]

[0553] R a’ is a hydrogen atom,

[0554] R a” is cyano,

[0555] R Z3 is a group; or an alkoxy group,

[0556] R Z4 is a hydrogen atom,

[0557] R Z5 is a hydrogen atom,

[0558] Partial structure:

[0559]

[0560] is the following formula (Ea):

[0561]

[0562] Partial structure:

[0563]

[0564] for

[0565]

[0566] Partial structure:

[0567]

[0568] for

[0569]

[0570] L is a group selected from the following: a divalent aromatic hydrocarbon group optionally substituted with 1 to 2 substituents selected from halogen atoms and alkyl groups; and a divalent aromatic heterocyclic group containing 1 to 2 nitrogen atoms,

[0571] T is -CO-NR 7c -, R 7c is a hydrogen atom,

[0572] M is -CH2-, -(CH2)2- or -CH(CH3)-,

[0573] R 8a and R 8b are hydrogen atoms,

[0574] R 9a and R 9b are each independently an alkyl group,

[0575] R 10a is an alkyl group optionally substituted by 1 alkoxycarbonyl group,

[0576] R 10b is a hydrogen atom, and

[0577] R 11 It is an alkyl group.

[0578] [Compound IG]

[0579] Compound (I), wherein A is a benzene ring,

[0580] Partial structure:

[0581]

[0582] is the following formula:

[0583]

[0584] R a’ is a hydrogen atom,

[0585] R a” is cyano,

[0586] R Z3 is a group; or an alkoxy group,

[0587] R Z4 is a hydrogen atom,

[0588] R Z5 is a hydrogen atom,

[0589] Partial structure:

[0590]

[0591] is the following formula (Ea):

[0592]

[0593] Partial structure:

[0594]

[0595] for

[0596]

[0597] Partial structure:

[0598]

[0599] for

[0600]

[0601] L is a group selected from the following: 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,

[0602] T is -CO-NR 7c -, R 7c is a hydrogen atom,

[0603] M is -CH2-, -(CH2)2- or -CH(CH3)-,

[0604] R 8a and R 8b are hydrogen atoms,

[0605] R 9a and R 9b are each independently an alkyl group,

[0606] R 10a is an alkyl group optionally substituted by 1 alkoxycarbonyl group,

[0607] R 10b is a hydrogen atom, and

[0608] R 11 It is an alkyl group.

[0609] [Compound IH]

[0610] Compound (I), wherein A is a benzene ring,

[0611] Partial structure:

[0612]

[0613] is the following formula:

[0614]

[0615] R a’ is a hydrogen atom,

[0616] R a” is cyano,

[0617] R Z3 is a group; or an alkoxy group,

[0618] R Z4 is a hydrogen atom,

[0619] R Z5 is a hydrogen atom,

[0620] Partial structure:

[0621]

[0622] is the following formula (Ea):

[0623]

[0624] Partial structure:

[0625]

[0626] for

[0627]

[0628] Partial structure:

[0629]

[0630] for

[0631]

[0632] L is a group selected from the following: a phenylene group optionally substituted with 1 to 2 substituents selected from a halogen atom and an alkyl group; and a pyrazinediyl group,

[0633] T is -CO-NR 7c -, R 7c is a hydrogen atom,

[0634] M is -CH2- or -CH(CH3)-,

[0635] R 8a and R 8b are hydrogen atoms,

[0636] R 9a and R 9b are each independently an alkyl group,

[0637] R 10ais an alkyl group substituted with one alkoxycarbonyl group,

[0638] R 10b is a hydrogen atom, and

[0639] R 11 It is an alkyl group.

[0640] [Compound II]

[0641] Compound (I), wherein A is a benzene ring,

[0642] Partial structure:

[0643]

[0644] is the following formula:

[0645]

[0646] R a is a hydrogen atom,

[0647] R a’ is a hydrogen atom,

[0648] R a” is cyano,

[0649] R Z3 is an alkyl group optionally substituted by 1 to 3 halogen atoms or a hydroxyl group; or an alkoxy group,

[0650] R Z4 is a hydrogen atom,

[0651] R Z5 is a hydrogen atom,

[0652] Partial structure:

[0653]

[0654] is the following formula (Ea):

[0655]

[0656] Partial structure:

[0657]

[0658] for

[0659]

[0660] Partial structure:

[0661]

[0662] for

[0663]

[0664] L is a divalent aromatic hydrocarbon group optionally substituted by 1 to 2 substituents selected from the group consisting of a halogen atom, an alkyl group optionally substituted by 1 to 3 halogen atoms, and an alkoxy group,

[0665] T is a single bond, -CO-, or -CO-NR 7c -、-NR 7c -CO- or -O-,

[0666] M is an alkylene group optionally substituted with one substituent selected from hydroxyl and cyano,

[0667] R 6a and R 6b are each independently a group selected from the group consisting of a hydrogen atom; a halogen atom; a cyano group; and an alkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group and a cyano group,

[0668] R 7a and R 7b are each independently a hydrogen atom; or an alkyl group optionally substituted by 1 to 3 substituents selected from halogen atoms, hydroxyl groups and cyano groups,

[0669] R 7c is a hydrogen atom,

[0670] R 7d is an alkyl group optionally substituted by 1 to 3 substituents selected from halogen atoms, hydroxyl groups and cyano groups,

[0671] R 7r is an alkylene group optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group,

[0672] R 8a and R 8b are hydrogen atoms,

[0673] R 9a and R 9b are each independently an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0674] R 10a is an alkyl group optionally substituted by 1 alkoxycarbonyl group,

[0675] R 10b is a hydrogen atom, and

[0676] R 11 is an alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl group and a cyano group.

[0677] [Compound IJ]

[0678] Compound (I), wherein A is a benzene ring,

[0679] Partial structure:

[0680]

[0681] is the following formula:

[0682]

[0683] R a is a hydrogen atom,

[0684] R a’ is a hydrogen atom,

[0685] R a” is cyano,

[0686] R Z3 is an alkyl group optionally substituted by 1 to 3 halogen atoms or a hydroxyl group; or an alkoxy group,

[0687] R Z4 is a hydrogen atom,

[0688] R Z5 is a hydrogen atom,

[0689] Partial structure:

[0690]

[0691] is the following formula (Ea):

[0692]

[0693] Partial structure:

[0694]

[0695] for

[0696]

[0697] Partial structure:

[0698]

[0699] for

[0700]

[0701] L is a divalent aromatic heterocyclic group containing 1 to 2 nitrogen atoms,

[0702] T is a single bond, -CO-, or -CO-NR 7c -、-NR 7c-CO- or -O-,

[0703] M is an alkylene group optionally substituted with one substituent selected from hydroxyl and cyano,

[0704] R 6a and R 6b are each independently a group selected from the group consisting of a hydrogen atom; a halogen atom; a cyano group; and an alkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group and a cyano group,

[0705] R 7a and R 7b are each independently a hydrogen atom; or an alkyl group optionally substituted by 1 to 3 substituents selected from halogen atoms, hydroxyl groups and cyano groups,

[0706] R 7c is a hydrogen atom,

[0707] R 7d is an alkyl group optionally substituted by 1 to 3 substituents selected from halogen atoms, hydroxyl groups and cyano groups,

[0708] R 7r is an alkylene group optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group,

[0709] R 8a and R 8b are hydrogen atoms,

[0710] R 9a and R 9b are each independently an alkyl group optionally substituted by a substituent selected from a halogen atom, a hydroxyl group and a cyano group,

[0711] R 10a is an alkyl group optionally substituted by 1 alkoxycarbonyl group,

[0712] R 10b is a hydrogen atom, and

[0713] R 11 is an alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxyl group and a cyano group.

[0714] Specific examples of the compound represented by formula (I) include the compounds of Examples 1 to 126 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 further preferably the compounds of Examples 1, 47, 74 and 106.

[0715] In the present invention, the term "pharmaceutically acceptable salt" is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples 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. In addition, hydrates, which are salts containing water, and solvates, which are salts containing solvents, are also included in the pharmaceutically acceptable salts of the present invention.

[0716] In this specification, "pharmaceutically acceptable" means generally safe and harmless, may be biologically undesirable, but is otherwise preferred, and can be used to prepare pharmaceutical compositions, including pharmaceutical compositions that can be used not only as human drugs but also as veterinary drugs.

[0717] The compounds of the present invention can be prepared by the following methods A to F. These methods and steps can be combined, and the preparation methods are not limited thereto.

[0718] The following is an example of R 10 R 10a or R 10b , R 10a and R 10b When one of the atoms is a hydrogen atom. 10a and R 10b When all are optionally substituted alkyl, the following method is applied (R 10a 、R 10b as defined above).

[0719] (Method A)

[0720] (1) The production method described herein is suitable for producing an intermediate of a compound represented by formula (I) wherein ring E is represented by the aforementioned formula (Ea), G is a nitrogen atom, and J is a nitrogen atom, that is, the following compound (A-1).

[0721]

[0722] Each symbol is as defined above.

[0723] Step A-1

[0724] Compound (1-2) can be obtained from compound (1-1) according to a known method (e.g., J. Med. Chem. 1973, 16, 214-219).

[0725] Step A-2

[0726] Compound (1-3) can be obtained by acylating compound (1-2). The reaction is carried out using a base in a suitable solvent, typically at a temperature from -20°C to the reflux temperature of the solvent. Although the reaction time varies depending on the raw materials and solvent to be used and the reaction temperature, it is typically 0.5 to 24 hours. Examples of acylating agents include trifluoroacetic anhydride, acetic anhydride, propionic anhydride, acetyl chloride, and the like. Examples of bases include triethylamine, pyridine, and the like. Examples of solvents include tetrahydrofuran, dichloromethane, toluene, 1,4-dioxane, and the like.

[0727] Step A-3

[0728] Compound (1-4) can be obtained by thioamidation of compound (1-3). The thioamidation reaction is carried out in a suitable solvent using a sulfating agent, typically at room temperature to the reflux temperature of the solvent. Although the reaction time varies depending on the raw materials and solvent to be used and the reaction temperature, it is generally 0.5 hours to 24 hours. Examples of sulfating agents include Lawesson reagent, phosphorus pentasulfide, etc. Examples of solvents include 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, etc.

[0729] Step A-4

[0730] Compound (1-5) can be obtained by reacting compound (1-4) with hydrazine. The reaction with hydrazine is carried out using hydrazine monohydrate in a suitable solvent, usually at room temperature to the reflux temperature of the solvent. Although the reaction time varies depending on the raw materials and solvent to be used and the reaction temperature, it is usually 1 hour to 24 hours. Examples of solvents include tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, etc.

[0731] Step A-5

[0732] Compound (1-6) can be prepared by using a halogenating agent to convert R 10The carboxylate form (1-10) of the substituent is converted into an acid halide and reacted with compound (1-5). The reaction is usually carried out in a suitable solvent using a base at a temperature of from 0°C to the reflux temperature of the solvent. Although the reaction time varies depending on the raw materials and solvent to be used and the reaction temperature, it is usually 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.

[0733] Step A-6

[0734] Compound (1-7) can be obtained by the cyclization reaction of compound (1-6). It is usually carried out at room temperature to the reflux temperature of the solvent in a suitable solvent. Although the reaction time varies according to the raw materials to be used and the solvent and the reaction temperature, it is usually 1 hour to 24 hours. The example of the solvent includes 2-propyl alcohol, 1-butyl alcohol, tetrahydrofuran etc.

[0735] Step A-7

[0736] Compound (1-8) can be obtained by the deprotection reaction of compound (1-7). The reaction is carried out using an acid in a suitable solvent, typically at room temperature to the reflux temperature of the solvent. Although the reaction time varies depending on the raw materials and solvent to be used and the reaction temperature, it is generally 1 hour to 24 hours. Examples of acids include hydrochloric acid, trifluoroacetic acid, etc. Examples of solvents include ethyl acetate, 1,4-dioxane, tetrahydrofuran, dichloromethane, chloroform, etc.

[0737] Step A-8

[0738] Compound (1-9) can be obtained by a cyclization reaction of compound (1-8). The reaction is carried out using a condensing agent in the presence of a suitable base in a suitable solvent at a temperature between 0°C and the reflux temperature of the solvent. Although the reaction time varies depending on the raw materials and solvent to be used and the reaction temperature, it is generally 1 to 24 hours. Examples of condensing agents include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC·HCl), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM), 2-chloro-1-methylpyridinium iodide, and the like. Examples of solvents include methanol, N,N-dimethylformamide, chloroform, dichloromethane, tetrahydrofuran, and the like. Sometimes the reaction is accelerated by adding 1-hydroxybenzotriazole (HOBt). Examples of bases include triethylamine, N,N-diisopropylethylamine, pyridine, and the like.

[0739] Step A-9

[0740] Compound (A-1) can be obtained by halogenating compound (1-9). The reaction is carried out using a halogenating agent, usually at room temperature to the reflux temperature of the solvent. Although the reaction time varies according to the raw materials to be used, the solvent and the reaction temperature, it is usually 1 hour to 24 hours. The example of the halogenating agent includes phosphorus oxychloride etc.

[0741] (2) The production method described herein is suitable for producing an intermediate of a compound represented by formula (I), wherein ring E is represented by the aforementioned formula (Ec), G is a nitrogen atom, and J is a nitrogen atom, namely the following compound (A-2).

[0742]

[0743] Each symbol is as defined above.

[0744] Compound (A-2) can be obtained from compound (2-1) according to a known method (e.g., J. Med. Chem. 2016, 59, 1426).

[0745] (3) The production method described herein is suitable for preparing an intermediate of a compound represented by formula (I) wherein G is a carbon atom and J is an oxygen atom, namely the following compound (A-3).

[0746]

[0747] Among them, B 1 is boronic acid or a boric acid ester optionally having a substituent, Z A is a halogen atom, P A is a protecting group, and other symbols are as defined above.

[0748] In this formula, B 1 The optionally substituted borate ester is pinacol boron, neopentyl glycol boron, etc., and Z A The halogen atom is a chlorine atom, a bromine atom or an iodine atom. A The carboxyl group is protected by a protecting group, and is not particularly limited as long as compound (3-7) is obtained. For example, an alkyl group (specifically, a methyl group, an ethyl group) and the like can be mentioned.

[0749] Compound (A-3) can be obtained from compound (3-1) according to a known method (for example, WO2012 / 075383).

[0750] (Method B)

[0751] (1) An intermediate of the compound represented by formula (I), that is, the following compound (B-1) can be synthesized by the following method.

[0752]

[0753] Among them, Z B is a chlorine atom or a hydroxyl group, and other symbols are as defined above.

[0754] Step B-1

[0755] Compound (B-1) can be obtained by the coupling reaction of compound (A-4) and boronic acid derivative (4-1). The reaction is preferably carried out in the presence of a palladium catalyst, a phosphine ligand and a base, in a suitable solvent, and at 0 ° C to heating, particularly at room temperature to the boiling point of the solvent. Although the reaction time varies according to the raw materials and solvent to be used and the reaction temperature, it is generally 1 hour to 24 hours. The example of the palladium catalyst includes palladium acetate (II), palladium chloride (II), tris (dibenzylideneacetone) dipalladium (0) or its chloroform adduct, etc. Examples of phosphine ligands include triphenylphosphine, 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, 2-(dicyclohexylphosphino)-2,6-diisopropoxy-1,1'-biphenyl, 2-di-tert-butylphosphino-2'-4' -6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2'-6'-dimethoxybiphenyl, 2-(dicyclohexylphosphino)-2-(N,N-dimethylamino)biphenyl, tri-o-tolylphosphine, 2-(dicyclohexylphosphino)biphenyl, 2-(di-tert-butylphosphino)biphenyl, 2-(di-tert-butylphosphino)-1,1-binaphthyl, tri-tert-butylphosphine, tri-tert-butylphosphonium tetrafluoroborate, etc. A reagent in which a palladium catalyst and a phosphine ligand form a complex can also be used, for example, tetrakis(triphenylphosphine)palladium(0), 1,1-bis(diphenylphosphino)ferrocene-dichloropalladium(II), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(tricyclohexylphosphine)palladium(II), bis(tri-tert-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)] palladium (II) methanesulfonate, (2-dicyclohexylphosphino-2,6-diisopropyloxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium (II) methanesulfonate, [(2-di-tert-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) imidazole-2-ylidene] (3-chloropyridyl) dichloropalladium (II), etc. Examples of the base include sodium tert-butoxide, potassium acetate, tripotassium phosphate, cesium carbonate, potassium carbonate, sodium hydrogen carbonate, lithium bis(trimethylsilyl)amide, triethylamine, diisopropylethylamine, dicyclohexylethylamine, potassium fluoride, cesium fluoride and the like.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 an organic solvent and water, etc.

[0756] (2) The production method described herein is suitable for preparing an intermediate of a compound represented by formula (I) wherein G is a nitrogen atom and J is a nitrogen atom, namely the following compound (B-2).

[0757]

[0758] Each symbol is as defined above.

[0759] Step B-2

[0760] Compound (5-2) can be prepared by using a halogenating agent to convert the compound having R 10 The carboxylic acid form (1-10) of the substituent is converted into an acid halide and reacted with compound (5-1). The reaction is carried out using a base in a suitable solvent, typically at -20°C to the reflux temperature of the solvent. Although the reaction time varies depending on the raw materials and solvent to be used and the reaction temperature, it is generally 0.5 to 24 hours. Examples of halogenating agents include thionyl chloride, oxalyl chloride, phenylphosphonyl dichloride, and the like. Examples of bases include triethylamine, pyridine, and the like. Examples of solvents include dichloromethane, 1,2-dichloroethane, chloroform, pyridine, toluene, and the like.

[0761] Step B-3

[0762] Compound (5-3) can be obtained by deprotection reaction and cyclization reaction of compound (5-2). The deprotection reaction is carried out using an acid in a suitable solvent, typically at 0°C to the reflux temperature of the solvent. Although the reaction time varies depending on the raw materials and solvent to be used and the reaction temperature, it is typically 0.5 to 24 hours. Examples of acids include trifluoroacetic acid, hydrochloric acid, etc. Examples of solvents include dichloromethane, chloroform, tetrahydrofuran, etc. The reaction can also be carried out using only acid. The cyclization reaction is carried out using an acid in a suitable solvent, typically at room temperature to the reflux temperature of the solvent. Although the reaction time varies depending on the raw materials and solvent to be used and the reaction temperature, it is typically 0.5 to 24 hours. Examples of acids include trifluoroacetic acid, acetic acid, etc. Examples of solvents include tetrahydrofuran, N,N-dimethylformamide, 1-butanol, 2-propanol, etc.

[0763] Step B-4

[0764] Compound (B-2) can be obtained from compound (5-3) by the following two methods.

[0765] The first type can be obtained through hydrazine addition, acylation, and cyclization reactions. The reaction with hydrazine is typically carried out using a base and hydrazine in a suitable solvent at temperatures between 0°C and room temperature. Examples of bases include sodium hydride, sodium tert-butoxide, and potassium tert-butoxide. The acylation reaction is typically carried out using an acylating agent in a suitable solvent at temperatures between room temperature and the reflux temperature of the solvent. While the reaction time varies depending on the starting materials, solvent, and reaction temperature, it is typically between 0.5 and 24 hours. Examples of acylating agents include trifluoroacetic anhydride, acetic anhydride, and propionic anhydride. Examples of solvents include tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and dichloromethane. The above reaction can also be carried out using acylhydrazides instead of hydrazine and an acyl chloride or anhydride. Examples of acylhydrazides include acetohydrazide. The cyclization reaction is typically carried out using an acid in a suitable solvent at temperatures between room temperature and the reflux temperature of the solvent. While the reaction time varies depending on the starting materials, solvent, and reaction temperature, it is typically between 0.5 and 24 hours. Examples of acids include acetic acid, trifluoroacetic acid, and the like. Examples of solvents include tetrahydrofuran, N,N-dimethylformamide, 1-butanol, 2-propanol, and the like. The reaction is carried out in a suitable solvent, typically at room temperature to the reflux temperature of the solvent, after adding hydrazine and using the corresponding orthoester form. Although the reaction time varies depending on the raw materials and solvent to be used and the reaction temperature, it is generally 0.5 to 24 hours. Examples of orthoester forms include 1,1,1-triethoxyethane, 1,1,1-trimethoxypentane, and the like. Examples of solvents include toluene, tetrahydrofuran, and the like.

[0766] The second type can be obtained by converting the amide group to a thioamide group and performing hydrazine addition, acylation, and cyclization reactions. The thioamidation reaction is typically carried out using a sulfating agent in a suitable solvent at temperatures between room temperature and the reflux temperature of the solvent. Although the reaction time varies depending on the starting materials, solvent, and reaction temperature, it is typically 0.5 to 24 hours. Examples of sulfating agents include Lawesson's reagent and phosphorus pentasulfide. Examples of solvents include 1,2-dichloroethane, tetrahydrofuran, and 1,4-dioxane. The hydrazine addition reaction is typically carried out using hydrazine in a suitable solvent at temperatures between room temperature and the reflux temperature of the solvent. Although the reaction time varies depending on the starting materials, solvent, and reaction temperature, it is typically 1 to 24 hours. Examples of solvents include tetrahydrofuran, 1,4-dioxane, and N,N-dimethylformamide. The acylation reaction is typically carried out using an acylating agent in a suitable solvent at temperatures between room temperature and the reflux temperature of the solvent. Although the reaction time varies depending on the starting materials, solvent, and reaction temperature, it is typically 1 to 24 hours. Examples of acylating agents include trifluoroacetic anhydride, acetic anhydride, and propionic anhydride. The above reaction can also be carried out using acylhydrazides instead of hydrazine and acyl chlorides or anhydrides. Examples of acylhydrazides include acetohydrazide. Examples of solvents include tetrahydrofuran and N,N-dimethylformamide. The cyclization reaction is typically carried out using an acid in a suitable solvent at temperatures ranging from room temperature to the reflux temperature of the solvent. While the reaction time varies depending on the starting materials, solvent, and reaction temperature, it is typically 0.5 to 24 hours. Examples of acids include acetic acid and trifluoroacetic acid. Examples of solvents include tetrahydrofuran, N,N-dimethylformamide, 1-butanol, and 2-propanol. Following the addition of hydrazine, the reaction is carried out using the corresponding orthoester in a suitable solvent, typically at temperatures ranging from room temperature to the reflux temperature of the solvent. While the reaction time varies depending on the starting materials, solvent, and reaction temperature, it is typically 0.5 to 24 hours. Examples of orthoesters include 1,1,1-triethoxyethane and 1,1,1-trimethoxypentane. Examples of the solvent include toluene, tetrahydrofuran and the like.

[0767] (3) An intermediate of the compound represented by formula (I) wherein G is a nitrogen atom and J is a nitrogen atom can also be synthesized by the following method, namely the following compound (B-2).

[0768]

[0769] Among them, P B is a protecting group, and other symbols are as defined above.

[0770] In this formula, P B There are no particular limitations as long as the carboxyl group is protected. Examples include alkyl groups (specifically, methyl, ethyl, tert-butyl, etc.), aralkyl groups (benzyl, etc.), and the like.

[0771] Compound (B-2) can also be synthesized from compound (6-1) according to a known method (for example, the method described in WO1993 / 007129 and WO1998 / 011111).

[0772] (4) The preparation method described herein is suitable for preparing an intermediate of a compound represented by formula (I), wherein R 10 -N(R 7c )-CO-OR 7d , namely the following compounds (B-3), (B-4) (R 7c and R 7d as defined above).

[0773]

[0774] Each symbol is as defined above.

[0775] Step B-8

[0776] Compound (B-3) can be prepared from compound (7-1) synthesized according to a known method (e.g., JP-A-7-17941) by reacting the compound with a corresponding acyl halide (Cl-CO-OR 7d ) or anhydride (R 7d O-CO-O-CO-OR 7d ) reaction. The reaction is usually carried out at -20°C to the reflux temperature of the solvent using a base in a suitable solvent. The reaction time varies depending on the raw materials and solvent to be used, the reaction temperature, etc., but it is usually 30 minutes to 24 hours. Examples of the base include triethylamine, N,N-diisopropylethylamine, pyridine, etc. Examples of the solvent include dichloromethane, 1,2-dichloroethane, chloroform, N-methylpyrrolidone, pyridine, toluene, etc. In this reaction, the base to be used can also serve as a solvent.

[0777] Step B-9

[0778] Compound (B-4) can be obtained by alkylating compound (B-3). The alkylation reaction is carried out using a base and an alkylating agent such as an alkyl halide in a suitable solvent, usually at 0°C to the reflux temperature of the solvent. Although the reaction time varies depending on the raw materials and solvent to be used and the reaction temperature, it is usually 10 minutes to 24 hours. Examples of bases include inorganic bases such as sodium hydride, potassium hydroxide, potassium carbonate, etc., alkoxides such as potassium tert-butoxide, etc. Examples of solvents include N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, etc.

[0779] (5) The preparation method described herein is suitable for preparing an intermediate of a compound represented by formula (I), wherein R 10 is a hydroxyl group, which is the following compound (B-5).

[0780]

[0781] Each symbol is as defined above.

[0782] Compound (B-5) can be obtained from compound (8-1) according to a known method (eg, US Pat. No. 4,959,361).

[0783] (6) The preparation method described herein is suitable for preparing an intermediate of a compound represented by formula (I), wherein R 10 -(CH2) k -CO-N(R 7a )(R 7b ), namely the following compound (B-6).

[0784]

[0785] Among them, P C is a hydrogen atom or a protecting group, k is an integer of 1 to 6, and other symbols are as defined above.

[0786] In this formula, P C The protecting group is not particularly limited as long as it protects the carboxyl group. For example, alkyl groups (specifically, methyl, ethyl, tert-butyl, etc.), aralkyl groups (benzyl, etc.), etc. can be mentioned.

[0787] Step B-13

[0788] Compound (9-2) can be prepared by removing the protective group P of compound (9-1). C And get. When P C When P is a hydrogen atom, this step can be omitted. The deprotection conditions are not particularly limited as long as they are used for C For example, when P C When it is a methyl group or an ethyl group, a method including using an inorganic base such as sodium hydroxide in a mixed solvent of an alcohol solution and water can be cited. When it is a tert-butyl group, a method including using an acid such as hydrochloric acid, trifluoroacetic acid, etc. can be cited. C In the case of benzyl or substituted benzyl, benzyloxymethyl or the like, a method including using a catalytic hydrogenation reaction can be mentioned.

[0789] Step B-14

[0790] Compound (B-6) is prepared by condensing compound (9-2) and a compound having R 7a 、R 7b The reaction is carried out using a condensing agent in the presence of a suitable base in a suitable solvent at a temperature from 0°C to the reflux temperature of the solvent. The reaction time, condensing agent, solvent, reaction accelerator, and base are the same as those in step A-8.

[0791] (7) The production method described herein is suitable for producing an intermediate of a compound represented by formula (I), wherein ring E is represented by the aforementioned formula (Eb), G is a nitrogen atom, and J is a nitrogen atom, namely the following compound (B-7).

[0792]

[0793] Among them, P D is a protecting group, and other symbols are as defined above.

[0794] In this formula, P D There are no particular limitations as long as the amide group is protected to produce compound (10-9). For example, 4-methoxybenzyl, 2,4-dimethoxybenzyl, and the like can be cited.

[0795] Compound (B-7) can be synthesized from compound (10-1) according to the methods described in SYNLETT, 2008, 15, 2360-2364 and J. Org. Chem., 2009, 74, 4975-4981.

[0796] (8) An intermediate of a compound represented by formula (I) can also be synthesized by the following preparation method, wherein ring E is represented by the aforementioned formula (Ea), G is a nitrogen atom, J is a nitrogen atom, and R 9a is a cyanomethyl group, which is the following compound (B-8).

[0797]

[0798] Each symbol is as defined above.

[0799] Step B-24

[0800] 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 a suitable time.

[0801] Step B-25

[0802] Compound (11-3) can be obtained by reacting compound (11-2) with a base. The reaction is usually carried out in a suitable solvent at 0°C to room temperature. Although the reaction time varies depending on the raw materials and solvent to be used, the reaction temperature, etc., it is usually 0.5 hours to 24 hours. Examples of bases include aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, etc. Examples of solvents include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, etc.

[0803] Step B-26

[0804] Compound (B-8) can be obtained by converting the hydroxyl group of compound (11-3) into a leaving group and replacing it with a cyano group (cyanated). The conversion into a leaving group is carried out using a protective agent and a base in a suitable solvent, usually at 0°C to room temperature. Examples of protective agents include p-toluenesulfonyl chloride, methanesulfonyl chloride, etc. Although the reaction time varies depending on the raw materials and solvent to be used, the reaction temperature, etc., it is usually 1 hour to 24 hours. Examples of bases include triethylamine, N,N-diisopropylethylamine, etc. Examples of solvents include dichloromethane, tetrahydrofuran, etc. The cyanation reaction is carried out using a cyanating agent in a suitable solvent, usually at 0°C to the reflux temperature of the solvent. Although the reaction time varies depending on the raw materials and solvent to be used, the reaction temperature, etc., it is usually 1 hour to 24 hours. Examples of cyanating agents include sodium cyanide, trimethylsilyl cyanide, etc. Examples of solvents include dimethyl sulfoxide, acetonitrile, tetrahydrofuran, etc. When trimethylsilyl cyanide is used, tetrabutylammonium fluoride is used.

[0805] (9) An intermediate of a compound represented by formula (I) can also be synthesized by the following preparation method, wherein ring E is represented by the aforementioned formula (Ea), G is a nitrogen atom, J is a nitrogen atom, and R 9a is an alkyl group having 1 to 6 carbon atoms and substituted with a cyano group, that is, the following compound (B-9).

[0806]

[0807] Here, k is an integer from 1 to 6, and other symbols are as defined above.

[0808] Step B-27

[0809] Compound (B-9) can be obtained by cyaniding compound (12-1). The reaction conditions may be similar to those in the aforementioned step B-26.

[0810] (10) An intermediate of a compound represented by formula (I) can be synthesized by the following preparation method, wherein ring E is represented by the aforementioned formula (Ea), G is a nitrogen atom, J is a nitrogen atom, and R 9a is a cyano group, which is the following compound (B-10).

[0811]

[0812] Each symbol is as defined above.

[0813] Step B-28

[0814] Compound (13-1) can be obtained by oxidizing compound (11-3). The reaction conditions include, for example, reacting a mixture of manganese dioxide and dichloromethane at room temperature for an appropriate time.

[0815] Step B-29

[0816] Compound (B-10) can be obtained by cyaniding compound (13-1). The reaction conditions are, for example, a mixture of hydroxylamine hydrochloride and dimethyl sulfoxide is reacted under heating for an appropriate time.

[0817] (11) An intermediate of a compound represented by formula (I) can be synthesized by the following preparation method, wherein ring E is represented by the aforementioned formula (Ea), G is a nitrogen atom, J is a nitrogen atom, and R 9a is a hydrogen atom, which is the following compound (B-11).

[0818]

[0819] Each symbol is as defined above.

[0820] Step B-30

[0821] Compound (14-1) can be obtained by oxidizing compound (13-1). The reaction is carried out using an oxidizing agent in a suitable solvent, typically at 0°C to the reflux temperature of the solvent. Although the reaction time varies depending on the raw materials and solvent to be used and the reaction temperature, it is typically 0.5 hours to 24 hours. Examples of oxidizing agents include hydrogen peroxide, tert-butyl hydroperoxide, sodium chlorite, potassium permanganate, and the like. Examples of solvents include methanol, acetonitrile, water, and the like. The reaction is carried out, for example, by adding 35% hydrogen peroxide water and a sodium chlorite aqueous solution to a mixture of acetonitrile and a sodium dihydrogen phosphate aqueous solution at 0°C to room temperature.

[0822] Step B-31

[0823] Compound (B-11) can be obtained by decarboxylating compound (14-1). The reaction conditions are, for example, 150°C in the presence of copper in quinoline.

[0824] (Method C)

[0825] (1) An intermediate of the compound represented by formula (I), that is, the following compound (C-1), can also be synthesized by the following method.

[0826]

[0827] Among them, Z A is a halogen atom, Z D is a hydroxyl activating group, B 2 is a hydrogen atom, amine, alkene, acetylene, thiol, ethanol, boronic acid or boric acid ester optionally having a substituent, and other symbols are as defined above.

[0828] In this formula, ZA The halogen atom is a chlorine atom, a bromine atom or an iodine atom, and Z D The hydroxyl activating group is a sulfonyl group, such as trifluoromethanesulfonyl, toluenesulfonyl, etc. In the formula, B 2 Examples of the optionally substituted borate ester include pinacol boron, neopentyl glycol boron, and the like.

[0829] Step C-1

[0830] In this step, the hydroxyl group of compound (16-2) is converted into the active group OZ D . The reaction is preferably carried out 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. The reaction can also be carried out by combining a sulfonic acid and a condensing agent. Examples of bases include triethylamine, pyridine, lutidine, and the like. Examples of solvents include dichloromethane, 1,2-dichloroethane, chloroform, pyridine, toluene, and the like.

[0831] Step C-2

[0832] Compound (C-1) can be obtained by reacting compound (16-1) or compound (16-3) with compound (16-4).

[0833] Compound (C-1) is prepared by reacting compound (16-1) or compound (16-3) with P C OC(O)-LB 2 Amine, olefin, acetylene, thiol or ethanol (where L and P C As defined above), obtained by coupling reaction of an aryl boronic acid derivative represented by LB(OH) 2 or an ester thereof (wherein L is as defined above). The palladium catalyst, phosphine ligand, reagent in which the palladium catalyst and the phosphine ligand form a complex, base and solvent to be used are the same as those in step B-1.

[0834] When L is an aromatic group having 6 to 12 carbon atoms, a heteroaromatic group containing 5 to 12 ring atoms, an alkene or an acetylene, compound (C-1) can also be obtained by a coupling reaction of an organic metal salt of L (e.g., tin, zinc, copper, etc.) or an alkyl metal derivative of L (e.g., alkylaluminum derivatives, alkyltin derivatives, alkylborane derivatives, etc.) with compound (16-1) or compound (16-3).

[0835] (2) An intermediate of the compound represented by formula (I), that is, the following compound (C-1) can also be produced by the following method.

[0836]

[0837] Each symbol is as defined above.

[0838] Compound (C-1) can be obtained by coupling reaction of compound (17-1) and boronic acid derivative (17-2). The reaction conditions are the same as those in the aforementioned step B-1.

[0839] (3) The following steps are suitable for preparing compound (C-1), wherein L can be introduced by reaction with boronic acid (18-1) (for example, L is an unsubstituted or substituted aryl group having 6 to 10 carbon atoms, an unsubstituted or substituted heteroaryl group having 1 to 5 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms and containing 3 to 10 ring atoms, an alkene, an acetylene, etc.).

[0840]

[0841] Each symbol is as defined above.

[0842] Step C-4

[0843] Boric acid (18-1) is obtained by reacting compound (16-1) with a boronic acid derivative (e.g., bispinacolatodiboron, bisneopentanedioldiboron, etc.). The reaction is preferably carried out in the presence of a palladium catalyst, a phosphine ligand, and a base in a suitable solvent at a temperature from 0°C to heating, particularly from room temperature to the boiling point of the solvent. The palladium catalyst, phosphine ligand, base, and solvent described in Step B-1 can be used.

[0844] Step C-5

[0845] Compound (C-1) is obtained by reacting boronic acid (18-1) with compound (18-2). The reaction is preferably carried out in the presence of a palladium catalyst, a phosphine ligand, and a base in a suitable solvent at a temperature from 0°C to heating, particularly from room temperature to the boiling point of the solvent. The palladium catalyst, phosphine ligand, base, and solvent described in Step B-1 can be used.

[0846] (4) An intermediate of a compound represented by formula (I) can also be prepared by the following method, wherein ring E is represented by the aforementioned formula (Ea), G is a nitrogen atom, J is a nitrogen atom, and R 9a is a halogen atom, which is the following compound (C-2).

[0847]

[0848] Each symbol is as defined above.

[0849] Step C-6

[0850] Compound (19-1) can be obtained by reacting compound (B-11) with compound (16-4) under the same reaction conditions as those in step C-2.

[0851] Step C-7

[0852] Compound (C-2) can be obtained by reacting compound (19-1) with sulfuryl chloride, N-bromosuccinimide or the like in acetic acid or a mixture of acetic acid and chloroform at room temperature to 50°C.

[0853] (Method D)

[0854] (1) The compound represented by formula (I) wherein T is -CO-NH- and n is 2 can be prepared by the following method, namely the following compound (D-1).

[0855]

[0856] Each symbol is as defined above.

[0857] Step D-1

[0858] Compound (20-1) can be prepared by removing the protecting group P from compound (C-1). C And get. When P C When it is a hydrogen atom, this step can be omitted. C The conditions are not particularly limited as long as they are used for P C For example, when P C When it is a methyl group, there can be mentioned a method using a Lewis acid such as boron tribromide in a dichloromethane solvent, and a method using an inorganic base such as sodium hydroxide in a mixed solvent of an alcohol solution and water. When it is an ethyl group, there can be mentioned a method using an inorganic base such as sodium hydroxide in a mixed solvent of an alcohol solution and water. When it is a tert-butyl group, there can be mentioned a method using an acid such as hydrochloric acid, trifluoroacetic acid, etc. When P C In the case of benzyl or substituted benzyl, benzyloxymethyl or the like, a method using a catalytic hydrogenation reaction can be mentioned.

[0859] Step D-2

[0860] Compound (D-1) can be obtained by condensation reaction of a carboxylic acid derivative (20-1) and an amine derivative (20-2) under the same reaction conditions as those in Step B-14.

[0861] (2) A compound represented by formula (I) wherein T is -CO-NH- and n is 2 can also be produced by, for example, the following production method, namely the following compound (D-1).

[0862]

[0863] Among them, Z F is a chlorine atom or a bromine atom, and the other symbols are as defined above.

[0864] Step D-3

[0865] In this step, compound (20-1) is converted into an acyl halide (21-1). The reaction is typically carried out in a suitable solvent at a temperature of 0°C to the reflux temperature of the solvent for 1 to 24 hours. Examples of halogenating agents include thionyl chloride, oxalyl chloride, and phenylphosphonyl dichloride. Examples of bases include triethylamine and pyridine. Examples of solvents include dichloromethane, 1,2-dichloroethane, chloroform, pyridine, and toluene.

[0866] Step D-4

[0867] Compound (D-1) can be obtained by reacting an acyl halide (21-1) with an amine derivative (20-2). The reaction is carried out using a base in a suitable solvent, usually at 0°C to the reflux temperature of the solvent. Although the reaction time varies depending on the raw materials and solvent to be used and the reaction temperature, it is usually 30 minutes to 12 hours. Examples of bases include triethylamine, pyridine, etc. Examples of solvents include dichloromethane, dichloroethane, chloroform, N-methylpyrrolidone, pyridine, toluene, etc.

[0868] (Method E)

[0869] (1) A compound represented by formula (I) wherein T is -CO-NH- and n is 2 can also be prepared by the following method, namely the following compound (D-1).

[0870]

[0871] Each symbol is as defined above.

[0872] Step E-1

[0873] Compound (22-2) can be prepared by reacting amine (20-2) with HOC(O)-LZ A (where Z A The reaction conditions are the same as those in the above step B-14.

[0874] Step E-2

[0875] In this step, compound (D-1) is obtained by reacting compound (22-2) with boronic acid or its ester derivative (18-1). The reaction conditions are the same as those in step B-1.

[0876] (2) A compound represented by formula (I) wherein T is -CO-NH- and n is 2 can also be prepared by the following method, namely the following compound (D-1).

[0877]

[0878] Each symbol is as defined above.

[0879] Step E-3

[0880] Compound (23-2) can be obtained by reacting an amine derivative (20-2) with a carboxylic acid derivative (23-1). The reaction conditions are the same as those in the aforementioned step B-14. If there is a possibility of self-condensation, such as when B 2 When the amine is used, protection and deprotection steps may be appropriately added.

[0881] Step E-4

[0882] In this step, the hydroxyl group of compound (16-2) is converted into an activated group OZ D The reaction conditions are the same as those in the aforementioned step C-1.

[0883] Step E-5

[0884] In this step, compound (D-1) is obtained by reacting compound (16-1) or compound (16-3) obtained in step E-4 with compound (23-2). The reaction conditions are the same as those in step C-2.

[0885] (3) A compound represented by formula (I) wherein T is -CO-NH- and n is 2 can also be prepared by the following method, namely the following compound (D-1).

[0886]

[0887] Each symbol is as defined above.

[0888] In the above-mentioned method E(2), compound (24-1) is used instead of compound (23-1) to obtain boronic acid derivative (24-2), which is then reacted with imino chloride (A-4) to obtain compound (D-1).

[0889] The reaction conditions of step E-6 are the same as those of step B-14.

[0890] The reaction conditions of Step E-7 are the same as those of Step B-1.

[0891] (Method F)

[0892] (1) A compound represented by formula (I) wherein T is -CO-NH- and n is 2 can also be prepared by the following method, namely the following compound (D-1).

[0893]

[0894] Among them, P E is a protecting group, and other symbols are each as described above.

[0895] P in the formula E There are no particular restrictions as long as it protects the thiol group and can provide compound (25-5). For example, benzyl and the like can be mentioned.

[0896] Step F-1

[0897] Compound (25-2) can be obtained by reacting a carboxylic acid derivative (20-1) with an amine derivative (25-1) under the same reaction conditions as those in Step B-14.

[0898] Step F-2

[0899] Compound (25-4) can be prepared by reacting compound (25-2) with P E The reaction conditions are the same as those in the above step C-2.

[0900] Step F-3

[0901] Compound (25-5) can be obtained by reacting compound (25-4) with N-chlorosuccinimide or the like in an acetonitrile-hydrochloric acid mixture or in acetic acid at 0°C to 50°C.

[0902] Step F-4

[0903] Compound (D-1) is obtained by reacting a sulfonyl chloride derivative (25-5) with an amine derivative (25-6). The reaction is carried out using a base in a suitable solvent, typically at 0°C to the reflux temperature of the solvent. Although the reaction time varies depending on the raw materials and solvent to be used and the reaction temperature, it is typically 0.5 hours to 24 hours. Examples of bases include triethylamine, pyridine, etc. Examples of solvents include tetrahydrofuran, dichloromethane, acetonitrile, etc.

[0904] (2) The compound represented by the aforementioned (20-2) wherein the fused ring portion is 3-cyano-1H-indole can be prepared, for example, by the following method, to obtain the following compound (F-1).

[0905]

[0906] Among them, PF is an amino-protecting group, and other symbols are as defined above.

[0907] P in the formula F There are no particular limitations as long as the amino group can be protected to obtain compound (26-6). Examples include tert-butoxycarbonyl and benzyloxycarbonyl.

[0908] Step F-5

[0909] Compound (26-3) can be obtained by reacting a nitro compound (26-1) with vinyl magnesium bromide (26-2). The reaction is carried out in a suitable solvent, usually at -78 ° C to room temperature. Although the reaction time varies depending on the raw materials and solvent to be used and the reaction temperature, it is usually 0.5 hours to 24 hours. Examples of solvents include tetrahydrofuran.

[0910] Step F-6

[0911] Compound (26-4) can be obtained by, for example, formylation of indole derivatives (26-3), continuous preparation of oximes, and dehydration reaction. The formylation reaction uses a halogenating agent and DMF, usually carried out at room temperature to the reflux temperature of the solvent. Although the reaction time varies depending on the raw materials and solvent to be used and the reaction temperature, it is usually 1 hour to 24 hours. Examples of halogenating agents include phosphorus oxychloride, phenylphosphonyl dichloride, etc. Examples of solvents include DMF, dichlorobenzene-DMF mixed solution, etc. Compound (26-4) is obtained by adding hydroxylamine hydrochloride to the above-mentioned reaction solution and heating the mixture. The reaction is usually carried out at 40 ° C to the reflux temperature of the solvent. Although the reaction time varies depending on the raw materials and solvent to be used and the reaction temperature, it is usually 0.5 hour to 24 hours.

[0912] Step F-7

[0913] Compound (26-5) can be obtained by coupling reaction of compound (26-4) with benzophenone imine and subsequent deprotection reaction. The reaction conditions of the coupling reaction are the same as those in step C-2. As the reaction conditions for deprotection, an acid such as hydrochloric acid is reacted, or hydroxylamine is reacted. The reaction is usually carried out at room temperature to the reflux temperature of the solvent. Although the reaction time varies according to the raw materials and solvent to be used and the reaction temperature, it is generally 1 hour to 24 hours. Examples of solvents include methanol, tetrahydrofuran, 1,4-dioxane, mixed solutions thereof, etc.

[0914] Step F-8

[0915] Compound (26-7) can be obtained by reacting a sulfonyl chloride derivative (26-6) with an amine derivative (26-5). The reaction conditions in Step F-8 are the same as those in Step F-4.

[0916] Step F-9

[0917] Compound (F-1) can be prepared by removing the protecting group P from compound (26-7). F The deprotection conditions are not particularly limited as long as they are used for P F For example, when P F When it is a tert-butoxycarbonyl group, an acid can be used for deprotection. Examples of the acid include inorganic acids such as hydrochloric acid and trifluoroacetic acid. Reaction conditions include an alcohol solvent such as ethanol, an ether solvent such as tetrahydrofuran, water or a mixed solvent thereof, and a reaction at ice-cooling to 80°C for 10 minutes to about 12 hours. When P F When it is a benzyloxycarbonyl group, deprotection can be carried out by catalytic hydrogenation reduction. The example of the catalyst includes palladium carbon etc. The reaction temperature is generally room temperature to the reflux temperature of the solvent, and the hydrogen pressure is 1 to 20atm. Although the reaction time varies according to the raw materials to be used and the solvent, the reaction temperature etc., it is generally 1 hour to 48 hours.

[0918] The compound represented by the formula (I) prepared by the aforementioned method can be purified to any purity by conventional purification methods, such as concentration, extraction, chromatography, reprecipitation, recrystallization, etc. If necessary, it can be converted into a pharmaceutically acceptable salt by processing with acid or alkali in a suitable solvent (water, ethanol, ether, etc.). In addition, the compound of the present invention obtained or its pharmaceutically acceptable salt can be converted into a hydrate or solvate by using water, aqueous solvent or other solvents.

[0919] Compounds of the present invention and pharmaceutically acceptable salts thereof include racemic compounds, stereoisomers, and mixtures of these compounds, and include isotope-labeled and radiolabeled compounds. These isomers can be separated by standard separation techniques including fractional crystallization and chiral column chromatography. In addition, compounds of the present invention have asymmetric carbon atoms. Therefore, they include enantiomers and diastereomers. Diastereomeric mixtures can be separated into each diastereomer based on their physical / chemical differences according to methods known in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by chiral column chromatography, or by reacting enantiomeric compounds with appropriate optically active compounds to obtain diastereomeric mixtures, separating each diastereomer and converting each diastereomer into corresponding enantiomers. Compounds of the present invention can be any such isomer, including diastereomers, enantiomers, and mixtures thereof.

[0920] The compounds of the present invention or their pharmaceutically acceptable salts have cytotoxic effects on cancer cells. Furthermore, they induce the degradation of BET proteins in cancer cells and inhibit the binding of BET proteins to acetylated histones. Therefore, the compounds of the present invention or their pharmaceutically acceptable salts can also be used as anticancer drugs, and can also be used as BET protein degraders or BET protein inhibitors. According to the present invention, methods for treating cancer, methods for inducing BET protein degradation, and methods for inhibiting BET proteins using the compounds of the present invention or their pharmaceutically acceptable salts can also be provided.

[0921] In addition, the compounds of the present invention or their pharmaceutically acceptable salts also have the effect of inducing the decomposition of BRD4 protein in cancer cells and inhibiting the binding of BRD4 protein to acetylated histones. Therefore, the compounds of the present invention or their pharmaceutically acceptable salts can also be used as BRD4 protein degraders or BRD4 protein inhibitors. According to the present invention, cancer treatment methods, methods for inducing BRD4 protein decomposition, and methods for inhibiting BRD4 protein using the compounds of the present invention or their pharmaceutically acceptable salts can also be provided.

[0922] In the present invention, the type of cancer is not important. Specific examples include oral cancer, pharyngeal cancer, laryngeal cancer, thyroid cancer, esophageal cancer, gastric cancer, duodenal cancer, small intestinal cancer, colorectal cancer, anal cancer, liver cancer, biliary tract cancer, pancreatic cancer, gastrointestinal stromal tumors, lung cancer, skin cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, kidney cancer, urothelial cancer, brain tumors, bone and soft tissue tumors, leukemia, malignant lymphoma, multiple myeloma, sarcomas (e.g., Ewing's sarcoma, rhabdomyosarcoma, bone and soft tissue sarcomas), and the like.

[0923] In medicine, colorectal cancer is sometimes called colon cancer or rectal cancer, liver cancer is sometimes called hepatocellular carcinoma, biliary tract cancer is sometimes called bile duct cancer or gallbladder cancer, pancreatic cancer is sometimes called pancreatic duct cancer or pancreatic endocrine tumor, lung cancer is sometimes called non-small cell lung cancer, small cell lung cancer, large cell lung cancer, malignant pleural mesothelioma, or thymic tumor, skin cancer is sometimes called cutaneous malignancy or cutaneous lymphoma, uterine cancer is sometimes called cervical cancer, uterine corpus cancer, or uterine sarcoma, kidney cancer is sometimes called renal cell carcinoma, urothelial cancer is sometimes called renal pelvis cancer or ureteral cancer, and brain tumors are sometimes called gliomas. In addition, breast cancer includes subtypes such as triple-negative breast cancer, HER2-positive breast cancer, luminal A breast cancer, and luminal B breast cancer; prostate cancer includes subtypes such as hormone-dependent prostate cancer, hormone-independent prostate cancer, and castration-resistant prostate cancer; and leukemia includes subtypes such as acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LBL), chronic myeloid leukemia (CML), myeloproliferative neoplasms (MPN), chronic lymphocytic leukemia (CLL), and small lymphocytic leukemia (SLL). The malignant lymphoma includes subtypes such as follicular lymphoma (FL), MALT lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma (LPL), Waldenstrom'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), Hodgkin lymphoma (HL), etc.

[0924] In one embodiment, the compounds of the present invention or pharmaceutically acceptable salts thereof can be used to treat acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, diffuse large B-cell lymphoma, adult T-cell leukemia / lymphoma, Burkitt 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.

[0925] In another embodiment, the compounds of the present invention or pharmaceutically acceptable salts thereof can be used to treat 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.

[0926] In yet another embodiment, the compounds of the present invention or pharmaceutically acceptable salts thereof may be used to treat acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, prostate cancer, non-small cell lung cancer, ovarian cancer, and breast cancer.

[0927] In another embodiment, the compounds of the present invention or pharmaceutically acceptable salts thereof can be used to treat acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, prostate cancer, ovarian cancer, and breast cancer.

[0928] In this specification, the term "anticancer drug" encompasses cancer suppressants, antitumor agents, and the like. For the purpose of treating cancer, it has the effect of destroying, killing, or weakening cancer cells and tumor cells, as well as reducing, eliminating, or preventing the increase in abnormal cell mass growth. Furthermore, treatment refers to the act of administering a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, to an individual who has already developed a disease, illness, or symptom. Therefore, administering a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, to an individual who has already developed a disease, illness, or symptom to prevent the symptoms from worsening and recurring is one embodiment of treatment.

[0929] When the compound of the present invention is used as a medicine, the compound of the present invention is mixed with pharmaceutically acceptable additives (excipients, binders, disintegrants, flavoring agents, flavoring agents, emulsifiers, diluents, solubilizers, etc.) to obtain a pharmaceutical composition that can be administered orally or parenterally. The pharmaceutical composition can be formulated by general methods.

[0930] Although the subject to which the compound or pharmaceutical composition of the present invention is administered is not particularly limited, mammals are preferred. Examples of mammals include primates (e.g., humans, monkeys, chimpanzees), rodents (e.g., mice, rats, guinea pigs), pets (e.g., dogs, cats, rabbits), workplace animals or livestock (e.g., cattle, horses, pigs, sheep, goats), and preferably humans.

[0931] In the present specification, parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, instillation or local administration (intra-articular administration, transdermal administration, ocular administration, pulmonary or bronchial administration, nasal administration, rectal administration, etc.) and the like.

[0932] The dosage of the compound of the present invention is determined based on the age, weight, general health, sex, diet, administration time, administration method, clearance rate and symptom level of the patient being treated at that time or further consideration of other factors. Although the daily dosage of the compound of the present invention varies depending on the patient's condition and weight, the type of compound, the administration route, etc., it is, for example, about 0.001 to 100 mg / patient / day by subcutaneous, intravenous, intramuscular, intraarticular, transdermal, ocular, pulmonary or bronchial, nasal or rectal administration for parenteral administration, or about 0.01 to 1000 mg / patient / day by oral administration.

[0933] Example

[0934] The present invention is described in detail below with reference to reference examples, embodiments and test examples, which should not be construed as limiting the present invention.

[0935] Reference Example 1

[0936] (1-1)[(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate (reference example compound 1)

[0937]

[0938] Under ice cooling for 1 hour, (6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine was added. To a suspension of -6-acetic acid (300 g) in methanol (1.5 L) was added thionyl chloride (320 g) dropwise (10-25 ° C), and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, chloroform (1.5 L) and water (1 L) were added for separation, and the mixture was further extracted with chloroform (500 mL). The organic layer was washed with saturated sodium bicarbonate aqueous solution (500 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure (azeotropic distillation with methanol twice). 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] +

[0939] Reference Example 2

[0940] (2-1) 3-(4-Bromophenyl)-3-oxopropionitrile (Reference Example Compound 2-1)

[0941]

[0942] To a suspension of sodium methoxide (12.4 g) in dimethyl sulfoxide (23 mL) was added acetonitrile (12.3 g) at room temperature, and the mixture was stirred at room temperature for 2 hours. 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 under ice-cooling, water and concentrated hydrochloric acid were added, and the mixture was stirred for 0.5 hours. The precipitate was collected by filtration, and the resulting residue was dried to give the title compound (22.4 g) as a light brown solid. 1 H NMR (400MHz, DMSO-d6) δ4.75 (brs, 2H), 7.87-7.70 (m, 4H)

[0943] (2-2) (2-amino-4,5-dimethylthiophen-3-yl) (4-bromophenyl)methanone (reference example compound 2-2)

[0944]

[0945] 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 evaporating the solvent, ethyl acetate was added. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide aqueous solution and saturated brine, dried over anhydrous sodium sulfate and filtered. 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 collected by filtration to give the title compound (13.5 g) as a yellow solid. MS (ESI) m / z: 310.2, 312.1 [M + H] +

[0946] (2-3)(3S)-5-(4-Bromophenyl)-3,6,7-trimethyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepine -2-ketone (Reference Example Compound 2-3)

[0947]

[0948] Under ice-cold, (2S) -2- (tert-butyloxycarbonylamino) propionic acid (27.6 g) and pyridine (200 mL) were added to reference example compound 2-2 (43.0 g), phenylphosphonic dichloride (29.7 g) was slowly added dropwise, and the mixture was stirred under ice-cold for 1 hour. After evaporating the solvent, ethyl acetate was added, and the organic layer was washed with saturated sodium bicarbonate aqueous solution and water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Trifluoroacetic acid (53 mL) was added to a solution of the obtained residue in dichloromethane (70 mL), and the mixture was stirred at room temperature for 2 hours. Trifluoroacetic acid (53 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and azeotropically distilled with toluene. Saturated sodium bicarbonate aqueous solution was added to the obtained mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. To a suspension of the obtained residue in 2-propanol (200 mL) was added acetic acid (12 mL), and the mixture was stirred at 90 ° C for 1 hour. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate and filtered. 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. The insoluble material was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (25.7 g) as a yellow solid. MS (ESI) m / z: 363.2, 365.2 [M + H] +

[0949] (2-4)(6S)-4-(4-Bromophenyl)-2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (Reference Example Compound 2)

[0950]

[0951] Under ice cooling, sodium hydride (60%, 1.1 g) was added to a solution of Reference Example Compound 2-3 (9.6 g) in tetrahydrofuran (65 mL), and the mixture was stirred for 0.5 hours. Diethylphosphonyl chloride (5.5 g) was added, and the mixture was stirred at room temperature for 0.25 hours. Acetylhydrazine (2.9 g) and n-butanol (10 mL) were added, and the mixture was stirred at 70°C for 0.5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-hexane: ethyl acetate) to give the title compound (8.9 g) as a yellow powder. MS (ESI) m / z: 401.1, 403.1 [M+H]+

[0952] Reference Example 3

[0953] (3-1){(6S)-2,3,9-trimethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl} methyl acetate (Reference Example Compound 3)

[0954]

[0955] Under argon gas flow, reference example compound 1 (5.00g), bis (pinacolato) diboron (4.59g), potassium acetate (2.37g) and dichlorobis (tricyclohexyl phosphine) palladium (445mg) were heated to reflux in tetrahydrofuran solvent for 25 hours. In addition, dichlorobis (tricyclohexyl phosphine) palladium (445mg), bis (pinacolato) diboron (1.53g) were added, and the mixture was heated to reflux for 7 hours. Bis (pinacolato) diboron (1.53g), potassium acetate (1.18g) and dichlorobis (tricyclohexyl phosphine) palladium (445mg) were added, and the mixture was heated to reflux for 16 hours. After being cooled to room temperature, ethyl acetate was used to pass through diatomite filtration reaction mixture. Filtrate was washed twice with saturated brine, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 100:0 to 97:3) and then 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] +

[0956] Reference Example 4

[0957] (4-1) 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]diazepine -4-yl][1,1'-biphenyl]-4-carboxylic acid tert-butyl ester (reference example compound 4-1)

[0958]

[0959] Reference Example Compound 1 (5.00g), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) tert-butyl benzoate (4.03g), potassium fluoride (2.10g), 2-dicyclohexylphosphino-2'-6'-dimethoxybiphenyl (hereinafter referred to as S-phos, 495mg), palladium acetate (271mg), tetrahydrofuran (40.2mL) and water (0.78mL) were heated under reflux with stirring for 40 hours. In addition, (4-tert-butoxycarbonylphenyl) boronic acid (803mg), S-phos (247mg), palladium acetate (135mg), water (0.78mL) were added, and the mixture was stirred for 20 hours. Ethyl acetate was added to the reaction mixture, the insoluble matter in the reaction mixture was filtered off 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 extracted again with chloroform. The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 95:5). Further purification was performed by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) to obtain the title compound (6.55 g) as a crude yellow solid. MS (ESI) m / z: 557.3 [M+H] +

[0960] (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]diazepine -4-yl][1,1'-biphenyl]-4-carboxylic acid (Reference Example Compound 4)

[0961]

[0962] 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 mixture was concentrated under reduced pressure and subjected to two azeotropic distillations with toluene. The mixture was dissolved in ethyl acetate, cooled to 0°C, and saturated aqueous sodium bicarbonate solution was added little by little to a pH of 8. The organic layer was separated and washed with ethyl acetate. 1N hydrochloric acid was slowly added to the aqueous layer until pH = 5, and the mixture was extracted twice with chloroform. The organic layer was concentrated under reduced pressure to obtain a light yellow solid (6.29 g). MS (ESI) m / z: 501.2 [M+H] +

[0963] Reference Example 5

[0964] (5-1) N-(3-cyano-4-methyl-1H-indol-7-yl)-4-formylphenyl-1-sulfonamide (Reference Example Compound 5-1)

[0965]

[0966] At room temperature, pyridine (0.29 mL) was added to a solution of reference example compound 9 (100 mg) and 4-formylbenzenesulfonyl chloride (132 mg) in tetrahydrofuran (6.0 mL), and the mixture was stirred at the same temperature for 16 hours. 4-Formylbenzenesulfonyl chloride (48 mg) was added, and the mixture was stirred at room temperature for 1 hour. 1N hydrochloric acid was added to acidify the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 ~ 40: 60), and the purified product was solidified by adding chloroform, and concentrated under reduced pressure to give the title compound (126 mg) as a yellow powder. MS (ESI) m / z: 340.1 [M + H] +

[0967] (5-2) 4-(Azidomethyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide (Reference Example Compound 5-2)

[0968]

[0969] To a solution of reference example compound 5-1 (730 mg) in methanol (21.0 mL) was added sodium borohydride (163 mg) at room temperature, and the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was separated by adding 1N hydrochloric acid-water-saturated brine and ethyl acetate-acetone. The aqueous layer was extracted once with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (30.0 mL), 1,8-diazabicyclo[5.4.0]-7-undecene (0.49 mL) and 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (736 mg) were added at room temperature, and stirred at the same temperature for 15 hours. 1,8-diazabicyclo[5.4.0]-7-undecene (0.486 mL) and 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (736 mg) were added at room temperature, and the mixture was stirred at the same temperature for 4 hours. 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0 to 60:40). The purified product was solidified by adding chloroform and concentrated under reduced pressure to give the title compound (355 mg) as a light yellow powder. MS (ESI) m / z: 365.3 [MH] -

[0970] (5-3) 4-(Aminomethyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide (Reference Example Compound 5)

[0971]

[0972] To a mixture of Reference Example Compound 5-2 (350 mg) and triphenylphosphine (326 mg) were added tetrahydrofuran (10.0 mL) and water (1.0 mL), and the mixture was stirred at 50°C for 3 hours. The reaction mixture was concentrated under reduced pressure, chloroform was added to the resulting residue, and 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] +

[0973] Reference Example 6

[0974] (6-1) 4-[(3-Cyano-4-methyl-1H-indol-7-yl)sulfamoyl]benzoic acid (Reference Example Compound 6)

[0975]

[0976] Under ice cooling, 4-chlorosulfonylbenzoic acid (1.42 g) was added to a mixture of reference compound 9 (1.00 g) and tetrahydrofuran (30.0 mL), and the mixture was stirred at room temperature for 24 hours. 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. Diethyl ether was added to the obtained residue, and the precipitate was collected by filtration to give the title compound (1.81 g) as a brown solid. MS (ESI) m / z: 354.1 [MH] -

[0977] Reference Example 7

[0978] (7-1) 7-Bromo-4-methyl-1H-indole (Reference Example Compound 7)

[0979]

[0980] To a tetrahydrofuran solution (35.0 mL) of 1-bromo-4-methyl-2-nitrobenzene (1.08 g) was added -40°C 1M vinylmagnesium bromide / tetrahydrofuran solution (15.0 mL). The mixture was stirred at the same temperature for 40 minutes. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture for liquid separation. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 98: 2 to 95: 5) to give the title compound (600 mg) as a yellow oil. 1 H NMR (400MHz, CDCl3) δppm2.52 (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)

[0981] Reference Example 8

[0982] (8-1) 7-Bromo-4-methyl-1H-indole-3-carbonitrile (Reference Example Compound 8)

[0983]

[0984] At room temperature, phenylphosphonic acid dichloride (0.23 mL) was added to a solution (1.35 mL) of Reference Example Compound 7 (284 mg) in N,N-dimethylformamide. After stirring at room temperature for 0.5 hours, phenylphosphonic acid dichloride (0.04 mL) was added, and the mixture was further stirred at the same temperature for 0.5 hours. Hydroxylamine hydrochloride (188 mg) was added to the reaction mixture at room temperature, and the mixture was heated and stirred at 60°C for 1 hour and at 100°C for 2 hours. The reaction mixture was diluted with ethyl acetate, washed twice with saturated sodium bicarbonate aqueous solution, washed once with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2) to give the title compound (220 mg) as a light brown solid. 1 H NMR (400MHz, CDCl3) δppm2.75 (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)

[0985] Reference Example 9

[0986] (9-1) 7-Amino-4-methyl-1H-indole-3-carbonitrile (Reference Example Compound 9)

[0987]

[0988] Reference Example Compound 8 (215 mg), benzophenone imine (240 mg), [1,3-bis (2,6-di-3-pentylphenyl) imidazole-2-ylidene] (3-chloropyridyl) dichloropalladium (II) (Pd-PEPPSI-IPent catalyst, 22 mg), tetrahydrofuran (2.3 mL) was added 1.3 M bis (trimethylsilyl) lithium amide / tetrahydrofuran solution (2.5 mL), and the mixture was stirred at 120 ° C under a nitrogen atmosphere and microwave irradiation for 0.5 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (2.3 mL)-methanol (2.3 mL), hydroxylamine hydrochloride (159 mg) and sodium acetate (225 mg) were added at room temperature, and the mixture was stirred at the same temperature for 4 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2) to give the title compound (139 mg) as a light brown solid. MS (ESI) m / z: 172.1 [M + H] +

[0989] Reference Example 10

[0990] (10-1)[(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]diazepine -6-yl] methyl acetate (reference example compound 10-1)

[0991]

[0992] To a solution of Reference Example Compound 4 (500 mg) and 4-bromobenzylamine (223 mg) in N,N-dimethylformamide (5.0 mL) was added N,N-diisopropylethylamine (0.52 mL) and HATU (456 mg) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed three times with saturated brine-water (1:1), washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform: methanol = 98:2 to 90:10) to obtain the title compound (643 mg) as a light yellow powder. MS (ESI) m / z: 668.3, 670.3 [M+H] +

[0993] (10-2) {(6S)-4-[4'-({[4-(benzylthio)phenyl]methyl}carbamoyl)[1,1'-biphenyl]-4-yl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl} methyl acetate (reference example compound 10-2)

[0994]

[0995] 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 a nitrogen atmosphere and microwave irradiation. After cooling to room temperature, the reaction mixture was directly purified by NH silica gel column chromatography (hexane:ethyl acetate = 50:50 to 0:100) to obtain the title compound (613 mg) as a light yellow powder. MS (ESI) m / z: 712.4 [M+H] +

[0996] (10-3){(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]diazepine -6-yl} methyl acetate (Reference Example Compound 10)

[0997]

[0998] Under ice cooling, N-chlorosuccinimide (390 mg) was added to a solution of acetonitrile (12.0 mL)-2N hydrochloric acid (2.4 mL) of reference example compound 10-2 (594 mg), and the mixture was stirred at the same temperature for 1.5 hours. N-chlorosuccinimide (23 mg) was added to the reaction mixture, and the mixture was stirred at the same temperature for 0.5 hours. Saturated brine-water (1: 1) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2) to give the title compound (570 mg) as a light yellow powder. MS (ESI) m / z: 670.4 [M-Cl + H2O] + ; 1 H NMR (400MHz, CDCl3) δppm1.75(3H,d,J=0.64Hz), 2.41-2.46(3H,m), 2.70(3H,s), 3.66(2H,dd,J=7.06,3.72Hz), 3.79(3H,s), 4.44(1H,d,J=5.65Hz ), 4.67(1H,dd,J=7.77,6.36Hz), 4.80(2H,d,J=6.04Hz), 7.55-7.63(6H, m), 7.68 (2H, m, J = 8.61Hz), 7.90 (2H, m, J = 8.61Hz), 8.02 (2H, d, J = 7.74Hz)

[0999] Reference Example 11

[1000] (11-1) tert-Butyl (2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamate (Reference Example Compound 11-1)

[1001]

[1002] A mixed solution of Reference Example Compound 9 (120 mg), tert-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 mixture was diluted with ethyl acetate, washed twice with 1N hydrochloric acid, washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The resulting residue was suspended and washed with hexane and collected by filtration to obtain the title compound (301 mg) as a light yellow solid. MS (ESI) m / z: 455.4 [M+H] +

[1003] (11-2) 4-(2-aminoethyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide hydrochloride (Reference Example Compound 11)

[1004]

[1005] To Example Compound 11-1 (301 mg) was added a 4M hydrogen chloride / 1,4-dioxane solution (3.0 mL) at room temperature. After stirring at the same temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. The residue was suspended and washed with diethyl ether and collected by filtration to obtain the title compound (260 mg) as a milky white solid. MS (ESI) m / z: 355.1 [M+H] +

[1006] Reference Example 12

[1007] (12-1) 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]diazepine -4-yl][1,1'-biphenyl]-4-carboxylic acid tert-butyl ester (Reference Example Compound 12-1)

[1008]

[1009] Reference example compound 3 (300 mg) was dissolved in tetrahydrofuran (3.0 mL), tert-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 a nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate and the insoluble matter was filtered off through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 ~ 98: 2, pre-column: NH silica gel) to obtain the title compound (346 mg) as a white crude purified powder. MS (ESI) m / z: 575.4 [M + H] +

[1010] (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]diazepine -4-yl][1,1'-biphenyl]-4-carboxylic acid (Reference Example Compound 12)

[1011]

[1012] Reference example compound 12-1 (240 mg) was dissolved in dichloromethane (2.0 mL), trifluoroacetic acid (2.0 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and extracted twice with saturated aqueous sodium bicarbonate solution. The aqueous layers were combined, and 2N hydrochloric acid was added little by little under ice cooling to pH = 4. The mixture was extracted twice with chloroform. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure to give the title compound (205 mg) as a white powder. MS (ESI) m / z: 519.1 [M + H] +

[1013] Reference Example 13

[1014] (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]diazepine -4-yl][1,1'-biphenyl]-4-carboxylic acid (Reference Example Compound 13)

[1015]

[1016] 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 a nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate and extracted twice with saturated sodium bicarbonate aqueous solution. The aqueous layers were combined and 2N hydrochloric acid was added little by little under ice cooling to pH = 1. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure to give the title compound (73 mg) as a white powder. MS (ESI) m / z: 535.1, 537.1 [M + H] +

[1017] Reference Example 14

[1018] (14-1) 4-Bromo-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide (Reference Example Compound 14)

[1019]

[1020] At room temperature, 4-bromobenzenesulfonyl chloride (929 mg) was added to a tetrahydrofuran solution (12.0 mL) of reference example compound 9 (622 mg) and pyridine (2.92 mL), and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed once with saturated brine-water (1: 1), washed once with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was suspended and washed with chloroform, and the title compound (1061 mg) was collected by filtration to obtain a beige powder. MS (ESI) m / z: 390.2, 392.1 [M+H] +

[1021] Reference Example 15

[1022] (15-1) 7-Amino-4-bromo-1H-indole-3-carbonitrile (Reference Example Compound 15)

[1023]

[1024] Phenylphosphonic 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 added, and the mixture was stirred at 70°C for 1 hour. Then, hydroxylamine hydrochloride (2.42 g) was added, and the mixture was stirred at 100°C for 2 hours. Ethylenediamine (2.02 mL) and methanol (22.0 mL) were added, and the mixture was stirred at 70°C for 1 hour. After cooling to room temperature, methanol was evaporated under reduced pressure, and the resulting residue was separated by adding ethyl acetate, saturated sodium bicarbonate aqueous solution, and saturated brine. The organic layer was washed twice with a mixture of saturated sodium bicarbonate aqueous solution and saturated brine, once with water, and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The resulting residue was suspended and washed with ethyl acetate, collected by filtration, and dried under reduced pressure to yield the title compound (260 mg) as a brown powder. The solvent was evaporated from the filtrate under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 50:50 to 75:25) to yield the title compound (104 mg) as a brown solid. MS (ESI) m / z: 236.0, 237.9 [M+H] +

[1025] Reference Example 16

[1026] (16-1) 7-Bromo-4-ethyl-1H-indole-3-carbonitrile (Reference Example Compound 16-1)

[1027]

[1028] To a solution of 7-bromo-4-ethyl-1H-indole (3.90 g) in N,N-dimethylformamide (17.4 mL) was added phenylphosphonic dichloride (3.64 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes and at 70°C for 40 minutes. Hydroxylamine hydrochloride (2.42 g) was added, and the mixture was stirred at 70°C for 30 minutes and at 80°C for 30 minutes. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, ice-cooled, and saturated aqueous sodium bicarbonate solution was added with stirring. The mixture was extracted twice with ethyl acetate, the extracts combined, washed twice with a mixed solution of saturated brine and saturated aqueous sodium bicarbonate solution, washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10 to 70:30). Toluene was added to the residue, and the mixture was concentrated under reduced pressure. This operation was repeated twice to obtain the title compound (3.12 g) as a light yellow solid. MS (ESI) m / z: 246.9, 248.9 [MH] -

[1029] (16-2) 7-Amino-4-ethyl-1H-indole-3-carbonitrile (Reference Example Compound 16)

[1030]

[1031] To a mixture of Reference Example compound 16-1 (2.12 g), benzophenone imine (2.16 g), and [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II) (Pd-PEPPSI-IPent catalyst, 202 mg) was added 1.3 M lithium bis(trimethylsilyl)amide / tetrahydrofuran solution (23.0 mL) at room temperature, and the mixture was stirred at 120 ° C. under a nitrogen atmosphere and microwave irradiation for 1 hour. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (11.0 mL)-methanol (11.0 mL), hydroxylamine hydrochloride (1.48 g) and sodium acetate (2.09 g) were added at room temperature, and the mixture was stirred at the same temperature for 16 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed once with a mixed solution of saturated brine and water, washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 ~ 98: 2) to give the title compound (954 mg) as a light brown solid. MS (ESI) m / z: 186.1 [M + H] +

[1032] Reference Example 17

[1033] (17-1) tert-Butyl [(1R)-1-(4-bromophenyl)ethyl]carbamate (Reference Example Compound 17-1)

[1034]

[1035] To a dichloromethane solution (45.0 mL) of (R)-1-(4-bromophenyl)ethylamine (3.00 g) and trimethylamine (2.50 mL) was added di-tert-butyl carbonate (3.60 g) at room temperature and stirred at room temperature for 14 hours. 1N hydrochloric acid was added to the reaction mixture for separation. The aqueous layer was extracted once with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The resulting residue was suspended and washed with hexane and collected by filtration to obtain the title compound (4.36 g) as a white solid. MS (ESI) m / z: 300.2, 302.1 [M+H] +

[1036] (17-2) tert-Butyl {(1R)-1-[4-(benzylthio)phenyl]ethyl}carbamate (Reference Example Compound 17-2)

[1037]

[1038] 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 a nitrogen atmosphere and microwave irradiation. Ethyl acetate was added to the reaction mixture, the insoluble matter was filtered off through celite, 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 give the title compound (4.91 g) as a light yellow solid. MS (ESI) m / z: 344.3 [M + H] +

[1039] (17-3) tert-Butyl {(1R)-1-[4-(chlorosulfonyl)phenyl]ethyl}carbamate (Reference Example Compound 17-3)

[1040]

[1041] Under ice-cold, N-chlorosuccinimide (4.30 g) was added to a solution of acetonitrile (50.0 mL)-2N hydrochloric acid (10.0 mL) of reference example compound 17-2 (2.72 g), and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90: 10 ~ 75: 25) to obtain the title compound (2.21 g) as a white solid. 1 H NMR (400MHz, CDCl3) δppm1.32-1.51(12H,m), 4.87(2H,brs), 7.48-7.60(2H,m), 7.93-8.06(2H,m)

[1042] (17-4) tert-Butyl [(1R)-1-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamate (Reference Example Compound 17-4)

[1043]

[1044] At room temperature, reference example compound 9 (1.18 g) and pyridine (2.77 mL) were added to a solution of reference example compound 17-3 (2.20 g) in tetrahydrofuran (66.0 mL), and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed twice with 1N hydrochloric acid, washed once with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The residue was suspended and washed with chloroform, filtered to give 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 give the title compound (0.84 g) as a light brown solid. MS (ESI) m / z: 455.3 [M+H] +

[1045] (17-5) 4-[(1R)-1-aminoethyl]-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide hydrochloride (Reference Example Compound 17)

[1046]

[1047] To Example Compound 17-4 (2.47 g) was added a 4M hydrogen chloride / 1,4-dioxane solution (25.0 mL) at room temperature. After stirring at the same temperature for 3 hours, the reaction mixture was diluted with diethyl ether, and the solid was suspended, washed, and collected by filtration to obtain the title compound (2.27 g) as a milky white solid. MS (ESI) m / z: 355.2 [M+H] +

[1048] Reference Example 18

[1049] (18-1) 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]diazepine -4-yl][1,1'-biphenyl]-4-carboxylic acid tert-butyl ester (Reference Example Compound 18-1)

[1050]

[1051] Reference example compound 3 (300 mg) was dissolved in tetrahydrofuran (3.0 mL), tert-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 a nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate and the insoluble matter was filtered off through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 50: 50 ~ 0: 100) to obtain the title compound (300 mg) as a white powder. MS (ESI) m / z: 575.3 [M + H] +

[1052] (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]diazepine -4-yl][1,1'-biphenyl]-4-carboxylic acid (Reference Example Compound 18)

[1053]

[1054] Reference example compound 18-1 (290 mg) was dissolved in dichloromethane (2.0 mL), trifluoroacetic acid (2.0 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and extracted twice with saturated aqueous sodium bicarbonate solution. The aqueous layers were combined, 2N hydrochloric acid was added little by little under ice cooling to pH = 4. The mixture was extracted twice with chloroform. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure to give the title compound (246 mg) as a white powder. MS (ESI) m / z: 519.3 [M + H] +

[1055] Reference Example 19

[1056] (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]diazepine -4-yl][1,1'-biphenyl]-4-carboxylic acid (Reference Example Compound 19)

[1057]

[1058] 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 a nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate and extracted twice with saturated sodium bicarbonate aqueous solution. The aqueous layers were combined and 2N hydrochloric acid was added in batches under ice cooling to pH = 1. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure to give the title compound (247 mg) as a light yellow powder. MS (ESI) m / z: 535.3, 537.3 [M + H] +

[1059] Reference Example 20

[1060] (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]diazepine -4-yl]-3-methyl[1,1'-biphenyl]-4-carboxylic acid (Reference Example Compound 20)

[1061]

[1062] 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 a nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate and extracted twice with saturated sodium bicarbonate aqueous solution. The aqueous layers were combined and 2N hydrochloric acid was added little by little under ice cooling to pH = 1. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure to give the title compound (229 mg) as a white crude purified powder. MS (ESI) m / z: 515.3 [M + H] +

[1063] Reference Example 21

[1064] (21-1) tert-Butyl ({4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamate (Reference Example Compound 21-1)

[1065]

[1066] To a solution of Reference Example Compound 16 (347 mg) in tetrahydrofuran (9.4 mL) was added tert-butyl N-[(4-chlorosulfonylphenyl)methyl]carbamate (630 mg) and pyridine (0.76 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed twice with 1N hydrochloric acid, washed once with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The resulting residue was suspended and washed with diethyl ether-hexane (1: 1), and the title compound (730 mg) was collected by filtration as a beige solid. MS (ESI) m / z: 453.3 [MH] -

[1067] (21-2) 4-(Aminomethyl)-N-(3-cyano-4-ethyl-1H-indol-7-yl)benzene-1-sulfonamide hydrochloride (Reference Example Compound 21)

[1068]

[1069] To Reference Example Compound 21-1 (720 mg) was added a 4M hydrogen chloride / 1,4-dioxane solution (7.2 mL) at room temperature. After stirring at the same temperature for 16 hours, the reaction mixture was diluted with diethyl ether, and the solid was suspended and washed, then collected by filtration to obtain the title compound (653 mg) as a beige solid. MS (ESI) m / z: 355.0 [M+H] +

[1070] Reference Example 22

[1071] (22-1) tert-Butyl [(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamate (Reference Example Compound 22-1)

[1072]

[1073] At room temperature, reference example compound 17-3 (570 mg) and pyridine (0.65 mL) were added to a solution of reference example compound 16 (300 mg) in tetrahydrofuran (8.0 mL), and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed twice with 1N hydrochloric acid, washed once with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was suspended and washed with hexane-chloroform (15: 1), and the title compound (710 mg) was collected by filtration to obtain a light brown solid. MS (ESI) m / z: 467.3 [MH] -

[1074] (22-2) 4-[(1R)-1-aminoethyl]-N-(3-cyano-4-ethyl-1H-indol-7-yl)benzene-1-sulfonamide hydrochloride (Reference Example Compound 22)

[1075]

[1076] To Reference Example Compound 22-1 (701 mg) was added a 4M hydrogen chloride / 1,4-dioxane solution (7.0 mL) at room temperature. After stirring at the same temperature for 16 hours, the reaction mixture was diluted with diethyl ether and the solid was collected by filtration to obtain the title compound (653 mg) as a beige solid. MS (ESI) m / z: 369.1 [M+H] +

[1077] Reference Example 23

[1078] (23-1) tert-Butyl (2-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamate (Reference Example Compound 23-1)

[1079]

[1080] To a solution of Reference Example Compound 16 (300 mg) in tetrahydrofuran (8.0 mL) was added tert-butyl N-2-[4-(chlorosulfonyl)phenyl]ethylcarbamate (570 mg) and pyridine (0.65 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed twice with 1N hydrochloric acid, washed once with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The resulting residue was suspended and washed with diethyl ether-hexane (1: 1), and the title compound (710 mg) was collected by filtration as a beige solid. MS (ESI) m / z: 467.3 [MH] -

[1081] (23-2) 4-(2-aminoethyl)-N-(3-cyano-4-ethyl-1H-indol-7-yl)benzene-1-sulfonamide hydrochloride (Reference Example Compound 23)

[1082]

[1083] To Reference Example Compound 23-1 (702 mg) was added a 4M hydrogen chloride / 1,4-dioxane solution (7.0 mL) at room temperature. After stirring at the same temperature for 16 hours, the reaction mixture was diluted with diethyl ether, and the solid was suspended and washed, then collected by filtration to obtain the title compound (610 mg) as a beige solid. MS (ESI) m / z: 369.1 [M+H] +

[1084] Example 1

[1085] (1-1)[(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate (Example Compound 1)

[1086]

[1087] At room temperature, 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), and the mixture was stirred at the same temperature for 5 hours. Under ice-cold conditions, water was added to the reaction mixture, and the mixture was extracted twice with chloroform. The combined organic layer was washed twice with water, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified using preparative HPLC (10 mM aqueous ammonium carbonate solution-acetonitrile) to obtain the title compound (49 mg) as a light yellow powder. MS (ESI) m / z:823.5[M+H] +

[1088] Example 2

[1089] (2-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 2)

[1090]

[1091] A mixture of Reference Example Compound 12 (78 mg), Reference Example Compound 5 (56 mg), N,N-diisopropylethylamine (0.052 mL), and HATU (86 mg) was stirred in N,N-dimethylformamide (3.0 mL) at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was stirred. The resulting solid was collected by filtration and purified by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) to obtain the title compound (86 mg) as a white solid. MS (ESI) m / z: 841.6 [M+H] +

[1092] Example 3

[1093] (3-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 3)

[1094]

[1095] A mixture of Reference Example Compound 13 (80 mg), Reference Example Compound 5 (56 mg), N,N-diisopropylethylamine (0.052 mL), and HATU (86 mg) was stirred in N,N-dimethylformamide (3 mL) at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was stirred. The resulting solid was collected by filtration and purified by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) to obtain the title compound (115 mg) as a light yellow solid. MS (ESI) m / z: 857.6, 859.6 [M+H] +

[1096] Example 4

[1097] (4-1) tert-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]diazepine -4-yl]phenyl}pyrrolidine-3-carboxylic acid tert-butyl ester (Example Compound 4-1)

[1098]

[1099] Under a nitrogen stream, Reference Example Compound 1 (200 mg), tert-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 to reflux for 100 minutes in a tetrahydrofuran (1.0 mL) solvent. The reaction mixture was cooled, diluted with ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the mixture was filtered through activated carbon, washed with methanol and tetrahydrofuran, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 100:0 to 95:5) to obtain the title compound (266 mg) as a light yellow powder. MS (ESI) m / z: 550.3 [M+H] +

[1100] (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]diazepine -4-yl]phenyl}pyrrolidine-3-carboxylic acid (Example Compound 4-2)

[1101]

[1102] To a solution of Example Compound 4-1 (266 mg) in dichloromethane (1.0 mL) was added trifluoroacetic acid (1.0 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was azeotropically distilled with chloroform-toluene 3 times. The residue was dissolved in ethyl acetate, and N,N-diisopropylethylamine (0.30 mL) was added in small portions with stirring. Hexane (2.5 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The resulting solid was filtered and washed with an ethyl acetate-hexane mixture (2: 1) to give the title compound (181 mg) as a yellow powder. MS (ESI) m / z: 494.3 [M+H] +

[1103] (4-3)[(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]diazepine -6-yl] methyl acetate (Example Compound 4)

[1104]

[1105] The title compound (111 mg) was obtained as a yellow powder by the same reaction and treatment as (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] +

[1106] Example 5

[1107] (5-1){(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]diazepine -6-yl}methyl acetate (Example Compound 5-1)

[1108]

[1109] 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 a nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate, washed twice with saturated brine-water (1: 1) and once with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2 ~ 90: 10, pre-column: NH silica gel) to give the title compound (63 mg) as a light yellow viscous compound. MS (ESI) m / z: 435.3 [M + H] +

[1110] (5-2){(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]diazepine -6-yl} methyl acetate (Example Compound 5-2)

[1111]

[1112] To Example Compound 5-1 (60 mg) in dichloromethane (1.2 mL) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benzidoyl-3-(1H)-one (Dess-Martin reagent, 71 mg), and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate solution and saturated sodium thiosulfate solution were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed twice with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2 to 90: 10) to give the title compound (59 mg) as a light yellow viscous compound. MS (ESI) m / z: 433.3 [M+H] +

[1113] (5-3)[(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]diazepine -6-yl] methyl acetate (Example Compound 5)

[1114]

[1115] To a solution of Example Compound 5-2 (57 mg) and 2-methyl-but-2-ene (0.021 mL) in acetonitrile (3.0 mL) was added a solution of 80% sodium chlorite (18 mg) and sodium dihydrogen phosphate (19 mg) in water (1.0 mL), and the mixture was stirred at room temperature for 30 minutes. 2-Methyl-but-2-ene (0.021 mL), 80% sodium chlorite (18 mg), and sodium dihydrogen phosphate (19 mg) were added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for an additional 30 minutes. The reaction mixture was concentrated under reduced pressure, ethanol was added, and the mixture was concentrated again under reduced pressure. To the resulting residue were added Reference Example Compound 5 (47 mg), N,N-diisopropylethylamine (0.11 mL), and N,N-dimethylformamide (2.0 mL) at room temperature, and finally HATU (57 mg) was added. The mixture was stirred at the same temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed three times with saturated brine-water (1:1) and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 90:10) to obtain the title compound (17 mg) as a beige powder. MS (ESI) m / z: 771.4 [M+H] +

[1116] Example 6

[1117] (6-1){(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]diazepine -6-yl} methyl acetate (Example Compound 6-1)

[1118]

[1119] 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 under a nitrogen atmosphere and microwave irradiation for 2 hours. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5 to 90: 10) to give the title compound (15 mg) as a beige powder. MS (ESI) m / z: 434.3 [M + H] +

[1120] (6-2) {(6S)-4-[4-(3-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]benzamide}prop-1-yn-1-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl}methyl acetate (Example Compound 6)

[1121]

[1122] At room temperature, N,N-diisopropylethylamine (0.11 mL) and HATU (15 mg) were added to a solution of Example Compound 6-1 (14 mg) and Reference Example Compound 6 (13 mg) in N,N-dimethylformamide (0.4 mL), and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed three times with saturated brine-water (1:1) and once with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 98:2 to 90:10) to give the title compound (20 mg) as a white powder. MS (ESI) m / z: 771.4 [M+H] +

[1123] Example 7

[1124] (7-1) 7-Bromo-3-chloro-1H-indole (Example Compound 7-1)

[1125]

[1126] To a solution of 7-bromo-1H-indole (500 mg) in N,N-dimethylformamide (5.0 mL) was added N-chlorosuccinimide (358 mg) at room temperature, and the mixture was stirred at the same temperature for 2 hours. Saturated aqueous sodium bicarbonate solution and saturated sodium thiosulfate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5 to 90: 10) to give the title compound (577 mg) as a light yellow solid. 1 H NMR (400MHz, CDCl3) δppm7.09 (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)

[1127] (7-2) 3-Chloro-1H-indol-7-amine (Example Compound 7-2)

[1128]

[1129] The title compound (163 mg) was obtained as a light brown solid by the same reaction and treatment as in Reference Example 9 except that Example Compound 7-1 (570 mg) was used instead of Reference Example Compound 8. MS (ESI) m / z: 167.0, 169.0 [M+H] +

[1130] (7-3)[(6S)-4-{4'-[({4-[(3-chloro-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate (Example Compound 7)

[1131]

[1132] At room temperature, 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), and the mixture was stirred at the same temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed once with 1N hydrochloric acid and once with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2 to 90: 10) to give the title compound (37 mg) as a white solid. MS (ESI) m / z: 818.4, 820.4 [M+H] +

[1133] Example 8

[1134] (8-1) 7-Bromo-3-chloro-4-methyl-1H-indole (Example Compound 8-1)

[1135]

[1136] The title compound (212 mg) was obtained as a yellow oil by the same reaction and treatment as in (7-1) except that 7-bromo-4-methyl-1H-indole (200 mg) was used instead of 7-bromo-1H-indole in Example 7. 1 HNMR (400MHz, CDCl3) δppm2.75 (3H, d, J = 0.64Hz), 6.77 (1H, d, J = 7.87Hz), 7.20 (1H, d, J = 2.70Hz), 7.24 (1H, d, J = 7.71Hz), 8.22 (1H, brd, J = 1.67Hz)

[1137] (8-2) 3-Chloro-4-methyl-1H-indol-7-amine (Example Compound 8-2)

[1138]

[1139] The title compound (56 mg) was obtained as a light brown solid by the same reaction and treatment as in Reference Example 9 except that Example Compound 8-1 (205 mg) was used instead of Reference Example Compound 8. MS (ESI) m / z: 181.0, 183.0 [M+H] +

[1140] (8-3)[(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]diazepine -6-yl] methyl acetate (Example Compound 8)

[1141]

[1142] The title compound (44 mg) was obtained as a gray powder by the same reaction and treatment as in (7-3), except that Example Compound 8-2 (20 mg) was used instead of Example Compound 7-2 and Reference Example Compound 10 (50 mg) was used in Example 7. MS (ESI) m / z: 832.4, 834.4 [M+H] +

[1143] Example 9

[1144] (9-1) 7-Bromo-1H-indole-3-carbonitrile (Example Compound 9-1)

[1145]

[1146] The title compound (548 mg) was obtained as a light brown solid by the same reaction and treatment as in Reference Example 8 except that 7-bromo-1H-indole (500 mg) was used instead of Reference Example Compound 7. 1 H NMR (400MHz, CDCl3) δppm7.20 (1H, t, J = 7.83Hz), 7.50 (1H, dd, J = 7.71, 0.77Hz), 7.73 (1H, d, J = 7.96Hz), 7.80 (1H, d, J = 2.95Hz), 8.84 (1H, brs)

[1147] (9-2) 7-Amino-1H-indole-3-carbonitrile (Example Compound 9-2)

[1148]

[1149] The title compound (322 mg) was obtained as a light brown solid by the same reaction and treatment as in Reference Example 9, except that Example compound 9-1 (542 mg) was used instead of Reference Example compound 8. 1H NMR (400MHz, DMSO-d6) δppm5.33(2H,s), 6.47(1H,dd,J=7.58,0.90Hz), 6.81(1H,dd,J=7.96,0.90Hz), 6.94(1H,t,J=7.77Hz), 8.13(1H,s), 11.73(1H,brs)

[1150] (9-3)[(6S)-4-{4'-[({4-[(3-cyano-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate (Example Compound 9)

[1151]

[1152] In Example 7, the title compound (40 mg) was obtained as a beige powder by the same reaction and treatment as (7-3) except that Example Compound 9-2 (15 mg) was used instead of Example Compound 7-2. MS (ESI) m / z: 809.4 [M+H] +

[1153] Example 10

[1154] (10-1) 4-Methyl-1H-indol-7-amine (Example Compound 10-1)

[1155]

[1156] The title compound (29 mg) was obtained as a light brown solid by the same reaction and treatment as in Reference Example 9 except that Reference Example Compound 7 (92 mg) was used instead of Reference Example Compound 8. MS (ESI) m / z: 147.1 [M+H] +

[1157] (10-2)[(6S)-2,3,9-trimethyl-4-{4'-[({4-[(4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate (Example Compound 10)

[1158]

[1159] In Example 7, except that Example Compound 10-1 (28 mg) was used instead of Example Compound 7-2 and Reference Example Compound 10 (120 mg) was used, the reaction and treatment were carried out in the same manner as (7-3) to obtain the title compound (107 mg) as a beige powder. MS (ESI) m / z: 798.5 [M+H] +

[1160] Example 11

[1161] (11-1)[(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate (Example Compound 11)

[1162]

[1163] A mixture of Reference Example Compound 4 (75 mg), Reference Example Compound 11 (65 mg), N,N-diisopropylethylamine (0.078 mL), and HATU (86 mg) was stirred in N,N-dimethylformamide (3.0 mL) at room temperature for 2 hours. Water was added to the reaction mixture, the mixture was stirred, and the resulting solid was collected by filtration. The solid was purified by silica gel column chromatography (chloroform: methanol = 100:0 to 95:5) to obtain the title compound (115 mg) as a light yellow solid. MS (ESI) m / z: 837.4 [M+H] +

[1164] Example 12

[1165] (12-1) Methyl 3-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]benzoate (Example Compound 12-1)

[1166]

[1167] Reference Example Compound 9 (200 mg), methyl 3-(chlorosulfonyl)benzoate (302 mg), and triethylamine (0.33 mL) were stirred in chloroform (5.0 mL) at room temperature for 7 hours. Water was added to the reaction mixture, 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 (hexane: ethyl acetate = 70:30 to 30:70) and silica gel column chromatography (chloroform: methanol = 100:0 to 95:5) to obtain the title compound (190 mg) as a light yellow solid. MS (ESI) m / z: 370.3 [M+H] +

[1168] (12-2) N-(3-cyano-4-methyl-1H-indol-7-yl)-3-(hydroxymethyl)benzene-1-sulfonamide (Example Compound 12-2)

[1169]

[1170] A solution of Example Compound 12-1 (190 mg) in tetrahydrofuran (5.0 mL) was cooled to 0°C, 2M lithium borohydride / tetrahydrofuran solution (0.77 mL) and methanol (0.063 mL) were added, and the mixture was stirred for 4 hours while allowing it to naturally warm to room temperature. 2M lithium borohydride / tetrahydrofuran solution (0.77 mL) was added, and the mixture was stirred at room temperature for 3 hours. 1N hydrochloric acid was added little by little to the reaction mixture, the mixture was stirred, and then chloroform was added and the mixture was stirred. The aqueous layer was removed by a phase separator, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 ~ 95: 5) to give the title compound (124 mg) as a white solid. MS (ESI) m / z: 342.1 [M + H] +

[1171] (12-3) 3-(Azidomethyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide (Example Compound 12-3)

[1172]

[1173] To a solution of Example Compound 12-2 (124 mg) in tetrahydrofuran (5.0 mL) were added 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (207 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (111 mg), and the mixture was stirred at room temperature for 4 hours. 1N hydrochloric acid and ethyl acetate were added to the reaction mixture, and the mixture was stirred. The organic layer was separated, washed twice with brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20 to 50:50) to obtain the title compound (69 mg) as a white solid. MS (ESI) m / z:367.1[M+H] +

[1174] (12-4) 3-(Aminomethyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide (Example Compound 12-4)

[1175]

[1176] Example compound 12-3 (69 mg), triphenylphosphine (64 mg) and water (0.5 mL) were stirred in tetrahydrofuran (5.0 mL) at 50° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and the resulting solid was suspended and washed with chloroform. The solid was collected by filtration and dried to obtain the title compound (60 mg) as a white solid. MS (ESI) m / z: 341.1 [M+H] +

[1177] (12-5)[(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]diazepine -6-yl] methyl acetate (Example Compound 12)

[1178]

[1179] The title compound was obtained as a white solid by the same reaction and treatment as (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] +

[1180] Example 13

[1181] (13-1) 7-Bromo-6-methyl-1H-indole (Example Compound 13-1)

[1182]

[1183] The title compound (1108 mg) was obtained as a white solid by the same reaction and treatment as in Reference Example 7, except that 2-bromo-3-nitrotoluene (2160 mg) was used instead of 1-bromo-4-methyl-2-nitrobenzene. 1 H NMR (400MHz, CDCl3) δppm2.52 (3H, s), 6.58 (1H, dd, J = 3.21, 2.18Hz), 7.00 (1H, d, J=7.96Hz), 7.19(1H,dd,J=3.08,2.44Hz), 7.46(1H,d,J=7.96Hz), 8.27(1H,brs)

[1184] (13-2) 7-Bromo-6-methyl-1H-indole-3-carbonitrile (Example Compound 13-2)

[1185]

[1186] The title compound (461 mg) was obtained as a beige solid by the same reaction and treatment as in Reference Example 8, except that Example compound 13-1 (500 mg) was used instead of Reference Example compound 7. 1 H NMR (400MHz, CDCl3) δppm2.54 (3H, s), 7.19 (1H, d, J = 8.1Hz), 7.61 (1H, d, J = 8.1Hz), 7.72 (1H, d, J = 2.8Hz), 8.72 (1H, brs)

[1187] (13-3) 7-Amino-6-methyl-1H-indole-3-carbonitrile (Example Compound 13-3)

[1188]

[1189] The title compound (146 mg) was obtained as a white solid by the same reaction and treatment as in Reference Example 9 except that Example Compound 13-2 (455 mg) was used instead of Reference Example Compound 8. MS (ESI) m / z: 172.1 [M+H] +

[1190] (13-4)[(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]diazepine -6-yl] methyl acetate (Example Compound 13)

[1191]

[1192] The title compound (34 mg) was obtained as a white powder by the same reaction and treatment as in Example 7 except that Example Compound 13-3 (17 mg) was used instead of Example Compound 7-2 and Reference Example Compound 10 (60 mg). MS (ESI) m / z: 823.5 [M+H] +

[1193] Example 14

[1194] (14-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 14)

[1195]

[1196] The title compound was obtained as a white solid by the same reaction and treatment as in Example 13-1 to 13-4, except that 1-bromo-4-chloro-2-nitrobenzene was used instead of 2-bromo-3-nitrotoluene. MS (ESI) m / z: 843.4, 845.5 [M+H] +

[1197] Example 15

[1198] (15-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 15)

[1199]

[1200] In Example 13, except that 4-bromo-3-nitroanisole was used instead of 2-bromo-3-nitrotoluene, the reaction and treatment were carried out in the same manner as (13-1) to (13-4) to obtain the title compound as a purple solid. MS (ESI) m / z: 839.5 [M+H] +

[1201] Example 16

[1202] (16-1)[(6S)-4-{4'-[({4-[(2,3-dimethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate (Example Compound 16)

[1203]

[1204] In Example 7, except that 2,3-dimethyl-1H-indole-7-amine (17 mg) was used instead of Example Compound 7-2 and Reference Example Compound 10 (50 mg) was used, the reaction and treatment were carried out in the same manner as in (7-3) to obtain the title compound (22 mg) as a brown solid. MS (ESI) m / z: 812.5 [M+H] +

[1205] Example 17

[1206] (17-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 17)

[1207]

[1208] In Example 13, except that 1-bromo-4-fluoro-2-nitrobenzene was used instead of 2-bromo-3-nitrotoluene, the reaction and treatment were carried out in the same manner as (13-1) to (13-4) to obtain the title compound as a beige powder. MS (ESI) m / z: 827.5 [M+H] +

[1209] Example 18

[1210] (18-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 18)

[1211]

[1212] In Example 13, except that 1-bromo-2-nitro-4-trifluoromethylbenzene was used instead of 2-bromo-3-nitrotoluene, the reaction and treatment were carried out in the same manner as (13-1) to (13-4) to obtain the title compound as a white powder. MS (ESI) m / z: 877.5 [M+H] +

[1213] Example 19

[1214] (19-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 19)

[1215]

[1216] In Example 13, except that 3-bromo-4-nitrotoluene was used instead of 2-bromo-3-nitrotoluene, the reaction and treatment were carried out in the same manner as (13-1) to (13-4) to obtain the title compound as a white powder. MS (ESI) m / z: 823.5 [M+H] +

[1217] Example 20

[1218] (20-1) Methyl 5-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]pyridine-2-carboxylate (Example Compound 20-1)

[1219]

[1220] Reference example compound 9 (300 mg), 5-(chlorosulfonyl)pyridine-2-carboxylic acid methyl ester (454 mg) and pyridine (0.71 mL) were stirred at room temperature in tetrahydrofuran (5.0 mL) for 4 hours. Ethyl acetate and 1N hydrochloric acid were added to the reaction mixture, the mixture was stirred, and the resulting solid was collected by filtration. Saturated sodium bicarbonate aqueous solution and tetrahydrofuran were added to the solid, the mixture was stirred, and chloroform was added. The water layer was removed by a phase separator, and the organic layer was concentrated under reduced pressure. The residue was suspended and washed with diethyl ether, and the title compound (210 mg) was collected by filtration to obtain a yellow solid. MS (ESI) m / z: 371.1 [M+H] +

[1221] (20-2) 6-(Azidomethyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)pyridine-3-sulfonamide (Example Compound 20-2)

[1222]

[1223] Under a nitrogen stream, 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. Saturated aqueous ammonium chloride solution was added to the reaction mixture, the mixture was stirred, and then chloroform was added and the mixture was stirred. The aqueous layer was removed by 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 give a white solid (75 mg). The 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. Saturated aqueous ammonium chloride solution and chloroform were added to the reaction mixture, and the mixture was stirred. The aqueous layer was removed by 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] +

[1224] (20-3) 6-(Aminomethyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)pyridine-3-sulfonamide (Example Compound 20-3)

[1225]

[1226] The title compound (24 mg) was obtained as a white solid by the same reaction and treatment as (12-4) except that Example Compound 20-2 (63 mg) was used instead of Example Compound 12-3 in Example 12. MS (ESI) m / z: 342.1 [M+H] +

[1227] (20-4)[(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]diazepine -6-yl] methyl acetate (Example Compound 20)

[1228]

[1229] The title compound was obtained as a light yellow solid by the same reaction and treatment as (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] +

[1230] Example 21

[1231] (21-1)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]diazepine -4-yl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (Example Compound 21-1)

[1232]

[1233] Under an argon stream, reference example compound 1 (500 mg), N- (tert-butoxycarbonyl) -1,2,3,6-tetrahydropyridine -4- boronic acid pinacol ester (447 mg), palladium acetate (7.1 mg), S-phos (99 mg), potassium fluoride (210 mg) and water (0.078 mL) were heated to reflux in tetrahydrofuran (5.0 mL) solvent for 7 hours. Using ethyl acetate, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 70: 30 ~ 20: 80) to give the title compound (680 mg) as a light yellow solid. MS (ESI) m / z: 562.5 [M + H] +

[1234] (21-2){(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]diazepine -6-yl}acetic acid methyl ester hydrochloride (Example Compound 21-2)

[1235]

[1236] To a solution of Example Compound 21-1 (217 mg) in methanol (0.5 mL) was added a 4M hydrogen chloride / 1,4-dioxane solution (2.0 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was suspended and washed with diisopropyl ether, collected by filtration, and dried to obtain the title compound (198 mg) as a yellow solid. MS (ESI) m / z: 462.2 [M+H] +

[1237] (21-3)[(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]diazepine -6-yl] methyl acetate (Example Compound 21)

[1238]

[1239] To a solution of dicarbonate (22 mg) in tetrahydrofuran (3.0 mL) were added reference example compound 5 (68 mg) and N,N-diisopropylethylamine (0.11 mL), and the mixture was stirred at room temperature for 15 minutes. Then, example compound 21-2 (100 mg) and N,N-dimethylformamide (0.5 mL) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, the mixture was stirred, extracted 3 times with ethyl acetate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 100:0 to 95:5), suspended and washed with diethyl ether, collected by filtration and dried to obtain the title compound (60 mg) as a milky white powder. MS (ESI) m / z: 828.4 [M+H] +

[1240] Example 22

[1241] (22-1) 7-Bromo-1H-indole-4-carbonitrile (Example Compound 22-1)

[1242]

[1243] The title compound (540 mg) was obtained as a pale yellow solid by the same reaction and treatment as in Reference Example 7 except that 4-bromo-3-benzonitrile (2270 mg) was used instead of 1-bromo-4-methyl-2-nitrobenzene. 1 H NMR (400MHz, CDCl3) δppm6.86 (1H, dd, J = 3.21, 2.18Hz), 7.36 (1H, d, J = 8.35Hz), 7.41 (1H, d, J = 7.83Hz), 7.46 (1H, t, J = 3.21Hz), 8.65 (1H, brs)

[1244] (22-2) 7-Amino-1H-indole-4-carbonitrile (Example Compound 22-2)

[1245]

[1246] The title compound (53 mg) was obtained as a pale yellow solid by the same reaction and treatment as in Reference Example 9 except that Example compound 22-1 (100 mg) was used instead of Reference Example compound 8. 1 H NMR (400MHz, DMSO-d6) δppm6.06 (2H, s), 6.34-6.41 (2H, m), 7.22 (1H, d, J = 7.96Hz), 7.49 (1H, t, J = 2.83Hz), 11.15 (1H, brs)

[1247] (22-3)[(6S)-4-{4'-[({4-[(4-cyano-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate (Example Compound 22)

[1248]

[1249] In Example 7, except that Example Compound 22-2 (29 mg) was used instead of Example Compound 7-2 and Reference Example Compound 10 (80 mg) was used, the reaction and treatment were carried out in the same manner as (7-3) to obtain the title compound (26 mg) as a white powder. MS (ESI) m / z: 809.4 [M+H] +

[1250] Example 23

[1251] (23-1) 7-Bromo-1H-indole-3,4-dicarbonitrile (Example Compound 23-1)

[1252]

[1253] The title compound (48 mg) was obtained as a light yellow solid by the same reaction and treatment as in Reference Example 8 except that Example Compound 22-1 (100 mg) was used instead of Reference Example Compound 7. MS (ESI) m / z: 246.0, 248.0 [M+H] +

[1254] (23-2) 7-Amino-1H-indole-3,4-dicarbonitrile (Example Compound 23-2)

[1255]

[1256] The title compound (10 mg) was obtained as a light yellow solid by the same reaction and treatment as in Reference Example 9 except that Example Compound 23-1 (45 mg) was used instead of Reference Example Compound 8. MS (ESI) m / z: 183.1 [M+H] +

[1257] (23-3)[(6S)-4-{4'-[({4-[(3,4-dicyano-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate (Example Compound 23)

[1258]

[1259] In Example 7, except that Example Compound 23-2 (9.4 mg) was used instead of Example Compound 7-2 and Reference Example Compound 10 (72 mg) was used, the reaction and treatment were carried out in the same manner as (7-3) to obtain the title compound (15 mg) as a light yellow powder. MS (ESI) m / z: 834.5 [M+H] +

[1260] Example 24

[1261] (24-1) N-(3-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}propyl)-2,2,2-trifluoroacetamide (Example Compound 24-1)

[1262]

[1263] The title compound was obtained as a brown powder by the same reaction and treatment as in Example 20-1, except that 4-[3-(trifluoroacetylamino)propyl]benzenesulfonyl chloride was used instead of 5-(chlorosulfonyl)pyridine-2-carboxylic acid methyl ester. MS (ESI) m / z: 465.2 [M+H] +

[1264] (24-2) 4-(3-aminopropyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide (Example Compound 24-2)

[1265]

[1266] Example compound 24-1 (610 mg), potassium carbonate (545 mg), water (0.8 mL) were stirred at room temperature in methanol (8.0 mL) for 2 hours. Methanol was evaporated under reduced pressure, water was added and the mixture was stirred. 1N hydrochloric acid (5 mL) was added and the mixture was stirred, and the resulting solid was collected by filtration. The solid was suspended with water for cleaning, and dried to give a gray solid. Potassium carbonate (273 mg), water (0.5 mL) and methanol (5.0 mL) were added to the solid, and the mixture was heated to reflux for 6 hours. Methanol was evaporated under reduced pressure, water was added and the mixture was stirred. 1N hydrochloric acid was added and the mixture was stirred, and the resulting solid was collected by filtration. The solid was suspended with water for cleaning, collected by filtration, and dried to give the title compound (453 mg) as a gray solid. MS (ESI) m / z:369.2[M+H] +

[1267] (24-3)[(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]diazepine -6-yl] methyl acetate (Example Compound 24)

[1268]

[1269] The title compound was obtained as a beige solid by the same reaction and treatment as (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] +

[1270] Example 25

[1271] (25-1){(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]diazepine -6-yl}methyl acetate (Example Compound 25-1)

[1272]

[1273] The title compound was obtained as a light yellow powder by the same reaction and treatment as (10-1) to (10-3), except that 4-bromo-3-fluorophenylmethylamine hydrochloride was used instead of 4-bromobenzylamine in Reference Example 10. MS (ESI) m / z: 688.4 [M-Cl+H2O] +

[1274] (25-2)[(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]diazepine -6-yl] methyl acetate (Example Compound 25)

[1275]

[1276] In Example 7, except that 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, the reaction and treatment were carried out in the same manner as (7-3) to obtain the title compound (69 mg) as a beige powder. MS (ESI) m / z: 841.5 [M+H] +

[1277] Example 26

[1278] (26-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 26-1)

[1279]

[1280] A mixed solution of Reference Example Compound 4 (100 mg), (1R)-1-(4-bromophenyl)ethylamine (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 mixture was diluted with ethyl acetate, washed three times with saturated brine-water (1:1), washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 90:10) to obtain the title compound (156 mg) as a pale yellow crude purified powder. MS (ESI) m / z: 682.4, 684.4 [M+H] +

[1281] (26-2) {(6S)-4-[4'-({(1R)-1-[4-(benzylthio)phenyl]ethyl}carbamoyl)[1,1'-biphenyl]-4-yl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl}methyl acetate (Example Compound 26-2)

[1282]

[1283] 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 a nitrogen atmosphere and microwave irradiation. After cooling to room temperature, the reaction mixture was directly purified by NH silica gel column chromatography (hexane:ethyl acetate = 50:50 to 0:100) to obtain the title compound (126 mg) as a light yellow powder. MS (ESI) m / z: 726.5 [M+H] +

[1284] (26-3)[(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]diazepine -6-yl] methyl acetate (Example Compound 26)

[1285]

[1286] Under ice-cold, N-chlorosuccinimide (80 mg) was added to a solution of acetonitrile (2.5 mL)-2N hydrochloric acid (0.50 mL) of embodiment compound 26-2 (124 mg), and the mixture was stirred at the same temperature for 2 hours. Saturated brine-water (1: 1) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. At room temperature, pyridine (0.14 mL) was added to a solution of tetrahydrofuran (5.0 mL) of the obtained residue and reference example compound 9 (33 mg), and the mixture was stirred at the same temperature for 16 hours. Saturated brine-water (1: 1) was added to the reaction mixture, and the mixture was extracted once with chloroform-methanol and twice with chloroform. The combined organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (chloroform:methanol = 90:10 to 50:50) and further purified by silica gel column chromatography (chloroform:methanol = 98:2 to 90:10) to obtain the title compound as a crude purified product. The total amount of the crude purified product was purified by preparative HPLC (10 mM aqueous ammonium carbonate-acetonitrile) to obtain the title compound (16 mg) as a white powder. MS (ESI) m / z: 837.5 [M+H] +

[1287] Example 27

[1288] (27-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 27)

[1289]

[1290] The title compound was obtained as a beige powder by the same reaction and treatment as (25-1) to (25-2), except that 4-bromo-2-fluorophenylmethylamine hydrochloride was used instead of 4-bromo-3-fluorophenylmethylamine hydrochloride in Example 25. MS (ESI) m / z: 841.5 [M+H] +

[1291] Example 28

[1292] (28-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 28)

[1293]

[1294] The title compound was obtained as a white powder by the same reaction and treatment as (25-1)-(25-2) except that 2-amino-2-(4-bromophenyl)ethanol was used instead of 4-bromo-3-fluorophenylmethylamine hydrochloride. MS (ESI) m / z: 853.5 [M+H] +

[1295] Example 29

[1296] (29-1) 3,4-Dimethyl-1H-indol-7-amine (Example Compound 29-1)

[1297]

[1298] 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. Saturated aqueous ammonium chloride solution and chloroform were added to the reaction mixture, 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, hydroxylamine hydrochloride (344 mg), and sodium acetate (487 mg) were stirred in a mixed solvent of methanol (3.0 mL)-tetrahydrofuran (3.0 mL) at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution and chloroform were 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 the title compound (279 mg) as a gray solid. MS (ESI) m / z: 161.2 [M+H] +

[1299] (29-2)[(6S)-4-{4'-[({4-[(3,4-dimethyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate (Example Compound 29)

[1300]

[1301] Example compound 29-1 (19 mg), reference example compound 10 (70 mg), and pyridine (0.041 mL) were stirred in tetrahydrofuran (3.0 mL) at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and azeotropically distilled with toluene. The residue was purified by silica gel column chromatography (chloroform: methanol = 100:0 to 95:5) and silica gel column chromatography (ethyl acetate: methanol = 100:0 to 95:5) to obtain the title compound (57 mg) as a light yellow solid. MS (ESI) m / z: 812.7 [M+H] +

[1302] Example 30

[1303] (30-1){(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]diazepine -6-yl}methyl acetate (Example Compound 30)

[1304]

[1305] The title compound was obtained as a white powder by the same reaction and treatment as (25-1)-(25-2), except that 4-(4-bromophenyl)piperidine hydrochloride was used instead of 4-bromo-3-fluorophenylmethylamine hydrochloride in Example 25. MS (ESI) m / z: 877.6 [M+H] +

[1306] Example 31

[1307] (31-1) tert-Butyl (3-{4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}prop-2-yn-1-yl)carbamate (Example Compound 31-1)

[1308]

[1309] A mixture of reference example compound 14 (300 mg), N-(tert-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 a nitrogen atmosphere and microwave irradiation. Saturated brine-water (1: 1) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2 ~ 95: 5) and then purified by NH silica gel column chromatography (chloroform: methanol = 95: 5 ~ 50: 50) to give the title compound (209 mg) as a light yellow powder. MS (ESI) m / z: 465.3 [M+H] +

[1310] (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)

[1311]

[1312] To Example Compound 31-1 (205 mg) was added a 4M hydrogen chloride / 1,4-dioxane solution (6.0 mL) at room temperature. After stirring at the same temperature for 1.5 hours, the reaction mixture was concentrated under reduced pressure. The residue was suspended in diethyl ether, washed, and collected by filtration to obtain the title compound (150 mg) as a brown solid. MS (ESI) m / z: 365.2 [M+H] +

[1313] (31-3)[(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]diazepine -6-yl] methyl acetate (Example Compound 31)

[1314]

[1315] At room temperature, N,N-diisopropylethylamine (0.083 mL) and HATU (73 mg) were added to a solution of Example Compound 31-2 (65 mg) and Reference Example Compound 4 (80 mg) in N,N-dimethylformamide (1.6 mL), and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with methanol and added to ethyl acetate and saturated brine-water (1:1). A small amount of insoluble matter was filtered out and the filtrate was separated. The organic layer was washed twice with saturated brine-water (1:1) and once with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (chloroform: methanol = 95:5~50:50, pre-column: silica gel) to obtain the title compound (103 mg) as a white powder. MS (ESI) m / z: 847.5 [M+H] +

[1316] Example 31

[1317] (32-1)4'-[(6S)-2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl][1,1'-biphenyl]-4-carboxylic acid methyl ester (Example Compound 32-1)

[1318]

[1319] Reference Example Compound 2 (150 mg), 4-(methoxycarbonyl)phenylboronic acid (81 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenylaminobiphenyl palladium chloride precatalyst (15 mg), sodium carbonate (79 mg), 1,4-dioxane (3.0 mL) and water (1.0 mL) were mixed and stirred at 100 ° C for 20 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 80: 20 ~ 0: 100) to give the title compound (161 mg) as a white powder. MS (ESI) m / z: 457.3 [M + H] +

[1320] (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]diazepine -4-yl][1,1'-biphenyl]-4-carboxamide (Example Compound 32)

[1321]

[1322] To a solution of Example Compound 32-1 (73 mg) in methanol (3.0 mL) was added 1N aqueous sodium hydroxide solution (0.32 mL), and the mixture was stirred at room temperature for 9 hours. 1N hydrochloric acid was added to the reaction mixture, the mixture was stirred and concentrated under reduced pressure. The resulting solid, Reference Example Compound 5 (60 mg), N,N-diisopropylethylamine (0.082 mL) and HATU (72 mg) were stirred in N,N-dimethylformamide (3.0 mL) at room temperature for 1 hour. Water was added to the reaction mixture, the mixture was stirred, and the resulting solid was collected by filtration. The solid was purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 95: 5) to give the title compound (100 mg) as a white solid. MS (ESI) m / z: 765.6 [M+H] +

[1323] Example 33

[1324] (33-1) 7-Bromo-1H-indole-4-carboxylic acid methyl ester (Example Compound 33-1)

[1325]

[1326] At -78 ° C, 1M vinyl magnesium bromide / tetrahydrofuran solution (25.0 mL) was added to a tetrahydrofuran solution (30.0 mL) of 4-bromo-3-nitrobenzoic acid methyl ester (2600 mg) over 5 minutes. After stirring at the same temperature for 1 hour, saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was heated to room temperature. After separation, the aqueous layer was extracted once with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90: 10) to give the title compound (1223 mg) as a white solid. MS (ESI) m / z: 254.1, 256.0 [M + H] +

[1327] (33-2) 7-Bromo-3-cyano-1H-indole-4-carboxylic acid methyl ester (Example Compound 33-2)

[1328]

[1329] To a solution of Example Compound 33-1 (1000 mg) in N,N-dimethylformamide (4.0 mL) was added phenylphosphonic dichloride (1.0 mL) at room temperature. After stirring at 100°C for 20 minutes, N,N-dimethylformamide (4.0 mL) was added, and the mixture was stirred at 100°C for 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 solution, washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated 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 (703 mg) as a crude purified brown solid. MS (ESI) m / z: 279.2, 281.2 [M+H] +

[1330] (33-3) 7-Bromo-4-(hydroxymethyl)-1H-indole-3-carbonitrile (Example Compound 33-3)

[1331]

[1332] Under ice cooling, 2.5M lithium aluminum hydride / tetrahydrofuran solution (1.70mL) was added dropwise to a suspension of example compound 33-2 (391mg) in tetrahydrofuran (16.0mL). After stirring at the same temperature for 10 minutes, 1N hydrochloric acid was added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was suspended, washed with chloroform, and collected by filtration to obtain the title compound (221mg) as a gray solid. MS (ESI) m / z: 233.0, 235.0 [M-OH] + ; 1 H NMR (400MHz, DMSO-d6) δppm4.94(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)

[1333] (33-4) 7-[(Diphenylmethylene)amino]-4-(hydroxymethyl)-1H-indole-3-carbonitrile (Example Compound 33-4)

[1334]

[1335] To Example Compound 33-3 (267 mg), benzophenone imine (270 mg), [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II) (Pd-PEPPSI-IPent catalyst, 26 mg), and tetrahydrofuran (7.0 mL) was added a 1.3 M lithium bis(trimethylsilyl)amide / tetrahydrofuran solution (2.9 mL) at room temperature, and the mixture was stirred at 140° C. under a nitrogen atmosphere and microwave irradiation for 0.5 hour. Pd-PEPPSI-IPent catalyst (85 mg) and a 1.3 M lithium bis(trimethylsilyl)amide / tetrahydrofuran solution (2.9 mL) were added, and the mixture was stirred at 160° C. under a nitrogen atmosphere and microwave irradiation for 0.5 hour. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform: methanol = 98:2) and further purified by NH silica gel column chromatography (chloroform: methanol = 98:2) to obtain the title compound (59 mg) as a light yellow solid. MS (ESI) m / z: 352.2 [M+H] +

[1336] (33-5) 7-Amino-4-(hydroxymethyl)-1H-indole-3-carbonitrile (Example Compound 33-5)

[1337]

[1338] Example compound 33-4 (57 mg) was dissolved in tetrahydrofuran (1.0 mL)-methanol (1.0 mL), hydroxylamine hydrochloride (28 mg) and sodium acetate (40 mg) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (chloroform: methanol = 98: 2 ~ 80: 20) to give the title compound (14 mg) as a light brown solid. MS (ESI) m / z: 170.1 [M-OH] + , 1 H NMR (400MHz, DMSO-d6) δppm4.74-4.83(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)

[1339] (33-6)[(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]diazepine -6-yl] methyl acetate (Example Compound 33)

[1340]

[1341] At room temperature, 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), and the mixture was stirred at the same temperature for 14 hours. The reaction mixture was diluted with ethyl acetate-methanol, washed once with saturated brine-water (1: 1), washed once with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified twice by silica gel column chromatography (chloroform: methanol = 98: 2 to 90: 10) to give the title compound (29 mg) as a beige powder. MS (ESI) m / z: 839.5 [M+H] +

[1342] Example 34

[1343] (34-1)[(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl]acetic acid (Example Compound 34)

[1344]

[1345] To a solution of Example Compound 1 (295 mg) in tetrahydrofuran (2.0 mL) and methanol (2.0 mL) was added 2N aqueous lithium hydroxide solution (0.72 mL), and the mixture was stirred at room temperature for 2 hours. 1N hydrochloric acid was added, the mixture was stirred, and concentrated under reduced pressure. The residue was suspended in water, washed, collected by filtration, and dried to obtain the title compound (258 mg) as a yellow powder. MS (ESI) m / z: 809.4 [M+H] +

[1346] Example 35

[1347] (35-1) tert-Butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran-2-carboxylate (Example Compound 35-1)

[1348]

[1349] To a mixture of tert-butyl 5-bromo-1-benzofuran-2-carboxylate (1.50 g), bis(pinacolato)diboron (1.41 g), 1,1'-(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (206 mg), and potassium acetate (991 mg) was added 1,4-dioxane (17 mL). After nitrogen substitution, the mixture was heated and stirred at 130°C under microwave irradiation for 30 minutes. Water, ethyl acetate, and activated carbon were added to the reaction mixture, the insoluble matter was filtered off through celite, and the filtered residue was washed with ethyl acetate. The filtrate was separated, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated 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 light yellow solid. 1 H NMR (400MHz, CDCl3) δppm1.37(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)

[1350] (35-2)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]diazepine -4-yl]phenyl}-1-benzofuran-2-carboxylic acid tert-butyl ester (Example Compound 35-2)

[1351]

[1352] 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 under a nitrogen atmosphere and microwave irradiation for 0.5 hours. The reaction mixture was diluted with ethyl acetate, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 50: 50 ~ 0: 100) to give the title compound (115 mg) as a white powder. MS (ESI) m / z: 597.5 [M + H] +

[1353] (35-3)[(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]diazepine -6-yl] methyl acetate (Example Compound 35)

[1354]

[1355] To a solution of Example Compound 35-2 (111 mg) in dichloromethane (1.0 mL) was added trifluoroacetic acid (1.0 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, toluene was added, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (2.0 mL), Reference Example Compound 5 (64 mg), N,N-diisopropylethylamine (0.32 mL) and HATU (85 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, added to a saturated aqueous sodium bicarbonate solution, and the obtained precipitate (A) was collected by filtration. The filtrate was separated. The water layer was extracted once with ethyl acetate. The combined organic layer (B) was washed twice with saturated brine-water (1: 1) and once with saturated brine. The filtered residue (A) was dissolved in chloroform, combined with the organic layer (B), and the mixture was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated 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 (104 mg) as a white powder. MS (ESI) m / z: 863.5 [M+H] +

[1356] Example 36

[1357] (36-1)[4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl]carbamic acid methyl ester (Example Compound 36-1)

[1358]

[1359] Under ice cooling, 6-amino-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine was added to a solution of dichloromethane (6.0 mL). Methyl chloroformate (0.048 mL) and N,N-diisopropylethylamine (0.15 mL) were added to a solution of (200 mg) (described in JP-A-7-17941, Raw Material Preparation Example 1), and the mixture was stirred at the same temperature for 0.5 hours. Water was added to the reaction mixture, the mixture was extracted twice with chloroform, and the extract was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated 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 light orange powder. MS (ESI) m / z: 416.3 [M + H] +

[1360] (36-2) 4'-{6-[(methoxycarbonyl)amino]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl}[1,1'-biphenyl]-4-carboxylic acid tert-butyl ester (Example Compound 36-2)

[1361]

[1362] A mixture of Example Compound 36-1 (30 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid tert-butyl ester (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 under a nitrogen atmosphere and microwave irradiation for 0.5 hours. The reaction mixture was diluted with ethyl acetate, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 50:50 to 0:100) to give the title compound (39 mg) as a white powder. MS (ESI) m / z: 558.4 [M + H] +

[1363] (36-3)(4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl)methyl carbamate (Example Compound 36)

[1364]

[1365] To a solution of Example Compound 36-2 (37 mg) in dichloromethane (1.0 mL) was added trifluoroacetic acid (1.0 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, toluene was added, and the solvent was evaporated. The resulting residue was dissolved in N,N-dimethylformamide (0.67 mL), Reference Example Compound 5 (25 mg), N,N-diisopropylethylamine (0.12 mL), and HATU (31 mg) were added at room temperature, and the mixture was stirred at the same temperature for 15 hours. The reaction mixture was diluted with ethyl acetate, washed once with a saturated aqueous sodium bicarbonate solution, washed twice with saturated brine-water (1:1), washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated 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 (43 mg) as a white powder. MS (ESI) m / z: 824.5 [M+H] +

[1366] Example 37

[1367] (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]diazepine -4-yl][1,1'-biphenyl]-4-carboxamide (Example Compound 37)

[1368]

[1369] Example compound 34 (100 mg), 2-aminoethanol (12 mg), N,N-diisopropylethylamine (0.064 mL) and HATU (56 mg) were stirred at room temperature in N,N-dimethylformamide (3.0 mL) for 2 hours. Water was added to the reaction mixture, the mixture was stirred, and extracted twice with ethyl acetate. The combined organic layer was washed twice with water and 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] +

[1370] Example 38

[1371] (38-1) N-({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)-4'-{(6S)-6-[2-(dimethylamino)-2-oxoethyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl}[1,1'-biphenyl]-4-carboxamide (Example Compound 38)

[1372]

[1373] The title compound was obtained as a milky white solid by the same reaction and treatment as in (37-1) except that dimethylamine hydrochloride was used instead of 2-aminoethanol in Example 37. MS (ESI) m / z: 836.5 [M+H] +

[1374] Example 39

[1375] (39-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 39)

[1376]

[1377] The title compound was obtained as a beige powder by the same reaction and treatment as (25-1) to (25-2), except that 2-(4-bromophenoxy)ethylamine was used instead of 4-bromo-3-fluorophenylmethylamine hydrochloride in Example 25. MS (ESI) m / z: 853.5 [M+H] +

[1378] Example 40

[1379] (40-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 40)

[1380]

[1381] At room temperature, N,N-diisopropylethylamine (0.063 mL) and HATU (56 mg) were added to a solution of Reference Example Compound 12 (63 mg) and Reference Example Compound 11 (53 mg) in N,N-dimethylformamide (1.3 mL), and the mixture was stirred at the same temperature for 1.5 hours. Water was added to the reaction mixture, the precipitate was collected by filtration, and washed with water. The filtered residue was dissolved in chloroform, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2 to 95: 5) to give the title compound (61 mg) as a light yellow powder. MS (ESI) m / z: 855.5 [M+H] +

[1382] Example 41

[1383] (41-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 41)

[1384]

[1385] The title compound (115 mg) was obtained as a white powder by the same reaction and treatment as in Example 40 except that Reference Example Compound 13 (80 mg) was used instead of Reference Example Compound 12. MS (ESI) m / z: 871.5 [M+H] +

[1386] Example 42

[1387] (42-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 42)

[1388]

[1389] In Example 7, except that Reference Example Compound 15 (24 mg) was used instead of Example Compound 7-2, the reaction and treatment were carried out in the same manner as in (7-3) to obtain the title compound (56 mg) as a light yellow solid. MS (ESI) m / z: 887.3, 889.3 [M+H] +

[1390] Example 43

[1391] (43-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 43)

[1392]

[1393] A mixture of reference example compound 16 (14 mg), pyridine (0.059 mL), tetrahydrofuran (2.0 mL) and reference example compound 10 (50 mg) was stirred at room temperature for 24 hours. The reaction mixture was diluted and dissolved in 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 brine and 1N hydrochloric acid water, once with saturated brine, once with a saturated sodium bicarbonate aqueous solution, once with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC (10 mM ammonium carbonate aqueous solution-acetonitrile) to give the title compound (42 mg) as a light yellow solid. MS (ESI) m / z:837.5[M+H] +

[1394] Example 44

[1395] (44-1) 7-Amino-4-cyclopropyl-1H-indole-3-carbonitrile (Example Compound 44-1)

[1396]

[1397] Under nitrogen atmosphere and ice cooling, a 0.5M cyclopropylzinc bromide / tetrahydrofuran solution (4.6mL) was added to a solution of methanesulfonyl[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) in tetrahydrofuran (1.9mL) of Reference Example Compound 15 (90mg), and the mixture was stirred at room temperature for 50 minutes. Under ice cooling, a saturated aqueous ammonium chloride solution was added to the reaction mixture. After stirring at room temperature for 1 hour, ethyl acetate and water were added for preparation. The organic layer was washed once with a saturated aqueous sodium bicarbonate solution and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50:50 to 20:80) and then purified by preparative HPLC (10mM aqueous ammonium carbonate solution-acetonitrile) to obtain the title compound (26mg) as a white solid. MS (ESI) m / z: 198.1[M+H] +

[1398] (44-2)[(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]diazepine -6-yl] methyl acetate (Example Compound 44)

[1399]

[1400] In Example 7, except that Example Compound 44-1 (18 mg) was used instead of Example Compound 7-2, the reaction and treatment were carried out in the same manner as in (7-3) to obtain the title compound (47 mg) as a light yellow solid. MS (ESI) m / z: 849.5 [M+H] +

[1401] Example 45

[1402] (45-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 45)

[1403]

[1404] 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. The reaction mixture was concentrated, toluene was added, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (1.5 mL), Reference Example Compound 5 (56 mg), N,N-diisopropylethylamine (0.26 mL) and HATU (68 mg) were added at room temperature, and the mixture was stirred at the same temperature for 16 hours. Water was added to the reaction mixture, the precipitate was collected by filtration, and washed with water. The filtered residue was dissolved in chloroform, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The obtained 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] +

[1405] Example 46

[1406] (46-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 46)

[1407]

[1408] Trifluoroacetic acid (1.0 mL) was added to a dichloromethane (1.0 mL) solution of Reference Example Compound 18-1 (85 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, toluene was added, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (1.5 mL), Reference Example Compound 11 (64 mg), N,N-diisopropylethylamine (0.26 mL) and HATU (68 mg) were added at room temperature, and the mixture was stirred at the same temperature for 16 hours. Water was added to the reaction mixture, the precipitate was collected by filtration, and washed with water. The filtered residue was dissolved in chloroform, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The obtained 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] +

[1409] Example 47

[1410] (47-1) 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]diazepine -4-yl][1,1'-biphenyl]-4-carboxylic acid tert-butyl ester (Example Compound 47-1)

[1411]

[1412] The title compound (374 mg) was obtained as a white crude purified powder by the same reaction and treatment as in Reference Example 18, except that tert-butyl 4-bromo-3-chlorobenzoate (207 mg) was used instead of tert-butyl 4-bromo-3-fluorobenzoate, using Reference Example Compound 3 (300 mg). MS (ESI) m / z: 591.4, 593.4 [M+H] +

[1413] (47-2)[(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]diazepine -6-yl] methyl acetate (Example Compound 47)

[1414]

[1415] The title compound (221 mg) was obtained as a beige powder by 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] +

[1416] Example 48

[1417] (48-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 48)

[1418]

[1419] The title compound (189 mg) was obtained as a beige powder by 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] +

[1420] Example 49

[1421] (49-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 49)

[1422]

[1423] Under a nitrogen atmosphere, under microwave irradiation at 100 ° C, reference compound 3 (200 mg), 5-bromo-benzoxazole-2-carboxylic acid methyl ester (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) for 1 hour. The mixture was filtered with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain an orange viscous compound. The obtained viscous compound, reference compound 5 (134 mg), 1H-1,2,4-triazole (6 mg) and triethylamine (0.055 mL) were heated to reflux in tetrahydrofuran (5.0 mL) for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 ~ 95: 5) to obtain the title compound (190 mg) as a milky white solid. MS (ESI) m / z: 864.4 [M + H] +

[1424] Example 50

[1425] (50-1)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]diazepine -4-yl]-3-methyl[1,1'-biphenyl]-4-carboxylic acid tert-butyl ester (Example Compound 50-1)

[1426]

[1427] Reference example compound 3 (100 mg) was dissolved in tetrahydrofuran (2.0 mL), tert-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 a nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate and the insoluble matter was filtered off through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 50: 50 ~ 0: 100) to obtain the title compound (117 mg) as a white crude purified powder. MS (ESI) m / z: 571.3 [M + H] +

[1428] (50-2)[(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]diazepine -6-yl] methyl acetate (Example Compound 50)

[1429]

[1430] 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. The reaction mixture was concentrated, toluene was added, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (2.0 mL), Reference Example Compound 5 (74 mg), N,N-diisopropylethylamine (0.34 mL) and HATU (90 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, the precipitate was collected by filtration, and washed with water. The filtered residue was dissolved in chloroform, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The obtained 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] +

[1431] Example 51

[1432] (51-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 51)

[1433]

[1434] In Example 50, except that tert-butyl 4-bromo-2-trifluoromethylbenzoate was used instead of tert-butyl 4-bromo-2-methylbenzoate, the reaction and treatment were carried out in the same manner as (50-1) to (50-2) to obtain the title compound as a white powder. MS (ESI) m / z: 891.5 [M+H] +

[1435] Example 52

[1436] (52-1)[(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]diazepine -6-yl] methyl acetate (Example Compound 52)

[1437]

[1438] In Example 50, except that tert-butyl 4-bromo-2-methoxybenzoate was used instead of tert-butyl 4-bromo-2-methylbenzoate, the reaction and treatment were carried out in the same manner as (50-1) to (50-2) to obtain the title compound as a white powder. MS (ESI) m / z: 853.5 [M+H] +

[1439] Example 53

[1440] (53-1)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]diazepine -4-yl]phenyl}pyridine-2-carboxylic acid tert-butyl ester (Example Compound 53-1)

[1441]

[1442] Example compound 3 (100 mg), tert-butyl 5-bromopyridine-2-carboxylate (77 mg), tetrakis(triphenylphosphine)palladium(0) (23 mg), potassium phosphate (126 mg), and water (0.014 mL) were stirred in tetrahydrofuran (4.0 mL) under a nitrogen atmosphere and microwave irradiation at 100° C. for 0.5 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain the title compound (109 mg) as a colorless viscous compound. MS (ESI) m / z: 558.5 [M+H] +

[1443] (53-2)[(6S)-4-(4-{6-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridin-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate (Example Compound 53)

[1444]

[1445] To a chloroform (1.0 mL) solution of Example Compound 53-1 (109 mg) was added trifluoroacetic acid (1.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and azeotropically distilled twice with toluene. The residue, Reference Example Compound 5 (73 mg), N,N-diisopropylethylamine (0.17 mL) and HATU (89 mg) were stirred in N,N-dimethylformamide (3.0 mL) at room temperature for 2 hours. Water was added to the reaction mixture, the mixture was stirred, and extracted twice with ethyl acetate. The combined organic layer was washed twice with water and 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] +

[1446] Example 54

[1447] (54-1)[(6S)-4-(4-{5-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridin-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate (Example Compound 54)

[1448]

[1449] In Example 53, except that tert-butyl 6-bromopyridine-3-carboxylate was used instead of tert-butyl 5-bromopyridine-2-carboxylate, the reaction and treatment were carried out in the same manner as (53-1) to (53-2) to obtain the title compound as a milky white solid. MS (ESI) m / z: 824.7 [M+H] +

[1450] Example 55

[1451] (55-1)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]diazepine -4-yl][1,1'-biphenyl]-4-carboxylic acid tert-butyl ester (Example Compound 55-1)

[1452]

[1453] [(6S)-4-(4-chlorophenyl)-2-(hydroxymethyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate (500 mg) (described in WO2006 / 129623), (4-tert-butoxycarbonylphenyl) boronic acid (386 mg), potassium phosphate (616 mg), tetrahydrofuran (5.0 mL), water (0.52 mL), 2-dicyclohexylphosphino-2'-6'-dimethoxybiphenylaminobiphenyl palladium chloride precatalyst (42 mg), and S-phos (24 mg) were stirred under heating reflux for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, 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 obtain the title compound (610 mg) as a milky white solid. MS (ESI) m / z: 573.2 [M+H] +

[1454] (55-2)[(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]diazepine -6-yl] methyl acetate (Example Compound 55)

[1455]

[1456] To a solution of Example Compound 55-1 (80 mg) in dichloromethane (1.0 mL) was added trifluoroacetic acid (1.0 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture 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 and tetrahydrofuran (1:1), and 1N hydrochloric acid and saturated brine were added for liquid separation. The organic layer was washed once with saturated brine, once with a saturated sodium bicarbonate aqueous solution, and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated 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 light yellow solid. MS (ESI) m / z: 839.4 [M+H] +

[1457] Example 56

[1458] (56-1){(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]diazepine -6-yl}methyl acetate (Example Compound 56-1)

[1459]

[1460] A mixture of reference compound 1 (200 mg), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (208 mg), X-Phos aminobiphenyl palladium chloride precatalyst (38 mg), X-Phos (23 mg), potassium phosphate (307 mg), water (0.031 mL) and tetrahydrofuran (2.4 mL) was stirred at 90 ° C for 0.5 hours under microwave irradiation. Ethyl acetate and saturated brine were added to the reaction mixture, the insoluble matter was filtered out, and the filtrate was separated. The organic layer was washed once with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in chloroform (1.0 mL), trifluoroacetic acid (1.0 mL) was added at room temperature, and stirred at the same temperature for 6 hours. The solvent was evaporated under reduced pressure, and the residue was concentrated azeotropically with toluene. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol = 100:0 to 96:4) to obtain the title compound (244 mg) as a light yellow powder. MS (ESI) m / z: 512.3 [M+H] +

[1461] (56-2)[(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]diazepine -6-yl] methyl acetate (Example Compound 56)

[1462]

[1463] At room temperature, sodium triacetoxyborohydride (50 mg) was added to a mixture of Example Compound 56-1 (60 mg), Reference Example Compound 5-1 (44 mg) and chloroform (2.0 mL), and the mixture was stirred at the same temperature for 22 hours. In addition, sodium triacetoxyborohydride (50 mg) was added at room temperature, and the mixture was stirred at the same temperature for 8 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Saturated brine was added, and the mixture was extracted 3 times with chloroform. The extract was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (10 mM ammonium carbonate aqueous solution-acetonitrile) to give the title compound (74 mg) as a light yellow solid. MS (ESI) m / z:835.5[M+H] +

[1464] Example 57

[1465] (57-1) N-(3-cyano-4-methyl-1H-indol-7-yl)-4-fluorobenzene-1-sulfonamide (Example Compound 57-1)

[1466]

[1467] At room temperature, 4-fluorobenzenesulfonyl chloride (375 mg) was added to a mixture of reference compound 9 (300 mg), pyridine (0.71 mL) and tetrahydrofuran (3.0 mL), and stirred at the same temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate and separated by adding saturated brine and 1N hydrochloric acid. The organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the title compound (580 mg) as a brown solid. MS (ESI) m / z: 328.1 [MH] -

[1468] (57-2) 4-[(2-aminoethyl)amino]-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide (Example Compound 57-2)

[1469]

[1470] A mixture of Example Compound 57-1 (200 mg), ethylenediamine (0.61 mL) and tetrahydrofuran (1.0 mL) was stirred at 150 ° C for 0.5 hours under heating and microwave irradiation. Saturated brine was added to the reaction mixture, and the mixture was washed with ethyl acetate-tetrahydrofuran (1: 1) mixture. Extracted 3 times. The extracts were combined, washed once with a small amount of saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was suspended and washed with ethyl acetate and collected by filtration to obtain the title compound (180 mg) as a brown powder. MS (ESI) m / z: 370.2 [M+H] +

[1471] (57-3)[(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]diazepine -6-yl] methyl acetate (Example Compound 57)

[1472]

[1473] Under ice cooling, HATU (49 mg) was added 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), and the mixture was stirred at the same temperature for 5 minutes and at room temperature for 3 hours. The reaction mixture was diluted with a mixture of ethyl acetate-tetrahydrofuran (1: 1), washed once with a saturated aqueous sodium bicarbonate solution, washed once with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The residue was washed with an acetonitrile-water suspension, collected by filtration, and washed with water to obtain the title compound (45 mg) as a pink powder. MS (ESI) m / z: 852.5 [M+H] +

[1474] Example 58

[1475] (58-1) 3-[4-(Benzylthio)phenyl]propan-1-ol (Example Compound 58-1)

[1476]

[1477] A mixture of 3-(4-bromophenyl)propan-1-ol (1000 mg), benzyl mercaptan (0.55 mL), N,N-diisopropylethylamine (2.41 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 269 mg), tris(dibenzylideneacetone)dipalladium (213 mg), and toluene (15.0 mL) was stirred at 100°C for 5 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was directly purified by silica gel column chromatography (hexane:ethyl acetate = 60:40 to 20:80, pre-column: NH silica gel) to obtain the title compound (681 mg) as a red solid. 1 H NMR (400MHz, CDCl3) δppm1.23 (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)

[1478] (58-2) 2-(4-{3-[4-(benzylthio)phenyl]propyloxy}phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Example Compound 58-2)

[1479]

[1480] To a toluene (3.0 mL) solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (200 mg) and Example Compound 58-1 (281 mg) was added cyanomethylenetrimethylphosphane (157 mg) at room temperature, and the mixture was stirred at 150° C. for 0.5 hours under a nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted w...

Claims

1. [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indol-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl] methyl acetate or a pharmaceutically acceptable salt thereof.

2. [(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]diazepine -6-yl] methyl acetate or a pharmaceutically acceptable salt thereof.

3. {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indol-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazin-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl} methyl acetate or a pharmaceutically acceptable salt thereof.

4. [(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]diazepine -6-yl] methyl acetate or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 5 , which is used for inducing BRD4 protein degradation.

7. The pharmaceutical composition according to claim 5 or 6, which is used for treating cancer.

8. The pharmaceutical composition according to claim 7, 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.

9. The pharmaceutical composition according to claim 7, wherein The cancer is selected from the group consisting of 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.

10. The pharmaceutical composition according to claim 7, wherein The cancer is selected from the group consisting of acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, prostate cancer, ovarian cancer, and breast cancer.

11. Use of the pharmaceutical composition according to any one of claims 5 to 10 in the manufacture of a medicament for treating cancer.

12. Use of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating cancer.

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