IDO / TDO inhibitors

Abstract

To provide a novel IDO / TDO inhibitor effective against various diseases.SOLUTION: Provided is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. [In the formula (I), a ring A represents an aromatic ring, an aliphatic ring, a heterocyclic ring, or a fused ring including two or more rings selected from aromatic rings, aliphatic rings, and heterocyclic rings, X, R1, and R2 each represent a substituent of a ring atom forming the ring A, m represents an integer of 0-6, X represents, for example, a halogen atom, and R1 and R2 may be the same or different and are, for example, selected from groups represented by formula (a) or formula (b)].SELECTED DRAWING: None

Description

[Technical Field]

[0001] 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 inhibitors of the present invention can be used in pharmaceutical compositions, particularly for the treatment of various diseases, conditions, and disorders, including tumors, infectious diseases, inflammatory conditions, and central nervous system diseases or disorders. [Background technology]

[0002] Cancer cells are known to exploit immune tolerance to suppress host immune responses and proliferate. Recently, the proteins responsible for this immune tolerance and their functions have become increasingly clear. Ibilimumab, an antibody drug targeting cytotoxic T-lymphocyte antigen 4 (CTLA4), one of the causative molecules, was approved by the FDA in 2011 for the treatment of malignant melanoma, demonstrating the efficacy of drugs designed to break cancer immune tolerance. Indoleamine-2,3-dioxygenase (IDO), discovered by Hayaishi et al. in the 1950s, is an oxygenase that catalyzes the initial reaction in the kynurenine pathway (KP), the primary pathway for tryptophan metabolism in vivo. It has since been revealed to play an important role in establishing immune tolerance in the tumor microenvironment, including regulating T cells, which control immune responses. Its mechanism of action is thought to be activation of the kynurenine pathway, which reduces local tryptophan levels, and then increases kynurenine levels, which suppresses antitumor immune cells. Human IDO (hIDO) is overexpressed in a variety of human cancers, including prostate, colon, pancreatic, gastric, ovarian, brain, and lung cancers.

[0003] The kynurenine pathway is responsible for more than 95% of the breakdown of the essential amino acid tryptophan. The kynurenine pathway for tryptophan metabolism produces the essential pyridine nucleotide NAD+ and numerous neuroactive metabolites, such as kynurenine (KYN), kynurenic acid (KYNA), the neurotoxic free radical generator 3-hydroxykynurenine (3-HK), anthranilic acid, 3-HAA, picolinic acid (PIC), and the excitatory N-methyl-D-aspartate (NMDA) receptor agonist and neurotoxin, quinolinic acid (QUIN). The remaining 5% of tryptophan is metabolized by tryptophan hydroxylase to 5-hydroxytryptophan, which is then further metabolized to 5-hydroxytryptamine (serotonin) and melatonin.

[0004] The first step in tryptophan catabolism is catalyzed by either TDO or IDO. Both enzymes catalyze the oxidative cleavage of the 2,3 double bond in the indole ring, converting tryptophan to N-formyl-L-kynurenine. This is the rate-limiting step in tryptophan catabolism via the kynurenine pathway. TDO is a homotetramer with a molecular weight of 48 kDa, while IDO has a molecular weight of 45 kDa and a monomeric structure. Despite intervening in the same reaction, TDO and IDO (IDO1 or IDO2) are structurally distinct, sharing only 10% homology, primarily within the active site. In contrast, the more related IDO1 and IDO2 share 43% homology. IDO1 and IDO2 are two distinct enzymes catalyzing the same reaction. The Michaelis constant of IDO2 for tryptophan is much higher than that of IDO1. That is, the affinity of IDO2 for its substrate, tryptophan, is much lower than that of IDO1. Nicolas van Baren et al. have reported tumor immune resistance mediated by tryptophan-degrading enzymes, namely IDO1, TDO, and IDO2 (Non-Patent Document 1).

[0005] TDO is expressed at high levels in the liver and is responsible for regulating whole-body tryptophan levels. Although TDO is not induced or regulated by signals from the immune system, its expression can be induced by tryptophan or corticosteroids. Furthermore, it has recently been shown that TDO is expressed in the brain and regulates the production of neuroactive tryptophan metabolites, such as kynurenic acid and quinolinic acid. TDO has been found to be highly activated and constitutively expressed in glioma cells. TDO-derived κYN has been shown to suppress antitumor immune responses and promote tumor cell survival and motility in an autocrine manner via the aryl hydrocarbon receptor (AhR). TDO has also been shown to be elevated in human hepatocellular carcinoma and sporadically detected in other cancers. In preclinical models, TDO expression prevented the rejection of tumor xenografts in pre-immunized mice, and systemic administration of the TDO inhibitor LM10 restored the ability of mice to reject TDO-expressing tumors.

[0006] IDO expression is found in many cell types, including macrophages, microglia, neurons, and astrocytes. IDO transcription is tightly regulated in response to specific inflammatory mediators. The mouse and human IDO gene promoters contain multiple sequence elements that regulate responsiveness to type I (IFN-α / β) and the more potent type II (IFN-γ) interferons. Certain myeloid lineage cells (monocyte-derived macrophages and DCs), fibroblasts, endothelial cells, and some tumor cell lines express IDO after exposure to IFN-γ. However, the regulation of IDO transcription is complex and cell type-specific. IDO activity is constitutively expressed by human extravillous trophoblast cells at the maternal-fetal boundary. Except for 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 reduced survival in patients with acute myeloid leukemia (AML), small cell lung cancer, melanoma, ovarian cancer, colorectal cancer, pancreatic cancer, and endometrial cancer. Indeed, sera from cancer patients have a higher kynurenine / tryptophan ratio than sera from healthy volunteers, and the level of IDO expression has also been shown to correlate with the number of tumor-infiltrating lymphocytes in colorectal cancer patients.

[0007] Tryptophan metabolites, such as kynurenine, kynurenic acid, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid, can suppress T cell function and induce T cell apoptosis. Recent studies have revealed that the aryl hydrocarbon receptor (AHR) is a direct target of kynurenine. Ahr is a basic helix-loop-helix Per-Arnt-Sim (PAS) family transcription factor. As kynurenine accumulates in tumors, KYN binds to Ahr, translocates to the nucleus, and activates the transcription of target genes controlled by dioxin response elements (DREs). In CD4+ cells, kynurenine induces the development of regulatory T cells (Tregs).

[0008] Therefore, TDO or IDO inhibitors may have broad therapeutic potential in cancer treatment. Furthermore, dual inhibitors that block both TDO and IDO may demonstrate stronger clinical efficacy by targeting both of these important Trp metabolic enzymes, potentially treating a wider range of patients.

[0009] Inhibitors of IDO and / or TDO have emerged as having utility in a wide range of indications, including oncology, infectious diseases, neurological conditions, and many other diseases.

[0010] Against this background, various IDO and / or TDO inhibitors have been proposed. In particular, many IDO and / or TDO inhibitors using indole derivatives with various structures have been proposed. For example, Patent Document 1 discloses that certain indole derivatives (680C91, LM10) are useful as TDO inhibitors, and that certain indole derivatives (Newlink 1) and certain oxadiazole derivatives (Incyte 1) are useful as IDO inhibitors. Patent Document 2 discloses various indole derivatives useful as IDO and / or TDO inhibitors. Patent Documents 3 and 4 disclose that various fused heterocyclic compounds having an indole skeleton are used as IDO and / or TDO inhibitors. Furthermore, Patent Document 5 discloses that certain indole derivatives have the activity as IDO inhibitors. Furthermore, Patent Document 6 discloses that compounds having three skeletons, namely, an indole skeleton, a pyrazole skeleton, and a cyclopropane skeleton, are used as IDO inhibitors.

[0011] As compounds other than indole derivatives, the use of five-membered heterocyclic compounds as TDO and / or IDO inhibitors (Patent Documents 7 and 8), the use of two six-membered fused heterocyclic compounds as TDO and / or IDO inhibitors (Patent Documents 9 and 10), the use of compounds having a benzene ring or a tetrahydronaphthyl skeleton as IDO inhibitors (Patent Document 11), the use of three-ring fused heterocyclic compounds as IDO inhibitors (Patent Documents 12 and 13), and the use of four-ring fused heterocyclic compounds as IDO inhibitors (Patent Documents 14 and 15) have been proposed. Amy B. Dounay et al. have introduced new therapeutic agents targeting the kynurenine pathway (Non-Patent Document 2). Non-Patent Document 2 teaches various IDO1 inhibitors and TDO inhibitors.

[0012] In response to this, the present inventors have discovered and reported that S-benzylthiourea and its derivatives inhibit IDO (Non-Patent Document 3). The present inventors have also discovered and reported that benzenesulfonamide derivatives and benzylthioimidocarbamate derivatives inhibit the production of kynurenine, a tryptophan metabolic product, in cancer cells (Non-Patent Document 4). Furthermore, the present inventors have reported that candesartan cilexetil and its derivatives, which are used as therapeutic agents for hypertension, renal parenchymal hypertension, and the like, inhibit IDO (Non-Patent Document 5). [Prior art documents] [Patent documents]

[0013] [Patent Document 1] WO2015 / 091862 publication [Patent Document 2] WO2015 / 150097 Publication (Special Publication No. 2017-509682) [Patent Document 3] WO2016 / 071293 publication [Patent Document 4] WO2017 / 007700 publication [Patent Document 5] Special Publication No. 2006-521377 [Patent Document 6] WO2017 / 048612 [Patent Document 7] WO2016 / 026772 [Patent Document 8] Special Publication No. 2017-526727 [Patent Document 9] WO2016 / 071283 [Patent Document 10] Japanese Patent Publication No. 2017-509667 [Patent Document 11] Patent No. 5583592 [Patent Document 12] Japanese Patent Publication No. 2017-149769 [Patent Document 13] Special Publication No. 2008-505937 [Patent Document 14] Japanese Patent Publication No. 2008-201756 [Patent Document 15] Japanese Patent Publication No. 2016-535788

Non-licensed literature

[0014]

Non-patent document 1

Non-patent document 2

Non-patent document 3

Non-patent document 4

Non-patented document 5

[0015] An object of the present invention is to provide a novel IDO inhibitor and / or TDO inhibitor that is useful for various diseases. [Means for solving the problem]

[0016] The present inventors have focused on a certain group of compounds that are structurally different from known IDO and / or TDO inhibitors, and as a result of extensive research, have found that a compound represented by the following formula (I) or a pharmaceutically acceptable salt of said compound has excellent inhibitory activity against IDO and / or TDO and can be used as an IDO and / or TDO inhibitor for a wide range of diseases. The present invention was completed based on these findings.

[0017] That is, the present invention is as follows. [1] A compound having the formula (I) or a pharmaceutically acceptable salt of said compound: [ka] [In the formula, ring A represents an aromatic ring, an aliphatic ring, a heterocyclic ring, or a fused ring of two or more rings selected from an aromatic ring, an aliphatic ring, and a heterocyclic ring, X, R 1 and R 2 is a substituent of a ring atom 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-chain or branched alkyl group, a substituted or unsubstituted straight-chain or branched alkoxy group, a substituted or unsubstituted straight-chain or branched alkenyl group, a substituted or unsubstituted straight-chain or branched alkenyloxy group, a substituted or unsubstituted straight-chain or branched alkynyl group, a substituted or unsubstituted straight-chain or branched alkynyloxy group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a halogenated alkyl group, a halogenated alkyloxy group, a cyano group, a hydroxy group, an amino group, a nitro group, a carboxyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted aralkyl group; when m is 2 to 6, X may be the same or different; R 1 and R 2 may be the same or different, R 1 is represented by formula (II) [ka] (In the formula, R 11 and R 12 each independently represents a hydrogen atom, a fluorine atom, or a substituted or unsubstituted alkyl group, and Y1 is O or NR 21 represents R 21 , R 22 and R 23 each independently 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; and R 21 and R 22 or R 23 may be bonded to form a ring, Z1 represents S, SO, SO2, O or Se, r1 represents an integer of 1 to 8, and when r1 is 2 or more, R 11Comrades and R 12 They may be the same or different.) or formula (III) [ka] (In the formula, R 31 and R 32 each independently represents a hydrogen atom, a fluorine atom, or a substituted or unsubstituted linear or branched alkyl group; Z2 is O or NR 61 (R 61 represents a hydrogen atom, a substituted or unsubstituted linear or branched alkyl group, or a substituted or unsubstituted aryl group; 33 represents a substituted or unsubstituted linear 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 cycloalkylalkyl group; r2 represents 0 or an integer of 1 to 8; when r2 is 2 or greater, R 31 Comrades and R 32 may be the same or different. 2 is R 1 and independently represent a group represented by formula (II) or formula (III).

[0018] [2] In formula (II), R 21 and R 22 or R 23 The functional groups bonded to form a ring are represented by the following formula (IV): [ka] [In the formula, R 11 ,R 12 ,r1,Z1,R 22 and R 23 represents the same meaning as in formula (II), and Z3 represents CH, CR 54 or N, R 51 and R 52each independently represents 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, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group; r3 represents an integer of 1 to 8; when r3 is 2 or more, R 51 Comrades and R 52 may be the same or different, r4 and r6 each independently represent 0 or 1, and r4 and r6 cannot be 0 at the same time, r5 represents 0 or an integer of 1 to 5, and when r5 is 2 or more, R 54 may be the same or different. 22 (R 23 ) is written as R 22 and R 23 or a pharmaceutically acceptable salt thereof.

[0019] [3] R 1 is a group consisting of the following groups: [ka] 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, SO, 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; R 3 represents a substituted or unsubstituted straight or branched chain alkyl group, R 4 is a substituted or unsubstituted heterocyclic group, -CONH2, or [ka] (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, or 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; 2 But R 1 and independently a group consisting of the groups shown below: [ka] (In the formula, Y, Z, n, p, q, r, s, R 3 , R 4 , R 5 , and R 6 has the same meaning as defined above.) The compound according to [1] or [2], or a pharmaceutically acceptable salt of said compound, selected from:

[0020] [4] R 1 and R 2 The compound according to any one of [1] to [3], wherein are bonded to adjacent ring atoms of ring A, or a pharmaceutically acceptable salt of the compound.

[0021] [5] R 1 and R 2The compound according to any one of [1] to [4], wherein each of the groups has the same meaning, or a pharmaceutically acceptable salt thereof.

[0022] [6] In the compound represented by formula (I), R 1 and R 2 is a group represented by formula (II), and in formula (II), R 11 and R 12 is a hydrogen atom, and Y1 is NR 21 and r1 is 1, or a pharmaceutically acceptable salt of the compound according to [5].

[0023] [7] The compound according to [6], which is any one of the following formulae, or a pharmaceutically acceptable salt of the compound: [ka] (wherein A, X, and m are Z, s, R as defined in [1]). 41 , R 42 , R 43 , and R 6 have the meaning as defined in [3])

[0024] [8] R 1 and R 2 or a pharmaceutically acceptable salt thereof, according to any one of [1] to [4], wherein

[0025] [9] The compound according to [8], having the following formula: or a pharmaceutically acceptable salt of the compound: [ka] (wherein A, X, and m have the meanings as defined in [1], and R 7 and R 8 -COOR 3 (In the formula, R 3 represents a substituted or unsubstituted straight or branched chain alkyl group), -(CH2) n -YR4 (Wherein, n, Y, and R 4 has the meaning as defined in [3]), -(CH2) p -CONH-(CH2) q -R 5 (Wherein, p, q, and R 5 has the meaning as defined in [3]), and [ka] (In the formula, r, s, R 6 and Z has the meaning as defined in [3]). and R is selected from the group consisting of 7 and R 8 are different from each other)

[0026]

[10] The compound according to any one of [1] to [9], 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, or a pharmaceutically acceptable salt of the compound.

[0027]

[11] X is a halogen atom, a substituted or unsubstituted straight-chain or branched C1-C8 alkyl group, a substituted or unsubstituted straight-chain or branched C1-C8 alkoxy group, a substituted or unsubstituted straight-chain or branched C2-C8 alkenyl group, a substituted or unsubstituted straight-chain or branched C2-C8 alkenyloxy group, a substituted or unsubstituted straight-chain or branched C2-C8 alkynyl group, a substituted or unsubstituted straight-chain or branched C2-C8 alkynyloxy group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C3-C8 cycloalkenyl group, a substituted or unsubstituted C3-C8 cycloalkynyl group, a C1-C3 halogenated alkyl group, a cyano group, a hydroxy group, an amino group, a carboxyl group, a substituted or unsubstituted C6-C 18Aryl groups and substituted or unsubstituted aralkyl groups (the number of carbon atoms in the aryl moiety is C6-C 10 and the number of carbon atoms in the alkylene moiety is C1-C4), or a pharmaceutically acceptable salt of the compound according to any one of [1] to

[10] .

[0028]

[12] The compound according to any one of [1] to

[11] , wherein X is a group selected from the group consisting of: Halogen atoms include fluorine, chlorine, bromine, and iodine atoms. Substituted or unsubstituted straight-chain or branched-chain alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-octyl, carboxymethyl, 2-carboxyethyl, 3-hydroxy-1-propyl, aminomethyl, 2-aminoethyl, hydroxymethyl, and 2-hydroxyethyl groups. Substituted or unsubstituted straight-chain or branched-chain alkoxy groups include methoxy, ethoxy, n-propoxy, and n-butoxy groups. Substituted or unsubstituted straight-chain or branched alkenyl groups include ethenyl (vinyl), 2-propenyl (allyl), and 3-butenyl groups. - Substituted or unsubstituted straight-chain or branched-chain alkenyloxy groups include ethenyloxy (vinyloxy) group, 2-propenyloxy (allyloxy) group, and 3-butenyloxy group. Substituted or unsubstituted straight-chain or branched-chain alkynyl groups include ethynyl, 2-propynyl, and 3-butynyl groups. - Substituted or unsubstituted straight-chain or branched-chain alkynyloxy groups include ethynyloxy, 2-propynyloxy, and 3-butynyloxy groups. Substituted or unsubstituted cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl groups. Substituted or unsubstituted cycloalkenyl groups include 1-cyclopropenyl, 1-cyclobutenyl, 1-cyclopentenyl, and 1-cyclohexenyl groups. -Halogenated alkyl groups include a fluoromethyl group, a difluoromethyl group, a chloromethyl group, a bromomethyl group, an iodomethyl group, a trifluoromethyl group, a trichloromethyl group, a tribromomethyl group, a triiodomethyl group, a 2,2,2-trifluoroethyl group, a 2,2,2-trichloroethyl group, a 2,2,2-tribromoethyl group, a 2,2,2-triiodoethyl group, and a pentafluoroethyl group. -Halogenated alkyloxy groups include a fluoromethoxy group, a difluoromethoxy group, a chloromethoxy group, a bromomethoxy group, an iodomethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a tribromomethoxy group, a triiodomethoxy group, a 2,2,2-trifluoroethoxy group, a 2,2,2-trichloroethoxy group, a 2,2,2-tribromoethoxy group, a 2,2,2-triiodoethoxy group, and a pentafluoroethoxy group. -cyano group -hydroxy group -Amino group -nitro group -Carboxyl group Substituted or unsubstituted aryl groups include phenyl, naphthalen-1-yl, and naphthalen-2-yl groups. Substituted or unsubstituted aralkyl groups include benzyl, phenethyl, and 3-phenyl-1-propyl groups.

[0029]

[13] Ring A is a benzene ring, and R is at the 1-position of the ring. 1 , R in second place 2 In the compound of the following formula (I-4) substituted with [ka] (In the formula, R 1 , and R 2 has the meaning defined in any one of paragraphs [1] to [3]. R 1 , and R 2 The following formula (I-4-a) excluding [ka] However, 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-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-CF3-Ph=, 4-CF3-Ph=, 5-CF3-Ph=, 6-CF3-Ph=, 3-C2F5-Ph=, 4-C2F5-Ph=, 5-C2F5-Ph=, 6-C2F5-Ph=, 3-CF3O -Ph=, 4-CF3O-Ph=, 5-CF3O-Ph=, 6-CF3O-Ph=, 3-C2F5O-Ph=, 4-C2F5O-Ph=, 5-C2F5O-Ph=, 6-C2F5O-Ph=, 3-CN-Ph=, 4-CN-Ph=, 5-CN-Ph=, 6-CN-Ph=, 3-O H-Ph=, 4-OH-Ph=, 5-OH-Ph=, 6-OH-Ph=, 3-NH2-Ph=, 4-NH2-Ph=, 5-NH2-Ph=, 6-NH2-Ph=, 3-NO2-Ph=, 4-NO2-Ph=, 5-NO2-Ph=, 6-NO2-Ph=, 3-COOH-Ph=, 4 -COOH-Ph=, 5-COOH-Ph=, 6-COOH-Ph=, -F2-Ph= (at any two positions of 3, 4, 5 and 6), -Cl2-Ph= (at any two positions of 3, 4, 5 and 6), -Br2-Ph= (at any two positions of 3, 4, 5 and 6), -I2-Ph= (at any two positions of 3, 4, 5 and 6), -Me2-Ph= (at any two positions of 3, 4, 5 or 6), -Et2-Ph- (at any two positions of 3, 4, 5 and 6), -Pr2-Ph= (at any two positions of 3, 4, 5 and 6), -Bu2-Ph= (at any two positions of 3,(any two positions among 4, 5 and 6 positions)-(CN)2-Ph=, (any two positions among 3, 4, 5 and 6 positions)-(OH)2-Ph=, (any two positions among 3, 4, 5 and 6 positions)-((NH2))2-Ph=, (any two positions among 3, 4, 5 and 6 positions)-(NO2)2-Ph=, (any two positions among 3, 4, 5 and 6 positions)-(MeO)2-Ph=, (any two positions among 3, 4, 5 and 6 positions)-(EtO)2 -Ph=, -(CF3)2-Ph= (at any two positions among the 3-, 4-, 5-, and 6-positions), -F3-Ph= (at any three positions among the 3-, 4-, 5-, and 6-positions), -Cl2-Ph= (at any three positions among the 3-, 4-, 5-, and 6-positions), -F4-Ph= (at four positions among the 3-, 4-, 5-, and 6-positions), and -Cl4-Ph= (at four positions among the 3-, 4-, 5-, and 6-positions) (wherein "Ph=" represents any of the formulae (I-4-a) to (X), m -), the compound according to any one of [1] to

[12] , or a pharmaceutically acceptable salt of said compound.

[0030]

[14] The compound according to any one of [1] to

[13] , which is any of the compounds represented by the following formulae, or a pharmaceutically acceptable salt of said compound: [ka] JPEG0007624184000014.jpg10959 JPEG0007624184000015.jpg10872 JPEG0007624184000016.jpg10761 JPEG0007624184000017.jpg10973 JPEG0007624184000018.jpg10971 JPEG0007624184000019.jpg10671 JPEG0007624184000020.jpg7171 JPEG0007624184000021.jpg10375 JPEG0007624184000022.jpg10163 JPEG0007624184000023.jpg10870 JPEG0007624184000024.jpg10577 JPEG0007624184000025.jpg7581

[0031]

[15] A pharmaceutical composition comprising one or more compounds according to any one of [1] to

[14] or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0032]

[16] An inhibitor of IDO and / or TDO, comprising one or more of the compounds according to any one of [1] to

[14] or pharmaceutically acceptable salts thereof as active ingredients.

[0033]

[17] A therapeutic agent for a disease or disorder selected from tumors, infectious diseases, neurodegenerative disorders, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to women's reproductive health, comprising one or more compounds according to any one of [1] to

[14] or pharmaceutically acceptable salts thereof as an active ingredient.

[0034]

[18] The therapeutic agent according to

[17] , which is an antitumor agent.

[0035]

[19] The tumor is selected from the group consisting of mesothelioma, hepatobiliary (biliary tract and bile duct), primary or secondary CNS tumors, primary or secondary brain tumors, pharyngeal cancer, oral cancer, cancer of the nasal cavity, lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, duodenal cancer, colorectal cancer, breast cancer, uterine cancer, cancer of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, The antitumor agent according to

[18] , wherein the tumor is selected from adrenal gland 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 or ureter cancer, renal cell carcinoma, renal pelvis carcinoma, central nervous system (CNS) neoplasm, primary CNS lymphoma, non-Hodgkin's lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, and retinoblastoma.

[0036]

[20] (a) One or more compounds according to any one of [1] to

[14] or pharmaceutically acceptable salts thereof (b) one or more additional therapeutic agents for treating a disease or disorder selected from tumors, infectious diseases, neurodegenerative disorders, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and disorders related to women's reproductive health; wherein said compound or a pharmaceutically acceptable salt thereof and said further agent are suitable for simultaneous, sequential or separate administration, for treating a disease or disorder selected from tumors, infectious diseases, neurodegenerative disorders, cataracts, organ transplant rejection, autoimmune diseases, post-operative cognitive impairment, and diseases related to female reproductive health.

[0037]

[21] (a) One or more compounds according to any one of [1] to

[14] or pharmaceutically acceptable salts thereof. (b) one or more additional anti-tumor agents; The pharmaceutical kit according to

[20] for treating a tumor, comprising: the compound or a pharmaceutically acceptable salt thereof and the additional agent, wherein the compound or the pharmaceutically acceptable salt thereof and the additional agent are suitable for simultaneous, sequential or separate administration.

[0038]

[22] The tumor is mesothelioma, hepatobiliary (biliary tract and bile duct), primary or secondary CNS tumor, primary or secondary brain tumor, pharyngeal cancer, oral cancer, cancer of the nasal cavity, lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, duodenal cancer, colorectal cancer, breast cancer, uterine cancer, cancer of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland , adrenal gland 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 or ureter cancer, renal cell carcinoma, renal pelvis carcinoma, central nervous system (CNS) neoplasm, primary CNS lymphoma, non-Hodgkin's lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, and retinoblastoma.

[0039]

[23] A compound according to any one of [1] to

[14] or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder selected from the group consisting of tumors, infectious diseases, neurodegenerative disorders, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to women's reproductive health.

[0040]

[24] The compound described in

[23] for use in the treatment of tumors.

[0041]

[25] The tumor is selected from the group consisting of mesothelioma, hepatobiliary (biliary tract and bile duct), primary or secondary CNS tumors, primary or secondary brain tumors, pharyngeal cancer, oral cancer, cancer of the nasal cavity, lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, duodenal cancer, colorectal cancer, breast cancer, uterine cancer, cancer of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, and cancer of the parathyroid gland. , adrenal gland 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 or ureter cancer, renal cell carcinoma, renal pelvis carcinoma, central nervous system (CNS) neoplasm, primary CNS lymphoma, non-Hodgkin's lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, and retinoblastoma.

[0042]

[26] Use of a compound according to any one of [1] to

[14] or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease or disorder selected from tumors, infectious diseases, neurodegenerative disorders, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health.

[0043]

[27] The use according to

[26] for the manufacture of a medicament for treating a tumor.

[0044]

[28] The tumor is mesothelioma, hepatobiliary (biliary tract and bile duct), primary or secondary CNS tumor, primary or secondary brain tumor, pharyngeal cancer, oral cancer, cancer of the nasal cavity, lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, duodenal cancer, colorectal cancer, breast cancer, uterine cancer, cancer of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland , adrenal gland 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 or ureter cancer, renal cell carcinoma, renal pelvis carcinoma, central nervous system (CNS) neoplasm, primary CNS lymphoma, non-Hodgkin's lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma.

[0045]

[29] A method for treating a disease or disorder selected from tumors, infectious diseases, neurodegenerative disorders, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health, comprising administering one or more of the compounds described in any one of [1] to

[14] or pharmaceutically acceptable salts thereof, or the pharmaceutical kit described in any one of

[20] to

[22] to a patient suffering from a disease or disorder selected from tumors, infectious diseases, neurodegenerative disorders, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health.

[0046]

[30] The method of treatment according to

[29] , wherein the disease is a tumor.

[0047]

[31] The tumor is selected from the group consisting of mesothelioma, hepatobiliary (biliary tract and bile duct), primary or secondary CNS tumors, primary or secondary brain tumors, pharyngeal cancer, oral cancer, cancer of the nasal cavity, lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, duodenal cancer, colorectal cancer, breast cancer, uterine cancer, cancer of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland,

[30] The method of treatment according to

[30] , wherein the cancer is selected from adrenal gland 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 or ureter cancer, renal cell carcinoma, renal pelvis carcinoma, central nervous system (CNS) neoplasm, primary CNS lymphoma, non-Hodgkin's lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, and retinoblastoma. [Effects of the Invention]

[0048] The compounds of the present invention have excellent inhibitory activity against IDO and / or TDO, and can be applied as IDO inhibitors and / or TDO inhibitors to a wide range of diseases including tumors. [Brief explanation of the drawings]

[0049] [Figure 1] 1 is a graph showing the results of a drug efficacy test of a combined use of an IDO / TDO inhibitor and an anti-PD-1 antibody using CT-26WT colon cancer allograft subcutaneously transplanted mice. [Figure 2] 1 is a graph showing the results of a drug efficacy test of the combined use of Compound 1 and oxaliplatin using mice allogeneically transplanted with CT-26CL25 colon cancer subcutaneously. [Figure 3] 1 is a graph showing the results of a drug efficacy test of the combined use of Compound 1, Compound 15, and Compound 29 with oxaliplatin using CT-26WT colon cancer allograft subcutaneously transplanted mice. [Figure 4]1 is a graph showing the results of a drug efficacy test of a combined use of an IDO / TDO inhibitor and oxaliplatin using CT-26WT colon cancer allogeneic subcutaneously transplanted mice. [Figure 5] 1 is a graph showing the results of a drug efficacy test of the combined use of Compounds 29 and 38 with an anti-PD-1 antibody using CT-26WT colon cancer allograft subcutaneously transplanted mice. [Figure 6] 1 is a graph showing the results of a drug efficacy test of the combined use of Compound 103 and an anti-PD-1 antibody using CT-26WT colon cancer allograft subcutaneously transplanted mice. DETAILED DESCRIPTION OF THE INVENTION

[0050] The present invention will now be described in further detail. The IDO inhibitors and / or TDO inhibitors of the present invention include compounds having formula (I) or pharmaceutically acceptable salts of said compounds: [ka] In the formula, ring A represents an aromatic ring, an aliphatic ring, a heterocyclic ring, or a fused ring of two or more rings selected from aromatic rings, aliphatic rings, and heterocyclic rings.

[0051] The term "aromatic ring" as used herein means a cyclic structure or a compound having such a cyclic structure, which is composed of a single or multiple rings consisting solely of hydrocarbons and has delocalized π electron orbitals. When the aromatic ring is composed of multiple rings, the aromatic rings may be fused or non-fused (e.g., biphenyl). Note that "as used in the present application" means "described in at least one of the specification, claims, abstract, and drawings of the present application."

[0052] As used herein, the term "fused ring" refers to a cyclic structure in which two or more rings are joined together by sharing two or more atoms.

[0053] The term "aliphatic ring" as used herein refers to a ring structure or a compound having such a ring structure that has the properties of both an aliphatic compound (a non-aromatic hydrocarbon compound) and a cyclic compound (a compound in which constituent atoms are bonded in a ring). The aliphatic ring contains one or more saturated or unsaturated carbon rings that do not have aromaticity. Spiro compounds having a structure in which two or more rings are connected by one carbon atom are also included in the "aliphatic ring." When the aliphatic ring comprises multiple rings, the aliphatic rings may be fused or non-fused rings.

[0054] The term "heterocycle" as used herein means a cyclic structure composed of two or more elements or a compound having such a cyclic structure. The heterocycle may consist of a single ring or multiple rings. When the heterocycle consists of multiple rings, the heterocycle may be a fused ring or a non-fused ring (e.g., 2,2'-bipyridine, 4,4'-bipyridine).

[0055] The term "fused ring of two or more rings selected from aromatic rings, aliphatic rings, and heterocyclic rings" used herein means a cyclic structure having a fused ring of an aromatic ring and an aliphatic ring, a fused ring of an aliphatic ring and a heterocyclic ring, a fused ring of an aromatic ring and a heterocyclic ring, or a fused ring of three types of rings, i.e., 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.

[0056] When ring A represents an aromatic ring, an aliphatic ring, a heterocyclic ring, or a fused 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 a group containing an aromatic ring, an aliphatic ring, a heterocyclic ring, or a fused ring of two or more rings selected from aromatic rings, aliphatic rings, and heterocyclic rings, the rings can be fully saturated, partially saturated, or fully unsaturated.Examples of such rings include benzene, naphthalene, anthracene, phenanthrene, phenalene, biphenylene, pentalene, indene, as-indacene, s-indacene, acenaphthylene, fluorene, fluoranthene, acephenanthrylene, azulene, heptalene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyrrolidine, furan, tetrahydrofuran, 2-aza-tetrahydrofuran, 3-aza-tetrahydrofuran, oxazole, and iso-aza-tetrahydrofuran. Oxazole, furazan, 1,2,4-oxadiazole, 1,3,4-oxadiazole, thiophene, isothiazole, thiazole, thiolane, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, 2-azapiperidine, 3-azapiperidine, piperazine, pyran, tetrahydropyran, 2-azapyran, 3-azapyran, 4-azapyran, 2-aza-tetrahydropyran, 3-aza-tetrahydropyran, morpholine, thiopyran, 2-azathiopyran, 3-azathiopyran, 4-azathiopyran, thia Indoles, indazoles, benzimidazoles, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindole, isoindole, 4-azaiisoindole, 5-azaiisoindole, 6-azaiisoindole, 7-azaiisoindole, indolizines, 1-azaiindolizines, 2-azaiindolizines, 3-azaiindolizines, 5-azaiindolizines, 6-azaiindolizines, 7-azaiindolizines, 8-azaiindolizines, 9-azaiindolizines, purines, carbazoles, carbolines, Benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, quinoline, cinnoline, quinazoline, quinoxaline, 5-azaquinoline, 6-azaquinoline, 7-azaquinoline, isoquinoline, phthalazine, 6-azaisoquinoline, 7-azaisoquinoline, pteridine, quinoxaline, chromene, isochromene, acridine, phenanthridine, perimidine, phenanthroline, phenoxazine, xanthene, phenoxathiin and / or thianthrene, and positional isomers of the above groups. In one embodiment of the invention, ring A is selected from the group of rings consisting of benzene, naphthalene, quinoxaline, thiophene, indole, and pyridine.

[0057] As used herein, "X, R 1 and R 2 The "substituents" in "substituents for ring atoms constituting ring A" are not particularly limited as long as they do not cause TDO or IDO inhibitory function. For example, X is selected from the group consisting of a halogen atom, a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted linear or branched alkoxy group, a substituted or unsubstituted linear or branched alkenyl group, a substituted or unsubstituted linear or branched alkenyloxy group, a substituted or unsubstituted linear or branched alkynyl group, a substituted or unsubstituted linear or branched alkynyloxy group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a halogenated alkyl group, a halogenated alkyloxy group, a cyano group, a hydroxy group, an amino group, a nitro group, a carboxyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted aralkyl group. X can be bonded to any available carbon atom and / or hetero atom of ring A (which represents an aromatic ring, an aliphatic ring, a heterocyclic ring, or a fused ring of two or more rings selected from aromatic rings, aliphatic rings, and heterocyclic rings). Thus, the substituent X can be bonded to any available carbon atom and / or hetero atom in an aromatic ring such as a benzene ring, as well as in a heterocyclic ring or a polycyclic ring such as naphthalene. For example, X is a halogen atom, a substituted or unsubstituted straight-chain or branched C1-C8 alkyl group, a substituted or unsubstituted straight-chain or branched C1-C8 alkoxy group, a substituted or unsubstituted straight-chain or branched C2-C8 alkenyl group, a substituted or unsubstituted straight-chain or branched C2-C8 alkenyloxy group, a substituted or unsubstituted straight-chain or branched C2-C8 alkynyl group, a substituted or unsubstituted straight-chain or branched C2-C8 alkynyloxy group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C3-C8 cycloalkenyl group, a substituted or unsubstituted C3-C8 cycloalkynyl group, a C1-C3 halogenated alkyl group, a cyano group, a hydroxy group, an amino group, a carboxyl group, a substituted or unsubstituted C6-C 18 Aryl groups and substituted or unsubstituted aralkyl groups (the number of carbon atoms in the aryl moiety is C6-C 10 The number of carbon atoms in the alkylene moiety may be selected from the group consisting of C1-C4). For example, X may be selected from the group: Halogen atoms include fluorine, chlorine, bromine, and iodine atoms. Substituted or unsubstituted straight-chain or branched-chain alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-octyl, carboxymethyl, 2-carboxyethyl, 3-hydroxy-1-propyl, aminomethyl, 2-aminoethyl, hydroxymethyl, and 2-hydroxyethyl groups. Substituted or unsubstituted straight-chain or branched-chain alkoxy groups include methoxy, ethoxy, n-propoxy, and n-butoxy groups. Substituted or unsubstituted straight-chain or branched alkenyl groups include ethenyl (vinyl), 2-propenyl (allyl), and 3-butenyl groups. - Substituted or unsubstituted straight-chain or branched-chain alkenyloxy groups include ethenyloxy (vinyloxy) group, 2-propenyloxy (allyloxy) group, and 3-butenyloxy group. Substituted or unsubstituted straight-chain or branched-chain alkynyl groups include ethynyl, 2-propynyl, and 3-butynyl groups. - Substituted or unsubstituted straight-chain or branched-chain alkynyloxy groups include ethynyloxy, 2-propynyloxy, and 3-butynyloxy groups. Substituted or unsubstituted cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl groups. Substituted or unsubstituted cycloalkenyl groups include 1-cyclopropenyl, 1-cyclobutenyl, 1-cyclopentenyl, and 1-cyclohexenyl groups. -Halogenated alkyl groups include fluoromethyl (-CH2F), 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), and pentafluoroethyl (-C2F5). -Halogenated alkyloxy groups include fluoromethoxy group (-OCH2F), difluoromethoxy group (-OCHF2), chloromethoxy group (-OCH2Cl), bromomethoxy group (-OCH2Br), iodomethoxy group (-OCH2I), trifluoromethoxy group (-OCF3), trichloromethoxy group (-OCCl3), tribromomethoxy group (-OCBr3), triiodomethoxy group (-OCI3), 2,2,2-trifluoroethoxy group (-OCH2CF3), 2,2,2-trichloroethoxy group (-OCH2CCl3), 2,2,2-tribromoethoxy group (-OCH2CBr3), 2,2,2-triiodoethoxy group (-OCH2CI3), and pentafluoroethoxy group (-OC2F5). -cyano group -hydroxy group -Amino group -nitro group -Carboxyl group Substituted or unsubstituted aryl groups include phenyl, naphthalen-1-yl, and naphthalen-2-yl groups. Substituted or unsubstituted aralkyl groups include benzyl, phenethyl, and 3-phenyl-1-propyl groups.

[0058] R 1 is represented by formula (II) [ka] (In the formula, R 11 and R 12 each independently represents a hydrogen atom, a fluorine atom, or a substituted or unsubstituted alkyl group, and Y1 is O or NR 21 represents R 21 , R 22 and R 23 each independently 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; and R 21 and R22 or R 23 may be bonded to form a ring, Z1 represents S, SO, SO2, O or Se, and r1 represents an integer of 1 to 8. or formula (III) [ka] (In the formula, R 31 and R 32 each independently represents a hydrogen atom, a fluorine atom, or a substituted or unsubstituted linear or branched alkyl group; Z2 is O or NR 61 (R 61 represents a hydrogen atom, a substituted or unsubstituted linear or branched alkyl group, or a substituted or unsubstituted aryl group; 33 represents a substituted or unsubstituted linear 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 cycloalkylalkyl group, and r2 represents 0 or an integer of 1 to 8. 2 is R 1 and independently represent a group represented by formula (II) or formula (III). In one 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). 2 is a group represented by formula (II), R 1 and R 2 The specific groups may be any groups that fall within the scope of the definition of formula (II), and do not necessarily have to be the same groups. In one 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 which R 1 and R 2The specific groups may be any groups that fall within the scope of the definition of formula (II), and do not necessarily have to be the same groups. In one 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 one 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 one 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 which R 1 and R 2 The specific groups may be any groups that fall within the scope of the definition of formula (III), and do not necessarily have to be the same groups.

[0059] In formula (II), R 21 and R 22 or R 23 The functional group bonded to form a ring is, for example, a group represented by the following formula (IV): [ka] [In the formula, R 11 ,R 12 ,r1,Z1,R 22 and R 23 represents the same meaning as in formula (II), and Z3 represents CH, CR 54 or N, R 51 and R 52 each independently represents 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 53represents a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group, r3 represents an integer of 1 to 8, r4 and r6 each independently represent 0 or 1, provided that r4 and r6 are not both 0, and r5 represents 0 or an integer of 1 to 5. 22 (R 23 ) is written as R 22 and R 23 It is a functional group represented by the following formula:

[0060] R 1 and R 2 may be the same or different and are, for example, independently selected from the group consisting of:

[0061] [ka] wherein Y is selected from the group consisting of O, S, and Se; Z is selected from the group consisting of O, S, 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; R 3 represents a substituted or unsubstituted straight or branched chain alkyl group, R 4 is a substituted or unsubstituted heterocyclic group, -CONH2, or

[0062] [ka] (wherein R 41 , R 42 and R 43may 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.

[0063] In one embodiment of the present invention, r1 is an integer of 1 to 8. In one embodiment of the present invention, r1 is an integer of 1 to 6. In one embodiment of the present invention, r1 is an integer of 1 to 4. In one embodiment of the present invention, r1 is an integer of 1 to 2. In one embodiment of the present invention, r1 is 1. In one embodiment of the present invention, r2 is 0 or an integer of 1 to 8. In one embodiment of the present invention, r2 is 0. In one embodiment of the present invention, r2 is an integer of 1 to 6. In one embodiment of the present invention, r2 is an integer of 1 to 4. In one embodiment of the present invention, r2 is an integer of 1 or 2. In one embodiment of the present invention, r2 is 1. In one embodiment of the present invention, r3 is an integer of 1 to 8. In one embodiment of the present invention, r3 is an integer of 1 to 6. In one embodiment of the present invention, r3 is an integer of 1 to 4. In one embodiment of the present invention, r3 is an integer of 1 to 2. In one embodiment of the present invention, r3 is 1. In one embodiment of the invention, r4 is 0 or 1. In one embodiment of the invention, r4 is 0. In one embodiment of the invention, r4 is 1. In one embodiment of the present invention, r5 is 0 or an integer of 1 to 5. In one embodiment of the present invention, r5 is 0. In one embodiment of the present invention, r5 is an integer of 1 to 5. In one embodiment of the present invention, r5 is an integer of 1 to 4. In one embodiment of the present invention, r5 is an integer of 1 or 2. In one embodiment of the present invention, r5 is 1. In one embodiment of the invention, r6 is 0 or 1. In one embodiment of the invention, r6 is 0. In one embodiment of the invention, r6 is 1. Note that r4 and r6 cannot be 0 at the same time. In one embodiment of the present invention, n is an integer of 1 to 8. In one embodiment of the present invention, n is an integer of 1 to 6. In one embodiment of the present invention, n is an integer of 1 to 4. In one embodiment of the present invention, n is an integer of 1 to 2. In one embodiment of the present invention, n is 1. In one embodiment of the present invention, p is an integer of 0 to 8. In one embodiment of the present invention, p is an integer of 0 to 6. In one embodiment of the present invention, p is an integer of 0 to 4. In one embodiment of the present invention, p is an integer of 0 to 2. In one embodiment of the present invention, p is 0. In one embodiment of the present invention, p is 1. In one embodiment of the present invention, q is an integer of 1 to 8. In one embodiment of the present invention, q is an integer of 1 to 6. In one embodiment of the present invention, q is an integer of 1 to 4. In one embodiment of the present invention, q is an integer of 1 to 2. In one embodiment of the present invention, q is 1. In one embodiment of the present invention, q is 2. In one embodiment of the present invention, q is 4. In one embodiment of the present invention, r is an integer of 1 to 8. In one embodiment of the present invention, r is an integer of 1 to 6. In one embodiment of the present invention, r is an integer of 1 to 4. In one embodiment of the present invention, r is an integer of 1 to 2. In one embodiment of the present invention, r is 1. In one embodiment of the present invention, s is an integer of 1 to 8. In one embodiment of the present invention, s is an integer of 1 to 6. In one embodiment of the present invention, s is an integer of 1 to 4. In one embodiment of the present invention, s is an integer of 1 to 2. In one embodiment of the present invention, s is 1. In one embodiment of the present invention, s is 2.

[0064] R 1 and R 2 The substitution position of the ring atom of the ring A in R is not particularly limited. 1 and R 2 may be bonded to adjacent ring atoms of ring A. For example, R 1 and R 2 may be bonded to adjacent ring atoms of ring A with one ring atom in between. R 1 and R 2 may have the same group. 1 and R 2 may have different groups.

[0065] As used herein, the term "halogen atom" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). As used herein, the term "halogenated" refers to a group in which one or more hydrogen atoms on one or more carbon atoms of the group have been replaced with halogen atoms. When two or more hydrogen atoms have been replaced with 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, may be referred to as a "halogen compound."

[0066] As used herein, the term "substituted or unsubstituted" means having one or more substituents, and "unsubstituted" means having no substituents.

[0067] The term "straight chain" as used herein means a structure in which atoms other than hydrogen atoms are connected in a straight line without branching.

[0068] As used herein, the term "branched chain" refers to a structure in which any one or more carbon atoms have two or more additional carbon atoms attached to them.

[0069] The term "alkyl group" as used herein refers to a group of the general formula C n H 2n+2 (n is a positive integer), the alkyl group refers to the hydrocarbon group remaining after removing one hydrogen atom from any carbon atom of an alkane (aliphatic saturated hydrocarbon). The number of carbon atoms in the alkyl group is not particularly limited. In one embodiment of the present invention, the alkyl group is an alkyl group having 1 to 20 carbon atoms. In one embodiment of the present invention, the alkyl group is an alkyl group having 1 to 16 carbon atoms. In one embodiment of the present invention, the alkyl group is an alkyl group having 1 to 12 carbon atoms. In one embodiment of the present invention, the alkyl group is an alkyl group having 1 to 10 carbon atoms. In one embodiment of the present invention, the alkyl group is an alkyl group having 1 to 8 carbon atoms. In one embodiment of the present invention, the alkyl group is an alkyl group having 1 to 6 carbon atoms. In one embodiment of the present invention, the alkyl group is an alkyl group having 1 to 4 carbon atoms. Examples of the "alkyl group" include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1-ethylpropyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, an n-hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 2,3-dimethylbutyl group, a 3,3-dimethylbutyl group, a 1,1,2-trimethylpropyl group, a 1-ethylbutyl group, a 2-ethylbutyl group, a 1-ethyl-1-methylpropyl group, a 1-ethyl-2 ... Examples of the alkyl group include a propyl group, an n-hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 2,3-dimethylbutyl group, a 3,3-dimethylbutyl group, a 1,1,2-trimethylpropyl group, a 1-ethylbutyl group, a 2-ethylbutyl group, a 1-ethyl-1-methylpropyl group, a 1-ethyl-2-methylpropyl group, an n-heptyl group, a 1-methylhexyl group, a 2-methylhexyl group, a 3-methylhexyl group, a 4-methylhexyl group, a 5-methylhexyl group, a 1-ethylpentyl group, a 2-ethylpentyl group, a 3-ethylpentyl group, a 4,4-dimethylpentyl group, a 1-propylbutyl group, and an n-octyl group.

[0070] The term "alkoxy group" as used herein means a group represented by "-O-alkyl group". "Alkyl group" is as defined above. The term "substituted or unsubstituted straight-chain or branched-chain alkoxy group" as used herein means "-O-substituted or unsubstituted straight-chain or branched-chain alkyl group". The number of carbon atoms in the alkyl group in the "alkoxy group" is not particularly limited. In one embodiment of the present invention, the alkyl group is an alkyl group having 1 to 20 carbon atoms. In one embodiment of the present invention, the alkyl group is an alkyl group having 1 to 16 carbon atoms. In one embodiment of the present invention, the alkyl group is an alkyl group having 1 to 12 carbon atoms. In one embodiment of the present invention, the alkyl group is an alkyl group having 1 to 10 carbon atoms. In one embodiment of the present invention, the alkyl group is an alkyl group having 1 to 8 carbon atoms. In one embodiment of the present invention, the alkyl group is an alkyl group having 1 to 6 carbon atoms. In one embodiment of the present invention, the alkyl group is an alkyl group having 1 to 4 carbon atoms. Examples of the "alkoxy group" include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentoxy group, a 1-methylbutoxy group, a 2-methylbutoxy group, a 3-methylbutoxy group, a 1-ethylpropoxy group, a 1,1-dimethylpropoxy group, a 1,2-dimethylpropoxy group, a 2,2-dimethylpropoxy group, an n-hexyloxy group, a 1-methylpentyloxy group, a 2-methylpentyloxy group, a 3-methylpentyloxy group, a 4-methylpentyloxy group, a 1,1-dimethylbutoxy group, a 1,2-dimethylbutoxy group, a 1,3-dimethylbutoxy group, Examples include a 2,2-dimethylbutoxy group, a 2,3-dimethylbutoxy group, a 3,3-dimethylbutoxy group, a 1,1,2-trimethylpropoxy group, a 1-ethylbutoxy group, a 2-ethylbutoxy group, a 1-ethyl-1-methylpropoxy group, a 1-ethyl-2-methylpropoxy group, an n-heptyloxy group, a 1-methylhexyloxy group, a 2-methylhexyloxy group, a 3-methylhexyloxy group, a 4-methylhexyloxy group, a 5-methylhexyloxy group, a 1-ethylpentyloxy group, a 2-ethylpentyloxy group, a 3-ethylpentyloxy group, a 4,4-dimethylpentyloxy group, a 1-propylbutoxy group, and an n-octyloxy group.

[0071] The term "alkenyl group" as used herein refers to an alkenyl group having only one carbon-carbon double bond in the molecule and having the general formula C n H 2n(n is a positive integer of 2 or 3 or more) and refers to the remaining hydrocarbon group obtained by removing one hydrogen atom from any carbon atom of an alkene (olefinic hydrocarbon) represented by the formula (N), where N is a positive integer of 2 or 3 or more. The number of carbon atoms in the alkenyl group is not particularly limited. In one embodiment of the present invention, the alkenyl group is an alkenyl group having 2 to 20 carbon atoms. In one embodiment of the present invention, the alkenyl group is an alkenyl group having 2 to 16 carbon atoms. In one embodiment of the present invention, the alkenyl group is an alkenyl group having 2 to 12 carbon atoms. In one embodiment of the present invention, the alkenyl group is an alkenyl group having 2 to 10 carbon atoms. In one embodiment of the present invention, the alkenyl group is an alkenyl group having 2 to 8 carbon atoms. In one embodiment 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 the "alkenyl group" include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-octenyl, 2-octenyl, 3-octenyl, and 4-octenyl groups.

[0072] The term "alkenyloxy group" as used herein means a group represented by "-O-alkenyl group." The term "alkenyl group" is as defined above. The term "substituted or unsubstituted straight-chain or branched-chain alkenyl group" as used herein means "-O-substituted or unsubstituted straight-chain or branched-chain alkenyl group." The number of carbon atoms in the alkenyl group in the "alkenyloxy group" is not particularly limited. In one embodiment of the present invention, the alkenyl group is an alkenyl group having 2 to 20 carbon atoms. In one embodiment of the present invention, the alkenyl group is an alkenyl group having 2 to 16 carbon atoms. In one embodiment of the present invention, the alkenyl group is an alkenyl group having 1 to 12 carbon atoms. In one embodiment of the present invention, the alkenyl group is an alkenyl group having 2 to 10 carbon atoms. In one embodiment of the present invention, the alkenyl group is an alkenyl group having 2 to 8 carbon atoms. In one embodiment 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 the "alkenyloxy group" include ethenyloxy group (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, and 4-octenyloxy group.

[0073] The term "alkynyl group" as used herein refers to an alkynyl group having only one carbon-carbon triple bond in the molecule and having the general formula C n H 2n-2(n is a positive integer of 2 or 3 or more) and refers to the hydrocarbon group remaining after removing one hydrogen atom from any carbon atom of an alkyne (acetylene hydrocarbon). 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 an ethynyl group, a 1-propynyl group, a 2-propynyl group (propargyl group), a 1-butynyl group, a 2-butynyl group, a 3-butynyl group, a 1-methyl-2-propynyl group, a 2-methyl-3-butynyl group, a 1-pentynyl group, a 2-pentynyl group, Examples include a 3-pentynyl group, a 4-pentynyl group, a 1-methyl-2-butynyl group, a 2-methyl-3-pentynyl group, a 1-hexynyl group, a 1,1-dimethyl-2-butynyl group, a 1-octynyl group, a 2-octynyl group, a 3-octynyl group, and a 4-octynyl group.

[0074] The term "alkynyloxy group" as used herein means a group represented by "-O-alkynyl group". The term "alkynyl group" is as defined above. The term "substituted or unsubstituted straight-chain or branched-chain alkynyl group" as used herein means "-O-substituted or unsubstituted straight-chain or branched-chain alkynyl group". The number of carbon atoms in the alkynyl group in the "alkynyloxy group" is not particularly limited. 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 "alkynyloxy group" include an ethynyloxy group, a 1-propynyloxy group, a 2-propynyloxy group (propargyloxy group), a 1-butynyloxy group, a 2-butynyloxy group, a 3-butynyloxy group, a 1-methyl-2-propynyloxy group, a 2-methyl-3-butynyloxy group, a 1-pentynyloxy group, a 2-pentynyloxy group, a 3-pentynyloxy group, a 4-pentynyloxy group, a 1-methyl-2-butynyloxy group, a 2-methyl-3-pentynyloxy group, a 1-hexynyloxy group, a 1,1-dimethyl-2-butynyloxy group, a 1-octynyloxy group, a 2-octynyloxy group, a 3-octynyloxy group, and a 4-octynyloxy group.

[0075] The term "cycloalkyl group" as used herein refers to a group of the general formula C n H 2n (n is a positive integer of 3 or more) and refers to the hydrocarbon group remaining after removing one hydrogen atom from any carbon atom of a cycloalkane (cyclic saturated hydrocarbon). In one embodiment of the present invention, the cycloalkyl group is a cycloalkyl group having 3 to 12 carbon atoms. In one embodiment of the present invention, the cycloalkyl group is a cycloalkyl group having 3 to 10 carbon atoms. In one embodiment of the present invention, the cycloalkyl group is a cycloalkyl group having 3 to 8 carbon atoms. In one embodiment of the present invention, the cycloalkyl group is a cycloalkyl group having 3 to 6 carbon atoms. In one embodiment of the present invention, the cycloalkyl group is a cycloalkyl group having 3 to 4 carbon atoms. Examples of the "cycloalkyl group" include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, and a cyclodecyl group.

[0076] As used herein, the term "cycloalkenyl group" refers to a group of the general formula C n H 2n-2(n is a positive integer of 3 or more) and refers to the remaining hydrocarbon group obtained by removing one hydrogen atom from any carbon atom of a cycloalkene (cyclic alkene). In one embodiment of the present invention, the cycloalkenyl group is a cycloalkenyl group having 3 to 12 carbon atoms. In one embodiment of the present invention, the cycloalkenyl group is a cycloalkenyl group having 3 to 10 carbon atoms. In one embodiment of the present invention, the cycloalkenyl group is a cycloalkenyl group having 3 to 8 carbon atoms. In one embodiment of the present invention, the cycloalkenyl group is a cycloalkenyl group having 3 to 6 carbon atoms. In one embodiment of the present invention, the cycloalkenyl group is a cycloalkenyl group having 3 to 4 carbon atoms. Examples of the "cycloalkenyl group" include a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclooctenyl group, a cyclononenyl group, and a cyclodecenyl group.

[0077] As used herein, the term "cycloalkynyl group" refers to a group of the general formula C n H 2n-4 (n is a positive integer of 3 or more) and refers to the remaining hydrocarbon group obtained by removing one hydrogen atom from any carbon atom of a cycloalkyne (cyclic alkyne). In one embodiment of the present invention, the cycloalkynyl group is a cycloalkynyl group having 8 to 20 carbon atoms. In one embodiment of the present invention, the cycloalkynyl group is a cycloalkynyl group having 10 to 16 carbon atoms. In one embodiment of the present invention, the cycloalkynyl group is a cycloalkynyl group having 10 to 12 carbon atoms. In one embodiment of the present invention, the cycloalkynyl group is a cycloalkynyl group having 8 to 12 carbon atoms. In one embodiment of the present invention, the cycloalkynyl group is a cycloalkynyl group having 8 to 10 carbon atoms. Examples of the "cycloalkynyl group" include a cyclooctynyl group, a cyclononynyl group, a cyclodecynyl group, a cycloundecynyl group, and a cyclododecynyl group.

[0078] The term "aryl group" as used herein refers to a compound having an aromatic ring, i.e., a hydrocarbon group remaining after removing one hydrogen atom bonded to a ring atom of an aromatic hydrocarbon. The meaning of an aromatic ring is as defined above. In one embodiment of the present invention, the aryl group is an aryl group having 6 to 22 ring carbon atoms. In one embodiment of the present invention, the aryl group is an aryl group having 6 to 18 ring carbon atoms. In one embodiment of the present invention, the aryl group is an aryl group having 6 to 14 ring carbon atoms. In one embodiment of the present invention, the aryl group is an aryl group having 6 to 10 ring carbon atoms. In one embodiment of the present invention, the aryl group is an aryl group having 6 ring carbon atoms (phenyl group). Examples of the "aryl group" include a phenyl group, an o-tolyl group, an m-tolyl group, a p-tolyl group, a naphthyl group, an o-xylyl group, an m-xylyl group, and a p-xylyl group.

[0079] As used herein, the term "aralkyl group" refers to an alkyl group (C n H 2n+1 ) means an alkyl group in which one of the hydrogen atoms is substituted with an aryl group. In one embodiment of the present invention, the aralkyl group is an aralkyl group having 7 to 26 carbon atoms (of which 6 to 22 ring carbon atoms). In one embodiment of the present invention, the aralkyl group is an aralkyl group having 7 to 22 carbon atoms (of which 6 to 18 ring carbon atoms). In one embodiment of the present invention, the aralkyl group is an aralkyl group having 7 to 18 carbon atoms (of which 6 to 14 ring carbon atoms). In one embodiment of the present invention, the aralkyl group is an aralkyl group having 7 to 14 carbon atoms (of which 6 to 14 ring carbon atoms). In one embodiment of the present invention, the aralkyl group is an aralkyl group having 7 to 8 ring carbon atoms (of which 6 ring carbon atoms). Examples of the "aralkyl group" include a benzyl group (phenylmethyl group) and a phenethyl group (phenylethyl group).

[0080] In one embodiment of the invention, compounds of formula (I) are 1 and R 2 is the following compound (I-0a), which has a group of the formula (II) and is bonded to adjacent ring atoms of ring A.

[0081] [ka] (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 (where R 21 represents a hydrogen atom, a substituted or unsubstituted straight-chain or branched-chain 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 SO2. For example, Z1 is O. For example, Z1 is Se.

[0082] In one embodiment of the present invention, in the compound of formula (I-0a), at least one of R 21 and R 22 or R 23 When the functional group to which the ring is formed by bonding is represented by the formula (IV), the compounds are the following compounds (I-0a-1) to (I-0a-3).

[0083] [ka] JPEG0007624184000034.jpg3550 (In the formula, A, X, m, Z1, Z3, R 11 ,R 12 ,R 22 , R 23 , R 51 , R 52 , R 53 , R 54 , r1, r3, r4, r5, and r6 have the same meanings as above.) For example, Z1 is S, SO or SO2. For example, Z1 is O. For example, Z1 is Se. For example, Z3 is. For example, Z3 is N. For example, the Z3 is a CR 54 (R 54 represents a halogen atom or a substituted or unsubstituted straight or branched chain alkyl group.

[0084] In one embodiment of the invention, compounds of formula (I) are 1 and R 2 have the same groups and are bonded to adjacent ring atoms of ring A, as shown in the following compound (I-0b).

[0085] [ka] (In the formula, A, X, m, Z2, R 31 , R 32 , R 33 , and r2 have the meanings as above) For example, Z2 is O. For example, Z2 is NR 61 (where R 61 represents a hydrogen atom, a substituted or unsubstituted straight-chain or branched-chain alkyl group, or a substituted or unsubstituted aryl group.

[0086] In one embodiment of the invention, compounds of formula (I) are 1 and R 2 are the following compounds in which the same groups are bonded to adjacent ring atoms of ring A.

[0087] [ka] (In the formula, A, X, Z, m, R 41 , R 42 , and R 43 have the meanings given above) For example, Z is S, SO, or SO2. For example, Z is O. For example, Z is Se.

[0088] In one embodiment of the invention, compounds of formula (I) are 1 and R 2 are the following compounds in which the same groups are bonded to adjacent ring atoms of ring A.

[0089] [ka] (Wherein A, X, Z, m, s, and R 6 have the meanings given above) For example, Z is S, SO, or SO2. For example, Z is O. For example, Z is Se.

[0090] In one embodiment of the invention, compounds of formula (I) are 1 and R 2 The following two compounds have different groups attached to adjacent ring atoms of ring A.

[0091] [ka] (In the formula, 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 (where R 21represents a hydrogen atom, a substituted or unsubstituted straight-chain or branched-chain 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 SO2. For example, Z1 is O. For example, Z1 is Se. For example, Z2 is O. For example, Z2 is NR 61 (where R 61 represents a hydrogen atom, a substituted or unsubstituted straight-chain or branched-chain alkyl group, or a substituted or unsubstituted aryl group.

[0092] In one embodiment of the present invention, in the compounds of formula (I-0c) and (I-0d), R 21 and R 22 or R 23 When the functional group to which the ring is bonded is represented by the formula (IV), the following two compounds are available.

[0093] [ka] (In the formula, 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 same meanings as above.) For example, Z1 is S, SO or SO2. For example, Z1 is O. For example, Z1 is Se. For example, Z2 is O. For example, Z2 is NR 61(where R 61 represents a hydrogen atom, a substituted or unsubstituted straight-chain or branched-chain alkyl group, or a substituted or unsubstituted aryl group. For example, Z3 is CH. For example, Z3 is N. For example, the Z3 is a CR 54 (R 54 represents a halogen atom or a substituted or unsubstituted straight or branched chain alkyl group.

[0094] In one embodiment of the invention, compounds of formula (I) are 1 and R 2 have different groups and are bonded to adjacent ring atoms of ring A.

[0095] [ka] (wherein A, X, and m have the same meanings as above, and R 7 and R 8 are different from each other and are selected from the group consisting of the following groups:

[0096] [ka] (In the formula, R 3 , R 4 , R 5 , R 6 , Y, Z, n, p, q, r, and s have the meanings as above.

[0097] 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.

[0098] R7 and R 8 Specific examples of the compound represented by formula (I-3) in which are different from each other include the following compounds.

[0099] [ka] JPEG0007624184000043.jpg3457 (In the formula, R 3 , R 4 , R 5 , R 6 , Y, Z, n, p, q, r, and s have the meanings as above.

[0100] 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.

[0101] In one embodiment of the present invention, there is provided a compound of formula (I), a compound of formula (I-0a), a compound of formula (I-0a-1), a compound of formula (I-0b), a compound of formula (I-0c), a compound of formula (I-0d), a compound of formula (I-0c-1), a compound of formula (I-0d-1), a compound of formula (I-1), a compound of formula (I-2), a compound of formula (I-3), and a compound of formula (1-3-a) to (I-3-h), wherein X is a halogen atom, a substituted or unsubstituted linear or branched C1-C8 alkyl group, a substituted or unsubstituted linear or branched C1-C8 alkoxy group, a substituted or unsubstituted linear or branched C2-C8 Alkenyl group, substituted or unsubstituted straight-chain or branched C2-C8 alkenyloxy group, substituted or unsubstituted straight-chain or branched C2-C8 alkynyl group, substituted or unsubstituted straight-chain or branched C2-C8 alkynyloxy group, substituted or unsubstituted C3-C8 cycloalkyl group, substituted or unsubstituted C3-C8 cycloalkenyl group, substituted or unsubstituted C3-C8 cycloalkynyl group, C1-C3 halogenated alkyl group, cyano group, hydroxy group, amino group, carboxyl group, substituted or unsubstituted C6-C 18 Aryl groups and substituted or unsubstituted aralkyl groups (the number of carbon atoms in the aryl moiety is C6-C 10 The number of carbon atoms in the alkylene moiety is selected from the group consisting of C1-C4.

[0102] In one embodiment of the present invention, in the compounds of formula (I), (I-0a), (I-0a-1) to (I-0a-3), (I-0b), (I-0c), (I-0d), (I-0c-1), (I-0d-1), (I-1), (I-2), (I-3), and (1-3-a) to (I-3-h), X is a group selected from the group consisting of: Halogen atoms include fluorine, chlorine, bromine, and iodine atoms. Substituted or unsubstituted straight-chain or branched-chain alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-octyl, carboxymethyl, 2-carboxyethyl, 3-hydroxy-1-propyl, aminomethyl, 2-aminoethyl, hydroxymethyl, and 2-hydroxyethyl groups. Substituted or unsubstituted straight-chain or branched-chain alkoxy groups include methoxy, ethoxy, n-propoxy, and n-butoxy groups. Substituted or unsubstituted straight-chain or branched alkenyl groups include ethenyl (vinyl), 2-propenyl (allyl), and 3-butenyl groups. - Substituted or unsubstituted straight-chain or branched-chain alkenyloxy groups include ethenyloxy (vinyloxy) group, 2-propenyloxy (allyloxy) group, and 3-butenyloxy group. Substituted or unsubstituted straight-chain or branched-chain alkynyl groups include ethynyl, 2-propynyl, and 3-butynyl groups. - Substituted or unsubstituted straight-chain or branched-chain alkynyloxy groups include ethynyloxy, 2-propynyloxy, and 3-butynyloxy groups. Substituted or unsubstituted cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl groups. Substituted or unsubstituted cycloalkenyl groups include 1-cyclopropenyl, 1-cyclobutenyl, 1-cyclopentenyl, and 1-cyclohexenyl groups. -Halogenated alkyl groups include fluoromethyl (-CH2F), 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), and pentafluoroethyl (-C2F5). -Halogenated alkyloxy groups include fluoromethoxy group (-OCH2F), difluoromethoxy group (-OCHF2), chloromethoxy group (-OCH2Cl), bromomethoxy group (-OCH2Br), iodomethoxy group (-OCH2I), trifluoromethoxy group (-OCF3), trichloromethoxy group (-OCCl3), tribromomethoxy group (-OCBr3), triiodomethoxy group (-OCI3), 2,2,2-trifluoroethoxy group (-OCH2CF3), 2,2,2-trichloroethoxy group (-OCH2CCl3), 2,2,2-tribromoethoxy group (-OCH2CBr3), 2,2,2-triiodoethoxy group (-OCH2CI3), and pentafluoroethoxy group (-OC2F5). -cyano group -hydroxy group -Amino group -nitro group -Carboxyl group Substituted or unsubstituted aryl groups include phenyl, naphthalen-1-yl, and naphthalen-2-yl groups. Substituted or unsubstituted aralkyl groups include benzyl, phenethyl, and 3-phenyl-1-propyl groups.

[0103] As described above, in the compound of formula (I), 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, and a pyridine ring. In one embodiment of the present invention, ring A is a benzene ring having R at the 1-position of the ring. 1 , R in second place 2 In the compound of the following formula (I-4) substituted with

[0104] [ka] (In the formula, R 1 , and R 2 has the meaning defined in any one of paragraphs [1] to [3] above) R 1 , and R 2 The following formula (I-4-a) excluding

[0105] [ka] However, 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-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-CF3-Ph=, 4-CF3-Ph=, 5-CF3-Ph=, 6-CF3-Ph=, 3-C2F5-Ph=, 4-C2F5-Ph=, 5-C2F5-Ph=, 6-C2F5-Ph=, 3-CF3O -Ph=, 4-CF3O-Ph=, 5-CF3O-Ph=, 6-CF3O-Ph=, 3-C2F5O-Ph=, 4-C2F5O-Ph=, 5-C2F5O-Ph=, 6-C2F5O-Ph=, 3-CN-Ph=, 4-CN-Ph=, 5-CN-Ph=, 6-CN-Ph=, 3-O H-Ph=, 4-OH-Ph=, 5-OH-Ph=, 6-OH-Ph=, 3-NH2-Ph=, 4-NH2-Ph=, 5-NH2-Ph=, 6-NH2-Ph=, 3-NO2-Ph=, 4-NO2-Ph=, 5-NO2-Ph=, 6-NO2-Ph=, 3-COOH-Ph=, 4 -COOH-Ph=, 5-COOH-Ph=, 6-COOH-Ph=, -F2-Ph= (at any two positions of 3, 4, 5 and 6), -Cl2-Ph= (at any two positions of 3, 4, 5 and 6), -Br2-Ph= (at any two positions of 3, 4, 5 and 6), -I2-Ph= (at any two positions of 3, 4, 5 and 6), -Me2-Ph= (at any two positions of 3, 4, 5 or 6), -Et2-Ph- (at any two positions of 3, 4, 5 and 6), -Pr2-Ph= (at any two positions of 3, 4, 5 and 6), -Bu2-Ph= (at any two positions of 3,(any two positions among 4, 5 and 6 positions)-(CN)2-Ph=, (any two positions among 3, 4, 5 and 6 positions)-(OH)2-Ph=, (any two positions among 3, 4, 5 and 6 positions)-((NH2))2-Ph=, (any two positions among 3, 4, 5 and 6 positions)-(NO2)2-Ph=, (any two positions among 3, 4, 5 and 6 positions)-(MeO)2-Ph=, (any two positions among 3, 4, 5 and 6 positions)-(EtO)2-P h=, (any two positions among the 3-, 4-, 5-, and 6-positions) -(CF3)2-Ph=, (any three positions among the 3-, 4-, 5-, and 6-positions) -F3-Ph=, (any three positions among the 3-, 4-, 5-, and 6-positions) -Cl2-Ph=, (four positions among the 3-, 4-, 5-, and 6-positions) -F4-Ph=, and (four positions among the 3-, 4-, 5-, and 6-positions) -Cl4-Ph= (wherein "Ph=" represents any of the formulae (I-4-a) to (X), m The part excluding - represents a divalent group.

[0106] In the definition of the formula (I-4-a), for example, in "Ph=", "Ph" represents a benzene ring and "=" represents a bond. Therefore, "Ph=" represents a phenylene group. In the definition of the formula (I-4-a) above, 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 formula (I-4-a), for example, "(any two of the 3-, 4-, 5-, and 6-positions)-(MeO)2-Ph=" represents a divalent group (phenylene group) in which any two of the 3-, 4-, 5-, and 6-positions of the benzene ring are substituted with methoxy groups (-OCH3).

[0107] The definitions of the above formula (I-4) and formula (I-4-a) can be rephrased as follows. In formula (I), ring A is a benzene ring, and R 1 and R 2 is adjacently substituted on ring A, and R 1 The substitution position of is the first position, and R 2When the substitution position of X is the 2nd position, X is 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 group, a 3-n-butyl group, a 4-n- Butyl group, 5-n-butyl group, 6-n-butyl group, 3-t-butyl group, 4-t-butyl group, 5-t-butyl group, 6-t-butyl group, 3-methoxy group, 4-methoxy group, 5-methoxy group, 6-methoxy group, 3-ethoxy group, 4-ethoxy group, 5-ethoxy group, 6-ethoxy group, 3-trifluoromethyl group, 4-trifluoromethyl group, 5-trifluoromethyl group, 6-trifluoromethyl group, 3-pentafluoroethyl group, 4-pentafluoroethyl group, 5-pentafluoroethyl group, 6-pentafluoroethyl group, 3-trifluoromethoxy group, 4-trifluoromethyl group 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 group, 3,4-difluoro group, 3,5-difluoro group, 3,6-difluoro group, 4,5-difluoro group, 4,6-difluoro group, 5,6-difluoro group, 3,4-dichloro group, 3,5-dichloro group, 3,6-dichloro group, 4,5-dichloro group, 4,6-dichloro group, 5,6-dichloro group, 3,4-dibromo group, 3,5-dibromo group, 3,6-dibromo group, 4,5-dibromo group, 4,6-dibromo group, 5,6-dibromo group, 3,4-dimethyl group, 3,5-dimethyl group, 3,6-dimethyl group, 4,5-dimethyl group, 4,6-dimethyl group, 5,6-dimethyl group, 3,4-diethyl group, 3,5-diethyl group, 3,6-diethyl group, 4,5-diethyl group, 4,6-diethyl group, 5,6-diethyl group, 3,4-di-n-propyl group, 3,5-di-n-propyl group, 3,6-di-n-propyl group, 4,5-di-n-propyl group, 4,6-di-n-propyl group, 5,6-di-n-propyl group, 3,4-di-n-butyl group, 3,5-di-n-butyl group, 3,6-di-n-butyl group, 4,5-di-n-butyl group, 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 group, 3,4-dinitro group, 3,5-dinitro group, 3,6-dinitro group, 4,5-dinitro group, 4,6-dinitro group, 5,6-dinitro group, 3,4-dimethoxy group, 3,5-dimethoxy group, 3,6-dimethoxy group, 4,5-dimethoxy group, 4,6-dimethoxy group, 5,6-dimethoxy group, 3,4-diethoxy group, 3,5-diethoxy group, 3,6-diethoxy group, 4,5-diethoxy group, 4,6-diethoxy group, 5,6-diethoxy group, 3,4-ditrifluoro group The alkyl group is selected from the group consisting of a 3,5-ditrifluoromethyl group, a 3,6-ditrifluoromethyl group, a 4,5-ditrifluoromethyl group, a 4,6-ditrifluoromethyl group, a 5,6-ditrifluoromethyl group, a 3,4,5-trifluoro group, a 3,4,6-trifluoro group, a 4,5,6-trifluoro group, a 3,4,5-trichloro group, a 3,4,6-trichloro group, a 4,5,6-trichloro group, a 3,4,5,6-tetrafluoro group, and a 3,4,5,6-tetrachloro group.

[0108] As used herein, the term "pharmaceutically acceptable salts" refers to those compounds, substances, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Such salts can be formed by conventional means, such as by reacting the free acid form of the product with one or more equivalents of an appropriate base, or the free base form of the product with one or more equivalents of an appropriate acid, in a solvent or vehicle in which the salt is insoluble or in a solvent such as water, and can be removed by vacuum or lyophilization, or by exchanging the anion of an existing salt for another anion on a suitable ion exchange resin.

[0109] The pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base salts. Examples of the pharmaceutically acceptable acid addition salts of the compounds of the present invention include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexylsulfamate, diethylenediamine, ethanesulfonate, formate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, and hydroiodide. Salts include hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate, and undecanoate.

[0110] Examples of pharmaceutically acceptable base salts of the compounds of the present invention include ammonium salts; alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as aluminum, calcium, and magnesium salts; salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine; and salts with amino acids such as arginine, lysine, ornithine, and the like. Furthermore, basic nitrogen-containing groups may be quaternized with materials such as lower alkyl halides such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates such as dimethyl, diethyl, and dibutyl; diamyl sulfate; long-chain halides such as decyl, lauryl, myristyl, and stearyl halides; aryl alkyl halides such as benzyl bromide, and the like. Non-toxic, physiologically acceptable salts are preferred, although other salts may be useful, for example, in isolating or purifying the product.

[0111] The scope of the present invention includes various isomers (e.g., optical isomers, positional isomers, tautomers, etc.), solvates such as hydrates, crystalline polymorphs, and prodrugs such as esters of the compounds of the present invention represented by formula (I). The present invention also includes compounds of the present invention represented by formula (I) in which one or more atoms constituting the compound of the present invention are isotopes, and pharmaceutically acceptable salts thereof. Examples of isotopes contained in the compound of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, bromine, and chlorine, for example, 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 Examples include Cl.

[0112] The compounds represented by formula (I), (I-0a), (I-0a-1) to (I-0a-3), (I-0b), (I-0c), (I-0d), (I-0c-1), (I-0d-1), (I-1), (I-2), (I-3), and (1-3-a) to (I-3-h) exhibit excellent inhibitory effects against IDO and / or TDO and can be used as inhibitors of IDO and / or TDO. Therefore, the compounds of formula (I), formula (I-0a), formulas (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 formulas (1-3-a) to (I-3-h) can be used as medicines for a wide range of diseases. Thus, one aspect of the present invention is an IDO and / or TDO inhibitor comprising, as an active ingredient, one or more compounds having the formula (I), formula (I-0a), formulas (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 pharmaceutically acceptable salts thereof. Another aspect of the present invention is a pharmaceutical composition comprising, as an active ingredient, one or more compounds having the formula (I), formula (I-0a), formulas (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 pharmaceutically acceptable salts thereof. Yet another aspect of the present invention is a therapeutic agent for a disease or disorder selected from tumors, infectious diseases, neurodegenerative disorders, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health, comprising, as an active ingredient, one or more compounds having the formula (I), (I-0a), (I-0a-1) to (I-0a-3), (I-0b), (I-0c), (I-0d), (I-0c-1), (I-0d-1), (I-1), (I-2), (I-3), (1-3-a), (1-3-b), (1-3-c), (1-3-d), (1-3-e), (1-3-f), (1-3-g), or (I-3-h) or pharmaceutically acceptable salts thereof. Yet another aspect of the present invention is an antitumor agent comprising, as an active ingredient, one or more compounds having the formula (I), formula (I-0a), formulas (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 pharmaceutically acceptable salts thereof. Yet another aspect of the present invention is a pharmaceutical kit comprising, as an active ingredient, one or more compounds having the formula (I), formula (I-0a), formulas (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 pharmaceutically acceptable salts thereof.

[0113] Formula (I), Formula (I-0a), Formula (I-0a-1)~(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 ( When a compound having formula (I-3-g) or formula (I-3-h) is used as an antitumor agent, the target tumors include mesothelioma, hepatobiliary (biliary tract and bile duct), primary or secondary CNS tumors, primary or secondary brain tumors, pharyngeal cancer, oral cancer, cancer of the nasal cavity, lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, duodenal cancer, colorectal cancer, breast cancer, uterine cancer, cancer of the fallopian tubes, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, acute bone marrow cancer, These tumors include, but are not limited to, myeloid leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis carcinoma, central nervous system (CNS) neoplasms, primary CNS lymphoma, non-Hodgkin's lymphoma, spinal axis tumors, brainstem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, and retinoblastoma.

[0114] The pharmaceutical compositions, IDO and / or TDO inhibitors, and therapeutic agents for diseases such as tumors of the present invention comprise a compound having formula (I), formula (I-0a), formulas (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 excipient.

[0115] The pharmaceutical compositions, inhibitors of IDO and / or TDO, and therapeutic agents for diseases such as tumors of the present invention may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as finely divided powders or liquid aerosols), administration by insufflation (e.g., as finely divided powders), or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, intraarterial, subcutaneous, intraperitoneal, intravesical, intrathoracic, intracranial, or intramuscular administration, or as a suppository for rectal administration). In some embodiments, the compounds and / or compositions of the present invention are administered by intravenous (IV) administration.

[0116] The pharmaceutical compositions of the present invention, IDO and / or TDO inhibitors, and therapeutic agents for diseases such as tumors can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents, and / or preservatives. Furthermore, because the interior of cyclodextrin is hydrophobic and the exterior is hydrophilic, cyclodextrin can form inclusion compounds (clathrates) by encapsulating hydrophobic molecules. Clathrates can increase the solubility in water or protect compounds that are sensitive to water or oxygen, and can be used as needed to prepare pharmaceuticals in various dosage forms. Cyclodextrins exist with various structures, including α-cyclodextrin (cyclohexaamylose, α-CD) with six glucose bonds, β-cyclodextrin (cycloheptaamylose, β-CD) with seven glucose bonds, and γ-cyclodextrin (cyclooctaamylose, γ-CD) with eight glucose bonds. For example, inclusion of cyclodextrins has been used to stabilize drugs such as prostaglandins and nitroglycerin.

[0117] Pharmaceutically acceptable excipients suitable for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate, calcium carbonate, etc.; granulating and disintegrating agents such as starch, carmellose calcium, croscarmellose sodium, etc.; binders such as starch; lubricants such as magnesium stearate, stearic acid, talc, etc.; preservatives such as ethyl and propyl p-hydroxybenzoate; and antioxidants such as ascorbic acid. Tablet formulations may be uncoated or may be coated using conventional coating agents and procedures well known in the art to alter their disintegration in the gastrointestinal tract and subsequent absorption of the active ingredient or to improve their stability and / or appearance.

[0118] The pharmaceutical compositions of the present invention for oral use, inhibitors of IDO and / or TDO, and therapeutic agents for diseases such as tumors, may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or may be in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.

[0119] Aqueous suspensions generally contain the active ingredient in finely divided form or in the form of nanoparticles or ultrafinely divided particles, together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic; a dispersing aid or wetting agent, such as lecithin; or a condensation product of a fatty acid with an alkylene oxide (e.g., polyoxyethylene stearate); or a condensation product of a long-chain aliphatic alcohol with ethylene oxide, for example, heptadecaethyleneoxycetanol; or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyoxyethylene sorbitol monooleate; or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example, polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl or propyl p-hydroxybenzoate; an antioxidant, such as ascorbic acid; a coloring agent; a flavoring agent; and / or a sweetening agent, such as sucrose, saccharin or aspartame.

[0120] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. These oily suspensions may further contain thickening agents such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners such as those listed above and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

[0121] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0122] The pharmaceutical compositions of the present invention, including IDO and / or TDO inhibitors and therapeutic agents for diseases such as tumors, may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as olive oil or arachis oil, or a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be, for example, naturally occurring gums such as gum arabic or gum tragacanth; naturally occurring phosphatides such as soybean and lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate); and condensation products of ethylene oxide with these partial esters, such as polyoxyethylene sorbitan monooleate. These emulsions may further contain sweeteners, flavoring agents, and preservatives. Furthermore, when the compounds of the present invention are used as injections, injectable liposomes or polymeric micelles can be used to concentrate the compounds in specific tissues. Injectable liposomes are closed vesicles composed of a phospholipid-based lipid bilayer. They consist of both a lipid membrane and an aqueous layer, allowing them to encapsulate both lipid-soluble and water-soluble drugs. Liposomes generally have a particle size of less than a few micrometers and can be used to prepare injections. On the other hand, polymeric micelles are very small (10-100 nm) and have a distinct bilayer structure consisting of an inner core and an outer shell. The outer shell determines the pharmacokinetics and distribution of drugs through interactions with the body, while the inner core can be physically or chemically encapsulated. Anticancer drug-encapsulated micelles with a polyethylene glycol shell can selectively concentrate drugs in cancer tissues, demonstrating sufficient efficacy while reducing side effects. Therefore, polymeric micelles encapsulating such compounds are advantageous as DDS (drug delivery system) formulations.

[0123] Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may further contain a demulcent, preservative, flavoring and / or coloring agent.

[0124] The pharmaceutical compositions, IDO and / or TDO inhibitors, and therapeutic agents for diseases such as tumors of the present invention may also be in the form of a sterile injectable aqueous or oily suspension, which can be formulated according to known procedures using one or more suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol.

[0125] Pharmaceutical compositions of the present invention for administration by inhalation, inhibitors of IDO and / or TDO, and therapeutic agents for diseases such as tumors, may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient as an aerosol containing finely divided solid or liquid particles. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used, and the aerosol device is conveniently arranged to dispense a metered amount of the active ingredient.

[0126] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans may contain, for example, 0.5 mg to 5 g of active ingredient, compounded with an appropriate and convenient amount of excipient, which may be about 5 to about 98% by weight of the total composition. A unit dosage form may contain, for example, from about 1 mg to about 500 mg of active ingredient.

[0127] Therapeutic dosages of the compounds of the invention can vary according to, for example, the particular application for which the treatment is given, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending on numerous factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, for oral administration, the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10 wt.% of the compound for parenteral administration. Typical dosage ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In one embodiment of the invention, the dosage range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. Dosages are likely to depend on such variables as the type and progression of the disease or disorder, the overall health of the particular patient, the relative bioavailability of the selected compound, the formulation of excipients, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0128] Yet another aspect of the present invention relates to a compound comprising: (a) one or more compounds having formula (I), (I-0a), (I-0a-1) to (I-0a-3), (I-0b), (I-0c), (I-0d), (I-0c-1), (I-0d-1), (I-1), (I-2), (I-3), (1-3-a), (1-3-b), (1-3-c), (1-3-d), (1-3-e), (1-3-f), (1-3-g), or (I-3-h) or pharmaceutically acceptable salts thereof; and (b) a compound comprising one or more compounds having formula (I), (I-0a), (I-0a-1) to (I-0a-3), (I-0b), (I-0c), (I-0d), (I-0c-1), (I-0d-1), (I-1), (I-2), (I-3), (1-3-a), (1-3-b), (1-3-c), (1-3-d), (1-3-e), (1-3-f), (1-3-g), or (I-3-h) or pharmaceutically acceptable salts thereof; and one or more additional anti-tumor agents for treating a disease or disorder selected from tumors, infectious diseases, neurodegenerative disorders, cataracts, organ transplant rejection, autoimmune diseases, post-operative cognitive impairment, and disorders related to female reproductive health, wherein the compound or a pharmaceutically acceptable salt thereof and the additional agent(s) are suitable for simultaneous, sequential, or separate administration. When (b) in the pharmaceutical kit is one or more additional anti-tumor agents, the pharmaceutical kit is a pharmaceutical kit for treating tumors.

[0129] The additional antitumor agents include alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, bendamustine, busulfan, temozolamide, and nitrosoureas); antimetabolites (e.g., gemcitabine, cpecitabine, and folate antagonists such as fluoropyrimidines such as 5-fluorouracil and tegafur; raltitrexate; antitumor antibiotics (e.g., anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin C, dactinomycin, and mithramycin); antimitotics (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine); and taxol and taxotere and inhibitors of polokinase or kinesin motor proteins); and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, camptothecin, pixantrone, and irinotecan); inhibitors of DNA repair mechanisms, such as CHK kinase, inhibitors of DNA-dependent protein kinase, and poly(ADP-ribose) polymerase (PARP inhibitors), ATM or inhibitors of ATR; and Hsp90 inhibitors such as tanespamycin and retaspimycin; compounds that inhibit progression through the cell cycle, such as antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine; epothilones such as ixabepilone; and taxoids such as taxol and taxotere;inhibitors of kinesin motor proteins, such as, but not limited to, polo-like kinase inhibitors; and Eg5 protein inhibitors; Aurora kinase inhibitors (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528, and AX39459, etc.), and cyclin-dependent kinase inhibitors, such as CDK2 and / or CDK4 inhibitors (e.g., flavopiridol / alvocidib, roscovitine, seliciclib); inhibitors of centromere protein function, such as CENP-E inhibitors, immune checkpoint inhibitors blockade) (for example, anti-PD-1 antibodies such as nivolumab and pembrolizumab; anti-PD-L1 antibodies such as atezolizumab, durvalumab and avelumab; anti-CTLA-4 antibodies such as ipilimumab and tremelimumab); Furthermore, known cytostatics, anti-invasive drugs, inhibitors of growth factor function, anti-angiogenic drugs, vascular damaging drugs, endothelin receptor antagonists, etc. can also be used in combination.

[0130] Specific examples of the compound of the present invention are listed below, but the present invention is not limited to these compounds.

[0131] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0132] The structural formulae of the above compounds Nos. 1 to 153 are shown below.

[0133] [ka] JPEG0007624184000053.jpg11467 JPEG0007624184000054.jpg10167 JPEG0007624184000055.jpg10067 JPEG0007624184000056.jpg9767 JPEG0007624184000057.jpg11867 JPEG0007624184000058.jpg10767 JPEG0007624184000059.jpg11667 JPEG0007624184000060.jpg11467 JPEG0007624184000061.jpg9967 JPEG0007624184000062.jpg10067 JPEG0007624184000063.jpg10867 JPEG0007624184000064.jpg10867 JPEG0007624184000065.jpg11767 JPEG0007624184000066.jpg11767 JPEG0007624184000067.jpg11167 JPEG0007624184000068.jpg10767 JPEG0007624184000069.jpg11867 JPEG0007624184000070.jpg11667 JPEG0007624184000071.jpg11567 JPEG0007624184000072.jpg11667 JPEG0007624184000073.jpg11867 JPEG0007624184000074.jpg11467 JPEG0007624184000075.jpg11867 JPEG0007624184000076.jpg9767 JPEG0007624184000077.jpg11367 JPEG0007624184000078.jpg11767 JPEG0007624184000079.jpg11867 JPEG0007624184000080.jpg11667 JPEG0007624184000081.jpg11767 JPEG0007624184000082.jpg11767

[0134] 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 can be synthesized by adding a general protecting group to a commercially available product (for example, some of the compounds (ia) in Scheme 1 are dicarboxylic acids). The acid was converted to a methyl ester.) The reduction of the carbonyl group and the halogenation of the alcohol group can be performed using reducing agents and halogenating reagents commonly used in organic chemistry. Furthermore, both steps can be applied to purification by protection and deprotection, which are commonly used in organic chemistry. Below, three schemes are presented as examples of general synthetic methods.

[0135] Scheme 1 [ka]

[0136] In Scheme 1, A, X, m, and R 3 , Z, R 41 , R 42 , and R 43 has the same meaning as defined above. The substituent X can be bonded to a carbon atom and / or a heteroatom of ring A (representing an aromatic ring, an aliphatic ring, a heterocyclic ring, or a fused ring of two or more rings selected from an aromatic ring, an aliphatic ring, and a heterocyclic ring).

[0137] [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 resulting solution is added to a solution (solvent, e.g., THF, 1,4-dioxane, methanol, ethanol, acetone, etc.) containing a reducing agent (e.g., LiAlH4 (lithium aluminum hydride), NaBH4 (1508299713358_13), DIBAH (1508299713358_14), etc.) and stirred, followed by heating to reflux. The reaction mixture is dried with a drying agent (e.g., magnesium sulfate) and then concentrated under reduced pressure. The residue obtained by vacuum concentration is purified by chromatography (e.g., silica gel chromatography) to obtain compound (ii). This synthesis is preferably carried out under an inert gas atmosphere such as nitrogen or argon.

[0138] [Synthesis of compound (iii)] Compound (ii) is dissolved in an organic solvent (e.g., a halogen compound such as methylene chloride, chloroform, or carbon tetrachloride), and a phosphorus trihalide (PHal3: Hal represents Cl, Br, or I) is added to the resulting solution and stirred. Water and a water-insoluble organic solvent (e.g., ethyl acetate) are added to the resulting reaction solution, and the organic layer is washed with saturated brine, dried with a drying agent (e.g., magnesium sulfate), and then concentrated under reduced pressure. The residue obtained by concentration under reduced pressure is purified by chromatography (e.g., silica gel chromatography) to obtain compound (iii). This synthesis is also preferably carried out under an inert gas atmosphere such as nitrogen or argon.

[0139] [Synthesis of Compound (I-1)] Compound (iii) is dissolved in an organic solvent (e.g., THF, 1,4-dioxane, methanol, ethanol, acetone, etc.), and the resulting solution is added with a compound represented by the above formula Z=C(NHR 41 )(NR 42 R 43 The reaction mixture is stirred and concentrated under reduced pressure, and the residue is recrystallized using a recrystallization solvent (e.g., a mixed solvent of ethanol and diethyl ether) to obtain compound (I-1).

[0140] Scheme 2 [ka]

[0141] In Scheme 2, A, X, m, Z, s, and R 6 has the meaning as defined above.

[0142] [Synthesis of Compound (I-2)] The above formula H2N-(CH2) S -R 6 A compound represented by the formula (I-1) is added to a formaldehyde solution (solvent, for example, THF, 1,4-dioxane, methanol, ethanol, acetone, etc.) and stirred, and then a solution of compound (iv) (solvent, for example, THF, 1,4-dioxane, methanol, ethanol, acetone, etc.) is added and stirred. An organic solvent (for example, benzene, toluene, hexane, etc.) is added to the resulting reaction mixture, and the mixture is concentrated under reduced pressure. The residue obtained by concentration under reduced pressure is recrystallized using a recrystallization solvent (for example, a mixed solvent of ethanol and diethyl ether) to obtain compound (I-2).

[0143] Scheme 3 [ka]

[0144] In Scheme 3, A, X, m, p, R5 , q, Z, R 41 , R 42 , and R 43 has the meaning as defined above.

[0145] [Synthesis of compound (vi)] The compound represented by the formula (v) is dissolved in an organic solvent (e.g., THF, 1,4-dioxane, methanol, ethanol, acetone, etc.), and the resulting solution is added with a compound represented by the formula R 5 A compound represented by -(CH2)q-NH2 is added and stirred. The resulting reaction solution is concentrated under reduced pressure, followed by addition of water and extraction with an organic solvent (e.g., methylene chloride, chloroform, carbon tetrachloride, or other halogen compounds). The organic layer is washed with brine, dried over a drying agent (e.g., magnesium sulfate), and then concentrated under reduced pressure to obtain compound (vi).

[0146] [Synthesis of compound (vii)] Compound (vi) is dissolved in an organic solvent (e.g., a halogen compound such as methylene chloride, chloroform, or carbon tetrachloride), and a phosphorus trihalide (PHal3: Hal represents Cl, Br, or I) is added to the resulting solution and stirred. Water and a water-insoluble organic solvent (e.g., ethyl acetate) are added to the resulting reaction solution, and the organic layer is washed with saturated brine, dried with a drying agent (e.g., magnesium sulfate), and then concentrated under reduced pressure. The residue obtained by concentration under reduced pressure is purified by chromatography (e.g., silica gel chromatography) to obtain compound (vii).

[0147] [Synthesis of Compound (I-3-a)] Compound (vii) is dissolved in an organic solvent (e.g., THF, 1,4-dioxane, methanol, ethanol, acetone, etc.), and the resulting solution is added with a compound represented by the above formula Z=C(NHR 41 )(NR 42 R 43 The reaction mixture is stirred and concentrated under reduced pressure, and the residue is recrystallized using a recrystallization solvent (e.g., a mixed solvent of ethanol and diethyl ether) to obtain compound (I-3-a). [Example]

[0148] The present invention will be described in more detail below based on examples, but the present invention is not limited to these examples.

[0149] [Compound synthesis] Nuclear magnetic resonance (NMR) spectra were measured on a JEOL JNM-GSX400 or JEOL JNM-ECA500. Chemical shifts are expressed in ppm using tetramethylsilane as an internal standard, and coupling constant J values ​​are expressed in Hz. The NMR abbreviations used are s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), br (broad), and brs (broad singlet). Liquid chromatography-mass spectrometry (LC / MS) was performed using a Waters Quattro micro, Waters 2795 separations module, and 2996 photodiode array detector. The XBridge™ C18-AR-II 5 μM column (2.1 × 50 mm, Waters) was used. The mobile phase A consisted of 0.1% AcOH and the mobile phase B consisted of 100% CH3CN. The analysis was performed at a flow rate of 1.0 mL / min for 5 minutes. The gradient volume ratio (v / v) of A:B was 9:1, changing to A:B = 0:10 after 4 minutes. The columns used for column chromatography were Wakogel C-200 (100-200 mesh, Wako Pure Chemical Industries, Ltd.) and Chromatorex NH (100-200 mesh, Fuji Silysia Chemical Co., Ltd.). The flash column chromatography was performed on SNAP KP-sil (Biotage) and YAMAZEN YFLC-5404-FC (Yamazen). The gel filtration column chromatography was performed on Sephadex LH-20 (GE Healthcare). For preparative thin-layer chromatography, Kiesel gel 60 F254 (1.0 mm, Merck) was used. For thin-layer chromatography, Kiesel gel 60 F254 (0.25 mm, Merck) and NHTLC-PLZTE (0.25 mm, Fuji Silysia Chemical) were used. Commercially available reagents and solvents were used unpurified.

[0150] Synthesis of Compound 1 1,2-Phenylenebis(methylene) dicarbamimidothioate dihydrochloride

[0151] [ka]

[0152] 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. The reaction mixture was then allowed to warm to room temperature and stirred for 2 days. The resulting precipitate was collected by suction filtration and dried to give the title compound 1 (white solid, 837 mg, 85% yield).

[0153] 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) + .

[0154] Synthesis of compound 2 (4-Fluoro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide

[0155] [ka]

[0156] Under an argon atmosphere, a THF solution (8 mL) of 4-fluorophthalic anhydride (compound 2a, 664 mg, 4.00 mmol) was gently added to a THF solution (10 mL) of LiAlH4 (304 mg, 8.00 mmol) at 0 °C. The mixture was stirred at room temperature for 5 hours and then heated to reflux for 12 hours. After cooling to room temperature, the reaction mixture was quenched by adding 10% NaOH (1.0 mL) and HO (1.0 mL) and stirring. The mixture was 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 give compound 2b (421 mg, 67% yield) as a colorless oil.

[0157] 1 H NMR (400 MHz, CDCl3): 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).

[0158] Under an argon atmosphere, phosphorous tribromide (0.265 mL, 2.79 mmol) was added to a CHCl solution (5 mL) of compound 2b (363 mg, 2.32 mmol) at 0 °C and stirred at the same temperature for 45 minutes. Water and ethyl acetate were added to the reaction mixture, 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 give compound 2c (155 mg, 24% yield) as white crystals.

[0159] 1 H NMR (400 MHz, CDCl3): 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).

[0160] 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. The reaction mixture was then allowed to warm to room temperature and stirred for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from EtOH and EtO (1:1) to give the title compound 2 (143 mg, 95% yield) as white crystals.

[0161] 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) + .

[0162] Synthesis of compound 3 Naphthalene-1,2-diylbis(methylene) dicarbamimidothioate dihydrobromide

[0163] [ka]

[0164] 1,2-Naphthalic anhydride (compound 3a, 793 mg, 4.00 mmol) and LiAlH4 (304 mg, 8.00 mmol) were reacted in the same manner as in the synthesis of compound 2b. The reaction residue was purified by silica gel chromatography (n-hexane / EtOAc = 4:1 to 1:2) to give compound 3b (195 mg, 26% yield) as white crystals.

[0165] 1H NMR (400 MHz, CDCl3): 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).

[0166] Compound 3b (145 mg, 0.77 mmol) and phosphorous tribromide (0.088 mL, 0.92 mmol) were reacted using the same procedure as in the synthesis of compound 2c, and the residue was purified by silica gel chromatography (n-hexane) to give compound 3c (68.3 mg, 28% yield) as white crystals.

[0167] 1 H NMR (400 MHz, CDCl3): 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).

[0168] Compound 3c (68.3 mg, 0.22 mmol) and Thiourea (33.1 mg, 0.44 mmol) were prepared in the same manner as in the synthesis of compound 2, and the residue was recrystallized from EtOH and EtO (1:1) to give compound 3 (35.3 mg, 53% yield) as white crystals.

[0169] 1HNMR (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) + .

[0170] Synthesis of compound 4 (4-t-Bu-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide

[0171] [ka]

[0172] Compound 4a (817 mg, 4.00 mmol) was prepared from 4-tert-buphthalic anhydride and LiAlH (304 mg, 8.00 mmol) in the same manner as in the synthesis of 2b. The residue was purified by silica gel chromatography (n-hexane / EtOAc = 3:1 to 2:1) to give compound 4b (389 mg, 50% yield) as a colorless oil.

[0173] 1 H NMR (400 MHz, CDCl3): δ = 7.39-7.28 (3H, m), 4.76 (2H, s), 4.74 (2H, s), 1.33 (9H, s).

[0174] The residue obtained from compound 4b (308 mg, 1.59 mmol) and phosphorous tribromide (0.181 mL, 1.90 mmol) in the same manner as in the synthesis of compound 2c was purified by silica gel chromatography (EtOAc) to give compound 4c (148 mg, 29% yield) as a yellow oil.

[0175] 1 H NMR (400 MHz, CDCl3): δ = 7.36-7.31 (3H, m), 4.68 (2H, s), 4.67 (2H, s), 1.31 (9H, s).

[0176] Compound 2 was synthesized from compound 4c (148 mg, 0.46 mmol) and Thiourea (70.4 mg, 0.93 mmol). The same procedure as in the synthesis was carried out, and the residue was recrystallized from EtOH and Et2O (1:1) to obtain compound 4 (159 mg, 73% yield) as white crystals.

[0177] 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) + .

[0178] Synthesis of compound 5 Quinoxaline-2,3-diylbis(methylene) dicarbamimidothioate dihydrobromide

[0179] [ka]

[0180] Compound 5a: 2,3-Bis(bromomethyl)quinoxaline (948 mg, 3.00 mmol) and Thiourea (457 mg, 6.00 mmol) was subjected to the same procedure as in the synthesis of 1 to give compound 5 (1.29 g, 92% yield) as pale yellow crystals.

[0181] 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) + .

[0182] Synthesis of compound 6 (3,4,5,6-Fluoro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide

[0183] [ka]

[0184] Compound 6a: 3,4,5,6-Fluorophthalic anhydride (880 mg, 4.00 mmol) and LiAlH4 (304 mg, 8.00 mmol) were reacted in the same manner as in the synthesis of compound 2b. The reaction residue was purified by silica gel chromatography (n-hexane / EtOAc = 5:1 to 3:1) to give compound 6b (219 mg, 26% yield) as white crystals.

[0185] 1H NMR (400 MHz, CDCl3): δ = 4.84 (4H, s), 2.78 (2H, brs).

[0186] The residue obtained from compound 6b (209 mg, 0.99 mmol) and phosphorous tribromide (0.113 mL, 1.19 mmol) in the same manner as in the synthesis of 2c was purified by silica gel chromatography (EtOAc) to give compound 6c (48.9 mg, 15% yield) as a yellow oil.

[0187] 1 H NMR (400 MHz, CDCl3): δ = 4.63-4.60 (4H, m).

[0188] Compound 6c (48.9 mg, 0.15 mmol) and Thiourea (22.2 mg, 0.29 mmol) were prepared in the same manner as in the synthesis of compound 2, and the residue was recrystallized from EtOH and EtO (1:1) to give compound 6 (17.2 mg, 24% yield) as white crystals. 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) + .

[0189] Synthesis of compound 7 (4-Chloro-1,2-phenylne)bis(methylene) dicarbamimidothioate dihydrobromide

[0190] [ka]

[0191] Compound 7a: 4-Chlorophthalic anhydride (913 mg, 5.00 mmol) and LiAlH4 (380 mg, 10.0 mmol) were prepared in the same manner as in the synthesis of compound 2b. The reaction residue was purified by silica gel chromatography (n-hexane / EtOAc = 6:1 to 1:1) to give compound 7b (567 mg, 66% yield) as white crystals.

[0192] 1 H NMR (400 MHz, CDCl3): δ = 7.37-7.35 (1H, m), 7.30-7.27 (2H, m), 4.70-4.68 (4H, m).

[0193] Compound 7b (567 mg, 3.29 mmol) and phosphorous tribromide (0.374 mL, 3.94 mmol) were synthesized in the same manner as in the synthesis of compound 2c. The residue was purified by silica gel chromatography (EtOAc) to give compound 7c (253 mg, 26% yield) as yellow crystals.

[0194] 1 H NMR (400 MHz, CDCl3): δ = 7.39-7.36 (1H, m), 7.32-7.29 (2H, m), 4.61 (2H, s), 4.59 (2H, s).

[0195] Compound 7c (225 mg, 0.75 mmol) and Thiourea (115 mg, 1.51 mmol) were prepared in the same manner as in the synthesis of compound 2, and the residue was recrystallized from EtOH and EtO (1:1) to give compound 7 (104 mg, 48% yield) as white crystals.

[0196] 1HNMR (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) + .

[0197] Synthesis of compound 8 1,2-Phenylenebis(methylene) bis(N,N'-dimethylcarbamimidothioate) dihydrochloride

[0198] [ka]

[0199] Compound 1a: 1,2-Bis(chloromethyl)benzene (700 mg, 4.00 mmol) and 1,3-dimethylthiourea (833 mg, 8.00 mmol) were reacted in the same manner as in the synthesis of compound 1, and the residue was recrystallized from EtOH and EtO (1:3) to give compound 8 (1.27 g, 83% yield) as white crystals.

[0200] 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) + .

[0201] Synthesis of compound 9 1,2-Bis{[(5-phenethyl-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio]methyl}benzene

[0202] [ka]

[0203] Phenethylamine (60.6 mg, 0.50 mmol) was gently added to a solution of formaldehyde (81 μL, 37% wt. solution in water, 1.0 mmol) in 1,4-dioxane (5.0 mL) and stirred at room temperature for 10 min. After that, a solution of 1,2-phenylenebis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 57.6 mg, 0.25 mmol) in 1,4-dioxane (2.0 mL) was added and stirred at 80 °C for 12 h. The reaction mixture was cooled to room temperature, toluene (3.0 mL) was added, and the mixture was concentrated under reduced pressure. The residue was recrystallized from EtOH and EtO (2:3) to give the title compound 9 (26.3 mg, 19% yield) as yellow crystals.

[0204] 1 H NMR (400 MHz, CDCl3): 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) + .

[0205] Synthesis of compound 10 (4-Bromo-1,2-phenylne)bis(methylene) dicarbamimidothioate dihydrobromide

[0206] [ka]

[0207] Compound 10a: 4-Bromophthalic anhydride (1135 mg, 5.00 mmol) and LiAlH4 (380 mg, 10.0 mmol) were prepared in the same manner as in the synthesis of compound 2b. The reaction residue was purified by silica gel chromatography (n-hexane / EtOAc = 5:1 to 1:1) to give compound 10b (539 mg, 50% yield) as white crystals.

[0208] 1 H NMR (400 MHz, CDCl3): 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).

[0209] Compound 10b (509 mg, 2.35 mmol) and phosphorous tribromide (0.267 mL, 2.82 mmol) were prepared in the same manner as in the synthesis of compound 2c. The residue was purified by silica gel chromatography using n-hexane / EtOAc (3:1) to give compound 10c (198 mg, 25% yield) as yellow crystals.

[0210] 1 H NMR (400 MHz, CDCl3): 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).

[0211] Compound 10c (174 mg, 0.51 mmol) and Thiourea (77.2 mg, 1.01 mmol) were prepared in the same manner as in the synthesis of compound 2, and the residue was recrystallized from EtOH and EtO (2:3) to give compound 10 (108 mg, 43% yield) as white crystals.

[0212] 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) + .

[0213] Synthesis of compound 11 1,2-Phenylenebis(methylene) bis(methylcarbamimidothioate) dihydrochloride

[0214] [ka]

[0215] 1,2-Bis(chloromethyl)benzene (compound 1a, 525 mg, 3.00 mmol) and N-methylthiourea (541 mg, 6.00 mmol) were reacted using the same procedure as in the synthesis of compound 1, and the residue was recrystallized from EtOH and EtO (2:3) to give compound 11 (1.09 g, 102% yield) as white crystals.

[0216] 1HNMR (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) + .

[0217] Synthesis of compound 12 (4-Methyl-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide

[0218] [ka]

[0219] Compound 12a (649 mg, 4.00 mmol) was prepared from 4-methylphthalic anhydride (12a, 649 mg, 4.00 mmol) and LiAlH (304 mg, 8.00 mmol) in the same manner as in the synthesis of compound 2b. The reaction residue was purified by silica gel chromatography (n-hexane / EtOAc = 5:1 to 2:1) to give compound 12b (296 mg, 49% yield) as a colorless oil.

[0220] 1 H NMR (400 MHz, CDCl3): 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).

[0221] Compound 12b (296 mg, 1.95 mmol) and phosphorous tribromide (0.222 mL, 2.34 mmol) were prepared in the same manner as in the synthesis of compound 2c. The residue was purified by silica gel chromatography using n-hexane / EtOAc (3:1) to give compound 12c (177 mg, 33% yield) as white crystals. 1 H NMR (400 MHz, CDCl3): 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).

[0222] Compound 12c (150 mg, 0.54 mmol) and Thiourea (82.3 mg, 1.08 mmol) were prepared in the same manner as in the synthesis of compound 2, and the residue was recrystallized from EtOH and EtO (2:3) to give compound 12 (85.5 mg, 37% yield) as white crystals.

[0223] 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) + .

[0224] Synthesis of compound 13 (3-Fluoro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide

[0225] [ka]

[0226] Compound 13a (664 mg, 4.00 mmol) was prepared from 3-fluorophthalic anhydride and LiAlH (304 mg, 8.00 mmol) in the same manner as in the synthesis of 2b. The residue was purified by silica gel chromatography (n-hexane / EtOAc = 5:1 to 2:1) to give compound 13b (282 mg, 45% yield) as white crystals.

[0227] 1 H NMR (400 MHz, CDCl3): 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).

[0228] Compound 13b (260 mg, 1.67 mmol) and phosphorous tribromide (0.190 mL, 2.00 mmol) were prepared in the same manner as in the synthesis of compound 2c. The residue was purified by silica gel chromatography using n-hexane / EtOAc (3:1) to give compound 13c (106 mg, 23% yield) as white crystals.

[0229] 1 H NMR (400 MHz, CDCl3): 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).

[0230] Compound 13c (95.1 mg, 0.34 mmol) and Thiourea (51.5 mg, 0.68 mmol) were prepared in the same manner as in the synthesis of compound 2, and the residue was recrystallized from EtOH and EtO (2:3) to give compound 13 (122 mg, 83% yield) as white crystals.

[0231] 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) + .

[0232] Synthesis of compound 14 1,2-Bis{[(5-benzyl-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio]methyl}benzene

[0233] [ka]

[0234] Benzylamine (107 mg, 1.00 mmol), formaldehyde (162 μL, 37% wt. solution in water, 2.00 mmol), and 1,2-Phenylenebis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 127 mg, 0.50 mmol) were reacted using the same procedure as in the synthesis of compound 9. The reaction residue was purified by silica gel chromatography (n-hexane: EtOAc = 1:2) to give the title compound 14 (78.9 mg, 31% yield) as white crystals.

[0235] 1 HNMR (400 MHz, CD3OD):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) + .

[0236] Synthesis of compound 15 Thiophene-3,4-diylbis(methylene) dicarbamimidothioate dihydrobromide

[0237] [ka]

[0238] 3,4-Thiophenedicarboxylic acid (compound 15a, 689 mg, 4.00 mmol) and LiAlH4 (304 mg, 8.00 mmol) were prepared in the same manner as in the synthesis of compound 2b. The reaction residue was purified by silica gel chromatography (n-hexane / EtOAc = 5:1 to 1:1) to give compound 15b (64.7 mg, 11% yield) as white crystals.

[0239] 1 H NMR (400 MHz, CDCl3): δ = 7.25 (2H, s), 4.67 (4H, s).

[0240] The residue obtained from compound 15b (47.7 mg, 0.33 mmol) and phosphorous tribromide (0.038 mL, 0.40 mmol) was purified by silica gel chromatography using n-hexane / EtOAc (3:1) to give compound 15c (43.7 mg, 49% yield) as a white solid. was obtained as crystals.

[0241] 1 H NMR (400 MHz, CDCl3): δ = 7.35 (2H, s), 4.63 (4H, s).

[0242] Compound 15c (38.0 mg, 0.14 mmol) and Thiourea (21.4 mg, 0.28 mmol) were prepared in the same manner as in the synthesis of compound 2, and the residue was recrystallized from EtOH and EtO (3:1) to give compound 15 (38.1 mg, 64% yield) as white crystals. 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) + .

[0243] Synthesis of compound 16 1,2-Bis[(pyrimidin-2-ylthio)methyl]benzene

[0244] [ka]

[0245] 2-Mercaptopyrimidine (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 min. 1,2-Bis(chloromethyl)benzene (compound 1a, 87.5 mg, 0.50 mmol) was then added to the reaction mixture, which was then heated and stirred at 70 °C for 6 h. After cooling to room temperature, water and chloroform were added. 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 give the title compound 16 (122 mg, 75% yield) as a colorless oil.

[0246] 1 H NMR (400 MHz, CDCl3): 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) + .

[0247] Synthesis of compound 17 1,2-Bis{{[5-(4-chlorophenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene

[0248] [ka]

[0249] A reaction was carried out using 2-(4-chlorophenyl)ethylamine (158 mg, 1.02 mmol), formaldehyde (166 μL, 37% wt. solution in water, 2.04 mmol), and 1,2-phenylenbis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 127 mg, 0.50 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was purified by silica gel chromatography (n-hexane: EtOAc = 3:1 to 1:1) to give the title compound 17 (46.5 mg, 15% yield) as a colorless oil.

[0250] 1 H NMR (400 MHz, CDCl3): 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) + .

[0251] 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

[0252] [ka]

[0253] A reaction was carried out using 2,5-dichlorobenzylamine (181 mg, 1.03 mmol), formaldehyde (168 μL, 37% wt. solution in water, 2.06 mmol), and 1,2-phenylenebis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 131 mg, 0.52 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was recrystallized from 2-propanol to give the title compound 18 (230 mg, 68% yield) as white crystals.

[0254] 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) + .

[0255] Synthesis of compound 19 1,2-Bis{{[5-(3-bromophenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene

[0256] [ka]

[0257] A reaction was carried out using 2-(3-Bromophenyl)ethylamine (208 mg, 1.04 mmol), formaldehyde (168 μL, 37% wt. solution in water, 2.08 mmol), and 1,2-Phenylenebis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 132 mg, 0.52 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was purified by silica gel chromatography (EtOAc) and recrystallized from 2-propanol to give the title compound 19 (97.5 mg, 27% yield) as white crystals.

[0258] 1 H NMR (400 MHz, CDCl3): 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) + .

[0259] Synthesis of compound 20 1,2-Bis{{[5-(4-bromophenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene

[0260] [ka]

[0261] A reaction was carried out using 2-(3-Bromophenyl)ethylamine (208 mg, 1.04 mmol), formaldehyde (168 μL, 37% wt. solution in water, 2.08 mmol), and 1,2-Phenylenebis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 132 mg, 0.52 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was purified by silica gel chromatography (EtOAc) and recrystallized from 2-propanol to give the title compound 20 (75.7 mg, 21% yield) as white crystals.

[0262] 1 H NMR (400 MHz, CDCl3): 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) + .

[0263] Synthesis of compound 21 1,2-Bis{{[5-(2,4-dichlorophenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene

[0264] [ka]

[0265] A reaction was carried out using 2-(2,4-Dichlorophenyl)ethylamine (198 mg, 1.04 mmol), formaldehyde (169 μL, 37% wt. solution in water, 2.08 mmol), and 1,2-Phenylenebis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 132 mg, 0.52 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (1:3 to 1:6) and recrystallized from 2-propanol to give the title compound 21 (51.3 mg, 14% yield) as white crystals.

[0266] 1 H NMR (400 MHz, CDCl3): 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) + .

[0267] Synthesis of compound 22 1,2-Bis{{[5-(3,4-dichlorophenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene

[0268] [ka]

[0269] A reaction was carried out using 3,4-dichlorophenethylamine (191 mg, 1.01 mmol), formaldehyde (163 μL, 37% wt. solution in water, 2.02 mmol), and 1,2-phenylenebis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 128 mg, 0.50 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (1:3 to 1:6) and recrystallized from 2-propanol to give the title compound 22 (61.0 mg, 18% yield) as white crystals.

[0270] 1 H NMR (400 MHz, CDCl3): 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) + .

[0271] Synthesis of compound 23 1,2-Bis{{[5-(3,4-dimethylphenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene

[0272] [ka]

[0273] A reaction was carried out using 3,4-dimethylphenethylamine (155 mg, 1.04 mmol), formaldehyde (169 μL, 37% wt. solution in water, 2.08 mmol), and 1,2-phenylenebis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 132 mg, 0.52 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (1:3 to 1:6) to give the title compound 23 (54.2 mg, 17% yield) as a colorless oil.

[0274] 1 H NMR (400 MHz, CDCl3): 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) + .

[0275] 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

[0276] [ka]

[0277] A reaction was carried out using 2,5-dimethylphenethylamine (157 mg, 1.05 mmol), formaldehyde (170 μL, 37% wt. solution in water, 2.10 mmol), and 1,2-phenylenebis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 134 mg, 0.53 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (1:3 to 1:6) to give the title compound 24 (70.0 mg, 22% yield) as a colorless oil.

[0278] 1 H NMR (400 MHz, CDCl3): 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) + .

[0279] Synthesis of compound 25 1,2-Bis{{[5-(4-ethylphenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene

[0280] [ka]

[0281] A reaction was carried out using 4-Ethylphenethylamine (155 mg, 1.04 mmol), formaldehyde (169 μL, 37% wt. solution in water, 2.10 mmol), and 1,2-Phenylenebis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 132 mg, 0.52 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (1:2 to 1:6) to give the title compound 25 (53.9 mg, 17% yield) as a colorless oil.

[0282] 1 H NMR (400 MHz, CDCl3): 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) + .

[0283] Synthesis of compound 26 1,2-Bis{{[5-(4-methoxybenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl]thio}methyl}benzene

[0284] [ka]

[0285] A reaction was carried out using 4-Methoxybenzylamine (144 mg, 1.05 mmol), formaldehyde (170 μL, 37% wt. solution in water, 2.10 mmol), and 1,2-Phenylenebis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 134 mg, 0.53 mmol) in the same manner as in the synthesis of compound 9. The residue was purified by silica gel chromatography using n-hexane / EtOAc (1:2 to 1:6) and recrystallized from 2-propanol to give the title compound 26 (23.0 mg, 7.5% yield) as white crystals.

[0286] 1 H NMR (400 MHz, CDCl3): 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) + .

[0287] 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

[0288] [ka]

[0289] A reaction was carried out using 2,4-Dimethoxybenzylamine (173 mg, 1.03 mmol), formaldehyde (167 μL, 37% wt. solution in water, 2.06 mmol), and 1,2-Phenylenebis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 132 mg, 0.52 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (1:3 to 1:7) and recrystallized from 2-propanol to give the title compound 27 (12.9 mg, 4.0% yield) as white crystals.

[0290] 1 H NMR (400 MHz, CDCl3): 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) + .

[0291] Synthesis of compound 28 1,2-Bis(((5-(2-chlorophenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl)benzene

[0292] [ka]

[0293] A reaction was carried out using 2-chlorophenethylamine (164 mg, 1.05 mmol), formaldehyde (171 μL, 37% wt. solution in water, 2.11 mmol), and 1,2-phenylenebis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 134 mg, 0.53 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (1:3 to 1:6) and recrystallized from 2-propanol to give the title compound 28 (57.1 mg, 17.7% yield) as white crystals.

[0294] 1 H NMR (400 MHz, CDCl3): 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) + .

[0295] Synthesis of compound 29 1,2-Bis{[(5-methylcyclohexyl-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio]methyl}benzene

[0296] [ka]

[0297] Aminomethylcyclohexane (115 mg, 1.01 mmol), formaldehyde (164 μL, 37% wt. solution in water, 2.03 mmol), and 1,2-Phenylenebis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 130 mg, 0.51 mmol) were reacted using the same procedure as in the synthesis of compound 9. The reaction residue was recrystallized from 2-propanol to give the title compound 29 (161 mg, 60% yield) as pale yellow crystals.

[0298] 1 H NMR (400 MHz, CDCl3): 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) + .

[0299] Synthesis of compound 30 2,2'-((1,2-phenylenebis(methylene))bis(sulfanediyl))bis(pyrimidine-4,6(1H,5H)-dione)

[0300] [ka]

[0301] A solution of 2-mercaptopyrimidine (112 mg, 1.00 mmol) in 1,4-dioxane / HO (3:1, 4.0 mL) was added with 1.1 mmol / L NaOH (2.0 mL, 2.20 mmol) and stirred at room temperature for 1 hour. A solution of 1,2-bis(chloromethyl)benzene (compound 1a; 175 mg, 1.00 mmol) in 1,4-dioxane (4.0 mL) was then added and stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from EtOH to give the title compound 30 (355 mg, 91% yield) as yellow crystals.

[0302] 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) + .

[0303] Synthesis of compound 31 Thiophene-2,3-diylbis(methylene) dicarbamimidothioate dihydrobromide

[0304] [ka]

[0305] 2,3-Thiophenedicarboxaldehyde (compound 31a, 561 mg, 4.00 mmol) and LiAlH4 (304 mg, 8.00 mmol) were prepared in the same manner as in the synthesis of compound 2b. The reaction residue was purified by silica gel chromatography (n-hexane / EtOAc = 5:1 to 1:4) to give compound 31b (428 mg, 74% yield) as a colorless oil.

[0306] 1 H NMR (400 MHz, CDCl3): 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).

[0307] The residue obtained from compound 31b (386 mg, 2.68 mmol) and phosphorous tribromide (0.305 mL, 3.21 mmol) in the same manner as in the synthesis of compound 2c was purified by silica gel chromatography using n-hexane / EtOAc (3:1) to give compound 31c (611 mg, 85% yield) as a yellow oil.

[0308] 1 H NMR (400 MHz, CDCl3): δ = 7.27-7.26 (1H, m), 7.02-7.01 (1H, m), 4.75 (2H, s), 4.53 (2H, s).

[0309] Compound 31c (537 mg, 1.99 mmol) and Thiourea (303 mg, 3.98 mmol) were prepared in the same manner as in the synthesis of compound 2, and the residue was recrystallized from EtOH and EtO (1:1) to give the title compound 31 (597 mg, 71% yield) as white crystals.

[0310] 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) + .

[0311] Synthesis of compound 32 Methyl 2-((carbamimidoylthio)methyl)-1H-indole-3-carboxylate hydrobromide

[0312] [ka]

[0313] Under an argon atmosphere, a THF solution (12 mL) of dimethyl 1H-indole-2,3-dicarboxylate (compound 32a, 670 mg, 3.00 mmol) was gently added to a THF solution (10 mL) of LiAlH4 (228 mg, 6.00 mmol) at 0 °C. The mixture was stirred at room temperature for 5 hours and then heated to reflux for 12 hours. After cooling to room temperature, the reaction mixture was quenched by adding 10% NaOH (1.0 mL) and HO (1.0 mL) and stirring. The mixture was 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 give compound 32b (213 mg, 42% yield) as pale yellow crystals.

[0314] 1 H NMR (400 MHz, CD3OD): 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) + .

[0315] The reaction residue obtained from compound 32b (350 mg, 1.97 mmol) and phosphorous tribromide (0.225 mL, 2.37 mmol) was purified by silica gel chromatography (n-hexane / EtOAc = 9:1 to 3:7) and concentrated under reduced pressure. The 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 h. The reaction mixture was then concentrated under reduced pressure and recrystallized from EtOH and EtO (1:1) to give the title compound 32 (25.6 mg, 3.8% yield from compound 32b) as white crystals.

[0316] 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) + .

[0317] Synthesis of compound 33 3,4-Bis{[(5-phenethyl-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio]methyl}thiophene dihydrochloride

[0318] [ka]

[0319] Phenethylamine (121 mg, 1.00 mmol), formaldehyde (162 μL, 37% wt. solution in water, 2.00 mmol), and thiophene-3,4-diylbis(methylene) dicarbamimidothioate dihydrobromide (compound 15, 130 mg, 0.50 mmol) were reacted using the same procedure as for the synthesis of compound 9. The reaction residue was purified by silica gel chromatography using EtOAc / EtOH (4:1 to 7:3) to give the free form of compound 33 as a colorless oil (23.3 mg, 8.5% yield). A solution of the free form of compound 33 in 1,4-dioxane (3.0 mL) was added to 4.0 mol / L HCl (19.5 μL, 0.078 mmol) and stirred at room temperature for 1 hour. The reaction residue was concentrated under reduced pressure and recrystallized from n-hexane to give the title compound 33 (23.8 mg, 98% yield) as white crystals.

[0320] 1 H NMR (400 MHz, CDCl3): 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) + .

[0321] Synthesis of compound 34 Pyridine-2,3-diylbis(methylene) dicarbamimidothioate dihydrobromide

[0322] [ka]

[0323] A solution of pyridine-2,3-dicarboxylic acid (compound 34a, 2.5 g, 15.0 mmol) in MeOH (10 ml) was added with concentrated sulfuric acid (1.0 ml) and refluxed for 6 hours, then stirred at room temperature for 2 days. The reaction mixture was concentrated, and then 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 give compound 34b (2.18 g, 74% yield) as pale yellow crystals.

[0324] 1 H NMR (400 MHz, CDCl3): 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) + .

[0325] Compound 34b (976 mg, 5.00 mmol) and LiAlH4 (380 mg, 10.0 mmol) were prepared in the same manner as in the synthesis of compound 2b. The reaction residue was purified by silica gel chromatography (CHCl3 / MeOH = 1:0 to 9:1) to give compound 34c (221 mg, 32% yield) as a colorless oil.

[0326] 1H NMR (400 MHz, CDCl3): 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) + .

[0327] Compound 34c (196 mg, 1.41 mmol) and phosphorous tribromide (0.161 mL, 1.69 mmol) were prepared in the same manner as in the synthesis of compound 2c. The residue was purified by silica gel chromatography (CHCl) to give compound 34d (42.1 mg, 11% yield) as a yellow oil.

[0328] 1 H NMR (400 MHz, CDCl3): 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) + .

[0329] Compound 34d (38.1 mg, 0.14 mmol) and Thiourea (21.9 mg, 0.28 mmol) were synthesized in the same manner as in the synthesis of compound 2, and the residue was recrystallized from EtOH and EtO (1:1) to give the title compound 34 (36.4 mg, 61% yield) as white crystals.

[0330] 1H 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) + .

[0331] Synthesis of compound 35 (4-Methoxy-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide

[0332] [ka]

[0333] Compound 35a (588 mg, 3.0 mmol) was dissolved in MeOH (7 ml) and concentrated sulfuric acid (0.5 ml) in the same manner as in the synthesis of compound 34b. The residue was purified by silica gel chromatography using EtOAc / EtOH (1:1) to give compound 35b (574 mg, 85% yield) as a pale yellow oil.

[0334] 1 H NMR (400 MHz, CDCl3): 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).

[0335] Compound 35b (497 mg, 2.22 mmol) and LiAlH4 (168 mg, 4.43 mmol) were prepared in the same manner as in the synthesis of compound 2b. The reaction residue was purified by silica gel chromatography (n-hexane / EtOAc = 4:1 to 1:2) to give compound 35c (222 mg, 59% yield) as a colorless oil.

[0336] 1 H NMR (400 MHz, CDCl3): 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).

[0337] Compound 35c (183 mg, 1.09 mmol) and phosphorous tribromide (0.124 mL, 1.31 mmol) were prepared in the same manner as in the synthesis of compound 2c. The residue was purified by silica gel chromatography (n-hexane / EtOAc = 3:1) to give compound 35d (72.7 mg, 23% yield) as a yellow oil.

[0338] 1 H NMR (400 MHz, CDCl3): 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).

[0339] Compound 35d (73.0 mg, 0.247 mmol) and Thiourea (38.0 mg, 0.495 mmol) were prepared in the same manner as in the synthesis of compound 2, and the residue was recrystallized from EtOH and EtO (1:1) to give the title compound 35 (62.8 mg, 57% yield) as white crystals.

[0340] 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) + .

[0341] Synthesis of compound 36 (4,5-Dichloro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide

[0342] [ka]

[0343] The reaction residue obtained from (4,5-Dichloro-1,2-phenylene)dimethanol (compound 36a, 2.18 g, 10.5 mmol) and phosphorous tribromide (1.103 mL, 12.6 mmol) was purified by silica gel chromatography (n-hexane / EtOAc = 4:1) to give compound 36b (823 mg, 24% yield) as white crystals.

[0344] 1 H NMR (400 MHz, CDCl3): δ = 7.47 (2H, s), 4.55 (4H, s).

[0345] Compound 36b (723 mg, 2.17 mmol) and Thiourea (331 mg, 4.34 mmol) were prepared in the same manner as in the synthesis of compound 2, and the residue was recrystallized from EtOH and EtO (1:2) to give the title compound 36 (856 mg, 82% yield) as white crystals.

[0346] 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) + .

[0347] 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)

[0348] [ka]

[0349] 2-Phenylethan-1-amine (121 mg, 1.00 mmol), formaldehyde (162 μL, 37% wt. solution in water, 2.00 mmol), and (4,5-Dichloro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide (compound 36, 162 mg, 0.50 mmol) were reacted in the same manner as in the synthesis of compound 9. The reaction residue was recrystallized from 2-propanol to give the title compound 37 (200 mg, 65% yield) as white crystals.

[0350] 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) + .

[0351] 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)

[0352] [ka]

[0353] A reaction was carried out using 2-(3,4-Dichlorophenyl)ethan-1-amine (190 mg, 1.00 mmol), formaldehyde (162 μL, 37% wt. solution in water, 2.00 mmol), and (4,5-Dichloro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide (compound 36, 162 mg, 0.50 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was purified by NH-silica gel chromatography using n-hexane / EtOAc (3:2 to 0:1) to give the title compound 38 (38.2 mg, 10% yield) as an amorphous substance.

[0354] 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) + .

[0355] Synthesis of compound 39 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)

[0356] [ka]

[0357] 2-(3,4-Dichlorophenyl)ethan-1-amine (190 mg, 1.00 mmol), formaldehyde (162 μL, 37% wt. solution in water, 2.00 mmol), and (4-Bromo-1,2-phenylne)bis(methylene) dicarbamimidothioate dihydrobromide (compound 10, 167 mg, 0.50 mmol) were reacted using the same procedure as in the synthesis of compound 9. The reaction residue was purified by NH-silica gel chromatography using n-hexane / EtOAc (3:2 to 0:1) and recrystallized from 2-propanol to give the title compound 39 (16.7 mg, 4.4% yield) as white crystals.

[0358] 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) + .

[0359] 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

[0360] [ka]

[0361] A reaction was carried out using 2-(Thiophen-2-yl)ethan-1-amine (763 mg, 6.00 mmol), formaldehyde (973 μL, 37% wt. solution in water, 4.00 mmol), and 1,2-Phenylenebis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 763 mg, 3.00 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was purified by NH-silica gel chromatography using n-hexane / EtOAc (3:2 to 0:1) to give the title compound 40 (9.5 mg, 5.7% yield) as a pale yellow oil.

[0362] 1 H NMR (400 MHz, CDCl3): 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) + .

[0363] Synthesis of compound 41 1,2-bis(((5-(4-chlorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl)benzene

[0364] [ka]

[0365] A reaction was carried out using (4-chlorophenyl)methanamine (566 mg, 4.00 mmol), formaldehyde (649 μL, 37% wt. solution in water, 800 mmol), and 1,2-phenylenebis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 509 mg, 2.00 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was purified by NH-silica gel chromatography using n-hexane / EtOAc (45:55 to 0:1) to give the title compound 41 (27.4 mg, 2.3% yield) as a colorless oil.

[0366] 1 H NMR (400 MHz, CDCl3): 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) + .

[0367] 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

[0368] [ka]

[0369] A reaction was carried out using (4-(Trifluoromethyl)phenyl)methanamine (701 mg, 4.00 mmol), formaldehyde (649 μL, 37% wt. solution in water, 800 mmol), and 1,2-Phenylenebis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 509 mg, 2.00 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was purified by NH-silica gel chromatography using n-hexane / EtOAc (45:55 to 0:1) to give the title compound 42 (303 mg, 23.2% yield) as a colorless oil.

[0370] 1 H NMR (400 MHz, CDCl3): 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) + .

[0371] 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

[0372] [ka]

[0373] A reaction was carried out using (3,4-Difluorophenyl)methanamine (573 mg, 4.00 mmol), formaldehyde (649 μL, 37% wt. solution in water, 800 mmol), and 1,2-Phenylenebis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 509 mg, 2.00 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was purified by NH-silica gel chromatography using n-hexane / EtOAc (3:2 to 0:1) to give the title compound 43 (300 mg, 25.4% yield) as a colorless oil.

[0374] 1 H NMR (400 MHz, CDCl3): 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) + .

[0375] Synthesis of compound 44 1,2-bis(((5-(2,5-dimethylbenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl)benzene

[0376] [ka]

[0377] A reaction was carried out using (2,5-dimethylphenyl)methanamine (541 mg, 4.00 mmol), formaldehyde (649 μL, 37% wt. solution in water, 800 mmol), and 1,2-Phenylenebis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 509 mg, 2.00 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was purified by NH-silica gel chromatography using n-hexane / EtOAc (3:2 to 0:1) to give the title compound 44 (157 mg, 13.7% yield) as a colorless amorphous substance.

[0378] 1 H NMR (400 MHz, CDCl3): 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) + .

[0379] 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

[0380] [ka]

[0381] A reaction was carried out using (3-Fluorophenyl)methanamine (501 mg, 4.00 mmol), formaldehyde (649 μL, 37% wt. solution in water, 800 mmol), and 1,2-Phenylenebis(methylene) dicarbamimidothioate dihydrochloride (compound 1, 509 mg, 2.00 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was purified by NH-silica gel chromatography using n-hexane / EtOAc (55:45 to 0:1) to give the title compound 45 (121 mg, 10.9% yield) as a colorless oil.

[0382] 1 H NMR (400 MHz, CDCl3): 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) + .

[0383] Synthesis of compound 46 (4-(Trifluoromethyl)-1,2-phenylene)bis(methylene)dicarbamimidothioate dihydrobromide

[0384] [ka]

[0385] Compound 46a was prepared from dimethyl 4-(trifluoromethyl)phthalate (compound 46a, 2621 mg, 10.00 mmol) and LiAlH (759 mg, 20.00 mmol) in the same manner as in the synthesis of 2b. The reaction residue was purified by silica gel chromatography (n-hexane / EtOAc = 5:1 to 1:2) to give compound 46b (1116 mg, 54.1% yield) as a pale yellow oil.

[0386] 1 HNMR (400 MHz, CDCl3): 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) +

[0387] The residue obtained from compound 46b (1025 mg, 4.97 mmol) and phosphorous tribromide (0.566 mL, 5.96 mmol) by the same procedure as in the synthesis of compound 2c was purified by silica gel chromatography using n-hexane / EtOAc (3:1) to give compound 46c (600 mg, 36.4% yield) as a pale yellow oil.

[0388] 1 HNMR (400 MHz, CDCl3): 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).

[0389] Compound 46c (585 mg, 1.76 mmol) and Thiourea (268 mg, 3.52 mmol) were synthesized in the same manner as in the synthesis of compound 2, and the residue was recrystallized from EtOH and EtO (1:2) to give compound 46 (659 mg, 77.3% yield) as white crystals.

[0390] 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) +

[0391] Synthesis of compound 47 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)

[0392] [ka]

[0393] A reaction was carried out using 2-(3,4-Dichlorophenyl)ethan-1-amine (0.239 mL, 1.60 mmol), formaldehyde (241 μL, 37% wt. solution in water, 3.20 mmol), and (4-(Trifluoromethyl)-1,2-phenylene)bis(methylene)dicarbamimidothioate ihydrobromide (compound 46, 258 mg, 0.80 mmol) in the same manner as in the synthesis of compound 9. The residue was purified twice by NH-silica gel chromatography using n-hexane / EtOAc (1:2 to 1:10), n-hexane / EtOAc (1:10) to give the title compound 47 (6.90 mg, 1.2% yield) as white crystals.

[0394] 1 H NMR (400 MHz, CDCl3): 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) +

[0395] Synthesis of compound 48 6,6'-(((4-(Trifluoromethyl)-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(2-chlorophenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

[0396] [ka]

[0397] A reaction was carried out using 2-(2-chlorophenyl)ethan-1-amine (0.220 mL, 1.60 mmol), formaldehyde (241 μL, 37% wt. solution in water, 3.20 mmol), and (4-(trifluoromethyl)-1,2-phenylene)bis(methylene)dicarbamimidothioate ihydrobromide (compound 46, 258 mg, 0.8 mmol) in the same manner as in the synthesis of compound 9. The residue was purified by NH-silica gel chromatography using n-hexane / EtOAc (1:2 to 1:5) to give the title compound 48 (13.7 mg, 2.5% yield) as a white oil.

[0398] 1 H NMR (400 MHz, CDCl3): 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) +

[0399] Synthesis of compound 49 (4-bromo-1,2-phenylene)bis(methylene) (E,E)-bis(N'-(4-bromophenyl)carbamimidothioate)

[0400] [ka]

[0401] 4-Bromo-1,2-bis(bromomethyl)benzene (compound 10c, 151 mg, 0.44 mmol) and 1-(4-Bromophenyl)thiourea (203 mg, 0.88 mmol) were synthesized in the same manner as in the synthesis of compound 10. The reaction residue was purified 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) to give the title compound 49 (17.3 mg, 6.1% yield) as white crystals.

[0402] 1 HNMR (400 MHz, CD3OD): 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) +

[0403] 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)

[0404] [ka]

[0405] Cyclohexylmethanamine (130 mL, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4,5-Dichloro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide (compound 36, 162 mg, 0.50 mmol) were reacted in the same manner as in the synthesis of compound 9. The reaction residue was recrystallized from 2-propanol to give the title compound 50 (130 mg, 43.5% yield) as white crystals.

[0406] 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) +

[0407] Synthesis of compound 51 2-(2-(carbamimidoylthio)ethyl)benzyl carbamimidothioate dihydrobromide

[0408] [ka]

[0409] 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) was prepared in the same manner as in the synthesis of compound 34b. The residue was purified by silica gel chromatography using EtOAc / n-hexane (1:1) to give compound 51b (10.56 g, 100% yield) as a colorless oil.

[0410] 1 HNMR (400 MHz, CDCl3): 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) +

[0411] Compound 51b (2.08 mg, 10.0 mmol) and LiAlH4 (759 mg, 20.0 mmol) were prepared in the same manner as in the synthesis of compound 2b, and the residue was purified by silica gel chromatography with EtOAc / n-hexane (35:65 to 3:2) to give compound 51c (971 mg, 63.8% yield) as a colorless oil.

[0412] 1 HNMR (400 MHz, CDCl3): 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) +

[0413] Compound 51c (307 mg, 2.02 mmol) and phosphorous tribromide (0.230 mL, 2.42 mmol) were prepared in the same manner as in the synthesis of compound 2c, and the residue was purified by silica gel chromatography using n-hexane / EtOAc (3:1) to give compound 51d (51.3 mg, 9.1% yield) as a yellow oil.

[0414] 1 HNMR (400 MHz, CDCl3): 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).

[0415] Compound 51d (50.8 mg, 0.18 mmol) and Thiourea (27.4 mg, 0.36 mmol) were treated in the same manner as in the synthesis of 2 to give compound 51 (62.8 mg, 57% yield) as a white oil.

[0416] 1 HNMR (500 MHz, CD3OD): 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) +

[0417] 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)

[0418] [ka]

[0419] Cyclohexylmethanamine (0.130 mL, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4-Bromo-1,2-phenylne)bis(methylene) dicarbamimidothioate dihydrobromide (compound 10, 167 mg, 0.50 mmol) were reacted in the same manner as in the synthesis of compound 9. The reaction residue was recrystallized from 2-propanol to give the title compound 52 (197 mg, 65% yield) as white crystals.

[0420] 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) +

[0421] Synthesis of compound 53 6,6'-(((4-bromo-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(2-chlorophenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

[0422] [ka]

[0423] A reaction was carried out using 2-(2-chlorophenyl)ethan-1-amine (0.138 mL, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4-Bromo-1,2-phenylne)bis(methylene) dicarbamimidothioate dihydrobromide (compound 10, 167 mg, 0.50 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was recrystallized from 2-propanol to give the title compound 53 (410 mg, 100% yield) as yellow crystals.

[0424] 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) +

[0425] 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)

[0426] [ka]

[0427] A reaction was carried out using (3,4-Dichlorophenyl)methanamine (0.132 mL, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4-Bromo-1,2-phenylne)bis(methylene) dicarbamimidothioate dihydrobromide (compound 10, 167 mg, 0.50 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was purified by gel filtration chromatography (MeOH) to give the title compound 54 (15.0 mg, 4% yield) as white crystals.

[0428] 1 HNMR (400 MHz, CD3OD): 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) +

[0429] Synthesis of compound 55 Methyl 2-((carbamimidoylthio)methyl)benzoate hydrochloride

[0430] [ka]

[0431] 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. The reaction mixture was then returned to room temperature, concentrated under reduced pressure, and recrystallized from ethyl acetate to give the title compound 55 (246 mg, 94% yield) as white crystals.

[0432] 1 HNMR (400 MHz, CD3OD): 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) +

[0433] 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)

[0434] [ka]

[0435] (3,4-Dichlorophenyl)methanamine (0.132 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4,5-Dichloro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide (compound 36, 162 mg, 0.50 mmol) were reacted in the same manner as in the synthesis of compound 9. The reaction residue was recrystallized from 2-propanol to give the title compound 56 (21.4 mg, 6% yield) as white crystals.

[0436] 1 HNMR (400 MHz, CD3OD): 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) +

[0437] Synthesis of compound 57 (4-Bromo-1,2-phenylene)bis(methylene) (E,E)-bis(N,N'-dicyclohexylcarbamimidothioate) dihydrobromide

[0438] [ka]

[0439] Compound 57 (615 mg, 83% yield) was obtained as white crystals from 4-Bromo-1,2-bis(bromomethyl)benzene (compound 10c, 343 mg, 1.00 mmol) and 1,3-Dicyclohexylthiourea (481 mg, 2.00 mmol) in the same manner as in the synthesis of compound 10.

[0440] 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) +

[0441] Synthesis of compound 58 1,2-Phenylenebis(methylene) (E,E)-bis(N,N'-dicyclohexylcarbamimidothioate) dihydrobromide

[0442] [ka]

[0443] Compound 58 (701 mg, 94% yield) was obtained as white crystals from 1,2-Bis(bromomethyl)benzene (compound 58a, 263 mg, 1.00 mmol) and 1,3-Dicyclohexylthiourea (481 mg, 2.00 mmol) using the same procedure as in the synthesis of compound 10.

[0444] 1HNMR (400 MHz, CD3OD): 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) +

[0445] Synthesis of compound 59 (E)-S-(2-(((N'-(3-Chloro-4-fluorophenyl)carbamimidoyl)thio)methyl)benzyl) carbamothioate hydrobromide

[0446] [ka]

[0447] 1-(3-Chloro-4-fluorophenyl)thiourea (205 mg, 1.00 mmol) was added to a solution of 1,2-bis(bromomethyl)benzene (compound 58a, 132 mg, 0.50 mmol) in EtOH (8 mL) at room temperature, and the reaction mixture was refluxed for 12 h. The reaction mixture was returned to room temperature and concentrated under reduced pressure. The residue was recrystallized from 2-propanol to give the title compound 59 (32.5 mg, 14% yield) as white crystals. 1 HNMR (500 MHz, DMSO-d): 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) +

[0448] 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)

[0449] [ka]

[0450] The reaction was carried out using 2-Cyclohexylethan-1-amine (0.146 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4-Bromo-1,2-phenylne)bis(methylene) dicarbamimidothioate dihydrobromide (compound 10, 167 mg, 0.50 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was purified by gel filtration chromatography (CDCl3). This gave the title compound 60 (14.7 mg, 5% yield) as white crystals.

[0451] 1 H-NMR (CDCl3) 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) +

[0452] 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)

[0453] [ka]

[0454] A reaction was carried out using 2-Cyclohexylethan-1-amine (0.146 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4,5-Dichloro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide (compound 36, 162 mg, 0.50 mmol) in the same manner as in the synthesis of compound 9. The reaction residue was recrystallized from 2-propanol to give the title compound 61 (171 mg, 55% yield) as white crystals.

[0455] 1 HNMR (400 MHz, CD3OD): 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) +

[0456] Synthesis of compound 62 2-(2-(Methylamino)-2-oxoethyl)benzyl carbamimidothioate hydrobromide

[0457] [ka]

[0458] To a solution of isochroman-3-one (compound 62a, 741 mg, 5.00 mmol) in THF (15 ml), 40% MeNH2 (1553 mg, 50.0 mmol) was added and stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, followed by addition of water and extraction with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give compound 62b (832 mg, 93% yield) as pale yellow crystals.

[0459] 1 HNMR (400 MHz, CDCl3): = 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) +

[0460] Compound 62b (358 mg, 2.00 mmol) and phosphorous tribromide (0.228 mL, 2.40 mmol) were treated in the same manner as in the synthesis of 2c to give compound 62c (428 mg, 88% yield) as an orange oil.

[0461] 1 HNMR (400 MHz, CDCl3): 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) +

[0462] The title compound 62 (434 mg, 77% yield) was obtained as white crystals from compound 62c (428 mg, 1.77 mmol) and Thiourea (135 mg, 1.77 mmol) by the same procedure as in the synthesis of compound 2.

[0463] 1 HNMR (400 MHz, CD3OD): 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) +

[0464] Synthesis of compound 63 (4,5-Dichloro-1,2-phenylene)bis(methylene) (E,E)-bis(N'-(2,4-difluorophenyl)carbamimidothioate) dihydrobromide

[0465] [ka]

[0466] Compound 36b (166 mg, 0.50 mmol) and 1-(2,4-Difluorophenyl)thiourea (188 mg, 1.00 mmol) were prepared in the same manner as in the synthesis of compound 2, and the reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (3:1 to 45:55) to give the title compound 63 (3.0 mg, 1% yield) as white crystals.

[0467] 1 HNMR (400 MHz, CDCl3): 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) +

[0468] Synthesis of compound 64 2-(2-oxo-2-(phenethylamino)ethyl)benzyl carbamimidothioate hydrobromide

[0469] [ka]

[0470] Isochroman-3-one (compound 62a, 445 mg, 3.00 mmol) and 2-phenylethan-1-amine (3.780 mL, 30.0 mmol) were synthesized in the same manner as in the synthesis of compound 62b. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (3:2 to 3:7) to give compound 64a (734 mg, 91% yield) as pale yellow crystals.

[0471] 1 HNMR (400 MHz, CDCl3): 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) +

[0472] Compound 64a (734 mg, 2.72 mmol) and phosphorous tribromide (0.310 mL, 3.27 mmol) were subjected to the same procedure as in the synthesis of compound 2c to give compound 64b (565 mg, 63% yield) as a pale yellow oil.

[0473] 1 HNMR (400 MHz, CDCl3): 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) +

[0474] Compound 64b (523 mg, 1.57 mmol) and Thiourea (120 mg, 1.57 mmol) were synthesized in the same manner as in the synthesis of compound 2, and the residue was recrystallized from EtOH to give the title compound 64 (92.8 mg, 14% yield) as white crystals.

[0475] 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) +

[0476] Synthesis of compound 65 2-(2-((Cyclohexylmethyl)amino)-2-oxoethyl)benzyl carbamimidothioate hydrobromide

[0477] [ka]

[0478] Isochroman-3-one (compound 62a, 445 mg, 3.00 mmol) and cyclohexylmethanamine (1.952 mL, 15.0 mmol) were synthesized in the same manner as in the synthesis of compound 62b. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (55:45 to 3:7) to give compound 65a (542 mg, 69% yield) as white crystals.

[0479] 1 HNMR (400 MHz, CDCl3): 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) +

[0480] Compound 65a (534 mg, 2.04 mmol) and phosphorous tribromide (0.233 mL, 2.45 mmol) were subjected to the same procedure as in the synthesis of compound 2c to give compound 65b (367 mg, 55% yield) as yellow crystals.

[0481] 1 HNMR (400 MHz, CDCl3): 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) +

[0482] The title compound 65 (224 mg, 49% yield) was obtained as white crystals from compound 65b (367 mg, 1.13 mmol) and Thiourea (86.0 mg, 1.13 mmol) by the same procedure as in the synthesis of compound 2.

[0483] 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) +

[0484] Synthesis of compound 66 2-(2-((2-chlorophenethyl)amino)-2-oxoethyl)benzyl carbamimidothioate hydrobromide

[0485] [ka]

[0486] Isochroman-3-one (compound 62a, 445 mg, 3.00 mmol) and 2-(2-chlorophenyl)ethan-1-amine (0.826 mL, 6.0 mmol) were synthesized in the same manner as in the synthesis of compound 62b. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (65:35 to 3:7) to give compound 66a (615 mg, 67% yield) as white crystals.

[0487] 1 HNMR (400 MHz, CDCl3): 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) +

[0488] Compound 66b (470 mg, 63% yield) was obtained as a white oily substance from compound 66a (613 mg, 2.02 mmol) and phosphorous tribromide (0.230 mL, 2.42 mmol) in the same manner as in the synthesis of compound 2c.

[0489] 1 HNMR (400 MHz, CDCl3): 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) +

[0490] Compound 66b (470 mg, 1.28 mmol) and Thiourea (97.6 mg, 1.28 mmol) were synthesized in the same manner as in the synthesis of compound 2, and the residue was recrystallized from EtOH to give the title compound 66 (170 mg, 30% yield) as white crystals.

[0491] 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) +

[0492] Synthesis of compound 67 2-(2-((4-Cyanobenzyl)amino)-2-oxoethyl)benzyl carbamimidothioate hydrobromide

[0493] [ka]

[0494] To a solution of isochroman-3-one (compound 62a, 296 mg, 2.00 mmol) in THF (8 mL), 4-(aminomethyl)benzonitrile hydrochloride (405 mg, 2.40 mmol) and triethylamine (418 μL, 3.00 mmol) were added and stirred at 50 °C for 24 hours. The reaction mixture was concentrated under reduced pressure, followed by addition of water and extraction 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 using n-hexane / EtOAc (3:2 to 0:1) to give compound 67a (438 mg, 78% yield) as white crystals.

[0495] 1 HNMR (400 MHz, CDCl3): 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) +

[0496] Compound 67a (438 mg, 1.56 mmol) and phosphorous tribromide (0.178 mL, 1.88 mmol) were treated in the same manner as in the synthesis of compound 2c to give compound 67b (189 mg, 35% yield) as pale yellow crystals.

[0497] 1HNMR (400 MHz, CDCl3): 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) +

[0498] The title compound 67 (88 mg, 38% yield) was obtained as white crystals from compound 67b (189 mg, 0.55 mmol) and Thiourea (41.9 mg, 0.55 mmol) by the same procedure as in the synthesis of compound 2.

[0499] 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) +

[0500] Synthesis of compound 68 2-(2-((4-Chlorophenethyl)amino)-2-oxoethyl)benzyl carbamimidothioate hydrobromide

[0501] [ka]

[0502] Isochroman-3-one (compound 62a, 445 mg, 3.00 mmol) and 2-(4-chlorophenyl)ethan-1-amine (0.504 mL, 3.60 mmol) were synthesized in the same manner as in the synthesis of compound 62b. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (2:3 to 1:9) to give compound 68a (751 mg, 82% yield) as white crystals.

[0503] 1 HNMR (400 MHz, CDCl3): 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) +

[0504] Compound 68b (445 mg, 49% yield) was obtained as a white oil from compound 68a (751 mg, 2.47 mmol) and phosphorous tribromide (0.282 mL, 2.97 mmol) by the same procedure as in the synthesis of compound 2.

[0505] 1 HNMR (400 MHz, CDCl3): 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) +

[0506] The title compound 68 (279 mg, 52% yield) was obtained as white crystals from compound 68b (445 mg, 1.21 mmol) and Thiourea (92.3 mg, 1.21 mmol) by the same procedure as in the synthesis of compound 2.

[0507] 1 HNMR (500 MHz, CD3OD): 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) +

[0508] Synthesis of compound 69 2-(2-((2-Cyclohexylethyl)amino)-2-oxoethyl)benzyl carbamimidothioate hydrobromide

[0509] [ka]

[0510] Isochroman-3-one (compound 62a, 296 mg, 2.00 mmol) and 2-cyclohexylethan-1-amine (0.322 mL, 2.20 mmol) were prepared in the same manner as in the synthesis of compound 62b. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (3:2 to 35:65) to give compound 69a (520 mg, 94% yield) as white crystals.

[0511] 1 HNMR (400 MHz, CDCl3): = 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) +

[0512] Compound 69b (320 mg, 50% yield) was obtained as white crystals from compound 69a (520 mg, 1.89 mmol) and phosphorous tribromide (0.215 mL, 2.57 mmol) by the same procedure as in the synthesis of compound 2c.

[0513] 1HNMR (400 MHz, CDCl3): 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) +

[0514] The title compound 69 (110 mg, 28% yield) was obtained as white crystals from compound 69b (320 mg, 0.94 mmol) and Thiourea (71.9 mg, 0.94 mmol) by the same procedure as in the synthesis of compound 2.

[0515] 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) +

[0516] Synthesis of compound 70 2-(2-((3,4-Dichlorophenethyl)amino)-2-oxoethyl)benzyl carbamimidothioate hydrobromide

[0517] [ka]

[0518] Isochroman-3-one (compound 62a, 296 mg, 2.00 mmol) and 2-(3,4-Dichlorophenyl)ethan-1-amine (0.329 mL, 2.20 mmol) were synthesized in the same manner as in the synthesis of compound 62b. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (1:1 to 1:4) to give compound 70a (392 mg, 58% yield) as white crystals.

[0519] 1 HNMR (400 MHz, CDCl3): 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) +

[0520] Compound 70a (392 mg, 1.16 mmol) and phosphorous tribromide (0.132 mL, 1.39 mmol) were subjected to the same procedure as in the synthesis of compound 2c to obtain compound 70b (386 mg, 83% yield) as white crystals. 1HNMR (400 MHz, CDCl3): 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) +

[0521] The title compound 70 (248 mg, 54% yield) was obtained as white crystals from compound 70b (386 mg, 0.96 mmol) and Thiourea (73.2 mg, 0.96 mmol) by the same procedure as in the synthesis of compound 2.

[0522] 1 HNMR (500 MHz, CD3OD): 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) +

[0523] Synthesis of compound 71 2-(2-((Cyclopropylmethyl)amino)-2-oxoethyl)benzyl carbamimidothioate hydrobromide

[0524] [ka]

[0525] Isochroman-3-one (compound 62a, 296 mg, 2.00 mmol) and cyclopropylmethanamine (0.189 mL, 2.20 mmol) were reacted in the same manner as in the synthesis of compound 62b. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (1:1 to 1:3) to give compound 71a (356 mg, 81% yield) as white crystals.

[0526] 1 HNMR (400 MHz, CDCl3): 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) +

[0527] Compound 71b (111 mg, 24% yield) was obtained as a white oily substance from compound 71a (356 mg, 1.62 mmol) and phosphorous tribromide (0.185 mL, 1.95 mmol) in the same manner as in the synthesis of compound 2c.

[0528] 1 HNMR (400 MHz, CDCl3): 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) +

[0529] The title compound 71 (57 mg, 41% yield) was obtained as white crystals from compound 71b (111 mg, 0.39 mmol) and Thiourea (30.0 mg, 0.39 mmol) by the same procedure as in the synthesis of compound 2.

[0530] 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) +

[0531] Synthesis of compound 72 2-(2-Oxo-2-((4-phenylbutyl)amino)ethyl)benzyl carbamimidothioate hydrobromide

[0532] [ka]

[0533] Isochroman-3-one (compound 62a, 246 mg, 2.00 mmol) and 4-phenylbutan-1-amine (349 mL, 2.20 mmol) were treated in the same manner as in the synthesis of compound 62b. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (55:45 to 3:7) to give compound 72a (509 mg, 85% yield) as white crystals.

[0534] 1 HNMR (400 MHz, CDCl3): 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) +

[0535] Compound 72b (251 mg, 41% yield) was obtained as a white oily substance from compound 72a (509 mg, 1.71 mmol) and phosphorous tribromide (0.195 mL, 2.05 mmol) by the same procedure as in the synthesis of compound 2c.

[0536] 1 HNMR (400 MHz, CDCl3): 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) +

[0537] Compound 72b (251 mg, 0.70 mmol) and Thiourea (53.0 mg, 0.70 mmol) were synthesized in the same manner as in the synthesis of compound 2, and the residue was recrystallized from EtOH to give the title compound 72 (198 mg, 65% yield) as white crystals.

[0538] 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) +

[0539] 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)

[0540] [ka]

[0541] Cyclopropylmethanamine (0.086 mL, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4,5-Dichloro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide (compound 36, 162 mg, 0.50 mmol) were reacted in the same manner as in the synthesis of compound 9. The reaction residue was recrystallized from EtOH to give the title compound 73 (115 mg, 45% yield) as white crystals.

[0542] 1 HNMR (400 MHz, CDCl3): 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) +

[0543] Synthesis of compound 74 5-Bromo-2-((cyclohexylmethyl)carbamoyl)benzyl carbamimidothioate hydrobromide

[0544] [ka]

[0545] Cyclohexylmethanamine (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 the mixture was stirred at room temperature for 8 hours. After concentrating under reduced pressure, water was added and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using n-hexane / EtOAc (4:1 to 1:1) to give compound 74b (210 mg, 13% yield) as white crystals.

[0546] 1 HNMR (400 MHz, CDCl3): 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) +

[0547] To a solution of compound 74b (65.2 mg, 0.20 mmol) in CHCl (4 mL) was added CBr (79.6 mg, 0.24 mmol) at 0 °C, followed by a solution of PPh (78.7 mg, 0.30 mmol) in CHCl (5 mL). The reaction mixture was stirred at room temperature for 1 hour, and then Thiourea (15.2 mg, 0.20 mmol) was added and the mixture was stirred at 40 °C for 12 hours. The precipitated crystals were collected by filtration to give the title compound 74 (61 mg, 66% yield) as white crystals.

[0548] 1HNMR (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) +

[0549] 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)

[0550]

Chemical Structure

[0551] Cyclopropylmethanamine (0.086 mL, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4-Bromo-1,2-phenylne)bis(methylene) dicarbamimidothioate dihydrobromide (compound 10, 167 mg, 0.50 mmol) were reacted in the same manner as in the synthesis of compound 9. The reaction residue was recrystallized from EtOH and EtO (1:2) to give the title compound 75 (115 mg, 44% yield) as white crystals.

[0552] 1 HNMR (500 MHz, CDCl3): 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) +

[0553] Synthesis of compound 76 5-Bromo-2-((4-cyanobenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

[0554] [ka]

[0555] To a solution of 5-Bromoisobenzofuran-1(3H)-one (compound 74a, 639 mg, 3.00 mmol) in THF (15 mL), 4-(Aminomethyl)benzonitrile Hydrochloride (556 mg, 3.30 mmol) and triethylamine (418 μL, 3.00 mmol) were added and stirred at 50 °C for 24 h. The reaction mixture was concentrated under reduced pressure, followed by addition of water and extraction with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using n-hexane / EtOAc (65:35 to 3:7) to give compound 76a (142 mg, 14% yield) as yellow crystals.

[0556] 1 HNMR (500 MHz, CDCl3): 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) +

[0557] Compound 76a (123 mg, 0.36 mmol), CBr4 (142 mg, 0.43 mmol), PPh3 (140 mg, 0.54 mmol), and Thiourea (27.2 mg, 0.36 mmol) were synthesized in the same manner as in the synthesis of compound 74. The residue was recrystallized from EtOH to give the title compound 76 (26.5 mg, 15% yield) as gray crystals.

[0558] 1HNMR (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) +

[0559] Synthesis of compound 77 5-Cyano-2-(methylcarbamoyl)benzyl carbamimidothioate hydrobromide

[0560] [ka]

[0561] Compound 77b (562 mg, 59% yield) was obtained as white crystals from 5-cyano-isobenzofuran-1(3H)-one (compound 77a, 796 mg, 5.00 mmol) and 40% MeNH2 (4.309 mL, 50.0 mmol) by the same procedure as in the synthesis of compound 74b.

[0562] 1 HNMR (400 MHz, CDCl3): 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) +

[0563] Compound 77b (190 mg, 1.00 mmol), CBr4 (398 mg, 1.20 mmol), PPh3 (393 mg, 1.50 mmol), and Thiourea (76.1 mg, 1.00 mmol) were synthesized in the same manner as in the synthesis of compound 74. The residue was recrystallized from EtOH to give the title compound 77 (29.5 mg, 9% yield) as pale green crystals.

[0564] 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) +

[0565] Synthesis of compound 78 5-Bromo-2-((4-chlorophenethyl)carbamoyl)benzyl carbamimidothioate hydrobromide

[0566] [ka]

[0567] 5-Bromoisobenzofuran-1(3H)-one (compound 74a, 1065 mg, 5.00 mmol) and 2-(4-chlorophenyl)ethan-1-amine (0.840 mL, 6.00 mmol) were synthesized in the same manner as in the synthesis of compound 74b. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (7:3 to 3:7) to give compound 78a (919 mg, 50% yield) as white crystals.

[0568] 1 HNMR (400 MHz, CDCl3): 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) +

[0569] Compound 78a (369 mg, 1.00 mmol), CBr4 (398 mg, 1.20 mmol), PPh3 (393 mg, 1.50 mmol), and Thiourea (76.1 mg, 1.00 mmol) were synthesized in the same manner as in the synthesis of compound 74. The residue was recrystallized from EtOH to give the title compound 78 (244 mg, 48% yield) as white crystals.

[0570] 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) +

[0571] Synthesis of compound 79 2-(2-(Methylamino)-2-oxoethyl)benzyl (E)-N'-(4-bromophenyl)carbamimidothioate hydrobromide

[0572] [ka]

[0573] The title compound 79 (74.2 mg, 37% yield) was obtained as white crystals from compound 62c (102 mg, 0.42 mmol) and 1-(4-Bromophenyl)thiourea (97.5 mg, 0.42 mmol) by the same procedure as in the synthesis of compound 2.

[0574] 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) +

[0575] Synthesis of Compound 80 2-(2-(Methylamino)-2-oxoethyl)benzyl (E)-N'-(3-chloro-4-fluorophenyl)carbamimidothioate hydrobromide

[0576] [ka]

[0577] Compound 62c (88.3 mg, 0.36 mmol) and 1-(3-chloro-4-fluorophenyl)thiourea (74.6 mg, 0.36 mmol) were synthesized in the same manner as in the synthesis of compound 2, and the residue was recrystallized from 2-propanol and hexane (1:1) to give the title compound 80 (64.7 mg, 40% yield) as white crystals.

[0578] 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) +

[0579] Synthesis of compound 81 5-Cyano-2-(methylcarbamoyl)benzyl (E)-N'-(4-bromophenyl)carbamimidothioate hydrobromide

[0580] [ka]

[0581] Compound 77b (190 mg, 1.00 mmol), CBr4 (398 mg, 1.20 mmol), PPh3 (393 mg, 1.50 mmol), and 1-(4-Bromophenyl)thiourea (231 mg, 1.00 mmol) were synthesized in the same manner as in the synthesis of compound 74. The residue was recrystallized from EtOH to give the title compound 81 (249 mg, 51% yield) as white crystals.

[0582] 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) +

[0583] Synthesis of compound 82 5-Bromo-2-((4-chlorobenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

[0584] [ka]

[0585] 5-Bromoisobenzofuran-1(3H)-one (compound 74a, 1065 mg, 5.00 mmol) and (4-chlorophenyl)methanamine (0.732 mg, 6.00 mmol) were synthesized in the same manner as in the synthesis of compound 74b. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (3:1 to 1:1) to give compound 82a (438 mg, 25% yield) as white crystals.

[0586] 1HNMR (400 MHz, CDCl3): 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) +

[0587] Compound 82a (142 mg, 0.40 mmol), CBr4 (159 mg, 0.48 mmol), PPh3 (157 mg, 0.60 mmol), and Thiourea (30.4 mg, 0.40 mmol) were synthesized in the same manner as in the synthesis of compound 74. The residue was recrystallized from EtOH to give the title compound 82 (112 mg, 57% yield) as white crystals.

[0588] 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) +

[0589] Synthesis of compound 83 5-Bromo-2-((4-chlorobenzyl)carbamoyl)benzyl (E)-N'-(3-chloro-4-fluorophenyl)carbamimidothioate hydrobromide

[0590] [ka]

[0591] Compound 82a (106 mg, 0.30 mmol), CBr4 (119 mg, 0.36 mmol), PPh3 (118 mg, 0.45 mmol), and 1-(3-chloro-4-fluorophenyl)thiourea (61.4 mg, 0.30 mmol) were prepared in the same manner as in the synthesis of compound 74. The residue was purified by silica gel chromatography using n-hexane / EtOAc (1:1) to give the title compound 83 (90.4 mg, 48% yield) as pale pink crystals.

[0592] 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) +

[0593] Synthesis of compound 84 5-Bromo-2-((4-chlorobenzyl)carbamoyl)benzyl (E)-N'-(4-bromophenyl)carbamimidothioate hydrobromide

[0594] [ka]

[0595] Compound 82a (130 mg, 0.37 mmol), CBr4 (146 mg, 0.44 mmol), PPh3 (144 mg, 0.50 mmol), and 1-(4-Bromophenyl)thiourea (84.7 mg, 0.37 mmol) were prepared in the same manner as in the synthesis of compound 74. The residue was purified by silica gel chromatography using n-hexane / EtOAc (1:1) to give the title compound 84 (63.4 mg, 26% yield) as white crystals.

[0596] 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) +

[0597] Synthesis of compound 85 5-Bromo-2-((4-cyanobenzyl)carbamoyl)benzyl (E)-N'-(3-chloro-4-fluorophenyl)carbamimidothioate hydrobromide

[0598] [ka]

[0599] Compound 76a (104 mg, 0.30 mmol), CBr4 (119 mg, 0.36 mmol), PPh3 (118 mg, 0.45 mmol), and 1-(3-chloro-4-fluorophenyl)thiourea (61.4 mg, 0.30 mmol) were synthesized in the same manner as in the synthesis of compound 74. The residue was recrystallized from EtOH to give the title compound 85 (128 mg, 70% yield) as white crystals.

[0600] 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) +

[0601] Synthesis of Compound 86 5-Bromo-2-((4-fluorobenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

[0602] [ka]

[0603] 5-Bromoisobenzofuran-1(3H)-one (compound 74a, 1065 mg, 5.00 mmol) and (4-Fluorophenyl)methanamine (0.683 mL, 6.00 mmol) were synthesized in the same manner as in the synthesis of compound 74b. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (3:1 to 1:1) to give compound 86a (229 mg, 14% yield) as pale yellow crystals.

[0604] 1 HNMR (500 MHz, CDCl3): 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) +

[0605] The title compound 86 (20.3 mg, 14% yield) was obtained as white crystals from compound 86a (102 mg, 0.30 mmol), CBr (119 mg, 0.36 mmol), PPh (118 mg, 0.45 mmol), and Thiourea (22.8 mg, 0.30 mmol) by the same procedure as in the synthesis of compound 74.

[0606] 1HNMR (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) +

[0607] Synthesis of compound 87 5-Bromo-2-((4-cyanobenzyl)carbamoyl)benzyl (E)-N'-(4-bromophenyl)carbamimidothioate hydrobromide

[0608] [ka]

[0609] The title compound 87 (66.1 mg, 52% yield) was obtained as white crystals from compound 76a (69 mg, 0.20 mmol), CBr4 (79.6 mg, 0.24 mmol), PPh3 (78.7 mg, 0.30 mmol), and 1-(4-Bromophenyl)thiourea (46.2 mg, 0.20 mmol) by the same procedure as in the synthesis of compound 74.

[0610] 1HNMR (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) +

[0611] Synthesis of compound 88 5-Bromo-2-((4-fluorobenzyl)carbamoyl)benzyl (E)-N'-(3-chloro-4-fluorophenyl)carbamimidothioate hydrobromide

[0612] [ka]

[0613] Compound 86a (121 mg, 0.36 mmol), CBr4 (143 mg, 0.43 mmol), PPh3 (141 mg, 0.54 mmol), and 1-(3-chloro-4-fluorophenyl)thiourea (73.3 mg, 0.36 mmol) were prepared in the same manner as in the synthesis of compound 74. The residue was purified by silica gel chromatography using n-hexane / EtOAc (1:1) to give the title compound 88 (91.4 mg, 42% yield) as pale yellow crystals.

[0614] 1HNMR (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) +

[0615] Synthesis of compound 89 5-Bromo-2-((2,4-dichlorobenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

[0616] [ka]

[0617] 5-Bromoisobenzofuran-1(3H)-one (compound 74a, 1065 mg, 5.00 mmol) and (2,4-Dichlorophenyl)methanamine (0.808 mL, 6.00 mmol) were prepared in the same manner as in the synthesis of compound 74b. The reaction residue was purified twice by silica gel chromatography using n-hexane / EtOAc (4:1 to 3:2) and n-hexane / EtOAc (4:1 to 3:2) to give compound 89a (105 mg, 5% yield) as white crystals.

[0618] 1HNMR (500 MHz, CDCl3): 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) +

[0619] Compound 89a (105 mg, 0.27 mmol), CBr (108 mg, 0.32 mmol), PPh (106 mg, 0.41 mmol), and Thiourea (20.6 mg, 0.27 mmol) were synthesized in the same manner as in the synthesis of compound 74. The residue was recrystallized from EtOH and EtO (1:1) to give the title compound 89 (76 mg, 54% yield) as white crystals.

[0620] 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) +

[0621] Synthesis of Compound 90 5-Bromo-2-((4-methylbenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

[0622] [ka]

[0623] 5-Bromoisobenzofuran-1(3H)-one (compound 74a, 1065 mg, 5.00 mmol) and p-Tolylmethanamine (0.757 mL, 6.00 mmol) were prepared in the same manner as in the synthesis of compound 74b. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (3:1 to 55:45) to give compound 90a (200 mg, 12% yield) as white crystals.

[0624] 1 HNMR (500 MHz, CDCl3): δ = 7.57 (1H, d, J= 1.7 Hz), 7.48 (1H, dd, J = 8.2, 2.0 Hz), 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) +

[0625] Compound 90a (94 mg, 0.28 mmol), CBr4 (112 mg, 0.34 mmol), PPh3 (111 mg, 0.42 mmol), and Thiourea (21 mg, 0.28 mmol) were synthesized in the same manner as in the synthesis of compound 74. The residue was recrystallized from EtOH to give the title compound 90 (60 mg, 46% yield) as white crystals.

[0626] 1 HNMR (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) +

[0627] Synthesis of Compound 91 5-Bromo-2-((4-methylbenzyl)carbamoyl)benzyl (E)-N'-(3-chloro-4-fluorophenyl)carbamimidothioate hydrobromide

[0628] [ka]

[0629] Compound 90a (100 mg, 0.30 mmol), CBr4 (119 mg, 0.36 mmol), PPh3 (118 mg, 0.45 mmol), and 1-(3-chloro-4-fluorophenyl)thiourea (61 mg, 0.30 mmol) were synthesized in the same manner as in the synthesis of compound 74. The residue was purified by silica gel chromatography using n-hexane / EtOAc (1:1) to give the title compound 91 (90 mg, 50% yield) as pale yellow crystals.

[0630] 1 HNMR (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) +

[0631] Synthesis of Compound 92 2-(Methylcarbamoyl)benzyl carbamimidothioate hydrobromide

[0632] [ka]

[0633] Compound 92b (577 mg, 70% yield) was obtained as white crystals from isobenzofuran-1(3H)-one (compound 92a, 671 mg, 5.00 mmol) and 40% MeNH2 (4.309 mL, 50.0 mmol) using the same procedure as for the synthesis of compound 74b.

[0634] 1 H-NMR (DMSO-d6) 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)+

[0635] The title compound 92 (69.5 mg, 57% yield) was obtained as white crystals from compound 92b (66 mg, 0.40 mmol), CBr4 (159 mg, 0.48 mmol), PPh3 (157 mg, 0.60 mmol), and Thiourea (30 mg, 0.40 mmol) by the same procedure as in the synthesis of compound 74.

[0636] 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) +

[0637] Synthesis of Compound 93 5-Bromo-2-((cyclopropylmethyl)carbamoyl)benzyl carbamimidothioate hydrobromide

[0638] [ka]

[0639] 5-Bromoisobenzofuran-1(3H)-one (compound 74a, 1065 mg, 5.00 mmol) and cyclopropylmethanamine (0.514 mL, 6.00 mmol) were treated in the same manner as in the synthesis of 74b. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (7:3 to 1:1) to give compound 93a (607 mg, 43% yield) as white crystals.

[0640] 1 HNMR (500 MHz, CDCl3): 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) +

[0641] The title compound 93 (124 mg, 59% yield) was obtained as white crystals from compound 93a (142 mg, 0.50 mmol), CBr (199 mg, 0.60 mmol), PPh (197 mg, 0.75 mmol), and Thiourea (38 mg, 0.50 mmol) by the same procedure as in the synthesis of compound 74.

[0642] 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) +

[0643] Synthesis of compound 94 5-Bromo-2-((3,4-dichlorobenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

[0644] [ka]

[0645] 5-Bromoisobenzofuran-1(3H)-one (compound 74a, 1065 mg, 5.00 mmol) and (3,4-Dichlorophenyl)methanamine (0.794 mg, 6.00 mmol) were prepared in the same manner as in the synthesis of compound 74b. The reaction residue was purified twice by silica gel chromatography using n-hexane / EtOAc (7:3 to 45:55) and n-hexane / EtOAc (7:3 to 1:1) to give compound 94a (133 mg, 7% yield) as white crystals.

[0646] 1 HNMR (500 MHz, CDCl3): δ = 7.59 (1H, d, J= 1.7 Hz), 7.52 (1H, dd, J = 7.9, 1.7 Hz), 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) +

[0647] Compound 94a (117 mg, 0.30 mmol), CBr4 (119 mg, 0.36 mmol), PPh3 (118 mg, 0.45 mmol), and Thiourea (22.8 mg, 0.30 mmol) were synthesized in the same manner as in the synthesis of compound 74. The residue was recrystallized from EtOH to give the title compound 94 (14.6 mg, 9% yield) as white crystals.

[0648] 1HNMR (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) +

[0649] Synthesis of Compound 95 1,2-Phenylenebis(methylene) (E,E)-bis(N'-(2,4-difluorophenyl)carbamimidothioate) dihydrobromide

[0650] [ka]

[0651] 1,2-Bis(bromomethyl)benzene (compound 58a, 132 mg, 0.50 mmol) and 1-(2,4-difluorophenyl)thiourea (188 mg, 1.00 mmol) were synthesized in the same manner as in the synthesis of compound 2, and the residue was recrystallized from 2-propanol and hexane (1:1) to give the title compound 95 (256 mg, 80% yield) as white crystals.

[0652] 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) +

[0653] Synthesis of Compound 96 2-((4-Cyanobenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

[0654] [ka]

[0655] 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) were synthesized in the same manner as in the synthesis of compound 76a. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (7:3 to 35:65) to give compound 96a (731 mg, 46% yield) as pale yellow crystals.

[0656] 1 HNMR (500 MHz, CDCl3): 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) +

[0657] Compound 96a (133 mg, 0.50 mmol), CBr4 (199 mg, 0.60 mmol), PPh3 (197 mg, 0.75 mmol), and Thiourea (38.1 mg, 0.50 mmol) were synthesized in the same manner as in the synthesis of compound 74. The residue was recrystallized from EtOH to give the title compound 96 (9.3 mg, 5% yield) as white crystals.

[0658] 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) +

[0659] Synthesis of compound 97 5-Bromo-2-((4-bromobenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

[0660] [ka]

[0661] 5-Bromoisobenzofuran-1(3H)-one (compound 74a, 639 mg, 3.00 mmol) and (4-Bromophenyl)methanamine (670 mg, 3.60 mmol) were synthesized in the same manner as in the synthesis of compound 74b. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (7:3 to 1:1) to give compound 97a (114 mg, 10% yield) as white crystals.

[0662] 1 HNMR (500 MHz, CDCl3): 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) +

[0663] Compound 97a (111 mg, 0.28 mmol), CBr4 (111 mg, 0.33 mmol), PPh3 (110 mg, 0.42 mmol), and Thiourea (21.2 mg, 0.28 mmol) were synthesized in the same manner as in the synthesis of compound 74. The residue was recrystallized from EtOH to give the title compound 97 (70.0 mg, 46% yield) as white crystals.

[0664] 1HNMR (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) +

[0665] Synthesis of compound 98 (2-(Methylcarbamoyl)pyridin-3-yl)methyl carbamimidothioate hydrobromide

[0666] [ka]

[0667] A solution of furo[3,4-b]pyridine-5,7-dione (compound 98a, 5.0 g, 34.0 mmol) in MeOH (25 ml) was stirred for 2 hours at 70° C. The reaction mixture was concentrated under reduced pressure and recrystallized from ethyl acetate to give compound 98b (3.94 g, 64% yield) as white crystals.

[0668] 1 HNMR (500 MHz, CDCl3): 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) +

[0669] A THF solution (4 mL) of 1,1'-Carbonyldiimidazole (CDI) (535 mg, 3.31 mmol) was added to a THF solution (7 mL) of compound 98b (450 mg, 2.50 mmol) at 0 °C and stirred at room temperature for 1 hour. NaBH4 was then added to the reaction mixture and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was cooled to 0 °C, and MeOH (3 mL) and water were added. The mixture was then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using n-hexane / EtOAc (1:3 to 0:1) to give compound 98c (116 mg, 34% yield) as white crystals.

[0670] 1 HNMR (500 MHz, CDCl3): 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).

[0671] To a solution of compound 98c (113 mg, 0.84 mmol) in THF (12 ml), 40% MeNH2 (260 mg, 8.38 mmol) was added and stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, followed by addition of water and extraction with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give compound 98d (104 mg, 75% yield) as white crystals.

[0672] 1 HNMR (500 MHz, CDCl3): 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).

[0673] To a solution of compound 98d (103 mg, 0.62 mmol) in CHCl (5 mL) was added CBr (146 mg, 0.74 mmol) at 0 °C, followed by a solution of PPh (243 mg, 0.93 mmol) in CHCl (4 mL). The reaction mixture was stirred at room temperature for 1 hour, and then thiourea (47.0 mg, 0.62 mmol) was added and the mixture was stirred at 40 °C for 12 hours. The precipitated crystals were collected by filtration to give the title compound 98 (11.7 mg, 6% yield) as white crystals.

[0674] 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) +

[0675] Synthesis of Compound 99 (2-((4-Cyanobenzyl)carbamoyl)pyridin-3-yl)methyl carbamimidothioate hydrobromide

[0676] [ka]

[0677] Compound 98c (511 mg, 3.78 mmol), 4-(Aminomethyl)benzonitrile Hydrochloride (702 mg, 4.16 mmol), and triethylamine (1.581 mL, 11.35 mmol) were prepared in the same manner as in the synthesis of compound 76a. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (2:3 to 1:4) to give compound 99a (519 mg, 51% yield) as pale yellow crystals.

[0678] 1 HNMR (500 MHz, CDCl3): 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) +

[0679] Compound 99a (245 mg, 0.92 mmol), CBr4 (365 mg, 1.10 mmol), PPh3 (361 mg, 1.38 mmol), and Thiourea (69.8 mg, 0.92 mmol) were prepared in the same manner as in the synthesis of compound 98 to give the title compound 99 (105 mg, 28% yield) as white crystals.

[0680] 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) +

[0681] Synthesis of Compound 100 (3-(Methylcarbamoyl)pyridin-2-yl)methyl carbamimidothioate hydrobromide

[0682] [ka]

[0683] A THF solution (5 ml) of NaBH4 (1.14 mg, 33.5 mmol) was added to a THF solution (30 ml) of furo[3,4-b]pyridine-5,7-dione (compound 100a, 5.0 g, 33.5 mmol) and acetic acid (4.0 g, 67.0 mmol) at 15 °C and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, and then acetic acid (13.5 ml) and acetic anhydride (13.5 ml) were added and refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure and then extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from 2-propanol to give compound 100b (1.29 g, 29% yield) as pale yellow crystals.

[0684] 1HNMR (500 MHz, CDCl3): 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).

[0685] To a solution of compound 100b (270 mg, 2.0 mmol) in THF (10 ml), 40% MeNH2 (621 mg, 20.0 mmol) was added and stirred at room temperature for 5 hours. The reaction mixture 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, added with toluene, and concentrated under reduced pressure to give compound 100c (222 mg, 67% yield) as yellow crystals.

[0686] 1 HNMR (500 MHz, CDCl3): 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).

[0687] To a solution of compound 100c (217 mg, 1.3 mmol) in CHCl (6 mL) was added CBr (519 mg, 1.6 mmol) at 0 °C, followed by a solution of PPh (514 mg, 2.0 mmol) in CHCl (4 mL). The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of Thiourea (99.4 mg, 1.3 mmol), and the mixture was stirred at 40 °C for 12 hours. The precipitated crystals were collected by filtration to give title compound 100 (98.4 mg, 25% yield) as pale orange crystals.

[0688] 1HNMR (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, 4.8Hz), 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) +

[0689] Synthesis of Compound 101 (2-((4-Cyanobenzyl)carbamoyl)pyridin-3-yl)methyl (E)-N'-(3-chloro-4-fluorophenyl)carbamimidothioate hydrobromide

[0690] [ka]

[0691] Compound 99a (134 mg, 0.50 mmol), CBr4 (199 mg, 0.60 mmol), PPh3 (197 mg, 0.75 mmol), and (3-chloro-4-fluorophenyl)thiourea (102 mg, 0.50 mmol) were prepared in the same manner as in the synthesis of compound 98. The residue was purified by silica gel chromatography using n-hexane / EtOAc (1:1) to give the title compound 101 (37.3 mg, 14% yield) as white crystals.

[0692] 1HNMR (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) +

[0693] Synthesis of Compound 102 5-bromo-2-((4-methoxybenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

[0694] [ka]

[0695] 5-Bromoisobenzofuran-1(3H)-one (compound 74a, 852 g, 4.00 mmol) and (4-Methoxyphenyl)methanamine (0.627 mL, 4.80 mmol) were reacted in the same manner as in the synthesis of compound 74b. The reaction residue was purified by silica gel chromatography using n-hexane / EtOAc (7:3 to 45:55) to give compound 102a (372 mg, 27% yield) as white crystals.

[0696] 1HNMR (500 MHz, CDCl3): 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)+

[0697] Compound 102a (175 mg, 0.50 mmol), CBr4 (199 mg, 0.60 mmol), PPh3 (197 mg, 0.75 mmol), and Thiourea (38.1 mg, 0.50 mmol) were synthesized in the same manner as in the synthesis of compound 74. The residue was recrystallized from EtOH to give the title compound 102 (22.4 mg, 9% yield) as white crystals.

[0698] 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) +

[0699] Synthesis of Compound 103 4-Bromo-2-((4-cyanobenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

[0700] [ka]

[0701] To a solution of isobenzofuran-1(3H)-one (compound 103a, 500 mg, 3.73 mmol) in acetic acid (3 mL), sulfuric acid (1.5 mL) was added, and NBS (995 mg, 5.59 mmol) was added portionwise over 9 hours with stirring at room temperature. Water (50 mL) was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using n-hexane / EtOAc (1:0 to 7:3) to give compound 103b (445 mg, 56% yield) as white crystals.

[0702] 1 HNMR (500 MHz, CDCl3): 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)+

[0703] To a solution of compound 103b (426 mg, 2.0 mmol) in THF (10 mL), 4-(aminomethyl)benzonitrile hydrochloride (371 mg, 2.2 mmol) and EtN (607 mg, 6.0 mmol) were added and stirred at 50 °C for 12 hours. After the reaction, water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. The residue was purified by silica gel chromatography using n-hexane / EtOAc (3:2 to 2:3) to give compound 103c (208 mg, 30% yield) as white crystals.

[0704] 1 HNMR (500 MHz, CDCl3): 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) +

[0705] To a solution of compound 103c (69.0 mg, 0.20 mmol) in CHCl (8 mL) was added CBr (79.6 mg, 0.24 mmol) at 0 °C, followed by a solution of PPh (78.7 mg, 0.30 mmol) in CHCl (4 mL). The reaction mixture was stirred at room temperature for 1 hour, and then Thiourea (15.2 mg, 0.20 mmol) was added and stirred at 40 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using CHCl / MeOH (19:1 to 7:3) and recrystallized from EtOH and EtO to give the title compound 103 (11.4 mg, 12% yield) as white crystals.

[0706] 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) +

[0707] Synthesis of Compound 104 2-((4-Cyanobenzyl)carbamoyl)benzyl carbamimidoselenoate hydrobromide

[0708] [ka]

[0709] Compound 96a (133 mg, 0.50 mmol), CBr (199 mg, 0.60 mmol), PPh (197 mg, 0.75 mmol), and Selenourea (61.5 mg, 0.50 mmol) were synthesized in the same manner as in the synthesis of compound 74. The residue was recrystallized from EtOH and EtO to give the title compound 104 (138 mg, 61% yield) as off-white crystals.

[0710] 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) +

[0711] Synthesis of Compound 105 5-Bromo-2-((3-methoxybenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

[0712] [ka]

[0713] 5-Bromoisobenzofuran-1(3H)-one (compound 74a, 1065 mg, 5.00 mmol) and (3-Methoxyphenyl)methanamine (0.776 mL, 6.00 mmol) were treated in the same manner as in the synthesis of compound 74b. The reaction residue was purified twice by silica gel chromatography using n-hexane / EtOAc (7:3 to 2:3) and n-hexane / EtOAc (7:3 to 1:1) to give compound 105a (364 mg, 21% yield) as white crystals.

[0714] 1 HNMR (500 MHz, CD3OD): 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) +

[0715] Compound 105a (105 mg, 0.30 mmol), CBr (119 mg, 0.36 mmol), PPh (118 mg, 0.45 mmol), and Thiourea (22.8 mg, 0.30 mmol) were prepared in the same manner as in the synthesis of compound 74. The residue was recrystallized from EtOH and EtO to give the title compound 105 (22.7 mg, 15% yield) as white crystals.

[0716] 1HNMR (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) +

[0717] Synthesis of Compound 106 5-Bromo-2-((3-methoxybenzyl)carbamoyl)benzyl carbamimidoselenoate hydrobromide

[0718] [ka]

[0719] The title compound 106 (74.6 mg, 46% yield) was obtained as white crystals from compound 105a (105 mg, 0.30 mmol), CBr4 (119 mg, 0.36 mmol), PPh3 (118 mg, 0.45 mmol), and Selenourea (22.8 mg, 0.19 mmol) by the same procedure as in the synthesis of compound 74.

[0720] 1HNMR (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) +

[0721] Synthesis of Compound 107 5-Bromo-2-((cyclopropylmethyl)carbamoyl)benzyl carbamimidoselenoate hydrobromide

[0722] [ka]

[0723] The title compound 107 (64.6 mg, 46% yield) was obtained as white crystals from compound 93a (85.2 mg, 0.30 mmol), CBr4 (119 mg, 0.336 mmol), PPh3 (118 mg, 0.45 mmol), and Selenourea (22.8 mg, 0.19 mmol) by the same procedure as in the synthesis of compound 74.

[0724] 1HNMR (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) +

[0725] Synthesis of Compound 108 1,2-Phenylenebis(methylene) dicarbamimidoselenoate dihydrobromide

[0726] [ka]

[0727] Compound 58a was synthesized from 1,2-bis(bromomethyl)benzene (compound 58a, 264 mg, 1.00 mmol) and selenourea (246 mg, 2.00 mmol) in the same manner as in the synthesis of compound 2. The residue was recrystallized from EtOH:EtO (5:3) to give the title compound 108 (393 mg, 77% yield) as pale orange crystals.

[0728] 1 HNMR (500 MHz, CD3OD): 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) + .

[0729] Synthesis of Compound 109 (4-Chloro-1,2-phenylene)bis(methylene) dicarbamimidoselenoate dihydrobromide

[0730] [ka]

[0731] Compound 7c was synthesized from 1,2-bis(bromomethyl)benzene (compound 7c, 308 mg, 1.00 mmol) and selenourea (246 mg, 2.00 mmol) in the same manner as in the synthesis of compound 2. The residue was recrystallized from EtOH:EtO (5:3) to give the title compound 109 (263 mg, 48.4% yield) as pale yellow crystals.

[0732] 1 HNMR (500 MHz, CD3OD): 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) + .

[0733] Synthesis of Compound 110 4-Bromo-2-((4-cyanobenzyl)carbamoyl)benzyl carbamimidoselenoate hydrobromide

[0734] [ka]

[0735] To a solution of compound 103c (69.0 mg, 0.20 mmol) in CHCl (8 ml) was added CBr (79.6 mg, 0.24 mmol) at 0 °C, followed by a solution of PPh (78.7 mg, 0.30 mmol) in CHCl (4 ml). The reaction mixture was stirred at room temperature for 1 hour, and then selenourea (24.6 mg, 0.20 mmol) was added and stirred at 40 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from EtOH and EtO to give title compound 110 (6.7 mg, 6% yield) as white crystals.

[0736] 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) +

[0737] Synthesis of Compound 111 2-Bromo-6-((4-cyanobenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

[0738] [ka]

[0739] To a solution of isobenzofuran-1(3H)-one (compound 111a, 5.0 g, 37.3 mmol) in acetic acid (10 ml), sulfuric acid (4.5 ml) was added, and NBS (N-bromosuccinimide, 9.95 g, 55.9 mmol) was added portionwise over 9 hours with stirring at room temperature. Water (100 ml) was added to the reaction solution, which was then extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using n-hexane / EtOAc (4:1 to 3:2) to give compound 111b (1.09 g, 14% yield) as white crystals.

[0740] 1 HNMR (500 MHz, CDCl3): 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)+

[0741] To a solution of compound 111b (426 mg, 2.0 mmol) in THF (10 mL), 4-(aminomethyl)benzonitrile hydrochloride (371 mg, 2.2 mmol) and EtN (607 mg, 6.0 mmol) were added and stirred at 50 °C for 12 hours. After the reaction, water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. The residue was purified by silica gel chromatography using n-hexane / EtOAc (3:2 to 2:3) to give compound 111c (99.6 mg, 14% yield) as white crystals.

[0742] 1HNMR (500 MHz, CDCl3): 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) +

[0743] To a solution of compound 111c (99.6 mg, 0.29 mmol) in CHCl (10 ml) was added CBr (115 mg, 0.35 mmol) at 0 °C, followed by a solution of PPh (114 mg, 0.43 mmol) in CHCl (4 ml). The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of Thiourea (22.0 mg, 0.29 mmol), and the mixture was stirred at 40 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from 2-propanol and n-hexane to give the title compound 111 (44.0 mg, 31% yield) as white crystals.

[0744] 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) +

[0745] Synthesis of Compound 112 Quinoxaline-2,3-diylbis(methylene) dicarbamimidoselenoate dihydrobromide

[0746] [ka]

[0747] 5a: 2,3-Bis(bromomethyl)quinoxaline (316 mg, 1.00 mmol) and selenourea (246 mg, 2.00 mmol) were prepared in the same manner as in the synthesis of 1, and the residue was recrystallized from EtOH:EtO (1:1) to give the title compound 112 (432 mg, 77% yield) as off-white crystals.

[0748] 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) + .

[0749] Synthesis of Compound 113 5-Bromo-2-((4-cyanobenzyl)carbamoyl)benzyl carbamimidoselenoate hydrobromide

[0750] [ka]

[0751] 76a (103 mg, 0.30 mmol), CBr4 (119 mg, 0.36 mmol), PPh3 (118 mg, 0.45 mmol), and Selenourea (22.8 mg, 0.30 mmol) were prepared in the same manner as in the synthesis of 74. The residue was recrystallized from 2-propanol to give the title compound 113 (62.8 mg, 40% yield) as white crystals.

[0752] 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) +

[0753] Synthesis of Compound 114 5-Bromo-2-((4-(trifluoromethyl)benzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

[0754] [ka]

[0755] 74a: To a solution of 5-Bromoisobenzofuran-1(3H)-one (1065 mg, 5.00 mmol) in THF (15 mL), (4-(Trifluoromethyl)phenyl)methanamine (0.848 mL, 6.00 mmol) was added and stirred at 50 °C for 24 hours. The reaction mixture was concentrated under reduced pressure, followed by addition of water and extraction with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using n-hexane / EtOAc (7:3 to 1:1) to give compound 114a (137 mg, 7.0% yield) as white crystals.

[0756] 1 HNMR (500 MHz, CDCl3): 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) +

[0757] 114a (137 mg, 0.35 mmol), CBr4 (140 mg, 0.42 mmol), PPh3 (138 mg, 0.53 mmol), and Thiourea (26.8 mg, 0.35 mmol) were prepared in the same manner as in the synthesis of 74. The residue was recrystallized from EtOH and Et2O to give the title compound 114 (11.3 mg, 6.1% yield) as white crystals.

[0758] 1HNMR (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) +

[0759] Synthesis of Compound 115 5-Bromo-2-((2-methoxyethyl)carbamoyl)benzyl carbamimidothioate hydrobromide

[0760] [ka]

[0761] 74a: To a solution of 5-Bromoisobenzofuran-1(3H)-one (1013 mg, 4.76 mmol) in THF (15 mL), 2-Methoxyethan-1-amine (0.491 mL, 5.71 mmol) was added and stirred at 50 °C for 24 hours. The reaction mixture was concentrated under reduced pressure, followed by addition of water and extraction with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using n-hexane / EtOAc (1:1 to 3:7) to give compound 115a (246 mg, 18% yield) as a colorless oil.

[0762] 1HNMR (400 MHz, CDCl3): 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) +

[0763] 115a (86.4 mg, 0.30 mmol), CBr4 (119 mg, 0.36 mmol), PPh3 (118 mg, 0.45 mmol), and Thiourea (22.8 mg, 0.30 mmol) were prepared in the same manner as in the synthesis of 74. The residue was recrystallized from EtOH and Et2O to give the title compound 115 (24.2 mg, 19% yield) as white crystals.

[0764] 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) +

[0765] Synthesis of Compound 116 5-Bromo-2-((3-chloro-4-fluorobenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

[0766] [ka]

[0767] 74a: To a solution of 5-Bromoisobenzofuran-1(3H)-one (1013 mg, 4.76 mmol) in THF (15 mL), (3-Chloro-4-fluorophenyl)methanamine (0.491 mL, 5.71 mmol) was added and stirred at 50 °C for 24 hours. The reaction mixture was concentrated under reduced pressure, followed by addition of water and extraction with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using n-hexane / EtOAc (7:3 to 1:1) to give compound 116a (260 mg, 23% yield) as yellow crystals.

[0768] 1 HNMR (500 MHz, CDCl3): 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) +

[0769] 116a (112 mg, 0.30 mmol), CBr4 (119 mg, 0.36 mmol), PPh3 (118 mg, 0.45 mmol), and Thiourea (22.8 mg, 0.30 mmol) were prepared in the same manner as in the synthesis of 74. The residue was recrystallized from EtOH and Et2O to give the title compound 116 (54.3 mg, 35% yield) as white crystals.

[0770] 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) +

[0771] Synthesis of Compound 117 4-Bromo-2-((4-bromobenzyl)carbamoyl)benzyl carbamimidothioate hydrobromide

[0772] [ka]

[0773] 103b: To a solution of 6-Bromoisobenzofuran-1(3H)-one (320 mg, 1.50 mmol) in THF (15 mL), (4-Bromophenyl)methanamine (335 mg, 1.80 mmol) was added and stirred at 50 °C for 24 hours. The reaction mixture was concentrated under reduced pressure, followed by addition of water and extraction with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using n-hexane / EtOAc (7:3 to 1:1) to give compound 117a (242 mg, 40% yield) as yellow crystals.

[0774] 1 HNMR (500 MHz, CDCl3): 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) +

[0775] 117a (112 mg, 0.30 mmol), CBr4 (119 mg, 0.36 mmol), PPh3 (118 mg, 0.45 mmol), and Thiourea (22.8 mg, 0.30 mmol) were prepared in the same manner as in the synthesis of 74. The residue was recrystallized from EtOH to give the title compound 117 (14.8 mg, 9.2% yield) as white crystals.

[0776] 1HNMR (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) +

[0777] Synthesis of Compound 118 4-Bromo-2-((4-cyanobenzyl)carbamoyl)benzyl (E)-N'-(3-chloro-4-fluorophenyl)carbamimidothioate hydrobromide

[0778] [ka]

[0779] 103c: 5-Bromo-N-(4-cyanobenzyl)-2-(hydroxymethyl)benzamide (173 mg, 0.50 mmol), CBr4 (199 mg, 0.60 mmol), PPh3 (197 mg, 0.75 mmol), and 1-(3-chloro-4-fluorophenyl)thiourea (102 mg, 0.50 mmol) were prepared in the same manner as in the synthesis of 74. The residue was recrystallized from EtOH to give the title compound 118 (232 mg, 76% yield) as white crystals.

[0780] 1HNMR (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) +

[0781] Synthesis of Compound 119 4-Bromo-2-((4-cyanobenzyl)carbamoyl)benzyl (E)-N'-(4-bromophenyl)carbamimidothioate hydrobromide

[0782] [ka]

[0783] 103c: 5-Bromo-N-(4-cyanobenzyl)-2-(hydroxymethyl)benzamide (173 mg, 0.50 mmol), CBr4 (199 mg, 0.60 mmol), PPh3 (197 mg, 0.75 mmol), and 1-(4-Bromophenyl)thiourea (102 mg, 0.50 mmol) were prepared in the same manner as in the synthesis of 74. The residue was recrystallized from EtOH to give the title compound 118 (143 mg, 45% yield) as white crystals.

[0784] 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) +

[0785] 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)

[0786] [ka]

[0787] Cyclopropylmethanamine (88.9 mg, 1.25 mmol), formaldehyde (187.5 μL, 37% wt. solution in water, 2.51 mmol), and (4-Fluoro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide (2, 272.2 mg, 0.63 mmol) were reacted using the same procedure as in the synthesis of 9. The residue was recrystallized from EtOH and EtO (1:2) followed by 2-propanol to give the title compound 120 (337.7 mg, 58.4% yield) as white crystals.

[0788] 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) +

[0789] 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)

[0790] [ka]

[0791] Cyclohexylmethanamine (56.6 mg, 0.50 mmol), formaldehyde (75.0 μL, 37% wt. solution in water, 1.00 mmol), and (4-Fluoro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide (2, 108.5 mg, 0.25 mmol) were reacted using the same procedure as in the synthesis of 9. The reaction residue was recrystallized from 2-propanol and EtO (1:1) to give the title compound 121 (147.1 mg, 53.8% yield) as white crystals.

[0792] 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) +

[0793] Synthesis of compound 122 1,2-Phenylenebis(methylene) (E,E)-bis(N'-(3-chloro-4-fluorophenyl)carbamimidothioate) dihydrobromide

[0794] [ka]

[0795] Under an argon atmosphere, 1-(3-chloro-4-fluorophenyl)thiourea (205 mg, 1.00 mmol) was added to a solution of 58a (1,2-bis(bromomethyl)benzene (132 mg, 0.50 mmol) in EtOH (8 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was returned to room temperature and concentrated under reduced pressure. The residue was recrystallized from EtOH and EtO (1:2) to give the title compound 122 (236.7 mg, 70% yield) as white crystals.

[0796] 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) +

[0797] Synthesis of compound 123 (4,5-Dichloro-1,2-phenylene)bis(methylene) (E,E)-bis(N'-(4-chlorophenyl)carbamimidothioate) dihydrobromide

[0798] [ka]

[0799] 36b: 1,2-Bis(bromomethyl)-4,5-dichlorobenzene (180 mg, 0.54 mmol) and 1-(4-chlorophenyl)thiourea (202 mg, 1.08 mmol) were treated in the same manner as in the synthesis of 2. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from EtOH and EtO (1:1) to give the title compound 123 (263 mg, 68.8% yield) as white crystals.

[0800] 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) +

[0801] Synthesis of compound 124 (4,5-Dichloro-1,2-phenylene)bis(methylene) (E,E)-bis(N'-(4-methoxyphenyl)carbamimidothioate) dihydrobromide

[0802] [ka]

[0803] 36b: 1,2-Bis(bromomethyl)-4,5-dichlorobenzene (370 mg, 1.11 mmol) and 1-(4-Methoxyphenyl)thiourea (405 mg, 2.22 mmol) were treated in the same manner as in the synthesis of 2. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from EtOH and EtO (1:1) to give the title compound 124 (770 mg, 99% yield) as white crystals.

[0804] 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) +

[0805] Synthesis of compound 125 (4,5-dichloro-1,2-phenylene)bis(methylene) (E,E)-bis(N'-(3-chlorophenyl)carbamimidothioate) dihydrobromide

[0806] [ka]

[0807] 36b: 1,2-Bis(bromomethyl)-4,5-dichlorobenzene (151 mg, 0.454 mmol) and 1-(3-chlorophenyl)thiourea (169 mg, 0.907 mmol) were treated in the same manner as in the synthesis of 2. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from EtOH and EtO (1:1) to give the title compound 125 (269 mg, 84% yield) as white crystals.

[0808] 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) +

[0809] Synthesis of Compound 126 (4-Fluoro-1,2-phenylene)bis(methylene) (E,E)-bis(N'-(4-bromophenyl)carbamimidothioate) dihydrobromide

[0810] [ka]

[0811] 2c: 1,2-Bis(bromomethyl)-4-fluorobenzene (211 mg, 0.75 mmol) and 1-(4-Bromophenyl)thiourea (347 mg, 1.50 mmol) were synthesized in the same manner as in the synthesis of 2. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from EtOH and EtO (1:1) to give the title compound 126 (468 mg, 84% yield) as white crystals.

[0812] 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) +

[0813] Synthesis of compound 127 (4-Fluoro-1,2-phenylene)bis(methylene) (E,E)-bis(N'-(4-fluorophenyl)carbamimidothioate) dihydrobromide

[0814] [ka]

[0815] 2c: 1,2-Bis(bromomethyl)-4-fluorobenzene (211 mg, 0.75 mmol) and 1-(4-Fluorophenyl)thiourea (256 mg, 1.50 mmol) were treated in the same manner as in the synthesis of 2. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from EtOH and EtO (1:1) to give the title compound 127 (409 mg, 88% yield) as white crystals.

[0816] 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) +

[0817] Synthesis of compound 128 (4-Fluoro-1,2-phenylene)bis(methylene) (E,E)-bis(N'-(4-methoxyphenyl)carbamimidothioate) dihydrobromide

[0818] [ka]

[0819] 2c: 1,2-Bis(bromomethyl)-4-fluorobenzene (211 mg, 0.75 mmol) and 1-(4-Methoxyphenyl)thiourea (274 mg, 1.50 mmol) were treated in the same manner as in the synthesis of 2. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from EtOH and EtO (1:1) to give the title compound 128 (400 mg, 83% yield) as white crystals.

[0820] 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) +

[0821] Synthesis of compound 129 (4-Fluoro-1,2-phenylene)bis(methylene) (E,E)-bis(N'-(3-chloro-4-fluorophenyl)carbamimidothioate) dihydrobromide

[0822] [ka]

[0823] 2c: 1,2-Bis(bromomethyl)-4-fluorobenzene (211 mg, 0.75 mmol) and 1-(3-chloro-4-fluorophenyl)thiourea (307 mg, 1.50 mmol) were synthesized in the same manner as in the synthesis of 2. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from EtOH and EtO (1:1). The crystals were washed with EtO:n-hexane (1:2) to give the title compound 129 (506 mg, 98% yield) as white crystals.

[0824] 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) +

[0825] Synthesis of Compound 130 (4-Fluoro-1,2-phenylene)bis(methylene) (E,E)-bis(N'-(2,4-difluorophenyl)carbamimidothioate) dihydrobromide

[0826] [ka]

[0827] 2c: 1,2-Bis(bromomethyl)-4-fluorobenzene (211 mg, 0.75 mmol) and 1-(2,4-Difluorophenyl)thiourea (283 mg, 1.50 mmol) were synthesized in the same manner as in the synthesis of 2. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from EtOH and EtO (1:1). The crystals were washed with EtO:n-hexane (1:2) to give the title compound 130 (420 mg, 85% yield) as white crystals.

[0828] 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) +

[0829] Synthesis of Compound 131 (4,5-Difluoro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide

[0830] [ka]

[0831] 131a: 5,6-Difluoroisobenzofuran-1,3-dione (1000 mg, 5.43 mmol) and LiAlH4 (618 mg, 16.3 mmol) were prepared in the same manner as in the synthesis of 2b. The reaction residue was purified by silica gel chromatography (n-hexane / EtOAc = 5:1 to 1:1) to give 131b (620 mg, 66% yield) as white crystals.

[0832] LC-MS: 95% purity, RT 1.13 min, MS (m / z): 197 (M + Na) + .

[0833] The residue obtained from 131b (548 mg, 3.15 mmol) and phosphorous tribromide (0.359 mL, 3.78 mmol) by the same procedure as in the synthesis of 2c was purified by silica gel chromatography using n-hexane / EtOAc (3:1) to give 131c (293 mg, 31% yield) as white crystals.

[0834] 131c (168 mg, 0.56 mmol) and Thiourea (85 mg, 1.12 mmol) were prepared in the same manner as in the synthesis of 2, and the residue was recrystallized from EtOH and EtO (2:3) to give 131 (229 mg, 91% yield) as white crystals. 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) + .

[0835] Synthesis of compound 132 (4,5-Difluoro-1,2-phenylene)bis(methylene) (E,E)-bis(N'-(4-chlorophenyl)carbamimidothioate) dihydrobromide

[0836] [ka]

[0837] 131c: 1,2-bis(bromomethyl)-4,5-difluorobenzene (117 mg, 0.39 mmol) and 1-(4-chlorophenyl)thiourea (146 mg, 0.78 mmol) were treated in the same manner as in the synthesis of 2. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from EtOH and EtO (1:1) to give the title compound 132 (119 mg, 45% yield) as white crystals.

[0838] 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) +

[0839] 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)

[0840] [ka]

[0841] The reaction was carried out using 2-(3,4-Dichlorophenyl)ethan-1-amine (190 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4-Fluoro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide (2, 217 mg, 0.50 mmol) in the same manner as in the synthesis of 9. The residue was purified by amino silica gel chromatography (n-hexane / EtOAc = 1:1 to 1:3) to give the title compound 133 (82 mg, 23.4% yield) as white crystals.

[0842] 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) +

[0843] Synthesis of compound 134 (4,5-Dichloro-1,2-phenylene)bis(methylene) (E,E)-bis(N'-(3-chloro-4-fluorophenyl)carbamimidothioate) dihydrobromide

[0844] [ka]

[0845] 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) were treated in the same manner as in the synthesis of 2. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from n-hexane and EtO (1:1) to give the title compound 134 (363 mg, 81% yield) as white crystals.

[0846] 1 HNMR (500 MHz, DMSO-d): 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) +

[0847] Synthesis of compound 135 (4,5-Dichloro-1,2-phenylene)bis(methylene) (E,E)-bis(N'-(4-bromophenyl)carbamimidothioate) dihydrobromide

[0848] [ka]

[0849] 36b: 1,2-Bis(bromomethyl)-4,5-dichlorobenzene (200 mg, 0.60 mmol) and 1-(4-Bromophenyl)thiourea (278 mg, 1.20 mmol) were treated in the same manner as in the synthesis of 2. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from n-hexane and EtO (1:3) to give the title compound 135 (460 mg, 96% yield) as white crystals.

[0850] 1 HNMR (500 MHz, DMSO-d): 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) +

[0851] Synthesis of compound 136 (4,5-Dichloro-1,2-phenylene)bis(methylene) (E,E)-bis(N'-(3-bromophenyl)carbamimidothioate) dihydrobromide

[0852] [ka]

[0853] 36b: 1,2-Bis(bromomethyl)-4,5-dichlorobenzene (200 mg, 0.60 mmol) and 1-(3-Bromophenyl)thiourea (278 mg, 1.20 mmol) were treated in the same manner as in the synthesis of 2. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from n-hexane and EtO (1:3) to give the title compound 136 (419 mg, 88% yield) as white crystals.

[0854] 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) +

[0855] Synthesis of compound 137 (4,5-Dichloro-1,2-phenylene)bis(methylene) (E,E)-bis(N'-(4-fluorophenyl)carbamimidothioate) dihydrobromide

[0856] [ka]

[0857] 36b: 1,2-Bis(bromomethyl)-4,5-dichlorobenzene (200 mg, 0.60 mmol) and 1-(4-Fluorophenyl)thiourea (204 mg, 1.20 mmol) were treated in the same manner as in the synthesis of 2. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from n-hexane and EtO (1:3) to give the title compound 137 (364 mg, 90% yield) as white crystals.

[0858] 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) +

[0859] Synthesis of compound 138 (4,5-Dichloro-1,2-phenylene)bis(methylene) (E,E)-bis(N'-(p-tolyl)carbamimidothioate) dihydrobromide

[0860] [ka]

[0861] 36b: 1,2-Bis(bromomethyl)-4,5-dichlorobenzene (290 mg, 0.87 mmol) and 1-(p-Tolyl)thiourea (290 mg, 1.74 mmol) were treated in the same manner as in the synthesis of 2. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from n-hexane and EtO (1:3) to give the title compound 138 (499 mg, 86% yield) as white crystals.

[0862] 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) +

[0863] 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)

[0864] [ka]

[0865] (3-Chloro-4-fluorophenyl)methanamine (160 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4,5-Dichloro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide (36, 242 mg, 0.50 mmol) were reacted in the same manner as in the synthesis of 9. The reaction residue was recrystallized from n-hexane and AcOEt (5:1) to give the title compound 139 (196 mg, 57% yield) as white crystals.

[0866] 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) + .

[0867] 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)

[0868] [ka]

[0869] 2-(4-(Trifluoromethyl)phenyl)ethan-1-amine (189 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4-Fluoro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide (2,217 mg, 0.50 mmol) were reacted in the same manner as in the synthesis of 9. The residue was recrystallized from n-hexane and AcOEt (5:1) to give the title compound 140 (187 mg, 54% yield) as pale yellow crystals.

[0870] 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) +

[0871] Synthesis of Compound 141 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)

[0872] [ka]

[0873] 2-(4-(Trifluoromethyl)phenyl)ethan-1-amine (189 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4-Bromo-1,2-phenylne)bis(methylene) dicarbamimidothioate dihydrobromide (10, 247 mg, 0.50 mmol) were reacted in the same manner as in the synthesis of 9. The residue was recrystallized from n-hexane and AcOEt (5:1) to give the title compound 141 (249 mg, 65% yield) as pale yellow crystals.

[0874] 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) + .

[0875] Synthesis of compound 142 1,2-Bis(((5-(4-(Trifluoromethyl)phenethyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)thio)methyl)benzene

[0876] [ka]

[0877] 2-(4-(Trifluoromethyl)phenyl)ethan-1-amine (189 mg, 1.00 mmol) was gently added to a solution of formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol) in 1,4-dioxane (5.0 mL) and stirred at room temperature for 20 min. 1,2-Phenylenebis(methylene) dicarbamimidothioate dihydrochloride (1,164 mg, 0.500 mmol) was then added and stirred at 80 °C for 12 h. The reaction mixture was cooled to room temperature, toluene (3.0 mL) was added, and the mixture was concentrated under reduced pressure. The residue was recrystallized from EtOH and EtO (2:3) to give the title compound 142 (199 mg, 58% yield) as white crystals.

[0878] 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) + .

[0879] 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)

[0880] [ka]

[0881] 2-(4-(Trifluoromethyl)phenyl)ethan-1-amine (189 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4,5-Dichloro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide (36, 243 mg, 0.50 mmol) were reacted in the same manner as in the synthesis of 9. The residue was recrystallized from 2-propanol to give the title compound 143 (268 mg, 71% yield) as white crystals.

[0882] 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) + .

[0883] 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)

[0884] [ka]

[0885] A reaction was carried out using (3-Chloro-4-fluorophenyl)methanamine (159 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4-Bromo-1,2-phenylne)bis(methylene) dicarbamimidothioate dihydrobromide (10, 247 mg, 0.50 mmol) in the same manner as in the synthesis of 9. The residue was purified by NH-silica gel chromatography using n-hexane / EtOAc (2:1 to 1:3) to give the title compound 144 (109 mg, 31% yield) as a pale yellow oil.

[0886] 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) + .

[0887] 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

[0888] [ka]

[0889] (3-Chloro-4-fluorophenyl)methanamine (319 mg, 2.00 mmol) was gently added to a solution of formaldehyde (301 μL, 37% wt. solution in water, 4.0 mmol) in 1,4-dioxane (5.0 mL) and stirred at room temperature for 10 min. After that, a solution of 1,2-phenylenebis(methylene) dicarbamimidothioate dihydrochloride (1,327 mg, 1.00 mmol) in 1,4-dioxane (2.0 mL) was added and stirred at 80 °C for 12 h. The reaction mixture was cooled to room temperature, toluene (3.0 mL) was added, and the mixture was concentrated under reduced pressure. The residue was recrystallized from EtOH and EtO (2:3) to give the title compound 145 (200 mg, 32% yield) as a pale yellow oil.

[0890] 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) +

[0891] 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)

[0892] [ka]

[0893] The reaction was carried out using (3-Chloro-4-fluorophenyl)methanamine (319 mg, 2.00 mmol), formaldehyde (301 μL, 37% wt. solution in water, 4.00 mmol), and (4-Fluoro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide (2,434 mg, 1.00 mmol) in the same manner as in the synthesis of 9. The residue was recrystallized from 2-propanol and EtO (1:1) to give the title compound 146 (209 mg, 32.7% yield) as white crystals.

[0894] 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) +

[0895] Synthesis of compound 147 6,6'-(((4-Fluoro-1,2-phenylene)bis(methylene))bis(sulfanediyl))bis(3-(4-methoxyphenethyl)-1,2,3,4-tetrahydro-1,3,5-triazine)

[0896] [ka]

[0897] The reaction was carried out using 2-(4-Methoxyphenyl)ethan-1-amine (151 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4-Fluoro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide (2, 217 mg, 0.50 mmol) in the same manner as in the synthesis of 9. The residue was recrystallized from 2-propanol and EtO (1:1) to give the title compound 147 (225 mg, 72% yield) as pale yellow crystals.

[0898] 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) +

[0899] 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)

[0900] [ka]

[0901] The reaction was carried out using 2-(4-Methoxyphenyl)ethan-1-amine (151 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4-Bromo-1,2-phenylne)bis(methylene) dicarbamimidothioate dihydrobromide (10, 248 mg, 0.50 mmol) according to the same procedure as in the synthesis of 9. The residue was recrystallized from 2-propanol and EtO (1:1) to give the title compound 148 (246 mg, 72% yield) as pale yellow crystals.

[0902] 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) +

[0903] Synthesis of compound 149 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)

[0904] [ka]

[0905] 2-(3-(Trifluoromethyl)phenyl)ethan-1-amine (189 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4-Bromo-1,2-phenylne)bis(methylene) dicarbamimidothioate dihydrobromide (10, 248 mg, 0.50 mmol) were reacted using the same procedure as in the synthesis of 9. The reaction residue was purified by NH-silica gel chromatography using n-hexane / EtOAc (3:2 to 0:1) and recrystallized from 2-propanol to give the title compound 149 (268 mg, 71% yield) as pale yellow crystals.

[0906] 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) + .

[0907] 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)

[0908] [ka]

[0909] The reaction was carried out using 2-(3-(Trifluoromethyl)phenyl)ethan-1-amine (189 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4-Fluoro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide (2, 217 mg, 0.50 mmol) according to the same procedure as in the synthesis of 9. The reaction residue was recrystallized from 2-propanol and EtO (1:1) to give the title compound 150 (316 mg, 90% yield) as pale yellow crystals.

[0910] 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) +

[0911] Synthesis of Compound 151 Benzo[b]thiophene-2,3-diylbis(methylene) dicarbamimidothioate dihydrobromide

[0912] [ka]

[0913] 151a: 2,3-Bis(bromomethyl)benzo[b]thiophene (1000 mg, 3.13 mmol) and Thiourea (476 mg, 6.25 mmol) were reacted in the same manner as in the synthesis of 1. The residue was recrystallized from EtOH and EtO (2:3) to give 151 (807 mg, 55% yield) as white crystals.

[0914] 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) + .

[0915] 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)

[0916] [ka]

[0917] 2-(3-(Trifluoromethyl)phenyl)ethan-1-amine (189 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4,5-Dichloro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide (36, 243 mg, 0.50 mmol) were reacted in the same manner as in the synthesis of 9. The reaction residue was recrystallized from 2-propanol to give the title compound 152 (269 mg, 72% yield) as white crystals.

[0918] 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) + .

[0919] Synthesis of compound 153 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)

[0920] [ka]

[0921] 2-(3-Methoxyphenyl)ethan-1-amine (189 mg, 1.00 mmol), formaldehyde (150 μL, 37% wt. solution in water, 2.00 mmol), and (4,5-Dichloro-1,2-phenylene)bis(methylene) dicarbamimidothioate dihydrobromide (36, 243 mg, 0.50 mmol) were reacted in the same manner as in the synthesis of 9. The reaction residue was recrystallized from 2-propanol to give the title compound 153 (222 mg, 66% yield) as white crystals.

[0922] 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) + .

[0923] [Test Example 1] In vitro compound evaluation experiment method The compounds were evaluated in vitro according to the following protocol.

[0924] Enzyme assay protocol using rhIDO (recombinant human IDO). 4 μL of compound solution was added to 176 μL of 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), HO (128 μL), rhIDO (2 μL)). After pipetting and preincubation at 37°C for 10 minutes, 20 μL of 2 mM tryptophan solution was added to bring the total volume to 200 μL. The reaction was then pipetted again and allowed to proceed at 37°C for 120 minutes. The enzyme reaction was terminated by adding 40 μL of 30% [v / v] trichloroacetic acid solution to the reaction solution. The mixture was mixed thoroughly by pipetting and heated at 50°C for 15 minutes to convert N-formylkynurenine to kynurenine. After heating, the mixture was centrifuged (15,000 rpm, 5 minutes, 24°C). 150 μL of the supernatant was transferred to a clear 96-well flat-bottom plate, and the absorbance at 490 nm was measured using a SpectraMax M5SK (background measurement). After the measurement, 150 μL / well of 2% [w / v] p-dimethylbenzaldehyde acetic acid solution was added and incubated for 5 minutes. The absorbance at 490 nm was then measured again. The kynurenine production rate was calculated using 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) / (absorbance at 490 nm in the tryptophan-containing aqueous solution without adding a compound solution - background absorbance)} × 100

[0925] Enzyme assay protocol using rhTDO (recombinant human TDO) 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), HO (128 μL), rhTDO (2 μL)), 4 μL of compound solution was added. After pipetting and preincubation at 37 °C for 10 minutes, 20 μL of 20 mM tryptophan solution was added to bring the total volume to 200 μL. The reaction was then continued at 37 °C for 120 minutes by pipetting. After the reaction, the enzyme reaction was stopped by adding 40 μL of 30% [v / v] trichloroacetic acid solution. The mixture was thoroughly mixed by pipetting and heated at 50 °C for 15 minutes to convert N-formylkynurenine to kynurenine. After heating, the mixture was centrifuged (15,000 rpm, 5 min, 24°C), and 150 μL of the supernatant was transferred to a clear 96-well flat-bottom plate. The absorbance at 490 nm was measured using a SpectraMax M5SK (background measurement). After the measurement, 150 μL / well of 2% [w / v] p-dimethylbenzaldehyde acetic acid solution was added and incubated for 5 minutes, after which the absorbance at 490 nm was measured again. The kynurenine production rate was calculated using the following formula: Kynurenine production rate (%) of each compound when using rhTDO = {(absorbance at 490 nm in a tryptophan-containing aqueous solution containing rhTDO and the compound of the present invention - background absorbance) / (absorbance at 490 nm in the tryptophan-containing aqueous solution without adding a compound solution - background absorbance)} × 100

[0926] IDO Cell-based assay protocol A431 cells (3.0 × 10 cells) suspended in assay medium (D-MEM; Wako 040-30095, 5% FBS, 50 units / mL penicillin, 50 μg / mL streptomycin, 2 mM L-glutamine) were used. 5Cells (100 μL / mL) were seeded into a 96-well flat-bottom plate at 100 μL / well and cultured at 37°C in 5% CO2 for 24 hours. After culture, the medium was removed, and tryptophan-containing medium (assay medium supplemented with L-tryptophan to a concentration of 178 μM) was added at 80 μL / well, followed by the addition of compound solution at 10 μL / well. After preincubation for 1 hour, 100 ng / mL IFN-γ diluted in tryptophan-containing medium was added at 10 μL / well, and the cells were cultured for 24 hours in a total volume of 100 μL / well. After culture, the absorbance at 460 nm was measured (background measurement) using a SpectraMax M5SK (Molecular Devices). After the measurement, 200 μL / well of kynurenine quantification reagent (prepared with 7% [v / v] trichloroacetic acid aqueous solution and 2% [w / v] p-dimethylbenzaldehyde acetic acid solution at a ratio of 2:5 [v / v]) was added and incubated for 5 minutes, after which the absorbance at 460 nm was measured again. The kynurenine production rate was calculated using the following formula: Kynurenine production rate (%) of each compound when using A431 cells = {(absorbance at 460 nm in a tryptophan-containing mediu...

Claims

1. A compound having the formula (I-1) or (I-2) or a pharma- ceutically acceptable salt of said compound. 【Chemistry 1】 [In the formula, ring A represents an aromatic ring, a heterocyclic ring, or a fused ring of two or more rings selected from an aromatic ring and a heterocyclic ring, X is a substituent of a ring atom constituting ring A, m represents an integer from 0 to 6; X is selected from the group consisting of halogen atoms; unsubstituted linear or branched alkyl groups; unsubstituted linear or branched alkoxy groups; halogenated alkyl groups; and cyano groups, and when m is 2 to 6, X may be the same or different; Z is selected from the group consisting of S and Se; s represents an integer from 1 to 8; R 41 , R 42 and R 43 may be the same or different and are selected from the group consisting of a hydrogen atom; an unsubstituted linear or branched alkyl group; an 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, an unsubstituted cycloalkyl group, and an unsubstituted heterocyclic group; However, when m is 0 or when m is 1 to 6 and X is a straight-chain or branched-chain alkyl group which is or is not substituted with a carboxy group, a hydroxy group, or an amino group, R 41 , R 42 , and R 43 are not hydrogen atoms at the same time.]

2. 2. The compound according to claim 1, wherein ring A is selected from the group consisting of a benzene ring, a naphthalene ring, a quinoxaline ring, a thiophene ring, a benzothiophene ring, and a pyridine ring, or a pharma- ceutically acceptable salt thereof.

3. X is a halogen atom; an unsubstituted linear or branched C １ -C ８ Alkyl group; unsubstituted straight or branched chain C １ -C ８ 3. The compound according to claim 1 or claim 2, or a pharma- ceutically acceptable salt thereof, wherein the aryl group is selected from the group consisting of an alkoxy group; a C1-C3 halogenated alkyl group, and a cyano group.

4. 4. The compound according to claim 1, wherein X is a group selected from the group consisting of: Halogen atoms include fluorine, chlorine, bromine, and iodine atoms. Examples of unsubstituted straight-chain or branched-chain alkyl groups include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, an s-butyl group, a t-butyl group, an n-pentyl group, an n-hexyl group, and an n-octyl group. - unsubstituted straight or branched chain alkoxy groups include methoxy, ethoxy, n-propoxy and n-butoxy groups; -Halogenated alkyl groups include 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, and pentafluoroethyl groups. -Cyano group

5. In the compound of the above formula (I-1) or (I-2), wherein ring A is a benzene ring, The following formula (I-4-a) excluding the substituents other than X 【Chemistry 2】 However, 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-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 ３ -Ph=, 4-CF ３ -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-CN-Ph=, 4-CN-Ph=, 5-CN-Ph=, 6-CN-Ph=, (any two of the 3-, 4-, 5- and 6-positions) -F 2 -Ph=, (any two of the 3-, 4-, 5- and 6-positions) -Cl ２ -Ph=(any two of the 3-, 4-, 5- and 6-positions)-Br ２ -Ph=(any two of the 3-, 4-, 5- and 6-positions)-I ２ -Ph=(any two of the 3-, 4-, 5- or 6-positions)-Me ２ -Ph=(any two of the 3-, 4-, 5- and 6-positions) -Et ２ -Ph-, (any two of the 3-, 4-, 5- and 6-positions)-Pr ２ -Ph=(any two of the 3-, 4-, 5- and 6-positions) -Bu ２ -Ph=, (any two positions among 3, 4, 5 and 6 positions)-(CN) 2 -Ph=, (any two positions among 3, 4, 5 and 6 positions)-(MeO) 2 -Ph=, (any two positions among 3, 4, 5 and 6 positions)-(EtO) ２ -Ph=(any two of the 3, 4, 5 and 6 positions)-(CF ３ ) ２ -Ph=(any three positions among 3, 4, 5 and 6 positions)-F ３ -Ph=, (any three positions of 3, 4, 5 and 6) -Cl3-Ph=, (four positions of 3, 4, 5 and 6) -F ４ -Ph=, and (4 positions: 3, 4, 5 and 6) -Cl ４ -Ph=, (wherein "Ph=" is selected from the group consisting of formulas (I-4-a) to (X) ｍ 5. The compound according to claim 1, or a pharma- ceutically acceptable salt of said compound.

6. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 5 or pharma- ceutically acceptable salts thereof, and a pharma- ceutically acceptable carrier.

7. 6. An IDO and / or TDO inhibitor comprising one or more of the compounds according to any one of claims 1 to 5 or pharma- ceutically acceptable salts thereof as active ingredients.

8. A therapeutic agent for a disease or disorder selected from tumors, infectious diseases, neurodegenerative disorders, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health, comprising one or more of the compounds according to any one of claims 1 to 5 or pharma- ceutical acceptable salts thereof as an active ingredient.

9. The therapeutic agent according to claim 8, which is an antitumor agent.

10. The tumor is selected from the group consisting of mesothelioma, hepatobiliary (biliary tract and bile duct), 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, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal region cancer, stomach cancer, duodenal cancer, colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, 10. The antitumor agent according to claim 9, which is selected from adrenal gland 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 or ureter cancer, renal cell carcinoma, renal pelvis carcinoma, central nervous system (CNS) neoplasm, primary CNS lymphoma, non-Hodgkin's lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, adrenal cortical carcinoma, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, and retinoblastoma.

11. (a) one or more of the compounds according to any one of claims 1 to 5 or pharma- ceutically acceptable salts thereof; (b) one or more additional therapeutic agents for treating a disease or disorder selected from tumors, infectious diseases, neurodegenerative disorders, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health; wherein said compound or a pharma- ceutical acceptable salt thereof and said further agent are suitable for simultaneous, sequential or separate administration, for treating a disease or disorder selected from tumors, infectious diseases, neurodegenerative disorders, cataracts, organ transplant rejection, autoimmune diseases, post-operative cognitive impairment, and diseases relating to female reproductive health.

12. (a) one or more of the compounds according to any one of claims 1 to 5 or pharma- ceutically acceptable salts thereof; (b) one or more additional antitumor agents; 12. The pharmaceutical kit according to claim 11 for treating a tumor, comprising: wherein said compound or a pharma- ceutically acceptable salt thereof and said further agent are suitable for simultaneous, sequential or separate administration.

13. The tumor is selected from the group consisting of mesothelioma, hepatobiliary (biliary tract and bile duct), 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, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal region cancer, stomach cancer, duodenal cancer, colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, 13. The kit of claim 12, wherein the cancer is selected from adrenal gland 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 or ureter cancer, renal cell carcinoma, renal pelvis carcinoma, central nervous system (CNS) neoplasm, primary CNS lymphoma, non-Hodgkin's lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, adrenal cortical carcinoma, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma.

14. 10. A compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from a tumor, an infectious disease, a neurodegenerative disorder, cataracts, organ transplant rejection, an autoimmune disease, post-operative cognitive impairment, and a disease related to female reproductive health.

15. 15. A compound as claimed in claim 14 or a pharma- ceutically acceptable salt thereof for use in the treatment of a tumor.

16. The tumor is selected from the group consisting of mesothelioma, hepatobiliary (biliary tract and bile duct), 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, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal region cancer, stomach cancer, duodenal cancer, colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue cancer, 16. The compound of claim 15, or a pharmacologic acceptable salt thereof, selected from the group consisting of sarcoma of the bladder, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the testes, chronic or acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, non-Hodgkin's lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, adrenal cortical carcinoma, gallbladder carcinoma, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, and retinoblastoma.

17. Use of a compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for treating a disease or disorder selected from tumors, infectious diseases, neurodegenerative disorders, cataracts, organ transplant rejection, autoimmune diseases, postoperative cognitive impairment, and diseases related to female reproductive health.

18. 18. The use according to claim 17 for the preparation of a medicament for treating a tumor.

19. The tumor is selected from the group consisting of mesothelioma, hepatobiliary (biliary tract and bile duct), 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, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal region cancer, stomach cancer, duodenal cancer, colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer.

19. The use of claim 18, wherein the cancer is selected from the group consisting of cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the testes, chronic or acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, non-Hodgkin's lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, adrenal cortical carcinoma, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, and retinoblastoma.

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