TW202408991A - Ido/tdo inhibitor - Google Patents

Abstract

A compound of formula (I) given below or a pharmaceutically acceptable salt of the compound is useful as an IDO/TDO inhibitor. Thus, the compound of formula (I) or the pharmaceutically acceptable salt of the compound can be used as, for example, a therapeutic agent for a disease or a disorder selected from tumor, infectious disease, neurodegenerative disorder, cataract, organ transplant rejection, autoimmune disease, postoperative cognitive impairment, and disease related to women's reproductive health [in the following formula (I), ring A represents an aromatic ring, a heterocyclic ring, or a condensed ring of two or more rings selected from an aromatic ring, and a heterocyclic ring, wherein ring A is selected from the group consisting of a benzene ring, a naphthalene ring, a quinoxaline ring, a thiophene ring, an indole ring, a benzothiophene ring, an imidazole ring, a quinoline ring, a quinazoline ring, and a pyridine ring; X, R ¹and R ²represent a substituent on a ring atom constituting ring A, wherein R ¹and R ²are bonded to adjacent ring atoms of ring A; m represents an integer of 1 or 2; X is a halogen atom, and when m is 2, each X is the same or different; R ¹and R ²are the same or different; R ¹and R ²independently represent a group represented from the following groups: wherein Y is selected from the group consisting of O, S, SO, SO ₂, and Se, n represents an integer of 1 to 8, R ⁴represents wherein R ⁴¹, R ⁴²and R ⁴³are the same and are a hydrogen atom

Description

IDO/TDO Inhibitor

[Cross-reference to related applications] This application is a continuation-in-part of U.S. Patent Application No. 16/755,953 filed on April 14, 2020, which claims priority to International Application No. PCT/JP2018/038648 filed on October 17, 2017, which claims priority to JP2017-202637 filed on October 19, 2017, the contents of each of which are incorporated herein by reference.

The present invention relates to indoleamine 2,3-dioxygenase (IDO [IDO1 or IDO2]) and/or tryptophan-2,3-dioxygenase (TDO) inhibitors for use in the medical field. The inhibitor of the present invention can be used as a pharmaceutical composition, particularly a pharmaceutical composition for the treatment of various diseases, conditions and disorders, including tumors, infectious diseases, inflammatory conditions, central nervous system diseases or disorders.

It is well known that cancer cells use their immune tolerance to suppress the host's immune response in order to proliferate. In recent years, the proteins that cause this immune tolerance and their functions have been elucidated. Ipilimumab, an antibody drug targeting CTLA4 (cytotoxic T-lymphocyte antigen 4), one of these causative molecules, was approved by the FDA in 2011 as a treatment for malignant melanoma. The effectiveness of the drug, which is based on the concept of relieving cancer's immune tolerance, has been confirmed. Indoleamine 2,3-dioxygenase (IDO), discovered by Hayashi et al. in the 1950s, is an oxygenase that catalyzes the initial reaction of the kynurenine pathway (KP), the main pathway of tryptophan metabolism in the body. Later, it has been shown that it plays an important role in establishing immune tolerance in the tumor microenvironment, such as controlling T cells responsible for immune action. Its mechanism of action is thought to be to inhibit anti-tumor immune cells by locally reducing tryptophan concentrations and increasing kynurenine concentrations by activating the kynurenine pathway. Human IDO (hIDO) is overexpressed in various human cancers including prostate, colon, pancreas, stomach, ovary, brain and lung cancer.

The kynurenine pathway is responsible for the breakdown of over 95% of the essential amino acid tryptophan. The kynurenine pathway for tryptophan metabolism produces the essential pyridine nucleotide NAD+ and many neuroactive metabolites, such as kynurenine (KYN), kynurenic acid (KYNA), neurotoxic free radical generation Agents 3-hydroxykynurenine (3-HK), anthranilic acid, 3-HAA, picolinic acid (PIC), and excitatory N-methyl-D-aspartate (NMDA) receptor agonists agent and neurotoxin, quinolinic acid (QUIN). The remaining 5% tryptophan is metabolized by tryptophan hydroxylase into 5-hydroxytryptophan (serotonin) and melatonin.

The first stage of tryptophan catabolism is catalyzed by either TDO or IDO. Both enzymes catalyze the oxidative cleavage of the 2,3 double bond on the indole ring to convert tryptophan to N-formyl-L-kynurenine. This is the rate-determining step in tryptophan catabolism via the kynurenine pathway. TDO is a homotetramer with each monomer having a molecular weight of 48 kDa, while IDO has a molecular weight of 45 kDa and a monomeric structure. Despite participating in the same reaction, TDO and IDO (IDO1 or IDO2) differ in structure, mainly in the active site with only 10% homology. On the other hand, the more related IDO1 and IDO2 have 43% homology. IDO1 and IDO2 are two different enzymes catalyzing the same reaction. The Michaelis constant of IDO2 for tryptophan is much higher than that of IDO1. In other words, the affinity of IDO2 for the substrate tryptophan is much lower than that of IDO1. Nicolas van Baren et al. reported that the enzymes that decompose tryptophan, namely IDO1, TDO and IDO2, are involved in tumor immune resistance (non-patent document 1).

TDO is expressed at high levels in the liver and is responsible for regulating systemic tryptophan levels. TDO is not induced or regulated by signals from the immune system, but expression of TDO can be induced by tryptophan or corticosteroids. Recently, TDO has been identified to be expressed in the brain, regulating the production of neurostimulatory tryptophan metabolites such as kynurenic acid and quinolinic acid. TDO has been identified to be highly activated and constitutively expressed in neuroglioma cells. TDO-derived KYN has been shown to suppress antitumor immune responses and promote tumor cell survival and motility through the autocrine aryl receptor (AhR). TDO is elevated in human hepatocellular carcinoma and has been shown to be occasionally detected in other cancers. In preclinical models, rejection of tumor xenografts in mice pre-immunized by TDO expression was prevented, and it was demonstrated that the ability of mice to reject TDO-expressing tumors was restored by systemic administration of the TDO inhibitor LM10.

IDO is thought to be expressed in many cells including macrophages, microglia, neurons and astrocytes. IDO transcription is tightly controlled in response to specific inflammatory mediators. The mouse and human IDO gene promoters contain multiple complex sequence factors that are responsive to type I (IFN-α/β) and more potent type II (IFN-γ) interferons. Certain myeloid cell lines (monocyte-derived macrophages and DCs), fibroblasts, endothelial cells and some tumor cell lines express IDO after exposure to IFN-γ. However, the control of IDO transcription is complex and cell type specific. IDO activity is continuously expressed by human extravillous trophoblasts at the maternal-fetal boundary. In addition to the placenta, functional IDO expression has been reported to be highest in the mouse epididymis, intestine (distal ileum and colon), lymph nodes, spleen, thymus, and lung. Increased IDO expression has been shown to be an independent prognostic variable for decreased survival in patients with acute myeloid leukemia (AML), small cell lung cancer, melanoma, colorectal cancer, pancreatic cancer, and uterine corpus cancer. Indeed, sera from cancer patients have a higher kynurenine/tryptophan ratio than sera from healthy volunteers, and IDO expression levels have also been shown to correlate with the number of tumor-infiltrating lymphocytes in colorectal cancer patients.

Tryptophan metabolites such as kynurenine, kynurenic acid, 3-hydroxy-kynurenine and 3-hydroxy-aminobenzoic acid can inhibit T cell function and induce T cell apoptosis. Recent studies have shown that aryl receptors are direct targets of kynurenine. Ahr is a basic helix-loop-helix Per-Arnt-Sim (PAS) family transcription factor. When kynurenine accumulates in tumors, KYN binds to Ahr and translocates to the cell nucleus and activates the transcription of target genes controlled by dioxin response elements (DREs). In CD4-positive cells, regulatory T cells (Tregs) are generated from kynurenine.

Therefore, it is believed that inhibitors of TDO or IDO may have broad therapeutic effects in cancer treatment. In addition, it is believed that dual inhibitors that block TDO and IDO can show more effective clinical effects by targeting these two important Trp metabolic enzymes and can also treat a wider patient population.

Inhibitors of IDO and/or TDO can be used for a wide range of indications, including tumors, infections, and many other diseases including neurological diseases.

Against this background, various IDO inhibitors and/or TDO inhibitors have been proposed so far. In particular, many IDO inhibitors and/or TDO inhibitors using indole derivatives having various structures have been proposed. For example, Patent Document 1 discloses that certain indole derivatives (680C91, LM10) can be used as TDO inhibitors, certain indole derivatives (Newlink 1) and certain ethadiazole derivatives (Incyte 1) can be used as TDO inhibitors. It is useful as an IDO inhibitor. Patent Document 2 discloses various indole derivatives useful as IDO and/or TDO inhibitors. Patent Document 3 and Patent Document 4 disclose that various condensed heterocyclic compounds having an indole skeleton are used as IDO and/or TDO inhibitors. In addition, Patent Document 5 discloses that certain indole derivatives function as IDO inhibitors. Furthermore, Patent Document 6 discloses that a compound having three skeletons of an indole skeleton, a pyrazole skeleton, and a cyclopropane skeleton is used as an IDO inhibitor.

As compounds other than indole derivatives, the use of a 5-membered ring heterocyclic compound as TDO and/or TDO inhibitor (Patent Documents 7 and 8), the use of a heterocyclic compound in which two 6-membered rings are condensed as TDO and/or IDO inhibitor (Patent Documents 9 and 10), the use of a compound having a benzene ring or a tetrahydronaphthalene skeleton as an IDO inhibitor (Patent Document 11), the use of a condensed heterocyclic compound composed of three rings as an IDO inhibitor (Patent Documents 12 and 13), the use of a condensed heterocyclic compound composed of four rings as an IDO inhibitor (Patent Documents 14 and 15), etc. have been proposed. Amy B. Dounay et al. introduced a new therapeutic agent targeting the kynurenine pathway (non-patent document 2). Non-patent document 2 teaches various IDO1 inhibitors and TDO inhibitors.

In contrast, the present inventors discovered and reported that S-benzylthiourea and its derivatives inhibit IDO (Non-Patent Document 3). The present inventors also discovered and reported benzenesulfonamide derivatives and benzylthioiminocarbamate derivatives, which inhibit the production of kynurenine, which is a metabolite of tryptophan in cancer cells (Non-Patent Document 4) . Furthermore, the present inventors reported that candesartan cilexetil and its derivatives are used as therapeutic drugs for hypertension, renal parenchymal hypertension, etc. to inhibit IDO (Non-Patent Document 5).

[Prior technical literature] [Patent literature] [Patent literature 1] WO2015/091862 publication [Patent literature 2] WO2015/150097 publication (Japanese Patent Publication No. 2017-509682 publication) [Patent literature 3] WO2016/071293 publication [Patent literature 4] WO2017/007700 publication [Patent literature 5] Japanese Patent Publication No. 2006-521377 publication [Patent literature 6] WO2017/048612 publication [Patent literature 7] WO2016/026772 publication [Patent literature 8] Japanese Patent Publication No. 2017-526727 publication [Patent Document 9] WO2016/071283 [Patent Document 10] Patent Publication No. 2017-509667 [Patent Document 11] Patent Publication No. 5583592 [Patent Document 12] Patent Publication No. 2017-149769 [Patent Document 13] Patent Table No. 2008-505937 [Patent Document 14] Patent Publication No. 2008-201756 [Patent Document 15] Patent Publication No. 2016-535788

[Non-patent literature] [Non-patent literature 1] Cancer Immunology Research; 3(9) September 2015, 978-985 [Non-patent literature 2] J. Medicinal Chemistry, 2015, 58, 8762-8782 [Non-patent literature 3] Bioorganic & Medicinal Chemistry Letters 20 (2010) 5126-5129 [Non-patent literature 4] Biochemical & Biophysical Research Communications 419 (2012)556-561 [Non-patent literature 5] Med. Chem. Commnun., 2012, 3, 475-479

[Problem to be solved by the invention] The problem of the present invention is to provide a novel IDO inhibitor and/or TDO inhibitor useful for various diseases.

[Means for Solving the Problem] The inventors of this case have focused on a certain group of compounds with different structures from known IDO inhibitors and/or TDO inhibitors, and have actively studied them. As a result, they have found that the compound represented by the following formula (I) or a pharmaceutically acceptable salt of the compound has a superior inhibitory effect on IDO inhibitors and/or TDO inhibitors, and can be used as an IDO inhibitor and/or TDO inhibitor for a wide range of diseases. The present invention was completed based on these findings.

That is, the present invention is as follows. [1] A compound having formula (I) or a pharmaceutically acceptable salt of the compound. [In the formula, Ring A represents an aromatic ring, an aliphatic ring, a heterocyclic ring, or a condensed ring of two or more rings selected from an aromatic ring, an aliphatic ring, and a heterocyclic ring; X, R ¹ , and R ² constitute ring A The substituent of the ring atom; m represents an integer from 0 to 6; Unsubstituted linear or branched alkenyl, substituted or unsubstituted linear or branched alkenyloxy, substituted or unsubstituted linear or branched alkynyl, substituted or unsubstituted linear or branched alkynoxy group, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, haloalkyl, haloalkoxy, cyano, hydroxyl, amino, nitro, carboxyl, and substituted or unsubstituted aryl, substituted or unsubstituted aralkyl group, when m is 2 to 6, X can be the same or different; R ¹ and R ² can be the same or different; R ¹ is represented by the formula (II ) or the base represented by formula (III), (In the formula, R ¹¹ and R ¹² each independently represent a hydrogen atom, a fluorine atom, or a substituted or unsubstituted alkyl group, Y1 represents O or NR ²¹ , R ²¹ , R ²² and R ²³ each independently represent a hydrogen atom, Substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted unsubstituted aryl, or substituted or unsubstituted heterocyclyl, in addition, R ²¹ and R ²² Or R ²³ may be combined to form a ring, Z1 represents S, SO, SO ₂ , O or Se, r1 represents any integer from 1 to 8, when r1 is 2 or more, R ¹¹ and R ¹² may be the same or different ) (In the formula, R ³¹ and R ³² each independently represent a hydrogen atom, a fluorine atom or a substituted or unsubstituted linear or branched alkyl group, and Z2 is O or NR ⁶¹ (R ⁶¹ represents a hydrogen atom, a substituted or unsubstituted Straight-chain or branched-chain alkyl, or substituted or unsubstituted aryl), R ³³ represents substituted or unsubstituted straight-chain or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl , a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group, r2 is 0 or any integer from 1 to 8, when r2 is 2 or more, R ³¹ and R ³² can be the same, or they can Different)), R ² is independent of R ¹ and represents a radical represented by formula (II) or formula (III)].

[2] The compound or a pharmaceutically acceptable salt of the compound according to [1], wherein in formula (II), the functional group formed by ^R21 and ^R22 or ^R23 combining to form a ring is a functional group represented by the following formula (IV). [In the formula, R ¹¹ , R ¹² , r1, Z1, R ²² , and R ²³ have the same meanings as in formula (II), Z3 represents CH, CR ⁵⁴ or N, R ⁵¹ and R ⁵² each independently represent a hydrogen atom, or a substituted or unsubstituted straight or branched alkyl group, R ⁵⁴ represents a halogen atom, or a substituted or unsubstituted straight or branched alkyl group, R ⁵³ represents a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group, r3 represents any integer from 1 to 8, and when r3 is 2 or more, R ⁵¹ and R ⁵² may be the same or different, r4 and r6 each independently represent 0 or 1, and r4 and r6 are not both 0, r5 represents 0 or any integer from 1 to 5, and when r5 is 2 or more, R ⁵⁴ may be the same or different, and R ²² The symbol (R ²³ ) represents either R ²² or R ²³ ).

[3] The compound or a pharmaceutically acceptable salt of the compound as described in [1] or [2], wherein ^R1 is selected from the group consisting of the following groups: [wherein, Y is selected from the group consisting of O, S, SO, _SO2 and Se; Z is selected from the group consisting of O, S, SO, _SO2 and Se; n is an integer of 1 to 8; p is an integer of 0 to 8; q is an integer of 1 to 8; r is an integer of 1 to 8; s is an integer of 1 to 8; ^R3 is a substituted or unsubstituted straight or branched alkyl group; ^R4 is a substituted or unsubstituted heterocyclic group, _-CONH2 or (wherein, R ⁴¹ , R ⁴² and R ⁴³ may be the same or different and are selected from the group consisting of a hydrogen atom, a substituted or unsubstituted straight or branched alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group and a substituted or unsubstituted heterocyclic group) R ⁵ is selected from the group consisting of a hydrogen atom, a substituted or unsubstituted cycloalkyl group and a substituted or unsubstituted aryl group: R ⁶ is selected from the group consisting of a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group and a substituted or unsubstituted heterocyclic group] R ² is independent of R ¹ and is selected from the group consisting of the following groups. (wherein, Y, Z, n, p, q, r, s, R ³ , R ⁴ , R ⁵ and R ⁶ have the same meanings as above).

[4] The compound or pharmaceutically acceptable salt of any one of [1] to [3], wherein ^R1 and ^R2 are bonded to adjacent ring atoms of ring A.

[5] The compound or a pharmaceutically acceptable salt of the compound described in any one of [1] to [4], wherein R ¹ and R ² have the same group.

[6] The compound or a pharmaceutically acceptable salt of the compound according to [5], wherein in the compound represented by formula (I), ^R1 and ^R2 are groups represented by formula (II), in which ^R11 and ^R12 are hydrogen atoms, Y1 represents ^NR21 , and r1 is 1.

[7] The compound according to [6] or a pharmaceutically acceptable salt of the compound, which is any one of the following formulae. (wherein A, X and m are as defined in [1], and Z, s, R ⁴¹ , R ⁴² , R ⁴³ and R ⁶ have the same meanings as defined in [3]).

[8] The compound or a pharmaceutically acceptable salt of the compound as described in any one of [1] to [4], wherein R ¹ and R ² have different groups.

[9] The compound described in [8] or a pharmaceutically acceptable salt of the compound, which has the following formula. ^{( In} the formula ^, A ^, , - (CH ₂ ) _n - Y - R ⁴ (where n, Y and R ⁴ have the meanings as defined in [3]), - (CH ₂ ) _p - CONH - (CH ₂ ) _q - R ⁵ (In the formula, p, q and R ⁵ have the meanings as defined in [3]), and the following formula (In the formula, r, s, R ⁶ and Z have the meaning as defined in [3]) form a group, and R ⁷ and R ⁸ are different from each other)

[10] The compound as described in any one of [1] to [9] or a pharmaceutically acceptable salt of the compound, wherein ring A is selected from the group consisting of benzene ring, naphthalene ring, quinoxaline ring, thiophene ring, and indole ring, benzothiophene ring, imidazole ring, quinoline ring, quinazoline ring, and pyridine ring.

[11] The compound or a pharmaceutically acceptable salt of the compound as described in any one of [1] to [10], wherein X is selected from a halogen atom, a substituted or unsubstituted linear or branched chain C ₁ to C ₈ alkyl, substituted or unsubstituted linear or branched C ₁ to C ₈ alkoxy group, substituted or unsubstituted linear or branched C ₂ to C ₈ alkenyl, substituted or unsubstituted linear or branched Chain C ₂ to C ₈ alkenyloxy group, substituted or unsubstituted straight chain or branched chain C ₂ to C ₈ alkynyl group, substituted or unsubstituted straight chain or branched chain C ₂ to C ₈ alkynyloxy group, substituted or unsubstituted Substituted C ₃ to C ₈ cycloalkyl group, substituted or unsubstituted C ₃ to C ₈ cycloalkenyl group, substituted or unsubstituted C ₃ to C ₈ cycloalkynyl group, C ₁ to C ₃ haloalkyl group, cyano group, Hydroxy group, amino group, carboxyl group, substituted or unsubstituted C ₆ to C ₁₈ aryl group, and substituted or unsubstituted aralkyl group (the carbon number of the aryl part is C ₆ to C ₁₀ , the carbon number of the alkylene part is It is the group composed of C ₁ ~ C ₄ ).

[12] The compound as described in any one of [1] to [11], or a pharmaceutically acceptable salt of the compound, wherein X is a group selected from the following groups. -As halogen atoms are fluorine atom, chlorine atom, bromine atom and iodine atom - As substituted or unsubstituted linear or branched alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-octyl, carboxymethyl, 2-carboxyethyl, 3-hydroxy-1-propyl, aminomethyl, 2-aminoethyl, hydroxymethyl, and 2-hydroxyethyl - As substituted or unsubstituted linear or branched alkoxy groups are methoxy, ethoxy, n-propoxy, and n-butoxy - As substituted or unsubstituted linear or branched alkenyl groups are vinyl, 2-propenyl (allyl), and 3-butenyl - As substituted or unsubstituted linear or branched alkenyloxy groups are vinyloxy, 2-propenoxy (allyloxy), and 3-butenoxy - As substituted or unsubstituted linear or branched alkynyl groups are ethynyl, 2-propynyl, and 3-butynyl - As substituted or unsubstituted linear or branched alkynyloxy groups are ethynyloxy, 2-propynyloxy and 3-butynyloxy - As substituted or unsubstituted cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl - As substituted or unsubstituted cycloalkenyl groups are 1-cyclopropenyl, 1-cyclobutenyl, 1-cyclopentenyl, and 1-cyclohexenyl - As haloalkyl groups are fluoromethyl, difluoromethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, 2,2 ,2-trifluoroethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, 2,2,2-triiodoethyl or pentafluoroethyl - As halogenated alkoxy groups are fluoromethoxy, difluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, trifluoromethoxy, Trichloromethoxy, tribromomethoxy, triiodomethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 2,2,2-tribromo Ethoxy, 2,2,2-triiodoethoxy or pentafluoroethoxy -cyano group -hydroxyl -Amino group - Nitro -carboxyl - As substituted or unsubstituted aryl groups are phenyl, naphth-1-yl, and naphth-2-yl - As substituted or unsubstituted aralkyl groups are benzyl, phenethyl, and 3-phenyl-1-propyl

[13] The compound or a pharmaceutically acceptable salt of the compound according to any one of [1] to [12], wherein ring A is a benzene ring, and in the following formula (I-4) the 1-position of the ring is substituted with R ¹ and the 2-position of the ring is substituted with R ² : (wherein ^R1 and ^R2 have the meanings as defined in any one of [1] to [3]) The following formula (I-4-a) except ^R1 and ^R2 in [1] to [3] is selected from Ph=、３－Ｆ－Ｐｈ＝、４－Ｆ－Ｐｈ＝、５－Ｆ－Ｐｈ＝、６－Ｆ－Ｐｈ＝、３－Ｃｌ－Ｐｈ＝、４－Ｃｌ－Ｐｈ＝、５－Ｃｌ－Ｐｈ＝、６－Ｃｌ－Ｐｈ＝、３－Ｂｒ－Ｐｈ＝、４－Ｂｒ－Ｐｈ＝、５－Ｂｒ－Ｐｈ＝、６－Ｂｒ－Ｐｈ＝、３－Ｉ－Ｐｈ＝、４－Ｉ－Ｐｈ＝、５－Ｉ－Ｐｈ＝、６－Ｉ－Ｐｈ＝、３－Ｍｅ－Ｐｈ＝、４－Ｍｅ－Ｐｈ＝、５－Ｍｅ－Ｐｈ＝、６－Ｍｅ－Ｐｈ＝、３－Ｅｔ－Ｐｈ＝、４－Ｅｔ－Ｐｈ＝、５－Ｅｔ－Ｐｈ＝、６－Ｅｔ t-Ph=、３-Pr-Ph=、４-Pr-Ph=、５-Pr-Ph=、６-Pr-Ph=、３-Bu-Ph=、４-Bu-Ph=、５-Bu-Ph=、６-Bu-Ph=、３-t-Bu-Ph=、４-t-Bu-Ph=、５-t-Bu-Ph=、６-t-Bu-Ph=、３-MeO-Ph=、４-MeO-Ph=、５-MeO-Ph=、６-MeO-Ph=、３-EtO-Ph=、４-EtO-Ph=、５-EtO-Ph=、６-EtO-Ph=、３-CF _５ －Ｃ _２ Ｆ ５ _Ｏ －Ｐｈ＝、３－Ｃ _２ Ｆ ５ Ｏ－Ｐｈ＝、４－Ｃ _２ Ｆ _{５ Ｏ－} Ｐｈ＝、５－Ｃ _２ Ｆ _５ Ｏ－Ｐｈ＝、６－Ｃ _２ Ｆ _{５ Ｏ} －Ｐｈ＝、３－ＣＦ _３ Ｏ－Ｐｈ＝、４－ＣＦ _３ Ｏ－Ｐｈ＝、５－ＣＦ _３ Ｏ－Ｐｈ＝、６－ＣＦ _３ Ｏ－Ｐｈ＝、３ _{－Ｃ ２ Ｆ ５} Ｏ－Ｐｈ＝、 _４ －Ｃ _２ Ｆ _５ Ｏ－Ｐｈ＝、５－ＣＦ _３ Ｏ－Ｐｈ＝、６－ _{ＣＦ ３} Ｏ－Ｐｈ＝、３－ＣＮ－Ｐｈ＝、４－ＣＮ－Ｐｈ＝、５－ＣＮ－Ｐｈ＝、６－ＣＮ－Ｐｈ＝、３－ＯＨ－Ｐｈ＝、４－ＯＨ－Ｐｈ＝、５－ＯＨ－Ｐｈ＝、６－ＯＨ－Ｐｈ＝、３－ＮＨ _２ －Ｐｈ＝、４－ＮＨ _２ －Ｐｈ＝、５－ＮＨ _２ －Ｐｈ＝、６－ＮＨ _２ －Ｐｈ＝、３－ＮＯ _２ －Ｐｈ＝、４－ＮＯ _２ －Ｐｈ＝、５－ＮＯ _２ －Ｐｈ＝、６－ＮＯ _２ －Ｐｈ＝、３－ＣＯＯＨ－Ｐｈ＝、４－ＣＯＯＨ－Ｐｈ＝、５－ＣＯＯＨ－Ｐｈ＝、６－ＣＯＯＨ－Ｐｈ＝、（Any two of the 3rd, 4th, 5th and 6th positions）－Ｆ _２ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-Cl ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-Br ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-I ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-Me ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-Et ₂ -Ph-、(any two of the 3rd, 4th, 5th and 6th positions)-Pr ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-Bu ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-(CN) ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-(OH) ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-(NH ₂ ) ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-(NO ₂ ) ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-(MeO) ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-(EtO) ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-(CF ₃ ) ₂ -Ph＝、(any three of the 3rd, 4th, 5th and 6th positions)-F ₃ -Ph＝、(any three of the 3rd, 4th, 5th and 6th positions)-Cl ₂ -Ph＝、(any four of the 3rd, 4th, 5th and 6th positions)-F ₄ -Ph＝、び(any four of the 3rd, 4th, 5th and 6th positions)-Cl ₄ -Ph=, the group formed (wherein "Ph=" represents the part obtained by removing (X)m- from formula (I-4-a))

[14] The compound or a pharmaceutically acceptable salt of the compound according to any one of [1] to [13], which is any compound represented by the following formula.

[15] A pharmaceutical composition comprising one or more compounds as described in any one of [1] to [14] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[16] An IDO and/or TDO inhibitor comprising one or more compounds described in any one of [1] to [14] or pharmaceutically acceptable salts thereof as active ingredients.

[17] A therapeutic agent for a disease or disorder selected from tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and female reproductive health-related diseases, comprising one or two The compound described in any one of [1] to [14] above or a pharmaceutically acceptable salt thereof is used as an active ingredient.

[18] The therapeutic agent described in [17] is an anti-tumor agent.

[19] The therapeutic agent of [18], wherein the tumor is selected from mesothelioma, hepatobiliary (bile tract and bile duct) tumor, primary or secondary CNS tumor, primary or secondary brain tumor, pharyngeal cancer, oral cancer, nasal cancer, lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal cancer, gastric cancer, duodenal cancer, colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, Thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer or ureteral cancer, renal cell cancer, renal pelvis cancer, central nervous system (CNS) cancer, primary CNS lymphoma, non-Hodgkin's lymphoma, cerebrospinal axonal tumor, brain stem neuroglioma, pituitary adenoma, adrenal cortical carcinoma, gallbladder cancer, multiple myeloma, bile duct cancer, fibrosarcoma, neuroblastoma, and retinoblastoma.

[20] A pharmaceutical kit for treating a disease or disorder selected from the group consisting of tumors, infections, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health, comprising: (a) one or more compounds as described in any one of [1] to [14] or their pharmaceutically acceptable salts; and (b) one or more advanced therapeutic agents for treating a disease or disorder selected from the group consisting of tumors, infections, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health, wherein the aforementioned compounds or their pharmaceutically acceptable salts and the aforementioned advanced therapeutic agents are suitable for simultaneous, sequential or separate use.

[21] The pharmaceutical set for treating tumors as described in [20], comprising: (a) One or more than two compounds as described in any one of [1] to [14] or pharmaceutically acceptable salts thereof; and (b) One or more than two advanced anti-tumor agents, wherein The aforementioned compound or its pharmaceutically acceptable salt and the aforementioned advanced therapeutic agent are suitable for simultaneous, sequential or individual administration.

[22] The pharmaceutical kit as described in [21], wherein the aforementioned tumor is selected from mesothelioma, hepatobiliary (bile tract and bile duct) tumor, primary or secondary CNS tumor, primary or secondary brain tumor, pharyngeal cancer, oral cancer, nasal cancer, lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal cancer, gastric cancer, duodenal cancer, colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, Thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer or ureteral cancer, renal cell cancer, renal pelvis cancer, central nervous system (CNS) cancer, primary CNS lymphoma, non-Hodgkin's lymphoma, cerebrospinal axonal tumor, brain stem neuroglioma, pituitary adenoma, adrenal cortical carcinoma, gallbladder cancer, multiple myeloma, bile duct cancer, fibrosarcoma, neuroblastoma, and retinoblastoma.

[23] The compound or pharmaceutically acceptable salt of any one of [1] to [14] is used for treating a disease or disorder selected from the group consisting of tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health.

[24] The compound or pharmaceutically acceptable salt of the compound as described in [23] is used for treating tumors.

[25] The compound or a pharmaceutically acceptable salt of the compound as described in [24], wherein the aforementioned tumor is selected from the group consisting of mesothelioma, hepatobiliary (biliary tract and bile duct) tumors, primary or secondary CNS tumors , primary or secondary brain tumors, pharyngeal cancer, oral cancer, nasal cavity cancer, lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, ovarian cancer, colon Cancer, rectal cancer, anal area cancer, stomach cancer, duodenal cancer, colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulva cancer, Hodgkin's lymphoma, Esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethra cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, acute myeloid leukemia, chronic myelogenous leukemia, Lymphocytic lymphoma, bladder cancer, kidney cancer or ureteral cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) cancer, primary CNS lymphoma, non-Hodgkin's lymphoma, cerebrospinal axis tumors, Brainstem glioma, pituitary adenoma, adrenocortical cancer, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, and retinoblastoma.

[26] Use of the compound or a pharmaceutically acceptable salt of the compound as described in any one of [1] to [14] for the manufacture of a medicament for treating a disease or disorder selected from the group consisting of tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health.

[27] The use as described in [26] is for manufacturing a medicine for treating tumors.

[28] The use of salt as described in [27], wherein the aforementioned tumor is selected from mesothelioma, hepatobiliary (bile tract and bile duct) tumor, primary or secondary CNS tumor, primary or secondary brain tumor, pharyngeal cancer, oral cancer, nasal cancer, lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal cancer, gastric cancer, duodenal cancer, colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, Thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer or ureteral cancer, renal cell cancer, renal pelvis cancer, central nervous system (CNS) cancer, primary CNS lymphoma, non-Hodgkin's lymphoma, cerebrospinal axonal tumor, brain stem neuroglioma, pituitary adenoma, adrenal cortical carcinoma, gallbladder cancer, multiple myeloma, bile duct cancer, fibrosarcoma, neuroblastoma, and retinoblastoma.

[29] A method for treating a disease or disorder selected from tumors, infections, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health, comprising: administering one or more compounds or pharmaceutically acceptable salts thereof as described in any one of [1] to [14], or a pharmaceutical kit as described in any one of [20] to [22] to a patient suffering from a disease or disorder selected from tumors, infections, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health.

[30] The treatment method according to [29], wherein the disease is a tumor.

[31] The compound or a pharmaceutically acceptable salt of the compound as described in [30], wherein the aforementioned tumor is selected from the group consisting of mesothelioma, hepatobiliary (biliary tract and bile duct) tumors, primary or secondary CNS tumors , primary or secondary brain tumors, pharyngeal cancer, oral cancer, nasal cavity cancer, lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, ovarian cancer, colon Cancer, rectal cancer, anal area cancer, stomach cancer, duodenal cancer, colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulva cancer, Hodgkin's lymphoma, Esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethra cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, acute myeloid leukemia, chronic myelogenous leukemia, Lymphocytic lymphoma, bladder cancer, kidney cancer or ureteral cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) cancer, primary CNS lymphoma, non-Hodgkin's lymphoma, cerebrospinal axis tumors, Brainstem glioma, pituitary adenoma, adrenocortical cancer, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, and retinoblastoma.

A compound represented by formula (I) or a pharmaceutically acceptable salt of the compound, [Wherein Ring A represents an aromatic ring, a heterocyclic ring or a condensed ring of two or more rings selected from an aromatic ring and a heterocyclic ring, wherein Ring A is selected from a benzene ring, a naphthalene ring, a quinoxaline ring, a thiophene ring, an indole ring, The group consisting of benzothiophene ^ring , ^imidazole ring, quinoline ^ring , quinazoline ring and pyridine ring ^; Adjacent ring atoms of A ^are bonded; m represents an ^integer of 1 or ^{2 ;} Independently represent the basis represented by: Among them, Y is selected from the group consisting of O, S, SO, SO ₂ and Se, n represents an integer from 1 to 8, and R ⁴ represents: Among them, R ⁴¹ , R ⁴² and R ⁴³ are the same and are hydrogen atoms]. In another aspect, R ¹ and R ² have the same base. In another view, the compound is represented by any one of the following formulas: (where A, X, m, Z, R ⁴¹ , R ⁴² and R ⁴³ have the same definitions as above). In another aspect, R ¹ and R ² have different bases. In another view, the compound is represented by the formula: _[ ^wherein _A ^{, ​ ​} In another point of view, in the compound of the following formula (I-4) containing a benzene ring as ring A, R ¹ and R ² are substituted at positions 1 and 2 of the ring, respectively, (where R ¹ and R ² have the same definitions as above) The following formula (I-4-a) excludes R ¹ and R ² : Is selected from 3-F-Ph=, 4-F-Ph=, 5-F-Ph=, 6-F-Ph=, 3-Cl-Ph=, 4-Cl-Ph=, 5-Cl-Ph =, 6-Cl-Ph=, 3-Br-Ph=, 4-Br-Ph=, 5-Br-Ph=, 6-Br-Ph=, 3-I-Ph=, 4- I-Ph= , 5-I-Ph=, 6-I-Ph=, (any two of the 3, 4, 5 and 6 digits) -F2-Ph=, (any two of the 3, 4, 5 and 6 digits) )-Cl2-Ph=, (any two of positions 3, 4, 5 and 6)-Br2-Ph=, (any two of positions 3, 4, 5 and 6)-I2-Ph= , (where “Ph=” indicates the part of formula (I-4-a) excluding (X) _m -). In another view, the compound is represented by the formula: .

In another aspect, the present invention is a pharmaceutical composition comprising one or more compounds as described above or a pharmaceutically acceptable salt of the compound, and a pharmaceutically acceptable carrier. In another aspect, the present invention is an IDO and/or TDO inhibitor, including a compound as described above or a pharmaceutically acceptable salt of the compound as an active ingredient.

In another aspect, the invention is a method for use in a disease or disorder selected from tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health. Therapeutic agents include one or more compounds as described above or pharmaceutically acceptable salts of the compounds as active ingredients.

In another aspect, the present invention is a method for treating a disease or disorder selected from tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and female reproductive health-related diseases. medicine package, including: (a) More than one compound as described in claim 1 or a pharmaceutically acceptable salt of the compound; and (b) more than one additional therapeutic agent for the treatment of a disease selected from the group consisting of neoplasms, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment and diseases related to women's reproductive health or Conditions wherein the compound or drug, an acceptable salt thereof, and the additional therapeutic agent are suitable for simultaneous, sequential or separate administration.

In another aspect, the present invention is a method of treating a disease or disorder selected from the group consisting of tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health. , including: administering more than one drug to patients with a disease or disorder selected from tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and female reproductive health-related diseases. A compound as described above or a pharmaceutically acceptable salt of the compound. In one view, the disease is a tumor. In another aspect, the aforementioned tumors are selected from the group consisting of mesothelioma, hepatobiliary (biliary tract and bile duct) tumors, primary or secondary central nervous system (CNS) tumors, primary or secondary brain tumors, pharyngeal tumors Cancer, oral cancer, nasal cavity cancer, lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal area cancer, stomach cancer, duodenum Cancer, colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulva cancer, Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer , parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, acute myeloid leukemia, chronic myelogenous leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer, or Ureteral cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) cancer, primary central nervous system (CNS) lymphoma, non-Hodgkin's lymphoma, cerebrospinal axis tumor, brainstem glioma, ptosis Somatic adenoma, adrenocortical cancer, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, and retinoblastoma.

[Effects of the invention] The compounds of the present invention have superior inhibitory effects on IDO and/or TDO inhibitors, and can be used as IDO inhibitors and/or TDO inhibitors for a wide range of diseases including tumors.

Hereinafter, the present invention will be described in more detail. The IDO inhibitor and/or TDO inhibitor of the present invention has a compound of formula (I) or a pharmaceutically acceptable salt of the compound. In the formula, Ring A represents an aromatic ring, an aliphatic ring, a heterocyclic ring, or a condensed ring of two or more rings selected from an aromatic ring, an aliphatic ring, and a heterocyclic ring.

The term "aromatic ring" used in this application refers to a cyclic structure or a compound having such a cyclic structure consisting of a single ring or a plurality of rings composed only of hydrocarbons and having a delocalized π electron orbit. When the above-mentioned aromatic ring constitutes a plurality of rings, the aromatic ring may be a condensed ring or a non-condensed ring (for example, biphenyl). In addition, "used in this application" means "described in at least one of the specification, patent scope, abstract, and drawings of this application."

The term "condensed ring" used in this application refers to a cyclic structure in which two or more rings share two or more atoms to bond.

The term "aliphatic ring" used in this application refers to a cyclic structure or ring having the properties of both aliphatic compounds (non-aromatic hydrocarbon compounds) and cyclic compounds (compounds in which constituent atoms are cyclically bonded). compounds with a similar structure. The aforesaid aliphatic ring includes one or more saturated or unsaturated carbocyclic rings that are not aromatic. Spirocyclic compounds in which two or more rings have a structure connected by one carbon atom are also included in the "aliphatic ring". When the aliphatic ring constitutes a plurality of rings, the aliphatic ring may be a condensed ring or a non-condensed ring.

The term "heterocycle" used in this application refers to a cyclic structure composed of two or more elements or a compound having such a cyclic structure. The aforementioned heterocycles constitute single or plural rings. When the aforementioned heterocyclic ring constitutes a plurality of rings, the heterocyclic ring may be a condensed ring or a non-condensed ring (for example, 2,2'-bipyridine, 4,4'-bipyridine).

The term "condensed ring of two or more rings selected from an aromatic ring, an aliphatic ring, and a heterocyclic ring" used in this application refers to a fused ring having an aromatic ring and an aliphatic ring, an aliphatic ring, and a heterocyclic ring. A cyclic structure of a condensed ring, a condensed ring of an aromatic ring and a heterocyclic ring, or a condensed ring of three kinds of rings: an aromatic ring, an aliphatic ring and a heterocyclic ring, or a compound having such a cyclic structure. The meanings of aromatic ring, aliphatic ring and heterocyclic ring are as defined above.

When Ring A represents an aromatic ring, an aliphatic ring, a heterocyclic ring, or a condensed ring of two or more rings selected from aromatic rings, aliphatic rings, and heterocyclic rings, and when any substituent of the compound of the present application represents an aromatic ring, an aliphatic ring, a heterocyclic ring, or a condensed ring of two or more rings selected from aromatic rings, aliphatic rings, and heterocyclic rings, these rings may be fully saturated, partially saturated, or fully unsaturated. The cyclic group may thus include benzene, naphthalene, anthracene, phenanthrene, phenalene, biphenyl, pentalene, indene, as-indacene, s-indacene, acenaphthylene, fluorene, benzoacenaphthylene, acephenanthrylene, azulene, heptene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyrrolidine, furan, tetrahydrofuran, 2-aza-tetrahydrofuran, 3-aza-tetrahydrofuran, oxazole, isoxazole, furazan, 1,2,4-oxadiazole, 1,3,4-oxadiazole, thiophene, isothiazole, thiazole, thiocyclopentane, pyridine, oxazine, pyrimidine, pyrazine, piperidine, 2-azapiperidine, 3-azapiperidine, piperazine, pyran, tetrahydropyran, 2-azapyran, 3-azapyran, 4-azapyran, 2-aza-tetrahydropyran, 3-aza-tetrahydropyran, morpholine, Thiophanate, 2-nitrothiopyran, 3-nitrothiopyran, 4-nitrothiopyran, thiocyclohexane, indole, indole, benzimidazole, 4-nitroindole, 5-nitroindole, 6-nitroindole, 7-nitroindole, isoindole, 4-nitroindole, 5-nitroindole, 6-nitroindole, 7-nitroindole, indolizine (Indole) dolizine), 1-azaindolizine, 2-azaindolizine, 3-azaindolizine, 5-azaindolizine, 6-azaindolizine, 7-azaindolizine, 8-azaindolizine, 9-azaindolizine, purine, carbazole, carboline, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, quinoline, oxazoline, quinoxaline , 5-azaquinoline, 6-azaquinoline, 7-azaquinoline, isoquinoline, phthalazine, 6-azaisoquinoline, 7-azaisoquinoline, pteridine, quinoline, isoquinoline, acridine, phenanthidine, perimidine, phenanthroline, phenazine, gadolinium, phenathiol and/or thione, and regioisomers of the foregoing groups.

In one aspect of the present invention, ring A is selected from the group consisting of benzene, naphthalene, quinoxaline, thiophene, indole and pyridine.

The "substituent" in "X, ^R1 and ^R2 are substituents of the ring atoms constituting ring A" used in the present application is not particularly limited as long as it does not induce TDO or IDO inhibitory function. For example, X is selected from the group consisting of a halogen atom, a substituted or unsubstituted straight or branched alkyl group, a substituted or unsubstituted straight or branched alkoxy group, a substituted or unsubstituted straight or branched alkenyl group, a substituted or unsubstituted straight or branched alkenyloxy group, a substituted or unsubstituted straight or branched alkynyl group, a substituted or unsubstituted straight or branched alkynyloxy group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a halogenated alkyl group, a halogenated alkoxy group, a cyano group, a hydroxyl group, an amino group, a nitro group, a carboxyl group, and a substituted or unsubstituted aryl group, and a substituted or unsubstituted aralkyl group. X represents a carbon atom and/or a heteroatom that can be arbitrarily bonded to the ring A (representing an aromatic ring, an aliphatic ring, a heterocyclic ring, or a condensed ring of two or more rings selected from aromatic rings, aliphatic rings, and heterocyclic rings). Therefore, the substituent X can also be bonded to a carbon atom and/or a heteroatom that can be arbitrarily bonded to an aromatic ring, a heterocyclic ring, a polycyclic ring such as a benzene ring, or naphthalene. For example, X can also be selected from a halogen atom, a substituted or unsubstituted straight or branched C ₁ ～ C ₈ alkyl group, a substituted or unsubstituted straight or branched C ₁ ～ C ₈ alkoxy group, a substituted or unsubstituted straight or branched C ₂ ～ C ₈ alkenyl group, a substituted or unsubstituted straight or branched C ₂ ～ C ₈ alkenyloxy group, a substituted or unsubstituted straight or branched C ₂ ～ C ₈ alkynyl group, a substituted or unsubstituted straight or branched C 2 ～ C 8 alkynyloxy group, a substituted or unsubstituted C ₃ ～ C ₈ cycloalkyl group, a substituted or unsubstituted C ₃ ～ C ₈ cycloalkenyl group, a substituted _or unsubstituted C ₃ ～ C ₈ cycloalkynyl group, _{a C 1 ～} C ₃ halogenated alkyl group, a cyano group, a hydroxyl group, an amino group, a carboxyl group, a substituted or unsubstituted C The group consisting of C ₆ to C ₁₈ aryl groups and substituted or unsubstituted aralkyl groups (the carbon number of the aryl part is C ₆ to C ₁₀ and the carbon number of the alkylene part is C ₁ to C ₄ ). For example, X may also be selected from the following groups. - as the halogen atom, fluorine atom, chlorine atom, bromine atom and iodine atom - as the substituted or unsubstituted straight-chain or branched-chain alkyl group, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-octyl, carboxymethyl, 2-carboxyethyl, 3-hydroxy-1-propyl, aminomethyl, 2-aminoethyl, hydroxymethyl and 2-hydroxyethyl - as the substituted or unsubstituted straight-chain or branched-chain alkoxy group, methoxy, ethoxy, n-propoxy and n-butoxy - as the substituted or unsubstituted straight-chain or branched-chain alkenyl group, vinyl, 2-propenyl (allyl) and 3-butenyl - as the substituted or unsubstituted straight-chain or branched-chain As substituted or unsubstituted straight or branched alkenyloxy, there are vinyloxy, 2-propenyloxy (allyloxy), and 3-butenyloxy. As substituted or unsubstituted straight or branched alkynyl, there are ethynyl, 2-propynyl, and 3-butynyl. As substituted or unsubstituted straight or branched alkynyl, there are ethynyloxy, 2-propynyloxy, and 3-butynyl. As substituted or unsubstituted cycloalkyl, there are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. As substituted or unsubstituted cycloalkenyl, there are 1-cyclopropenyl, 1-cyclobutenyl, 1-cyclopentenyl, and 1-cyclohexenyl. As halogenated alkyl, there is fluoromethyl (-CH _２ Ｆ), difluoromethyl (－ＣＨＦ _２ ), chloromethyl (－ＣＨ _２ Ｃｌ), bromomethyl (－ＣＨ _２ Ｂｒ), iodomethyl (－ＣＨ _２ Ｉ), trifluoromethyl (－ＣＦ _３ ), trichloromethyl (－ＣＣｌ _３ ), tribromomethyl (－ＣＢｒ _３ ), triiodomethyl (－ＣＩ _３ ), 2,2,2-trifluoroethyl (－ＣＨ _２ ＣＦ _３ ), 2,2,2-trichloroethyl (－ＣＨ _２ ＣＣｌ _３ ), 2,2,2-tribromoethyl (－ＣＨ _２ ＣＢｒ _３ ), 2,2,2-triiodoethyl (－ＣＨ _２ ＣＩ _３ ) or pentafluoroethyl (－Ｃ _２ Ｆ _５ ) - As the halogenated alkoxy group is fluoromethoxy (－ＯＣＨ _２ Ｆ), difluoromethoxy (－ＯＣＨＦ _２ ), chloromethoxy (－ＯＣＨ _２ Ｃｌ), bromomethoxy (-ＯＣＨ _２ Ｂｒ), iodomethoxy (-ＯＣＨ _２ Ｉ), trifluoromethoxy (-ＯＣＦ _３ ), trichloromethoxy (-ＯＣＣｌ _３ ), tribromomethoxy (-ＯＣＢｒ ３ ), triiodomethoxy (-ＯＣＩ _３ ), 2,2,2-trifluoroethoxy (-ＯＣＨ _２ ＣＦ _３ ), 2,2,2 _- trichloroethoxy (-ＯＣＨ _２ ＣＣｌ _３ ), 2,2,2-tribromoethoxy (-ＯＣＨ _２ ＣＢr _３ ), 2,2,2-triiodoethoxy (-ＯＣＨ _２ ＣＩ _３ ) or pentafluoroethoxy (-ＯＣ _２ Ｆ _５ ) - Cyano-Hydroxy-Amino-Nitro-Carboxyl - As substituted or unsubstituted aryl, phenyl, naphth-1-yl, and naphth-2-yl - As substituted or unsubstituted aralkyl, benzyl, phenethyl, and 3-phenyl-1-propyl

^R1 is a group represented by formula (II) or formula (III), (wherein, R ¹¹ and R ¹² each independently represent a hydrogen atom, a fluorine atom, or a substituted or unsubstituted alkyl group, Y1 represents O or NR ²¹ , R ²¹ , R ²² and R ²³ each independently represent a hydrogen atom, a substituted or unsubstituted straight or branched alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group, and R ²¹ and R ²² or R ²³ may also be combined to form a ring, Z1 represents S, SO, SO ₂ , O or Se, and r1 represents any integer from 1 to 8) (wherein, R ³¹ and R ³² each independently represent a hydrogen atom, a fluorine atom or a substituted or unsubstituted straight or branched alkyl group, Z2 is O or NR ⁶¹ (R ⁶¹ represents a hydrogen atom, a substituted or unsubstituted straight or branched alkyl group, or a substituted or unsubstituted aryl group), R ³³ represents a substituted or unsubstituted straight or branched alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkanealkyl group, and R2 is 0 or any integer from 1 to 8), R ² is independent of R ¹ and represents a group represented by formula (II) or formula (III). In a preferred embodiment of the present invention, R ¹ is a group represented by formula (II), and R ² is a group represented by formula (II) or formula (III). When R ² is a group represented by formula (II), if the specific groups of R ¹ and R ² are groups included in the definition of formula (II), any group may be used, and they do not have to be the same group. In a preferred embodiment of the present invention, R ¹ is a group represented by formula (II), and R ² is a group represented by formula (II). In this case, if the specific groups of R ¹ and R ² are groups included in the definition of formula (II), any group may be used, and they do not have to be the same group. In a preferred embodiment of the present invention, R ¹ is a group represented by formula (II), and R ² is a group represented by formula (III). In a preferred embodiment of the present invention, R ¹ is a group represented by formula (III), and R ² is a group represented by formula (II). In a preferred embodiment of the present invention, R ¹ is a group represented by formula (III), and R ² is a group represented by formula (III). In this case, the specific groups of R ¹ and R ² may be any group as long as they are included in the definition of formula (II), and they do not have to be the same group.

In formula (II), the functional group formed by combining R ²¹ with R ²² or R ²³ to form a ring is a functional group represented by the following formula (IV). [wherein, R ¹¹ , R ¹² , r1, Z1, R ²² , and R ²³ have the same meanings as in formula (II), Z3 represents CH, CR ⁵⁴ or N, R ⁵¹ and R ⁵² each independently represent a hydrogen atom, or a substituted or unsubstituted straight or branched alkyl group, R ⁵⁴ represents a halogen atom, or a substituted or unsubstituted straight or branched alkyl group, R ⁵³ represents a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group, r3 represents any integer of 1 to 8, r4 and r6 each independently represent 0 or 1, and r4 and r6 are not simultaneously 0, r5 represents 0 or any integer of 1 to 5, and the symbol of R ²² (R ²³ ) represents any one of R ²² and R ²³ ).

^R1 and ^R2 may be the same or different, and are, for example, independently selected from the group consisting of the following groups:

In the formula, Y is selected from the group consisting of O, S, SO, SO ₂ and Se; Z is selected from the group consisting of O, S, SO, SO ₂ and Se; n represents an integer from 1 to 8; p represents 0 q represents an integer of 1 to 8; r represents an integer of 1 to 8; s represents an integer of 1 to 8; R ³ represents a substituted or unsubstituted linear or branched alkyl group; R ⁴ represents a substituted or Unsubstituted heterocyclyl, -CONH ₂ or

(In the formula, R ⁴¹ , R ⁴² and R ⁴³ may be the same or different, and are selected from a hydrogen atom, a substituted or unsubstituted linear or branched alkyl group, a substituted or substituted unsubstituted cycloalkyl group, a substituted or R ⁵ is selected from the group consisting of a hydrogen atom, a substituted or unsubstituted cycloalkyl group, and a substituted or unsubstituted aryl group: R ⁶ Selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl.

In one aspect of the present invention, r1 is an integer from 1 to 8. In one aspect of the present invention, r1 is an integer from 1 to 6. In one aspect of the present invention, r1 is an integer from 1 to 4. In one aspect of the present invention, r1 is an integer from 1 to 2. In one aspect of the invention, r1 is 1. In one aspect of the present invention, r2 is 0 or an integer from 1 to 8. In one aspect of the invention, r2 is zero. In one aspect of the present invention, r2 is an integer from 1 to 6. In one aspect of the present invention, r2 is an integer from 1 to 4. In one aspect of the present invention, r2 is an integer from 1 to 2. In one aspect of the invention, r2 is 1. In one aspect of the present invention, r3 is an integer from 1 to 8. In one aspect of the present invention, r3 is an integer from 1 to 6. In one aspect of the present invention, r3 is an integer from 1 to 4. In one aspect of the present invention, r3 is an integer of 1 to 2. In one aspect of the invention, r3 is 1. In one aspect of the invention, r4 is 0 or 1. In one aspect of the invention, r4 is zero. In one aspect of the invention, r4 is 1. In one aspect of the invention, r5 is 0 or any integer from 1 to 5. In one aspect of the invention, r5 is zero. In one aspect of the present invention, r5 is an integer from 1 to 5. In one aspect of the present invention, r5 is an integer from 1 to 4. In one aspect of the present invention, r5 is an integer from 1 to 2. In one aspect of the invention, r5 is 1. In one aspect of the invention, r6 is 0 or 1. In one aspect of the invention, r6 is zero. In one aspect of the invention, r6 is 1. Also, r4 and r6 are not 0 at the same time. In one aspect of the present invention, n is an integer from 1 to 8. In one aspect of the present invention, n is an integer from 1 to 6. In one aspect of the present invention, n is an integer from 1 to 4. In one aspect of the present invention, n is an integer from 1 to 2. In one aspect of the invention, n is 1. In one aspect of the present invention, p is an integer from 0 to 8. In one aspect of the present invention, p is an integer from 0 to 6. In one aspect of the present invention, p is an integer from 0 to 4. In one aspect of the present invention, p is an integer from 0 to 2. In one aspect of the invention, p is 0. In one aspect of the invention, p is 1. In one aspect of the present invention, q is an integer from 1 to 8. In one aspect of the present invention, q is an integer from 1 to 6. In one aspect of the present invention, q is an integer from 1 to 4. In one aspect of the present invention, q is an integer from 1 to 2. In one aspect of the invention, q is 2. In one aspect of the invention, q is 4. In one aspect of the present invention, r is an integer from 1 to 8. In one aspect of the present invention, r is an integer from 1 to 6. In one aspect of the present invention, r is an integer from 1 to 4. In one aspect of the present invention, r is an integer from 1 to 2. In one aspect of the invention, r is 1. In one aspect of the present invention, s is an integer from 1 to 8. In one aspect of the present invention, s is an integer from 1 to 6. In one aspect of the present invention, s is an integer from 1 to 4. In one aspect of the present invention, s is an integer from 1 to 2. In one aspect of the invention, s is 1. In one aspect of the invention, s is 2.

The substitution positions of R ¹ and R ² with respect to the ring atoms of ring A are not particularly limited. For example, R ¹ and R ² may be bonded to adjacent ring atoms of ring A. For example, R ¹ and R ² may have a ring atom sandwiched between them, that is, they may be bonded to adjacent ring atoms adjacent to each other. R ¹ and R ² may have the same group. R ¹ and R ² may have different bases.

The term "halogen atom" used in this application refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). The term "halogenated" used in this application refers to a group in which one or more hydrogen atoms on one or more carbon atoms of the group are replaced by halogen atoms. When two or more hydrogen atoms are replaced by halogen atoms, the two or more halogens may be the same or different. A compound having a halogen atom as a substituent or a compound having a substituent containing a halogen atom is sometimes called a "halogen compound".

In the term "substituted or unsubstituted" used in this application, "substituted" means having one or more substituents, and "unsubstituted" means having no substituents at all.

The term "straight chain" used in this application refers to a structure in which atoms other than hydrogen atoms are connected in a straight line without branches.

The term "branched chain" used in this application refers to a structure in which one or more arbitrary carbon atoms are bonded to two or more other carbon atoms.

The term "alkyl group" used in this application refers to the residue after removing one hydrogen atom from any carbon atom of an alkane (saturated aliphatic hydrocarbon group) represented by the general formula C _n H _{2n + 2} (n is a positive integer). hydrocarbyl. The number of carbon atoms in the alkyl group is not particularly limited. In one aspect of the present invention, the alkyl group is an alkyl group having 1 to 20 carbon atoms. In one aspect of the present invention, the alkyl group is an alkyl group having 1 to 16 carbon atoms. In one aspect of the present invention, the alkyl group is an alkyl group having 1 to 12 carbon atoms. In one aspect of the present invention, the alkyl group is an alkyl group having 1 to 10 carbon atoms. In one aspect of the present invention, the alkyl group is an alkyl group having 1 to 8 carbon atoms. In one aspect of the present invention, the alkyl group is an alkyl group having 1 to 6 carbon atoms. In one aspect of the present invention, the alkyl group is an alkyl group having 1 to 4 carbon atoms. Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and 1-methyl Butyl, 2-methylbutyl, 3-methylbutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, 1-methyl Pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylpentyl Methylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1-ethyl Butyl, 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl base, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2- Dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl base, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4- Methylhexyl, 5-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 4,4-dimethylpropyl, 1-propylenebutyl, and N-octyl et al.

The term "alkoxy" used in this application refers to a group represented by "-O-alkyl". "Alkyl" is as defined above. The term "substituted or unsubstituted straight or branched alkoxy" used in this application refers to "-O-substituted or unsubstituted straight or branched alkyl". The carbon number of the alkyl group in "alkoxy" is not particularly limited. In one aspect of the present invention, the alkyl group is an alkyl group with 1 to 20 carbon atoms. In one aspect of the present invention, the alkyl group is an alkyl group with 1 to 16 carbon atoms. In one aspect of the present invention, the alkyl group is an alkyl group with 1 to 12 carbon atoms. In one aspect of the present invention, the alkyl group is an alkyl group with 1 to 10 carbon atoms. In one aspect of the present invention, the alkyl group is an alkyl group with 1 to 8 carbon atoms. In one aspect of the present invention, the alkyl group is an alkyl group with 1 to 6 carbon atoms. In one aspect of the present invention, the alkyl group is an alkyl group with 1 to 4 carbon atoms. Examples of the "alkoxy" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-ethylpropoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, n-hexyloxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, Oxygen, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1,1,2-trimethylpropoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxy, n-heptyloxy, 1-methylhexyloxy, 2-methylhexyloxy, 3-methylhexyloxy, 4-methylhexyloxy, 5-methylhexyloxy, 1-ethylpentyloxy, 2-ethylpentyloxy, 3-ethylpentyloxy, 4,4-dimethylpentyloxy, 1-propylbutoxy, and n-octyloxy, etc.

The term "alkenyl" used in this application refers to an alkenyl group having only one carbon-carbon double bond in the molecule and represented by the general formula C _n H _2n (n is a positive integer of 2 or 3 or more). (Alkene) The remaining hydrocarbon group after removing a hydrogen atom from any carbon atom. The number of carbon atoms in the alkenyl group is not particularly limited. In one aspect of the present invention, the alkenyl group is an alkenyl group having 2 to 20 carbon atoms. In one aspect of the present invention, the alkenyl group is an alkenyl group having 2 to 16 carbon atoms. In one aspect of the present invention, the alkenyl group is an alkenyl group having 2 to 12 carbon atoms. In one aspect of the present invention, the alkenyl group is an alkenyl group having 2 to 10 carbon atoms. In one aspect of the present invention, the alkenyl group is an alkenyl group having 2 to 8 carbon atoms. In one aspect of the present invention, the alkenyl group is an alkenyl group having 2 to 6 carbon atoms. In one aspect of the present invention, the alkenyl group is an alkenyl group having 2 to 4 carbon atoms. Examples of "alkenyl" include vinyl group, 1-propenyl, 2-propenyl (allyl), 1-butenyl, 2-butenyl, and 3-butenyl. , isobutenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-octene base, 2-octenyl, 3-octenyl, and 4-octenyl, etc.

The term "alkenyloxy" used in the present application refers to a group represented by "-O-alkenyl". "Alkenyl" is as defined above. The term "substituted or unsubstituted straight or branched alkenyloxy" used in the present application refers to "-O-substituted or unsubstituted straight or branched alkenyl". The number of carbon atoms of the alkenyl group in "alkenyloxy" is not particularly limited. In one aspect of the present invention, the alkenyl group is an alkenyl group having 2 to 20 carbon atoms. In one aspect of the present invention, the alkenyl group is an alkenyl group having 2 to 16 carbon atoms. In one aspect of the present invention, the alkenyl group is an alkenyl group having 1 to 12 carbon atoms. In one aspect of the present invention, the alkenyl group is an alkenyl group having 1 to 10 carbon atoms. In one aspect of the present invention, the alkenyl group is an alkenyl group having 2 to 8 carbon atoms. In one aspect of the present invention, the alkenyl group is an alkenyl group having 2 to 6 carbon atoms. In one embodiment of the present invention, the alkenyl group is an alkenyl group having 2 to 4 carbon atoms. Examples of "alkenyloxy" include vinyloxy group, 1-propenyloxy group, 2-propenyloxy group (allyloxy group), 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, isobutenyloxy group, 1-pentenyloxy group, 2-pentenyloxy group, 3-pentenyloxy group, 4-pentenyloxy group, 1-hexenyloxy group, 2-hexenyloxy group, 3-hexenyloxy group, 1-octenyloxy group, 2-octenyloxy group, 3-octenyloxy group, 4-octenyloxy group, etc.

The term "alkynyl" used in this application refers to a alkyl group remaining after removing a hydrogen atom from any carbon atom on an alkyne (ethynyl) represented by the general formula C _n H _2n-2 (n is a positive integer greater than or equal to 2 or 3) having only one carbon-carbon triple bond in the molecule. In one embodiment of the present invention, the alkynyl group is an alkynyl group having 1 to 12 carbon atoms. In one embodiment of the present invention, the alkynyl group is an alkynyl group having 2 to 10 carbon atoms. In one embodiment of the present invention, the alkynyl group is an alkynyl group having 2 to 8 carbon atoms. In one embodiment of the present invention, the alkynyl group is an alkynyl group having 2 to 6 carbon atoms. In one embodiment of the present invention, the alkynyl group is an alkynyl group having 2 to 4 carbon atoms. Examples of the “alkynyl group” include ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-methyl-3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-pentynyl, 1-hexynyl, 1,1-dimethyl-2-butynyl, 1-octynyl, 2-octynyl, 3-octynyl, and 4-octynyl.

The term "alkynyloxy" used in this application refers to the group represented by "-O-alkynyl". "Alkynyl" is as defined above. The term "substituted or unsubstituted linear or branched alkynyl" used in this application refers to "-O-substituted or unsubstituted linear or branched alkynyl". The number of carbon atoms in the alkynyl group in the "alkynyloxy group" is not particularly limited. In one aspect of the present invention, the alkynyl group is an alkynyl group having 1 to 12 carbon atoms. In one aspect of the present invention, the alkynyl group is an alkynyl group having 2 to 10 carbon atoms. In one aspect of the present invention, the alkynyl group is an alkynyl group having 2 to 8 carbon atoms. In one aspect of the present invention, the alkynyl group is an alkynyl group having 2 to 6 carbon atoms. In one aspect of the present invention, the alkynyl group is an alkynyl group having 2 to 4 carbon atoms. Examples of "alkynyloxy" include ethynyloxy, 1-propynyloxy, 2-propynyloxy (propargyloxy), 1-butynoxy, and 2-butynyloxy. , 3-butynyloxy, 1-methyl-2-propynyloxy, 2-methyl-3-butynyloxy, 1-pentynyloxy, 2-pentynyloxy, 3-pentynyl Oxygen, 4-pentynyloxy, 1-methyl-2-butynyloxy, 2-methyl-3-pentynyloxy, 1-hexyloxy, 1,1-dimethyl-2- Butynyloxy, 1-octynyloxy, 2-octynyloxy, 3-octynyloxy, and 4-octynyloxy, etc.

The term "cycloalkyl" used in the present application refers to the alkyl group remaining after removing one hydrogen atom from any carbon atom of a _cycloalkane (cyclic saturated hydrocarbon) represented by the general formula _CnH2n (n is a positive integer greater than or equal to 3). In one aspect of the present invention, the cycloalkyl group is a cycloalkyl group having 3 to 12 carbon atoms. In one aspect of the present invention, the cycloalkyl group is a cycloalkyl group having 3 to 10 carbon atoms. In one aspect of the present invention, the cycloalkyl group is a cycloalkyl group having 3 to 8 carbon atoms. In one aspect of the present invention, the cycloalkyl group is a cycloalkyl group having 3 to 6 carbon atoms. In one aspect of the present invention, the cycloalkyl group is a cycloalkyl group having 3 to 4 carbon atoms. Examples of the "cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

The term "cycloalkenyl" used in this application refers to a cyclic olefin (cyclic olefin) represented by the general formula C _n H _2n-2 (n is a positive integer of 3 or more) except for one carbon atom. The remaining hydrocarbon group after the hydrogen atom. In one aspect of the present invention, the cycloalkenyl group is a cycloalkenyl group having 3 to 12 carbon atoms. In one aspect of the present invention, the cycloalkenyl group is a cycloalkenyl group having 3 to 10 carbon atoms. In one aspect of the present invention, the cycloalkenyl group is a cycloalkenyl group having 3 to 8 carbon atoms. In one aspect of the present invention, the cycloalkenyl group is a cycloalkenyl group having 3 to 6 carbon atoms. In one aspect of the present invention, the cycloalkenyl group is a cycloalkenyl group having 3 to 4 carbon atoms. Examples of "cycloalkenyl" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, and cyclodecanyl. Alkenyl etc.

The term "cycloalkynyl" used in this application refers to any carbon atom of a cycloalkyne (cyclic alkyne) represented by the general formula C _n H _2n-4 (n is a positive integer of 3 or more) The remaining hydrocarbon group after removing one hydrogen atom. In one aspect of the present invention, the cycloalkynyl group is a cycloalkynyl group having 8 to 20 carbon atoms. In one aspect of the present invention, the cycloalkynyl group is a cycloalkynyl group having 10 to 16 carbon atoms. In one aspect of the present invention, the cycloalkynyl group is a cycloalkynyl group having 10 to 12 carbon atoms. In one aspect of the present invention, the cycloalkynyl group is a cycloalkynyl group having 8 to 12 carbon atoms. In one aspect of the present invention, the cycloalkynyl group is a cycloalkynyl group having 8 to 10 carbon atoms. Examples of "cycloalkynyl" include cyclooctynyl, cyclononenyl, cyclodecynyl, cycloundecynyl, and cyclododecynyl.

The term "aryl" used in this application refers to a compound having an aromatic ring, that is, a alkyl group remaining after removing a hydrogen atom bonded to a ring atom of the aromatic ring of the aromatic hydrocarbon. The meaning of the aromatic ring is as defined above. In one embodiment of the present invention, the aryl group is an aryl group having 6 to 22 carbon atoms in the ring. In one embodiment of the present invention, the aryl group is an aryl group having 6 to 18 carbon atoms in the ring. In one embodiment of the present invention, the aryl group is an aryl group having 6 to 14 carbon atoms in the ring. In one embodiment of the present invention, the aryl group is an aryl group having 6 to 10 carbon atoms in the ring. In one embodiment of the present invention, the aryl group is an aryl group having 6 carbon atoms in the ring (phenyl). Examples of "aryl" include phenyl, o-tolyl, m-tolyl, p-tolyl, naphthyl, o-xylyl, m-xylyl, and p-xylyl.

The term "aralkyl" used in this application refers to an alkyl group in which one hydrogen atom of the alkyl group ( _Cn H _2n+1 ) is replaced by an aryl group. In one aspect of the present invention, the aralkyl group is an aralkyl group having 7 to 26 carbon atoms (of which the number of carbon atoms in the ring is 6 to 22). In one aspect of the present invention, the aralkyl group is an aralkyl group having 7 to 22 carbon atoms (of which the number of carbon atoms in the ring is 6 to 18). In one aspect of the present invention, the aralkyl group is an aralkyl group having 7 to 18 carbon atoms (of which the number of carbon atoms in the ring is 6 to 14). In one aspect of the present invention, the aralkyl group is an aralkyl group having 7 to 14 carbon atoms (of which the number of carbon atoms in the ring is 6 to 14). In one aspect of the present invention, the aralkyl group is an aralkyl group having 7 to 8 carbon atoms (of which the number of carbon atoms in the ring is 6). Examples of the "aralkyl group" include benzyl (phenylmethyl), phenylethyl (phenylethyl), and the like.

In one embodiment of the present invention, the compound of formula (I) is the following compound (I-0a) in which ^R1 and ^R2 have a group of the aforementioned formula (II) and are bonded to adjacent ring atoms of ring A.

(In the formula, A, X, m, Y1, Z1, R ¹¹ , R ¹² , R ²² , R ²³ and r1 have the same meanings as above.) For example, Y1 is O. For example, Y1 is NR ²¹ (Herein, R ²¹ represents a hydrogen atom, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group.) For example, Z1 is S, SO or SO _2. For example, Z1 is O. For example, Z1 is Se.

In one aspect of the present invention, in the compound of formula (I-0a), at least one R ²¹ is bonded to R ²² or R ²³ to form a ring. When the functional group is the formula (IV), the compound is the following compound (I-0a-1) ~ (I-0a-3).

^{( In the formula , A , ​} meaning.) For example, Z1 is S, SO or SO ₂ . For example, Z1 is O. For example, Z1 is Se. For example, Z3 is. For example, Z3 is N. For example, Z3 is CR ⁵⁴ (R ⁵⁴ represents a halogen atom or a substituted or unsubstituted linear or branched alkyl group).

In one aspect of the present invention, the compound of formula (I) is the following compound (I-0b) in which R ¹ and R ² have the same group and are bonded to adjacent ring atoms of ring A.

(wherein A, X, m, Z2, ^R31 , ^R32 , ^R33 and r2 have the meanings as described above) For example, Z2 is O. For example, Z2 is ^NR61 (wherein ^R61 represents a hydrogen atom, a substituted or unsubstituted linear or branched alkyl group, or a substituted or unsubstituted aryl group).

In one embodiment of the present invention, the compound of formula (I) is the following compound wherein R ¹ and R ² have the same group and are bonded to adjacent ring atoms of ring A. (wherein A, X, Z, m, R ⁴¹ , R ⁴² and R ⁴³ have the meanings as described above) For example, Z is S, SO or SO ₂ . For example, Z is O. For example, Z is Se.

In one aspect of the present invention, the compound of formula (I) is a compound wherein R ¹ and R ² have the same group and are bonded to adjacent ring atoms of ring A. (wherein A, X, Z, m, s and R ⁶ have the meanings as described above) For example, Z is S, SO or SO ₂ . For example, Z is O. For example, Z is Se.

In one embodiment of the present invention, the compound of formula (I) is the following two compounds in which ^R1 and ^R2 have different groups and are bonded to adjacent ring atoms of ring A.

[Chemistry 25] (wherein A, X, m, Y1, Z1, Z2, R ¹¹ , R ¹² , R ²² , R ²³ , R ³¹ , R ³² , R ³³ , r1 and r2 have the same meanings as above) For example, Y1 is O. For example, Y1 is NR ²¹ , (herein, R ²¹ represents a hydrogen atom, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group). For example, Z1 is S, SO or SO ₂ . For example, Z1 is O. For example, Z1 is Se. For example, Z2 is O. For example, Z2 is NR ⁶¹ (herein, R ⁶¹ represents a hydrogen atom, a substituted or unsubstituted linear or branched alkyl group, or a substituted or unsubstituted aryl group).

In one aspect of the present invention, in the compound of the formula (I-0c) and the compound of the formula (I-0d), the functional group in which R ²¹ and R ²² or R ²³ are bonded to form a ring is the formula (IV). The compounds are the following two compounds.

[Chemistry 26] (wherein, A, X, m, Z1, Z2, Z3, R ¹¹ , R ¹² , R 22 , R ²³ , R ³¹ , R ³² , R ³³ , R ⁵¹ , R ⁵² , R ⁵³ , R ⁵⁴ , r1, ^r2 , r3, r4, r5 and r6 have the aforementioned meanings). For example, Z1 is S, SO or SO ₂ . For example, Z1 is O. For example, Z1 is Se. For example, Z2 is O. For example, Z2 is NR ⁶¹ (herein, R ⁶¹ represents a hydrogen atom, a substituted or unsubstituted linear or branched alkyl group, or a substituted or unsubstituted aryl group). For example, Z3 is CH. For example, Z3 is N. For example, Z3 is CR ⁵⁴ (R ⁵⁴ represents a halogen atom or a substituted or unsubstituted linear or branched alkyl group).

In one embodiment of the present invention, the compound of formula (I) is the following compound wherein ^R1 and ^R2 have different groups and are bonded to adjacent ring atoms of ring A.

(wherein A, X and m have the same meanings as above, ^R7 and ^R8 are different from each other and are selected from the group consisting of the following groups)

(In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ , Y, Z, n, p, q, r and s have the meanings as mentioned above)

For example, Y is S, SO, or _SO2 . For example, Y is O. For example, Y is Se. For example, Z is S, SO or _SO2 . For example, Z is O. For example, Z is Se.

Specific examples of compounds represented by formula (I-3) in which R ⁷ and R ⁸ are different from each other include the following compounds.

(In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ , Y, Z, n, p, q, r and s have the meanings as mentioned above)

For example, Y is S, SO or SO ₂ . For example, Y is O. For example, Y is Se. For example, Z is S, SO or SO ₂ . For example, Z is O. For example, Z is Se.

As one aspect of the present invention, in the compounds of formula (I), (I-0a), (I-0a-1), (I-0b), (I-0c), (I-0d), (I-0c-1), (I-0d-1), (I-1), (I-2), (I-3), and (1-3-a) to (1-3-h), X is selected from a halogen atom, a substituted or unsubstituted straight or branched C ₁ ～C ₈ alkyl group, a substituted or unsubstituted straight or branched C ₁ ～C ₈ alkoxy group, a substituted or unsubstituted straight or branched C ₂ ～C ₈ alkenyl group, a substituted or unsubstituted straight or branched C ₂ ～C 8 The group consisting of: a substituted or unsubstituted straight chain or branched C ₂ ～C _{8 alkenyloxy} group, a substituted or unsubstituted straight chain or branched C ₂ ～C ₈ alkynyl group, a substituted or unsubstituted straight chain or branched C 2 ～C ₈ alkynyloxy group, a substituted or unsubstituted C ₃ ～C ₈ cycloalkyl group, a substituted or unsubstituted C ₃ ～C 8 cycloalkenyl group, a substituted or unsubstituted C ₃ ～C ₈ cycloalkynyl group, a C ₁ ～C ₃ halogenated alkyl group, a cyano group, a hydroxyl group, an amino group, a carboxyl group, a substituted or unsubstituted C ₆ ～C ₁₈ aryl group, and a substituted or unsubstituted aralkyl group (the number of carbon atoms in the aryl part is C ₆ ～C ₁₀ , and the number of carbon atoms in the alkylene part is C ₁ ～C ₄ ).

As one aspect of the present invention, in the compound of formula (I), the compound of formula (I-0a), the compound of formula (I-0a-1), the compound of formula (I-0b), the compound of formula (I-0c), the compound of formula (I-0d), the compound of formula (I-0c-1), the compound of formula (I-0d-1), the compound of formula (I-1), the compound of formula (I-2), the compound of formula (I-3), and the compounds of formulas (1-3-a) to (1-3-h), X is a group selected from the following group. - as the halogen atom, fluorine atom, chlorine atom, bromine atom and iodine atom - as the substituted or unsubstituted straight-chain or branched-chain alkyl group, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-octyl, carboxymethyl, 2-carboxyethyl, 3-hydroxy-1-propyl, aminomethyl, 2-aminoethyl, hydroxymethyl and 2-hydroxyethyl - as the substituted or unsubstituted straight-chain or branched-chain alkoxy group, methoxy, ethoxy, n-propoxy and n-butoxy - as the substituted or unsubstituted straight-chain or branched-chain alkenyl group, vinyl, 2-propenyl (allyl) and 3-butenyl - as the substituted or unsubstituted straight-chain or branched-chain alkyl group, As substituted or unsubstituted straight or branched alkenyloxy, there are vinyloxy, 2-propenyloxy (allyloxy), and 3-butenyloxy. As substituted or unsubstituted straight or branched alkynyl, there are ethynyl, 2-propynyl, and 3-butynyl. As substituted or unsubstituted straight or branched alkynyl, there are ethynyloxy, 2-propynyloxy, and 3-butynyl. As substituted or unsubstituted cycloalkyl, there are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. As substituted or unsubstituted cycloalkenyl, there are 1-cyclopropenyl, 1-cyclobutenyl, 1-cyclopentenyl, and 1-cyclohexenyl. As halogenated alkyl, there is fluoromethyl (-CH _２ Ｆ), difluoromethyl ( _{－ＣＨＦ２} ), chloromethyl ( _{－ＣＨ２Ｃｌ} ), bromomethyl ( _{－ＣＨ２Ｂｒ} ), iodomethyl ( _{－ＣＨ２Ｉ} ), trifluoromethyl ( _－ＣＦ３ ), trichloromethyl ( _{－ＣＣｌ３} ), tribromomethyl ( _{－ＣＢｒ３} ), triiodomethyl ( _－ＣＩ３ ), 2,2,2-trifluoroethyl _{( －ＣＨ２ＣＦ３} ), 2,2,2-trichloroethyl ( _{－ＣＨ２ＣＣｌ３} ), 2,2,2-tribromoethyl ( _{－ＣＨ２ＣＢｒ３} ), _2,2,2 -triiodoethyl ( _{－ＣＨ２ＣＩ３} ) or _{pentafluoroethyl} ( _{－Ｃ２Ｆ５} ) - as the halogenated alkoxy group is _{fluoromethoxy (－ＯＣＨ２Ｆ )} , _{difluoromethoxy (－ＯＣＨＦ２ )} , chloromethoxy ( _{－ＯＣＨ２Ｃ} Ｃｌ), bromomethoxy (-ＯＣＨ _２ Ｂｒ), iodomethoxy (-ＯＣＨ _２ Ｉ), trifluoromethoxy (-ＯＣＦ _３ ), trichloromethoxy (-ＯＣＣｌ _３ ), tribromomethoxy (-ＯＣＢｒ ３ ), triiodomethoxy (-ＯＣＩ _３ ), 2,2,2-trifluoroethoxy (-ＯＣＨ _２ ＣＦ _３ ), 2,2,2 _- trichloroethoxy (-ＯＣＨ _２ ＣＣｌ _３ ), 2,2,2-tribromoethoxy (-ＯＣＨ _２ ＣＢr _３ ), 2,2,2-triiodoethoxy (-ＯＣＨ _２ ＣＩ _３ ) or pentafluoroethoxy (-ＯＣ _２ Ｆ _５ ) - Cyano-Hydroxy-Amino-Nitro-Carboxyl - As substituted or unsubstituted aryl, phenyl, naphth-1-yl, and naphth-2-yl - As substituted or unsubstituted aralkyl, benzyl, phenethyl, and 3-phenyl-1-propyl

As mentioned above, ring A can be selected from the group consisting of a benzene ring, a naphthalene ring, a quinoxaline ring, a thiophene ring, an indole ring, a benzothiophene ring, an imidazole ring, a quinoline ring, a quinazoline ring, and a pyridine ring. In one embodiment of the present invention, ring A is a benzene ring, and in the following formula (I-4) wherein the 1-position of the ring is substituted with R ¹ and the 2-position is substituted with R ² , (wherein, ^R1 and ^R2 have the meanings as defined in any one of [1] to [3]) The following formula (I-4-a) other than ^R1 and ^R2 may also be selected from Ph=、３－Ｆ－Ｐｈ＝、４－Ｆ－Ｐｈ＝、５－Ｆ－Ｐｈ＝、６－Ｆ－Ｐｈ＝、３－Ｃｌ－Ｐｈ＝、４－Ｃｌ－Ｐｈ＝、５－Ｃｌ－Ｐｈ＝、６－Ｃｌ－Ｐｈ＝、３－Ｂｒ－Ｐｈ＝、４－Ｂｒ－Ｐｈ＝、５－Ｂｒ－Ｐｈ＝、６－Ｂｒ－Ｐｈ＝、３－Ｉ－Ｐｈ＝、４－Ｉ－Ｐｈ＝、５－Ｉ－Ｐｈ＝、６－Ｉ－Ｐｈ＝、３－Ｍｅ－Ｐｈ＝、４－Ｍｅ－Ｐｈ＝、５－Ｍｅ－Ｐｈ＝、６－Ｍｅ－Ｐｈ＝、３－Ｅｔ－Ｐｈ＝、４－Ｅｔ－Ｐｈ＝、５－Ｅｔ－Ｐｈ＝、６－Ｅｔ t-Ph=、３-Pr-Ph=、４-Pr-Ph=、５-Pr-Ph=、６-Pr-Ph=、３-Bu-Ph=、４-Bu-Ph=、５-Bu-Ph=、６-Bu-Ph=、３-t-Bu-Ph=、４-t-Bu-Ph=、５-t-Bu-Ph=、６-t-Bu-Ph=、３-MeO-Ph=、４-MeO-Ph=、５-MeO-Ph=、６-MeO-Ph=、３-EtO-Ph=、４-EtO-Ph=、５-EtO-Ph=、６-EtO-Ph=、３-CF _５ －Ｃ _２ Ｆ ５ _Ｏ －Ｐｈ＝、３－Ｃ _２ Ｆ ５ Ｏ－Ｐｈ＝、４－Ｃ _２ Ｆ _{５ Ｏ－} Ｐｈ＝、５－Ｃ _２ Ｆ _５ Ｏ－Ｐｈ＝、６－Ｃ _２ Ｆ _{５ Ｏ} －Ｐｈ＝、３－ＣＦ _３ Ｏ－Ｐｈ＝、４－ＣＦ _３ Ｏ－Ｐｈ＝、５－ＣＦ _３ Ｏ－Ｐｈ＝、６－ＣＦ _３ Ｏ－Ｐｈ＝、３ _{－Ｃ ２ Ｆ ５} Ｏ－Ｐｈ＝、 _４ －Ｃ _２ Ｆ _５ Ｏ－Ｐｈ＝、５－ＣＦ _３ Ｏ－Ｐｈ＝、６－ _{ＣＦ ３} Ｏ－Ｐｈ＝、３－ＣＮ－Ｐｈ＝、４－ＣＮ－Ｐｈ＝、５－ＣＮ－Ｐｈ＝、６－ＣＮ－Ｐｈ＝、３－ＯＨ－Ｐｈ＝、４－ＯＨ－Ｐｈ＝、５－ＯＨ－Ｐｈ＝、６－ＯＨ－Ｐｈ＝、３－ＮＨ _２ －Ｐｈ＝、４－ＮＨ _２ －Ｐｈ＝、５－ＮＨ _２ －Ｐｈ＝、６－ＮＨ _２ －Ｐｈ＝、３－ＮＯ _２ －Ｐｈ＝、４－ＮＯ _２ －Ｐｈ＝、５－ＮＯ _２ －Ｐｈ＝、６－ＮＯ _２ －Ｐｈ＝、３－ＣＯＯＨ－Ｐｈ＝、４－ＣＯＯＨ－Ｐｈ＝、５－ＣＯＯＨ－Ｐｈ＝、６－ＣＯＯＨ－Ｐｈ＝、（Any two of the 3rd, 4th, 5th and 6th positions）－Ｆ _２ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-Cl ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-Br ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-I ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-Me ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-Et ₂ -Ph-、(any two of the 3rd, 4th, 5th and 6th positions)-Pr ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-Bu ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-(CN) ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-(OH) ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-(NH ₂ ) ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-(NO ₂ ) ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-(MeO) ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-(EtO) ₂ -Ph＝、(any two of the 3rd, 4th, 5th and 6th positions)-(CF ₃ ) ₂ -Ph＝、(any three of the 3rd, 4th, 5th and 6th positions)-F ₃ -Ph＝、(any three of the 3rd, 4th, 5th and 6th positions)-Cl ₂ -Ph＝、(any four of the 3rd, 4th, 5th and 6th positions)-F ₄ -Ph＝、び(any four of the 3rd, 4th, 5th and 6th positions)-Cl ₄ -Ph=, group (wherein "Ph=" represents a divalent group by removing (X)m- from formula (I-4-a))

In the definition of the previous formula (I-4-a), for example, in "Ph＝", "Ph" represents a benzene ring, and "=" represents an atomic bond. Therefore, "Ph＝" represents a phenylene group. In the definition of the previous formula (I-4-a), for example, "5-F-Ph＝" represents a divalent group (phenylene group) in which the 5-position of the benzene ring is substituted with fluorine (F). In the definition of the previous formula (I-4-a), for example, "(any two places of digits 3, 4, 5, and 6) - (MeO) ₂ -Ph＝" means digits 3, 4, 5, and 6 Any two divalent groups (phenylene groups) substituted by methoxy groups (-OCH ₃ ).

The definitions of the above formula (I-4) and formula (I-4-a) can be converted as follows. In formula (I), ring A is a benzene ring, ^R1 and ^R2 are adjacent and substituted to form ring A, and when the substitution position of ^R1 is 1 and the substitution position of ^R2 is 2, X is selected from a hydrogen atom, a 3-fluoro group, a 4-fluoro group, a 5-fluoro group, a 6-fluoro group, a 3-chloro group, a 4-chloro group, a 5-chloro group, a 6-chloro group, a 3-bromo group, a 4-bromo group, a 5-bromo group, a 6-bromo group, a 3-iodo group, a 4-iodo group, a 5-iodo group, a 6-iodo group, a 3-methyl group, a 4-methyl group, a 5-methyl group, a 6-methyl group, a 3-ethyl group, a 4-ethyl group, a 5-ethyl group, a 6-ethyl group, a 3-n-propyl group, a 4-n-propyl group, a 5-n-propyl group, a 6- n-propyl, 3-n-butyl, 4-n-butyl, 5-n-butyl, 6-n-butyl, 3-tert-butyl, 4-tert-butyl, 5-tert-butyl, 6-tert-butyl, 3-methoxy, 4-methoxy, 5-methoxy, 6-methoxy, 3-ethoxy, 4-ethoxy, 5-ethoxy, 6-ethoxy, 3-trifluoromethyl, 4-trifluoromethyl, 5-trifluoromethyl, 6-trifluoromethyl, 3-pentafluoroethyl, 4-pentafluoroethyl, 5-pentafluoroethyl, 6-pentafluoroethyl, 3- trifluoromethoxy, 4-trifluoromethoxy, 5-trifluoromethoxy, 6-trifluoromethoxy, 3-pentafluoroethoxy, 4-pentafluoroethoxy, 5-pentafluoroethoxy, 6-pentafluoroethoxy, 3-cyano, 4-cyano, 5-cyano, 6-cyano, 3-hydroxy, 4-hydroxy, 5-hydroxy, 6-hydroxy, 3-amino, 4-amino, 5-amino, 6-amino, 3-nitro, 4-nitro, 5-nitro, 6-nitro, 3-carboxyl, 4-carboxyl, 5-carboxyl, 6 -carboxyl, 3,4-difluoro, 3,5-difluoro, 3,6-difluoro, 4,5-difluoro, 4,6-difluoro, 5,6-difluoro, 3,4-dichloro, 3,5-dichloro, 3,6-dichloro, 4,5-dichloro, 4,6-dichloro, 5,6-dichloro, 3,4-dibromo, 3,5-dibromo, 3,6-dibromo, 4,5-dibromo, 4,6-dibromo, 5,6-dibromo, 3,4-dimethyl, 3, 5-dimethyl, 3,6-dimethyl, 4,5-dimethyl, 4,6-dimethyl, 5,6-dimethyl, 3,4-diethyl, 3,5-diethyl, 3,6-diethyl, 4,5-diethyl, 4,6-diethyl, 5,6-diethyl, 3,4-di-n-propyl, 3,5-di-n-propyl, 3,6-di-n-propyl, 4,5-di-n-propyl, 4,6-di-n-propyl, 5,6-di-n-propyl, 3,4-di-n-butyl, 3,5-di-n-butyl, 3,6-di-n-butyl, 4,5-di-n-butyl, 4,6-di-n-butyl, 5,6-di-n-butyl, 3,4-dicyano, 3,5-dicyano, 3,6-dicyano, 4,5-dicyano, 4,6-dicyano, 5,6-dicyano, 3,4-dihydroxy, 3,5-dihydroxy, 3,6-dihydroxy, 4,5-dihydroxy, 4,6-dihydroxy, 5,6-dihydroxy, 3,4-diamino, 3,5-diamino, 3,6-diamino, 4, 5-diamino, 4,6-diamino, 5,6-diamino, 3,4-dinitro, 3,5-dinitro, 3,6-dinitro, 4,5-dinitro, 4,6-dinitro, 5,6-dinitro, 3,4-dimethoxy, 3,5-dimethoxy, 3,6-dimethoxy, 4,5-dimethoxy, 4,6-dimethoxy, 5,6-dimethoxy, 3,4-diethoxy, 3,5-diethoxy, 3,6-diethoxy, 4,5-diethoxy 4,6-trifluoromethyl, 3,4,5-trifluoromethyl, 3,4,6-trifluoromethyl, 4,5,6-trifluoromethyl, 3,4,5-trichloromethyl, 3,4,6-trichloromethyl, 4,5,6-trichloromethyl, 3,4,5,6-tetrafluoromethyl or 3,4,5,6-tetrachloromethyl.

The term "pharmaceutically acceptable salt" as used in this application refers to those compounds, substances, compositions and/or dosage forms which are suitable for reasonable benefit/risk ratios and are used in contact with humans and animals without excessive toxicity, irritation, allergic reactions, or other problems or complications within the scope of reasonable medical judgment. Such salts can be prepared by conventional means by reacting the product in the form of a free acid with one or more equivalents of a suitable base, or by reacting the product in the form of a free base with one or more equivalents of a suitable acid in a solvent or base in which the salt is insoluble or in a solvent such as water, or by exchanging the anions of the existing salt for other anions on a suitable ion exchange resin.

Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and basic salts. Examples of pharmaceutically acceptable acid addition salts of the compounds of the present invention include acetate, adipate, ascorbate, benzoate, sodium benzenesulfonate, bicarbonate, bisulfate, butyrate, and camphor Acid, camphorsulfonate, choline, citrate, cyclohexylamine sulfonate, diethylenediamine, ethanesulfonate, formate, fumarate, glutamate, glycolic acid Salt, hemisulfate, 2-isethionate, enanthate, caproate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, Maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, naphthoate, persulfate, phenylacetate, phosphate, diphosphate, picrate , propionate, quinate, salicylate, stearate, succinate, amine sulfonate, p-aminobenzene sulfonate, sulfate, tartrate, tosylate (p- tosylate), trifluoroacetate, and undecanoate.

Examples of pharmaceutically acceptable bases of the compounds of the present invention may include ammonium salts; alkali metal salts such as sodium salts, lithium salts and potassium salts; alkali earth metal salts such as aluminum salts, calcium salts and magnesium salts; salts of organic bases such as dicyclohexylamine salts and N-methyl-D-glucosamine; and salts of amino acids such as arginine, lysine and ornithine. Furthermore, basic nitrogen-containing groups can also be quaternized by lower alkyl halides such as methyl, ethyl, propyl and butyl halides; dialkyl sulfates such as dimethyl, diethyl, dibutyl; dimethyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl halides; benzyl bromide and other aryl alkyl halides. Although non-toxic physiologically acceptable salts are preferred, other salts are useful in the case of isolating or purifying products.

Various isomers (such as optical isomers, regioisomers, tautomers, etc.), solvates such as hydrates, polymorphs, and esters of the compound of the present invention represented by formula (I) Prodrugs, etc., are all included in the scope of the present invention. In addition, compounds in which one or more atoms constituting the compound of the present invention represented by formula (I) are isotopes, and pharmaceutically acceptable salts thereof are also included in the present invention. Examples of isotopes included in the compound of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, bromine and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ¹⁸ F, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ⁸² Br, and ³⁷ C l etc.

Compounds having formula (I), formula (I-0a), formula (I-0a-1) to (I-0a-3), formula (I-0b), formula (I-0c), formula (I-0d), formula (I-0c-1), formula (I-0d-1), formula (I-1), formula (I-2), formula (I-3), and formula (1-3-a) to formula (I-3-h) have superior inhibitory effects on IDO and/or TDO and can be used as IDO and/or TDO inhibitors. Therefore, compounds having formula (I), formula (I-0a), formula (I-0a-1) to (I-0a-3), formula (I-0b), formula (I-0c), formula (I-0d), formula (I-0c-1), formula (I-0d-1), formula (I-1), formula (I-2), formula (I-3), and formula (1-3-a) to formula (I-3-h) can be used as medicines for a wide range of diseases. Therefore, one aspect of the present invention is an IDO and/or TDO inhibitor comprising one or more compounds having formula (I), formula (I-0a), formula (I-0a-1) to (I-0a-3), formula (I-0b), formula (I-0c), formula (I-0d), formula (I-0c-1), formula (I-0d-1), formula (I-1), formula (I-2), formula (I-3), formula (1-3-a), formula (1-3-b), formula (1-3-c), formula (1-3-d), formula (1-3-e), formula (1-3-f), formula (1-3-g), or formula (I-3-h) or their pharmaceutically acceptable salts as active ingredients. Another aspect of the present invention is a pharmaceutical composition comprising one or more compounds of formula (I), formula (I-0a), formula (I-0a-1) to (I-0a-3), formula (I-0b), formula (I-0c), formula (I-0d), formula (I-0c-1), formula (I-0d-1), formula (I-1), formula (I-2), formula (I-3), formula (1-3-a), formula (1-3-b), formula (1-3-c), formula (1-3-d), formula (1-3-e), formula (1-3-f), formula (1-3-g), or formula (I-3-h) or their pharmaceutically acceptable salts as active ingredients. Yet another aspect of the present invention is a therapeutic agent for a disease or disorder selected from tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health, comprising one or more compounds of formula (I), formula (I-0a), formula (I-0a-1) to (I-0a-3), formula (I-0b), formula (I-0c), formula (I-0d), formula (I-0c-1), formula (I-0d-1), formula (I-1), formula (I-2), formula (I-3), formula (1-3-a), formula (1-3-b), formula (1-3-c), formula (1-3-d), formula (1-3-e), formula (1-3-f), formula (1-3-g), or formula (I-3-h) or their pharmaceutically acceptable salts as active ingredients. Yet another aspect of the present invention is an antitumor agent comprising one or more compounds of formula (I), formula (I-0a), formula (I-0a-1) to (I-0a-3), formula (I-0b), formula (I-0c), formula (I-0d), formula (I-0c-1), formula (I-0d-1), formula (I-1), formula (I-2), formula (I-3), formula (1-3-a), formula (1-3-b), formula (1-3-c), formula (1-3-d), formula (1-3-e), formula (1-3-f), formula (1-3-g), or formula (I-3-h) or their pharmaceutically acceptable salts as active ingredients. Yet another aspect of the present invention is a pharmaceutical kit comprising one or more compounds of formula (I), formula (I-0a), formula (I-0a-1) to (I-0a-3), formula (I-0b), formula (I-0c), formula (I-0d), formula (I-0c-1), formula (I-0d-1), formula (I-1), formula (I-2), formula (I-3), formula (1-3-a), formula (1-3-b), formula (1-3-c), formula (1-3-d), formula (1-3-e), formula (1-3-f), formula (1-3-g), or formula (I-3-h) or their pharmaceutically acceptable salts as active ingredients.

Formula (I), formula (I-0a), formula (I-0a-1) to (I-0a-3), formula (I-0b), formula (I-0c), formula (I-0d), formula (I-0c-1), formula (I-0d-1), formula (I-1), formula (I-2), formula (I-3), formula (1-3-a), formula (1-3-b), formula (1-3-c), formula (1-3-d), formula (1 When the compound of formula (I-3-e), formula (I-3-f), formula (I-3-g), or formula (I-3-h) is used as an antitumor agent, the target tumors include mesothelioma, hepatobiliary (bile tract and bile duct) tumors, primary or secondary CNS tumors, primary or secondary brain tumors, pharyngeal cancer, oral cancer, nasal cancer, lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma , ovarian cancer, colon cancer, rectal cancer, anal cancer, stomach cancer, duodenal cancer, colon and rectal cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, acute myeloid Leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer or ureteral cancer, renal cell cancer, renal pelvis cancer, central nervous system (CNS) cancer, primary CNS lymphoma, non-Hodgkin's lymphoma, cerebrospinal axis tumor, brain stem neuroglioma, pituitary adenoma, adrenal cortical carcinoma, gallbladder cancer, multiple myeloma, bile duct cancer, fibrosarcoma, neuroblastoma, and retinoblastoma. However, the tumors that can be treated are not limited to these.

The pharmaceutical composition, IDO and/or TDO inhibitor, and therapeutic agent for diseases such as tumors of the present invention comprise a compound of formula (I), formula (I-0a), formula (I-0a-1) to (I-0a-3), formula (I-0b), formula (I-0c), formula (I-0d), formula (I-0c-1), formula (I-0d-1), formula (I-1), formula (I-2), formula (I-3), formula (1-3-a), formula (1-3-b), formula (1-3-c), formula (1-3-d), formula (1-3-e), formula (1-3-f), formula (1-3-g), or formula (I-3-h) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or formulator.

The pharmaceutical composition, IDO and/or TDO inhibitor, and therapeutic agent for diseases such as tumors of the present invention can also be used for oral administration (e.g., as tablets, buccal tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical administration (e.g., as creams, ointments, gels, or The compounds and/or compositions of the invention may be administered intravenously (e.g., as a sterile aqueous or oily solution or suspension), by inhalation (e.g., as a finely divided powder or liquid spray), by insufflation (e.g., as a finely divided powder), or parenterally (e.g., as an intravenous, intraarterial, subcutaneous, intraperitoneal, intravesical, intrapleural, intracranial, or as a sterile aqueous or oily solution for intramuscular administration, or as a suppository for rectal administration). In some embodiments, the compounds and/or compositions of the invention are administered by intravenous (I.V.) administration.

The pharmaceutical composition, IDO and/or TDO inhibitor, and therapeutic agent for diseases such as tumors of the present invention can be obtained by conventional procedures using drug formulations commonly known in the art. Therefore, the composition intended for oral use may also contain, for example, one or more coloring agents, sweeteners, flavoring agents and/or preservatives. Since the inside of cyclodextrin represents hydrophobicity and the outside represents hydrophilicity, cyclodextrin can form a cage compound (enclosed compound) by enclosing hydrophobic molecules. Since the cage compound can increase the solubility in water and protect compounds that are easily reactive with water or oxygen, it can be used as needed when manufacturing drugs in different dosage forms. Cyclodextrin has various structures, such as α-cyclodextrin (cyclohexyl linear starch, α-CD) with 6 glucose units bonded, β-cyclodextrin (cycloheptyl linear starch, β-CD) with 7 glucose units bonded, and γ-cyclodextrin (cyclooctyl linear starch, γ-CD) with 8 glucose units bonded. For example, in order to stabilize drugs such as prostaglandins and nitroglycerin, inclusion of cyclodextrin is applied.

Pharmaceutically acceptable excipients suitable for tablet preparations include inert diluents such as lactose, sodium carbonate, calcium phosphate, calcium carbonate; starch, carboxymethylcellulose calcium, croscarmellose sodium, etc. Granulating agents and disintegrants; binders such as starch; lubricants such as magnesium stearate, stearic acid, and talc; preservatives such as ethyl parahydroxybenzoate and propyl parahydroxybenzoate; and antioxidants such as ascorbic acid. . Tablet preparations may be uncoated, or in order to modify the disintegration and subsequent absorption of the active ingredients in the gastrointestinal tract, or to improve the stability and/or appearance of these, in either case also known in the art Apply with the usual coating agents and procedures.

The pharmaceutical composition, IDO and/or TDO inhibitor, and therapeutic agent for diseases such as tumors of the present invention for oral administration may be in the form of a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or in the form of a soft gelatin capsule in which the active ingredient is mixed with water or oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions usually contain a suspending agent of one or more active ingredients in the form of fine powder or nanoparticles or ultrafine particles, and the suspending agent together includes sodium carboxymethyl cellulose, methyl cellulose, hydroxyl Propyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth, gum arabic, etc.; dispersing aids or wetting agents, lecithin; or condensates of fatty acids and alkylene oxides (such as polyoxyethylene stearin acid esters); or condensates of long-chain aliphatic alcohols and ethylene oxide (such as heptadecanethyleneoxycetyl ester); or fatty acids and hexoses derived from polyoxyethylene sorbitol monooleate, etc. Condensates of partial esters of alcohols and ethylene oxide; or condensates of partial esters and ethylene oxide derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl or propyl paraben; antioxidants, such as ascorbic acid; colorants; flavors; and/or sucrose, saccharin or aspartame and other sweeteners.

Oily suspensions can be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, or in mineral oils such as liquid paraffin. Oily suspensions may further contain thickening agents such as beeswax, hard paraffin or cetyl alcohol. In order to provide a delicious oral preparation, sweeteners and flavoring agents such as those listed above may also be added. These compositions can be preserved by adding antioxidants such as ascorbic acid.

Dispersible powders and granules suitable for preparing aqueous suspensions by adding water usually contain the active ingredient together with a dispersing aid or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing agents or wetting agents and suspending agents are represented by those mentioned above. Additional excipients such as sweeteners, flavoring agents and coloring agents may also be present.

The pharmaceutical composition, IDO and/or TDO inhibitor, and therapeutic agent for diseases such as tumors of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin, or any mixture of these. Suitable emulsifiers are, for example, naturally occurring gums such as gum arabic or gum tragacanth; naturally occurring phospholipids such as soybeans and lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides (such as sorbitan monooleate); and condensates of ethylene oxide and these partial esters such as polyoxyethylene sorbitan monooleate. These emulsions may also contain sweeteners, flavoring agents and preservatives. When the compound of the present invention is used as an injection, in order to concentrate the compound in a specific tissue, injectable liposomes or polymer micelles can also be used. Injectable liposomes are closed vesicles composed of a lipid bilayer membrane based on phospholipids. They are composed of a lipid membrane part and an aqueous layer part, so both fat-soluble drugs and water-soluble drugs can be contained. The particle size of liposomes is usually less than a few μm, and can be used to manufacture injections. On the other hand, the particle size of polymer micelles is very small (10 to 100 nanometers). In order to have a clear double-layer structure of an inner core and an outer shell, the dynamic distribution in the body is determined by the interaction between the outer shell and the organism, and the drug can be physically or chemically enclosed in the inner core. The anticancer drug-encapsulating micelles having polyethylene glycol in the outer shell can show sufficient effects by selectively concentrating the drug in cancer tissues while reducing side effects. Therefore, polymer micelles encapsulating such compounds are convenient as DDS (drug delivery system) formulations.

Syrups and elixirs can be formulated with sweeteners such as glycerin, propylene glycol, sorbitol, aspartame or sucrose, and can also contain viscosity agents, preservatives, flavors and/or colorants.

The pharmaceutical compositions, IDO and/or TDO inhibitors, and therapeutic agents for tumors and other diseases of the present invention can also be in the form of sterile injectable aqueous or oily suspensions, which can be used according to known procedures. Or a variety of suitable dispersing aids or wetting agents and suspending agents to prepare. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol.

The pharmaceutical compositions, IDO and/or TDO inhibitors, and therapeutic agents for diseases such as tumors of the present invention can be prepared by preparing the active ingredients into a conventional pressurized spray containing finely divided solid sprays or dispensed as liquid particles. form. Conventional pressurized sprays of volatile fluorinated hydrocarbons or hydrocarbons may be used, and the spray device may be conveniently configured to dispense the active ingredient as measured by a fixed meter.

The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will vary depending upon the host treated and the particular route of administration. For example, formulations intended for administration to the human population may be formulated with suitable and convenient amounts of excipients, which may be from about 5 to about 98% by weight of the total composition, and may, for example, contain from 0.5 mg to 5 g. of active agents. Unit dosage forms may contain, for example, from about 1 mg to about 500 mg of active ingredient.

Therapeutic dosages of the compounds of the present invention may vary depending, for example, on the specific use for which the treatment is to be performed, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportions or concentrations of the compounds of the invention in pharmaceutical compositions can vary depending on a number of factors including dosage, chemical properties (eg hydrophobicity) and route of administration. For example, for oral administration, or, for example, for parenteral administration, a compound of the invention may be provided in an aqueous physiological buffer solution containing from about 0.1 to about 10 w/v%. The typical dosage range is about 1 μg/kg body weight to about 1 g/kg body weight per day. In one aspect of the invention, the dosage range is about 0.01 mg/kg body weight to about 100 mg/kg body weight per day. Dosage is highly likely to depend on variables such as the type and extent of the disease or disorder, the general health of the particular patient, the relative bioavailability of the selected compound, the form of the excipient, and the route of administration. Effective dosage can be estimated from dosage response curves derived from catheter or animal model test systems.

Another aspect of the present invention is a medical kit for treating a disease or disorder selected from tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health, comprising: (a) one or more of formula (I), formula (I-0a), formula (I-0a-1) to (I-0a-3), formula (I-0b), formula (I-0c), formula (I-0d), formula (I-0c-1), formula (I-0d-1), formula (I-1), formula (I-2), formula (I-3), formula (1-3-a), A compound of formula (1-3-b), formula (1-3-c), formula (1-3-d), formula (1-3-e), formula (1-3-f), formula (1-3-g), or formula (1-3-h) or a pharmaceutically acceptable salt thereof, and (b) one or more advanced anti-tumor agents for treating diseases or disorders selected from tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health, wherein the aforementioned compound or its pharmaceutically acceptable salt and the aforementioned advanced therapeutic agent are suitable for simultaneous, sequential or individual use. In the pharmaceutical kit, when (b) is one or more advanced anti-tumor agents, the pharmaceutical kit is a pharmaceutical kit for treating tumors.

Examples of the above-mentioned advanced anti-tumor agents include alkylating agents (such as cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, and bendadine). bendamustine, busulfan, temozolamide and nitrosourea); antimetabolites (such as gemcitabine, capecitabine, and 5-fluorouracil and fluoropyrimidines such as tegafur, etc. Folic acid antagonists; raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); anti-tumor antibiotics (such as doxorubicin, bleomycin, doxorubicin, daunorubicin, anthracyclines such as epirubicin, idarubicin, mitomycin C, dactinomycin, and photomycin); antimitotic agents (such as vincristine, vinblastine, vindesine, and vinblastine Vincristines such as vinorelbine; and taxanes such as paclitaxel and taxotere; and inhibitors of Polo-like kinases or kinesin motor proteins); and topoisomerase inhibitors (such as etopol Epipodophyllotoxins, amsacrine, topotecan, camptothecin, pixantrone, and irinotecan); inhibitors of DNA repair mechanisms For CHK kinase, DNA-dependent protein kinase inhibitors and poly (ADP-ribose) polymerase (PARP inhibitors), ATM or ATR inhibitors, etc., but not limited to these; and tanespamycin and retaspimycin, etc. Hsp90 inhibitors; compounds that inhibit progression through the cell cycle are antimitotic agents (e.g., vincristines such as vincristine, vinblastine, vindesine, and vinorelbine; epothilones such as ixabepilone) epothilones); as well as paclitaxel and cancer-resistant paclitaxel; Polo-like kinase inhibitors; and inhibitors of kinesin motor proteins such as Eg5 protein inhibitors, but not limited to these); Aurora kinase inhibitors (such as AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459, but not limited to these), and CDK 2 and/or cyclin-dependent kinase inhibitors such as CDK4 inhibitors (e.g., flavopiridol / Alvocidib, roscovitine, seliciclib); inhibitors of midsection protein function such as CENP-E inhibitors, immune checkpoint blockade (e.g., nivolmab, pembrolizumab, etc. Anti-PD-1 antibodies; anti-PD-L1 antibodies such as atezolizumab, durvalumab, avelumab, etc.; anti-CTLA-4 antibodies such as ipilimumab, tremelimumab, etc. In addition, known cytostatic agents, anti-invasive agents, growth factor function inhibitors, anti-angiogenic agents, vascular damaging agents, endothelin receptor antagonists, etc. may be used in combination.

Specific examples of the compounds of the present invention are disclosed above, but the present invention is not limited to these compounds.

[Table 1-1] Compound No. 1 1,2-phenylene bis(methylene)dimethylamidine thiodihydrochloride 2 (4-Fluoro-1,2-phenylene)bis(methylene)dimethylamidinethiodihydrobromide 3 Naphthalene-1,2-diyl bis(methylene)dimethylamidine thiodihydrobromide 4 (4-t-Butyl-1,2-phenylene)bis(methylene)dimethylamidinethiohydrobromide 5 Quinoxaline-2,3-diylbis(methylene)dimethylamidinethiohydrobromide 6 (3,4,5,6-Fluoro-1,2-phenylene)bis(methylene)dimethylamidinethiodihydrobromide 7 (4-Chloro-1,2-phenylene)bis(methylene)dimethylamidinethiohydrobromide 8 1,2-phenylenebis(methylene)bis(N,N'-dimethylthioformamidine) dihydrochloride 9 1,2-Bis{[(5-phenylethyl-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio]methyl}benzene 10 (4-Bromo-1,2-phenylene)bis(methylene)dimethylamidinethiodihydrobromide 11 1,2-phenylenebis(methylene)bis(methylthioformamidine)dihydrochloride 12 (4-Methyl-1,2-phenylene)bis(methylene)dimethylamidine thiodihydrobromide 13 (3-Fluoro-1,2-phenylene)bis(methylene)dimethylamidinethiodihydrobromide 14 1,2-Bis{[(5-benzyl-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio]methyl}benzene 15 Thiophene-3,4-diylbis(methylene)dimethylamidine thiodihydrobromide 16 1,2-bis[(pyrimidin-2-ylthio)methyl]benzene 17 1,2-Bis{{[5-(4-chlorophenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene 18 1,2-bis{{[5-(2,5-dichlorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl }benzene 19 1,2-bis{{[5-(3-bromophenylethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene 20 1,2-Bis{{[5-(4-bromophenylethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene twenty one 1,2-Bis{{[5-(2,4-dichlorophenylethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl Benzene twenty two 1,2-Bis{{[5-(3,4-dichlorophenylethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl Benzene twenty three 1,2-bis{{[5-(3,4-dimethylphenylethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio} Methylbenzene twenty four 1,2-bis{{[5-(2,5-dimethylphenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio} Methylbenzene 25 1,2-bis{{[5-(4-ethylphenylethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl} benzene 26 1,2-bis{{[5-(4-methoxybenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl} benzene 27 1,2-bis{{[5-(2,4-dimethoxybenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio} Methylbenzene 28 1,2-Bis(((5-(2-chlorophenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl)benzene 29 1,2-bis{[(5-methylcyclohexyl-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio]methyl}benzene 30 2,2'-((1,2-phenylenebis(methylene))bis(sulfanediyl))bis(pyrimidine-4,6(1H,5H)-dione) 31 Thiophene-2,3-diylbis(methylene)dimethylamidine thiodihydrobromide 32 2-((formamidinylthio)methyl)-1H-indole-3-carboxylic acid methyl ester hydrobromide [Table 1-2] 33 3,4-Bis{[(5-phenylethyl-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio]methyl}thiophene dihydrochloride 34 Pyridine-2,3-diylbis(methylene)dimethylamidinethiodihydrobromide 35 (4-Methoxy-1,2-phenylene)bis(methylene)dimethylamidinethiohydrobromide 36 (4,5-Dichloro-1,2-phenylene)bis(methylene)dimethylamidinethiodihydrobromide 37 6,6'-(((4,5-dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-phenylethyl-1,2, 3,4-tetrahydro-1,3,5-triazine) 38 6,6'-(((4,5-dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3,4-dichlorobenzene) Ethyl)-1,2,3,4-tetrahydro-1,3,5-triazine) 39 6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3,4-dichlorophenylethyl) -1,2,3,4-tetrahydro-1,3,5-triazine) 40 1,2-bis(((5-(2-(thiophen-2-yl)ethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio) )methyl)benzene 41 1,2-Bis(((5-(4-chlorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl)benzene 42 1,2-bis(((5-(4-(trifluoromethyl)benzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio) Methyl)benzene 43 1,2-Bis(((5-(3,4-difluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl )benzene 44 1,2-Bis(((5-(2,5-dimethylbenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl Benzene 45 1,2-Bis(((5-(3-fluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl)benzene 46 (4-(Trifluoromethyl)-1,2-phenylene)bis(methylene)dimethylamidine thiodihydrobromide 47 6,6'-(((4-(trifluoromethyl)-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3,4-di Chlorophenylethyl)-1,2,3,4-tetrahydro-1,3,5-triazine) 48 6,6'-(((4-(trifluoromethyl)-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(2-chlorophenylene) base)-1,2,3,4-tetrahydro-1,3,5-triazine) 49 (4-Bromo-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-bromophenyl)formamidinethioester) 50 6,6'-(((4,5-dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(cyclohexylmethyl)-1 ,2,3,4-tetrahydro-1,3,5-triazine) 51 2-(2-(Formamidinethio)ethyl)benzylformamidinethiodihydrobromide 52 6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(cyclohexylmethyl)-1,2, 3,4-tetrahydro-1,3,5-triazine) 53 6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(2-chlorophenylethyl)-1, 2,3,4-tetrahydro-1,3,5-triazine) 54 6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3,4-dichlorobenzyl)- 1,2,3,4-tetrahydro-1,3,5-triazine) 55 Methyl 2-((formamidinothio)methyl)benzoate hydrochloride 56 6,6'-(((4,5-dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3,4-dichlorobenzyl) base)-1,2,3,4-tetrahydro-1,3,5-triazine) [Table 1-3] 57 (4-Bromo-1,2-phenylene)bis(methylene)(E,E)-bis(N,N'-dicyclohexylcarboxamidine)dihydrobromide 58 1,2-phenylenebis(methylene)(E,E)-bis(N,N'-dicyclohexylthioformamidine)dihydrobromide 59 (E)-S-(2-(((N'-(3-chloro-4-fluorophenyl)formamidino)thio)methyl)benzyl)thiocarbamate hydrobromide 60 6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(2-cyclohexylethyl)-1, 2,3,4-tetrahydro-1,3,5-triazine) 61 6,6'-(((4,5-dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(2-cyclohexylethyl) -1,2,3,4-tetrahydro-1,3,5-triazine) 62 2-(2-(Methylamino)-2-oxoethyl)benzylformamidinethiohydrobromide 63 (4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(2,4-difluorophenyl)formamidinethio)dihydro bromate 64 2-(2-Oxo-2-(phenethylamino)ethyl)benzylformamidinethiohydrobromide 65 2-(2-((cyclohexylmethyl)amino)-2-oxoethyl)benzylformamidinethiohydrobromide 66 2-(2-((2-Chlorophenylethyl)amino)-2-oxoethyl)benzylformamidinethiohydrobromide 67 2-(2-((4-cyanobenzyl)amino)-2-oxoethyl)benzylformamidinethiohydrobromide 68 2-(2-((4-Chlorophenylethyl)amino)-2-oxoethyl)benzylformamidinethiohydrobromide 69 2-(2-((2-Cyclohexylethyl)amino)-2-oxoethyl)benzylformamidinethiohydrobromide 70 2-(2-((3,4-Dichlorophenylethyl)amino)-2-oxoethyl)benzylformamidinethiohydrobromide 71 2-(2-((Cyclopropylmethyl)amino)-2-oxoethyl)benzylformamidinethiohydrobromide 72 2-(2-Oxo-2-((4-phenylbutyl)amino)ethyl)benzylformamidinethiohydrobromide 73 6,6'-(((4,5-dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(cyclopropylmethyl)- 1,2,3,4-tetrahydro-1,3,5-triazine) 74 5-Bromo-2-((cyclohexylmethyl)aminomethyl)benzylformamidinethiohydrobromide 75 6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(cyclopropylmethyl)-1,2 ,3,4-tetrahydro-1,3,5-triazine) 76 5-Bromo-2-((4-cyanobenzyl)aminoformamide)benzylformamidine thiobromide 77 5-cyano-2-(methylaminoformyl)benzylformamidinethiohydrobromide 78 5-Bromo-2-((4-chlorophenethyl)aminoformamidine)benzylthioformamidine hydrobromide 79 2-(2-(Methylamino)-2-oxoethyl)benzyl(E)-N'-(4-bromophenyl)formamidinethiohydrobromide 80 2-(2-(Methylamino)-2-oxoethyl)benzyl(E)-N'-(3-chloro-4-fluorophenyl)formamidinethiohydrobromide 81 5-Cyano-2-(methylaminoformyl)benzyl(E)-N'-(4-bromophenyl)formamidinethiohydrobromide 82 5-Bromo-2-((4-chlorobenzyl)aminomethanoyl)benzylformamidinethiohydrobromide 83 5-Bromo-2-((4-chlorobenzyl)aminoformyl)benzyl(E)-N'-(3-chloro-4-fluorophenyl)formamidine thiobromide 84 5-Bromo-2-((4-chlorobenzyl)aminoformyl)benzyl(E)-N'-(4-bromophenyl)formamidinethiohydrobromide [Table 1-4] 85 5-Bromo-2-((4-cyanobenzyl)aminomethanoyl)benzyl(E)-N'-(3-chloro-4-fluorophenyl)formamidinethiohydrobromide 86 5-Bromo-2-((4-fluorobenzyl)aminomethanoyl)benzylformamidinethiohydrobromide 87 5-Bromo-2-((4-cyanobenzyl)aminomethyl)benzyl(E)-N'-(4-bromophenyl)formamidinethiohydrobromide 88 5-Bromo-2-((4-fluorobenzyl)aminoformyl)benzyl(E)-N'-(3-chloro-4-fluorophenyl)formamidine thiobromide 89 5-Bromo-2-((2,4-dichlorobenzyl)carbamocarbamate)benzylformamidine thiobromide 90 5-Bromo-2-((4-methylbenzyl)aminoformamide)benzylformamidine thiobromide 91 5-Bromo-2-((4-methylbenzyl)aminoformyl)benzyl(E)-N'-(3-chloro-4-fluorophenyl)formamidine thiobromide 92 2-(Methylamineformyl)benzylformamidinethiohydrobromide 93 5-Bromo-2-((cyclopropylmethyl)aminomethyl)benzylformamidinethiohydrobromide 94 5-Bromo-2-((3,4-dichlorobenzyl)carbamate)benzylformamidine thiobromide 95 1,2-phenylenebis(methylene)(E,E)-bis(N'-(2,4-difluorophenyl)formamidinethio)dihydrobromide 96 2-((4-cyanobenzyl)aminomethanoyl)benzylformamidinethiohydrobromide 97 5-Bromo-2-((4-bromobenzyl)aminomethyl)benzylformamidinethiohydrobromide 98 (2-(Methylamineformyl)pyridin-3-yl)methylformamidinethiohydrobromide 99 (2-((4-cyanobenzyl)aminoformyl)pyridin-3-yl)methylformamidine thiobromide 100 (3-(Methylamineformyl)pyridin-2-yl)methylformamidinethiohydrobromide 101 (2-((4-cyanobenzyl)aminoformyl)pyridin-3-yl)methyl(E)-N'-(3-chloro-4-fluorophenyl)formamidinethiohydrobromic acid salt 102 5-Bromo-2-((4-methoxybenzyl)carbamate)benzylformamidine thiobromide 103 4-Bromo-2-((4-cyanobenzyl)aminoformamide)benzylformamidine thiobromide 104 2-((4-cyanobenzyl)aminoformyl)benzylformamidine selenate hydrobromide 105 5-Bromo-2-((3-methoxybenzyl)aminoformamidine)benzylformamidinethiohydrobromide 106 5-Bromo-2-((3-methoxybenzyl)carbamate)benzylformamidine selenate hydrobromide 107 5-Bromo-2-((cyclopropylmethyl)aminoformyl)benzylformamidine selenate hydrobromide 108 1,2-phenylenebis(methylene)dimethylamidineselenate dihydrobromide 109 (4-Chloro-1,2-phenylene)bis(methylene)dimethylamidinoselenate dihydrobromide 110 4-Bromo-2-((4-cyanobenzyl)carboxamido)benzylformamidine selenate hydrobromide 111 2-Bromo-6-((4-cyanobenzyl)aminoformamide)benzylformamidine thiobromide 112 Quinoxaline-2,3-diyl bis(methylene)dimethylamidine selenate dihydrobromide 113 5-Bromo-2-((4-cyanobenzyl)carbamate)benzylformamidine selenate hydrobromide 114 5-Bromo-2-((4-(trifluoromethyl)benzyl)aminoformamide)benzylformamidine thiobromide [Table 1-5] 115 5-Bromo-2-((2-methoxyethyl)aminomethyl)benzylformamidinethiohydrobromide 116 5-Bromo-2-((3-chloro-4-fluorobenzyl)aminomethyl)benzylformamidinethiohydrobromide 117 4-Bromo-2-((4-bromobenzyl)aminomethyl)benzylformamidinethiohydrobromide 118 4-Bromo-2-((4-cyanobenzyl)aminomethanoyl)benzyl(E)-N'-(3-chloro-4-fluorophenyl)formamidinethiohydrobromide 119 4-Bromo-2-((4-cyanobenzyl)aminomethyl)benzyl(E)-N'-(4-bromophenyl)formamidinethiohydrobromide 120 6,6'-(((4-fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(cyclopropylmethyl)-1,2 ,3,4-tetrahydro-1,3,5-triazine) 121 6,6'-(((4-fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(cyclohexylmethyl)-1,2, 3,4-tetrahydro-1,3,5-triazine) 122 1,2-phenylenebis(methylene)(E,E)-bis(N'-(3-chloro-4-fluorophenyl)formamidinethio)dihydrobromide 123 (4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-chlorophenyl)formamidinethio)dihydrobromide 124 (4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-methoxyphenyl)formamidinethio)dihydrobromide acid salt 125 (4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(3-chlorophenyl)formamidinethio)dihydrobromide 126 (4-Fluoro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-bromophenyl)formamidinethio)dihydrobromide 127 (4-Fluoro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-fluorophenyl)formamidinethio)dihydrobromide 128 (4-Fluoro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-methoxyphenyl)formamidinethio)dihydrobromide 129 (4-Fluoro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(3-chloro-4-fluorophenyl)formamidinethio)dihydrobromide salt 130 (4-Fluoro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(2,4-difluorophenyl)formamidinethio)dihydrobromide 131 (4,5-Difluoro-1,2-phenylene)bis(methylene)dimethylamidinethiohydrobromide 132 (4,5-Difluoro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-chlorophenyl)formamidinethio)dihydrobromide 133 6,6'-(((4-fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3,4-dichlorophenylethyl) -1,2,3,4-tetrahydro-1,3,5-triazine) 134 (4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(3-chloro-4-fluorophenyl)formamidinethio)bis Hydrobromide [Table 1-6] 135 (4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-bromophenyl)formamidinethio)dihydrobromide 136 (4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(3-bromophenyl)thioformamidine)dihydrobromide 137 (4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-fluorophenyl)formamidinethio)dihydrobromide 138 (4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(p-tolyl)thioformamidine)dihydrobromide 139 6,6'-(((4,5-dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3-chloro-4-fluoro) Benzyl)-1,2,3,4-tetrahydro-1,3,5-triazine) 140 6,6'-(((4-fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(4-(trifluoromethyl)styrene) base)-1,2,3,4-tetrahydro-1,3,5-triazine) 141 6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanyl))bis(3-(4-(trifluoromethyl)phenylethyl) )-1,2,3,4-tetrahydro-1,3,5-triazine) 142 1,2-bis(((5-(4-(trifluoromethyl)phenylethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio )methyl)benzene 143 6,6'-(((4,5-dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(4-(trifluoromethyl) )phenylethyl)-1,2,3,4-tetrahydro-1,3,5-triazine) 144 6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3-chloro-4-fluorobenzyl) -1,2,3,4-tetrahydro-1,3,5-triazine) 145 1,2-Bis(((5-(3-chloro-4-fluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl Benzene 146 6,6'-(((4-fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3-chloro-4-fluorobenzyl) -1,2,3,4-tetrahydro-1,3,5-triazine) 147 6,6'-(((4-fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(4-methoxyphenylethyl)- 1,2,3,4-tetrahydro-1,3,5-triazine) 148 6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(4-methoxyphenylethyl)- 1,2,3,4-tetrahydro-1,3,5-triazine) 149 6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3-(trifluoromethyl)styrene) base)-1,2,3,4-tetrahydro-1,3,5-triazine) 150 6,6'-(((4-fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3-(trifluoromethyl)styrene) base)-1,2,3,4-tetrahydro-1,3,5-triazine) 151 Benzo[b]thiophene-2,3-diylbis(methylene)dimethylamidinethiohydrobromide 152 6,6'-(((4,5-dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3-(trifluoromethyl) )phenylethyl)-1,2,3,4-tetrahydro-1,3,5-triazine) 153 6,6'-(((4,5-dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3-methoxyphenylene) base)-1,2,3,4-tetrahydro-1,3,5-triazine)

The structural formulas of the above-mentioned compounds Nos. 1 to 153 are shown below.

[Chemistry 32]

The compound of the present invention represented by formula (I) can be synthesized by appropriately combining known reactions. The raw materials can be purchased commercially, or a general protecting group can be added to the commercially purchased product for synthesis (for example, a part of the compound (i-a) in Scheme 1 is methylated with a dicarboxylic acid). Reduction of the carbonyl group or halogenation of the alcohol group can be synthesized using a reducing agent or halogenating reagent commonly used in organic chemistry. In addition, purification by protection/deprotection widely used in organic chemistry can also be applied to any process. The following three schemes are listed as examples of general synthesis methods.

plan 1

In Scheme 1, A, X, m, R ³ , Z, R ⁴¹ , R ⁴² and R ⁴³ have the same meanings as defined above. The substituent X may bond to a carbon atom and/or a heteroatom of the ring A (representing an aromatic ring, an aliphatic ring, a heterocyclic ring or a condensed ring of two or more rings selected from aromatic rings, aliphatic rings and heterocyclic rings).

[Synthesis of compound (ii)] Compound (ia) or compound (ib) is dissolved in an organic solvent (e.g., THF, 1,4-dioxane, methanol, ethanol, acetone, etc.), and the obtained solution is added to a solution (solvent is THF, 1,4-dioxane, methanol, ethanol, acetone, etc.) containing a reducing agent (e.g., LiAlH ₄ (lithium aluminum hydride), NaBH ₄ (1508299713358_13), DIBAH (1508299713358_14), etc.), stirred, and then heated to reflux. The reaction mixture is dried with a desiccant (e.g., magnesium sulfate), and then concentrated under reduced pressure. The residue obtained by the reduced pressure concentration is purified by chromatography (e.g. silica gel chromatography) to obtain compound (ii). This synthesis is preferably carried out under an inert gas such as nitrogen or argon.

[Synthesis of compound (iii)] Dissolve compound (ii) in an organic solvent (such as dichloromethane, chloroform, carbon tetrachloride and other halogen compounds), and add phosphorus trihalide (PHal ₃ : Hal represents Cl, Br or I ) to the resulting solution and stir. Water and a water-insoluble organic solvent (such as ethyl acetate) are added to the obtained reaction solution, and the organic layer is washed with saturated brine, dried with a desiccant (such as magnesium sulfate), and concentrated under reduced pressure. The residue obtained by concentrating under reduced pressure is purified by chromatography (for example, silica gel chromatography) to obtain compound (iii). This synthesis is preferably carried out under inert gases such as nitrogen or argon.

[Synthesis of compound (I-1)] Dissolve compound (iii) in an organic solvent (such as THF, 1,4-dioxane, methanol, ethanol, acetone, etc.), and add the above formula Z=C (NHR ⁴¹ ) The compound represented by (NR ⁴² R ⁴³ ) was added to the obtained solution, and the reaction mixture was refluxed. The reaction liquid is stirred, and the reaction product is concentrated under reduced pressure. The residue is then recrystallized using a recrystallization solvent (for example, a mixed solvent of ethanol and diethyl ether) to obtain compound (I-1).

Scenario 2

In Scheme 2, A, X, m, Z, S and R ⁶ have the meanings as defined above.

[Synthesis of Compound (I-2)] After adding the compound represented by the above formula _H2N- ( _CH2 ) _S - ^R6 to a formaldehyde solution (solvent such as THF, 1,4-dioxane, methanol, ethanol, acetone, etc.) and stirring, a solution of compound (iv) (solvent such as THF, 1,4-dioxane, methanol, ethanol, acetone, etc.) is added and stirred. An organic solvent (such as benzene, toluene, hexane, etc.) is added to the obtained reaction mixture and concentrated under reduced pressure. The obtained residue is recrystallized with a recrystallization solvent (such as a mixed solvent of ethanol and diethyl ether) and concentrated under reduced pressure to obtain compound (I-2).

Solution 3

In Scheme 3, A, X, m, p, R ⁵ , q, Z, R ⁴¹ , R ⁴² and R ⁴³ have the meanings as defined above.

[Synthesis of Compound (vi)] Dissolve the compound represented by the above formula (v) in an organic solvent (such as THF, 1,4-dioxane, methanol, ethanol, acetone, etc.), and add the above formula to the obtained solution. ^R5- ( _CH2 )q- _NH2 compound and stir. The obtained reaction liquid is concentrated under reduced pressure, water is added, and the mixture is extracted with an organic solvent (for example, methylene chloride, chloroform, halogen compounds such as carbon tetrachloride, etc.). The organic layer is washed with brine, dried with a desiccant (such as magnesium sulfate), and concentrated under reduced pressure to obtain compound (vi).

[Synthesis of compound (vii)] Dissolve compound (vi) in an organic solvent (e.g., a halogen compound such as dichloromethane, chloroform, carbon tetrachloride, etc.), add phosphorus trihalide (PHal ₃ : Hal represents Cl, Br or I) to the obtained solution and stir. Add water and a water-insoluble organic solvent (e.g., ethyl acetate) to the obtained reaction solution, wash the organic layer with saturated salt water, dry it with a desiccant (e.g., magnesium sulfate), and concentrate it under reduced pressure. Purify the residue obtained by reduced pressure concentration by chromatography (e.g., silica gel chromatography) to obtain compound (vii).

[Synthesis of Compound (I-3-a)] Compound (vii) is dissolved in an organic solvent (the solvent is, for example, THF, 1,4-dioxane, methanol, ethanol, acetone, etc.), and the above formula Z= The compound represented by C (NHR ⁴¹ ) (NR ⁴² R ⁴³ ) was added to the obtained solution, and the reaction mixture was refluxed. The reaction liquid is stirred, and the reaction product is concentrated under reduced pressure. The residue is then recrystallized using a recrystallization solvent (for example, a mixed solvent of ethanol and diethyl ether) to obtain compound (I-3-a).

[Examples] The present invention is further described below in detail based on examples. However, the present invention is not limited to these examples.

[Synthesis of the compound] Use JEOL JNM-GSX 400 or JEOL JNM-ECA 500 to measure the nuclear magnetic resonance spectrum (NMR). The chemical shift value is expressed in ppm using tetramethylsilane as the internal standard material. The coupling constant J value is in Hz. express. In addition, the abbreviations in NMR use s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), br (broad), brs (broad singlet) . In liquid chromatography-mass spectrometry (LC/MS), Waters Quattro micro, Waters 2795 separations module, and 2996 photodiode array detector are used. On the chromatographic column, use XBridgeTM C18-AR-II 5μM (size 2.1×50 mm, Waters), use 0.1% AcOH in mobile phase A, use 100% CH ₃ CN in mobile phase B, and measure at a flow rate of 1.0 mL/min. 5 minutes. The gradient ratio of the volume ratio (v/v) was analyzed from A:B = 9:1 to A:B = 0:10 after 4 minutes. Wakogel C-200 (100-200 mesh, Wako Pure Chemical Industries, Ltd.) and CHROMATOREX NH (100-200 mesh, Fuji Silysia Chemicals) were used for column chromatography, and SNAP KP-SIL was used for flash column chromatography (Biotage ), YAMAZEN YFLC-5404-FC (Yamazen), and Sephadex LH-20 (GE Healthcare) was used in gel filtration column chromatography. Kiesel gel 60 F254 (1.0 mm, Merk) was used for thin layer chromatography for fractionation. Kiesel gel 60 F 254 (0.25 mm, Merk), NHTLC-PLZTE (0.25 mm, Fuji Silysia Chemical) was used in thin layer chromatography. Commercially available reagents and solvents were used in the reaction without purification.

Synthesis of Compound 1 1,2-Phenylenebis(methylene) dicarbamimidothioate dihydrochloride

Thiourea (457 mg, 6.00 mmol) was added to a solution of 1,2-bis(chloromethyl)benzene (compound 1a, 525 mg, 3.00 mmol) in EtOH (8 mL) at room temperature, and the reaction mixture was refluxed for 7 hours. Afterwards, the reaction solution was returned to room temperature and stirred for 2 days. The resulting precipitate was collected by filtration and dried to obtain the title compound 1 (white solid, 837 mg, 85% recovery).

¹ H NMR (400 MHz, DMSO-d6): δ = 9.29 (6H, brs), 7.48-7.50 (2H, m), 7.37-7.39 (2H, m), 4.67 (4H, s).LC-MS: >99% purity, RT 0.36 min, MS (m/z): 255 (M+H) ⁺ .

Synthesis of Compound 2 (4-Fluoro-1,2-phenylene)bis(methylene)dicarbamidioate dihydrobromide

Under an argon atmosphere, 4-fluorophthalic anhydride (compound 2a, 664 mg, 4.00 mmol) in THF (8 mL) was gently added to a solution of LiAlH ₄ (304 mg, 8.00 mmol) in THF (10 mL) at 0°C, stirred at room temperature for 5 hours, and then heated to reflux for 12 hours. After the reaction mixture was cooled to room temperature, 10% NaOH (1.0 mL) and H ₂ O (1.0 mL) were added to stop the reaction, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/EtOAc=4:1 to 1:1) to obtain compound 2b (421 mg, 67% recovery) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.31-7.26 (1H, m), 7.08-7.05 (1H, m), 7.00-6.95 (1H, m), 4.66 (4H, s), 3.31 (1H, brs), 3.11 (1H, brs).

Under argon atmosphere, phosphorus tribromide (0.265 mL, 2.79 mmol) was added to a solution of compound 2b (363 mg, 2.32 mmol) in CH ₂ Cl ₂ (5 mL) at 0 °C, and stirred at the same temperature for 45 min. Water and ethyl acetate were added to the reaction solution, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane) to obtain white crystal compound 2c (155 mg, 24% recovery rate).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.36-7.31 (1H, m), 7.11-7.08 (1H, m), 7.02-6.97 (1H, m), 4.67 (2H, s), 4.60 (2H, s).

Thiourea (83.6 mg, 1.10 mmol) was added to a solution of compound 2c (155 mg, 0.550 mmol) in EtOH (3 mL) at room temperature, and the reaction mixture was refluxed for 7 h. After that, the reaction solution was returned to room temperature, and the mixture was stirred for 3 days. After the reaction was concentrated under reduced pressure, the residue was recrystallized with EtOH and Et ₂ O (1:1) to obtain the title compound 2 (143 mg, 95% recovery) as white crystals.

¹ HNMR (400 MHz, DMSO-d6): δ = 9.08 (6H, brs), 7.52-7.55 (1H, m), 7.34-7.37 (1H,m), 7.25-7.29 (1H, m), 4.56 (4H , s).LC-MS: ＞99% purity, RT 0.41 min, MS (m/z): 273 (M + H) ⁺ .

Synthesis of compound 3 Naphthalene-1,2-diylbis(methylene) dicarbamimidothioate dihydrobromide/Naphthalene-1,2-diylbis(methylene) dicarbamimidothioate dihydrobromide

1,2-Naphthalene dicarboxylic anhydride (Compound 3a, 793 mg, 4.00 mmol) and LiAlH ₄ (304 mg, 8.00 mmol) were reacted in the same manner as for the synthesis of Compound 2b. The reaction residue was purified by silica gel chromatography (n-hexane/EtOAc=4:1-1:2) to obtain white crystalline Compound 3b (195 mg, 26% recovery).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 8.28 (1H, d, J = 8.0 Hz), 7.88-7.83 (2H, m), 7.60-7.57 (1H, m), 7.54-7.47 (2H, m ), 5.26 (2H, s), 4.98 (2H, s).

Compound 3b (145 mg, 0.77 mmol) and phosphorus tribromide (0.088 mL, 0.92 mmol) were reacted with the same operation as the synthesis of compound 2c, and the residue was purified by silica gel chromatography (n-hexane) to obtain a white crystal compound. 3c (68.3 mg, 28% recovery).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 8.15 (1H, d, J = 8.0 Hz), 7.85 (2H, dd, J = 8.0, 8.0 Hz), 7.65 (1H, dd, J = 8.0, 8.0 Hz), 7.54 (1H, dd, J = 8.0, 8.0 Hz), 7.44 (1H, d, J = 8.0 Hz), 5.11 (2H, s), 4.77 (2H, s).

From compound 3c (68.3 mg, 0.22 mmol) and thiourea (33.1 mg, 0.44 mmol), the same operation as the synthesis of compound 2 was performed, and the residue was recrystallized with EtOH and Et ₂ O (1:1) to obtain white crystal compound 3 (35.3mg, 53% recovery).

¹ HNMR (400 MHz, DMSO-d6): δ = 9.14 (6H, brs), 8.26-8.23 (1H, m), 8.03-8.00 (2H,m), 7.60-7.72 (3H, m), 5.06 (2H , s), 4.77 (2H, s).LC-MS: >99% purity, RT 0.59 min, MS (m/z): 305 (M + H) ⁺ .

Synthesis of compound 4 (4-t-butyl-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide/(4-t-Bu-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide

From 4-t-terephthalic anhydride (compound 4a, 817 mg, 4.00 mmol) and LiAlH ₄ (304 mg, 8.00 mmol), the same operation as that for synthesizing 2b was carried out, and the reaction residue was purified by silica gel chromatography (n-hexane/EtOAc=3:1-2:1) to obtain compound 4b (389 mg, 50% recovery) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.39-7.28 (3H, m), 4.76 (2H, s), 4.74 (2H, s), 1.33 (9H, s).

By the same operation as the synthesis of compound 2c, the residue obtained from compound 4b (308 mg, 1.59 mmol) and phosphorus tribromide (0.181 mL, 1.90 mmol) was purified by silica gel chromatography (EtOAc) to obtain a yellow oily substance of compound 4c (148 mg, 29% recovery).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.36-7.31 (3H, m), 4.68 (2H, s), 4.67 (2H, s), 1.31 (9H, s).

From compound 4c (148 mg, 0.46 mmol) and thiourea (70.4 mg, 0.93 mmol), perform the same operation as the synthesis of compound 2, and recrystallize the residue with EtOH and Et ₂ O (1:1) to obtain white crystals Compound 4 (159 mg, 73% recovery).

¹ HNMR (400 MHz, DMSO-d6): δ = 9.11 (6H, brs), 7.54-7.51 (1H, m), 7.43-7.39 (2H,m), 4.58 (2H, s), 4.55 (2H, s ), 1.27 (9H, s).LC-MS: >99% purity, RT 0.55 min, MS (m/z): 311 (M + H) ⁺ .

Synthesis of compound 5 Quinoxaline-2,3-diylbis(methylene) dicarbamimidothioate dihydrobromide

By carrying out the same operation as the synthesis of compound 1 from compound 5a; 2,3-bis(bromomethyl)quinoxaline (948 mg, 3.00 mmol) and thiourea (457 mg, 6.00 mmol), a yellow-white crystalline compound was obtained 5 (1.29g, 92% recovery).

¹ HNMR (400 MHz, DMSO-d6): δ = 9.21 (3H, brs), 9.05 (3H, brs), 8.08-8.06 (2H, m), 7.93-7.90 (2H, m), 4.98 (4H, s ).LC-MS:>99% purity, RT 0.41 min, MS (m/z): 307 (M+H) ⁺ .

Synthesis of compound 6 (3,4,5,6-Fluoro-1,2-phenylene)bis(methylene)dimethylamidinethiodihydrobromide/(3,4,5,6-Fluoro-1,2 -phenylene)bis(methylene) dicarbamimidothioate dihydrobromide

By carrying out the same operation as the synthesis of compound 2b from compound 6a; 3,4,5,6-fluorophthalic anhydride (880 mg, 4.00 mmol) and LiAlH ₄ (304 mg, 8.00 mmol), the reaction was carried out by silica gel chromatography. The reaction residue was purified using the method (n-hexane/EtOAc=5:1-3:1) to obtain white crystal compound 6b (219 mg, 26% recovery rate).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 4.84 (4H, s), 2.78 (2H, brs).

The residue obtained from compound 6b (209 mg, 0.99 mmol) and phosphorus tribromide (0.113 mL, 1.19 mmol) in the same manner as in the synthesis of compound 2c was purified by silica gel chromatography (EtOAc) to obtain compound 6c (48.9 mg, recovery rate 15%) as a yellow oily substance.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 4.63-4.60 (4H, m).

The same operation as compound 2 was performed from compound 6c (48.9 mg, 0.15 mmol) and thiourea (22.2 mg, 0.29 mmol), and the residue was recrystallized with EtOH and Et ₂ O (1:1) to obtain white crystals of compound 6 (17.2 mg, 24% recovery). ¹ HNMR (400 MHz, DMSO-d6):δ = 9.25 (6H, brs), 4.67 (4H, s).LC-MS:＞99％ purity, RT 0.49 min, MS (m/z): 327 (M + H) ⁺ .

Synthesis of compound 7 (4-Chloro-1,2-phenylne)bis(methylene) dicarbamimidothioate dihydrobromide

By performing the same operation as synthesizing compound 2b from compound 7a; 4-chlorophthalic anhydride (913 mg, 5.00 mmol) and LiAlH ₄ (380 mg, 10.0 mmol), silica gel chromatography (n-hexane/EtOAc=6 :1～1:1) The reaction residue was purified to obtain white crystal compound 7b (567 mg, 66% recovery rate).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.37-7.35 (1H, m), 7.30-7.27 (2H, m), 4.70-4.68 (4H, m).

The residue obtained from compound 7b (567 mg, 3.29 mmol) and phosphorus tribromide (0.374 mL, 3.94 mmol) was purified by silica gel chromatography (EtOAc) in the same manner as for the synthesis of compound 2c to give yellow crystalline compound 7c (253 mg, 26% recovery).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.39-7.36 (1H, m), 7.32-7.29 (2H, m), 4.61 (2H, s), 4.59 (2H, s).

From compound 7c (225 mg, 0.75 mmol) and thiourea (115 mg, 1.51 mmol), the same operation as for the synthesis of compound 2 was performed, and the residue was recrystallized with EtOH and Et ₂ O (1:1) to obtain compound 7 as white crystals. (104mg, 48% recovery).

¹ HNMR (400 MHz, DMSO-d6): δ = 9.17 (6H, brs), 7.60-7.59 (1H, m), 7.51-7.48 (2H,m), 4.61 (4H, s).LC-MS:＞ 99% purity, RT 0.47 min, MS (m/z): 289 (M + H) ⁺ .

Synthesis of compound 8 1,2-Phenylenebis(methylene) bis(N,N'-dimethylcarbamimidothioate) dihydrochloride/1,2-Phenylenebis(methylene) bis(N,N'-dimethylcarbamimidothioate) dihydrochloride

By reacting from compound 1a; 1,2-bis(chloromethyl)benzene (700mg, 4.00mmol) and 1,3-dimethylthiourea (833mg, 8.00mmol) in the same operation as the synthesis of compound 1, The residue was recrystallized with EtOH and Et ₂ O (1:3) to obtain compound 8 as white crystals (1.27 g, 83% recovery rate).

¹ HNMR (400 MHz, DMSO-d6): δ = 9.91 (1H, brs), 9.52 (1H, brs), 7.52-7.48 (2H, m), 7.41-7.37 (2H, m), 4.83 (4H, s ), 2.95 (12H, s).LC-MS: >99% purity, RT 0.57 min, MS (m/z): 311 (M + H) ⁺ .

Synthesis of Compound 9 1,2-Bis{[(5-phenylethyl-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio]methyl}benzene/1,2- Bis{[(5-phenethyl-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio]methyl}benzene

Phenylethylamine (60.6 mg, 0.50 mmol) was gently added to a solution of formaldehyde (81 μL, 37% wt, aqueous, 1.0 mmol) in 1,4-dihexane (5.0 mL) and stirred at room temperature for 10 min. After that, 1,4-dioxane (2.0 mL) of 1,2-phenylene bis (methylene) diaminothiamidine sulfate dihydrochloride (compound 1, 57.6 mg, 0.25 mmol) was added. Stir at 80°C for 12 hours. The reaction mixture was cooled to room temperature, toluene (3.0 mL) was added, and concentrated under reduced pressure. The residue was recrystallized from EtOH and Et ₂ O (2:3) to obtain the title compound 9 as yellow crystals (26.3 mg, 19% recovery).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.33-7.18 (12H, m), 7.12-7.09 (2H, m), 4.47-4.07 (12H, m), 2.88-2.79 (8H, m). LC-MS:＞99％ purity, RT 2.25 min, MS (m/z): 545 (M + H) ⁺ .

Synthesis of compound 10 (4-Bromo-1,2-phenylne)bis(methylene)dicarbamimidioate dihydrobromide

By performing the same operation as synthesizing compound 2b from compound 10a; 4-bromophthalic anhydride (1135 mg, 5.00 mmol) and LiAlH ₄ (380 mg, 10.0 mmol), silica gel chromatography (n-hexane/EtOAc=5 :1～1:1) The reaction residue was purified to obtain white crystal compound 10b (539 mg, 50% recovery rate).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.52-7.51 (1H, m), 7.45 (1H, dd, J = 8.0, 4.0 Hz), 7.23 (1H, d, J = 8.0 Hz), 4.69-4.68 (4H, m), 2.82 (2H, brs).

The residue obtained from compound 10b (509 mg, 2.35 mmol) and phosphorus tribromide (0.267 mL, 2.82 mmol) was purified by silica gel chromatography with n-hexane/EtOAc (3:1). , compound 10c (198 mg, 25% recovery) was obtained as yellow crystals.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.53 (1H, d, J = 4.0 Hz), 7.44 (1H, dd, J = 8.0, 4.0 Hz), 7.24 (1H, d, J = 8.0 Hz), 4.59 (2H, s), 4.58 (2H, s).

From compound 10c (174 mg, 0.51 mmol) and thiourea (77.2 mg, 1.01 mmol), the same operation as the synthesis of compound 2 was performed, and the residue was recrystallized with EtOH and Et2O (2:3) to obtain white crystal compound 10 (108mg, 43% recovery).

¹ HNMR (400 MHz, DMSO-d6):δ = 9.09 (6H, brs), 7.71 (1H, s), 7.61 (1H, d, J = 8.4 Hz), 7.43 (1H, d, J = 8.4 Hz), 4.55 (4H, s).LC-MS:＞99％ purity, RT 0.45 min, MS (m/z): 335 ( ⁷⁹ BrM + H) ⁺ , 333 ( ⁷⁷ BrM + H) ⁺ .

Synthesis of compound 11 1,2-Phenylenebis(methylene) bis(metylcarbamimidothioate) dihydrochloride

1,2-Bis(chloromethyl)benzene (Compound 1a, 525 mg, 3.00 mmol) and N-methylthiourea (541 mg, 6.00 mmol) were reacted in the same manner as in the synthesis of Compound 1, and the residue was recrystallized with EtOH and _Et2O (2:3) to obtain white crystals of Compound 11 (1.09 g, 102% recovery).

¹ HNMR (400 MHz, DMSO-d6):δ = 9.62 (4H, brs), 7.46-7.43 (2H, m), 7.38-7.35 (2H, m), 4.74 (4H, s), 2.89 (6H, s).LC-MS: ＞99％ purity, RT 0.39 min, MS (m/z): 283 (M + H) ⁺ .

Synthesis of Compound 12 (4-Methyl-1,2-phenylene)bis(methylene)dicarbamidioate dihydrobromide

From 4-methylphthalic anhydride (compound 12a, 649 mg, 4.00 mmol) and LiAlH ₄ (304 mg, 8.00 mmol), the same operation as the synthesis of compound 2b was performed, by silica gel chromatography (n-hexane/EtOAc = 5:1～2:1) The reaction residue was purified to obtain compound 12b (296 mg, 49% recovery rate) as a colorless oily substance.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.24 (1H, d, J = 8.0 Hz), 7.18 (1H, s), 7.13 (1H, d, J = 8.0 Hz), 4.71 (4H, s) , 2.82 (2H, brs), 2.35 (3H, s).

The residue obtained from compound 12b (296 mg, 1.95 mmol) and phosphorus tribromide (0.222 mL, 2.34 mmol) in the same operation as that for synthesizing compound 2c was purified by silica gel chromatography with n-hexane/EtOAc (3:1) to obtain compound 12c (177 mg, 33% recovery) as white crystals. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.26 (1H, d, J = 8.0 Hz), 7.19(1H, s), 7.12 (1H, d, J = 8.0 Hz), 4.65 (2H, s), 4.64 (2H, s), 2.34 (3H, s).

From compound 12c (150 mg, 0.54 mmol) and thiourea (82.3 mg, 1.08 mmol), the same operation as the synthesis of compound 2 was performed, and the residue was recrystallized with EtOH and Et ₂ O (2:3) to obtain white crystals. Compound 12 (85.5 mg, 37% recovery).

¹ HNMR (400 MHz, DMSO-d6):δ = 9.13 (6H, brs), 7.37 (1H, d, J = 8.0 Hz), 7.29 (1H, s), 7.21 (1H, d, J = 8.0 Hz), 4.57 (2H, s), 4.56 (2H, s), 2.30 (3H, s).LC-MS:＞99％ purity, RT 0.41 min, MS (m/z): 269 (M + H) ⁺ .

Synthesis of compound 13 (3-Fluoro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide/(3-Fluoro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide

The same operation as that for synthesizing compound 2b was carried out from 3-fluorophthalic anhydride (compound 13a, 664 mg, 4.00 mmol) and LiAlH ₄ (304 mg, 8.00 mmol). The reaction residue was purified by silica gel chromatography (n-hexane/EtOAc=5:1-2:1) to obtain compound 13b (282 mg, 45% recovery) as white crystals.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.32-7.28 (1H, m), 7.16 (1H, d, J = 8.0 Hz), 7.09-7.04 (1H, m), 4.85-4.84 (2H, m ), 4.77 (2H, s), 2.87 (2H, brs).

The residue obtained from compound 13b (260 mg, 1.67 mmol) and phosphorus tribromide (0.190 mL, 2.00 mmol) was purified by silica gel chromatography with n-hexane/EtOAc (3:1) to give compound 13c (106 mg, 23% recovery) as white crystals by the same procedure as for the synthesis of compound 2c.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.32-7.28 (1H, m), 7.18 (1H, d, J = 8.0 Hz), 7.08-7.04 (1H, m), 4.70-4.68 (2H, m), 4.63 (2H, s).

From compound 13c (95.1 mg, 0.34 mmol) and thiourea (51.5 mg, 0.68 mmol), the same operation as the synthesis of compound 2 was performed, and the residue was recrystallized with EtOH and Et ₂ O (2:3) to obtain white crystals. Compound 13 (122 mg, 83% recovery).

¹ HNMR (400 MHz, DMSO-d6):δ = 9.14 (6H, brs), 7.51-7.45 (1H, m), 7.36-7.30 (2H, m), 4.62-4.60 (4H, m). LC-MS:＞99％ purity, RT 0.38 min, MS (m/z): 273 (M + H) ⁺ .

Synthesis of compound 14 1,2-Bis{[(5-benzyl-1,4,5,6-tetrahydoro-1,3,5-triazin-2-yl)thio]methyl}benzene/1,2-Bis{[(5-benzyl-1,4,5,6-tetrahydoro-1,3,5-triazin-2-yl)thio]methyl}benzene

From benzylamine (107 mg, 1.00 mmol), formaldehyde (162 μL, 37% wt, aqueous solution, 2.00 mmol) and 1,2-phenylenebis(methylene)diaminothiamidine sulfate dihydrochloride (compound 1 , 127 mg, 0.50 mmol), the reaction was carried out by the same operation as the synthesis of compound 9, and the reaction residue was purified by silica gel chromatography (n-hexane: EtOAc = 1:2) to obtain the title compound 14 (78.9 mg, 31) as white crystals %Recovery rate).

¹ HNMR (400 MHz, CD ₃ OD):δ = 7.42-7.24 (14H, m), 4.34 (4H, s), 4.16 (8H, s), 3.67(4H, s).LC-MS: ＞99％ purity, RT 2.15 min, MS (m/z): 517 (M + H) ⁺ .

Synthesis of compound 15 Thiophene-3,4-diylbis(methylene) dicarbamimidothioate dihydrobromide

The same operation as that for compound 2b was performed from 3,4-thiophenedicarboxylic acid (compound 15a, 689 mg, 4.00 mmol) and LiAlH4 (304 mg, 8.00 mmol). The reaction residue was purified by silica gel chromatography (n-hexane/EtOAc = 5:1 to 1:1) to obtain compound 15b (64.7 mg, 11% recovery) as white crystals.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.25 (2H, s), 4.67 (4H, s).

From compound 15b (47.7 mg, 0.33 mmol) and phosphorus tribromide (0.038 mL, 0.40 mmol), the residue obtained by the same operation as the synthesis of compound 2c was purified by silica gel chromatography with n-hexane/EtOAc (3:1) , compound 15c (43.7 mg, 49% recovery) was obtained as white crystals.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.35 (2H, s), 4.63 (4H, s).

Compound 15c (38.0 mg, 0.14 mmol) and thiourea (21.4 mg, 0.28 mmol) were subjected to the same operation as compound 2, and the residue was recrystallized with EtOH and Et ₂ O (3:1) to obtain white crystals of compound 15 (38.1 mg, 64% recovery). ¹ HNMR (400 MHz, DMSO-d6):δ = 9.07 (6H, brs), 7.62 (2H, s), 4.51 (4H, s).LC-MS:＞99％ purity, RT 0.38 min, MS (m/z): 261 (M + H) ⁺ .

Synthesis of Compound 16 1,2-Bis[(pyrimidin-2-ylthio)methyl]benzene/1,2-Bis[(pyrimidin-2-ylthio)methyl]benzene

2-Hydroxypyrimidine (112 mg, 1.00 mmol) was added to a solution of KOH (66.0 mg, 1.00 mmol) in EtOH (3.5 mL) and stirred at room temperature for 30 minutes. Then, 1,2-bis(chloromethyl)benzene (Compound 1a, 87.5 mg, 0.50 mmol) was added to the reaction solution, heated at 70°C and stirred for 6 hours. After the reaction mixture was cooled to room temperature, water and chloroform were added, and the organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane: EtOAc = 2:1) to obtain the title compound 16 (122 mg, 75% recovery) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 8.52-8.51 (4H, m), 7.51-7.47 (2H, m), 7.24-7.21 (2H, m), 6.97-6.95 (2H, m), 4.61 (4H, s).LC-MS: >99% purity, RT 3.45 min, MS (m/z): 327 (M + H) ⁺ .

Synthesis of Compound 17 1,2-Bis{{[5-(4-chlorophenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene/1,2-Bis{{[5-(4-chlorophenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene

From 2-(4-chlorophenyl)ethylamine (158 mg, 1.02 mmol), formaldehyde (166 μL, 37% wt, aqueous solution, 2.04 mmol) and 1,2-phenylenebis(methylene)diaminothioamidine sulfate dihydrochloride (compound 1, 127 mg, 0.50 mmol), the reaction was carried out by the same operation as the synthesis of compound 9, and the reaction residue was purified by silica gel chromatography (n-hexane: EtOAc = 3:1 to 1:1) to obtain the title compound 17 (46.5 mg, 15% recovery) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.33-7.08 (14H, m), 4.29-4.22 (12H, m), 2.86-2.70 (8H, m). LC-MS: >99% purity, RT 2.74 min, MS (m/z): 614 (M + H) ⁺ .

Synthesis of compound 18 1,2-bis{{[5-(2,5-dichlorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl }Benzene/1,2-Bis{{[5-(2,5-dichlorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene

From 2,5-dichlorobenzylamine (181 mg, 1.03 mmol), formaldehyde (168 μL, 37% wt, aqueous solution, 2.06 mmol) and 1,2-phenylenebis(methylene)diaminothiamidine sulfate di Hydrochloride (compound 1, 131 mg, 0.52 mmol) was reacted by the same operation as the synthesis of compound 9, and the reaction residue was recrystallized with 2-propanol to obtain the title compound 18 as white crystals (230 mg, 68% recovery rate) .

¹ HNMR (400 MHz, DMSO-d6): δ = 7.55-7.37 (10H, m), 4.82 (4H, s), 4.39 (4H, s), 3.73 (4H, s). LC-MS: >99% purity, RT 2.70 min, MS (m/z): 655 (M + H) ⁺ .

Synthesis of Compound 19 1,2-Bis{{[5-(3-bromophenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene/1,2-Bis{{[5-(3-bromophenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene

From 2-(3-bromophenyl)ethylamine (208 mg, 1.04 mmol), formaldehyde (168 μL, 37% wt, aqueous solution, 2.08 mmol) and 1,2-phenylenebis(methylene)diaminothiamidine Sulfate dihydrochloride (compound 1, 132 mg, 0.52 mmol) was reacted by the same operation as the synthesis of compound 9, purified by silica gel chromatography (EtOAc), and the reaction residue was recrystallized with 2-propanol to obtain The title compound 19 was obtained as white crystals (97.5 mg, 27% recovery).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.35-7.11 (12H, m), 4.29 (12H, brs), 2.84-2.74 (8H, m). LC-MS: ＞99％ purity, RT 2.76 min, MS (m/z): 703 (M + H) ⁺ .

Synthesis of compound 20 1,2-Bis{{[5-(4-bromophenylethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene /1,2-Bis{{[5-(4-bromophenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene

From 2-(3-bromophenyl)ethylamine (208 mg, 1.04 mmol), formaldehyde (168 μL, 37% wt, aqueous solution, 2.08 mmol) and 1,2-phenylenebis(methylene)diaminothiamidine Sulfate dihydrochloride (compound 1, 132 mg, 0.52 mmol) was reacted by the same operation as the synthesis of compound 9, purified by silica gel chromatography (EtOAc), and the reaction residue was recrystallized with 2-propanol to obtain The title compound 20 was obtained as white crystals (75.7 mg, 21% recovery).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.40 (4H, d, J = 8.0 Hz), 7.32 (2H, dd, J = 8.0, 4.0 Hz), 7.12 (2H, dd, J = 8.0, 4.0 Hz), 7.06 (4H, d, J = 8.0 Hz), 4.28 (12H, brs), 2.84-2.73 (8H, m).LC-MS: >99% purity, RT 2.87 min, MS (m/z) : 703 (M + H) ⁺ .

Synthesis of Compound 21 1,2-Bis{{[5-(2,4-dichlorophenylethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl 1,2-Bis{{[5-(2,4-dichlorophenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene

From 2-(2,4-dichlorophenyl)ethylamine (198 mg, 1.04 mmol), formaldehyde (169 μL, 37% wt, aqueous solution, 2.08 mmol) and 1,2-phenylenebis(methylene)bis Thiamidine sulfate dihydrochloride (compound 1, 132 mg, 0.52 mmol) was reacted by the same operation as the synthesis of compound 9, and purified by silica gel chromatography with n-hexane/EtOAc (1:3 ~ 1:6) , and the reaction residue was recrystallized with 2-propanol to obtain the title compound 21 (51.3 mg, 14% recovery rate) as white crystals.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.37 (2H, d, J = 8.0 Hz), 7.30 (2H, dd, J = 8.0, 4.0 Hz), 7.17-7.16 (4H, m), 7.08 ( 2H, dd, J = 8.0, 4.0 Hz), 4.31-4.26 (12H, m), 2.91-2.86 (4H, m), 2.82-2.77 (4H, m).LC-MS: >99% purity, RT 2.74 min, MS (m/z): 683 (M + H) ⁺ .

Synthesis of compound 22 1,2-Bis{{[5-(3,4-dichlorophenylethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl 1,2-Bis{{[5-(3,4-dichlorophenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene

From 3,4-dichlorophenethylamine (191 mg, 1.01 mmol), formaldehyde (163 μL, 37% wt, aqueous solution, 2.02 mmol) and 1,2-phenylenebis(methylene)diaminothioamidine sulfate dihydrochloride (compound 1, 128 mg, 0.50 mmol), the same operation as that for compound 9 was used for reaction, and the product was purified by silica gel chromatography with n-hexane/EtOAc (1:3-1:6), and the reaction residue was recrystallized from 2-propanol to obtain the title compound 22 (61.0 mg, 18% recovery) as white crystals.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.35 (2H, d, J = 8.0 Hz), 7.33-7.28 (4H, m), 7.13 (2H, dd, J = 8.0, 4.0 Hz), 7.03 ( 2H, dd, J = 8.0, 4.0 Hz), 4.34-4.21 (12H, m), 2.83-2.72 (8H, m). LC-MS: >99% purity, RT 2.88 min, MS (m/z): 683 (M + H) ⁺ .

Synthesis of compound 23 1,2-bis{{[5-(3,4-dimethylphenylethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio} Methyl}benzene/1,2-Bis{{[5-(3,4-dimethylphenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene

From 3,4-dichlorophenylethylamine (155mg, 1.04mmol), formaldehyde (169μL, 37%wt, aqueous solution, 2.08mmol) and 1,2-phenylenebis(methylene)diaminothiamidine sulfate Dihydrochloride (compound 1, 132 mg, 0.52 mmol) was reacted by the same operation as the synthesis of compound 9, and the reaction residue was purified by silica gel chromatography with n-hexane/EtOAc (1:3 ~ 1:6) to obtain colorless The title compound 23 was obtained as an oil (54.2 mg, 17% recovery).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.32 (2H, dd, J = 8.0, 4.0 Hz), 7.12 (2H, dd, J = 8.0, 4.0 Hz), 7.05 (2H, d, J = 8.0 Hz), 6.96-6.91 (4H, m), 4.28-4.24 (12H, m), 2.83-2.72 (8H, m), 2.24 (6H, s), 2.22 (6H, s). LC-MS: ＞99％ purity, RT 2.88 min, MS (m/z): 601 (M + H) ⁺ .

Synthesis of Compound 24 1,2-Bis{{[5-(2,5-dimethylphenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene/1,2-Bis{{[5-(2,5-dimethylphenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene

From 2,5-dimethylaniline (157 mg, 1.05 mmol), formaldehyde (170 μL, 37% wt, aqueous solution, 2.10 mmol) and 1,2-phenylenebis(methylene)diaminothioamidine sulfate dihydrochloride (compound 1, 134 mg, 0.53 mmol), the reaction was carried out by the same operation as the synthesis of compound 9, and the reaction residue was purified by silica gel chromatography with n-hexane/EtOAc (1:3-1:6) to obtain the title compound 24 (70.0 mg, 22% recovery) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.30 (2H, dd, J = 8.0, 4.0 Hz), 7.08 (2H, dd, J = 8.0, 4.0 Hz), 7.02 (2H, d, J = 8.0 Hz), 6.94-6.92 (4H, m), 4.30-4.27 (12H, m), 2.79-2.77 (8H, m), 2.29 (6H, s), 2.25 (6H, s). LC-MS: ＞99％ purity, RT 3.10 min, MS (m/z): 601 (M + H) ⁺ .

Synthesis of compound 25 1,2-bis{{[5-(4-ethylphenylethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl} Benzene/1,2-Bis{{[5-(4-ethylphenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene

From 4-ethylaniline (155 mg, 1.04 mmol), formaldehyde (169 μL, 37% wt, aqueous solution, 2.10 mmol) and 1,2-phenylenebis(methylene)diaminothioamidine sulfate dihydrochloride (compound 1, 132 mg, 0.52 mmol), the reaction was carried out by the same operation as the synthesis of compound 9, and the reaction residue was purified by silica gel chromatography with n-hexane/EtOAc (1:2-1:6) to obtain the title compound 25 (53.9 mg, 17% recovery) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.33-7.29 (2H, m), 7.14-7.09 (10H, m), 4.29-4.23 (12H, m), 2.86-2.75 (8H, m), 2.62 (4H, q, J = 8.0 Hz), 1.22 (6H, t, J = 8.0 Hz). LC-MS: ＞99％ purity, RT 2.88 min, MS (m/z): 601 (M + H) ⁺ .

Synthesis of Compound 26 1,2-Bis{{[5-(4-methoxybenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene/1,2-Bis{{[5-(4-methoxybenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene

From 4-methoxybenzylamine (144 mg, 1.05 mmol), formaldehyde (170 μL, 37% wt, aqueous solution, 2.10 mmol) and 1,2-phenylenebis(methylene)diaminothioamidine sulfate dihydrochloride (compound 1, 134 mg, 0.53 mmol), the reaction was carried out by the same operation as the synthesis of compound 9, and the residue was purified by silica gel chromatography with n-hexane/EtOAc (1:2-1:6) and recrystallized from 2-propanol to obtain the title compound 26 as white crystals (23.0 mg, 7.5% recovery).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.42-7.40 (2H, m), 7.25-7.21 (6H, m), 6.87-6.83 (4H, m), 4.39-4.12 (8H, m), 4.36 (4H, s), 3.80 (6H, s), 3.68 (4H, s). LC-MS: ＞99％ purity, RT 2.17 min, MS (m/z): 577 (M + H) ⁺ .

Synthesis of Compound 27 1,2-Bis{{[5-(2,4-dimethoxybenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene/1,2-Bis{{[5-(2,4-dimethoxybenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene

From 2,4-dimethoxybenzylamine (173 mg, 1.03 mmol), formaldehyde (167 μL, 37% wt, aqueous solution, 2.06 mmol) and 1,2-phenylenebis(methylene)diaminothioamidine sulfate dihydrochloride (compound 1, 132 mg, 0.52 mmol), the reaction was carried out by the same operation as the synthesis of compound 9, and the reaction residue was purified by silica gel chromatography with n-hexane/EtOAc (1:3-1:7) and recrystallized from 2-propanol to obtain the title compound 27 (12.9 mg, 4.0% recovery) as white crystals.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.42-7.40 (2H, m), 7.21-7.19 (2H, m), 7.14 (4H, d,J = 8.0 Hz), 6.45-6.42 (4H, m ), 4.39-4.18 (8H, m), 4.37 (4H, s), 3.80 (12H, s), 3.71 (4H, s).LC-MS: >99% purity, RT 2.27 min, MS (m/z ): 637 (M + H) ⁺ .

Synthesis of Compound 28 1,2-Bis(((5-(2-chlorophenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl)benzene/1,2-Bis(((5-(2-chlorophenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl)benzene

From 2-chlorophenethylamine (164 mg, 1.05 mmol), formaldehyde (171 μL, 37% wt, aqueous solution, 2.11 mmol) and 1,2-phenylenebis(methylene)diaminothioamidine sulfate dihydrochloride (compound 1, 134 mg, 0.53 mmol), the reaction was carried out by the same operation as the synthesis of compound 9, and the reaction residue was purified by silica gel chromatography with n-hexane/EtOAc (1:3-1:6) and recrystallized from 2-propanol to obtain the title compound 28 (57.1 mg, 17.7% recovery) as white crystals.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.35-7.14 (10H, m), 7.07-7.05 (2H, m), 4.36-4.25 (8H, m), 4.28 (4H, s), 2.95-2.80 (8H, m).LC-MS: >99% purity, RT 2.96 min, MS (m/z): 614 (M + H) ⁺ .

Synthesis of compound 29 1,2-Bis{[(5-methylcyclohexyl-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio]methyl}benzene/1,2 -Bis{[(5-methylcyclohexyl-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio]methyl}benzene

Cyclohexylamine (115 mg, 1.01 mmol), formaldehyde (164 μL, 37% wt, aqueous solution, 2.03 mmol) and 1,2-phenylenebis(methylene)diaminothioamidine sulfate dihydrochloride (compound 1, 130 mg, 0.51 mmol) were reacted by the same operation as that for compound 9, and the reaction residue was recrystallized from 2-propanol to obtain the title compound 29 (161 mg, 60% recovery) as pale yellow crystals.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 10.64 (2H, brs), 7.42 (2H, dd, J = 8.0, 4.0 Hz), 7.19 (2H, dd, J = 8.0, 4.0 Hz), 4.69 ( 4H, s), 4.34 (8H, s), 2.29-2.27 (4H, m), 1.71-0.81 (22H, m).LC-MS: >99% purity, RT 2.62 min, MS (m/z): 529 (M + H) ⁺ .

Synthesis of compound 30 2,2'-((1,2-phenylenebis(methylene))bis(sulfanediyl))bis(pyrimidine-4,6(1H,5H)-dione)/2,2'-((1,2-phenylenebis(methylene))bis(sulfanediyl))bis(pyrimidine-4,6(1H,5H)-dione)

Add 1.1mmol/L NaOH (2.0mL, 2.20mmol) to the 1,4-dioxane/H ₂ O mixed solution (3:1, 4.0mL) of 2-mercaptopyrimidine (112mg, 1.00mmol), in the chamber Stir at warm temperature for 1 hour. After that, a 1,4-dioxane solution (4.0 mL) of 1,2-bis(chloromethyl)benzene (compound 1a; 175 mg, 1.00 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. After the reaction mixture was concentrated under reduced pressure, the residue was recrystallized from EtOH to obtain the title compound 30 (355 mg, 91% recovery) as yellow crystals.

¹ H NMR (400 MHz, DMSO-d6): δ = 10.44 (2H, brs), 7.51 (2H, dd, J = 8.0, 4.0 Hz), 7.26 (2H, dd, J = 8.0, 4.0 Hz), 5.24 (2H, brs), 4.49 (4H, s), 4.09 (2H, brs).LC-MS: >99% purity, RT 1.96 min, MS (m/z): 391 (M + H) ⁺ .

Synthesis of Compound 31 Thiophene-2,3-diylbis(methylene) dicarbamimidothioate dihydrobromide

The same operation as compound 2b was carried out from 2,3-thiophenedicarbaldehyde (compound 31a, 561 mg, 4.00 mmol) and LiAlH ₄ (304 mg, 8.00 mmol), and the reaction residue was purified by silica gel chromatography (n-hexane/EtOAc=5:1-1:4) to obtain compound 31b (428 mg, 74% recovery) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.19-7.18 (1H, m), 7.00-6.98 (1H, m), 4.74 (2H, s), 4.64 (2H, s), 3.25 (1H, brs ), 2.95 (1H, brs).

Compound 31b (386 mg, 2.68 mmol) and phosphorus tribromide (0.305 mL, 3.21 mmol) were prepared from the same residue as compound 2c and purified by silica gel chromatography with n-hexane/EtOAc (3:1) to give compound 31c (611 mg, 85% recovery) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.27-7.26 (1H, m), 7.02-7.01 (1H, m), 4.75 (2H, s), 4.53 (2H, s).

From compound 31c (537 mg, 1.99 mmol) and thiourea (303 mg, 3.98 mmol), the same operation as for the synthesis of compound 2 was performed, and the residue was recrystallized with EtOH and Et ₂ O (1:1) to obtain the title compound as white crystals 31 (597mg, 71% recovery).

¹ H NMR (400 MHz, DMSO-d6):δ = 4.53 (2H, s), 4.80 (2H, s), 7.08 (1H, d, J = 4.0 Hz), 7.59 (1H, d, J = 4.0 Hz), 9.12 (6H, brs).LC-MS: ＞99％ purity, RT 0.35 min, MS (m/z): 261 (M + H) ⁺ .

Synthesis of compound 32 Methyl 2-((carbamimidoylthio)methyl)-1H-indole-3-carboxylate hydrobromide

A solution of 1H-indole-2,3-dicarboxylic acid dimethyl ester (compound 32a, 670 mg, 3.00 mmol) in THF (10 mL) was gently added to LiAlH ₄ (228 mg, 6.00 mmol) at 0°C under an argon atmosphere. mmol) in THF (12 mL), stirred at room temperature for 5 hours, and then heated to reflux for 12 hours. After the reaction mixture was cooled to room temperature, 10% NaOH (1.0 mL) and H ₂ O (1.0 mL) were added and stirred to stop the reaction, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/EtOAc = 9:1 to 3:7) to obtain compound 32b (213 mg, 42% recovery) as pale yellow crystals.

¹ H NMR (400 MHz, CD ₃ OD): δ = 3.89 (3H, s), 5.08 (2H, s), 7.13-7.16 (2H, m), 7.41-7.44 (1H, m), 7.97-8.00 ( 1H, m). LC-MS: >99% purity, RT 2.39 min, MS (m/z): 188 (M - OH) ⁺ .

The reaction residue obtained from compound 32b (350 mg, 1.97 mmol) and phosphorus tribromide (0.225 mL, 2.37 mmol) was subjected to the same operation as the synthesis of compound 2c, and was subjected to silica gel chromatography (n-hexane/EtOAc=9:1 ~3:7) After purification and concentration under reduced pressure, the obtained purified product (123 mg, 0.46 mmol) was added to a solution of thiourea (77.5 mg, 1.02 mmol) in EtOH (5 mL) at room temperature, and the reaction mixture was refluxed for 12 hours. After that, the reaction solution was concentrated under reduced pressure and recrystallized with EtOH and Et ₂ O (1:1) to obtain the title compound 32 (25.6 mg) as white crystals. A recovery rate of 3.8% was obtained from compound 32b (3.8% recovery rate was Recovery rate using compound 32b as starting material)).

¹ H NMR (400 MHz, DMSO-d6): δ = 9.08 (3H, brs), 7.96 (1H, d, J = 8.0 Hz), 7.49 (1H, d, J = 8.0 Hz), 7.27-7.19 (2H, m), 4.87 (2H, s), 3.87 (3H, s). LC-MS: ＞99％ purity, RT 1.13 min, MS (m/z): 264 (M + H) ⁺ .

Synthesis of compound 33 3,4-Bis{[(5-phenethyl-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio]methyl}thiophene dihydrochloride/3,4-Bis{[(5-phenethyl-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio]methyl}thiophene dihydrochloride

Phenylethylamine (121 mg, 1.00 mmol), formaldehyde (162 μL, 37% wt, aqueous solution, 2.00 mmol) and thieno-3,4-diylbis(methylene)dicarbonamide dithiodihydrobromide (compound 15, 130 mg, 0.50 mmol) were reacted by the same operation as the synthesis of compound 9, and the reaction residue was purified by silica gel chromatography with EtOAc/EtOH (4:1-7:3) to obtain a colorless oily compound 33 (23.3 mg, 8.5% recovery). 4.0 mol/L HCl (19.5 μL, 0.078 mmol) was added to a 1,4-dioxane solution (3.0 mL) of the compound 33 free body and stirred at room temperature for 1 hour. The reaction residue was concentrated under reduced pressure and recrystallized with n-hexane to obtain the title compound 33 (23.8 mg, 98% recovery) as white crystals.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 10.56 (2H, brs), 7.50-7.17 (12H, m), 4.61 (4H, s), 4.36-4.20 (8H, m), 2.98-2.58 (8H , m).LC-MS: >99% purity, RT 2.29 min, MS (m/z): 551 (M + H) ⁺ .

Synthesis of compound 34 Pyridine-2,3-diylbis(methylene) dicarbamimidothioate dihydrobromide

Concentrated sulfuric acid (1.0 ml) was added to a MeOH solution (10 ml) of pyridine-2,3-dicarboxylic acid (compound 34a, 2.5 g, 15.0 mmol), refluxed for 6 hours, and then stirred at room temperature for 2 days. After concentrating the reaction solution, an aqueous sodium bicarbonate solution was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain light yellow crystals of compound 34b (2.18 g, 74% recovery).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 8.78 (1H, dd, J = 4.9, 1.5 Hz), 8.18 (1H, dd, J = 7.8, 1.5 Hz), 7.51 (1H, dd, J = 7.8 , 4.9 Hz), 4.01 (3H, s), 3.95 (3H, s). LC-MS: >99% purity, RT 1.23 min, MS (m/z): 196 (M + H) ⁺ .

From compound 34b (976 mg, 5.00 mmol) and LiAlH ₄ (380 mg, 10.0 mmol), the same operation as for synthesizing compound 2b was performed, and the reaction residue was purified by silica gel chromatography (CHCl ₃ /MeOH = 1:0 to 9:1). , Compound 34c (221 mg, 32% recovery) was obtained as a colorless oily substance.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 8.50 (1H, d, J = 4.4 Hz), 7.76 (1H, d, J = 7.8 Hz), 7.29-7.25 (1H, m), 4.80 (2H, s), 4.71 (2H, s), 4.51 (1H, brs), 2.09 (1H, brs). LC-MS: ＞99％ purity, RT 0.35 min, MS (m/z): 140 (M + H) ⁺ .

Compound 34c (196 mg, 1.41 mmol) and phosphorus tribromide (0.161 mL, 1.69 mmol) were subjected to the same operation as that for synthesizing compound 2c. The resulting reaction residue was purified by silica gel chromatography (CHCl ₃ ) to obtain compound 34d (42.1 mg, 11% recovery) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 8.55-8.53 (1H, m), 7.71-7.69 (1H, m), 7.28-7.25 (1H, m), 4.73 (2H, s), 4.62 (2H , s).LC-MS: >99% purity, RT 2.58 min, MS (m/z): 266 (M + H) ⁺ .

Compound 34d (38.1 mg, 0.14 mmol) and thiourea (21.9 mg, 0.28 mmol) were subjected to the same operation as for the synthesis of compound 2, and the residue was recrystallized with EtOH and Et ₂ O (1:1) to obtain the title compound 34 (36.4 mg, 61% recovery) as white crystals.

¹ H NMR (400 MHz, DMSO-d6): δ = 9.21 (6H, brs), 8.55 (1H, dd, J = 4.8, 1.6 Hz), 7.93 (1H, dd, J = 7.8, 1.6 Hz), 7.48 (1H, dd, J = 7.8, 4.8 Hz), 4.74 (2H, s), 4.64 (2H, s).LC-MS: >99% purity, RT 0.35 min, MS (m/z): 256 (M + H) ⁺ .

Synthesis of compound 35 (4-Methoxy-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide

From a MeOH solution (7 ml) of 4-methoxyphthalic acid (compound 35a, 588 mg, 3.0 mmol) and concentrated sulfuric acid (0.5 ml), the same operation as that for the synthesis of compound 34b was carried out, and the residue was purified by silica gel chromatography with EtOAc/EtOH (1:1) to obtain compound 35b (574 mg, 85% recovery) as a light yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.82 (1H, d, J = 8.4 Hz), 7.07 (1H, d, J = 2.8 Hz), 6.99 (1H, dd, J = 8.4, 2.8 Hz) , 3.92 (3H, s), 3.87 (3H, s), 3.87 (3H, s).

From compound 35b (497 mg, 2.22 mmol) and LiAlH ₄ (168 mg, 4.43 mmol), the same operation as the synthesis of compound 2b was performed, and purified by silica gel chromatography (n-hexane/EtOAc=4:1~1:2) From the reaction residue, compound 35c (222 mg, 59% recovery rate) was obtained as a colorless oily substance.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.27-7.25 (1H, m), 6.92 (1H, d, J = 2.9 Hz), 6.82 (1H, dd, J = 8.3, 2.9 Hz), 4.69 ( 2H, s), 4.67 (2H, s), 3.82 (3H, s).

Compound 35c (183 mg, 1.09 mmol) and phosphorus tribromide (0.124 mL, 1.31 mmol) were reacted with the same procedure as for synthesizing compound 2c. The resulting reaction residue was purified by silica gel chromatography (n-hexane/EtOAc=3:1) to give compound 35d (72.7 mg, 23% recovery) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.29 (1H, d, J = 8.3 Hz), 6.90 (1H, d, J = 2.4 Hz), 6.83 (1H, dd, J = 8.3, 2.9 Hz) , 4.66 (2H, s), 4.62 (2H, s), 3.82 (3H, s).

The same operation as for the synthesis of compound 2 was performed from compound 35d (73.0 mg, 0.247 mmol) and thiourea (38.0 mg, 0.495 mmol), and the residue was recrystallized with EtOH and Et ₂ O (1:1) to obtain the title compound as white crystals. 35 (62.8mg, 57% recovery).

¹ H NMR (400 MHz, DMSO-d6): δ = 9.13 (6H, brs), 7.41 (1H, d, J = 8.0 Hz), 7.07 (1H, d, J = 2.8 Hz), 6.97 (1H, dd, J = 8.0, 2.8 Hz), 4.55-4.54 (4H, m), 3.77 (3H,s). LC-MS: ＞99％ purity, RT 0.34 min, MS (m/z): 285 (M + H) ⁺ .

Synthesis of compound 36 (4,5-Dichloro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide

From (4,5-dichloro-1,2-phenylene) dimethanol (compound 36a, 2.18g, 10.5mmol) and phosphorus tribromide (1.103mL, 12.6mmol), the same method as that used to synthesize compound 2c The reaction residue obtained was purified by silica gel chromatography (n-hexane/EtOAc = 4:1) to obtain white crystalline compound 36b (823 mg, 24% recovery rate).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.47 (2H, s), 4.55 (4H, s).

The same operation as for the synthesis of compound 2 was carried out from compound 36b (723 mg, 2.17 mmol) and thiourea (331 mg, 4.34 mmol), and the residue was recrystallized with EtOH and Et ₂ O (1:2) to obtain the title compound as white crystals. 36 (856mg, 82% recovery).

¹ H NMR (400 MHz, DMSO-d6): δ = 9.21 (6H, brs), 7.80 (2H, s), 4.62 (4H, s).LC-MS: ＞99％ purity, RT 0.45 min, MS (m/z): 324 (M + H) ⁺ .

Synthesis of compound 37 6,6'-(((4,5-Dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-phenethyl-1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4,5-Dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-phenethyl-1,2,3,4-tetrahydro-1,3,5-triazine)

From 2-phenylethyl-1-amine (121 mg, 1.00 mmol), formaldehyde (162 μL, 37% wt, aqueous solution, 2.00 mmol) and (4,5-dichloro-1,2-phenylene)bis(methylene)dicarbonamide dithiodihydrobromide (compound 36, 162 mg, 0.50 mmol), the same operation as that for synthesizing compound 9 was reacted, and the reaction residue was recrystallized from 2-propanol to obtain the title compound 37 (200 mg, 65% recovery) as white crystals.

¹ H NMR (400 MHz, DMSO-d6): δ = 10.25 (2H, brs), 7.72 (2H, s), 7.32-7.20 (10H, m), 4.60 (4H, brs), 4.41 (8H, brs), 2.78-2.63 (8H, m). LC-MS: ＞99％ purity, RT 3.87 min, MS (m/z): 614 (M + H) ⁺ .

Synthesis of compound 38 6,6'-(((4,5-Dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3,4-dichlorophenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4,5-Dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3,4-dichlorophenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From 2-(3,4-dichlorophenyl)ethan-1-amine (190 mg, 1.00 mmol), formaldehyde (162 μL, 37% wt, aqueous solution, 2.00 mmol) and (4,5-dichloro-1,2-phenylene)bis(methylene)dicarbonamide dithiodihydrobromide (compound 36, 162 mg, 0.50 mmol), the reaction was carried out in the same manner as for the synthesis of compound 9, and the reaction residue was purified by NH-silica gel chromatography with n-hexane/EtOAc (3:2 to 0:1) to obtain the title compound 38 (38.2 mg, 10% recovery) as an amorphous substance.

¹ H NMR (400 MHz, DMSO-d6): δ = 7.51-7.48 (6H, m), 7.21-7.18 (2H, m), 4.24 (4H, brs), 4.17 (4H, brs), 3.99 (4H, brs), 2.73-2.65 (8H, m).LC-MS: >99% purity, RT 2.54 min, MS (m/z): 752 (M + H) ⁺ .

Synthesis of compound 39 6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3,4-dichlorophenylethyl) -1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl)) bis(3-(3,4-dichlorophenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From 2-(3,4-dichlorophenyl)ethyl-1-amine (190 mg, 1.00 mmol), formaldehyde (162 μL, 37% wt, aqueous solution, 2.00 mmol) and (4-bromo-1,2-phenyl ) Bis(methylene)dicarbamide dithiodihydrobromide (compound 10, 167 mg, 0.50 mmol), reacted with the same operation as the synthesis of compound 9, and used NH-silica gel chromatography n-hexane/ The reaction residue was purified with EtOAc (3:2～0:1) and recrystallized with 2-propanol to obtain the title compound 39 (16.7 mg, 4.4% recovery) as white crystals.

¹ H NMR (400 MHz, DMSO-d6): δ = 7.53-7.47 (6H, m), 7.23-7.20 (2H, m), 6.88-6.85 (1H, m), 4.24 (4H, brs), 4.17-4.15 (4H, m), 4.17-4.15 (4H, m), 2.74-2.67 (8H, m). LC-MS: ＞99％ purity, RT 2.74 min, MS (m/z): 763 (M + H) ⁺ .

Synthesis of compound 40 1,2-bis(((5-(2-(thiophen-2-yl)ethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio) )methyl)benzene/1,2-bis(((5-(2-(thiophen-2-yl)ethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl )thio)methyl)benzene

From 2-(thiophen-2-yl)ethan-1-amine (763 mg, 6.00 mmol), formaldehyde (973 μL, 37% wt, aqueous solution, 4.00 mmol) and 1,2-phenylenebis(methylene)diaminothioguanidine sulfate dihydrochloride (compound 1, 763 mg, 3.00 mmol), the same operation as that for synthesizing compound 9 was carried out, and the reaction residue was purified by NH-silica gel chromatography with n-hexane/EtOAc (3:2 to 0:1) to obtain the title compound 40 (9.5 mg, 5.7% recovery) as a light yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.33-7.30 (2H, m), 7.15-7.11 (4H, m), 6.93-6.91 (2H, m), 6.82-6.81 (2H, m), 4.48-4.06 (12H, m), 3.03-2.87 (8H, m). LC-MS: ＞99％ purity, RT 1.66 min, MS (m/z): 557 (M + H) ⁺ .

Synthesis of Compound 41 1,2-Bis(((5-(4-chlorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl)benzene/ 1,2-bis(((5-(4-chlorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl)benzene

From (4-chlorophenyl)methanamine (566 mg, 4.00 mmol), formaldehyde (649 μL, 37% wt, aqueous solution, 800 mmol), and 1,2-phenylenebis(methylene)diaminothiamidine Sulfate dihydrochloride (compound 1, 509 mg, 2.00 mmol) was reacted with the same operation as the synthesis of compound 9, and the reaction residue was purified by NH-silica gel chromatography with n-hexane/EtOAc (45:55～0:1). , the title compound 41 (27.4 mg, 2.3% recovery) was obtained as a colorless oily substance.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.42-7.39 (2H, m), 7.30-7.21 (10H, m), 4.34 (4H, s), 4.23 (8H, brs), 3.70 (4H, brs ).LC-MS: >99% purity, RT 2.13 min, MS (m/z): 586 (M + H) ⁺ .

Synthesis of compound 42 1,2-bis(((5-(4-(trifluoromethyl)benzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl)benzene/1,2-bis(((5-(4-(trifluoromethyl)benzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl)benzene

From (4-(trifluoromethyl)phenyl)methanamine (701 mg, 4.00 mmol), formaldehyde (649 μL, 37% wt, aqueous solution, 800 mmol) and 1,2-phenylenebis(methylene)diaminethiourea disulfate dihydrochloride (compound 1, 509 mg, 2.00 mmol), the same operation as that for synthesizing compound 9 was carried out, and the reaction residue was purified by NH-silica gel chromatography with n-hexane/EtOAc (45:55 to 0:1) to obtain the title compound 42 (303 mg, 23.2% recovery) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.59-7.57 (4H, m), 7.45-7.40 (6H, m), 7.25-7.22 (2H, m), 4.36 (4H, brs), 4.31-4.21 (8H, m), 3.79 (4H, brs).LC-MS: >99% purity, RT 1.91 min, MS (m/z): 653 (M + H) ⁺ .

Synthesis of compound 43 1,2-bis(((5-(3,4-difluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl)benzene/1,2-bis(((5-(3,4-difluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl)benzene

From (3,4-difluorophenyl)methanamine (573 mg, 4.00 mmol), formaldehyde (649 μL, 37% wt, aqueous solution, 800 mmol), and 1,2-phenylenebis(methylene)diaminothio Urea disulfate dihydrochloride (compound 1, 509 mg, 2.00 mmol) was reacted with the same operation as the synthesis of compound 9, and purified by NH-silica gel chromatography with n-hexane/EtOAc (3:2~0:1) The reaction residue gave the title compound 43 (300 mg, 25.4% recovery rate) as a colorless oily substance.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.42-7.39 (2H, m), 7.24-7.02 (8H, m), 4.35 (4H, brs), 4.31-4.20 (8H, m), 3.69 (4H, brs). LC-MS: ＞99％ purity, RT 2.42 min, MS (m/z): 589 (M + H) ⁺ .

Synthesis of compound 44 1,2-Bis(((5-(2,5-dimethylbenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl 1,2-bis(((5-(2,5-dimethylbenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl)benzene

From (2,5-dimethylphenyl)methanamine (541 mg, 4.00 mmol), formaldehyde (649 μL, 37% wt, aqueous solution, 800 mmol), and 1,2-phenylenebis(methylene)diamine Thiamidine sulfate dihydrochloride (compound 1, 509 mg, 2.00 mmol) was reacted with the same operation as the synthesis of compound 9, and purified by NH-silica gel chromatography with n-hexane/EtOAc (3:2~0:1) The reaction residue gave the title compound 44 (157 mg, 13.7% recovery) as a colorless amorphous substance.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.44-7.41 (2H, m), 7.22-7.20 (2H, m), 7.05-6.98 (6H, m), 4.40 (4H, brs), 4.37-4.13 (8H, m), 3.71 (4H, brs), 2.30 (6H, s), 2.28 (6H, s). LC-MS: ＞99％ purity, RT 2.50 min, MS (m/z): 573 (M + H) ⁺ .

Synthesis of compound 45 1,2-bis(((5-(2,5-dimethylbenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl)benzene/1,2-bis(((5-(2,5-dimethylbenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl)benzene

From (3-fluorophenyl)methanamine (501 mg, 4.00 mmol), formaldehyde (649 μL, 37% wt, aqueous solution, 800 mmol) and 1,2-phenylenebis(methylene)diaminothioguanidine sulfate dihydrochloride (compound 1, 509 mg, 2.00 mmol), the same operation as that for synthesizing compound 9 was followed, and the reaction residue was purified by NH-silica gel chromatography with n-hexane/EtOAc (55:45 to 0:1) to obtain the title compound 45 (121 mg, 10.9% recovery) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.42-7.40 (2H, m), 7.28-7.23 (4H, m), 7.09-7.05 (4H, m), 6.98-6.93 (2H, m), 4.36 (4H, brs), 4.32-4.20 (8H, m), 3.73 (4H, brs). LC-MS: ＞99％ purity, RT 2.33 min, MS (m/z): 553 (M + H) ⁺ .

Synthesis of compound 46 (4-(Trifluoromethyl)-1,2-phenylene)bis(methylene)dimethylamidinium thiodihydrobromide/(4-(Trifluoromethyl)-1,2-phenylene)bis( methylene) dicarbamimidothioate dihydrobromide

From 4-(trifluoromethyl)phthalate dimethyl ester (compound 46a, 2621 mg, 10.00 mmol) and LiAlH ₄ (759 mg, 20.00 mmol), the same operation as the synthesis of compound 2b was performed, and silica gel chromatography ( n-hexane/EtOAc=5:1～1:2), the reaction residue was purified to obtain compound 46b (1116 mg, 54.1% recovery rate) as a light yellow oily substance.

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.63 (1H, s), 7.59 (1H, d, J = 7.8 Hz), 7.49 (1H, d, J= 7.8 Hz), 4.79 (4H, d, J = 5.9 Hz), 2.88 (2H, dt, J = 15.1, 5.9 Hz). LC-MS: >99 % purity, RT 1.97 min, MS (m/z): 189 (M+H) ⁺

From compound 46b (1025 mg, 4.97 mmol) and phosphorus tribromide (0.566 mL, 5.96 mmol), the residue obtained by the same operation as the synthesis of compound 2c was purified by silica gel chromatography with n-hexane/EtOAc (3:1) , Compound 46c (600 mg, 36.4% recovery) was obtained as a light yellow oily substance.

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.63 (1H, s), 7.57 (1H, d, J = 7.8 Hz), 7.50 (1H, d, J= 7.8 Hz), 4.66 (4H, d, J = 2.9 Hz).

The same operation as that for the synthesis of compound 2 was carried out from compound 46c (585 mg, 1.76 mmol) and thiourea (268 mg, 3.52 mmol), and the residue was recrystallized with EtOH and Et ₂ O (1:2) to obtain compound 46 (659 mg, 77.3% recovery) as white crystals.

¹ HNMR (400 MHz, DMSO-d6): δ = 9.17 (6H, brs), 7.89 (1H, s), 7.80 (1H, d, J = 8.29 Hz), 7.72 (1H, d, J = 8.29 Hz) , 4.36 (4H, brs).LC-MS: >99 % purity, RT 0.47 min, MS (m/z): 323 (M+H) ⁺

Synthesis of compound 47 6,6'-(((4-(trifluoromethyl)-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3,4-di Chlorophenylethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4-(Trifluoromethyl)-1,2-phenylene)bis(methylene) ))bis(sulfanediyl))bis(3-(3,4-dichlorophenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From 2-(3,4-dichlorophenyl)ethan-1-amine (0.239 mL, 1.60 mmol), formaldehyde (241 μL, 37% wt, aqueous solution, 3.20 mmol) and (4-(trifluoromethyl)-1,2-phenylene)bis(methylene)dicarbonamidethiocarboxylate hydrobromide (compound 46, 258 mg, 0.80 mmol), the same operation as that for synthesizing compound 9 was used for the reaction, and the residues from the two reactions were purified by NH-silica gel chromatography with n-hexane/EtOAc (1:2 to 1:10) and n-hexane/EtOAc (1:10) to obtain the title compound 47 (6.90 mg, 1.2% recovery) as white crystals.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.64-7.25 (7H, m), 7.04-6.99 (2H, m), 4.37-4.20 (12H, m), 2.89-2.69 (8H, m). LC-MS: ＞99 % purity, RT 2.47 min, MS (m/z): 751 (M+H) ⁺

Synthesis of compound 48 6,6'-(((4-(trifluoromethyl)-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(2-chlorophenylene) base)-1,2,3,4-tetrahydro-1,3,5-triazine)6,6'-(((4-(Trifluoromethyl)-1,2-phenylene)bis(methylene))bis( sulfanediyl))bis(3-(2-chlorophenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From 2-(2-chlorophenyl)ethan-1-amine (0.220 mL, 1.60 mmol), formaldehyde (241 μL, 37% wt, aqueous solution, 3.20 mmol) and (4-(trifluoromethyl)-1,2 -Phenylene) bis(methylene)dicarbamide thiocarbamate hydrobromide (compound 46, 258 mg, 0.8 mmol), reacted by the same operation as the synthesis of compound 9, using NH-silica gel The reaction residue was purified by chromatography using n-hexane/EtOAc (1:2-1:5) to obtain the title compound 48 (13.7 mg, 2.5% recovery) as a white oily substance.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.37-7.00 (11H, m), 4.28-4.21 (12H, m), 3.00-2.89 (8H, m). LC-MS: ＞99 % purity, RT 3.32 min, MS (m/z): 682 (M+H) ⁺

Synthesis of compound 49 (4-Bromo-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-bromophenyl)formamidinethioester)/(4-bromo-1 ,2-phenylene)bis(methylene) (E,E)-bis(N'-(4-bromophenyl)carbamimidothioate)

From 4-bromo-1,2-bis(bromomethyl)benzene (compound 10c, 151 mg, 0.44 mmol) and 1-(4-bromophenyl)thiourea (203 mg, 0.88 mmol), the same operation as the synthetic compound was carried out, and the title compound 49 (17.3 mg, 6.1% recovery) was obtained by NH-silica gel chromatography with n-hexane/EtOAc (1:1 to 1:4) and silica gel chromatography with n-hexane/EtOAc (4:1 to 2:1) as white crystals.

¹ HNMR (400 MHz, CD ₃ OD): δ = 7.60 (1H, brs), 7.40-7.37 (5H, m), 7.32-7.30 (1H, m), 6.78 (4H, d, J = 7.8 Hz), 4.40-4.36 (4H, m).LC-MS: >99 % purity, RT 3.42 min, MS (m/z): 644 (M+H) ⁺

Synthesis of compound 50 6,6'-(((4,5-dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(cyclohexylmethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4,5-dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(cyclohexylmethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From cyclohexylmethylamine (130 mL, 1.00 mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol) and (4,5-dichloro-1,2-phenylene)bis(methylene)bis Carboamide dithiodihydrobromide (compound 36, 162 mg, 0.50 mmol) was reacted by the same operation as the synthesis of compound 9, and the reaction residue was recrystallized from 2-propanol to obtain the title compound 50 as white crystals. (130mg, 43.5% recovery).

¹ HNMR (400 MHz, DMSO-d6): δ = 10.17 (2H, brs), 7.71 (2H, s), 4.52 (4H, brs), 4.31 (8H, brs), 2.04 (4H, d, J = 6.8 Hz), 1.64-1.61 (10H, m), 1.36 (2H, brs), 1.21-1.16 (6H, m), 0.82-0.79 (4H, m).LC-MS: 86 % purity, RT 3.02 min, MS (m/z): 597 (M+H) ⁺

Synthesis of compound 51 2-(2-(carbamimidoylthio)ethyl)benzyl carbamimidothioate dihydrobromide/2-(2-(carbamimidoylthio)ethyl)benzyl carbamimidothioate dihydrobromide

From a solution of 2-(carboxymethyl)benzoic acid (compound 51a, 9.008 g, 50 mmol) in MeOH (180 ml) and concentrated sulfuric acid (5.0 ml), the same operation as for the synthesis of compound 34b was carried out, and the residue was purified by silica gel chromatography with EtOAc/n-hexane (1:1) to obtain compound 51b (10.56 g, 100% recovery) as a colorless oil.

¹ HNMR (400 MHz, CDCl ₃ ): δ = 8.02 (1H, dd, J= 7.8, 1.5 Hz), 7.49 (1H, td, J= 7.6, 1.5 Hz), 7.37 (1H, td, J= 7.6, 1.5 Hz), 7.26 (1H, d, J= 7.3 Hz), 4.01 (2H, s), 3.87 (3H, s), 3.70 (3H, s).LC-MS: ＞99 % purity, RT 2.59 min, MS (m/z): 231 (M+Na) ⁺

From compound 51b (2.08mg, 10.0mmol) and LiAlH ₄ (759mg, 20.0mmol), perform the same operation as the synthesis of compound 2b, and purify the residue with silica gel chromatography EtOAc/n-hexane (35:65~3:2) to obtain Compound 51c was a colorless oil (971 mg, 63.8% recovery).

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.33-7.30 (2H, m), 7.24-7.22 (2H, m), 4.65 (2H, s), 3.89 (2H, t, J = 5.9 Hz), 2.96 (2H, t, J = 6.1 Hz).LC-MS: >99 % purity, RT 0.88 min, MS (m/z): 135 (M-OH) ⁺

From compound 51c (307mg, 2.02mmol) and phosphorus tribromide (0.230mL, 2.42mmol), perform the same operation as the synthesis of compound 2c, and purify the residue with silica gel chromatography with n-hexane/EtOAc (3:1) to obtain yellow color Compound 51d was an oily material (51.3 mg, 9.1% recovery).

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.37-7.24 (4H, m), 4.56 (2H, s), 3.64 (2H, t, J = 7.8 Hz), 3.30 (2H, t, J = 7.8 Hz).

Compound 51 (62.8 mg, 57% recovery) was obtained as a white oil from compound 51d (50.8 mg, 0.18 mmol) and thiourea (27.4 mg, 0.36 mmol) by the same procedure as for the synthesis of compound 2.

¹ HNMR (500 MHz, CD ₃ OD): δ = 7.43 (1H, d, J = 7.4 Hz), 7.37-7.37 (2H, m), 7.31-7.29 (1H, m), 4.56 (2H, s), 3.50 (2H, t, J = 7.7 Hz), 3.17 (2H, t, J = 7.4 Hz).LC-MS: ＞99 % purity, RT 0.35 min, MS (m/z): 269 (M+H) ⁺

Synthesis of compound 52 6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(cyclohexylmethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(cyclohexylmethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From cyclohexylmethylamine (0.130 mL, 1.00 mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol) and (4-bromo-1,2-phenyl)bis(methylene)dicarbamide di Thiodihydrobromide (compound 10, 167 mg, 0.50 mmol) was reacted by the same operation as the synthesis of compound 9, and the reaction residue was recrystallized from 2-propanol to obtain the title compound 52 (197 mg, 197 mg, 65% recovery rate).

¹ HNMR (400 MHz, DMSO-d6): δ = 7.68-7.34 (3H, m), 4.59-4.57 (4H, m), 4.32 (8H, brs), 2.15-2.03 (4H, m), 1.66-1.64 (10H, m), 1.38 (2H, s), 1.22-1.12 (6H, m), 0.84-0.79 (4H, m).LC-MS: 75 % purity, RT 2.65 min, MS (m/z): 609 (M+H) ⁺

Synthesis of compound 53 6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(2-chlorophenylethyl)-1, 2, 3,4-tetrahydro-1, 3,5-triazine)/6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3 -(2-chlorophenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From 2-(2-chlorophenyl)ethyl-1-amine (0.138 mL, 1.00 mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol) and (4-bromo-1,2-phenyl)bis (Methylene) dicarboxamide dithiodihydrobromide (compound 10, 167 mg, 0.50 mmol) was reacted with the same operation as the synthesis of compound 9, and the reaction residue was recrystallized with 2-propanol. The title compound 53 was obtained as yellow crystals (410 mg, 100% recovery).

¹ HNMR (400 MHz, DMSO-d6): δ = 7.43-7.29 (11H, m), 4.67 (4H, brs), 4.42 (8H, brs), 2.88-2.84 (8H, m).LC-MS: RT 2.42 min, MS (m/z): 693 (M+H) ⁺

Synthesis of compound 54 6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3,4-dichlorobenzyl)- 1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis (3-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From (3,4-dichlorophenyl)methanamine (0.132 mL, 1.00 mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol) and (4-bromo-1,2-phenyl)bis(sub) Methyl) dicarboxamide dithiodihydrobromide (compound 10, 167 mg, 0.50 mmol) was reacted by the same operation as the synthesis of compound 9, and the reaction residue was purified by gel filtration chromatography (MeOH). , the title compound 54 (15.0 mg, 4% recovery) was obtained as white crystals.

¹ HNMR (400 MHz, CD ₃ OD): δ = 7.61-7.50 (9H, m), 4.77-4.74 (4H, m), 4.46 (8H, brs), 3.77 (4H, d, J = 6.3 Hz).LC-MS: ＞99 % purity, RT 3.66 min, MS (m/z): 733 (M+H) ⁺

Synthesis of compound 55 Methyl 2-((carbamimidoylthio)methyl)benzoate hydrochloride

Thiourea (76.1 mg, 1.00 mmol) was added to a solution of methyl 2-(chloromethyl)benzoate (compound 55a, 185 mg, 1.00 mmol) in MeOH (3 mL) at room temperature, and the reaction mixture was refluxed for 12 h. Afterwards, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and recrystallized from ethyl acetate to obtain the title compound 55 (246 mg, 94% recovery rate) as white crystals.

¹ HNMR (400 MHz, CD ₃ OD): δ = 8.04 (1H, dd, J= 7.8, 1.5 Hz), 7.60 (1H, td, J= 7.6, 1.5 Hz), 7.52 (1H, dd, J= 6.1, 4.6 Hz), 7.49 (1H, td, J= 7.6, 1.3 Hz), 4.77 (2H, s), 3.93 (3H, s).LC-MS: ＞99 % purity, RT 0.59 min, MS (m/z): 225 (M+H) ⁺

Synthesis of compound 56 6,6'-(((4,5-Dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4,5-Dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From (3,4-dichlorophenyl)methanamine (0.132 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol) and (4,5-dichloro-1,2-phenylene ) Bis(methylene)dicarbamide dithiodihydrobromide (compound 36, 162 mg, 0.50 mmol) was reacted by the same operation as the synthesis of compound 9, and the reaction residue was reacted with 2-propanol. Crystallization gave the title compound 56 as white crystals (21.4 mg, 6% recovery).

¹ HNMR (400 MHz, CD ₃ OD): δ = 7.78 (2H, s), 7.51 (4H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz), 4.64 (4H, brs) , 4.43 (8H, brs), 3.76 (4H, brs).LC-MS: 95 % purity, RT 3.02 min, MS (m/z): 723 (M+H) ⁺

Synthesis of compound 57 (4-Bromo-1,2-phenylene)bis(methylene)(E,E)-bis(N,N'-dicyclohexylthioformamidine)dihydrobromide/(4-Bromo -1,2-phenylene)bis(methylene)(E,E)-bis(N,N'-dicyclohexylcarbamimidothioate) dihydrobromide

The same procedure as for the synthesis of compound 10 was carried out from 4-bromo-1,2-bis(bromomethyl)benzene (compound 10c, 343 mg, 1.00 mmol) and 1,3-dicyclohexylthiourea (481 mg, 2.00 mmol). After the operation, compound 57 (615 mg, 83% recovery) was obtained as white crystals.

¹ HNMR (400 MHz, DMSO-d6) δ: = 7.44-7.36 (3H, m), 4.72-4.70 (4H, m), 3.73-3.67 (4H, m), 1.90-1.76 (22H, m), 1.37 -1.24 (22H, m).LC-MS: RT 3.82 min, MS (m/z): 663 (M+H) ⁺

Synthesis of compound 58 1,2-Phenylenebis(methylene)(E,E)-bis(N,N'-dicyclohexylthioformamidine)dihydrobromide/1,2-Phenylenebis(methylene)(E ,E)-bis(N,N'-dicyclohexylcarbamimidothioate) dihydrobromide

By performing the same procedure as for the synthesis of compound 10 from 1,2-bis(bromomethyl)benzene (compound 58a, 263 mg, 1.00 mmol) and 1,3-dicyclohexylthiourea (481 mg, 2.00 mmol), a white color was obtained Crystallized compound 58 (701 mg, 94% recovery).

¹ HNMR (400 MHz, CD ₃ OD): δ = 7.48-7.40 (4H, m), 4.70 (4H, brs), 3.73 (4H, brs), 1.95-1.69 (22H, m), 1.42-1.17 (22H , m).LC-MS: >99 % purity, RT 2.69 min, MS (m/z): 583 (M+H) ⁺

Synthesis of compound 59 (E)-S-(2-(((N'-(3-chloro-4-fluorophenyl)carbamimidoyl)thio)methyl)benzyl) carbamothioate hydrobromide/(E)-S-(2-(((N'-(3-Chloro-4-fluorophenyl)carbamimidoyl)thio)methyl)benzyl) carbamothioate hydrobromide

1-(3-Chloro-4-fluorophenyl)thiourea (205 mg, 1.00 mmol) was added to 1,2-bis(bromomethyl)benzene (Compound 58a, 132 mg, 0.50 mmol) in EtOH at room temperature. (8 mL) solution, the reaction mixture was refluxed for 12 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized from 2-propanol to obtain the title compound 59 (32.5 mg, 14% recovery) as white crystals. ¹ HNMR (500 MHz, DMSO-d6): δ ⁼ 7.66-7.28 (7H, m), 4.68 (2H, s), 4.19 (2H, s). LC-MS: >99 % purity, RT 2.45 min, MS (m/z): 384 (M+H) ⁺

Synthesis of compound 60 6,6'-(((4-Bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(2-cyclohexylethyl)-1,2,3,4-tetrahydro-1,3,5-triazine) /6,6'-(((4-Bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(2-cyclohexylethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From 2-cyclohexylethan-1-amine (0.146 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol), and (4-bromo-1,2-phenyl)bis(methylene) ) Dicarboxamide dithiodihydrobromide (compound 10, 167 mg, 0.50 mmol) was reacted by the same operation as the synthesis of compound 9, and the reaction residue was purified by gel filtration chromatography (CDCl ₃ ), The title compound 60 was obtained as white crystals (14.7 mg, 5% recovery).

¹ H-NMR (CDCl ₃ ) δ: = 7.63 (1H, s), 7.33 (2H, brs), 4.73 (4H, d, J = 4.4 Hz), 4.40 (8H, s), 2.47 (4H, q, J = 6.3 Hz), 1.71-1.64 (10H, m), 1.40-1.12 (12H, m), 0.93-0.85 (4H, m). LC-MS: 95 % purity, RT 2.19 min, MS (m/z ): 637 (M+H) ⁺

Synthesis of Compound 61 6,6'-(((4,5-dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(2-cyclohexylethyl) -1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4,5-Dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl ))bis(3-(2-cyclohexylethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From 2-cyclohexylethan-1-amine (0.146 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol), and (4,5-dichloro-1,2-phenylene)bis (Methylene) dicarboxamide dithiodihydrobromide (compound 36, 162 mg, 0.50 mmol) was reacted by the same operation as the synthesis of compound 9, and the reaction residue was recrystallized from 2-propanol. The title compound 61 was obtained as white crystals (171 mg, 55% recovery).

¹ HNMR (400 MHz, CD ₃ OD): δ = 7.69 (2H, s), 4.59 (4H, s), 4.43 (8H, s), 2.50 (4H,t, J = 7.6 Hz), 1.70-1.68 (10H, m), 1.39-1.24 (12H, m), 0.94-0.91 (4H, m).LC-MS: 72 % purity, RT 3.00 min, MS (m/z): 627 (M+H) ⁺

Synthesis of compound 62 2-(2-(Methylamino)-2-oxoethyl)benzyl carbamimidothioate hydrobromide/2-(2-(Methylamino)-2-oxoethyl)benzyl carbamimidothioate hydrobromide

40% MeNH ₂ (1553 mg, 50.0 mmol) was added to a THF solution (15 ml) of 3-isochromone (compound 62a, 741 mg, 5.00 mmol), and stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain compound 62b (832 mg, 93% recovery rate) as pale yellow crystals.

¹ HNMR (400 MHz, CDCl ₃ ): = δ 7.41-7.38 (1H, m), 7.31-7.28 (2H, m), 7.25-7.24 (1H, m), 5.97 (1H, brs), 4.68 (2H, d, J = 5.9 Hz), 3.77 (1H, t, J = 5.6 Hz), 3.63 (2H, s), 2.77 (3H, d, J = 4.9 Hz).LC-MS: ＞99 % purity, RT 0.68 min, MS (m/z): 162 (M-OH) ⁺

From compound 62b (358 mg, 2.00 mmol) and phosphorus tribromide (0.228 mL, 2.40 mmol), the same operation as the synthesis of compound 2c was performed to obtain compound 62c (428 mg, 88% recovery rate) as an orange oily substance.

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.49-7.31 (4H, m), 4.55-4.52 (2H, m), 3.72 (2H, s),2.78 (3H, d, J = 4.9 Hz).LC-MS: ＞99 % purity, RT 2.09 min, MS (m/z): 243 (M+H) ⁺

The title compound 62 (434 mg, 77% recovery) was obtained as white crystals by performing the same operation as for the synthesis of compound 2 from compound 62c (428 mg, 1.77 mmol) and thiourea (135 mg, 1.77 mmol).

¹ HNMR (400 MHz, CD ₃ OD): δ = 7.50-7.49 (1H, m), 7.32-7.26 (3H, m), 4.57 (2H, s), 3.68 (2H, s), 2.73 (3H, s ).LC-MS: >99 % purity, RT 0.47 min, MS (m/z): 238 (M+H) ⁺

Synthesis of compound 63 (4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(2,4-difluorophenyl)carbamimidothioate) dihydrobromide/(4,5-Dichloro-1,2-phenylene)bis(methylene) (E,E)-bis(N'-(2,4-difluorophenyl)carbamimidothioate) dihydrobromide

The same operation as for the synthesis of compound 2 was carried out from compound 36b (166 mg, 0.50 mmol) and 1-(2,4-difluorophenyl)thiourea (188 mg, 1.00 mmol), and the reaction residue was purified by silica gel chromatography with n-hexane/EtOAc (3:1-45:55) to obtain the title compound 63 (3.0 mg, 1% recovery) as white crystals.

¹ HNMR (400 MHz, CDCl ₃ ): δ = 6.91-6.88 (8H, m), 4.55 (4H, s), 4.44 (4H, s). LC-MS: >99 % purity, RT 4.11 min, MS ( m/z): 548 (M+H) ⁺

Synthesis of compound 64 2-(2-oxo-2-(phenethylamino)ethyl)benzyl carbamimidothioate hydrobromide/2-(2-oxo-2-(phenethylamino)ethyl)benzyl carbamimidothioate hydrobromide

The same operation as for the synthesis of compound 62b was carried out from 3-isochromone (compound 62a, 445 mg, 3.00 mmol) and 2-phenylethyl-1-amine (3.780 mL, 30.0 mmol), and silica gel chromatography was carried out with n-hexane/EtOAc ( 3:2～3:7) The reaction residue was purified to obtain light yellow crystal compound 64a (734 mg, 91% recovery rate).

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.37-7.21 (7H, m), 7.03-7.01 (2H, m), 6.05 (1H, brs), 4.60 (2H, d, J = 4.9 Hz), 3.56 (2H, s), 3.47 (2H, q, J = 6.5 Hz), 3.32 (1H, t, J = 5.4 Hz), 2.73 (2H, t, J = 6.6 Hz). LC-MS: >99 % purity , RT 2.65 min, MS (m/z): 270 (M+H) ⁺

Compound 64b (565 mg, 63% recovery) was obtained as a light yellow oily substance by performing the same operation as the synthesis of compound 2c from compound 64a (734 mg, 2.72 mmol) and phosphorus tribromide (0.310 mL, 3.27 mmol).

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.48-7.12 (7H, m), 7.05-7.03 (2H, m), 4.45-4.41 (2H, m), 3.67 (2H, s), 3.51-3.46 ( 2H, m), 2.76-2.73 (2H, m).LC-MS: >99 % purity, RT 3.44 min, MS (m/z): 333 (M+H) ⁺

The same procedure as for the synthesis of compound 2 was carried out from compound 64b (523 mg, 1.57 mmol) and thiourea (120 mg, 1.57 mmol), and the title compound 64 (92.8 mg, 14% recovery) was obtained as white crystals by recrystallizing the residue from EtOH. Rate).

¹ HNMR (400 MHz, DMSO-d6): δ = 8.98 (3H, brs), 8.30 (1H, brs), 7.43-7.17 (9H, m), 4.52 (2H, s), 3.56 (2H, s), 3.28 (2H, t, J= 6.6 Hz), 2.72 (2H, t, J = 7.3 Hz). LC-MS: >99 % purity, RT 1.72 min, MS (m/z): 328 (M+H) ⁺

Synthesis of Compound 65 2-(2-((Cyclohexylmethyl)amino)-2-oxoethyl)benzylformamidinethiohydrobromide/2-(2-((Cyclohexylmethyl)amino)-2-oxoethyl) benzyl carbamimidothioate hydrobromide

The same operation as that for compound 62b was carried out from 3-isochromone (compound 62a, 445 mg, 3.00 mmol) and cyclohexylmethylamine (1.952 mL, 15.0 mmol), and the reaction residue was purified by silica gel chromatography with n-hexane/EtOAc (55:45-3:7) to obtain compound 65a (542 mg, 69% recovery) as white crystals.

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.41 (1H, brs), 7.31-7.23 (3H, m), 5.92 (1H, brs), 4.68 (2H, d, J = 5.9 Hz), 3.81 (1H, brs), 3.63 (2H, s), 3.05 (2H, t, J = 6.3 Hz), 1.70-1.61 (5H, m), 1.41 (1H, brs), 1.23-1.10 (3H, m), 0.90-0.81 (2H, m). LC-MS: ＞99 % purity, RT 2.96 min, MS (m/z): 262 (M+H) ⁺

Compound 65b (367 mg, 55% recovery) was obtained as yellow crystals by performing the same procedure as for the synthesis of compound 2c from compound 65a (534 mg, 2.04 mmol) and phosphorus tribromide (0.233 mL, 2.45 mmol).

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.40-7.26 (4H, m), 5.48 (1H, brs), 4.66-4.56 (2H, m), 3.72 (2H, s), 3.07-3.03 (2H, m), 1.69-1.58 (5H, m), 1.39 (1H, brs), 1.19-1.11(3H, m), 0.87-0.82 (2H, m).LC-MS: >99 % purity, RT 3.66 min, MS (m/z): 326 (M+H) ⁺

Compound 65b (367 mg, 1.13 mmol) and thiourea (86.0 mg, 1.13 mmol) were subjected to the same operation as that for compound 2 to obtain the title compound 65 (224 mg, 49% recovery) as white crystals.

¹ HNMR (400 MHz, DMSO-d6): δ = 9.09 (4H, brs), 8.25 (1H, brs), 7.42 (1H, d, J = 5.9 Hz), 7.28 (3H, s), 4.56 (2H, s), 3.59 (2H, s), 2.90 (2H, t, J= 6.1 Hz), 1.66(5H, d, J = 11.2 Hz), 1.38 (1H, s), 1.16-1.11 (3H, m), 0.88-0.82 (2H, m).LC-MS: ＞99 % purity, RT 1.87 min, MS (m/z): 320 (M+H) ⁺

Synthesis of compound 66 2-(2-((2-chlorophenethyl)amino)-2-oxoethyl)benzylformamidinethiohydrobromide/2-(2-((2-chlorophenethyl)amino)- 2-oxoethyl)benzyl carbamimidothioate hydrobromide

Compound 62b was synthesized from 3-isochromone (compound 62a, 445 mg, 3.00 mmol) and 2-(2-chlorophenyl)eth-1-amine (0.826 mL, 6.0 mmol) by silica gel chromatography. The reaction residue was purified with n-hexane/EtOAc (65:35～3:7) to obtain white crystal compound 66a (615 mg, 67% recovery rate).

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.40-7.29 (4H, m), 7.23-7.09 (3H, m), 6.99 (1H, dd,J = 7.6, 1.7 Hz), 6.03 (1H, brs) , 4.63 (2H, d, J = 6.3 Hz), 3.59 (2H, s), 3.53-3.48 (3H, m), 2.90 (2H, t, J= 6.8 Hz). LC-MS: >99 % purity, RT 2.83 min, MS (m/z): 304 (M+H) ⁺

Compound 66b (470 mg, 63% recovery) was obtained as a white oily substance by performing the same operation as that for synthesizing compound 2c from compound 66a (613 mg, 2.02 mmol) and phosphorus tribromide (0.230 mL, 2.42 mmol).

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.48-6.97 (8H, m), 5.50 (1H, brs), 4.48 (2H, s), 3.68 (2H, s), 3.54-3.49 (2H, m), 2.92-2.89 (2H, m).LC-MS: ＞99 % purity, RT 3.64 min, MS (m/z): 367 (M+H) ⁺

Compound 66b (470 mg, 1.28 mmol) and thiourea (97.6 mg, 1.28 mmol) were subjected to the same operation as for the synthesis of compound 2, and the residue was recrystallized from EtOH to give the title compound 66 (170 mg, 30% recovery) as white crystals.

¹ HNMR (400 MHz, DMSO-d6): δ = 9.02 (3H, brs), 8.38 (1H, t, J = 5.6 Hz), 7.44-7.41 (2H, m), 7.31-7.26 (6H, m), 4.52 (2H, s), 3.56 (2H, s), 3.32-3.29 (2H, m), 2.85 (2H, t, J = 7.3 Hz).LC-MS: ＞99 % purity, RT 1.95 min, MS (m/z): 362 (M+H) ⁺

Synthesis of compound 67 2-(2-((4-cyanobenzyl)amino)-2-oxoethyl)benzylformamidinethiohydrobromide/2-(2-((4-Cyanobenzyl)amino)- 2-oxoethyl)benzyl carbamimidothioate hydrobromide

4-(Aminomethyl)benzonitrile hydrochloride (405 mg, 2.40 mmol) and triethylamine (418 μL, 3.00 mmol) were added to a THF solution (8 ml) of 3-isochromone (compound 62a, 296 mg, 2.00 mmol) and stirred at 50°C for 24 hours. The reaction solution was concentrated under reduced pressure, and water was added and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The reaction residue was purified by silica gel chromatography with n-hexane/EtOAc (3:2-0:1) to obtain white crystals of compound 67a (438 mg, 78% recovery).

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.56 (2H, d, J= 8.3 Hz), 7.39-7.23 (6H, m), 6.61 (1H, brs), 4.72 (2H, d, J = 5.4 Hz ), 4.44 (2H, d, J = 5.9 Hz), 3.73 (2H, s), 3.07 (1H, t, J = 5.4 Hz). LC-MS: >99 % purity, RT 2.03 min, MS (m/ z): 281 (M+H) ⁺

Compound 67b (189 mg, 35% recovery) was obtained from compound 67a (438 mg, 1.56 mmol) and phosphorus tribromide (0.178 mL, 1.88 mmol) by the same operation as that for compound 2c.

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.59 (2H, d, J = 8.3 Hz), 7.41 (1H, d, J = 6.8 Hz), 7.31-7.29 (5H, m), 5.90 (1H, brs), 4.56 (2H, d, J = 1.5 Hz), 4.47 (2H, d, J = 6.3Hz), 3.79 (2H, s).LC-MS: ＞99 % purity, RT 3.06 min, MS (m/z): 344 (M+H) ⁺

By performing the same procedure as for the synthesis of compound 2 from compound 67b (189 mg, 0.55 mmol) and thiourea (41.9 mg, 0.55 mmol), the title compound 67 (88 mg, 38% recovery) was obtained as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.03 (3H, brs), 8.81 (1H, s), 7.80 (2H, d, J = 8.5 Hz), 7.44-7.28 (6H, m), 4.55 (2H, s), 4.37 (2H, d, J = 5.7 Hz), 3.69 (2H, s).LC-MS: ＞99 % purity, RT 0.74 min, MS (m/z): 339 (M+H) ⁺

Synthesis of Compound 68 2-(2-((4-Chlorophenethyl)amino)-2-oxoethyl)benzylformamidinethiohydrobromide/2-(2-((4-Chlorophenethyl)amino)- 2-oxoethyl)benzyl carbamimidothioate hydrobromide

The same operation as that for compound 62b was carried out from 3-isochromone (compound 62a, 445 mg, 3.00 mmol) and 2-(4-chlorophenyl)ethan-1-amine (0.504 mL, 3.60 mmol). The reaction residue was purified by silica gel chromatography with n-hexane/EtOAc (2:3-1:9) to obtain compound 68a (751 mg, 82% recovery) as white crystals.

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.39-7.19 (6H, m), 6.95 (2H, d, J = 7.8 Hz), 5.98 (1H, brs), 4.63 (2H, d, J = 5.9 Hz), 3.58 (2H, s), 3.44 (2H, q, J = 6.3 Hz), 3.26(1H, t, J = 5.9 Hz), 2.71 (2H, t, J = 6.8 Hz).LC-MS: ＞99 % purity, RT 2.92 min, MS (m/z): 304 (M+H) ⁺

Compound 68b (445 mg, 49% recovery) was obtained as a white oily substance by performing the same operation as for synthesizing compound 2 from compound 68a (751 mg, 2.47 mmol) and phosphorus tribromide (0.282 mL, 2.97 mmol).

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.48-7.09 (6H, m), 6.97 (2H, d, J = 8.8 Hz), 5.40 (2H, brs), 4.47 (2H, s), 3.66 (2H , s), 3.46 (2H, q, J = 6.5 Hz), 2.72 (2H, t, J =6.8 Hz). LC-MS: >99 % purity, RT 3.68 min, MS (m/z): 367 ( M+H) ⁺

The title compound 68 (279 mg, 52% recovery) was obtained as white crystals by the same operation as that for the synthesis of compound 2 from compound 68b (445 mg, 1.21 mmol) and thiourea (92.3 mg, 1.21 mmol).

¹ HNMR (500 MHz, CD ₃ OD): δ = 7.49 (1H, t, J = 4.5 Hz), 7.30 (2H, t, J = 4.0 Hz), 7.23-7.20 (3H, m), 7.13 (2H, d, J = 8.5 Hz), 4.53 (2H, s), 3.63 (2H, s), 3.43 (2H, t, J= 6.8 Hz), 2.78 (2H, t, J = 7.1 Hz).LC-MS: ＞99 % purity, RT 2.11 min, MS (m/z): 362 (M+H) ⁺

Synthesis of compound 69 2-(2-((2-Cyclohexylethyl)amino)-2-oxoethyl)benzylformamidinethiohydrobromide/2-(2-((2-Cyclohexylethyl)amino)- 2-oxoethyl)benzyl carbamimidothioate hydrobromide

The same operation as that for compound 62b was carried out from 3-isochromone (compound 62a, 296 mg, 2.00 mmol) and 2-ethylcyclohexane-1-amine (0.322 mL, 2.20 mmol). The reaction residue was purified by silica gel chromatography with n-hexane/EtOAc (3:2-35:65) to obtain compound 69a (520 mg, 94% recovery) as white crystals.

¹ HNMR (400 MHz, CDCl ₃ ): = δ 7.41-7.39 (1H, m), 7.29 (2H, dd, J = 5.6, 3.7 Hz), 7.23 (1H, dd, J = 5.1, 3.7 Hz), 5.85 (1H, brs), 4.68 (2H, d, J= 5.9 Hz), 3.87 (1H, t, J = 5.9 Hz), 3.62 (2H, s), 3.25-3.20 (2H, m), 1.66-1.64 ( 5H, m), 1.34 (2H, q, J = 7.3 Hz), 1.21-1.09 (4H, m), 0.89-0.83 (2H, m).LC-MS: >99 % purity, RT 3.26 min, MS ( m/z): 276 (M+H) ⁺

Compound 69b (320 mg, 50% recovery) was obtained from compound 69a (520 mg, 1.89 mmol) and phosphorus tribromide (0.215 mL, 2.57 mmol) by the same operation as that for synthesizing compound 2c.

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.41-7.24 (4H, m), 5.36 (1H, brs), 4.65-4.56 (2H, m), 3.70 (2H, s), 3.26-3.20 (2H, m), 1.69-1.50 (5H, m), 1.32-1.29 (2H, m), 1.21-1.09 (4H, m), 0.89-0.81 (2H, m). LC-MS: ＞99 % purity, RT 4.05 min, MS (m/z): 340 (M+H) ⁺

The title compound 69 (110 mg, 28% recovery) was obtained as white crystals by the same operation as that for the synthesis of compound 2 from compound 69b (320 mg, 0.94 mmol) and thiourea (71.9 mg, 0.94 mmol).

¹ HNMR (500 MHz, DMSO-d6): δ = 8.97 (3H, brs), 8.13 (1H, t, J = 5.7 Hz), 7.39 (1H, d, J= 7.4 Hz), 7.25-7.21 (3H, m), 4.51 (2H, s), 3.52 (2H, s), 3.05-3.02 (2H, m), 1.62-1.55 (5H, m), 1.32-1.11 (6H, m), 0.84-0.80 (2H, m).LC-MS: ＞99 % purity, RT 2.49 min, MS (m/z): 334 (M+H) ⁺

Synthesis of compound 70 2-(2-((3,4-Dichlorophenethyl)amino)-2-oxoethyl)benzyl carbamimidothioate hydrobromide/2-(2-((3,4-Dichlorophenethyl)amino)-2-oxoethyl)benzyl carbamimidothioate hydrobromide

The same operation as that for compound 62b was performed from 3-isochromone (compound 62a, 296 mg, 2.00 mmol) and 2-(3,4-dichlorophenyl)ethan-1-amine (0.329 mL, 2.20 mmol). The reaction residue was purified by silica gel chromatography with n-hexane/EtOAc (1:1-1:4) to obtain compound 70a (392 mg, 58% recovery) as white crystals.

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.39-7.38 (1H, m), 7.32-7.28 (3H, m), 7.21-7.16 (2H, m), 6.86 (1H, dd, J = 8.3, 2.0 Hz), 6.00 (1H, brs), 4.65 (2H, d, J= 5.9 Hz), 3.59 (2H, s), 3.44 (2H, q, J= 6.5 Hz), 3.28 (1H, t, J = 5.6 Hz), 2.70 (2H, t, J =6.6 Hz). LC-MS: >99 % purity, RT 3.26 min, MS (m/z): 339 (M+H) ⁺

Compound 70b (386 mg, 83% recovery) was obtained from compound 70a (392 mg, 1.16 mmol) and phosphorus tribromide (0.132 mL, 1.39 mmol) in the same manner as compound 2c. ¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.49-7.12 (6H, m), 6.89 (1H, dd, J = 8.0, 2.2 Hz), 5.42 (1H, brs), 5.32 (2H, s), 3.67 (2H, s), 3.48-3.43 (2H, m), 2.73-2.70 (2H, m). LC-MS: ＞99 % purity, RT 4.01 min, MS (m/z): 402 (M+H) ⁺

The title compound 70 (248 mg, 54% recovery) was obtained as white crystals by the same operation as that for the synthesis of compound 2 from compound 70b (386 mg, 0.96 mmol) and thiourea (73.2 mg, 0.96 mmol).

¹ HNMR (500 MHz, CD ₃ OD): δ = 7.49 (1H, t, J = 4.5 Hz), 7.37-7.35 (2H, m), 7.30-7.29 (2H, m), 7.18 (1H, t, J = 4.5 Hz), 7.08 (1H, dd, J = 8.2, 2.0 Hz), 4.52 (2H, s), 3.62 (2H, s), 3.44 (2H, t, J = 6.8 Hz), 2.78 (2H, t, J = 6.8 Hz). LC-MS: ＞99 % purity, RT 2.55 min, MS (m/z): 398 (M+H) ⁺

Synthesis of Compound 71 2-(2-((Cyclopropylmethyl)amino)-2-oxoethyl)benzylformamidinethiohydrobromide/2-(2-((Cyclopropylmethyl)amino)-2-oxoethyl )benzyl carbamimidothioate hydrobromide

The same operation as that for synthesizing compound 62b was performed from 3-isochromone (compound 62a, 296 mg, 2.00 mmol) and cyclopropylmethylamine (0.189 mL, 2.20 mmol), and the reaction residue was purified by silica gel chromatography with n-hexane/EtOAc (1:1-1:3) to obtain compound 71a (356 mg, 81% recovery) as white crystals.

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.41 (1H, t, J= 4.4 Hz), 7.31-7.27 (3H, m), 4.68 (2H, d, J = 6.3 Hz), 3.98 (1H, t , J= 5.9 Hz), 3.65 (2H, s), 3.08 (2H, dd, J= 7.3, 5.4 Hz), 0.92 (1H, s), 0.50-0.48 (2H, m), 0.17 (2H, q, J = 5.2 Hz).LC-MS: >99 % purity, RT 1.77 min, MS (m/z): 220 (M+H) ⁺

Compound 71b (111 mg, 24% recovery) was obtained as a white oily substance by performing the same procedure as for the synthesis of compound 2c from compound 71a (356 mg, 1.62 mmol) and phosphorus tribromide (0.185 mL, 1.95 mmol). .

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.49-7.30 (4H, m), 4.59-4.58 (2H, m), 3.72 (2H, s),3.11-3.08 (2H, m), 0.88 (1H, brs), 0.69-0.13 (4H, m).LC-MS: ＞99 % purity, RT 2.90 min, MS (m/z): 284 (M+H) ⁺

The title compound 71 (57 mg, 41% recovery) was obtained as white crystals by the same operation as that for the synthesis of compound 2 from compound 71b (111 mg, 0.39 mmol) and thiourea (30.0 mg, 0.39 mmol).

¹ HNMR (500 MHz, DMSO-d6): δ = 8.94 (3H, brs), 8.30 (1H, t, J = 5.4 Hz), 7.42 (1H, d, J= 5.7 Hz), 7.29-7.25 (3H, m), 4.53 (2H, s), 3.59 (2H, s), 2.95 (2H, t, J = 6.0 Hz), 0.91-0.88 (1H, m), 0.43-0.40 (2H, m), 0.16-0.13 (2H, m).LC-MS: ＞99 % purity, RT 0.68 min, MS (m/z): 278 (M+H) ⁺

Synthesis of compound 72 2-(2-Oxo-2-((4-phenylbutyl)amino)ethyl)benzylformamidinethiohydrobromide/2-(2-Oxo-2-((4-phenylbutyl )amino)ethyl)benzyl carbamimidothioate hydrobromide

The same procedure as for the synthesis of compound 62b was carried out from 3-isochromone (compound 62a, 246 mg, 2.00 mmol) and 4-phenylbutan-1-amine (349 mL, 2.20 mmol), followed by silica gel chromatography with n-hexane/EtOAc (55 :45～3:7) The reaction residue was purified to obtain white crystal compound 72a (509 mg, 85% recovery rate).

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.40 (1H, dd, J= 5.6, 3.7 Hz), 7.30-7.19 (6H, m), 7.12 (2H, d, J = 6.8 Hz), 5.88 (1H, brs), 4.67 (2H, d, J = 5.9 Hz), 3.71 (1H, t, J = 5.9 Hz), 3.61 (2H, s), 3.23 (2H, q, J = 6.5 Hz), 2.58 (2H, t, J = 7.6 Hz), 1.60-1.47 (4H, m). LC-MS: ＞99 % purity, RT 3.18 min, MS (m/z): 298 (M+H) ⁺

Compound 72b (251 mg, 41% recovery) was obtained as a white oily substance by performing the same procedure as for the synthesis of compound 2c from compound 72a (509 mg, 1.71 mmol) and phosphorus tribromide (0.195 mL, 2.05 mmol). .

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.49-7.11 (9H, m), 4.54-4.52 (2H, m), 3.69 (2H, s), 3.26-3.21 (2H, m), 2.67-2.63 ( 2H, m), 1.85-1.28 (4H, m).LC-MS: >99 % purity, RT 3.84 min, MS (m/z): 362 (M+H) ⁺

By performing the same procedure as for the synthesis of compound 2 from compound 72b (251 mg, 0.70 mmol) and thiourea (53.0 mg, 0.70 mmol), the residue was recrystallized from EtOH to give the title compound 72 as white crystals (198 mg, 65% Recovery rate).

¹ HNMR (500 MHz, DMSO-d6): δ = 9.04 (4H, brs), 8.21 (1H, t, J = 5.4 Hz), 7.42 (1H, t, J= 3.7 Hz), 7.28-7.25 (5H, m), 7.17-7.15 (3H, m), 4.56 (2H, s), 3.56 (2H, s), 3.08 (2H, q, J = 6.4 Hz), 2.57 (2H, d, J = 7.9 Hz), 1.58-1.52 (2H, m), 1.45-1.39 (2H, m).LC-MS: >99 % purity, RT 2.27 min, MS (m/z): 356 (M+H) ⁺

Synthesis of Compound 73 6,6'-(((4,5-Dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(cyclopropylmethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4,5-Dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(cyclopropylmethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From cyclopropylmethylamine (0.086 mL, 1.00 mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol), and (4,5-dichloro-1,2-phenylene)bis(methylene) Dicarboxamide dithiodihydrobromide (compound 36, 162 mg, 0.50 mmol) was reacted with the same operation as the synthesis of compound 9, and the reaction residue was recrystallized with EtOH to obtain the title compound 73 (115 mg, 115 mg, 45% recovery rate).

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.60 (2H, s), 4.76 (4H, s), 4.52 (8H, s), 2.35 (4H,d, J = 5.9 Hz), 0.90 (2H, s), 0.58 (4H, q, J = 5.2 Hz), 0.18 (4H, q, J = 5.2 Hz).LC-MS: ＞99 % purity, RT 1.64 min, MS (m/z): 514 (M+H) ⁺

Synthesis of compound 74 5-Bromo-2-((cyclohexylmethyl)carbamoyl)benzyl carbamimidothioate hydrobromide

Cyclohexylmethylamine (623 mg, 5.50 mmol) was added to a THF solution (15 ml) of 5-bromoisobenzofuran-1(3H)-one (compound 74a, 1.07 g, 5.00 mmol) and stirred at room temperature for 8 hours. After the reaction solution was concentrated by decompression, water was added and extracted with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. The concentrated residue was decompressed and purified by silica gel chromatography with n-hexane/EtOAc (4:1 to 1:1) to obtain white crystals of compound 74b (210 mg, 13% recovery).

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.57 (1H, d, J= 2.0 Hz), 7.50 (1H, dd, J = 8.3, 2.0Hz), 7.39 (1H, d, J = 7.8 Hz), 6.28 (1H, brs), 4.57 (2H, d, J= 6.8 Hz), 4.29 (1H, t, J = 6.8 Hz), 3.30 (2H, t, J = 6.6 Hz), 1.75-1.70 (5H, m ), 1.59-1.58 (1H, m), 1.28-1.16 (3H, m), 1.04-1.01 (2H, m).LC-MS: >99 % purity, RT 3.28 min, MS (m/z): 327 (M+H) ⁺

At 0°C, CBr ₄ (79.6 mg, 0.24 mmol) was added to a CH ₂ Cl ₂ solution (4 ml) of compound 74b (65.2 mg, 0.20 mmol), and then a CH ₂ Cl ₂ solution (5 ml) of PPh ₃ (78.7 mg, 0.30 mmol) was added. After stirring the reaction solution at room temperature for 1 hour, thiourea (15.2 mg, 0.20 mmol) was added, and the mixture was stirred at 40°C for 12 hours. The crystals precipitated during the reaction were filtered to obtain the title compound 74 (61 mg, 66% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.38 (1H, brs), 8.90 (2H, brs), 8.79 (1H, t, J = 5.7 Hz), 7.81 (1H, d, J = 1.7 Hz) , 7.66 (1H, dd, J = 8.2, 2.0 Hz), 7.45 (1H, d, J = 8.5 Hz), 4.51 (2H, s), 3.09 (2H, t, J = 6.2 Hz), 1.71 (4H, t, J = 14.5 Hz), 1.63 (1H, d, J = 8.5 Hz), 1.55-1.53 (1H, m), 1.21-1.15 (3H, m), 0.93 (2H, q, J= 10.8 Hz). LC-MS: >99 % purity, RT 2.33 min, MS (m/z): 386 (M+H) ⁺

Synthesis of Compound 75 6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(cyclopropylmethyl)-1,2 ,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4-Bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3- (cyclopropylmethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

Cyclopropylmethylamine (0.086 mL, 1.00 mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol) and (4-bromo-1,2-phenyl)bis(methylene)dicarboamide dithiodihydrobromide (compound 10, 167 mg, 0.50 mmol) were reacted in the same manner as compound 9, and the reaction residue was recrystallized with EtOH and Et ₂ O (1:2) to give the title compound 75 (115 mg, 44% recovery) as white crystals.

¹ HNMR (500 MHz, CDCl ₃ ): δ = 7.48-7.22 (3H, m), 4.64 (4H, brs), 4.54 (8H, brs), 2.36-2.34 (4H, m), 0.91 (2H, brs), 0.58-0.55 (4H, m), 0.19-0.16 (4H, m). LC-MS: RT 1.70 min, MS (m/z): 525 (M+H) ⁺

Synthesis of Compound 76 5-Bromo-2-((4-cyanobenzyl)carbamoyl)benzylcarbamidioate hydrobromide

4-(Aminomethyl)benzonitrile hydrochloride (556 mg, 3.30 mmol) and triethylamine (418 μL, 3.00 mmol) were added to a THF solution (15 ml) of 5-bromoisobenzofuran-1(3H)-one (compound 74a, 639 mg, 3.00 mmol), and the mixture was stirred at 50°C for 24 hours. After the reaction solution was concentrated by reducing pressure, water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and the concentrated residue was purified by silica gel chromatography with n-hexane/EtOAc (65:35-3:7) to obtain yellow crystals of compound 76a (142 mg, 14% recovery rate).

¹ HNMR (500 MHz, CDCl ₃ ): δ = 7.67-7.65 (2H), 7.58 (1H, d, J = 1.7 Hz), 7.52 (1H,dd, J = 8.2, 2.0 Hz), 7.49-7.46 (3H, m), 6.99 (1H, brs), 4.69 (2H, d, J = 5.7 Hz), 4.60 (2H, d, J = 6.8 Hz), 3.83 (1H, t, J = 6.8 Hz).LC-MS: ＞99 % purity, RT 2.61 min, MS (m/z): 347 (M+H) ⁺

The same procedure as for the synthesis of compound 74 was performed from compound 76a (123 mg, 0.36 mmol), CBr ₄ (142 mg, 0.43 mmol), PPh ₃ (140 mg, 0.54 mmol), and thiourea (27.2 mg, 0.36 mmol), from The residue was recrystallized from EtOH to give the title compound 76 as gray crystals (26.5 mg, 15% recovery).

¹ HNMR (500 MHz, DMSO-d6): δ = 9.43 (1H, t, J= 6.0 Hz), 9.32 (1H, brs), 8.95 (2H, brs), 7.78-7.76 (3H, m), 7.65 ( 1H, dd, J = 8.5, 2.3 Hz), 7.53-7.48 (3H, m), 4.55 (4H, brs).LC-MS: >99 % purity, RT 1.79 min, MS (m/z): 405 ( M+H) ⁺

Synthesis of compound 77 5-Cyano-2-(methylcarbamoyl)benzyl carbamimidothioate hydrobromide

Compound 77b (562 mg, 59% recovery) was obtained from 5-cyano-isobenzofuran-1(3H)-one (Compound 77a, 796 mg, 5.00 mmol) and 40% MeNH ₂ (4.309 mL, 50.0 mmol) by the same operation as that for compound 74b.

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.73 (1H, d, J= 1.5 Hz), 7.68-7.62 (2H, m), 6.40 (1H, brs), 4.66 (2H, d, J = 6.8 Hz ), 3.91 (1H, t, J = 6.8 Hz), 3.05 (3H, d, J = 4.9 Hz). LC-MS: >99 % purity, RT 0.51 min, MS (m/z): 191 (M+ H) ⁺

The same operation as for compound 74 was carried out from compound 77b (190 mg, 1.00 mmol), CBr ₄ (398 mg, 1.20 mmol), PPh ₃ (393 mg, 1.50 mmol) and thiourea (76.1 mg, 1.00 mmol), and the residue was recrystallized from EtOH to give the title compound 77 (29.5 mg, 9% recovery) as light green crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.04 (3H, s), 8.83 (1H, d, J = 5.1 Hz), 8.04 (1H,s), 7.94 (1H, d, J = 7.9 Hz), 7.67 (1H, d, J= 7.9 Hz), 4.55 (2H, s), 2.80 (3H, d, J= 4.5 Hz).LC-MS: ＞99 % purity, RT 0.41 min, MS (m/z): 249 (M+H) ⁺

Synthesis of Compound 78 5-Bromo-2-((4-chlorophenethyl)carbamoyl)benzylcarbamoylthioate hydrobromide

By starting from 5-bromoisobenzofuran-1(3H)-one (compound 74a, 1065 mg, 5.00 mmol) and 2-(4-chlorophenyl)eth-1-amine (0.840 mL, 6.00 mmol), The same procedure was used to synthesize compound 74b, and the reaction residue was purified using silica gel chromatography with n-hexane/EtOAc (7:3-3:7) to obtain white crystalline compound 78a (919 mg, 50% recovery rate).

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.56 (1H, d, J= 2.0 Hz), 7.48-7.47 (1H, m), 7.31-7.18 (5H, m), 6.28 (1H, brs), 4.52 (2H, d, J = 6.8 Hz), 4.03 (1H, t, J = 7.1 Hz), 3.71 (2H, q, J = 6.5 Hz), 2.93 (2H, t, J = 6.8 Hz).LC-MS : ＞99 % purity, RT 3.30 min, MS (m/z): 370 (M+H) ⁺

The same operation as for compound 74 was carried out from compound 78a (369 mg, 1.00 mmol), CBr ₄ (398 mg, 1.20 mmol), PPh ₃ (393 mg, 1.50 mmol) and thiourea (76.1 mg, 1.00 mmol), and the residue was recrystallized from EtOH to give the title compound 78 (244 mg, 48% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.10 (3H, brs), 8.85 (1H, t, J = 5.7 Hz), 7.80 (1H, d, J= 2.3 Hz), 7.65 (1H, dd, J = 8.2, 2.0 Hz), 7.37-7.35 (3H, m), 7.28 (2H, d, J = 8.5 Hz), 4.45 (2H, s), 3.48 (2H, q, J = 6.6 Hz), 2.85 (2H, t, J= 7.1 Hz).LC-MS: ＞99 % purity, RT 2.29 min, MS (m/z): 428 (M+H) ⁺

Synthesis of compound 79 2-(2-(Methylamino)-2-oxoethyl)benzyl (E)-N'-(4-bromophenyl)carbamimidothioate hydrobromide

By carrying out the same procedure as for the synthesis of compound 2 from compound 62c (102 mg, 0.42 mmol) and 1-(4-bromophenyl)thiourea (97.5 mg, 0.42 mmol), the title compound 79 (74.2 mg, 74.2 mg, as white crystals) was obtained. 37% recovery rate).

¹ HNMR (500 MHz, DMSO-d6): δ = 8.07 (1H. brs), 7.66 (2H, d, J= 7.9 Hz), 7.39 (1H, d, J = 7.4 Hz), 7.28-7.18 (5H, m), 4.62 (2H, s), 3.56 (2H, s), 2.56 (3H, d, J = 4.5 Hz). LC-MS: >99 % purity, RT 1.83 min, MS (m/z): 394 (M+H) ⁺

Synthesis of Compound 80 2-(2-(Methylamino)-2-oxoethyl)benzyl(E)-N'-(3-chloro-4-fluorophenyl)formamidinethiohydrobromide/2-( 2-(Methylamino)-2-oxoethyl)benzyl(E)-N'-(3-chloro-4-fluorophenyl)carbamimidothioate hydrobromide

Compound 62c (88.3 mg, 0.36 mmol) and 1-(3-chloro-4-fluorophenyl)thiourea (74.6 mg, 0.36 mmol) were subjected to the same operation as that for compound 2, and the residue was recrystallized from 2-propanol and hexane (1:1) to give the title compound 80 (64.7 mg, 40% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 8.09 (1H, brs), 7.54 (2H, brs), 7.43 (1H, d, J = 6.2 Hz), 7.38-7.18 (4H, m), 4.64 ( 2H, s), 3.59 (2H, s), 2.59 (3H, d, J= 4.5 Hz). LC-MS: >99 % purity, RT 2.21 min, MS (m/z): 366 (M+H) ⁺

Synthesis of compound 81 5-Cyano-2-(methylcarbamoyl)benzyl (E)-N'-(4-bromophenyl)carbamimidothioate hydrobromide

Compound 77b (190 mg, 1.00 mmol), CBr ₄ (398 mg, 1.20 mmol), PPh ₃ (393 mg, 1.50 mmol) and 1-(4-bromophenyl)thiourea (231 mg, 1.00 mmol) were used in the same manner as for compound 74. The residue was recrystallized from EtOH to give the title compound 81 (249 mg, 51% yield) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 8.79 (1H, brs), 8.06 (1H, s), 7.94 (1H, d, J = 7.9 Hz), 7.68-7.65 (3H, m), 7.22 ( 2H, brs), 4.63 (2H, s), 2.78 (3H, d, J= 4.5 Hz). LC-MS: >99 % purity, RT 1.77 min, MS (m/z): 405 (M+H) ⁺

Synthesis of Compound 82 5-Bromo-2-((4-chlorobenzyl)carbamoyl)benzylcarbamidioate hydrobromide

The same procedure as for the synthesis of compound 74b was performed from 5-bromoisobenzofuran-1(3H)-one (compound 74a, 1065 mg, 5.00 mmol) with (4-chlorophenyl)methanamine (0.732 mg, 6.00 mmol). The reaction residue was purified by silica gel chromatography with n-hexane/EtOAc (3:1～1:1) to obtain white crystal compound 82a (438 mg, 25% recovery rate).

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.58 (1H, d, J = 2.0 Hz), 7.50 (1H, dd, J = 8.3, 2.0 Hz), 7.43 (1H, d, J = 8.3 Hz), 7.34 (2H, d, J= 8.3 Hz), 7.29 (2H, d, J = 8.3 Hz), 4.61 (2H, d, J = 3.4 Hz), 4.59 (2H, d, J = 4.9 Hz), 4.06-4.04 (1H, m).LC-MS: ＞99 % purity, RT 3.13 min, MS (m/z): 355 (M+H) ⁺

The same procedure as for the synthesis of compound 74 was performed from compound 82a (142 mg, 0.40 mmol), CBr ₄ (159 mg, 0.48 mmol), PPh ₃ (157 mg, 0.60 mmol) and thiourea (30.4 mg, 0.40 mmol). The residue was recrystallized from EtOH to give the title compound 82 as white crystals (112 mg, 57% recovery).

¹ HNMR (500 MHz, DMSO-d6): δ = 9.32 (3H, brs), 8.93 (1H, brs), 7.83 (1H, d, J = 2.3 Hz), 7.68 (1H, dd, J = 8.2, 2.0 Hz), 7.54 (1H, d, J = 8.5 Hz), 7.41 (2H, d, J = 8.5 Hz), 7.37 (2H, d, J = 8.5 Hz), 4.56 (2H, s), 4.45 (2H, d, J = 6.2 Hz).LC-MS: ＞99 % purity, RT 2.01 min, MS (m/z): 414 (M+H) ⁺

Synthesis of Compound 83 5-Bromo-2-((4-chlorobenzyl)aminoformyl)benzyl(E)-N'-(3-chloro-4-fluorophenyl)formamidinethiohydrobromide/5- Bromo-2-((4-chlorobenzyl)carbamoyl)benzyl(E)-N'-(3-chloro-4-fluorophenyl)carbamimidothioate hydrobromide

The same operation as for compound 74 was carried out from compound 82a (106 mg, 0.30 mmol), CBr ₄ (119 mg, 0.36 mmol), PPh ₃ (118 mg, 0.45 mmol) and 1-(3-chloro-4-fluorophenyl)thiourea (61.4 mg, 0.30 mmol), and the residue was purified by silica gel chromatography with n-hexane/EtOAc (1:1) to obtain the title compound 83 (90.4 mg, 48% recovery) as light pink crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.09 (1H, t, J= 6.0 Hz), 7.75 (1H, d, J = 1.7 Hz), 7.56 (1H, dd, J = 7.9, 2.3 Hz) , 7.42-7.24 (7H, m), 6.84 (1H, dd, J= 6.8, 2.3 Hz), 6.70-6.67 (1H, m), 6.60 (1H, brs), 4.41 (2H, d, J = 5.7 Hz ), 4.37 (2H, s).LC-MS: >99 % purity, RT 3.44 min, MS (m/z): 542 (M+H) ⁺

Synthesis of Compound 84 5-Bromo-2-((4-chlorobenzyl)aminoformyl)benzyl(E)-N'-(4-bromophenyl)formamidinethiohydrobromide/5-Bromo-2- ((4-chlorobenzyl)carbamoyl)benzyl(E)-N'-(4-bromophenyl)carbamimidothioate hydrobromide

The synthesis was carried out from compound 82a (130 mg, 0.37 mmol), CBr ₄ (146 mg, 0.44 mmol), PPh ₃ (144 mg, 0.50 mmol) and 1-(4-bromophenyl)thiourea (84.7 mg, 0.37 mmol). The same operation was performed for compound 74, and the residue was purified by silica gel chromatography with n-hexane/EtOAc (1:1) to obtain the title compound 84 (63.4 mg, 26% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.09 (1H, t, J= 6.0 Hz), 7.75 (1H, d, J = 1.7 Hz), 7.55 (1H, dd, J = 8.2, 2.0 Hz) , 7.40-7.36 (7H, m), 6.69 (2H, d, J= 8.5 Hz), 6.51 (2H, brs), 4.41 (2H, d, J= 5.7 Hz), 4.37 (2H, s).LC- MS: >99 % purity, RT 3.24 min, MS (m/z): 568 (M+H) ⁺

Synthesis of compound 85 5-Bromo-2-((4-cyanobenzyl)carbamoyl)benzyl (E)-N'-(3-chloro-4-fluorophenyl)carbamimidothioate hydrobromide

From compound 76a (104 mg, 0.30 mmol), CBr ₄ (119 mg, 0.36 mmol), PPh ₃ (118 mg, 0.45 mmol) and 1-(3-chloro-4-fluorophenyl)thiourea (61.4 mg, 0.30 mmol) ) The same procedure as for the synthesis of compound 74 was performed, and the residue was recrystallized from EtOH to obtain the title compound 85 (128 mg, 70% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.41 (1H, t, J = 6.0 Hz), 7.88 (1H, d, J = 1.7 Hz), 7.82 (2H, d, J = 8.5 Hz), 7.71 (1H, dd, J = 8.2, 2.0 Hz), 7.61-7.54 (5H, m), 7.31 (1H, brs), 4.65 (2H, s), 4.54 (2H, d, J = 6.2 Hz), 1.06 (2H, t, J = 6.8 Hz).LC-MS: ＞99 % purity, RT 3.00 min, MS (m/z): 533 (M+H) ⁺

Synthesis of compound 86 5-Bromo-2-((4-fluorobenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

The same operation as that for compound 74b was carried out from 5-bromoisobenzofuran-1(3H)-one (compound 74a, 1065 mg, 5.00 mmol) and (4-chlorophenyl)methanamine (0.683 mL, 6.00 mmol). The reaction residue was purified by silica gel chromatography with n-hexane/EtOAc (3:1 to 1:1) to obtain compound 86a (229 mg, 14% recovery) as pale yellow crystals.

¹ HNMR (500 MHz, CDCl ₃ ): δ = 7.58 (1H, d, J= 2.3 Hz), 7.49 (1H, dd, J = 8.2, 2.0 Hz), 7.42 (1H, d, J = 7.9 Hz), 7.33 (2H, dd, J = 8.8, 5.4 Hz), 7.06 (2H, dd, J = 8.8, 2.0 Hz), 6.67 (1H, brs), 4.61-4.58 (4H, m), 4.08 (1H, t, J = 6.8 Hz).LC-MS: >99 % purity, RT 2.88 min, MS (m/z): 340 (M-OH) ⁺

The title compound 86 (20.3 mg, 14% recovery) was obtained as white crystals by the same operation as that for compound 74 from compound 86a (102 mg, 0.30 mmol), CBr ₄ (119 mg, 0.36 mmol), PPh ₃ (118 mg, 0.45 mmol) and thiourea (22.8 mg, 0.30 mmol).

¹ HNMR (500 MHz, DMSO-d6): δ = 9.31 (1H, t, J= 6.0 Hz), 9.04 (3H, brs), 7.82 (1H, d, J= 2.3 Hz), 7.67 (1H, dd, J = 8.2, 2.0 Hz), 7.52 (1H, d, J = 8.5 Hz), 7.39 (2H, dd, J = 8.5, 5.7 Hz), 7.17 (2H, t, J = 9.1 Hz), 4.54 (2H, s), 4.45 (2H, d, J= 5.7 Hz).LC-MS: ＞99 % purity, RT 1.81 min, MS (m/z): 398 (M+H) ⁺

Synthesis of compound 87 5-Bromo-2-((4-cyanobenzyl)carbamoyl)benzyl(E)-N'-(4-bromophenyl)carbamimidothioate hydrobromide

The title compound 87 (66.1 mg, 52% recovery) was obtained as white crystals by the same operation as that for compound 74 from compound 76a (69 mg, 0.20 mmol), CBr ₄ (79.6 mg, 0.24 mmol), PPh ₃ (78.7 mg, 0.30 mmol) and 1-(4-bromophenyl)thiourea (46.2 mg, 0.20 mmol).

¹ HNMR (500 MHz, DMSO-d6): δ = 9.38 (1H, t, J= 6.0 Hz), 7.87 (1H, d, J = 1.7 Hz), 7.82 (2H, d, J = 8.5 Hz), 7.72 -7.68 (3H, m), 7.59 (1H, d, J= 8.5 Hz), 7.54 (2H, d, J = 8.5 Hz), 7.23 (2H, d, J = 8.5 Hz), 4.65 (2H, s) , 4.53 (2H, d, J = 5.7 Hz).LC-MS: >99 % purity, RT 2.83 min, MS (m/z): 559 (M+H) ⁺

Synthesis of compound 88 5-Bromo-2-((4-fluorobenzyl)aminoformyl)benzyl(E)-N'-(3-chloro-4-fluorophenyl)formamidinethiohydrobromide/5- Bromo-2-((4-fluorobenzyl)carbamoyl)benzyl(E)-N'-(3-chloro-4-fluorophenyl)carbamimidothioate hydrobromide

By starting from compound 86a (121 mg, 0.36 mmol), CBr ₄ (143 mg, 0.43 mmol), PPh ₃ (141 mg, 0.54 mmol) and 1-(3-chloro-4-fluorophenyl)thiourea (73.3 mg, 0.36 mmol), the same operation as for the synthesis of compound 74 was performed, and the residue was purified by silica gel chromatography with n-hexane/EtOAc (1:1) to obtain the title compound 88 (91.4 mg, 42% recovery) as pale yellow crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.07 (1H, t, J= 6.0 Hz), 7.75 (1H, d, J = 1.1 Hz), 7.55 (1H, dd, J = 8.2, 2.0 Hz) , 7.41 (1H, d, J = 8.5 Hz), 7.36 (2H, t, J = 7.1Hz), 7.26 (1H, t, J = 9.1 Hz), 7.14 (2H, t, J = 8.8 Hz), 6.84 (1H, dd, J = 6.5,2.0 Hz), 6.69 (1H, t, J = 4.5 Hz), 6.60 (2H, brs), 4.40 (2H, d, J = 5.7 Hz), 4.37 (2H, s) .LC-MS: >99 % purity, RT 3.20 min, MS (m/z): 526 (M+H) ⁺

Synthesis of compound 89 5-Bromo-2-((2,4-dichlorobenzyl)carbamoyl)benzylformamidinethiohydrobromide/5-Bromo-2-((2,4-dichlorobenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

The same operation as for the synthesis of compound 74b was carried out from 5-bromoisobenzofuran-1(3H)-one (compound 74a, 1065 mg, 5.00 mmol) and (2,4-dichlorophenyl)methane (0.808 mL, 6.00 mmol). The residues from the two reactions were purified by silica gel chromatography with n-hexane/EtOAc (4:1-3:2) and n-hexane/EtOAc (4:1-3:2) to obtain compound 89a (105 mg, 5% recovery) as white crystals.

¹ HNMR (500 MHz, CDCl ₃ ): δ = 7.57 (1H, d, J = 1.7 Hz), 7.50 (1H, dd, J = 8.2, 2.0 Hz), 7.43-7.41 (3H, m), 7.27-7.25 (1H, m), 6.85 (1H, brs), 4.67 (2H, d, J = 6.2 Hz), 4.57 (2H, d, J = 6.8 Hz), 3.96 (1H, t, J = 6.5 Hz).LC-MS: 81 % purity, RT 3.42 min, MS (m/z): 390 (M+H) ⁺

The same procedure as for the synthesis of compound 74 was carried out from compound 89a (105 mg, 0.27 mmol), CBr ₄ (108 mg, 0.32 mmol), PPh ₃ (106 mg, 0.41 mmol) and thiourea (20.6 mg, 0.27 mmol). The residue was recrystallized from EtOH and Et ₂ O (1:1) to obtain the title compound 89 as white crystals (76 mg, 54% recovery).

¹ HNMR (500 MHz, DMSO-d6): δ = 9.32 (1H, t, J= 6.0 Hz), 9.28 (2H, brs), 8.94 (2H, brs), 7.84 (1H, d, J = 2.3 Hz) , 7.70 (1H, dd, J = 8.2, 2.0 Hz), 7.65 (1H, d, J= 1.7 Hz), 7.58 (1H, d, J= 8.5 Hz), 7.45 (2H, t, J = 2.0 Hz) , 4.56 (2H, s), 4.50 (2H, d, J= 5.7 Hz).LC-MS: >99 % purity, RT 2.53 min, MS (m/z): 448 (M+H) ⁺

Synthesis of compound 90 5-Bromo-2-((4-methylbenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

The same procedure as for the synthesis of compound 74b was performed from 5-bromoisobenzofuran-1(3H)-one (compound 74a, 1065 mg, 5.00 mmol) with p-tolylmethylamine (0.757 mL, 6.00 mmol) and chromatographed on silica gel The reaction residue was purified using n-hexane/EtOAc (3:1-55:45) to obtain white crystal compound 90a (200 mg, 12% recovery rate).

¹ HNMR (500 MHz, CDCl ₃ ): δ = 7.57 (1H, d, J= 1.7 Hz), 7.48 (1H, dd, J = 8.2, 2.0Hz), 7.40 (1H, d, J = 7.9 Hz), 7.24 (2H, d, J = 7.9 Hz), 7.18 (2H, d, J = 7.9 Hz), 6.53 (1H, brs), 4.60 (2H, d, J= 2.8 Hz), 4.58 (2H, s), 4.20 (1H, t, J= 6.8 Hz), 2.35 (3H, s).LC-MS: >99 % purity, RT 3.06 min, MS (m/z): 336 (M+H) ⁺

The same procedure as for the synthesis of compound 74 was carried out from compound 90a (94 mg, 0.28 mmol), CBr ₄ (112 mg, 0.34 mmol), PPh ₃ (111 mg, 0.42 mmol) and thiourea (21 mg, 0.28 mmol). The residue was recrystallized from EtOH to give the title compound 90 as white crystals (60 mg, 46% recovery).

^1HNMR (500 MHz, DMSO-d6): δ = 9.27 (1H, t, J= 5.7 Hz), 9.12 (3H, brs), 7.82 (1H, d, J= 1.7 Hz), 7.67 (1H, dd, J = 8.5, 2.3 Hz), 7.50 (1H, d, J = 8.5 Hz), 7.23 (2H, d, J = 7.9 Hz), 7.15 (2H, d, J = 7.9 Hz), 4.55 (2H, s), 4.42 (2H, d, J = 6.2 Hz), 2.29 (3H, s).LC-MS: ＞99 % purity, RT 1.95 min, MS (m/z): 394 (M+H) ⁺

Synthesis of Compound 91 5-Bromo-2-((4-methylbenzyl)aminoformyl)benzyl(E)-N'-(3-chloro-4-fluorophenyl)formamidinethiohydrobromide/5 -Bromo-2-((4-methylbenzyl)carbamoyl)benzyl(E)-N'-(3-chloro-4-fluorophenyl)carbamimidothioate hydrobromide

By starting from compound 90a (100 mg, 0.30 mmol), CBr ₄ (119 mg, 0.36 mmol), PPh ₃ (118 mg, 0.45 mmol) and 1-(3-chloro-4-fluorophenyl)thiourea (61 mg, 0.30 mmol), the same operation as for the synthesis of compound 74 was performed, and the residue was purified by silica gel chromatography with n-hexane/EtOAc (1:1) to obtain the title compound 91 (90 mg, 50% recovery) as pale yellow crystals.

¹ H NMR (500 MHz, DMSO-d6): δ = 9.01 (1H, t, J = 6.0 Hz), 7.75 (1H, s), 7.54 (1H, dd, J = 8.2, 2.0 Hz), 7.39 (1H, d, J = 7.9 Hz), 7.26 (1H, t, J = 9.1 Hz), 7.21 (2H, d, J = 7.9 Hz), 7.13 (2H, d, J = 7.9 Hz), 6.84 (1H, dd, J = 6.8, 2.3 Hz), 6.70-6.67 (1H, m), 6.60 (2H, brs), 4.38-4.36 (4H, m), 2.28 (3H, s).LC-MS: ＞99 % purity, RT 3.30 min, MS (m/z): 522 (M+H) ⁺

Synthesis of compound 92 2-(Methylcarbamoyl)benzyl carbamimidothioate hydrobromide

The same operation as for the synthesis of compound 74b was performed from isobenzofuran-1(3H)-one (compound 92a, 671 mg, 5.00 mmol) with 40% MeNH ₂ (4.309 mL, 50.0 mmol) to obtain white crystalline compound 92b (577 mg, 70% recovery).

¹ H-NMR (DMSO-d ₆ ) δ: = 8.27 (1H, brs), 7.53 (1H, d, J = 7.9 Hz), 7.45-7.39 (2H, m), 7.30 (1H, t, J = 7.4 Hz), 5.23 (1H, t, J = 5.4 Hz), 4.58 (2H, d, J = 5.1 Hz), 2.75 (3H, d, J = 4.5 Hz). LC-MS: >99 % purity, RT 1.49 min, MS (m/z): 166 (M+H)+

The same operation as the synthesis of compound 74 was performed from compound 92b (66 mg, 0.40 mmol), CBr ₄ (159 mg, 0.48 mmol), PPh ₃ (157 mg, 0.60 mmol) and thiourea (30 mg, 0.40 mmol) to obtain The title compound 92 was obtained as white crystals (69.5 mg, 57% recovery).

¹ HNMR (500 MHz, DMSO-d6): δ = 9.05 (3H, brs), 8.67 (1H, d, J = 4.5 Hz), 7.57 (1H, d, J= 7.4 Hz), 7.51 (2H, t, J = 8.5 Hz), 7.42 (1H, t, J = 7.4 Hz), 4.54 (2H, s), 2.79 (3H, d, J = 4.5 Hz). LC-MS: >99 % purity, RT 0.49 min, MS (m/z): 224 (M+H) ⁺

Synthesis of Compound 93 5-Bromo-2-((cyclopropylmethyl)carbamoyl)benzylcarbamidothioate hydrobromide

The same procedure as for the synthesis of compound 74b was performed from 5-bromoisobenzofuran-1(3H)-one (compound 74a, 1065 mg, 5.00 mmol) with cyclopropylmethylamine (0.514 mL, 6.00 mmol) and chromatographed on silica gel The reaction residue was purified with n-hexane/EtOAc (7:3～1:1) to obtain white crystal compound 93a (607 mg, 43% recovery rate).

¹ HNMR (500 MHz, CDCl ₃ ): δ = 7.57 (1H, s), 7.50 (1H, d, J = 7.9 Hz), 7.42 (1H, d, J= 8.5 Hz), 6.41 (1H, s), 4.57 (2H, d, J= 6.8 Hz), 4.29 (1H, t, J = 6.5 Hz), 3.31 (2H, t, J = 6.2 Hz), 1.09-1.04 (1H, m), 0.58 (2H, q, J= 4.8 Hz), 0.29 (2H, q, J = 4.9 Hz).LC-MS: ＞99 % purity, RT 2.27 min, MS (m/z): 285 (M+H) ⁺

The same operation as the synthesis of compound 74 was performed from compound 93a (142 mg, 0.50 mmol), CBr ₄ (199 mg, 0.60 mmol), PPh ₃ (197 mg, 0.75 mmol) and thiourea (38 mg, 0.50 mmol) to obtain The title compound 93 was obtained as white crystals (124 mg, 59% recovery).

¹ HNMR (500 MHz, DMSO-d6): δ = 9.09 (3H, brs), 8.89 (1H, t, J = 5.4 Hz), 7.81 (1H, s), 7.66 (1H, d, J = 7.9 Hz) , 7.45 (1H, d, J= 7.9 Hz), 4.53 (2H, s), 3.14 (2H, t, J= 6.2 Hz), 1.05-1.00 (1H, m), 0.46 (2H, q, J = 4.8 Hz), 0.24 (2H, q, J= 4.7 Hz). LC-MS: >99 % purity, RT 1.06 min, MS (m/z): 344 (M+H) ⁺

Synthesis of Compound 94 5-Bromo-2-((3,4-dichlorobenzyl)carbamoyl)benzylformamidinethiohydrobromide/5-Bromo-2-((3,4-dichlorobenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

The same procedure as for the synthesis of compound 74b was performed from 5-bromoisobenzofuran-1(3H)-one (compound 74a, 1065 mg, 5.00 mmol) and (3,4-dichlorophenyl)methanamine (0.794 mL, 6.00 mmol). The reaction residue was purified twice using silica gel chromatography with n-hexane/EtOAc (7:3～45:55) and n-hexane/EtOAc (7:3～1:1) to obtain white crystalline compound 94a (133 mg , 7% recovery rate).

¹ HNMR (500 MHz, CDCl ₃ ): δ = 7.59 (1H, d, J= 1.7 Hz), 7.52 (1H, dd, J = 7.9, 1.7Hz), 7.46-7.43 (3H, m), 7.21 (1H , dd, J = 8.2, 2.0 Hz), 6.79 (1H, brs), 4.61-4.58 (4H, m), 3.85 (1H, t, J = 6.8 Hz). LC-MS: >99 % purity, RT 3.46 min, MS (m/z): 390 (M+H) ⁺

The same procedure as for compound 74 was carried out from compound 94a (117 mg, 0.30 mmol), CBr ₄ (119 mg, 0.36 mmol), PPh ₃ (118 mg, 0.45 mmol) and thiourea (22.8 mg, 0.30 mmol), and the residue was recrystallized from EtOH to give the title compound 94 (14.6 mg, 9% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.33 (1H, t, J= 6.0 Hz), 9.02 (3H, s), 7.82 (1H, d, J= 1.7 Hz), 7.69 (1H, dd, J = 8.2, 1.4 Hz), 7.62-7.61 (2H, m), 7.54 (1H, d, J= 7.9 Hz), 7.35 (1H, dd, J = 7.9, 1.7 Hz), 4.54 (2H, s), 4.46 (2H, d, J = 5.7 Hz).LC-MS: >99 % purity, RT 6.76 min, MS (m/z): 448 (M+H) ⁺

Synthesis of Compound 95 1,2-Phenylenebis(methylene)(E,E)-bis(N'-(2,4-difluorophenyl)formamidinethio)dihydrobromide/1,2-Phenylenebis (methylene)(E,E)-bis(N'-(2,4-difluorophenyl)carbamimidothioate)dihydrobromide

The same operation as for the synthesis of compound 2 was carried out from 1,2-bis(bromomethyl)benzene (compound 58a, 132 mg, 0.50 mmol) and 1-(2,4-difluorophenyl)thiourea (188 mg, 1.00 mmol), and the residue was recrystallized from 2-propanol and hexane (1:1) to give the title compound 95 (256 mg, 80% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.51 (4H, s), 7.52-7.41 (8H, m), 7.26-7.23 (2H, m), 4.78 (4H, brs).LC-MS: ＞99 % purity, RT 1.51 min, MS (m/z): 479 (M+H) ⁺

Synthesis of compound 96 2-((4-Cyanobenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

From isobenzofuran-1(3H)-one (compound 92a, 805 mg, 6.00 mmol), 4-(aminomethyl)benzonitrile hydrochloride (1113 mg, 50.0 mmol) and triethylamine (2.509 mL, 18.00 mmol), the same operation as for the synthesis of compound 76a was carried out, and the reaction residue was purified by silica gel chromatography with n-hexane/EtOAc (7:3~35:65) to obtain compound 96a (731 mg, 46% recovery rate) as pale yellow crystals.

¹ HNMR (500 MHz, CDCl ₃ ): δ = 7.66 (2H, d, J = 7.9 Hz), 7.61 (1H, d, J = 7.4 Hz), 7.50-7.47 (3H, m), 7.43-7.38 (2H, m), 6.95 (1H, brs), 4.72 (2H, d, J = 6.2 Hz), 4.64 (2H, d, J = 6.8 Hz), 3.92 (1H, t, J = 6.8 Hz).LC-MS: ＞99 % purity, RT 2.42 min, MS (m/z): 249 (M-OH) ⁺

The same operation as for compound 74 was carried out from compound 96a (133 mg, 0.50 mmol), CBr ₄ (199 mg, 0.60 mmol), PPh ₃ (197 mg, 0.75 mmol) and thiourea (38.1 mg, 0.50 mmol), and the residue was recrystallized from EtOH to give the title compound 96 (9.3 mg, 5% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.34 (1H, t, J= 6.0 Hz), 9.26 (2H, brs), 8.87 (1H, brs), 7.82 (2H, d, J = 7.9 Hz) , 7.62 (1H, d, J= 7.4 Hz), 7.59-7.53 (4H, m), 7.47 (1H, t, J = 7.4 Hz), 4.57 (2H, s), 4.56 (2H, d, J = 5.7 Hz).LC-MS: >99 % purity, RT 0.92 min, MS (m/z): 325 (M+H) ⁺

Synthesis of Compound 97 5-Bromo-2-((4-bromobenzyl)carbamoyl)benzylcarbamidioate hydrobromide

The same operation as that for compound 74b was carried out from 5-bromoisobenzofuran-1(3H)-one (compound 74a, 639 mg, 3.00 mmol) and (4-bromophenyl)methanamine (670 mg, 3.60 mmol). The reaction residue was purified by silica gel chromatography with n-hexane/EtOAc (7:3-1:1) to give compound 97a (114 mg, 10% recovery) as white crystals.

¹ HNMR (500 MHz, CDCl ₃ ): δ = 7.58 (1H, d, J= 2.3 Hz), 7.51-7.47 (3H, m), 7.43 (1H, d, J = 8.5 Hz), 7.24 (2H, d, J= 8.5 Hz), 6.68 (1H, brs), 4.60-4.58 (4H, m), 3.97 (1H, t, J = 6.8 Hz).LC-MS: ＞99 % purity, RT 8.23 min, MS (m/z): 382 (M-OH) ⁺

The same operation as for compound 74 was carried out from compound 97a (111 mg, 0.28 mmol), CBr ₄ (111 mg, 0.33 mmol), PPh ₃ (110 mg, 0.42 mmol) and thiourea (21.2 mg, 0.28 mmol), and the residue was recrystallized from EtOH to give the title compound 97 (70.0 mg, 46% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.34-9.31 (2H, m), 8.93 (2H, brs), 7.83 (1H, d, J = 1.7 Hz), 7.69 (1H, dd, J = 8.2 , 2.0 Hz), 7.55-7.53 (3H, m), 7.31 (2H, d, J = 8.5 Hz), 4.56 (2H, s), 4.43 (2H, d, J= 5.7 Hz).LC-MS: ＞ 99% purity, RT 5.99 min, MS (m/z): 458 (M+H) ⁺

Synthesis of Compound 98 (2-(Methylcarbamoyl)pyridin-3-yl)methylcarbamidioate hydrobromide/(2-(Methylcarbamoyl)pyridin-3-yl)methyl carbamimidothioate hydrobromide

A solution of quinolinic anhydride (compound 98a, 5.0 g, 34.0 mmol) in MeOH (25 ml) was stirred at 70°C for 2 hours. The reaction solution was concentrated under reduced pressure and recrystallized from ethyl acetate to obtain compound 98b (3.94 g, 64% recovery rate) as white crystals.

¹ HNMR (500 MHz, CDCl ₃ ): δ = 8.84 (1H, d, J = 5.1 Hz), 8.34 (1H, d, J= 7.9 Hz), 7.56 (1H, dd, J = 7.9, 4.5 Hz), 4.02 (3H, s).LC-MS: ＞99 % purity, RT 0.58 min, MS (m/z): 182 (M+H) ⁺

1,1'-Carbonyldiimidazole; CDI (535 mg, 3.31 mmol) in THF solution (4 ml) was added to a THF solution (7 ml) of compound 98b (450 mg, 2.50 mmol) at 0°C, and the mixture was stirred at room temperature for 1 hour. Afterwards, _NaBH4 was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was cooled to 0°C, MeOH (3 ml) and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with magnesium sulfate, and the concentrated residue was decompressed and purified by silica gel chromatography with n-hexane/EtOAc (1:3 to 0:1) to obtain white crystals of compound 98c (116 mg, 34% recovery rate).

¹ HNMR (500 MHz, CDCl ₃ ): δ = 8.92 (1H, d, J= 4.5 Hz), 7.92 (1H, d, J = 7.4 Hz), 7.59 (1H, dd, J = 7.7, 4.8 Hz), 5.40 (2H, s).

40% MeNH ₂ (260 mg, 8.38 mmol) was added to a solution of compound 98c (113 mg, 0.84 mmol) in THF (12 ml), and the mixture was stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain compound 98d (104 mg, 75% recovery rate) as white crystals.

¹ HNMR (500 MHz, CDCl ₃ ): δ = 8.50 (1H, d, J= 4.0 Hz), 8.36 (1H, brs), 7.74 (1H, d, J= 6.8 Hz), 7.41 (1H, dd, J = 7.7, 4.8 Hz), 5.31 (1H, t, J = 7.4 Hz), 4.82 (2H, d, J = 7.4 Hz), 3.05 (3H, d, J = 5.1 Hz).

CBr ₄ (146 mg, 0.74 mmol) was added to a solution of compound 98d (103 mg, 0.62 mmol) in CH ₂ Cl ₂ (5 ml) at 0 °C, followed by PPh ₃ (243 mg, 0.93 mmol) in CH _{2 Cl2} solution (4ml). After stirring the reaction solution at room temperature for 1 hour, thiourea (47.0 mg, 0.62 mmol) was added, and the mixture was stirred at 40°C for 12 hours. By filtering the crystals precipitated during the reaction, the title compound 98 (11.7 mg, 6% recovery) was obtained as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.06-8.94 (4H, m), 8.61 (1H, d, J = 4.5 Hz), 8.01(1H, d, J= 7.4 Hz), 7.62 (1H, dd, J = 7.9, 4.5 Hz), 4.80 (2H, s), 2.81 (3H, d, J= 4.5 Hz).LC-MS: ＞99 % purity, RT 0.38 min, MS (m/z): 225 (M+H) ⁺

Synthesis of compound 99 (2-((4-Cyanobenzyl)carbamoyl)pyridin-3-yl)methyl carbamimidothioate hydrobromide

The same procedure as for the synthesis of compound 76a was carried out from compound 98c (511 mg, 3.78 mmol), 4-(aminomethyl)benzonitrile hydrochloride (702 mg, 4.16 mmol) and triethylamine (1.581 mL, 11.35 mmol) to The reaction residue was purified by silica gel chromatography using n-hexane/EtOAc (2:3-1:4) to obtain compound 99a (519 mg, 51% yield) as pale yellow crystals.

¹ HNMR (500 MHz, CDCl ₃ ): δ = 8.84 (1H, br s), 8.51 (1H, d, J = 4.5 Hz), 7.79 (1H, d, J= 7.9 Hz), 7.65 (2H, d, J = 7.9 Hz), 7.48-7.44 (3H, m), 4.98 (1H, t, J= 7.4 Hz), 4.86 (2H, d, J = 7.9 Hz), 4.73 (2H, d, J = 6.2 Hz) .LC-MS: >99 % purity, RT 2.15 min, MS (m/z): 250 (M-OH) ⁺

The same operation as the synthesis of compound 98 was performed from compound 99a (245 mg, 0.92 mmol), CBr ₄ (365 mg, 1.10 mmol), PPh ₃ (361 mg, 1.38 mmol) and thiourea (69.8 mg, 0.92 mmol) to obtain The title compound 99 was obtained as white crystals (105 mg, 28% recovery).

^1HNMR (500 MHz, DMSO-d6): δ = 9.68 (1H, t, J= 6.2 Hz), 9.06 (3H, brs), 8.66 (1H, d, J= 4.5 Hz), 8.03 (1H, d, J = 7.9 Hz), 7.81 (2H, d, J = 7.9 Hz), 7.67 (1H, dd, J = 7.7, 4.8 Hz), 7.52 (2H, d, J = 7.9 Hz), 4.80 (2H, s), 4.56 (2H, d, J = 6.2 Hz).LC-MS: ＞99 % purity, RT 0.81 min, MS (m/z): 326 (M+H) ⁺

Synthesis of compound 100 (3-(Methylcarbamoyl)pyridin-2-yl)methyl carbamimidothioate hydrobromide

At 15°C, a THF solution (30 ml) of quinoline anhydride (compound 100a, 5.0 g, 33.5 mmol) and acetic acid (4.0 g, 67.0 mmol) were added to a THF solution (5 ml) of NaBH ₄ (1.14 mg, 33.5 mmol) and stirred for 4 hours. After the reaction solution was concentrated by decompression, acetic acid (13.5 ml) and acetic anhydride (13.5 ml) were added and refluxed for 3 hours. After the reaction solution was concentrated by decompression, it was extracted with dichloromethane. The organic layer was washed with brine, dried with magnesium sulfate, and the concentrated residue was decompressed and recrystallized with 2-propanol to obtain light yellow crystals of compound 100b (1.29 g, 29% recovery rate).

¹ HNMR (500 MHz, CDCl ₃ ): δ = 8.89 (1H, d, J= 4.0 Hz), 8.23 (1H, d, J = 6.8 Hz), 7.50 (1H, dd, J = 7.4, 5.1 Hz), 5.36 (2H, s).

40% MeNH ₂ (621 mg, 20.0 mmol) was added to a THF solution (10 ml) of compound 100b (270 mg, 2.0 mmol), and stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over magnesium sulfate, added with toluene and concentrated under reduced pressure to obtain compound 100c (222 mg, 67% recovery rate) as yellow crystals.

¹ HNMR (500 MHz, CDCl ₃ ): δ = 8.62 (1H, d, J = 4.5 Hz), 7.89 (1H, d, J = 7.9 Hz), 7.31 (1H, t, J = 6.2 Hz), 6.38 (1H, brs), 4.89 (2H, s), 4.24 (1H, brs), 3.03 (3H, d, J = 4.5 Hz).

At 0°C, CBr ₄ (519 mg, 1.6 mmol) was added to a CH ₂ Cl ₂ solution (6 ml) of compound 100c (217 mg, 1.3 mmol), and then a CH ₂ Cl ₂ solution (4 ml) of PPh ₃ (514 mg, 2.0 mmol) was added. After stirring the reaction solution at room temperature for 1 hour, thiourea (99.4 mg, 1.3 mmol) was added, and the mixture was stirred at 40°C for 12 hours. The crystals precipitated during the reaction were filtered to obtain the title compound 100 (98.4 mg, 25% recovery) as light orange crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.20 (3H, brs), 8.77 (1H, d, J = 4.0 Hz), 8.66 (1H, d, J= 4.5 Hz), 7.99 (1H, d, J = 7.4 Hz), 7.52 (1H, dd, J = 7.7, 4.8 Hz), 4.64(2H, s), 2.80 (3H, d, J= 4.5 Hz). LC-MS: >99% purity, RT 0.38 min, MS (m/z): 225 (M+H) ⁺

Synthesis of compound 101 (2-((4-Cyanobenzyl)carbamoyl)pyridin-3-yl)methyl (E)-N'-(3-chloro-4-fluorophenyl)carbamimidothioate hydrobromide

The same operation as for the synthesis of compound 98 was carried out from compound 99a (134 mg, 0.50 mmol), CBr ₄ (199 mg, 0.60 mmol), PPh ₃ (197 mg, 0.75 mmol) and (3-chloro-4-fluorophenyl)thiourea (102 mg, 0.50 mmol), and the residue was purified by silica gel chromatography with n-hexane/EtOAc (1:1) to give the title compound 101 (37.3 mg, 14% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.44 (1H, d, J= 6.2 Hz), 8.54 (1H, d, J = 4.0 Hz), 7.98 (1H, d, J = 7.9 Hz), 7.78 (2H, d, J = 8.5 Hz), 7.57-7.50 (3H, m), 7.24 (1H, t, J= 9.1 Hz), 6.85 (1H, brs), 6.69 (1H, brs), 6.53 (2H, brs), 4.61 (2H, s), 4.54 (2H, d, J = 6.2 Hz). LC-MS: >99 % purity, RT 6.72 min, MS (m/z): 454 (M+H) ⁺

Synthesis of Compound 102 5-bromo-2-((4-methoxybenzyl)carbamoyl)benzylcarbamidioate hydrobromide

The same procedure as for the synthesis of compound 74b was carried out from 5-bromoisobenzofuran-1(3H)-one (compound 74a, 852 g, 4.00 mmol) and (4-bromophenyl)methanamine (0.627 mL, 4.80 mmol). , the reaction residue was purified by silica gel chromatography with n-hexane/EtOAc (7:3～45:55) to obtain white crystal compound 102a (372 mg, 27% recovery rate).

¹ HNMR (500 MHz, CDCl ₃ ): δ = 7.57 (1H, d, J= 1.7 Hz), 7.48 (1H, dd, J = 8.5, 1.7Hz), 7.39 (1H, d, J = 7.9 Hz), 7.28 (2H, d, J = 9.1 Hz), 6.90 (2H, d, J = 8.5 Hz), 6.50 (1H, brs), 4.59-4.56 (4H, m), 4.23 (1H, t, J = 6.8 Hz ), 3.81 (3H, s).LC-MS: >99 % purity, RT 2.77 min, MS (m/z): 351 (M+H)+

The same operation as for compound 74 was carried out from compound 102a (175 mg, 0.50 mmol), CBr ₄ (199 mg, 0.60 mmol), PPh ₃ (197 mg, 0.75 mmol) and thiourea (38.1 mg, 0.50 mmol), and the residue was recrystallized from EtOH to give the title compound 102 (22.4 mg, 9% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.27 (1H, t, J = 6.0 Hz), 7.82 (1H, d, J = 1.7 Hz), 7.67 (1H, dd, J = 8.2, 2.0 Hz), 7.49 (1H, d, J = 8.5 Hz), 7.27 (2H, d, J = 8.5Hz), 6.91 (2H, d, J = 8.5 Hz), 4.54 (2H, s), 4.39 (2H, d, J = 6.2 Hz), 3.74 (3H, s).LC-MS: ＞99 % purity, RT 1.81 min, MS (m/z): 409 (M+H) ⁺

Synthesis of compound 103 4-Bromo-2-((4-cyanobenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

After adding sulfuric acid (1.5 ml) to an acetic acid solution (3 ml) of isofuran-1(3H)-one (compound 103a, 500 mg, 3.73 mmol), stir at room temperature for 9 hours, and gradually add NBS (995 mg, 5.59 mmol). Water (50 ml) was added to the reaction solution, and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and the residue concentrated under reduced pressure was purified by silica gel chromatography with n-hexane/EtOAc (1:0-7:3) to obtain white crystalline compound 103b (445 mg, 56%). Recovery rate).

¹ HNMR (500 MHz, CDCl ₃ ): δ = 8.07 (1H, d, J= 1.1 Hz), 7.81 (1H, dd, J = 7.9, 1.7Hz), 7.39 (1H, d, J = 7.9 Hz), 5.29 (2H, s).LC-MS: ＞99 % purity, RT 2.17 min, MS (m/z): 214 (M+H)+

4-(Aminomethyl)benzonitrile hydrochloride (371 mg, 2.2 mmol) and Et ₃ N (607 mg, 6.0 mmol) were added to a solution of compound 103b (426 mg, 2.0 mmol) in THF (10 ml) at 50 Stir for 12 hours at ℃. After the reaction, water was added to the reaction liquid, and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and the residue was purified using silica gel chromatography with n-hexane/EtOAc (3:2 to 2:3) to obtain white crystalline compound 103c (208 mg, 30% recovery rate).

^1HNMR (500 MHz, CDCl ₃ ): δ = 7.74 (1H, d, J = 1.7 Hz), 7.67 (2H, d, J = 7.9 Hz), 7.60 (1H, dd, J = 8.2, 2.0 Hz), 7.48 (2H, d, J = 7.9 Hz), 7.29 (1H, d, J = 7.9 Hz), 7.03 (1H, brs), 4.70 (2H, d, J = 5.7 Hz), 4.60 (2H, d, J = 6.8 Hz), 3.71 (1H, t, J = 6.8 Hz).LC-MS: ＞99 % purity, RT 2.62 min, MS (m/z): 346 (M+H) ⁺

CBr ₄ (79.6 mg, 0.24 mmol) was added to a solution of compound 103c (69.0 mg, 0.20 mmol) in CH ₂ Cl ₂ (8 ml) at 0 °C, followed by PPh ₃ (78.7 mg, 0.30 mmol) in CH _{2 Cl2} solution (4ml). After the reaction solution was stirred at room temperature for 1 hour, thiourea (15.2 mg, 0.20 mmol) was added, and the mixture was stirred at 40°C for 12 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel chromatography with CHCl ₃ /MeOH (19:1 to 7:3), and recrystallized with EtOH and Et ₂ O to obtain the title compound 103 (11.4 mg, 12 %Recovery rate).

¹ HNMR (500 MHz, DMSO-d6): δ = 9.44 (1H, t, J= 6.0 Hz), 9.04 (3H, brs), 7.83-7.81 (3H, m), 7.77 (1H, dd, J = 8.2, 2.0 Hz), 7.56-7.52 (3H, m), 4.55-4.53 (4H, m).LC-MS: ＞99 % purity, RT 1.95 min, MS (m/z): 404 (M+H) ⁺

Synthesis of compound 104 2-((4-Cyanobenzyl)carbamoyl)benzyl carbamimidoselenoate hydrobromide

The same operation as for the synthesis of compound 74 was carried out from compound 96a (133 mg, 0.50 mmol), CBr ₄ (199 mg, 0.60 mmol), PPh ₃ (197 mg, 0.75 mmol) and selenourea (61.5 mg, 0.50 mmol), and the residue was purified from EtOH Recrystallization from Et ₂ O gave the title compound 104 as off-white crystals (138 mg, 61% recovery).

¹ HNMR (500 MHz, DMSO-d6): δ = 9.35-9.32 (2H, m), 9.05 (2H, brs), 7.83 (2H, d, J= 8.5 Hz), 7.64 (1H, d, J = 6.8 Hz), 7.55-7.51 (4H, m), 7.43 (1H, td, J = 7.4, 1.7 Hz), 4.55 (2H, d, J = 5.7 Hz), 4.50 (2H, s).LC-MS: ＞99 % purity, RT 0.65 min, MS (m/z): 372 (M+H) ⁺

Synthesis of compound 105 5-Bromo-2-((3-methoxybenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

From 5-bromoisobenzofuran-1(3H)-one (compound 74a, 1065 mg, 5.00 mmol) and (3-methoxyphenyl)methanamine (0.776 mL, 6.00 mmol), proceed in the same manner as for the synthesis of compound 74b The reaction residue was purified twice using silica gel chromatography with n-hexane/EtOAc (7:3~2:3) and n-hexane/EtOAc (7:3~1:1) to obtain white crystalline compound 105a (364 mg , 21% recovery rate).

¹ HNMR (500 MHz, CD ₃ OD): δ = 7.73 (1H, d, J = 1.7 Hz), 7.51 (1H, dd, J = 7.9, 1.7Hz), 7.41 (1H, d, J = 7.9 Hz), 7.25 (1H, t, J = 7.9 Hz), 6.93 (2H, dd, J = 4.3,2.0 Hz), 6.82 (1H, dd, J = 8.5, 2.3 Hz), 4.69 (2H, s), 4.51 (2H, s), 3.79 (3H, s).LC-MS: ＞99 % purity, RT 2.81 min, MS (m/z): 351 (M+H) ⁺

The same procedure as for the synthesis of compound 74 was carried out from compound 105a (105 mg, 0.30 mmol), CBr ₄ (119 mg, 0.36mmol), PPh ₃ (118 mg, 0.45mmol) and thiourea (22.8 mg, 0.30mmol). The residue was recrystallized from EtOH and _Et2O to give the title compound 105 as white crystals (22.7 mg, 15% recovery).

¹ HNMR (500 MHz, DMSO-d6): δ = 9.32 (1H, t, J= 6.0 Hz), 9.04 (3H, brs), 7.82 (1H, d, J= 1.7 Hz), 7.68 (1H, dd, J = 8.2, 2.0 Hz), 7.52 (1H, d, J = 8.5 Hz), 7.27 (1H, t, J = 7.9 Hz), 6.92-6.91 (2H, m), 6.84 (1H, dd, J= 8.2 , 2.0 Hz), 5.76 (1H, s), 4.54 (2H, s), 4.44 (2H, d, J = 5.7 Hz), 3.75 (3H, s).LC-MS: >99 % purity, RT 2.08 min , MS (m/z): 409 (M+H) ⁺

Synthesis of Compound 106 5-Bromo-2-((3-methoxybenzyl)carbamoyl)benzylcarbamidoselenoate hydrobromide

The same operation as the synthesis of compound 74 was performed from compound 105a (105 mg, 0.30 mmol), CBr ₄ (119 mg, 0.36 mmol), PPh ₃ (118 mg, 0.45mmol) and selenourea (22.8 mg, 0.19mmol) to obtain The title compound 106 was obtained as white crystals (74.6 mg, 46% recovery).

¹ HNMR (500 MHz, DMSO-d6): δ = 9.33-9.28 (2H, m), 9.07 (2H, brs), 7.81 (1H, d, J= 2.3 Hz), 7.65 (1H, dd, J = 8.2 , 2.0 Hz), 7.53 (1H, d, J = 7.9 Hz), 7.27 (1H, t, J = 7.9 Hz), 6.92-6.90 (2H, m), 6.84 (1H, d, J = 8.5 Hz), 4.45-4.43 (4H, m), 3.75 (3H, s).LC-MS: >99 % purity, RT 1.95 min, MS (m/z): 456 (M+H) ⁺

Synthesis of compound 107 5-Bromo-2-((cyclopropylmethyl)carbamoyl)benzyl carbamimidoselenoate hydrobromide

The title compound 107 (64.6 mg, 46% recovery) was obtained as white crystals from compound 93a (85.2 mg, 0.30 mmol), CBr ₄ (119 mg, 0.336 mmol), PPh ₃ (118 mg, 0.45 mmol) and selenourea (22.8 mg, 0.19 mmol) by the same operation as that for compound 74.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.36 (2H, brs), 9.06 (2H, brs), 8.87 (1.0H, t, J = 5.7 Hz), 7.80 (1H, d, J = 2.3 Hz ), 7.63 (1H, dd, J = 8.5, 2.3 Hz), 7.47 (1H, d, J = 8.5 Hz), 4.45 (2H, s), 3.13 (2H, t, J = 6.2 Hz), 1.02-1.01 (1H, m), 0.47-0.44 (2H, m), 0.23 (2H, q, J= 4.9 Hz). LC-MS: >99 % purity, RT 1.40 min, MS (m/z): 391 (M +H) ⁺

Synthesis of Compound 108 1,2-Phenylenebis(methylene) dicarbamimidoselenoate dihydrobromide

The same operation as for the synthesis of compound 2 was carried out from 1,2-bis(bromomethyl)benzene (compound 58a, 264 mg, 1.00 mmol) and selenourea (246 mg, 2.00 mmol), and the residue was recrystallized from EtOH: _Et2O (5:3) to give the title compound 108 (393 mg, 77% recovery) as light orange crystals.

¹ HNMR (500 MHz, CD ₃ OD): δ = 7.42 (2H, dd, J= 8.0, 4.0 Hz), 7.33 (2H, dd, J= 8.0, 4.0 Hz), 4.65 (4H, s). LC-MS:＞99％ purity, RT 0.34 min, MS (m/z): 349 (M+H) ⁺ .

Synthesis of compound 109 (4-Chloro-1,2-phenylene)bis(methylene) dicarbamimidoselenoate dihydrobromide

From 1,2-bis(bromomethyl)benzene (compound 7c, 308 mg, 1.00 mmol) and selenourea (246 mg, 2.00 mmol), the same operation as that for compound 2 was carried out, and the residue was recrystallized with EtOH:Et ₂ O (5:3) to obtain the title compound 109 (263 mg, 48.4% recovery) as light yellow crystals.

¹ HNMR (500 MHz, CD ₃ OD): δ = 7.47-7.34 (3H, m), 4.67-4.60 (4H, m). LC-MS: >99% purity, RT 0.37 min, MS (m/z) : 385 (M+H) ⁺ .

Synthesis of compound 110 4-Bromo-2-((4-cyanobenzyl)carbamoyl)benzyl carbamimidoselenoate hydrobromide

CBr ₄ (79.6 mg, 0.24 mmol) was added to a CH ₂ Cl ₂ solution (8 ml) of compound 103c (69.0 mg, 0.20 mmol) at 0°C, and then a CH ₂ Cl ₂ solution (4 ml) of PPh ₃ (78.7 mg, 0.30 mmol) was added. After stirring the reaction solution at room temperature for 1 hour, selenourea (24.6 mg, 0.20 mmol) was added, and stirred at 40°C for 12 hours. After the reaction solution was concentrated under reduced pressure, the residue was recrystallized with EtOH and Et ₂ O to obtain the title compound 110 (6.7 mg, 6% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.39 (1H, t, J= 5.7 Hz), 7.81-7.78 (3H, m), 7.72-7.70 (1H, m), 7.52 (2H, d, J = 8.5 Hz), 7.46 (1H, d, J = 8.5 Hz), 4.50 (2H, d, J= 5.7 Hz), 4.42 (2H, s).LC-MS: RT 2.06 min, MS (m/z): 451 (M+H) ⁺

Synthesis of compound 111 2-Bromo-6-((4-cyanobenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

After adding sulfuric acid (4.5 ml) to an acetic acid solution (10 ml) of isobenzofuran-1(3H)-one (compound 111a, 5.0 g, 37.3 mmol), stir at room temperature for 9 hours, and gradually add NBS (N -Bromosuccinimide, 9.95g, 55.9mmol). Water (100 ml) was added to the reaction solution, and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and the residue concentrated under reduced pressure was purified by silica gel chromatography with n-hexane/EtOAc (4:1-3:2) to obtain white crystalline compound 111b (1.09 g, 14 %Recovery rate).

¹ HNMR (500 MHz, CDCl ₃ ): δ = 7.89 (1H, d, J= 7.4 Hz), 7.81 (1H, d, J = 7.4 Hz), 7.46 (1H, t, J = 7.9 Hz), 5.24 ( 2H, s).LC-MS: >99 % purity, RT 5.95 min, MS (m/z): 215 (M+H)+

4-(Aminomethyl)benzonitrile hydrochloride (371 mg, 2.2 mmol) and Et ₃ N (607 mg, 6.0 mmol) were added to a THF solution (10 ml) of compound 111b (426 mg, 2.0 mmol) and stirred at 50°C for 12 hours. After the reaction, water was added to the reaction solution and extracted with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate, and the residue was purified by silica gel chromatography with n-hexane/EtOAc (3:2 to 2:3) to obtain white crystals of compound 111c (99.6 mg, 14% recovery).

¹ HNMR (500 MHz, CDCl ₃ ): δ = 7.72 (1H, dd, J= 7.9, 1.1 Hz), 7.67 (2H, d, J= 8.5 Hz), 7.53 (1H, dd, J = 7.9, 1.1 Hz), 7.49 (2H, d, J = 8.5 Hz), 7.24-7.23 (1H, m), 6.97 (1H, brs), 4.83 (2H, d, J = 6.8 Hz), 4.71 (2H, d, J = 6.2 Hz), 3.34 (1H, t, J = 7.1 Hz).LC-MS: ＞99 % purity, RT 2.45 min, MS (m/z): 346 (M+H) ⁺

At 0°C, CBr ₄ (115 mg, 0.35 mmol) was added to a CH ₂ Cl ₂ solution (10 ml) of compound 111c (99.6 mg, 0.29 mmol), and then a CH ₂ Cl ₂ solution (4 ml) of PPh ₃ (114 mg, 0.43 mmol) was added. After stirring the reaction solution at room temperature for 1 hour, thiourea (22.0 mg, 0.29 mmol) was added, and the mixture was stirred at 40°C for 12 hours. After the reaction solution was concentrated under reduced pressure, the residue was recrystallized with 2-propanol and n-hexane to obtain the title compound 111 (44.0 mg, 31% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.37 (1H, t, J = 5.7 Hz), 9.08 (3H, brs), 7.86 (1H, d, J = 6.8 Hz), 7.82 (2H, d, J = 8.5 Hz), 7.60 (1H, d, J = 7.4 Hz), 7.54 (2H,d, J = 8.5 Hz), 7.44 (1H, t, J = 7.9 Hz), 4.57 (2H, s), 4.55 (2H, d, J = 6.2 Hz).LC-MS: >99 % purity, RT 0.80 min, MS (m/z): 404 (M+H) ⁺

Synthesis of compound 112 Quinoxaline-2,3-diylbis(methylene) dicarbamimidoselenoate dihydrobromide

From compound 5a; 2,3-bis(bromomethyl)quinoxaline (316 mg, 1.00 mmol) and selenourea (246 mg, 2.00 mmol) were carried out in the same manner as for the synthesis of compound 1, and the residue was treated with EtOH: Et ₂ O ( 1:1) and recrystallized to obtain the title compound 112 (432 mg, 77% recovery) as off-white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.38 (3H, brs), 9.25 (3H, brs), 8.08-8.06 (2H, m), 7.93-7.90 (2H, m), 5.05 (4H, s).LC-MS: 96％ purity, RT 0.35 min, MS (m/z): 403 (M+H) ⁺ .

Synthesis of compound 113 5-Bromo-2-((4-cyanobenzyl)carbamoyl)benzyl carbamimidoselenoate hydrobromide

The title compound 113 (62.8 mg, 40% recovery) was obtained as white crystals from compound 76a (103 mg, 0.30 mmol), CBr ₄ (119 mg, 0.36 mmol), PPh ₃ (118 mg, 0.45 mmol) and selenourea (22.8 mg, 0.30 mmol) by the same operation as that for compound 74.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.35-9.33 (1H, m), 9.10 (3H, brs), 7.80-7.78 (3H, m), 7.63-7.61 (1H, m), 7.55-7.49 (3H, m), 4.50 (2H, d, J = 5.67 Hz), 4.42 (2H, s).LC-MS: ＞99 % purity, RT 1.64 min, MS (m/z): 451 (M+H) ⁺

Synthesis of compound 114 5-Bromo-2-((4-(trifluoromethyl)benzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

Add (4-(trifluoromethyl)phenyl)methanamine (0.848 mL, 6.00 mmol) to a THF solution (15 ml) of compound 74a; 5-bromoisobenzofuran-1(3H)-one (1065 mg, 5.00 mmol) and stir at 50°C for 24 hours. After the reaction solution was concentrated by reducing pressure, water was added and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and the concentrated residue was reduced in pressure and purified by silica gel chromatography with n-hexane/EtOAc (7:3-1:1) to obtain white crystals of compound 114a (137 mg, 7.0% recovery).

¹ HNMR (500 MHz, CDCl ₃ ): δ = 7.63 (2H, d, J = 8.5 Hz), 7.58 (1H, d, J = 1.7 Hz), 7.51 (1H, dd, J = 8.5, 1.7 Hz), 7.49 (1H, s), 7.46 (2H, d, J = 8.5 Hz), 6.86 (1H, brs), 4.70 (2H, d, J = 6.2 Hz), 4.60 (2H, d, J = 6.8 Hz), 3.97 (1H, t, J = 7.1 Hz).LC-MS: ＞99 % purity, RT 3.35 min, MS (m/z): 389 (M+H) ⁺

The same procedure as for the synthesis of compound 74 was carried out from compound 114a (137 mg, 0.35 mmol), CBr ₄ (140 mg, 0.42mmol), PPh ₃ (138 mg, 0.53mmol) and thiourea (26.8 mg, 0.35mmol). The residue was recrystallized from EtOH and Et ₂ O to give the title compound 114 as white crystals (11.3 mg, 6.1% recovery).

¹ HNMR (400 MHz, DMSO-d6): δ = 9.41 (1H, t, J = 6.3 Hz), 8.96 (3H, brs), 7.83 (1H, d, J = 2.0 Hz), 7.73-7.68 (3H, m), 7.58-7.55 (3H, m), 4.56-4.53 (4H, m).LC-MS: ＞99 % purity, RT 2.72 min, MS (m/z): 447 (M+H) ⁺

Synthesis of compound 115 5-Bromo-2-((2-methoxyethyl)carbamoyl)benzyl carbamimidothioate hydrobromide

2-Methoxyeth-1-amine (0.491 mL, 5.71 mmol) was added to a solution of compound 74a; 5-bromoisobenzofuran-1(3H)-one (1013 mg, 4.76 mmol) in THF (15 ml) , stir at 50°C for 24 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over magnesium sulfate, and the residue concentrated under reduced pressure was purified by silica gel chromatography with n-hexane/EtOAc (1:1-3:7) to obtain compound 115a (246 mg) as a colorless oily substance. , 18% recovery rate).

¹ HNMR (400 MHz, CDCl ₃ ): δ = 7.57 (1H, d, J = 2.0 Hz), 7.50 (1H, dd, J = 8.3, 2.0 Hz), 7.41 (1H, d, J = 8.3 Hz), 6.64 (1H, brs), 4.57 (2H, d, J = 6.3 Hz), 4.37 (1H, t, J = 7.1 Hz), 3.67-3.63 (2H, m), 3.60-3.56 (2H, m), 3.40 (3H, s).LC-MS: >99 % purity, RT 1.65 min, MS (m/z): 289 (M+H) ⁺

The same procedure as for the synthesis of compound 74 was carried out from compound 115a (86.4 mg, 0.30 mmol), CBr ₄ (119 mg, 0.36mmol), PPh ₃ (118 mg, 0.45mmol) and thiourea (22.8 mg, 0.30mmol). The residue was recrystallized from EtOH and Et ₂ O to give the title compound 115 as white crystals (24.2 mg, 19% recovery).

¹ HNMR (500 MHz, DMSO-d6): δ = 8.82 (1H, brs), 7.76 (H, d, J = 2.3 Hz), 7.61 (1H, dd, J = 7.9, 2.3 Hz), 7.39 (1H, d, J = 7.9 Hz), 4.46 (2H, s), 3.44-3.35 (4H, m), 3.24 (3H, s).LC-MS: >99 % purity, RT 0.72 min, MS (m/z) : 347 (M+H) ⁺

Synthesis of compound 116 5-Bromo-2-((3-chloro-4-fluorobenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

Add (3-chloro-4-fluorophenyl)methylamine (0.491 mL, 5.71 mmol) to a THF solution (15 ml) of compound 74a and 5-bromoisobenzofuran-1(3H)-one (1013 mg, 4.76 mmol) and stir at 50°C for 24 hours. After the reaction solution was concentrated by reducing pressure, water was added and extracted with dichloromethane. The organic layer was washed with brine, dried with magnesium sulfate, and the concentrated residue was reduced in pressure and purified by silica gel chromatography with n-hexane/EtOAc (7:3-1:1) to obtain yellow crystals of compound 116a (260 mg, 23% recovery).

¹ HNMR (500 MHz, CDCl ₃ ): δ = 7.57 (1H, d, J = 1.7 Hz), 7.51 (1H, dd, J = 8.2, 2.0 Hz), 7.45 (1H, d, J = 8.5 Hz), 7.40 (1H, dd, J = 6.8, 2.3 Hz), 7.24-7.22 (1H, m), 7.14 (1H, t, J = 8.5 Hz), 6.80 (1H, brs), 4.59-4.57 (4H, m) , 3.96 (1H, t, J = 6.8 Hz).LC-MS: >99 % purity, RT 3.21 min, MS (m/z): 373 (M+H) ⁺

The same procedure as for the synthesis of compound 74 was carried out from compound 116a (112 mg, 0.30 mmol), CBr ₄ (119 mg, 0.36mmol), PPh ₃ (118 mg, 0.45mmol) and thiourea (22.8 mg, 0.30mmol). The residue was recrystallized from EtOH and _Et2O to give the title compound 116 as white crystals (54.3 mg, 35% recovery).

¹ HNMR (500 MHz, DMSO-d6): δ = 9.33 (1H, t, J = 6.0 Hz), 9.03 (3H, brs), 7.82 (1H, d, J = 1.7 Hz), 7.68 (1H, dd, J = 8.2, 2.0 Hz), 7.57-7.53 (2H, m), 7.41-7.36 (2H, m), 4.53 (2H, s), 4.45 (2H, d, J = 5.7 Hz).LC-MS: ＞99 % purity, RT 2.24 min, MS (m/z): 431 (M+H) ⁺

Synthesis of compound 117 4-Bromo-2-((4-bromobenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

(4-Bromophenyl)methylamine (335 mg, 1.80 mmol) was added to a THF solution (15 ml) of compound 103b and 6-bromoisobenzofuran-1(3H)-one (320 mg, 1.50 mmol), and stirred at 50°C for 24 hours. After the reaction solution was concentrated by reducing pressure, water was added and extracted with dichloromethane. The organic layer was washed with brine, dried with magnesium sulfate, and the concentrated residue was reduced in pressure and purified by silica gel chromatography with n-hexane/EtOAc (7:3-1:1) to obtain yellow crystals of compound 117a (242 mg, 40% recovery rate).

¹ HNMR (500 MHz, CDCl ₃ ): δ = 7.69 (1H, d, J = 2.3 Hz), 7.58 (1H, dd, J = 8.2, 2.0 Hz), 7.50 (2H, d, J = 8.5 Hz), 7.29 (1H, d, J = 7.9 Hz), 7.24 (2H, d, J = 8.5 Hz), 6.75 (1H, brs), 4.60-4.58 (4H, m), 3.89 (1H, t, J = 6.8 Hz ).LC-MS: >99 % purity, RT 3.28 min, MS (m/z): 400 (M+H) ⁺

The same operation as that for compound 74 was carried out from compound 117a (112 mg, 0.30 mmol), CBr ₄ (119 mg, 0.36 mmol), PPh ₃ (118 mg, 0.45 mmol) and thiourea (22.8 mg, 0.30 mmol), and the residue was recrystallized from EtOH to obtain the title compound 117 (14.8 mg, 9.2% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.38 (1H, t, J = 6.0 Hz), 8.97 (3H, brs), 7.76-7.75 (2H, m), 7.55 (2H, d, J = 8.5 Hz), 7.52 (1H, d, J = 9.1 Hz), 7.32 (2H, d, J = 7.9 Hz), 4.51 (2H, s), 4.43 (2H, d, J = 5.7 Hz).LC-MS: ＞99 % purity, RT 2.51 min, MS (m/z): 458 (M+H) ⁺

Synthesis of Compound 118 4-Bromo-2-((4-cyanobenzyl)aminoformyl)benzyl(E)-N'-(3-chloro-4-fluorophenyl)formamidinethiohydrobromide/4 -Bromo-2-((4-cyanobenzyl)carbamoyl)benzyl(E)-N'-(3-chloro-4-fluorophenyl)carbamimidothioate hydrobromide

From compound 103c; 5-bromo-N-(4-cyanobenzyl)-2-(hydroxymethyl)benzamide (173 mg, 0.50 mmol), CBr ₄ (199 mg, 0.60 mmol), PPh ₃ (197 mg, 0.75 mmol) and 1-(3-chloro-4-fluorophenyl)thiourea (102 mg, 0.50 mmol). The same operation as for the synthesis of compound 74 was performed. The residue was recrystallized from EtOH to obtain white crystals. Title compound 118 (232 mg, 76% recovery).

¹ HNMR (500 MHz, DMSO-d6): δ = 9.41-9.38 (1H, m), 7.79-7.74 (5H, m), 7.53-7.48 (5H, m), 7.25 (1H, brs), 4.58 (2H, s), 4.50-4.49 (2H, m).LC-MS: ＞99 % purity, RT 3.14 min, MS (m/z): 533 (M+H) ⁺

Synthesis of compound 119 4-Bromo-2-((4-cyanobenzyl)carbamoyl)benzyl(E)-N'-(4-bromophenyl)carbamimidothioate hydrobromide

Compound 103c; 5-bromo-N-(4-cyanobenzyl)-2-(hydroxymethyl)benzamide (173 mg, 0.50 mmol), CBr ₄ (199 mg, 0.60 mmol), PPh ₃ (197 mg, 0.75 mmol) and 1-(4-bromophenyl)thiourea (102 mg, 0.50 mmol) were subjected to the same operation as that for compound 74, and the residue was recrystallized from EtOH to give the title compound 119 (143 mg, 45% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.40 (1H, brs), 7.83-7.81 (4H, m), 7.78-7.77 (1H, m), 7.67-7.65 (2H, m), 7.55-7.53 (4H, m), 7.19 (1H, brs), 4.60 (2H, brs), 4.53 (2H, d, J = 5.7 Hz).LC-MS: ＞99 % purity, RT 2.84 min, MS (m/z): 559 (M+H) ⁺

Synthesis of Compound 120 6,6'-(((4-fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(cyclopropylmethyl)-1,2 ,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4-Fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3- (cyclopropylmethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

Cyclopropylmethylamine (88.9 mg, 1.25 mmol), formaldehyde (187.5 μL, 37% wt, aqueous solution, 2.51 mmol) and (4-fluoro-1,2-phenylene)bis(methylene)dicarbonamide dithiodihydrobromide (compound 2, 272.2 mg, 0.63 mmol) were reacted in the same manner as compound 9. The reaction residue was recrystallized with EtOH and _Et2O (1:2) and then with 2-propanol to give the title compound 120 (337.7 mg, 58.4% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 7.50-7.48 (1H, m), 7.33-7.31 (1H, m), 7.26-7.22 (1H, m), 4.60 (4H, brs), 4.43 (8H, brs), 2.23-2.20 (4H, m), 0.84-0.82 (2H, m), 0.49-0.46 (4H, m), 0.03-0.01 (4H, m).LC-MS: 92 % purity, RT 0.45 min, MS (m/z): 464 (M+H) ⁺

Synthesis of Compound 121 6,6'-(((4-fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(cyclohexylmethyl)-1,2, 3,4-Tetrahydro-1,3,5-triazine)/6,6'-(((4-Fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-( cyclohexylmethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

Cyclopropylmethylamine (56.6 mg, 0.50 mmol), formaldehyde (75.0 μL, 37% wt, aqueous solution, 1.00 mmol) and (4-fluoro-1,2-phenylene)bis(methylene)dicarbonamide dithiodihydrobromide (compound 2, 108.5 mg, 0.25 mmol) were reacted in the same manner as compound 9. The reaction residue was recrystallized from 2-propanol and _Et2O (1:1) to give the title compound 121 (147.1 mg, 53.8% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 7.51-7.49 (1H, m), 7.34-7.33 (1H, m), 7.22-7.20 (1H, m), 4.62-4.60 (4H, m), 4.34-4.31 (8H, m), 2.13-2.07 (4H, m), 1.65-1.62 (10H, m), 1.44-1.42 (2H, m), 1.21-1.11 (6H, m), 0.89-0.80 (4H, m). LC-MS: 91 % purity, RT 2.00 min, MS (m/z): 547 (M+H) ⁺

Synthesis of compound 122 1,2-Phenylenebis(methylene)(E,E)-bis(N'-(3-chloro-4-fluorophenyl)carbamimidothioate) dihydrobromide

1-(3-Chloro-4-fluorophenyl)thiourea (205 mg, 1.00 mmol) was added to compound 58a at room temperature under argon atmosphere; 1,2-bis(bromomethyl)benzene (132 mg, 0.50 mmol) in EtOH (8 mL), and the reaction mixture was stirred at 80 °C for 3 h. After the reaction solution was cooled to room temperature and concentrated under reduced pressure, the residue was recrystallized from EtOH and Et ₂ O (1:2) to obtain the title compound 122 (236.7 mg, 70% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 7.62-7.43 (8H, m), 7.30-7.14 (2H, m), 4.72 (4H, brs).LC-MS: ＞99 % purity, RT 3.03 min, MS (m/z): 512 (M+H) ⁺

Synthesis of Compound 123 (4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-chlorophenyl)formamidinethio)dihydrobromide /(4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-chlorophenyl)carbamimidothioate) dihydrobromide

Compound 36b; 1,2-bis(bromomethyl)-4,5-dichlorobenzene (180 mg, 0.54 mmol) and 1-(4-chlorophenyl)thiourea (202 mg, 1.08 mmol) were subjected to the same operation as that for synthesizing compound 2. After the reactants were concentrated under reduced pressure, the residue was recrystallized with EtOH and _Et2O (1:1) to obtain the title compound 123 (263 mg, 68.8% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 7.81 (2H, s), 7.59 (4H, d, J = 8.5 Hz), 7.32 (4H, d, J = 8.5 Hz), 4.81 (4H, brs) .LC-MS: >99 % purity, RT 4.19 min, MS (m/z): 545 (M+H) ⁺

Synthesis of Compound 124 (4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-methoxyphenyl)formamidinethio)dihydrobromide Acid acid/(4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-methoxyphenyl)carbamimidothioate) dihydrobromide

From compound 36b; 1,2-bis(bromomethyl)-4,5-dichlorobenzene (370 mg, 1.11mmol) was performed with 1-(4-chlorophenyl)thiourea (405 mg, 2.22mmol) The same procedure was used to synthesize compound 2. After concentrating the reaction product under reduced pressure, the residue was recrystallized with EtOH and Et ₂ O (1:1) to obtain the title compound 124 (770 mg, 99% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 7.77 (2H, s), 7.21-7.11 (4H, m), 7.03 (4H, d, J = 8.5 Hz), 4.75 (4H, brs), 3.75 ( 6H, s).LC-MS: >99 % purity, RT 2.02 min, MS (m/z): 536 (M+H) ⁺

Synthesis of Compound 125 (4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(3-chlorophenyl)formamidinethio)dihydrobromide /(4,5-dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(3-chlorophenyl)carbamimidothioate) dihydrobromide

Compound 36b; 1,2-bis(bromomethyl)-4,5-dichlorobenzene (151 mg, 0.454 mmol) and 1-(3-chlorophenyl)thiourea (169 mg, 0.907 mmol) were subjected to the same operation as that for synthesizing compound 2. After the reactants were concentrated under reduced pressure, the residue was recrystallized with EtOH and _Et2O (1:1) to obtain the title compound 125 (269 mg, 84% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 7.82 (2H, s), 7.56-7.47 (4H, m), 7.40 (2H, s), 7.27 (2H, d, J = 7.9 Hz ), 4.87 (4H, s).LC-MS: ＞99 % purity, RT 4.72 min, MS (m/z): 545 (M+H) ⁺

Synthesis of Compound 126 (4-Fluoro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-bromophenyl)formamidinethio)dihydrobromide/(4 -Fluoro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-bromophenyl)carbamimidothioate) dihydrobromide

Compound 2c was synthesized from 1,2-bis(bromomethyl)-4-fluorobenzene (211 mg, 0.75mmol) and 1-(4-bromophenyl)thiourea (347 mg, 1.50mmol). The same operation was performed. After concentrating the reactant under reduced pressure, the residue was recrystallized with EtOH and Et ₂ O (1:1) to obtain the title compound 126 (468 mg, 84% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.67 (4H, brs), 7.73-7.71 (4H, m), 7.58-7.57 (1H, m), 7.42-7.40 (1H, m), 7.32-7.26 (5H, m), 4.86-4.85 (4H, m).LC-MS: 90 % purity, RT 3.39 min, MS (m/z): 583 (M+H) ⁺

Synthesis of compound 127 (4-Fluoro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-fluorophenyl)carbamimidothioate) dihydrobromide/(4-Fluoro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-fluorophenyl)carbamimidothioate) dihydrobromide

Compound 2c; 1,2-bis(bromomethyl)-4-fluorobenzene (211 mg, 0.75 mmol) and 1-(4-fluorophenyl)thiourea (256 mg, 1.50 mmol) were subjected to the same operation as that for synthesizing compound 2. After the reactants were concentrated under reduced pressure, the residue was recrystallized with EtOH and _Et2O (1:1) to obtain the title compound 127 (409 mg, 88% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 9.75 (4H, brs), 7.58-7.28 (11H, m), 4.85 (4H, brs).LC-MS: 93 % purity, RT 1.70 min, MS (m/z): 461 (M+H) ⁺

Synthesis of Compound 128 (4-Fluoro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-methoxyphenyl)formamidinethio)dihydrobromide/ (4-Fluoro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-methoxyphenyl)carbamimidothioate) dihydrobromide

Synthesis from compound 2c; 1,2-bis(bromomethyl)-4-fluorobenzene (211 mg, 0.75mmol) and 1-(4-methoxyphenyl)thiourea (274 mg, 1.50mmol) The same operation was performed for compound 2. After concentrating the reaction product under reduced pressure, the residue was recrystallized with EtOH and Et ₂ O (1:1) to obtain the title compound 128 (400 mg, 83% recovery rate) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 7.59-7.56 (1H, m), 7.41-7.39 (1H, m), 7.32-7.31 (1H, m), 7.23-7.20 (4H, m), 7.07 -7.06 (4H, m), 4.80 (4H, brs) , 3.79 (6H, s).LC-MS: >99 % purity, RT 1.60 min, MS (m/z): 485 (M+H) ⁺

Synthesis of compound 129 (4-Fluoro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(3-chloro-4-fluorophenyl)formamidinethio)dihydrobromide Salt/(4-Fluoro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(3-chloro-4-fluorophenyl)carbamimidothioate) dihydrobromide

From compound 2c; 1,2-bis(bromomethyl)-4-fluorobenzene (211 mg, 0.75mmol) with 1-(3-chloro-4-fluorophenyl)thiourea (307 mg, 1.50mmol) The same operation as for synthesizing compound 2 was performed. After concentrating the reactant under reduced pressure, the residue was recrystallized with EtOH and Et ₂ O (1:1), and the crystals were washed with Et ₂ O: n-hexane (1:2) to obtain a white color. The title compound 129 crystallized (506 mg, 98% recovery).

¹ HNMR (500 MHz, DMSO-d6): δ = 9.65 (4H, brs), 7.66-7.57 (5H, m), 7.43-7.30 (4H, m), 4.87-4.86 (4H, m).LC-MS : 92% purity, RT 3.74 min, MS (m/z): 530 (M+H) ⁺

Synthesis of Compound 130 (4-Fluoro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(2,4-difluorophenyl)carbamimidothioate) dihydrobromide/(4-Fluoro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(2,4-difluorophenyl)carbamimidothioate) dihydrobromide

From compound 2c; 1,2-bis(bromomethyl)-4-fluorobenzene (211 mg, 0.75mmol) and 1-(2,4-difluorophenyl)thiourea (283 mg, 1.50mmol) were compared The same operation was used to synthesize compound 2. After concentrating the reactants under reduced pressure, the residue was recrystallized with EtOH and Et ₂ O (1:1), and the crystals were washed with Et ₂ O: n-hexane (1:2) to obtain white crystals. The title compound 130 (420 mg, 85% recovery).

¹ HNMR (500 MHz, DMSO-d6): δ = 9.67 (4H, brs), 7.61-7.43 (6H, m), 7.31-7.24 (3H, m), 4.86 (4H, brs). LC-MS: 95 % purity, RT 3.22 min, MS (m/z): 497 (M+H) ⁺

Synthesis of Compound 131 (4,5-Difluoro-1,2-phenylene)bis(methylene)dimethylamidinethiodihydrobromide/(4,5-Difluoro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide

Compound 131a; 5,6-difluoroisobenzofuran-1,3-dione (1000 mg, 5.43 mmol) and LiAlH ₄ (618 mg, 16.3 mmol) were subjected to the same operation as that for synthesizing compound 2b. The reaction residue was purified by silica gel chromatography (n-hexane/EtOAc=5:1 to 1:1) to obtain compound 131b (620 mg, 66% recovery) as white crystals.

LC-MS: 95％ purity, RT 1.13 min, MS (m/z): 197 (M + Na) ⁺ .

Compound 131b (548 mg, 3.15 mmol) and phosphorus tribromide (0.359 mL, 3.78 mmol) were prepared by the same operation as for the synthesis of compound 2c. The residue was purified by silica gel chromatography with n-hexane/EtOAc (3:1) to obtain compound 131c (293 mg, 31% recovery) as white crystals.

Compound 131c (168 mg, 0.56 mmol) and thiourea (85 mg, 1.12 mmol) were subjected to the same operation as that for compound 2. The residue was recrystallized with EtOH and Et ₂ O (2:3) to obtain compound 131 as white crystals (229 mg, 91% recovery). ¹ HNMR (500 MHz, DMSO-d6): δ = 9.22 (6H, brs), 7.67-7.63 (2H, m), 4.64 (4H, brs). LC-MS:＞99％ purity, RT 0.37 min, MS (m/z): 291 (M + H) ⁺ .

Synthesis of compound 132 (4,5-Difluoro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-chlorophenyl)carbamimidothioate) dihydrobromide/(4,5-Difluoro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-chlorophenyl)carbamimidothioate) dihydrobromide

From compound 131c; 1,2-bis(bromomethyl)-4,5-difluorobenzene (117 mg, 0.39 mmol) and 1-(4-chlorophenyl)thiourea (146 mg, 0.78 mmol), the same operation as that for synthesizing compound 2 was performed. After the reactants were concentrated under reduced pressure, the residue was recrystallized with EtOH and _Et2O (1:1) to obtain compound 132 (119 mg, 45% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 7.67-7.58 (6H, m), 7.36-7.32 (4H, m), 4.82 (4H, brs). LC-MS: 91 % purity, RT 3.41 min, MS (m/z): 512 (M+H) ⁺

Synthesis of compound 133 6,6'-(((4-fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3,4-dichlorophenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4-fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3,4-dichlorophenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

2-(3,4-Dichlorophenyl)ethan-1-amine (190 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol) and (4-fluoro-1,2-phenylene)bis(methylene)dicarbonamide dithiodihydrobromide (compound 2, 217 mg, 0.50 mmol) were reacted by the same operation as that for synthesizing compound 9. The reaction residue was purified by amino-silica gel chromatography (n-hexane/EtOAc = 1:1 to 1:3) to obtain the title compound 133 (82 mg, 23.4% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 7.52-7.48 (4H, m), 7.33-7.30 (1H, m), 7.23-7.20 (2H, m), 7.13-7.11 (1H, m), 6.92 -6.88 (1H, m), 4.24-3.99 (12H, m), 2.77-2.68 (8H, m).LC-MS: 85 % purity, RT 2.36 min, MS (m/z): 701 (M+H ) ⁺

Synthesis of Compound 134 (4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(3-chloro-4-fluorophenyl)formamidinethio)bis Hydrobromide/(4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(3-chloro-4-fluorophenyl)carbamimidothioate) dihydrobromide

From compound 36b; 1,2-bis(bromomethyl)-4,5-dichlorobenzene (200 mg, 0.60 mmol) and 1-(3-chloro-4-fluorophenyl)thiourea (246 mg, 1.20 mmol) The same operation as for the synthesis of compound 2 was performed. After concentrating the reaction product under reduced pressure, the residue was recrystallized from n-hexane and Et ₂ O (1:1) to obtain the title compound 134 (363 mg, 81% recovery rate) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 7.79 (2H, s), 7.57-7.52 (4H, m), 7.31-7.29 (2H, m), 4.82 (4H, s).LC-MS: 97 % purity, RT 4.47 min, MS (m/z): 581 (M+H) ⁺

Synthesis of compound 135 (4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-bromophenyl)carbamimidothioate) dihydrobromide

Synthesis from compound 36b; 1,2-bis(bromomethyl)-4,5-dichlorobenzene (200 mg, 0.60 mmol) and 1-(4-bromophenyl)thiourea (278 mg, 1.20 mmol) The same operation was performed for compound 2. After concentrating the reaction product under reduced pressure, the residue was recrystallized from n-hexane and Et ₂ O (1:3) to obtain the title compound 135 (460 mg, 96% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 7.82 (2H, s), 7.72 (4H, d, J = 8.5 Hz), 7.27 (4H, d, J = 8.5 Hz), 4.84 (4H, s) .LC-MS: 95 % purity, RT 4.48 min, MS (m/z): 634 (M+H) ⁺

Synthesis of compound 136 (4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(3-bromophenyl)carbamimidothioate) dihydrobromide

Synthesis from compound 36b; 1,2-bis(bromomethyl)-4,5-dichlorobenzene (200 mg, 0.60 mmol) and 1-(3-bromophenyl)thiourea (278 mg, 1.20 mmol) The same operation was performed for compound 2. After concentrating the reaction product under reduced pressure, the residue was recrystallized from n-hexane and Et ₂ O (1:3) to obtain the title compound 136 (419 mg, 88% recovery rate) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 7.82 (2H, s), 7.61 (2H, d, J = 7.9 Hz), 7.51 (2H, s), 7.48 (2H, t, J = 7.9 Hz) , 7.31 (2H, d, J = 7.9 Hz), 4.85 (4H, s).LC-MS: 93 % purity, RT 4.79 min, MS (m/z): 634 (M+H) ⁺

Synthesis of compound 137 (4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(4-fluorophenyl)carbamimidothioate) dihydrobromide

From compound 36b; 1,2-bis(bromomethyl)-4,5-dichlorobenzene (200 mg, 0.60 mmol) and 1-(4-fluorophenyl)thiourea (204 mg, 1.20 mmol) were subjected to the same operation as that for synthesizing compound 2. After the reactants were concentrated under reduced pressure, the residue was recrystallized with n-hexane and _Et2O (1:3) to obtain the title compound 137 (364 mg, 90% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 7.83 (2H, s), 7.40-7.34 (8H, m), 4.86 (4H, brs). LC-MS: 98 % purity, RT 2.78 min, MS ( m/z): 512 (M+H) ⁺

Synthesis of compound 138 (4,5-Dichloro-1,2-phenylene)bis(methylene)(E,E)-bis(N'-(p-tolyl)carbamimidothioate) dihydrobromide

Compound 2 was synthesized from compound 36b; 1,2-bis(bromomethyl)-4,5-dichlorobenzene (290 mg, 0.87 mmol) and 1-(p-tolyl)thiourea (290 mg, 1.74 mmol). The same operation was performed. After concentrating the reaction product under reduced pressure, the residue was recrystallized from n-hexane and Et ₂ O (1:3) to obtain the title compound 138 (499 mg, 86% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 7.77 (2H, s), 7.29 (4H, d, J = 7.9 Hz), 7.12 (4H, d, J = 8.5 Hz), 4.78 (4H, brs), 2.30 (6H, s).LC-MS: 99 % purity, RT 2.54 min, MS (m/z): 504 (M+H) ⁺

Synthesis of compound 139 6,6'-(((4,5-Dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3-chloro-4-fluorobenzyl)-1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4,5-Dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3-chloro-4-fluorobenzyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From (3-chloro-4-fluorophenyl)methanamine (160 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol) and (4,5-dichloro-1,2-phenylene)bis(methylene)dicarbonamide dithiodihydrobromide (compound 36, 242 mg, 0.50 mmol), the reaction was carried out by the same operation as the synthesis of compound 9, and the reaction residue was recrystallized with n-hexane and AcOEt (5:1) to obtain the title compound 139 (196 mg, 57% recovery) as white crystals.

¹ H NMR (500 MHz, DMSO-d6): δ = 10.39 (2H, brs), 7.89 (2H, s), 7.50-7.48 (2H, m), 7.45-7.41 (2H, m), 7.33-7.30 (2H, m), 4.79 (4H, s), 4.38 (8H, s), 3.62 (4H, s).LC-MS: 89％ purity, RT 2.31 min, MS (m/z): 691 (M + H) ⁺ .

Synthesis of Compound 140 6,6'-(((4-Fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(4-(trifluoromethyl)phenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4-Fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(4-(trifluoromethyl)phenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From 2-(4-(trifluoromethyl)phenyl)ethan-1-amine (189 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol) and (4-fluoro-1,2-phenylene)bis(methylene)dicarbonamide dithiodihydrobromide (compound 2, 217 mg, 0.50 mmol), the reaction was carried out by the same operation as the synthesis of compound 9, and the reaction residue was recrystallized with n-hexane and AcOEt (5:1) to obtain the title compound 140 (187 mg, 54% recovery) as pale yellow crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 10.29 (2H, brs), 7.66-7.65 (4H, m), 7.49-7.45 (5H, m), 7.31-7.28 (1H, m), 6.96-6.94 (1H, m), 4.70-4.68 (4H, m), 4.42 (8H, s), 2.88-2.85 (4H, m), 2.64-2.59 (4H, m).LC-MS: 91 % purity, RT 2.27 min, MS (m/z): 699 (M+H) ⁺

Synthesis of Compound 141 6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(4-(trifluoromethyl)styrene) (base)-1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4-Bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl ))bis(3-(4-(trifluoromethyl)phenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From 2-(4-(trifluoromethyl)phenyl)ethan-1-amine (189 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol) and (4-bromo-1,2-phenyl)bis(methylene)dicarboamide dithiodihydrobromide (compound 10, 247 mg, 0.50 mmol), the reaction was carried out by the same operation as the synthesis of compound 9, and the reaction residue was recrystallized with n-hexane and AcOEt (5:1) to obtain the title compound 141 (249 mg, 65% recovery) as pale yellow crystals.

¹ H NMR (500 MHz, DMSO-d6): δ = 10.32 (2H, brs), 7.67-7.33 (11H, m), 4.70-4.69 (4H, m), 4.42 (8H, s), 2.87 (4H, t, J = 6.5 Hz), 2.65-2.62 (4H, m). LC-MS: 87 % purity, RT 2.74 min, MS (m/z): 761 (M + H) ⁺ .

Synthesis of Compound 142 1,2-bis(((5-(4-(trifluoromethyl)phenylethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio )methyl)benzene/1,2-Bis(((5-(4-(Trifluoromethyl)phenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl )benzene

2-(4-(Trifluoromethyl)phenyl)eth-1-amine (189 mg, 1.00 mmol) was gently added to formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol) in 1,4-dioxane (5.0 mL) solution, after stirring at room temperature for 20 minutes, add 1,2-phenylenebis(methylene)diaminothiamidine sulfate dihydrochloride (compound 1, 164 mg, 0.500 mmol) , stir at 80°C for 12 hours. The reaction mixture was returned to room temperature, toluene (3.0 mL) was added and concentrated under reduced pressure. The residue was recrystallized from EtOH and Et ₂ O (2:3) to obtain the title compound 142 (199 mg, 58% recovery) as white crystals.

¹ H NMR (500 MHz, DMSO-d6): δ = 10.73 (2H, brs), 7.65 (4H, d, J = 7.9 Hz), 7.47-7.44 (6H, m), 7.10-7.08 (2H, m) , 4.82 (4H, brs), 4.38 (8H, s), 2.83 (4H, t, J = 7.4 Hz), 2.56 (4H, t, J = 7.4 Hz).LC-MS: 90 % purity, RT 2.18 min , MS (m/z): 681 (M + H) ⁺ .

Synthesis of Compound 143 6,6'-(((4,5-Dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(4-(trifluoromethyl)phenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine))/6,6'-(((4,5-Dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(4-(trifluoromethyl)phenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From 2-(4-(trifluoromethyl)phenyl)ethyl-1-amine (189 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol) and (4,5-dichloro-1 , 2-phenylene)bis(methylene)dicarboxamide dithiodihydrobromide (compound 36, 243 mg, 0.50 mmol), reacted by the same operation as the synthesis of compound 9, to 2 -The reaction residue was recrystallized from propanol to obtain the title compound 143 (268 mg, 71% recovery) as white crystals.

¹ H NMR (500 MHz, DMSO-d6): δ = 10.33 (2H, brs), 7.72 (2H, s), 7.65 (4H, d, J = 7.9 Hz), 7.46 (4H, d, J = 7.9 Hz), 4.70 (4H, s), 4.43 (8H, s), 2.86 (4H, t, J = 7.4 Hz), 2.64-2.61 (4H, m).LC-MS: 92 % purity, RT 2.51 min, MS (m/z): 751 (M + H) ⁺ .

Synthesis of Compound 144 6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3-chloro-4-fluorobenzyl) -1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4-Bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl)) bis(3-(3-chloro-4-fluorobenzyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

(3-Chloro-4-fluorophenyl)methanamine (159 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol) and (4-bromo-1,2-phenyl) bis(methylene) base) dicarboxamide dithiodihydrobromide (compound 10, 247 mg, 0.50 mmol), reacted by the same operation as the synthesis of compound 9, and the reaction residue was subjected to NH-silica gel chromatography with n-hexane/EtOAc (2:1～1:3) purification, the title compound 144 (109 mg, 31% recovery rate) was obtained as a light yellow oily substance.

¹ H NMR (500 MHz, DMSO-d6): δ = 7.59-7.29 (9H, m), 4.25-4.00 (8H, m), 3.63 (8H, s). LC-MS: 87 % purity, RT 2.26 min , MS (m/z): 701 (M + H) ⁺ .

Synthesis of Compound 145 1,2-Bis(((5-(3-Chloro-4-fluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl)benzene/1,2-Bis(((5-(3-Chloro-4-fluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl)benzene

(3-Chloro-4-fluorophenyl)methanamine (319 mg, 2.00 mmol) was added gently to a solution of formaldehyde (301 μL, 37% wt, aqueous, 4.0 mmol) in 1,4-dioxane (5.0 mL) In, after stirring at room temperature for 10 minutes, add 1,2-phenylenebis(methylene)diaminothiamidine sulfate dihydrochloride (compound 1, 327 mg, 1.00mmol), and stir at 80°C. Stir for 12 hours. The reaction mixture was returned to room temperature, toluene (3.0 mL) was added and concentrated under reduced pressure. The residue was recrystallized from EtOH and Et ₂ O (2:3) to obtain the title compound 145 (200 mg, 32% recovery) as a pale yellow oily substance.

¹ HNMR (500 MHz, DMSO-d6): δ = 10.83 (2H, brs), 7.62-7.60 (2H, m), 7.51-7.49 (2H, m), 7.42-7.38 (4H, m), 7.32-7.29 (2H, m), 4.93 (4H, s), 4.34 (8H, s), 3.56 (4H, s).LC-MS: 96 % purity, RT 1.88 min, MS (m/z): 622 (M+ H) ⁺

Synthesis of Compound 146 6,6'-(((4-Fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3-chloro-4-fluorobenzyl)-1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4-Fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3-chloro-4-fluorobenzyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From (3-chloro-4-fluorophenyl)methanamine (319 mg, 2.00 mmol), formaldehyde (301 μL, 37% wt, aqueous solution, 4.00 mmol) and (4, fluoro-1,2-phenylene)bis(methylene)dicarbonamide dithiodihydrobromide (compound 2, 434 mg, 1.00 mmol), the reaction was carried out by the same operation as the synthesis of compound 9, and the reaction residue was recrystallized from 2-propanol and _Et2O (1:1) to obtain the title compound 146 (209 mg, 32.7% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 10.39-10.35 (2H, m), 7.65-7.31 (9H, m), 4.82-4.80 (4H, m), 4.39 (8H, s), 3.66-3.65 (4H, m).LC-MS: 75 % purity, RT 2.17 min, MS (m/z): 641 (M+H) ⁺

Synthesis of Compound 147 6,6'-(((4-fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(4-methoxyphenylethyl)- 1,2,3,4-Tetrahydro-1,3,5-triazine)/6,6'-(((4-Fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis (3-(4-methoxyphenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From 2-(4-methoxyphenyl)eth-1-amine (151 mg, 1.00mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00mmol) and (4,fluoro-1,2-phenylene (Compound 2, 217 mg, 0.50 mmol) was reacted by the same operation as the synthesis of compound 9, and the reaction residue was treated with 2-propane Recrystallization of the alcohol with Et ₂ O (1:1) gave the title compound 147 as pale yellow crystals (225 mg, 72% recovery).

¹ HNMR (500 MHz, DMSO-d6): δ = 10.28-10.25 (2H, m), 7.49-7.46 (1H, m), 7.33-7.31 (1H, m), 7.13-7.10 (4H, m), 7.00-6.98 (1H, m), 6.86-6.84 (4H, m), 4.69-4.68 (4H, m), 4.40 (8H, s), 3.72 (6H, s), 2.70-2.67 (4H, m), 2.57-2.53 (4H, m).LC-MS: 96 % purity, RT 1.70 min, MS (m/z): 623 (M+H) ⁺

Synthesis of Compound 148 6,6'-(((4-Bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(4-methoxyphenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4-Bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(4-methoxyphenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From 2-(4-methoxyphenyl)ethan-1-amine (151 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol) and (4-bromo-1,2-phenyl)bis(methylene)dicarboamide dithiodihydrobromide (compound 10, 248 mg, 0.50 mmol), the reaction was carried out by the same operation as the synthesis of compound 9, and the reaction residue was recrystallized from 2-propanol and _Et2O (1:1) to obtain the title compound 148 (246 mg, 72% recovery) as a light yellow oil.

¹ H NMR (500 MHz, DMSO-d6): δ = 10.27-10.25 (2H, m), 7.65 (1H, brs), 7.37-7.35 (1H, m), 7.31-7.29 (1H, m), 7.11-7.07 (4H, m), 6.83-6.81 (4H, m), 4.68 (4H, brs), 4.36 (8H, brs), 3.69 (6H, s), 2.67-2.62 (4H, m), 2.54-2.48 (4H, m). LC-MS: 80 % purity, RT 1.86 min, MS (m/z): 685 (M+H) ⁺

Synthesis of compound 149 6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3-(trifluoromethyl)styrene) (base)-1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4-Bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl ))bis(3-(3-(trifluoromethyl)phenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From 2-(3-(trifluoromethyl)phenyl)ethan-1-amine (189 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol) and (4-bromo-1,2-phenyl)bis(methylene)dicarboamide dithiodihydrobromide (compound 10, 248 mg, 0.50 mmol), the reaction was carried out by the same operation as the synthesis of compound 9. The reaction residue was purified by NH-silica gel chromatography with n-hexane/EtOAc (3:2-0:1) and recrystallized from 2-propanol to obtain the title compound 149 (268 mg, 71% recovery) as pale yellow crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 10.29-10.26 (2H, m), 7.63-7.54 (9H, m), 7.35-7.26 (2H, m), 4.66 (4H, s), 4.42 (8H, s), 2.86 (4H, brs), 2.65-2.60 (4H, m).LC-MS: 81% purity, RT 2.35 min, MS (m/z): 761 (M + H) ⁺ .

Synthesis of Compound 150 6,6'-(((4-Fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3-(trifluoromethyl)phenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4-Fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3-(trifluoromethyl)phenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From 2-(3-(trifluoromethyl)phenyl)ethan-1-amine (189 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol) and (4, fluoro-1,2-phenylene)bis(methylene)dicarboamide dithiodihydrobromide (compound 2, 217 mg, 0.50 mmol), the reaction residue was recrystallized from 2-propanol and _Et2O (1:1) to obtain the title compound 150 (316 mg, 90% recovery) as pale yellow crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 10.31-10.28 (2H, m), 7.66-7.27 (10H, m), 6.89-6.87 (1H, m), 4.70 (4H, s), 4.43 (8H , s), 2.89-2.85 (4H, m), 2.65-2.61 (4H, m).LC-MS: 84 % purity, RT 2.25 min, MS (m/z): 700 (M+H) ⁺

Synthesis of compound 151 Benzo[b]thiophene-2,3-diylbis(methylene) dicarbamimidothioate dihydrobromide

From compound 151a; 2,3-bis(bromomethyl)benzo[b]thiophene (1000 mg, 3.13 mmol) and thiourea (476 mg, 6.25 mmol), the same operation as that for compound 1 was performed, and the residue was recrystallized with EtOH and Et ₂ O (2:3) to obtain white crystals of compound 151 (807 mg, 55% recovery).

¹ HNMR (500 MHz, DMSO-d6): δ = 9.34-9.16 (6H, m), 8.04-7.94 (2H, m), 7.51-7.46 (2H, m), 4.98 (2H, s), 4.89 (2H, s).LC-MS: 95% purity, RT 0.45 min, MS (m/z): 311 (M + H) ⁺ .

Synthesis of Compound 152 6,6'-(((4,5-Dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3-(trifluoromethyl)phenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4,5-Dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3-(trifluoromethyl)phenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From 2-(3-(trifluoromethyl)phenyl)ethan-1-amine (189 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol) and (4,5-dichloro-1,2-phenylene)bis(methylene)dicarboamide dithiodihydrobromide (compound 36, 243 mg, 0.50 mmol), the reaction was carried out by the same operation as the synthesis of compound 9, and the reaction residue was recrystallized from 2-propanol to obtain the title compound 152 (269 mg, 72% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 10.33 (2H, brs), 7.71 (2H, s), 7.62 (2H, s), 7.57-7.54 (6H, m), 4.71 (4H, s), 4.44 (8H, s), 2.89-2.86 (4H, m), 2.68-2.65 (4H, m).LC-MS: 78% purity, RT 2.52 min, MS (m/z): 751 (M + H) ⁺ .

Synthesis of Compound 153 6,6'-(((4,5-dichloro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(3-methoxyphenylene) (base)-1,2,3,4-tetrahydro-1,3,5-triazine)/6,6'-(((4,5-Dichloro-1,2-phenylene)bis(methylene))bis (sulfanediyl))bis(3-(3-methoxyphenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

From 2-(3-methoxyphenyl)ethan-1-amine (189 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt, aqueous solution, 2.00 mmol) and (4,5-dichloro-1,2-phenylene)bis(methylene)dicarboamide dithiodihydrobromide (compound 36, 243 mg, 0.50 mmol), the reaction was carried out by the same operation as that for the synthesis of compound 9, and the reaction residue was recrystallized from 2-propanol to obtain the title compound 153 (222 mg, 66% recovery) as white crystals.

¹ HNMR (500 MHz, DMSO-d6): δ = 7.74 (2H, s), 7.22-7.19 (2H, m), 6.84-6.76 (6H, m), 4.69 (4H, s), 4.41 (8H, s), 3.74 (6H, s), 2.75-2.72 (4H, m), 2.66-2.63 (4H, m).LC-MS: 86% purity, RT 2.00 min, MS (m/z): 675 (M + H) ⁺ .

[Test Example 1] In vitro compound evaluation experimental method In vitro compounds were evaluated according to the following procedures.

Using the enzyme assay protocol of rhIDO (recombinant human IDO: recombinant human IDO), add 4 μL of the compound solution to the rhIDO reaction solution (0.5 M potassium phosphate buffer (20 μL), 0.2 M ascorbic acid (20 μL), 0.5 mM methylene blue (4 μL), 10 mg/mL catalase (2 μL), H ₂ O (128 μL), rhIDO (2 μL)) 176 μL. After pipetting and pre-incubating at 37°C for 10 minutes, add 20 μL of 2mM tryptophan aqueous solution to bring the total volume to 200 μL, pipet again and react at 37°C for 120 minutes. After the reaction, the enzyme reaction was stopped by adding 40 μL of 30% [v/v] trichloroacetic acid aqueous solution to the reaction solution. Stir thoroughly with a pipette and heat at 50°C for 15 minutes. To convert N-methyl kynurenine into kynurenine. After heating, centrifuge (15000 rpm, 5 minutes, 24°C), transfer 150 μL of the supernatant to a transparent 96-well flat plate, and measure the absorbance at 490 nm (background measurement) using SpectraMax M5SK. After the measurement, 2% [w/v] p-dimethylbenzaldehyde acetic acid solution was added at 150 μL/well and reacted for 5 minutes, and then the absorbance was measured again at 490 nm. The kynurenine production rate was calculated by the following formula. Kynurenine production rate (%) of each compound when using rhIDO = {(absorbance at 490 nm in a tryptophan-containing aqueous solution containing rhIDO and the compound of the present invention - background absorbance) / (when no compound solution is added) Absorbance at 490 nm in an aqueous solution containing tryptophan - background absorbance)}×100

Enzyme assay protocol using rhTDO (recombinant human TDO) 4 μL of compound solution was added to 176 μL of rhTDO reaction solution (0.5 M potassium phosphate buffer (20 μL), 0.2 M ascorbic acid (20 μL), 0.5 mM methylene blue (4 μL), 10 mg/mL catalase (2 μL), H2O (128 μL), rhTDO (2 μL)). After pipetting and pre-incubation at 37°C for 10 minutes, 20 μL of 2 mM tryptophan aqueous solution was added to a total volume of 200 μL, and pipetting was again performed and reacted at 37°C for 120 minutes. After the reaction, the enzyme reaction was stopped by adding 40 μL of 30% [v/v] trichloroacetic acid aqueous solution to the reaction solution. Stir thoroughly with a pipette and heat at 50°C for 15 minutes to convert N-formylkynurenine to kynurenine. After heating, centrifuge (15,000 rpm, 5 minutes, 24°C), transfer 150 μL of the supernatant to a transparent 96-well flat-bottom plate, and measure the absorbance at 490 nm (background measurement) using a SpectraMax M5SK. After the measurement, add 2% [w/v] p-dimethylbenzaldehyde acetic acid solution at 150 μL/well and react for 5 minutes, then measure the absorbance at 490 nm again. The kynurenine production rate is calculated as follows. Kynurenine production rate of each compound when using rhTDO (%) = {(absorbance at 490 nm in the aqueous solution containing tryptophan containing rhTDO and the compound of the present invention - background absorbance) / (absorbance at 490 nm in the aqueous solution containing tryptophan without adding the compound solution - background absorbance)} × 100

IDO Cell-based assay protocol A431 cells (3.0×10 ⁵ cells/mL) suspended in assay medium (D-MEM; Wako 040-30095, 5% FBS, 50 units/mL penicillin, 50 μg/mL streptomycin, 2 mM L-glutamine) were seeded at 100 μL/well in a transparent 96-well flat-bottom plate and incubated at 37°C and 5% CO ₂ for 24 hours. After incubation, the medium was removed, and a medium containing tryptophan was added at 80 μL/well (L-tryptophan was added to the assay medium to 178 μM), and further, a compound solution was added at 10 μL/well. After 1 hour of pre-incubation, 100 ng/mL IFN-γ diluted with a culture medium containing tryptophan was added at 10 μL/well to a total volume of 100 μL/well and cultured for 24 hours. After incubation, the absorbance at 460 nm was measured using SpectraMax M5SK (Molecular Device) (background measurement). After measurement, kynurenine quantification reagent (prepared with 7% [v/v] aqueous trichloroacetic acid and 2% [w/v] p-dimethylbenzaldehyde acetate solution at a ratio of 2:5 [v/v]) was added at 200 μL/well, and after 5 minutes of reaction, the absorbance was measured again at 460 nm. The kynurenine production rate was calculated as follows. Kynurenine production rate (%) of each compound when using A431 cells = {(absorbance at 460 nm in a culture medium containing tryptophan containing A431 cells and the compound of the present invention - background absorbance) / (absorbance at 460 nm in a culture medium containing tryptophan without adding the compound solution - background absorbance)} × 100

TDO Cell-based assay protocol A172 cells (3.0 × 10 ^{5 )} suspended in assay medium (PRMI-1640; Wako 186-02155, 5% FBS, 50 units/mL penicillin, 50 μg/mL streptomycin) cells/mL), seeded into a transparent 96-well flat-bottomed plate at 100 μL/well, and cultured at 37°C and 5% CO _for 24 hours. After the culture, the medium was removed, and the measurement medium was added at 80 μL/well, and the compound solution was added at 10 μL/well. After preincubation for 1 hour, 5mM tryptophan aqueous solution (final concentration of L-tryptophan 524 μM) was added at 10 μL/well to bring the total volume to 100 μL/well and incubated for 24 hours. After incubation, the absorbance at 460 nm (background measurement) was measured using SpectraMax M5SK (Molecular Device). After measurement, add kynurenic acid quantitative reagent (7% [v/v] aqueous trichloroacetic acid and 2% [w/v] p-dimethylbenzaldehyde acetate solution at 2:5 at 200 μL/well [v/v] preparation), after 5 minutes of reaction, the absorbance was measured again at 460 nm. The kynurenine production rate was calculated by the following formula. Kynurenine production rate (%) of each compound when using A172 cells = {(absorbance at 460 nm in a tryptophan-containing medium containing A172 cells and the compound of the present invention - background absorbance) / (in a solution without adding the compound Absorbance at 460 nm in tryptophan-containing culture medium - background absorbance)} × 100

The experimental results of the above four procedures are shown in the table below.

[Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

"<10 μM>" in Table 2 refers to the final concentration of the compound of the present invention. However, the data assigned "*", that is, the final concentration of the compound in the rhTDO kynurenine production rate of compound 63 and the rhIDO kynurenine production rate of compound 73 was 3 μM. It can be clearly seen from Table 2 that the compounds of the present invention have excellent IDO and/or TDO inhibitory activity.

[Test Example 2] Efficacy test of IDO/TDO inhibitor combined with anti-PD-1 antibody in CT-26WT colorectal cancer subcutaneous transplanted mice <Legend, Materials, Methods> 5×10 ⁵ homologous colorectal cancer cell line CT26WT were subcutaneously transplanted into 6-week-old female Balb/c mice. After 11 days, when the average tumor size reached 212 mm ³ , the mice were divided into 6 groups, with 6 to 8 mice in each group, and oral medication (oral medication solvent and 40 mg/kg of Epacadostat, compound 1 was administered twice a day every five hours for days 1 to 5, days 8 to 12, and days 15 to 19) and intraperitoneal administration (once a day, on days 1, 4, 8, 11, 15, and 18, PBS and 200 micrograms of anti-PD-1 antibody were administered each), after which the long and short diameters of subcutaneous tumors were measured three times a week with a caliper, and the mean and standard deviation of the volume of each group were plotted. The calculation formula is volume (mm ³ ) = [width ² (mm ² ) × length (mm)]/2. The oral medication was dissolved in an oral medication solvent of DMSO: PEG 400: PBS = 5:20:75. The results are shown in Figure 1.

The meaning of each symbol is as follows. ○: Oral pharmaceutical solvent and PBS, ●: Oral pharmaceutical solvent and anti-PD-1 antibody, □: Epacadostat and PBS, ■: Epacadostat and anti-PD-1 antibody, △: Compound 1 and PBS, ▲: Compound 1 with anti-PD1 antibodies.

As shown in Figure 1, when compound 1 of the present invention is used in combination with an anti-PD-1 antibody, tumor growth can be inhibited.

[Test Example 3] Efficacy test of compound 1 combined with oxaliplatin using CT-26CL25 colorectal cancer subcutaneously transplanted mice <Figure, Materials, Methods> 5×10 ⁵ homologous colorectal cancer cell line CT-26CL25 were subcutaneously transplanted into 8-week-old female Balb/c mice. The average tumor size was 185 mm after 10 days. At the time point of ³ , the mice were divided into 4 groups, each with 8 mice. They started oral medication (oral medication solvent, 40 mg/kg of compound 1, twice a day every five hours, for 1 to 5 days, 8 to 12 days) and intravenous injection (5% glucose solution and 10 mg/kg of oxaliplatin were given once a day on the 1st and 8th days). After that, the long and short diameters of the subcutaneous tumors were measured three times a week with a caliper, and the mean and standard deviation of each group were calculated from the ratio of the volume from the start of medication. The calculation formula is volume (mm ³ ) = [width ² (mm ² ) × length (mm)]/2. Compound 1 was dissolved in an oral medication solvent of DMSO:PEG400:PBS = 5:20:75. The results are shown in Figure 2.

The meanings of the symbols are as follows: ○: oral pharmaceutical solvent and 5% glucose solution, ●: oral pharmaceutical solvent and oxaliplatin, △: compound 1 and 5% glucose solution, ▲: compound 1 and oxaliplatin.

As can be seen from Figure 2, when compound 1 of the present invention is used in combination with oxaliplatin, tumor growth can be inhibited.

[Test Example 4] Efficacy test of the combined use of Compound 1, Compound 15, and Compound 29 with oxaliplatin using CT-26WT colorectal cancer homogeneous subcutaneously transplanted mice <Illustration, Materials, Methods> 5 × 10 ⁵ homogeneous large intestines The cancer cell line CT-26WT was subcutaneously transplanted into 6-week-old female Balb/c mice. After 10 days, when the average tumor size was 139 mm ³ , they were divided into 5 groups of 6 mice each, and oral administration (oral administration) was started. Use pharmaceutical solvents, 40 mg/kg each of Compound 1, Compound 15, and Compound 29 twice daily every five hours for days 1 to 5 and 8 to 12) and intravenously (once daily on days 1 and 8). After administration of 5% glucose solution and 10 mg/kg oxaliplatin), the long and short diameters of the subcutaneous tumors were measured three times a week with calipers, and the ratio of the calculated volume from the day of drug administration to the standard was plotted. Difference. The calculation formula is volume (mm ³ ) = [width ² (mm ² ) × length (mm)]/2. Compound 1 and compound 15 were dissolved in an oral pharmaceutical solvent of DMSO:PEG400:PBS =10:40:150, and compound 29 was dissolved in an oral pharmaceutical solvent of DMSO:PEG400:PBS =20:80:50. . The results are shown in Figure 3.

The meaning of each symbol is as follows. ○: Oral pharmaceutical solvent and 5% glucose solution, ●: Oral pharmaceutical solvent and oxaliplatin, ▲: Compound 1 and oxaliplatin, ■: Compound 15 and oxaliplatin, ×: Compound 29 with oxaliplatin.

As shown in FIG3 , when compound 1, compound 15 or compound 29 is used in combination with oxaliplatin, tumor proliferation can be inhibited.

[Test Example 5] Efficacy test of combined use of an IDO/TDO inhibitor and oxaliplatin using CT-26WT colorectal cancer homogeneous subcutaneously transplanted mice <Illustration, Materials, Methods> 5 × 10 ⁵ homogeneous colorectal cancer cell lines CT-26WT was subcutaneously transplanted into 6-week-old female Balb/c mice. After 10 days, the average tumor size was in the range of 41 to 427 mm ^3. They were divided into 1 group of 6 mice and oral administration was started (oral administration of medicinal solvent and 40 mg/kg each of Epacadostat, Compounds 37, 31, 7, 15, 1, 50, 52, 76, 95, 33, 49, 2, 10, 36, 103, 38, 29, twice daily every five hours , lasting 1 to 5 days, 8 to 12 days) and intravenous injection (5% glucose solution and 10 mg/kg oxaliplatin given once a day on days 1 and 8), after which subcutaneous tumors were measured with calipers three times a week The long diameter and short diameter, and the mean and standard deviation of each group were plotted as the ratio of the calculated volume from the day of medication start. The calculation formula is volume (mm ³ ) = [width ² (mm ² ) × length (mm)]/2. Oral pharmaceuticals are suspended in an oral pharmaceutical solvent of 0.5% Methyl Cellulose. The results are shown in Figure 4. (A total of multiple experiments on the same medicine)

The meanings of the symbols are as follows. Solid line in ●: oral pharmaceutical solvent and 5% glucose solution, solid line in ■: compound 37 and oxaliplatin, solid line in ▲: epacadostat and oxaliplatin, solid line in X: compound 31 and oxaliplatin, solid line in ○: oral pharmaceutical solvent and oxaliplatin, solid line in □: compound 7 and oxaliplatin, solid line in △: compound 15 and oxaliplatin, solid line in m: compound 1 and oxaliplatin, dotted line in ●: compound 50 and oxaliplatin, dotted line in ■: compound 52 and Oxaliplatin, dotted line in ▲: compound 76 and oxaliplatin, dotted line in X: compound 95 and oxaliplatin, dotted line in ○: compound 33 and oxaliplatin, dotted line in □: compound 49 and oxaliplatin, dotted line in △: compound 2 and oxaliplatin, solid line in +: compound 10 and oxaliplatin, solid line in rectangle: compound 36 and oxaliplatin, dotted line in ●: compound 103 and oxaliplatin, dotted line in ■: compound 38 and oxaliplatin, dotted line in ▲: compound 29 and oxaliplatin

As can be seen from Figure 4, when compounds 37, 31, 7, 15, 1, 50, 52, 76, 95, 33, 49, 2, 10, 36, 103, 38, 29 of the present invention and oxaliplatin are used in combination , can inhibit tumor proliferation.

[Test Example 6] Efficacy test of the combined use of compounds 29 and 38 with anti-PD-1 antibodies using CT-26WT colorectal cancer homogeneous subcutaneously transplanted mice <Illustration, Materials, Methods> 5 × 10 ⁵ homogeneous colorectal cancer cell lines CT-26WT was subcutaneously transplanted into 6-week-old female Balb/c mice. After 10 days, when the average tumor size reached 250 mm ³ , they were divided into 6 groups, 6 mice in each group, and oral medication (medicated solvent was administered orally) Compounds 29 and 38 were administered with 40 mg/kg each twice daily every five hours for days 1 to 5 and 8 to 12) and intravenously (once daily in PBS on days 1 and 8 with 200 mg/kg each). micrograms of anti-PD1 antibody), and then use calipers to measure the long and short diameters of subcutaneous tumors three times a week, and plot the average and standard deviation of each group of calculated volumes. The calculation formula is volume (mm ³ ) = [width ² (mm ² ) × length (mm)]/2. Compounds 29 and 38 were suspended in an oral pharmaceutical solvent of 0.5% methyl cellulose. The results are shown in Figure 5.

The meaning of each symbol is as follows. Solid line in ●: oral pharmaceutical solvent and PBS, dotted line in X: oral pharmaceutical solvent and anti-PD-1 antibody, solid line in □: compound 29 and PBS, solid line in ■: compound 29 and anti-PD-1 antibody, dotted line in △: compound 38 and PBS, dotted line in ▲: compound 38 and anti-PD-1 antibody

As shown in FIG5 , when the compounds 29 and 38 of the present invention are used in combination with anti-PD-1 antibodies, tumor proliferation can be inhibited.

[Test Example 7] Efficacy test of the combined use of compound 103 and anti-PD-1 antibody using CT-26WT colorectal cancer homogeneous subcutaneously transplanted mice <Illustration, Materials, Methods> 5×10 ⁵ homogeneous colorectal cancer cell lines CT- 26WT was subcutaneously transplanted into 6-week-old female Balb/c mice. At the time point when the average tumor size was 176 mm ¹⁰ days later, they were divided into 3 groups, 8 mice in each group, and oral administration (40 mg/kg of compound 103, Twice a day every five hours for days 1 to 5, 8 to 12) and intravenously (once a day on days 1 and 8 in PBS with 200 micrograms of anti-PD1 antibody each), after which, use a caliper The long and short diameters of subcutaneous tumors were measured three times a week, and the mean and standard deviation of each group of calculated volumes were plotted. The calculation formula is volume (mm ³ ) = [width ² (mm ² ) × length (mm)]/2. Compound 103 was suspended in 0.5% Methyl Cellulose in an oral pharmaceutical solvent. The results are shown in Figure 6.

The meanings of the symbols are as follows: Solid line with ●: 5% glucose solution and PBS, dotted line with X: 5% glucose solution and anti-PD-1 antibody, solid line with ○: Compound 103 and anti-PD-1 antibody

As can be seen from Figure 6, compound 103 can inhibit tumor growth when used in combination with an anti-PD-1 antibody.

The following items numbered from [1] to [31] provide various aspects of the present invention. [1] A compound having formula (I) or a pharmaceutically acceptable salt of the compound. [Chemical 189] [wherein, ring A represents an aromatic ring, an aliphatic ring, a heterocyclic ring, or a condensed ring of two or more rings selected from aromatic rings, aliphatic rings, and heterocyclic rings; X, ^R1 , and ^R2 are substituents of the ring atoms constituting ring A; m represents an integer of 0 to 6; X is selected from the group consisting of a halogen atom, a substituted or unsubstituted straight or branched alkyl group, a substituted or unsubstituted straight or branched alkoxy group, a substituted or unsubstituted straight or branched alkenyl group, a substituted or unsubstituted straight or branched alkenyloxy group, a substituted or unsubstituted straight or branched alkynyl group, a substituted or unsubstituted straight or branched alkynyloxy group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a halogenated alkyl group, a halogenated alkoxy group, a cyano group, a hydroxyl group, an amino group, a nitro group, a carboxyl group, and a substituted or unsubstituted aryl group, or a substituted or unsubstituted aralkyl group. When m is 2 to 6, X may be the same or different; ^R1 and ^R2 may be the same or different; ^R1 is a group represented by formula (II) or formula (III), [Chemical 190] (wherein, R ¹¹ and R ¹² each independently represent a hydrogen atom, a fluorine atom, or a substituted or unsubstituted alkyl group, Y1 represents O or NR ²¹ , R ²¹ , R ²² and R ²³ each independently represent a hydrogen atom, a substituted or unsubstituted straight or branched alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group, and R ²¹ and R ²² or R ²³ may also be combined to form a ring, Z1 represents S, SO, SO ₂ , O or Se, r1 represents any integer from 1 to 8, and when r1 is 2 or more, R ¹¹ and R ¹² may be the same or different) [Chemical 191] (wherein, R ³¹ and R ³² each independently represent a hydrogen atom, a fluorine atom or a C1-6 alkyl group, Z2 is O or NR ⁶¹ (R ⁶¹ represents a hydrogen atom, a substituted or unsubstituted straight or branched alkyl group, or a substituted or unsubstituted aryl group), R ³³ represents a substituted or unsubstituted straight or branched alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkanealkyl group, r2 is 0 or any integer from 1 to 8, and when r2 is 2 or more, R ³¹ and R ³² may be the same or different)), R ² is independent of R ¹ and represents a group represented by formula (II) or formula (III)].

[2] The compound as described in [1] or a pharmaceutically acceptable salt of the compound, wherein in formula (II), the functional group in which R ²¹ and R ²² or R ²³ combine to form a ring is the following formula (IV ) represents the functional group. [Chemical 192] [In the formula, R ¹¹ , R ¹² , r1 , Z1 , R ²² , and R ²³ have the same meanings as in formula (II), Z3 represents CH, CR ⁵⁴ or N, and R ⁵¹ and R ⁵² each independently represent a hydrogen atom. , or a substituted or unsubstituted linear or branched alkyl group, R ⁵⁴ represents a halogen atom, or a substituted or unsubstituted linear or branched alkyl group, R ⁵³ represents a substituted or unsubstituted aryl group, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl, r3 represents any integer from 1 to 8, when r3 is 2 or more, R ⁵¹ and R ⁵² may be the same or different, r4 and r6 are each independently represents 0 or 1, r4 and r6 are different when they are 0, r5 represents 0 or any integer from 1 to 5, when r5 is 2 or more, R ⁵⁴ can be the same or different, in addition, the sign of R ²² (R ²³ ) Indicates either R ²² or R ²³ ).

[3] The compound or a pharmaceutically acceptable salt of the compound as described in [1] or [2], wherein ^R1 is selected from the group consisting of the following groups: [wherein, Y is selected from the group consisting of O, S, SO, _SO2 and Se; Z is selected from the group consisting of O, S, SO, _SO2 and Se; n represents an integer of 1 to 8; p represents an integer of 0 to 8; q represents an integer of 1 to 8; r represents an integer of 1 to 8; s represents an integer of 1 to 8; ^R3 represents a substituted or unsubstituted straight or branched alkyl group; ^R4 represents a substituted or unsubstituted heterocyclic group, _-CONH2 or [Chemical 194] (wherein, R ⁴¹ , R ⁴² and R ⁴³ may be the same or different and are selected from the group consisting of hydrogen atom, substituted or unsubstituted straight or branched alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group and substituted or unsubstituted heterocyclic group) R ⁵ is selected from the group consisting of hydrogen atom, substituted or unsubstituted cycloalkyl group and substituted or unsubstituted aryl group: R ⁶ is selected from the group consisting of substituted or unsubstituted aryl group, substituted or unsubstituted cycloalkyl group and substituted or unsubstituted heterocyclic group] R ² is independent of R ¹ and is selected from the group consisting of the following groups. [Chemical 195] (wherein, Y, Z, n, p, q, r, s, R ³ , R ⁴ , R ⁵ and R ⁶ have the same meanings as above).

[4] The compound or pharmaceutically acceptable salt of any one of [1] to [3], wherein ^R1 and ^R2 are bonded to adjacent ring atoms of ring A.

[5] The compound or a pharmaceutically acceptable salt of the compound described in any one of [1] to [4], wherein R ¹ and R ² have the same group.

[6] The compound or a pharmaceutically acceptable salt of the compound according to [5], wherein in the compound represented by formula (I), ^R1 and ^R2 are groups represented by formula (II), in which ^R11 and ^R12 are hydrogen atoms, Y1 represents ^NR21 , and r1 is 1.

[7] The compound described in [6] or a pharmaceutically acceptable salt thereof, which is any one of the following formulae. (wherein A, X and m are as defined in [1], and Z, s, R ⁴¹ , R ⁴² , R ⁴³ and R ⁶ have the same meanings as defined in [3]).

[8] The compound or a pharmaceutically acceptable salt of the compound as described in any one of [1] to [4], wherein R ¹ and R ² have different groups.

[9] The compound described in [8] or a pharmaceutically acceptable salt of the compound, which has the following formula. [Chemical 197] ^{( In} the formula ^, A ^, , - (CH ₂ ) _n - Y - R ⁴ (where n, Y and R4 have the meanings as defined in [3]), - (CH ₂ ) _p - CONH - (CH ₂ ) _q - R ⁵ ( In the formula, p, q and R ⁵ have the meanings as defined in [3]), and the following formula [Chemical Formula 198] (In the formula, r, s, R ⁶ and Z have the meanings as defined in Item 3 of the patent application), and R ⁷ and R ⁸ are different from each other)

[10] The compound as described in any one of [1] to [9] or a pharmaceutically acceptable salt of the compound, wherein ring A is selected from benzene ring, naphthalene ring, quinoxaline ring, thiophene ring, indole ring, benzothiophene ring, imidazole ring, quinoline ring, quinazoline ring, and pyridine ring.

[11] The compound or a pharmaceutically acceptable salt of the compound as described in any one of [1] to [10], wherein X is selected from a halogen atom, substituted or unsubstituted linear or branched chain C ₁ to C ₈ alkyl, substituted or unsubstituted linear or branched C ₁ to C ₈ alkoxy group, substituted or unsubstituted linear or branched C ₂ to C ₈ alkenyl, substituted or unsubstituted linear or branched Chain C ₂ to C ₈ alkenyloxy group, substituted or unsubstituted straight chain or branched chain C ₂ to C ₈ alkynyl group, substituted or unsubstituted straight chain or branched chain C ₂ to C ₈ alkynyloxy group, substituted or unsubstituted Substituted C ₃ to C ₈ cycloalkyl group, substituted or unsubstituted C ₃ to C ₈ cycloalkenyl group, substituted or unsubstituted C ₃ to C ₈ cycloalkynyl group, C ₁ to C ₃ haloalkyl group, cyano group, Hydroxy group, amino group, carboxyl group, substituted or unsubstituted C ₆ to C ₁₈ aryl group, and substituted or unsubstituted aralkyl group (the carbon number of the aryl part is C ₆ to C ₁₀ , the carbon number of the alkylene part is It is the group composed of C ₁ ~ C ₄ ).

[12] A compound as described in any one of [1] to [11] or a pharmaceutically acceptable salt thereof, wherein X is a group selected from the following group. - As a halogen atom, fluorine atom, chlorine atom, bromine atom and iodine atom are selected. - As a substituted or unsubstituted straight or branched alkyl group, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-octyl, carboxymethyl, 2-carboxyethyl, 3-hydroxy-1-propyl, aminomethyl, 2-aminoethyl, hydroxymethyl and 2-hydroxyethyl are selected. - As a substituted or unsubstituted straight or branched alkoxy group, methoxy, ethoxy, n-propoxy and n-butoxy are selected. - As a substituted or unsubstituted straight or branched alkenyl group, vinyl, 2-propenyl (allyl) and 3-butenyl are selected. - As substituted or unsubstituted straight or branched alkenyloxy, there are ethyleneoxy, 2-propyleneoxy (allyloxy), and 3-butenyloxy - As substituted or unsubstituted straight or branched alkynyl, there are ethynyl, 2-propynyl, and 3-butynyl - As substituted or unsubstituted straight or branched alkynyloxy, there are ethynyloxy, 2-propynyloxy, and 3-butynyloxy - As substituted or unsubstituted cycloalkyl, there are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl - As substituted or unsubstituted cycloalkenyl, there are 1-cyclopropenyl, 1-cyclobutenyl, 1-cyclopentenyl, and 1-cyclohexenyl - As halogenated alkyl, fluoromethyl, difluoromethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, 2,2,2-triiodoethyl or pentafluoroethyl - As halogenated alkoxy, fluoromethoxy, difluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, triiodomethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 2,2,2-tribromoethoxy, 2,2,2-triiodoethoxy or pentafluoroethoxy - Cyano - Hydroxyl - Amino - Nitro - Carboxyl - As substituted or unsubstituted aryl, phenyl, naphth-1-yl, and naphth-2-yl - Substituted or unsubstituted aralkyl groups include benzyl, phenethyl, and 3-phenyl-1-propyl

[13] The compound or a pharmaceutically acceptable salt of the compound as described in any one of [1] to [12], wherein ring A is a benzene ring, and R 1 is substituted at the 1-position of the ring, and R ¹ is substituted at the 2-position. In the following formula (I-4) substituted with R ² , [Chemical Formula 199] (In the formula, R ¹ and R ² have the meanings defined in any one of [1] to [3]) The following formulas of [1] to [3] except R ¹ and R ² (I-4- a) is selected from [Chemical 200] Ｐｈ＝、３-Ｆ-Ｐｈ＝、４-Ｆ-Ｐｈ＝、５-Ｆ-Ｐｈ＝、６-Ｆ-Ｐｈ＝、３-ＣａＰｈ＝、４-ＣｌＰ＝＝、５-Ｃｌ- Ph ＝, 6-Cl-Ph＝, 3-Br-Ph＝, 4-Br-Ph＝, 5-Br-Ph＝, 6-Br-Ph＝, 3-I-Ph＝, 4-I- Ph＝ , 5-I-Ph＝, 6-I-Ph＝, 3-Me-Ph＝, 4-Me-Ph＝, 5-Me-Ph＝, 6-Me-Ph＝, 3-Et-P h=, 4-Et-Ph＝, 5-Et-Ph＝, 6-Et-Ph＝, 3-Pr-Ph＝, 4-Pr-Ph＝, 5-Pr-Ph＝, 6-P r-Ph=、3 -Bu-Ph＝, 4-Bu-Ph＝, 5-Bu-Ph＝, 6-Bu-Ph＝, 3-t-Bu-Ph＝, 4-t-Bu-Ph＝, 5- t-Bu -Ph＝, 6-t-Bu-Ph＝, 3-MeO-Ph＝, 4-MeO-Ph＝, 5-MeO-Ph＝, 6-MeO-Ph＝, 3 -EtO-Ph＝、4- ＥｔＯＰｈ＝, ５-ＥｔＯＰｈ＝, ６-ＥｔＯＰｈ＝, ３-ＣＦ ₃ -Ｐｈ＝, ４- _ＣＦ３ -Ｐｈ＝, ５-ＣＦ _３－ Ｐｈ＝、６－ＣＦ _３－ Ｐｈ＝ , 3-C ₂ F ₅ -Ph＝, 4-C ₂ F ₅ -Ph＝, 5-C ₂ F ₅ -Ph＝, 6-C ₂ F ₅ -Ph＝, 3-CF ₃ ＯＰｈ＝、 4-CF ₃ O-Ph＝, 5-CF ₃ O-Ph＝, 6-CF ₃ O-Ph＝, 3-C ₂ F ₅ O-Ph＝, 4-C ₂ Ｆ _５ Ｏ-Ｐｈ＝、５ -C ₂ F ₅ O-Ph＝, 6-C ₂ F ₅ O-Ph＝, 3-CN-Ph＝, 4-CN-Ph＝, 5-CN-Ph＝, 6-C Ｎ－Ｐｈ＝、３ -OH-Ph＝, 4-OH-Ph＝, 5-OH-Ph＝, 6-OH-Ph＝, 3-NH ₂ -Ph＝, 4-NH ₂ -Ph＝, 5- NH ₂ - Ph = , 6-NH ₂ -Ph＝, 3-NO ₂ -Ph＝, 4-NO ₂ -Ph＝, 5-NO ₂ -Ph＝, 6-NO ₂ -Ph＝, 3-CO ＯＨ－Ｐｈ＝、４－ ＣＯＯＨＰｈ＝, ５-ＣＯＯＨＰｈ＝, ６ＣＯＯＨ-Ｐｈ＝, (any two of the 3, 4, 5 and 6 digits) -F ₂ -Ｐｈ＝, (the 3, 4, 5 and 6 digits Any two places) - Cl ₂ - Ph =, (any two places at digits 3, 4, 5 and 6) - Br ₂ - Ph =, (any two places at digits 3, 4, 5 and 6) - I ₂ - Ｐｈ＝, (any two places of digits 3, 4, 5 and 6) - Me ₂ -Ｐｈ＝, (any two places of digits 3, 4, 5 and 6) - Et ₂ -Ｐｈ-, (3, 4, Any two places in digits 5 and 6) -Pr ₂ -Ph＝, (any two places in digits 3, 4, 5 and 6) -Bu ₂ -Ph＝, (any two places in digits 3, 4, 5 and 6) ) - (CN) ₂ - Ph =, (any two places in digits 3, 4, 5 and 6) - (OH) ₂ - Ph =, (any two places in digits 3, 4, 5 and 6) - (NH ₂ ) ₂ - Ph =, (any two places of digits 3, 4, 5 and 6) - (NO ₂ ) ₂ - Ph =, (any two places of digits 3, 4, 5 and 6) - (MeO) ₂ -Ｐｈ＝, (any two places of digits 3, 4, 5 and 6) - (EtO) ₂ -Ｐｈ＝, (any two places of digits 3, 4, 5 and 6) - (ＣＦ ₃ ) ₂ -Ｐｈ＝ , (any three places in digits 3, 4, 5 and 6) - F ₃ - Ph =, (any three places in digits 3, 4, 5 and 6) - Cl ₂ - Ph =, (3, 4, 5 and Any four places of 6 digits) -F ₄ -Ph＝, and び (any four places of 3, 4, 5 and 6 digits) -Cl ₄ -Ph＝, the group formed by (in the formula, "Ph＝" means that it is from the formula (I-4-a) excluding (X) m- part)

The definitions of the above formula (I-4) and formula (I-4-a) can be explained as follows. In formula (I), ring A is a benzene ring, R ¹ and R ² are adjacent and substituted to form ring A. When the substitution position of R ¹ is taken as the 1-position and the substitution position of R ² is taken as the 2-position, X is selected From hydrogen atom, 3-fluoro group, 4-fluoro group, 5-fluoro group, 6-fluoro group, 3-chloro group, 4-chloro group, 5-chloro group, 6-chloro group, 3-bromo group, 4 -Bromo, 5-bromo, 6-bromo, 3-iodo, 4-iodo, 5-iodo, 6-iodo, 3-methyl, 4-methyl, 5-methyl, 6 -Methyl, 3-ethyl, 4-ethyl, 5-ethyl, 6-ethyl, 3-n-propyl, 4-n-propyl, 5-n-propyl, 6-n-propyl, 3- n-butyl, 4-n-butyl, 5-n-butyl, 6-n-butyl, 3-tert-butyl, 4-tert-butyl, 5-tert-butyl, 6-tert-butyl, 3-methoxy base, 4-methoxy, 5-methoxy, 6-methoxy, 3-ethoxy, 4-ethoxy, 5-ethoxy, 6-ethoxy, 3-trifluoromethyl , 4-trifluoromethyl, 5-trifluoromethyl, 6-trifluoromethyl, 3-pentafluoroethyl, 4-pentafluoroethyl, 5-pentafluoroethyl, 6-pentafluoroethyl, 3-trifluoromethoxy, 4-trifluoromethoxy, 5-trifluoromethoxy, 6-trifluoromethoxy, 3-pentafluoroethoxy, 4-pentafluoroethoxy, 5- Pentafluoroethoxy, 6-pentafluoroethoxy, 3-cyano, 4-cyano, 5-cyano, 6-cyano, 3-hydroxy, 4-hydroxy, 5-hydroxy, 6-hydroxy, 3-amino, 4-amino, 5-amino, 6-amino, 3-nitro, 4-nitro, 5-nitro, 6-nitro, 3-carboxy, 4-carboxy, 5- Carboxyl, 6-carboxy, 3,4-difluoro, 3,5-difluoro, 3,6-difluoro, 4,5-difluoro, 4,6-difluoro, 5,6- Difluoro, 3,4-dichloro, 3,5-dichloro, 3,6-dichloro, 4,5-dichloro, 4,6-dichloro, 5,6-dichloro base, 3,4-dibromo base, 3,5-dibromo base, 3,6-dibromo base, 4,5-dibromo base, 4,6-dibromo base, 5,6-dibromo base, 3,4-dimethyl, 3,5-dimethyl, 3,6-dimethyl, 4,5-dimethyl, 4,6-dimethyl, 5,6-dimethyl, 3, 4-diethyl, 3,5-diethyl, 3,6-diethyl, 4,5-diethyl, 4,6-diethyl, 5,6-diethyl, 3,4- Di-n-propyl, 3,5-di-n-propyl, 3,6-di-n-propyl, 4,5-di-n-propyl, 4,6-di-n-propyl, 5,6-di-n-propyl, 3,4-di-n-butyl, 3,5-di-n-butyl, 3,6-di-n-butyl, 4,5-di-n-butyl, 4,6-di-n-butyl, 5,6-di n-butyl, 3,4-dicyano, 3,5-dicyan, 3,6-dicyan, 4,5-dicyan, 4,6-dicyan, 5,6-dicyan base, 3,4-dihydroxy, 3,5-dihydroxy, 3,6-dihydroxy, 4,5-dihydroxy, 4,6-dihydroxy, 5,6-dihydroxy, 3,4-diamine base, 3,5-diamino group, 3,6-diamino group, 4,5-diamino group, 4,6-diamino group, 5,6-diamino group, 3,4-dinitro group, 3,5-dinitro, 3,6-dinitro, 4,5-dinitro, 4,6-dinitro, 5,6-dinitro, 3,4-dimethoxy, 3 ,5-dimethoxy, 3,6-dimethoxy, 4,5-dimethoxy, 4,6-dimethoxy, 5,6-dimethoxy, 3,4-diethyl Oxygen, 3,5-diethoxy, 3,6-diethoxy, 4,5-diethoxy, 4,6-diethoxy, 5,6-diethoxy, 3, 4-difluoromethyl, 5-difluoromethyl, 3,6-difluoromethyl, 4,5-difluoromethyl, 4,6-difluoromethyl, 5,6-difluoromethyl , 3,4,5-trifluoro, 3,4,6-trifluoro, 4,5,6-trifluoro, 3,4,5-trichloro, 3,4,6-trichloro , 4,5,6-trichloro, 3,4,5,6-tetrafluoro or 3,4,5,6-tetrachloro.

[14] The compound described in any one of [1] to [13] or a pharmaceutically acceptable salt of the compound is any compound represented by the following formula. [Chemistry 201]

[15] A pharmaceutical composition comprising one or more compounds as described in any one of [1] to [14] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[16] An IDO and/or TDO inhibitor comprising one or more compounds described in any one of [1] to [14] or pharmaceutically acceptable salts thereof as active ingredients.

[17] A therapeutic agent for a disease or disorder selected from tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and female reproductive health-related diseases, comprising one or two The compound described in any one of [1] to [14] above or a pharmaceutically acceptable salt thereof is used as an active ingredient.

[18] The therapeutic agent described in [17] is an anti-tumor agent.

[19] The therapeutic agent of [18], wherein the tumor is selected from mesothelioma, hepatobiliary (bile tract and bile duct) tumor, primary or secondary CNS tumor, primary or secondary brain tumor, pharyngeal cancer, oral cancer, nasal cancer, lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal cancer, gastric cancer, duodenal cancer, colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, Thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer or ureteral cancer, renal cell cancer, renal pelvis cancer, central nervous system (CNS) cancer, primary CNS lymphoma, non-Hodgkin's lymphoma, cerebrospinal axonal tumor, brain stem neuroglioma, pituitary adenoma, adrenal cortical carcinoma, gallbladder cancer, multiple myeloma, bile duct cancer, fibrosarcoma, neuroblastoma, and retinoblastoma.

[20] A pharmaceutical kit for treating a disease or disorder selected from the group consisting of tumors, infections, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health, comprising: (a) one or more compounds as described in any one of [1] to [14] or their pharmaceutically acceptable salts; and (b) one or more advanced therapeutic agents for treating a disease or disorder selected from the group consisting of tumors, infections, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health, wherein the aforementioned compounds or their pharmaceutically acceptable salts and the aforementioned advanced therapeutic agents are suitable for simultaneous, sequential or separate use.

[21] The pharmaceutical set for treating tumors as described in [20], comprising: (a) one or more compounds as described in any one of [1] to [14] or a pharmaceutically acceptable salt thereof; and (b) one or more additional anti-tumor agents, wherein the aforementioned The compound or its pharmaceutically acceptable salt and the aforementioned additional therapeutic agent are suitable for simultaneous, sequential or separate administration.

[22] The pharmaceutical kit as described in [21], wherein the aforementioned tumor is selected from mesothelioma, hepatobiliary (bile tract and bile duct) tumor, primary or secondary central nervous system (CNS) tumor, primary or secondary brain tumor, pharyngeal cancer, oral cancer, nasal cancer, lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal cancer, gastric cancer, duodenal cancer, colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, Thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer or ureteral cancer, renal cell cancer, renal pelvis cancer, central nervous system (CNS) cancer, primary central nervous system (CNS) lymphoma, non-Hodgkin's lymphoma, cerebrospinal axonal tumor, brain stem neuroglioma, pituitary adenoma, adrenal cortical carcinoma, gallbladder cancer, multiple myeloma, bile duct cancer, fibrosarcoma, neuroblastoma, and retinoblastoma.

[23] The compound as described in any one of [1] to [14] or a pharmaceutically acceptable salt of the compound is used in the treatment of tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autologous Used in diseases or disorders related to autoimmune diseases, postoperative cognitive impairment, and female reproductive health-related diseases.

[24] The compound described in [23] is used for treating tumors.

[25] The compound of [24], wherein the tumor is selected from mesothelioma, hepatobiliary (bile tract and bile duct) tumor, primary or secondary central nervous system (CNS) tumor, primary or secondary brain tumor, pharyngeal cancer, oral cancer, nasal cancer, lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal cancer, gastric cancer, duodenal cancer, colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, Thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer or ureteral cancer, renal cell cancer, renal pelvis cancer, central nervous system (CNS) cancer, primary central nervous system (CNS) lymphoma, non-Hodgkin's lymphoma, cerebrospinal axonal tumor, brain stem neuroglioma, pituitary adenoma, adrenal cortical carcinoma, gallbladder cancer, multiple myeloma, bile duct cancer, fibrosarcoma, neuroblastoma, and retinoblastoma.

[26] The compound as described in any one of [1] to [14] or a pharmaceutically acceptable salt of the compound is used for manufacturing a treatment selected from the group consisting of tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, and autoimmune diseases. The use of pharmaceuticals for diseases or disorders related to autoimmune diseases, postoperative cognitive impairment, and female reproductive health-related diseases.

[27] The use as described in [26] is used to manufacture a medicament for treating tumors.

[28] The use as described in [27], wherein the aforementioned tumor is selected from mesothelioma, hepatobiliary (biliary tract and bile duct) tumors, primary or secondary CNS tumors, primary or secondary brain tumors , pharyngeal cancer, oral cancer, nasal cavity cancer, lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal area cancer, stomach cancer , Duodenal cancer, colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulva cancer, Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, Thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, acute myeloid leukemia, chronic myelogenous leukemia, lymphocytic lymphoma, bladder cancer, kidney Carcinoma or ureteral cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) cancer, primary CNS lymphoma, non-Hodgkin's lymphoma, cerebrospinal axis tumor, brainstem glioma, pituitary adenoma , adrenocortical cancer, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, and retinoblastoma.

[29] A treatment method for a disease or disorder selected from tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and female reproductive health-related diseases, comprising: treating patients with Patients with diseases or disorders selected from tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and female reproductive health-related diseases are administered one or more than two drugs such as [1 ] to [14] or a pharmaceutically acceptable salt thereof, or a pharmaceutical set as described in any one of [20] to [22].

[30] The treatment method as described in [29], wherein the disease is a tumor.

[31] The compound or a pharmaceutically acceptable salt of the compound as described in [30], wherein the aforementioned tumor is selected from the group consisting of mesothelioma, hepatobiliary (biliary tract and bile duct) tumors, primary or secondary central nervous system tumors Systemic (CNS) tumors, primary or secondary brain tumors, pharyngeal cancer, oral cancer, nasal cavity cancer, lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma , ovarian cancer, colon cancer, rectal cancer, anal cancer, stomach cancer, duodenal cancer, colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulva cancer, Hodge King's lymphoma, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethra cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, acute myeloid leukemia, Chronic myelogenous leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) cancer, primary central nervous system (CNS) lymphoma, non-Hodge King's lymphoma, cerebrospinal axis tumors, brainstem glioma, pituitary adenoma, adrenocortical cancer, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, and retinoblastoma.

In another embodiment, the present invention includes a compound represented by formula (I) or a pharmaceutically acceptable salt of the compound, (Ring A represents an aromatic ring, a heterocyclic ring, or a condensed ring of two or more rings selected from an aromatic ring and a heterocyclic ring. Ring A is selected from a benzene ring, a naphthalene ring, a quinoxaline ring, a thiophene ring, an indole ring. The group consisting of indole ring, benzothiophene ring, imidazole ring, quinoline ring, quinazoline ring and pyridine ring; X, R ¹ and R ² are substituents on the ring atoms constituting ring A, where R ¹ and R ² is bonded to the adjacent ring atom of ring A; m represents an integer of 1 or 2; X is a halogen atom, and when m is 2, each X is the same or different; R ¹ and R ² are the same or different; R ¹ and R ² independently represent a group represented by: Where Y is selected from the group consisting of O, S, SO, SO ₂ and Se, n represents an integer from 1 to 8, and R ⁴ represents: (wherein R ⁴¹ , R ⁴² and R ⁴³ are the same and are hydrogen atoms). In another aspect, R ¹ and R ² have the same group. In another view, the compound is represented by any of the following formulas: (where A, X, m, Z, R ⁴¹ , R ⁴² and R ⁴³ have the same definitions as defined in claim 1). In another aspect, R ¹ and R ² have different groups. As claimed in claim 35, the compound or a pharmaceutically acceptable salt of the compound is represented by the following formula: _{( wherein} ^{A , ​ ​} Same definition)). In another point of view, in the compound of the following formula (I-4) containing a benzene ring as ring A, R ¹ and R ² are substituted at positions 1 and 2 of the ring, respectively, (where R ¹ and R ² have the same definitions as defined in claim 1) The following formula (I-4-a) removes R ¹ and R ² : Selected from 3-F-Ph=, 4-F-Ph=, 5-F-Ph=, 6-F-Ph=, 3-Cl-Ph=, 4-Cl-Ph=, 5-Cl-Ph= , 6-Cl-Ph=, 3-Br-Ph=, 4-Br-Ph=, 5-Br-Ph=, 6-Br-Ph=, 3-I-Ph=, 4-I-Ph=, 5-I-Ph=, 6-I-Ph=, (any two of the 3, 4, 5 and 6 digits) -F ₂ -Ph=, (any two of the 3, 4, 5 and 6 digits) ) -Cl ₃ -Ph=, (any two of positions 3, 4, 5 and 6) -Br ₂ -Ph=, (any two of positions 3, 4, 5 and 6) -I ₂ - Ph=, (where “Ph=” means the part of formula (I-4-a) excluding (X) _m -). In another view, the compound is represented by the formula: .

In another aspect, the present invention is a pharmaceutical composition comprising one or more compounds as described above or a pharmaceutically acceptable salt of the compound, and a pharmaceutically acceptable carrier. In another aspect, the present invention is an IDO and/or TDO inhibitor, including a compound as described above or a pharmaceutically acceptable salt of the compound as an active ingredient.

In another aspect, the invention is a method for use in a disease or disorder selected from tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health. Therapeutic agents include one or more compounds as described above or pharmaceutically acceptable salts of the compounds as active ingredients.

In another aspect, the present invention is a pharmaceutical kit for treating diseases or disorders selected from tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to women's reproductive health, comprising: (a) one or more compounds as described above or pharmaceutically acceptable salts of the compounds; and (b) one or more additional therapeutic agents for treating diseases or disorders selected from tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to women's reproductive health, wherein the compound or drug and its acceptable salt and the additional therapeutic agent are suitable for simultaneous, sequential or separate administration.

In another aspect, the present invention is a method for treating a disease or disorder selected from tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and female reproductive health-related diseases. A method comprising: administering one or More compounds as described above or pharmaceutically acceptable salts of the compounds. In one view, the disease is a tumor. In another aspect, the aforementioned tumors are selected from the group consisting of mesothelioma, hepatobiliary (biliary tract and bile duct) tumors, primary or secondary central nervous system (CNS) tumors, primary or secondary brain tumors, pharyngeal tumors Cancer, oral cancer, nasal cavity cancer, lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal area cancer, stomach cancer, duodenum Cancer, colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulva cancer, Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer , parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, acute myeloid leukemia, chronic myelogenous leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer, or Ureteral cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) cancer, primary central nervous system (CNS) lymphoma, non-Hodgkin's lymphoma, cerebrospinal axis tumor, brainstem glioma, ptosis Somatic adenoma, adrenocortical cancer, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, and retinoblastoma.

Generation of mouse IDO1 stably expressing CT26 (CT26-1G4 cells) To generate a retroviral vector colonized with the mouse IDO1 gene, a mouse IDO1 expression vector (MC202318) was purchased from OriGene for PCR amplification of mice The IDO1 gene was then subcloned into pMXs-Puro retroviral expression vector (Cell Biolabs). The retroviral expression vector introducing the mouse IDO1 gene was transfected into Platinum-A cells (Cell Biolabs) of the retrovirus packaging cell line using X-tremeGENE 9 DNA transfection reagent (Roche), and then cultured for 48 hours. Next, the culture supernatant is recovered as a virus solution. The recovered virus solution was quickly frozen in liquid nitrogen and stored in a -80°C ultra-low temperature freezer until use. A virus solution containing a retrovirus cloned with the mouse IDO1 gene was used to transfect this gene into the mouse colon cancer cell line CT26 cells (ATCC). Cells were cultured in medium containing puromycin (InvivoGen) and 1 mM L-tryptophan (Sigma-Aldrich) for 10 days, and cells transfected with the gene of interest were then selected, followed by limiting dilution to obtain introduced small Mouse IDO1 gene (CT26-1G4) and a cell line that stably expresses the mouse IDO1 gene. Use RPMI medium containing 10% FBS supplemented with 2 mM L-glutamine (Gibco), 1 mM L-tryptophan, 50 U/mL penicillin, and 50 µg/mL streptomycin (Gibco) (supplemented with tryptamine CT26-1G4 cells were cultured at 37°C in the presence of 5% _CO2 .

Mouse tumor transplantation 6-week-old female BALB/c mice (16 mice) were purchased from Japan SLC and acclimated for 7 days before the experiment was performed at the Animal Experiment Center of Shizuoka University. The back and abdomen of the BALB/c mice were shaved, and then 5×10 ⁵ mouse colon cancer cell line CT26-1G4 cells introduced with the mouse IDO1 gene were subcutaneously transplanted into the left and right abdomen (first day). Five days after transplantation, the major diameter (mm) and minor diameter (mm) of the tumor were measured using a digital caliper (A&D) to calculate the tumor volume. The mathematical formula for calculating the tumor volume is [Tumor volume (mm ³ ) = 0.5×(major diameter (mm))×(minor diameter (mm)) ² ]. The mean value of left and right tumor volumes was calculated for each mouse, and then the mice were divided into 2 groups (8 mice in each group) based on the calculated mean values to equalize the differences in tumor volumes between the mice in each group.

Administration Compound 36 was orally administered at 25 mg/kg for nine consecutive days. Specifically, a suspension was prepared using a 0.5% methylcellulose solution (FUJIFILM) to a concentration of 2.5 mg/mL, and 0.01 mL per gram of body weight was orally administered to BALB/c mice using a metal probe (φ 0.7×50 mm, Natsume Seisakusho). Administration was scheduled from the day of grouping to the last day of the experiment (Day 6 to Day 14). For each mouse in the group that was not administered with Compound 36, a 0.5% methylcellulose solution was orally administered.

The specific composition of the group is as follows. A. Control group B. Compound 36 x 9 doses (25 mg/kg, orally for 6-14 days)

Evaluation items The evaluation items are the average tumor volume and the average tumor weight on the last day of the experiment. Starting from day 6, the major diameter (mm) and minor diameter (mm) of the tumor were measured every other day using a digital caliper to calculate the tumor volume. The mathematical formula for calculating tumor volume is [tumor volume (mm ³ ) = 0.5 × (major diameter (mm)) × (minor diameter (mm)) ² ], and the average tumor volume in each group was calculated. On the last day of the experiment (day 14), collect tumors from mice into 2 mL tubes to measure tumor weight. Measure the weight using an electronic scale (AB104-S, METTLER TOLEDO) and subtract the container weight of the 2 mL tube from it to calculate the weight. The collected tumors were disrupted with gentleMACS Dissociator (Miltenyi Biotec) to prepare tumor suspension. Centrifuge 1.5 mL of the suspension at 4,000 g for 5 minutes to recover 1 mL of supernatant. Use the kynurenine ELISA kit (BA-E-2200) and tryptophan ELISA kit ( BA-E-2700) (ImmuSmol) to quantify Kyn and Trp concentrations.

Evaluation indicators In order to evaluate the effect of drug administration on tumor volume and tumor weight, t-test was performed on the evaluation items of the drug-administered group and the control group. P < 0.05 or P < 0.01 was considered to be significantly different, in which case it was determined that drug administration had an anti-tumor growth effect.

Figure 7 is a time course of tumor volume in mice treated with Vehicle or Compound 36 (25 mg/kg PO QD x 9 days). Statistical significance was tested by Welch's t test. *, P ＜ 0.05, compared with the blank control group.

FIG8 shows the tumor weight of mice treated with vehicle or compound 36 (25 mg/kg PO QD x 9 days) on day 14. Statistical significance was tested by Welch's t test. **, P < 0.01, compared with the blank control group.

Figure 9 is the intratumoral Kyn/Trp ratio at day 14 in mice treated with vehicle or compound 36 (25 mg/kg PO QD x 9 days).

[Industrial Applicability] The compound of the present invention has extremely superior activity as an IDO/TDO inhibitor and also has superior anti-tumor activity. Therefore, it is expected that IDO/TDO inhibitors can be used as effective therapeutic agents for various diseases including tumors.

without

[Fig. 1] A graph showing the results of a drug efficacy experiment using the combined use of an IDO/TDO inhibitor and an anti-PD-1 antibody using CT-26WT colorectal cancer allograft subcutaneously transplanted mice. [Fig. 2] A graph showing the results of a pharmacodynamic experiment using compound 1 and oxaliplatin in combination with CT-26CL25 colorectal cancer allograft subcutaneously in mice. [Fig. 3] Figure 3 is a graph showing the results of a drug efficacy experiment using the combined use of Compound 1, Compound 15, Compound 29 and oxaliplatin in CT-26WT colorectal cancer homologous subcutaneously transplanted mice. [Fig. 4] A graph showing the results of a drug efficacy experiment using the combined use of an IDO/TDO inhibitor and oxaliplatin in mice with CT-26WT colorectal cancer homologous subcutaneous transplantation. [Fig. 5] A graph showing the results of a pharmacodynamic experiment using compounds 29 and 38 in combination with an anti-PD-1 antibody using CT-26WT colorectal cancer homologous subcutaneously transplanted mice. [Fig. 6] A graph showing the results of a pharmacodynamic experiment using compound 103 in combination with an anti-PD-1 antibody using CT-26WT colorectal cancer allograft subcutaneously transplanted mice. [Figure 7] Time course of tumor volume in mice treated with vehicle or compound 36 (25 mg/kg PO QD x 9 days). Statistical significance was tested by Welch's t test. *P ＜ 0.05, compared with the blank control group. [Figure 8] Tumor weight on day 14 of mice treated with vehicle or compound 36 (25 mg/kg PO QD x 9 days). Statistical significance was tested by Welch's t test. **P ＜ 0.01, compared with the blank control group. [Figure 9] Intra-tumor Kyn/Trp ratio on day 14 of mice treated with vehicle or compound 36 (25 mg/kg PO QD x 9 days).

Claims (14)

A compound represented by formula (I) or a pharmaceutically acceptable salt of the compound, Ring A represents an aromatic ring, a heterocyclic ring, or a condensed ring of two or more rings selected from an aromatic ring and a heterocyclic ring. Ring A is selected from a benzene ring, a naphthalene ring, a quinoxaline ring, a thiophene ring, and an indole ring. A group consisting of ^{benzothiophene} ring, ^imidazole ring, quinoline ^ring , quinazoline ring and pyridine ring; ² is bonded to the adjacent ring atom of ring A; m represents an integer of 1 or 2; X is a halogen atom, and when m is 2, each X is the same or different; R ¹ and R ² are the same or different; R ¹ and R ² independently represent a group represented by: Among them, Y is selected from the group consisting of O, S, SO, SO ₂ and Se, n represents an integer from 1 to 8, and R ⁴ represents: Among them, R ⁴¹ , R ⁴² and R ⁴³ are the same and are hydrogen atoms. The compound of claim 1 or a pharmaceutically acceptable salt of the compound, wherein R ¹ and R ² have the same group. The compound of claim 1 or a pharmaceutically acceptable salt of the compound, wherein the compound is represented by any one of the following formulas: (where A, X, m, Z, R ⁴¹ , R ⁴² and R ⁴³ have the same definitions as in claim 1). The compound of claim 1 or a pharmaceutically acceptable salt of the compound, wherein R ¹ and R ² have different groups. The compound of claim 4 or a pharmaceutically acceptable salt of the compound, wherein the compound is represented by the following formula: _{( wherein} ^{A , ​ ​} Same definition)). The compound or a pharmaceutically acceptable salt of the compound as claimed in claim 1, wherein in the compound of the following formula (I-4) containing a benzene ring as ring A, ^R1 and ^R2 are substituted at the 1-position and 2-position of the ring, respectively, (wherein R ¹ and R ² have the same definitions as defined in claim 1) The following formula (I-4-a) does not include R ¹ and R ² : Selected from 3-F-Ph=, 4-F-Ph=, 5-F-Ph=, 6-F-Ph=, 3-Cl-Ph=, 4-Cl-Ph=, 5-Cl-Ph=, 6-Cl-Ph=, 3-Br-Ph=, 4-Br-Ph=, 5-Br-Ph=, 6-Br-Ph=, 3-I-Ph=, 4-I-Ph=, 5-I-Ph=, 6-I-Ph=, (any two of the positions 3, 4, 5 and 6)-F ₂ -Ph=, (any two of the positions 3, 4, 5 and 6)-Cl ₂ -Ph=, (any two of the positions 3, 4, 5 and 6)-Br ₂ -Ph=, (any two of the positions 3, 4, 5 and 6)-I ₂ -Ph=, (wherein "Ph=" represents a portion of the formula (I-4-a) excluding (X) _m -). The compound of claim 1 or a pharmaceutically acceptable salt of the compound, wherein the compound is represented by the following formula: . A pharmaceutical composition comprising one or more compounds as described in claim 1 or a pharmaceutically acceptable salt of the compound, and a pharmaceutically acceptable carrier. An inhibitor of IDO and/or TDO, comprising the compound of claim 1 or a pharmaceutically acceptable salt of the compound as an active ingredient. A therapeutic agent for a disease or disorder selected from tumors, infections, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health, comprising one or more compounds as described in claim 1 or a pharmaceutically acceptable salt of the compound as an active ingredient. A pharmaceutical set for treating a disease or a disorder selected from the group consisting of tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and female reproductive health-related diseases, comprising: (a) One or more compounds as described in claim 1 or a pharmaceutically acceptable salt of the compound; and (b) One or more additional therapeutic agents for the treatment of tumors, infectious diseases, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to women's reproductive health A disease or condition wherein the compound or drug, an acceptable salt thereof, and the additional therapeutic agent are suitable for simultaneous, sequential or separate administration. A method for treating a disease or disorder selected from tumors, infections, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health, comprising: administering one or more compounds as described in claim 1 or a pharmaceutically acceptable salt of the compound to a patient suffering from the disease or disorder selected from tumors, infections, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health. The treatment method of claim 12, wherein the disease is a tumor. The treatment method as described in claim 13, wherein the aforementioned tumors are selected from the group consisting of mesothelioma, hepatobiliary (biliary tract and bile duct) tumors, primary or secondary central nervous system (CNS) tumors, primary or secondary Brain tumors, pharyngeal cancer, oral cavity cancer, nasal cavity cancer, lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal area Cancer, stomach cancer, duodenal cancer, colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulva cancer, Hodgkin's lymphoma, esophageal cancer, small bowel cancer, endocrine cancer Systemic cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, acute myeloid leukemia, chronic myelogenous leukemia, lymphocytic lymphoma, bladder Cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) cancer, primary central nervous system (CNS) lymphoma, non-Hodgkin's lymphoma, cerebrospinal axis tumors, brainstem Glioma, pituitary adenoma, adrenocortical cancer, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, and retinoblastoma.

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