TW201225956A - Glycine transporter inhibitory substance - Google Patents

Abstract

The purpose of the present invention is to provide a novel compound or a pharmaceutically acceptable salt thereof useful in the prophylaxis or the treatment of diseases/disorders, such as schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific phobias, acute stress disorder, etc.), depression, drug dependence, convulsion, tremor, pain, and sleep disorder, based on the action of inhibiting glycine uptake. Disclosed is a compound represented by formula [I], or a pharmaceutically acceptable salt thereof.

Description

201225956 VI. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to a compound having a hindrance effect of a glycine transporter. [Prior Art] The NMDA receptor, one of the glutamate receptors, is present on the nerve cell membrane of the brain and is involved in various neurophysiological phenomena such as nerve plasticity, cognition, attention, and memory. There is a complex isomer binding site at the NMD A receptor, and the glycine acid binding site is also one of them (the NMDA receptor complex glycine binding site). The NMDA receptor complex glycine-binding site has been reported to be involved in the activation of the NMDA receptor (Non-Patent Document 1). When the activity potential on the presynaptic end of the glycine active nerve arrives, glycine is released from the synaptic cleft. The released glycine is bound to the receptor at the posterior synapse and the like, and is removed by the transporter from the synaptic cleft. Thereby, the glycine transporter may regulate the function of the NMDA receptor by regulating the amount of glycine in the extracellular fluid. The glycine transporter (GlyT) is a protein involved in intracellular resorption of extracellular glycine, and two subtypes of GlyTl and GlyT2 are known to date. GlyT 1 is mainly found in the cerebral cortex, hippocampus and thalamus, and schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder (general anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder). Related diseases such as post-traumatic stress disorder, specific phobia, acute stress disorder, etc., depression, drug dependence, convulsions, hand shocks, pain, and sleep disorders have been reported (Non-Patent Documents 2 to 4). 201225956 A compound having a GlyTl inhibitory action and having a 5-membered ring heteroarylamine structure has been reported in the following documents (Patent Documents 1 to 3, Non-Patent Documents 5 to 6). The compounds described in Patent Documents 1 to 3 and Non-Patent Documents 5 to 6 are compounds characterized in that a nitrogen-containing group is bonded to a position adjacent to a nitrogen atom of the guanamine structure. [PRIOR ART DOCUMENT] [Patent Document 1] [Patent Document 1] W02005/03 72 1 6 [Patent Document 2] W02006/106425 [Patent Document 3] W02008/065500 [Non-Patent Document] [Non-Patent Document 1] Molecular Psychiatry ( 2004) 9, 984-997 [Non-Patent Document 2] Current Medicinal Chemistry, 2006, 13, 1017-1044 [Non-Patent Document 3] Neuropsychopharmacology (2005), 1-23 [Non-Patent Document 4] Expert Opinion on Therapeutic Patents ( 2004) 14 (2) 201-214 [Non-Patent Document 5] Bioorganic & Medicinal Chemistry Letters (2009) 1 9 2974-2976 [Non-Patent Document 6] Bioorganic & Medicinal Chemistry s -6- 201225956

Letters (20 1 0) 20 907-9 1 1 SUMMARY OF THE INVENTION Problems to be Solved by the Invention The present invention provides schizophrenia, Alzheimer's disease, cognitive dysfunction, which is based on the inhibition of glycine absorption, Dementia, anxiety disorder (general anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific phobia, acute stress disorder, etc.), depression, drug dependence, paralysis, hand shock, The prevention or treatment of diseases such as pain or sleep disorders is a useful novel compound or a pharmaceutically acceptable salt thereof. Means for Solving the Invention The inventors of the present invention conducted a detailed review of a compound having a novel skeleton which has an inhibitory effect on GlyTl, and found that among the compounds shown below, the nitrogen atom of the indoleamine structure is interposed at a distance of biphenyl. The compound which is structurally characterized by having a nitrogen-containing group at a specific position is an excellent GlyTl inhibitor, and the present invention has been completed. The invention is described in detail below. The form of the present invention (hereinafter referred to as "the compound of the present invention") is as follows. (1) Formula [I] 201225956 [Chemical 1]

R1 represents a hydrogen atom or a -6-alkyl group, and R2 represents a Ci_6 alkyl group which may be substituted by 1 to 3 substituents selected from the substituent group 1, and may be composed of 1 to 3 substituents selected from a hydroxyl group and a pendant oxy group. a substituted C3_8 cycloalkyl group (when substituted by a pendant oxy group, the carbonyl group formed by the pendant oxy group and the substituted carbon atom may be protected), and a 4 to 6 membered saturated heterocyclic group having an oxygen atom in the ring Or a tetrahydrothiopyranyl group in which a sulfur atom can be oxidized, and the substituent group 1 is a hydroxyl group, a Cu alkoxy group, a halogen atom, a C3-6 cycloalkyl group, and a 4 to 6-membered saturated impurity having an oxygen atom in the ring. The ring group is grouped, Y represents a nitrogen atom or a formula CH, and R3 and R4 represent the same or different hydrogen atom, a halogen atom, an alkyl group, a halogenated Ci-6 alkyl group, a Cu alkoxy group, or a halogenated alkoxy group. ' R5 represents a formula W-R6, and W represents an O-Cu alkyl group, an oxygen atom or a bond which may be substituted by 1 to 3 halogen atoms, which may be substituted by 1 to 3 halogen atoms. And R6 represents a 4- to 8-membered heterocyclic group which may be substituted by 1 to 3 substituents selected from the substituent group 2, and may have at least one nitrogen atom in the ring, and may be selected from a substituent. 1 or 2 substituents for substituted amine or sulfur atom

-8- S 201225956 The thiomorpholinyl group which can be oxidized, the substituent group 2 is composed of a hydroxyl group, a halogen atom, a Ci6 alkyl group, a halogenated Cu alkyl group, a hydroxyl group c, a 6 alkyl group, a C 6 alkoxy group Ci 6 Alkyl, Ci 6 alkoxy, halogenated Cu alkoxy, c2.7 alkoxycarbonyl, C3.6 cycloalkyl Cu alkoxy, C 3 6 cycloalkyl, Cl 6 alkyl alkyl, Cl 6 alkoxy An imine group and a group of the formula CONR7R8 (wherein R7 and R8 represent the same or different hydrogen atoms or C!-6 alkyl group), and the substituent group 3 is composed of a Cm alkyl group, a c3.6 cycloalkyl group, and a hydroxyl group. A compound represented by a group of Cl.6 alkyl groups or a pharmaceutically acceptable salt thereof. (2) A compound described in (1), wherein R1 is a Cm alkyl group, R3 is a halogen atom, and R4 is a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof. (3) R2 is a C 6 alkyl group which may be substituted by a Ci-6 alkoxy group, which may be substituted by a hydroxyl group (: 3.8 cycloalkyl group or a 5- to 6-membered saturated heterocyclic group having an oxygen atom in the ring (1) Or a pharmaceutically acceptable salt of the compound of the formula (2). (4) Y is a compound of any one of (1) to (3) of the formula CH or a pharmaceutically acceptable salt thereof. (5) The compound of any one of (1) to (4), or a pharmaceutically acceptable salt thereof, wherein W is an O-Cm alkyl group. (6) R6 is a) may be selected from a hydroxyl group and a hydroxyl group C. , 6 alkyl, and C -6 alkoxy substituted by 1 to 3 substituents, 4 to -9-201225956 8 membered saturated heterocyclic group having at least 1 nitrogen atom in the ring, or b) A compound according to any one of (1) to (5) which may be an amine group which is substituted with one or two substituents of a hydroxy group, and a pharmaceutically acceptable salt thereof. (7) A medicine containing the compound according to any one of the above (1) to (6) or a pharmaceutically acceptable salt thereof as an active ingredient. (8) Containing the above (1) to (6) Any of the compounds described in 1 or their pharmaceuticals may be licensed A preventive or therapeutic agent for a disease in which schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, drug dependence, convulsion, hand shock, pain, or sleep disorder is an active ingredient EFFECTS OF THE INVENTION The compound of the present invention has a glycine transporter (GlyTl) hindering activity. The form of the invention is "Cx-y (X, and y represents a natural number)" used in the present specification, and the number of carbon atoms is represented by X. The "C^6 alkyl group" used in the present specification means a linear or branched chain having a carbon number of 1 to 6 alkyl groups, and examples thereof include a methyl group, an ethyl group, and a propyl group. , isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl.

S -10- 201225956 The "c3_8 cycloalkyl group" used in the present specification means a carbon number of 3 to 8 cycloalkyl groups, which is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group. , cyclooctyl. The "C3-6 cycloalkyl group" means a carbon number of 3 to 6 cycloalkyl groups, and is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. The "^-alkoxy group" used in the present specification means a straight-chain or branched-chain carbon number of 1 to 6 alkoxy groups, and examples thereof include a methoxy group, an ethoxy group, and a propylene group. Oxyl, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, hexyloxy. The "Cu alkoxyalkyl group" used in the present specification means a Cu alkyl group substituted by a C!-6 alkoxy group, and examples thereof include a methoxymethyl group, a methoxyethyl group, and a methoxy group. , methoxybutyl, methoxypentyl, methoxyhexyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, isopropoxymethyl, isopropoxyethyl , isopropoxypropyl, 1-methoxyethyl, 1-ethoxyethyl, 2-methoxypropyl, 2-ethoxypropyl. The "halogen atom" used in the present specification means a fluorine atom, a chlorine atom, a bromine atom, or a Yao atom. The "halogenated Ci.6 alkyl group" used in the present specification means a straight or branched chain carbon number of 1 to 6 alkyl groups substituted by a halogen atom, and a preferred substitution number of a halogen atom is 1~. Examples of the three examples include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and a trichloromethyl group. The "halogenated C.6 alkoxy group" used in the present specification means a linear or branched carbon number of 1 to 6 alkoxy groups substituted by a halogen atom, and the preferred number of halogen atoms is substituted. Examples thereof include 1 to 3, and examples thereof include fluorine-11 - 201225956 methoxy group, difluoromethoxy group, and trifluoromethoxy group. The "c3.6 cycloalkyl Cu alkoxy group" used in the present specification means a straight or branched chain carbon number of 1 to 6 alkoxy groups substituted by a C3-6 cycloalkyl group, for example, A cyclopropyl methoxy group, a cyclopropyl ethoxy group, and a cyclobutyl methoxy group are mentioned. The "hydroxyl G_6 alkyl group" used in the present specification means a straight or branched chain carbon number of 1 to 6 alkyl groups substituted by a hydroxyl group, and examples thereof include a hydroxymethyl group and a 2-hydroxy group B. Base, hydroxyethyl, 3-hydroxypropyl, 2 hydroxypropyl, 1-hydroxypropyl. The "(^_alkylalkyl) group used in the present specification means a chain or branched chain having a carbon number of 1 to 6 alkyl fluorenyl groups, and examples thereof include a methyl group, an ethyl group, a propyl group, and The "methylene-6 alkoxyimino group" used in the present specification means an imido group substituted with a C!-6 alkoxy group, and examples thereof include a methoxyimino group. Ethoxyimino group and propoxy imine group. The "C2_7 alkoxycarbonyl group" used in the present specification means a group in which a Cu alkoxy group is substituted via a carbonyl group, and examples thereof include a methoxycarbonyl group and a The oxycarbonyl group and the propoxycarbonyl group. The "4 to 6 membered saturated heterocyclic group having an oxygen atom in the ring" used in the present specification is an oxocyclobutane group, a tetrahydrofuranyl group or a tetrahydropyranyl group. The heterocyclic ring of "4 to 8 membered heterocyclic group having at least one nitrogen atom in the ring" used herein is a saturated heterocyclic ring or a partially unsaturated heterocyclic ring, for example, as a saturated heterocyclic group, and examples thereof include a saturated heterocyclic group. Such as azetidinyl, pyrrolidinyl, piperidinyl, azetidinyl, azacyclooctylalkyl, generally in the ring

S -12- 201225956 A radical having one nitrogen atom, such as 8-azabicyclo[3.2.1]octyl, 3-azabicyclo[3.1.0]hexyl, generally having a crosslinked structure, such as piperazinyl A group having two nitrogen atoms in the ring, and a group such as a morpholinyl group having one nitrogen atom and one oxygen atom in the ring. As the partially unsaturated heterocyclic group, for example, a tetrahydroindene ratio steep group can be mentioned. The alkylene group used in the present specification means a linear or branched chain having a carbon number of 1 to 6 alkylene groups, and examples thereof include a methyl group, an ethyl group, a propyl group, and an extended stretching group. Base, butyl, methyl propyl, pentyl, and hexyl. In the present specification, the protected carbonyl group when the "carbonyl group can be protected" is exemplified by a di-Cb6 alkyl acetal or a cyclic acetal, and specific examples thereof include a dimethoxymethyl group and a 1,3-methyl group. Dioxocyclopentane-2-ylidene and the like. In the present specification, the "medicinally acceptable salt" means an acid addition salt which can be allowed to be pharmaceutically acceptable. Examples of the acid to be used include sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, and the like. Organic acids such as inorganic acids or acetic acid, oxalic acid, lactic acid, citric acid, malic acid 'gluconic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and P-toluenesulfonic acid. The method of converting from a free form to the salt can carry out the past method. Among the compounds of the present invention, preferred forms are exemplified below. The compound wherein R1 is a Cl.6 compound is preferable, and a compound which is a methyl group is preferred. R2 is preferably a Cu alkyl group substituted by a Cu alkoxy group, a C3_8 cycloalkyl group which may be substituted by a hydroxyl group, or a compound having a 5- to 6-membered saturated heterocyclic group having an oxygen atom in the ring, and a branched C3_6. Alkyl or a C3-8 cycloalkane-13-201225956 compound is preferred. A compound wherein R3 is a halogen atom is preferred, and a compound having a fluorine atom is preferably a compound wherein βR4 is a hydrogen atom or a halogen atom, and a compound having a hydrogen atom is preferred. A compound wherein W is an O-Ci-6 alkylene group is preferred. R6 is a) which may be substituted by 1 to 3 substituents selected from the group consisting of a hydroxyl group, a hydroxyl group <^6 alkyl group, and a Ci.6 alkoxy group, and has 4 to 8 membered saturated impurities having at least one nitrogen atom in the ring. The ring group, or b) may preferably be a compound selected from the group consisting of a Cu alkyl group and an amine group substituted with one or two substituents of a hydroxyl group (^-6 alkyl group. Y is preferably a compound of the formula CH. R3 to R5 The position of substitution is preferably as shown in the following formula [II].

The compounds of the invention may contain complex asymmetric centers. Therefore, the above compound may also exist as a racemate in the presence of an optically active substance, and a plurality of diastereomers may also be present. All of the foregoing forms are included in the scope of the present invention. Each isomer can be optically selective or diastereoselective, or intermediate or final, by the use of known methods, such as the use of optically active starting materials or intermediates, in the manufacture of intermediates or final products, or in the final Product

The chromatography in the manufacture of S-14-201225956 is obtained by separation or the like. Further, when the compound of the present invention forms a hydrate or a solvate, these are also included in the scope of the present invention. Likewise, pharmaceutically acceptable salts of hydrates or solvates of the compounds of the invention are also included within the scope of the invention. The compounds of the invention may be administered orally or parenterally. The dosage form can be a tablet, a capsule, a granule, a powder, a powder, a lozenge, an ointment, an emulsion, an emulsion, a suspension, a suppository, an injection, etc., all of which can be prepared by a conventional preparation technique (for example, Manufactured by correcting the method prescribed by the Japanese Pharmacopoeia. These dosage forms can be formulated to suit the patient's symptoms, age, and therapeutic goals. These preparations may be added to the composition containing the compound of the present invention by pharmacologically acceptable carriers, i.e., excipients (e.g., crystalline cellulose, starch, lactose, mannitol), binding agents (e.g., hydroxypropyl fibers). Or polyvinylpyrrolidone), a slip agent (such as magnesium stearate, talc), a breaker (such as carboxymethylcellulose calcium), and other pharmacologically acceptable additives. Further, the compound of the present invention may be combined with one or more other therapeutic agents, various antipsychotics, anti-anxiety drugs, for example, with a 5HT3 antagonist, a 5HT2 antagonist, a serotonin promoter, an NK-1 antagonist. Selective serotonin relapse inhibitor (SSRI) 'Serotonin norepinephrine re-take-in inhibitor (SNRI), tricyclic antidepressant, dopamine active antidepressant, H3 antagonist, 5HT1A antagonist 5HT1B antagonist, 5 HT 1 D antagonist, D 1 accelerator, Μ 1 promoter, anticonvulsant, cognitive function enhancing drug, and other psychoactive drugs (psychoactive 201225956 drug ) are used together. Other therapeutic agents which can be used in combination with the compound of the present invention include, for example, ondansetron, granisetron, metoclopramide, sumatriptan, rauwolscine, yohimbine, metoclopramide, (fluoxetine, citalopram 'escitalopram, femoxetine, fluvoxamine, paroxetine, indalpine, Sertraline, zimeldine, venlafaxine, reboxetine, Milnacipran, duloxetine, imipramine, amitripti 1 ine, chlomipramine, nortriptiline, bupropion 'amineptine' divalproex, carbamazepine, diazepam, risperidone, olanzapine, ziprasidone, aripiprazole, quetiapine, perospirone, clozapine, haloperidol, pimozide, Droperidol, chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, acetophenazine, thiothixene, chlorprothixene, lamotrigine, loxapine, molindone, etc. These combinations can be simultaneously (in the same pharmaceutical prescription or in different medical prescriptions), respectively Or a continuous administration. The special advantages associated with the use and the treatment method achieved by the combination of the compounds of the present invention are obtained by administering a smaller amount of each component than the amount of administration generally used. Equivalent or improved effects. Further, the therapeutic effect of positive symptoms and/or negative symptoms and/or cognitive dysfunction of mental disorders may be expected to be further enhanced. With the use and treatment of the combination of the present invention, for certain nerves The treatment of tempering drugs has not reached sufficient

S -16- 201225956 The effect, or the treatment of patients who are patient with this treatment, is also beneficial. The administration amount of the compound of the present invention is ～2 000 mg in the treatment of an adult, and the administration amount may be divided into one or several times a day, and the administration amount may be appropriately increased or decreased depending on the age, body weight and symptoms of the patient.

The compound of the formula [Π can be produced by various synthetic methods. The exemplified method for producing the compound of the present invention is not limited to the "inert solvent" in the general production method, and examples thereof include alcohols such as ethanol, isopropyl alcohol, η-butanol, and ethylene glycol, and diethyl ether. Ethers such as ether, diisopropyl ether, tetrahydrofuran '1,4-dioxane, oxyethane, hydrocarbons such as pentane, hexane, heptane, toluene, benzene, ethyl acetate, ethyl formate Examples include esters, ketones such as acetonide and methyl ketone, halogenated carbon solvents such as chloroform and dichloromethane, guanamines such as dimethyl and fluorene-methylpyrrolidone, and mixed solvents such as acetonitrile and dimethyl sulfoxide. Examples of the "base" include a hydrogenated product of an alkali metal or an alkaline earth metal such as lithium hydride, sodium hydride or calcium hydride; lithium decylamine, lithium diisopropyl decylamine, lithium dicyclohexyl decylamine, and lithium hexa Base group, sodium hexamethyldidecylamino group, potassium hexamethyldidecylamino group or alkaline earth metal decylamine: low-alkane of alkali metal or alkaline earth metal such as sodium methoxide, sodium ethoxide or potassium Oxide; alkyl lithium such as butyl butyl lithium, t-butyl lithium or methyl lithium; alkali metal or alkaline earth metallization such as potassium hydroxide, lithium hydroxide or barium hydroxide: sodium carbonate, potassium carbonate, An alkali metal or alkaline earth such as carbonic acid planing can provide a benefit of 1 day. This is the same as the following method. Methanol, t-butyl 1,2-dimethyl, xylyl ethyl ketone carbamide, water or lithium hydride, sodium decylamine didecylamine, etc. -17- 201225956 carbonate of sodium and oxyhydrogen metal oxides; alkali metal or alkaline earth metal hydrogencarbonate such as sodium hydrogencarbonate or potassium hydrogencarbonate: triethylamine, N-methylmorpholine, hydrazine, Ν-Diisopropylethylamine, hydrazine, 8_diazabicyclo[5·4·〇]undec-7-ene (DBU), 1,5-diazabicyclo[4·3.0] ketone-5 - an amine such as olefin (DBN) or N,N-dimethylaniline; or a basic heterocyclic compound such as pyridine, imidazole or 2,6-dimethylpyridine. These bases are suitably selected in accordance with various reaction conditions known to those skilled in the art. The "acid" is, for example, an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or an organic acid such as hydrazine-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, citric acid or oxalic acid. These acids are suitably selected in accordance with various reaction conditions known to those skilled in the art. Examples of the "Lie's acid" include boron trifluoride, aluminum trichloride, titanium tetrachloride, iron trichloride, zinc chloride, and tin tetrachloride. In the formula, X1 is a halogen atom such as a helium atom, a chlorine atom, a bromine atom or a tear atom, or a sulfonyloxy group, a phenylsulfonyloxy group, a fluorene-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group. The organic sulfonyloxy group, X2 represents a halogen atom or a hydroxyl group, and Μ represents a substituent generally used in the coupling reaction (for example, a group containing an atom such as boron, tin, zinc or ruthenium, preferably a boronic acid group, Ethyl decyl, 4,4,5,5-tetramethyl-[1,3,2]dioxolylborane, tri-n-butylstannyl, etc.), 1163 means that it can be selected from the group of substituents 3 Substituted by 1 to 3 substituents, a 4 to 8 membered saturated heterocyclic group having at least one nitrogen atom in the ring, an amine group or sulfur which may be substituted by one or two substituents selected from the substituent group 4. A thiomorpholinyl group whose atom can be oxidized, a nitrogen atom of these groups bonded to CH2 in the structural formula, \\^ represents a C which can be substituted by 1 to 3 halogen atoms, and an alkyl group, which can be 1 to 3 〇 replaced by a halogen atom _

S -18- 201225956

Cu alkyl group, wb represents a 0-Ci.6 alkyl group or an oxygen atom which may be substituted by 1 to 3 halogen atoms, and other symbols are synonymous with the foregoing. General Manufacturing Method 1 [Chemical 3]

Step 1: Compound (2) can be obtained by subjecting a ketone or an aldehyde of the corresponding compound (1) to a reductive amination reaction in the presence or absence of an acid in an inert solvent using a reducing agent. The so-called reducing agent is, for example, hydrogenated sodium triethoxyborohydride, sodium cyanoborohydride, sodium borohydride or the like. Step 2: Compound (2) is obtained by reacting compound (2) with compound (3) wherein X2 is a halogen atom in the presence or absence of a base in an inert solvent. Alternatively, the compound (4) can be obtained by subjecting the compound (2) and the compound (3) wherein X2 is a hydroxyl group to various amide amination reactions known to those skilled in the art. This so-called guanidation reaction is, for example, in the presence or absence of a base in an inert solvent, using 〇-(7-azabenzotriazol-1-yl)-yi:^,>}',&gt ;^'-Tetramethylurea hexahydrophosphate (11 VIII 1 '11), 〇-(benzotriazol-1-yl)-oxime, hydrazine, Ν', Ν'-tetramethylurea hexahydrophosphate ( -19- 201225956 HBTU ), Yi 1^'-dicyclohexylcarbodiimide (0(:(:) , 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide salt Amidation reaction of a condensing agent such as acid salt (EDC.HC1), diphenylphosphonium azide (DPPA) or carbonyl diimidazole (CDI), ethyl chlorocarbonate, isobutyl chlorocarbonate or trimethyl ethane A hydrazide reaction such as a mercapto chloride or the like via a mixed acid anhydride, etc. When a condensing agent is used for the guanidation reaction, 1 hydroxybenzotriazole (HOBt) or hydroxy amber succinimide (HOSu) may be used as necessary. Additives, etc. Step 3: The compound (4) can be obtained by coupling reaction of the compound (4) with the compound (5). The coupling reaction can be exemplified by the general coupling reaction conditions such as the Suzuki-Miyaura coupling reaction and the Stille coupling reaction. , for example It is carried out according to the method described in Angew. Chem. Int. Ed., 40, 4544, (2001). Step 4: Synthesis of Compound (6) and Compound (7) by the same method as Step 1 of General Manufacturing Method 1. Compound (2) Step 5: A substituent having a generally used substituent is obtained by a coupling reaction (for example, a group containing an atom such as boron, tin, zinc or ruthenium, preferably a boronic acid group or a diethyl boron group) a step of the compound (8) of 4,4,5,5-tetramethyl-[1,3,2]dioxacyclopentanyl, tri-n-butylstannyl, etc.), for example, having a boronic acid group The compound can be produced according to the method described in J. 〇rg. Chem., 60, 7508 (1995). Step 6: Compound (8) and compound (9) can be obtained by the same method as Step 3 of General Manufacturing Method 1. Synthesis of the compound (I) of the present invention. General Manufacturing Method 2

S -20- 201225956 【化4】

Step 7: Compound (11) can be synthesized from Compound (4) and Compound (1) by the same procedure as in Step 3 of General Process 1. Step 8: Compound (12) can be obtained from Compound (1 1 ) by a general oxidation reaction of an alcohol to an aldehyde by using an oxidizing agent. The oxidizing agent used in the present reaction may, for example, be manganese dioxide, 2-iododecylbenzoic acid or 1,1,1-triethoxycarbonyl-1,1-dihydro-1,2彳6112 1〇. (1(^〇1-3(111)-ketone, etc.) Examples of the solvent used in the reaction include alcohols such as methanol, ethanol, and isopropanol; and ethers such as tetrahydrofuran '1,4-dioxane. Hydrocarbons such as toluene and benzene; halogenated hydrocarbons such as chloroform and dichloromethane; N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, etc. Amidoxime; a ketone such as acetone or 2-butanone; dimethyl hydrazine; acetonitrile; water or a mixed solvent. Step 9: by the same method as in the first step 1 of the general production method 1, from the corresponding compound (1) The compound (I) of the present invention can be synthesized from the amine of 2). Step 10: By the same method as in the step 3 of the general production method 1, 、··21 - 201225956 from the compound (8) and the compound (1 3 ) The compound (1 1 ) can be synthesized. Step 1 1 : a step of obtaining a compound ( 14 ) having a leaving group from the compound (1 1 ). As a general method for converting an alcohol into a halide, an Appel reaction or the like can be mentioned. For example, it can be carried out according to the method described in Angew. Chem. Int. Ed., 14, 80 1 (1 975). Further, as the leaving group, the compound having an organic expanded oxy group can be used according to Greene's Protective Groups in Organic Synthesis (Wiley). -Interscience) Manufactured by the method described in. Step 12: The compound (I) of the present invention can be obtained by reacting an amine of the corresponding compound (14) in the presence or absence of a base in a solvent or without a solvent. Additions such as potassium iodide or sodium bromide may be added as necessary. Examples of the base used in the reaction include organic bases such as pyridine, triethylamine and diisopropylethylamine; and potassium third potassium hydride. An inorganic test such as potassium carbonate, carbonic acid, sodium hydrogencarbonate, sodium hydroxide, potassium hydroxide or sodium hydride. Examples of the solvent used in the reaction include alcohols such as methanol, ethanol and isopropanol; and tetrahydrofuran. And ethers such as 1,4-dioxane; hydrocarbons such as toluene and benzene; halogenated hydrocarbons such as chloroform and dichloromethane; N,N-dimethylformamide, hydrazine, hydrazine-dimethylacetamide , phthalamides such as N-methyl-2-pyrrolidone; acetone, 2 a ketone such as methyl ethyl ketone; dimethyl sulfite; acetonitrile; water or a mixed solvent thereof, preferably tetrahydrofuran, hydrazine, hydrazine-dimethylformamide or acetonitrile. The reaction temperature in the reaction is generally 〇° C to 150 ° C, preferably 15. (: ~ l ° ° C, the reaction time is generally 1 to 48 hours, preferably 1 to 12 hours. General manufacturing method 3 -22- 3 201225956

Step 13: Compound (16) can be synthesized from Compound (4) and Compound (15) by the same procedure as in Step 3 of General Method 1. Step 14: The compound (I) of the present invention can be obtained by subjecting a compound having a leaving group of the corresponding compound (16) or a corresponding alcohol to a coupling reaction and condensing. In the case of a compound having a leaving group, the coupling reaction can be carried out by a general method of performing the hydroxy grouping of hydrazine in a solvent or in the absence of a solvent in the presence or absence of a test. Further, an additive such as potassium iodide or sodium bromide may be added as necessary. Examples of the base to be used in the reaction include organic bases such as pyridine, triethylamine, and diisopropylethylamine; potassium third potassium hydride, potassium carbonate, carbonic acid, sodium hydrogencarbonate, and sodium hydroxide. Inorganic bases such as potassium hydroxide and sodium hydride. Examples of the solvent to be used in the reaction include alcohols such as methanol, ethanol, and isopropyl alcohol; ethers such as tetrahydrofuran and 1,4-dioxane; hydrocarbons such as toluene and benzene; chloroform, dichloromethane, and the like. Halogenated hydrocarbons; N,N-dimethylformamide, phthalamides such as N,N-dimethylacetamide, N-methyl-2-pyrrolidone; ketones such as acetone and 2-butanone; Dimethyl hydrazine; acetonitrile; water or a mixture of these solvents, preferably tetrahydrofuran, toluene, N,N-dimethylformamide, 2-butanone or acetonitrile. The reaction temperature in the reaction is usually from 0 ° C to 200 ° C, preferably from 15 t: to 120 ° C, and the reaction time is usually from 1 to 48 hours, preferably from 1 to 12 hours. -23- 201225956 In the case of an alcohol, the coupling reaction may be a light-relay reaction, for example, an organic phosphorus compound such as triphenylphosphine or tributylphosphine, and diethyl azodicarboxylate or azodicarboxylic acid. a combination of a propyl group, an azo compound such as dibutyl azodicarboxylate, or a phosphorous ylide reagent such as cyanide methyltributylthiophosphorus The method carried out in the solvent can be exemplified. Examples of the solvent to be used in the reaction include ethers such as tetrahydrofuran and 1,4-dioxane; hydrocarbons such as toluene and benzene; halogenated hydrocarbons such as chloroform and dichloromethane; and hydrazine-dimethyl-methyl a guanamine such as guanamine, hydrazine, hydrazine-dimethylacetamide or hydrazine-methyl-2·pyrrolidone; a ketone such as acetone or 2-butanone; dimethyl hydrazine; acetonitrile or a mixed solvent thereof; Among them, tetrahydrofuran or toluene is preferred. The reaction temperature in the reaction is usually from 〇 ° C to 120 ° C, preferably from 15 ° C to 80 ° C. The reaction time is usually from 1 to 48 hours, preferably from 1 to 12 hours. [Embodiment] [Embodiment] Next, the present invention will be described in more detail by way of Production Examples, Examples and Test Examples, but the present invention is limited to these Examples. In the following production examples and examples, the microwave reaction apparatus used Biotage's Initiator. For the following production examples and examples, "NH Zheng capsule" used for purification by column chromatography uses Biotage SNAPCartridge KP-NH, "Biocapsule" uses Biotage SNAPCartridge KP-Sil or HP-Sil, "reverse "矽胶矽" uses M0RITEX company purif_

S -24- 201225956 P ack OD S. For the following production examples and examples, the "NH 矽 胶" used in the purification by fractional thin layer chromatography ( PTLC ) was used with Wako Pure Chemicals Co., Ltd. NH2 grit 60F25 4plate wako 20cm x 20cm, and the "sand rubber" used Merck 矽 60F254, 20 cm x 20 cm ° For the following production examples and examples, purification by fractional high-speed liquid chromatography (HPLC) was carried out under the following conditions. However, in the case of a compound having a basic functional group, when trifluoroacetic acid is used in the present operation, a neutralization operation or the like may be carried out in some cases. Instrument: Gilson preparative HPLC system Column: Shiseido Capcelpak Cl 8 MGII 5μιη 2〇χ 1 50mm Solvent: Liquid A; water containing 0.1% trifluoroacetic acid, solution B; acetonitrile gradient containing 0.1% trifluoroacetic acid: 〇 minutes (A liquid / B liquid = 90/10), 22 minutes (A liquid / B liquid = 20/80), 25 minutes (A liquid / B liquid = 10 / 9 0) Flow rate: 20mL / min, detection method : UV 254 nm For the following production examples and examples, the mass spectrum (MS) can be measured by the following conditions.

MS measuring machine: Shimadzu Corporation LCMS-2Q10EV or micromass company Platform LC For the following production examples and examples, high-speed liquid chromatography mass spectrometry (LCMS) was measured by the following conditions.

Measuring instruments: MicroMass Corporation Platform LC and Agilent AgilentllOO -25- 201225956 Column: Waters SunFireC18 2.5pm4.6x50mm Solvent: water containing 0.1% trifluoroacetic acid, solution B; acetonitrile gradient containing 0.1% trifluoroacetic acid: 0 Minutes (eight liquids / 8 liquids = 90/10), 0.5 minutes (eight liquids / B liquid = 90/10), 5.5 minutes (A liquid / B liquid = 2 0/80), 6.0 minutes (A liquid / B liquid =1/99), 6_3 minutes (A liquid / B liquid = 1/99) Flow rate: 1 m L / mi η, detection method: 2 5 4 η Μ Ionization method: Electron Spray Ionization: ESI) The structures of the following production examples and examples were confirmed to use nuclear magnetic resonance spectroscopy (NMR). Nuclear magnetic resonance spectroscopy (NMR) was measured by the following conditions. NMR spectrum: [lH-NMR] 600MHz: JNM-ECA600 (Sakamoto Electronics Co., Ltd.), 500MHz: JNM-ECA500 (Japan Electronics Co., Ltd.), 300MHz: UNITYNOVA300 (Varian), 200MHz: GEMINI2000/200 (Varian) For the following In the production examples and examples, the compound names are named after ACD/Name (ACD/Labs 12.01, Advanced Chemistry Development Inc.). Production Example 1 N-(3-Bromo-4-fluorobenzyl)tetrahydro-2H-pyran-4-amine [Chem. 6]

a solution of 3-bromo-4-fluoro-benzaldehyde (12.0 g) in chloroform (80 mL)

Tetrahydro-2H-pyran-4-amine (7.20 g) was added to S-26-201225956. Hydrogenated sodium triethoxyborohydride (18-9 g) and acetic acid (18.0 g) were added to the reaction mixture for 3 hours. A 6.0 M aqueous sodium hydroxide solution was added to the reaction mixture to separate a chloroform layer. After concentration under reduced pressure, the residue was purified by column chromatography eluting elut elut elut elut elut elut elut elut ). (ESI pos.) m/z: 288 ( [M + H] + ) The following compounds were synthesized in the same manner. N-(3-Bromo-4-fluorobenzyl)-1,4-dioxaspiro[4.5]decane-8-amine (ESI pos.) m/z : 344 ( [M + H]+ ) N-(3-Bromo-4-fluorobenzyl)tetrahydro-2H-thiopyran-4-amine N-(3-bromo-4-fluorobenzyl)propan-2-amine N-( 3- Bromo-4-fluorobenzyl)cyclobutaneamine (ESI pos.) m/z : 25 8 ( [M + H]+ ) Bu (2'-fluoro-5'- {[(oxocyclobutane- 2-ylmethyl)amino]methyl}biphenyl-3-yl)-indole, fluorene-dimethylmethaneamine (3S)-Ν-( { 3'-[(dimethylamino)methyl) ]_6-Fluorobiphenyl-3_yl}methyl)tetrahydrofuran-3-amine (ESI pos.) m/z : 329 ( [M + H]+ ) (3R) -N- ( { 3,-[(2 Methylamino)methyl]_6_fluorobiphenyl-3-yl}methyl)tetrahydrofuran-3-amine (ESI pos.) m/z : 329 ( [M + H]+ ) l-[2 '-Fluoro-5'-( { [ ( 2R) _tetrahydrofuran 2 -ylmethyl]amino} methyl)biphenyl-3-yl]-N,N-dimethylmethaneamine 201225956 (ESI pos. m/z : 343 ( [M + H]+ ) l-[2'-fluoro-5'-( { [ ( 2S)-tetrahydrofuran-2-ylmethyl]amino} methyl)biphenyl-3 -yl]-oxime, Ν-dimethylmethaneamine (ESI pos.) m/z : 3 43 ( [M + H]+ ) N-( {3'-[(dimethylamino)methyl] -6-fluorobiphenyl -3-yl}methyl)cyclopropanamine (ESI pos.) m/z : 2 9 9 ( [M + H] + ) 1-(5'-{[(cyclobutylmethyl)amino]methyl} -2'-Fluorobiphenyl-3-yl)-indole, hydrazine-dimethylmethaneamine (ESI pos.) m/z : 3 27 ( [M + H]+ ) N-( {3'-[( Dimethylamino)methyl]-6-fluorobiphenyl-3-yl}methyl)oxocyclobutane-3-amine (ESI pos.) m/z : 3 15 ( [Μ + Η] + ) Ν-( {3'-[(Dimethylamino)methyl]-6-fluorobiphenyl-3-yl}methyl)-2-methylpropan-2-amine (ESI pos.) m/z : 315 ( [M + H]+ ) N-( {3'-[(Dimethylamino)methyl]-6-fluorobiphenyl-3-yl}methyl)cycloheptylamine (ESI pos. m/z : 3 5 5 ( [M + H]+ ) N-( {3'-[(dimethylamino)methyl]-6-fluorobiphenyl-3-yl}methyl)-3 , 3,3-trifluoropropan-1-amine (ESI pos.) m/z : 355 ( [M + H]+) Ν·{ [2'-( {[T-butyl(dimethyl)) Alkyloxy}methyl)-6-fluorobiphenyl-3-yl]methyl}tetrahydro-2H-pyran-4-amine

S -28- 201225956 (ESI pos.) m/z : 430 ( [M + H]+) {5'-[(cyclopentylamino)methyl]-2'-fluorobiphenyl-3-yl} Methanol (ESI pos.) m/z : 3 00 ([M + H]+ ) {5'-[(cyclobutylamino)methyl]-2'-fluorobiphenyl-3-yl}methanol (ESI Pos.) m/z : 2 8 6 ( [Μ + Η] + ) 1-(2'-fluoro-5'-{[(tetrahydrofuran-2-ylmethyl)amino]methyl}biphenyl-3 -yl)-N,N-dimethylmethaneamine (ESI pos.) m/z ·· 3 4 3 ( [M + H] + ) N-( {3'-[(dimethylamino)) -6-fluorobiphenyl-3-yl}methyl)-2-methylpropan-1-amine (ESI pos.) m/z : 315 ( [M + H]+ ) N-( {3' -[(Dimethylamino)methyl]-6-fluorobiphenyl-3-yl}methyl)-2-methoxyethaneamine (ESI pos.) m/z : 3 17 ( [M + H]+ ) N-( {3'-[(Dimethylamino)methyl]-6-fluorobiphenyl-3-yl}methyl)propan-1-amine (ESI pos.) m/z : 30 1 ( [M + H]+ ) {2'-Fluoro-5'-[(pentan-3-ylamino)methyl]biphenyl-3-yl}methanol (ESI pos.) m/z : 3 02 ( [M + H]+ ) N-( 3-bromo-4-fluorobenzyl)cyclohexaneamine (ESI pos. ) m/z : 286 ( [M + H]+ ) 3-[( {3'-[2-(azetidin-1-yl)ethyl]-6-fluorobiphenyl-3- Methyl)amino]-2,2-dimethylpropan-1-ol (ESI pos.) m/z : 371 ( [M + H]+) 201225956 3- [( {6-Fluoro-3 '-[2-(Pyrrolidin-1-yl)ethyl]biphenyl-3-yl}methyl)amino]-2,2-dimethylpropan-1-ol (ESI pos.) m/z : 3 8 5 ( [M + H]+ ) N-( {6-fluoro·3'-[2-(pyrrolidin-1-yl)ethyl]biphenyl-3-yl}methyl)-3- Methoxypropan-1-amine (ESI pos.) m/z : 371 ( [M + H]+ ) N-( {6-fluoro-3'-[2-(pyrrolidin-1-yl)ethyl Biphenyl-3-yl}methyl)-2-methoxyethaneamine (ESI pos.) m/z : 3 5 7 ( [M + H]+ ) l-[( {6-fluoro-3 '-[2-(Pyrrolidin-1-yl)ethyl]biphenyl-3-yl}methyl)amino]-2-methylpropan-2-ol (ESI pos.) m/z : 371 ( [M + H]+ ) (3R ) -N- ( { 6-fluoro-3'-[2-(pyrrolidin-1-yl)ethyl]biphenyl-3-yl}methyl)tetrahydrofuran-3- Amine (ESI pos.) m/z : 3 69 ( [M + H]+ ) 4- [( {6-fluoro-3'-[2-(pyrrolidin-1-yl)ethyl]biphenyl-3 -yl}methyl)amino]-2-methylbutan-2-ol (ESI pos.) m/z : 3 8 5 ( [Μ + Η] + ) (2R) -1-[( {6 -Fluoro-3'-[2-(pyrrolidin-1-yl)ethyl]biphenyl-3-yl}methyl)amino]propan-2-ol (ES I pos.) m/z : 357 ( [M + H]+) b {6-fluoro-3'-[2-(pyrrolidin-1-yl)ethyl]biphenyl-3-yl}-N- (tetrahydro-2H-pyran-4-ylmethyl)methaneamine (ESI pos.) m/z : 3 97 ( [M + H]+ ) s -30- 201225956 (2S ) -2-[ ( { 6·Fluoric 3'_[2·(pyrrolidin-1-yl)ethyl]biphenyl-3-yl}methyl)amino]propan-1-ol (ESI pos.) m/z : 3 5 7 ( [M + H]+ ) N-( {6-fluoro-3'-[2-(pyrrolidin-1-yl)ethyl]biphenyl-3-yl}methyl)-2-methoxy -2-methylpropan-1-amine (ESI pos.) m/z : 3 85 ( [M + H]+ ) 3-[( {6-fluoro-3'-[2-(pyrrolidin-1- Ethyl]biphenyl-3-yl}methyl)amino]-2,2·dimethylpropan-1-ol (ESI pos.) m/z : 3 85 ( [M + H]+ ) 2-[({6-Fluoro-3'-[2-(pyrrolidin-1-yl)ethyl]biphenyl-3-yl}methyl)amino]ethanol] Production Example 2 N-(3·Bromo- 4-fluorobenzyl)-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1 Η-imidazole-4-amine formazan [Chemical 7]

Ν-(3-Bromo-4-fluorobenzyl)tetrahydro-2-indole-pyran-4-amine hydrochloride (10 〇 7 g), 1-methyl-1H-imidazole-4-carboxylic acid ( 4_20g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.50g), 1-hydroxybenzotriazole monohydrate (5.10g), triethyl A mixture of amine (12.5 g) and hydrazine, hydrazine-dimethylformamide (25 OmL) was stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the residue and stirred at room temperature for 30 minutes. Extraction was carried out with ethyl acetate. The organic layer was washed with water -31 - 201225956, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (EtOAc / EtOAc(EtOAc) (ESI pos.) m/z : 396 ( [M + H]+ ) The following compound was synthesized: N-( 3-bromo-4-fluorobenzyl)-N-(1,4-dioxaspiro) [4.5] 癸- 8-yl)-bumethyl-1H-imidazol-4-aminecarboxamide (ESI pos.) m/z : 452 ( [M + H]+ ) N- ( 3-bromo-4-fluorobenzene Methyl)-1-methyl-N-(tetrahydro-2H-thiopyran-4-yl)-1H-imidazol-4-aminecarboxamide N-(3-bromo-4-fluorobenzyl)- 1-methyl-N-(propan-2-yl)-1H-imidazol-4-aminemethyl hydrazine^[-(3-bromo-4-fluorobenzyl)-:^-cyclobutyl-1-methyl --111-imidazole-4-aminocarboxamidine (ESI pos.) m/z · 366 ( [M + H]+) N-{ [2,-( {[T-butyl(dimethyl)decyl) ]oxy}methyl)-6-fluorobiphenyl-3-yl]methyl}-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-amine Formazan (ESI pos.) m/z : 538 ( [M + H]+) N-cyclopentyl-N- { [6-fluoro-3'-(hydroxymethyl)biphenyl-3-yl]- -1-methyl-1H-imidazol-4-aminecarboxamidine (ESI pos.) m/z : 408 ( [M + H]+) N-cyclobutyl·Ν- { [6-fluoro-3 '-(Hydroxymethyl)biphenyl-3-yl]methyl}-1-methyl-1Η-imidazole-4-amine formazan

-32- 201225956 (ESI pos. ) m/z : 3 94 ( [M + HJ+ ) N- { [6-fluoro-3'-(hydroxymethyl)biphenyl-3-yl]methyl} -1- Methyl-N-(pentan-3-yl)-1H-imidazol-4-aminecarboxamidine (ESI pos.) m/z : 4 10 ( [M + H]+ ) N- (3-bromo-4 -fluorobenzyl)-N-cyclohexyl-1-methyl-1H-imidazole- 4-aminecarboxamidine (ESI pos.) m/z : 3 94 ( [M + H]+ ) 1 (3-bromo 4-fluorobenzyl)-1(tetrahydro-211-pyran-4-yl)-1H-1,2,4-triazolyl-3-aminecarboxamide N- (3-bromo-4- Fluorobenzyl)-N-cyclohexyl-1H-1,2,4-triazolyl-3-amine, 1^-(3-bromo-4-fluorobenzyl)-1 (propane-2-) Base)-111-1,2,4-triazolyl-3-aminecarboxamidine. Production Example 3 N-{[6-Fluoro-3'-(2-hydroxyethyl)biphenyl-3-yl]- -1_Methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-amine formazan [Chemical 8]

N-(3-Bromo-4-fluorobenzyl)-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-aminecarboxamide (5.00 g) , 2-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaboran-2-yl)phenyl)ethanol (3·45 g), hydrazine (triphenylphosphine) A mixture of palladium (1.45 g), potassium carbonate (3.50 g), N,N-dimethyl 201225956 carbamide (20 ml) and ethanol (10 ml) was stirred at 100 ° C for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The residue was purified by column chromatography (yield: EtOAc/MeOH:MeOH:MeOH: (ESI pos.) m/z: 43 8 ([M + H] + ) The following compound was synthesized in the same manner. > 1-(1,4-Dioxaspiro[4.5]dec-8-yl)-:^-{[6-fluoro-3'-(2-hydroxyethyl)biphenyl-3-yl]- -1-methyl-1H-imidazol-4-aminecarboxamide (ESI pos.) m/z : 494 ( [M + H]+ ) N-{ [6-fluoro-3,- (2-hydroxyl Ethyl)biphenyl-3-yl]methylindole-p-methyl-N.(tetrahydro-2H-thiopyran-4-yl)-1H-imidazol-4-aminecarboxamide (ESI pos.) m/z : 454 ( [M + H]+ ) N-[ ( 4,6-Difluoro-3'-hydroxybiphenyl-3-yl)methyl]-1-methyl-N-(tetrahydro-2H- Pyran-4-yl)-1H-imidazol-4-aminecarboxamidine (ESI pos.) m/z : 428 ( [M + H]+) N-[ ( 4,6-difluoro-3,- Hydroxybiphenyl-3-yl)methyl]-bumethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-aminecarboxamide (ESI pos.) m/z : 456 ( [M + H]+) N- { [6-Gas-3'-(2-propionyl)biphenyl-3-yl]methyl}methyl-N-(propan-2-yl)-1H -Imidazole-4-aminecarboxamidine (ESI pos.) m/z : 396 ( [M + H]+) N- { [6-fluoro-4,-(3-hydroxypropyl)biphenyl-3-yl Methyl hydrazine - benzyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-aminecarboxamidine (ESI pos.) m/z : 452 ( [M + H]+ ) S -34- 201225956 N-cyclobutyl-N- { [6-fluoro-3'-(3-hydroxypropyl)biphenyl -3-yl]methyl}-1-methyl-1H-imidazol-4-aminecarboxamide (ESI pos.) m/z : 422 ( [M + H]+ ) N- {[6-fluoro-3 '-(3-Hydroxypropyl)biphenyl-3-yl]methyl}-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-aminecarboxamidine (ESI pos. ) m/z : 45 2 ( [M + H]+ ) N-[ (6-Silent-4'-trans-biphenyl-3-yl)methyl]-1-methyl-N- (propan-2-yl)-1H-imidazol-4-aminecarboxamidine (ESI pos.) m/z : 3 6 8 ( [M + H]+ ) N-[ (6-gas-4'-transcarbyl) Benzene-3-yl)methyl]-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-aminecarboxamide (ESI pos.) m/z : 410( [M + H]+ ) N- { [6-fluoro-4'-(2-hydroxyethyl)biphenyl-3-yl]methyl} -1-methyl-N-(propane-2- -> -1H-imidazol-4-aminecarboxamidine (ESI pos.) m/z : 3 96 ( [M + H]+ ) N-[(6-fluoro-3'-hydroxybiphenyl-3-yl) )methyl]-1-methyl-N-(propan-2-yl)-1H-imidazol-4-aminecarboxamidine (ESI pos.) m/z : 3 6 8 ( [M + H]+ ) N - {[6-Fluoro-3'-(hydroxymethyl)biphenyl-3-yl]methyl}-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazole 4-aminoformamidine (ESI pos.) m/z : 424 ( [M + H]+ ) N-{ [6-fluoro-4'-(2-hydroxyethyl)biphenyl -3-yl]methyl}-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-aminecarboxamidine (ESI pos.) m/z : 43 8 ( [M + H]+ ) 201225956 N-[(6-Fluoro-3'-hydroxybiphenyl-3-yl)methyl]-1-methyl-N-(tetrahydro-2H-pyran-4- -1H-imidazol-4-aminecarboxamidine (ESI pos.) m/z : 4 10( [M + H]+ ) N-{ [4',6-difluoro-3'-(hydroxymethyl Biphenyl-3-yl]methyl}-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-aminecarboxamide (ESI pos.) m/z : 442 ( [M + H]+ ) N-cyclohexyl-N- { [6-fluoro-3'-(hydroxymethyl)biphenyl-3-yl]methyl}-1-methyl-1H-imidazole 4-Aminoguanidine (ESI pos.) m/z : 422 ( [M + H]+) N-{[6-fluoro-3'-(hydroxymethyl)biphenyl-3-yl]methyl} -1-methyl-N-(propan-2-yl)-1H-imidazol-4-aminecarboxamidine (ESI pos.) m/z : 3 82 ( [M + H]+ ) N-[(6- Fluoro-3'-hydroxybiphenyl-3-yl)methyl]-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-1,2,4-triazolyl- 3-Aminoguanidine (ESI pos.) m/z : 411 ( [M + Η] + ) 5'-( {cyclohexyl[(1-methyl-1H-1,2,4-triazolyl-3) -yl)carbonyl]amino}methyl)_2'-fluorobiphenyl-3-carboxylic acid methyl (ESI pos.) m/z : 45 1 ( [M + H]+ ) 2'-fluoro-5'-({[(imethyl-1H-1,2,4-triazolyl-3-yl)carbonyl](propan-2-yl)amino}methyl) Biphenyl-3-carboxylic acid methyl (ESI pos.) m/z : 4 11 ( [M + H]+ ) 2'-fluoro-5'- ( { [ ( 1-methyl-1H-1, 2 ,4-triazolyl-3-yl)carbonyl](tetrahydro-2H-pyran-4-yl)amino.}methyl)biphenyl-4-carboxylic acid methyl (ESI pos.) m/z : 453 ( [M + H]+) 201225956 2'-Fluoro-5'-( {[(1-methyl-1H-1,2,4-triazolyl-3-yl)carbonyl](tetrahydro- 2H-pyran-4-yl)amino}methyl)biphenyl-3-carboxylic acid methyl (ESI pos.) m/z · 453 ([M + H]+) Production Example 4 Methanesulfonic acid 2- [2'-Fluoro-5'-( { [(1-methyl-1H-imidazol-4-yl)carbonyl](tetrahydro-2H-pyran-4-yl)amino}methyl)biphenyl- 3-yl] ethyl [chemical 9]

N-{[6-Fluoro-3'-(2-hydroxyethyl)biphenyl-3-yl]methyl}-1-propenyl-N-(tetrahydro-2H-pyran-4-yl) Methylsulfonyl chloride (0.74 ml) and triethylamine (1.14 ml) were added to a solution of -1H-imidazol-4-aminecarboxamide (3.0 g) in chloroform (30 ml), and stirred at room temperature for 10 min. Further, methanesulfonyl chloride (〇.74 ml) and triethylamine (1.14 ml) were added and stirred at room temperature for 1 minute. Water was added to the reaction mixture, and the mixture was extracted with chloroform and concentrated under reduced pressure. The residue was purified by column chromatography (yield: chloroform/methanol = 99: 1 to 90: 10) to give the title compound (3.8 g). (ESI pos.) m/z : 516 ( [M + H]+) The same compound was synthesized: 2-[5'-( {1,4-Dioxaspiro[4.5]癸-8- [[1-Methyl-1H-imidazol-4-yl)carbonyl]amino}methyl)-2'-fluorobiphenyl-3-yl]ethyl-37- 201225956 (ESI pos.) m/z : 5 7 2 ( [M + H]+ ) 2-[5'-( { (1,1-dihydrotetrahydro-2H-thiopyran-4-yl)[(1-methyl-) 1H-imidazol-4-yl)carbonyl]amino}methyl)-2'·fluorobiphenyl-3-yl]ethyl (ESI pos.) m/z : 564 ( [M + H]+) methyl sulfonate 2-{[2',4-Difluoro-5'-( { [(1-methyl-1H-imidazol-4-yl)carbonyl](tetrahydro-2H-pyran-4-yl)amine丨Methyl)biphenyl-3-yl]oxy}ethyl (ESI pos.) m/z : 5 5 0 ( [M + H]+ ) 2-[2',4-difluoro-methanesulfonate 5'-( {[(1-Methyl-1H-imidazol-4-yl)carbonyl](tetrahydro-2H-pyran-4-yl)amino}methyl)biphenyl-3-yl]ethyl (ESI pos.) m/z : 534 ( [M + H]+) 2-[2'-fluoro-5'-({[(1-methyl-1H-imidazol-4-yl)carbonyl) ](propan-2-yl)amino}methyl)biphenyl-3-yl]ethyl methanesulfonic acid 3-[2'-fluoro-5'-({[(1-methyl-111-imidazole-) 4-yl)carbonyl](tetrahydro-2Η-pyran-4 -yl)amino}methyl)biphenyl-4-yl]propyl (ESI pos.) m/z : 530 ( [M + H]+) 3-[5'-({cyclobutyl) [(1-Methyl-1H-imidazol-4-yl)carbonyl]amino}methyl)-2'-fluorobiphenyl-3-yl]propyl (ESI pos.) m/z : 500 ( [M + H]+) 3-[2'-fluoro-5'-({[(1-methyl-1H-imidazol-4-yl)carbonyl)](tetrahydro-2H-pyran-4-yl) Amino}methyl)biphenyl-3-yl]propyl-38- 201225956 (ESI pos.) m/z : 53 0 ( [M + H]+) 2-[2,-fluoro-methanesulfonate 5'-( { [(1-Methyl-1H-imidazol-4-yl)carbonyl](propan-2-yl)amino}methyl)biphenyl-4-yl]ethyl (ESI pos.) m /z : 474 ( [M + H]+ ) 2-[2'-Fluoro-5'-( { [ ( 1-methyl-1H-imidazol-4-yl)carbonyl](tetrahydro-2H) -pyran-4-yl)amino}methyl)biphenyl-4-yl]ethyl (ESI pos.) m/z : 5 16 ( [M + H]+ ) methanesulfonic acid 3- { [2 ,-fluoro-5'-( { [(1-methyl-1H-imidazol-4-yl)carbonyl](tetrahydro-2H-pyran-4-yl)amino}methyl)biphenyl-3· EMI]oxy}propyl (ESI pos.) m/z : 546 ( [M + H]+ ) methanesulfonic acid [2,-fluoro-5'- ( {[ ( 1-methyl-1H-imidazole) 4-yl)carbonyl](tetrahydro-2H-pyran-4-yl)amine (Methyl)biphenyl-3-yl]methyl (ESI pos.) m/z : 5 02 ( [M + H]+ ) Production Example 5 N-( 1,1-dihydrotetrahydro-2H- Thiopyran-4-yl)-N_ {[6-fluoro-3'-(2-hydroxyethyl)biphenyl-3-yl]methyl} -1-methyl_ιΗ_imidazole-4-amine A醯【化1 0】

N-{[6-Fluoro-3'-(2-hydroxyethyl)biphenyl-3-yl]methyl}methyl-N-(tetrahydro-2H-thiopyran-4-yl)-1H - Imidazole-4-amine ugly (-3⁄4. -39- 201225956 340 mg), a mixture of 3-chloroperbenzoic acid (400 ng) and ethyl acetate (4.0 ml) was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was extracted with chloroform. The residue was purified by column chromatography (yield: chloroform/methanol = <RTI ID=0.0>> (ESI pos.) m/z : 486 ( [M + H]+ ) Production Example 6 N-( { 3'-[2-(Benzyloxy)ethoxy]-4',6-difluoro Phen-3-yl}methyl)-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-aminecaramidine [Chemical 1 1]

N-[(4',6-Difluoro-3'-hydroxybiphenyl-3-yl)methyl]-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H a mixture of imidazole-4-amineformamidine (2.05 g), 2-(benzyloxy)ethanol (2.18 g), cyanide methyltri-n-butylthiocyclophosphorane (2.79 g) and tetrahydrofuran (25 ml) Stirring was carried out at 70 ° C for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform and concentrated under reduced pressure. The obtained residue was purified by column chromatography (reverse phase hydrazine column water/acetonitrile = 90:10 to 1 0:90), followed by column chromatography (NH 矽 匣, hexane / Ethyl acetate = 80: 20~0: 1 〇〇) Purified to give the title compound (2.25 g). (ESI pos.) m/z : 562 ( [M + H] +) s -40 - 201225956 The following compounds were synthesized in the same manner. N-( {3'-[3-(Benzyloxy)propoxy]-6-fluorobiphenyl-3-yl}methyl)-1-methyl-N-(tetrahydro-2H-pyran -4-yl)-1H-imidazol-4-aminecarboxamidine (ESI pos.) m/z : 55 8 ( [M + H]+ ) N-( {3'-[2-(benzyloxy)) Ethoxy]-6-fluorobiphenyl-3-yl}methyl)-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-aminecarboxamide ESI pos.) m/z : 544 ( [M + H] + ) Production Example 7 1^-{[4',6-Difluoro-3'-(2-hydroxyethoxy)biphenyl-3-yl ]Methyl}-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-aminecarboxamidine. [1 2]

N-( {3'-[2-(Benzyloxy)ethoxy]-4',6-difluorobiphenyl-3-yl}methyl)-1-methyl-N-(tetraamine -2H - indole-4 -yl)-1H - miso_ 4-Aminoguanidine (2.25g) in methanol (50ml) was added 10% palladium on carbon (2.50g) in a hydrogen atmosphere at room temperature Stir for 2 days. After filtration of the diatomaceous stone, the residue was concentrated under reduced pressure to give the title compound (1.77 g). (ESI pos.) m/z : 472 ( [M + H] + ) The following compounds were synthesized in the same manner. -41 - 201225956 N- { [6-Fluoro-3,-(3-hydroxypropoxy)biphenyl-3-yl]methyl} _1 methyl-N-(tetrahydro-2H-pyran-4- -1H-imidazol-4-aminecarboxamidine (ESI pos.) m/z : 490 ( [M + Na]+ ) N- { [6-fluoro-3,-(2-hydroxyethoxy) Benz-3-yl]methyl丨_1 methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-aminecarboxamidine (ESI pos.) m/z : 476 ( [M + Na]+ ) Production Example 8 N- { [6-Fluoro-3,-(2-o-oxyethyl)biphenyl-3-yl]methyl}-1-methyl-N-(propane -2-yl)-1H-imidazole-4-amine formazan [Chemical 1 3]

N-{[6-Fluoro-3,-(2-hydroxyethyl)biphenyl-3-yl]methyl}methyl-N-(propan-2-yl)-1H-imidazol-4-amine A A mixture of hydrazine (60 〇 mg), iodonyl benzoic acid (510 mg) and dimethyl amide (15 ml) was stirred at room temperature for 1 day. Water was added to the reaction mixture, and the diatomite was filtered, and extracted with ethyl acetate. The title compound (299 mg) was obtained after concentration under reduced pressure. (ESI pos.) m/z : 476 ([M + Na]+) The following compounds were synthesized in the same manner. N-[(6-Fluoro-3'-carbamimid-3-yl)methylmethyl_ν·(tetrahydro-2Η-pyran-4-yl)-1Η-imidazole-4-amine A ESI (ESI pos.) m/z : 476 ( [Μ+ Na] + ) N- { [6-fluoro-3,-(2-sideoxyethoxy)biphenyl-3 ·yl]methyl} -42- 201225956 bmethyl_Ν·(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-aminecarboxamidine (ESI pos.) m/z : 452 ( [M + H]+ ) 1^-[(4',6-Difluoro-3'-methionylbiphenyl-3-yl)methyl]-1-methyl-N-(tetrahydro-2H-pyran-4-yl) -1H-imidazol-4-aminecarboxamidine (ESI pos.) m/z : 440 ( [M + H]+ ) N-[ (6-fluoro-2'-formamylbiphenyl-3-yl) Methyl]-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-aminecarboxamidine (ESI pos.) m/z : 422 ( [M + H] + ) N-cyclopentyl-N-[(6-fluoro-3'-formamidobiphenyl-3-yl)methyl]-1-methyl-1H-imidazol-4-amine oxime (ESI pos . ) m/z : 406 ( [M + H]+ ) N-cyclobutyl-N-[(6-fluoro-3'-formamidin-3-yl)methyl]-1-methyl -1H-imidazol-4-aminecarboxamidine (ESI pos.) m/z : 392 ( [M + H]+ ) N-[ (6-fluoro-3'-methanylbiphenyl-3-yl) A -1-methyl-N-(pentan-3-yl)-1H-imidazol-4-aminecarboxamidine (ESI pos.) m/z : 40 8 ( [M + H]+ ) N-cyclohexyl-N-[(6-fluoro-3'-formylbiphenyl-3-yl)methyl]-1-methyl-1H-imidazole- 4-Aminoformamidine (ESI pos.) m/z : 420 ( [M + H]+ ) N-[(6-Fluoro-3'-carboxamido-3-yl)methyl]-1- Methyl-N-(propan-2-yl)-1H-imidazol-4-amine formazan pos.) m/z : 3 8 0 ( [M + H]+)

-43-

201225956 Production Example 9 N-[4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzyl]--methyl-N- (propane 2 -yl)-1H-imidazole-4-amine formazan [Chemical 1 4]

N-(3-Bromo-4-fluorobenzyl)-1-methyl-N-(propan-2-yl)-1H-imidazol-4-aminecarboxamide (300 mg), 4,4,4' , 4',5,5,5',5'-octamethyl-2,2'-linked-1,3,2-dioxaborane (258mg), 1,1'-bis(diphenylphosphine) A mixture of ferrocene-palladium dichloride (69 mg), potassium acetate (249 mg) and dimethyl sulfoxide (4.5 ml) was stirred at 1 ° C for 6 hours. After the diatomaceous earth was filtered, it was washed with water and dried over anhydrous sodium sulfate. After concentrating under reduced pressure, the residue was purified by column chromatography eluting elut elut elut elut elut elut (ESI pos.) m/z : 402 ( [M + H]+ ) Production Example 10 4-methylbenzenesulfonic acid 2,2-difluoro-2- { [2,-fluoro-5,- ( { [ (1-methyl-1H-imidazolyl-4-yl)carbonyl](propan-2-yl)amino}methyl)biphenyl-4-yl]oxy}ethyl [Chemical 1 5]

Ν-[(6-Fluoro-4'-hydroxybiphenyl-3-yl)methyl]_1-methyl-indole-(propan-2-yl)-1Η-imidazol-4-aminecarboxamide (400 mg) 4_Methylbenzenesulfonic acid-44 - 201225956 A mixture of 2,2-difluoroethylene (31〇1^), potassium hydroxide (74 mg) and acetonitrile (4.0 ml) was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The residue was purified by column chromatography (plugree, chloroform/methanol = 100: 0 to 95: 5) to give the title compound (5 30 m). (ESI pos.) m/z : 602 ( [M + H] + ) The following compounds were synthesized in the same manner. 2-methylbenzenesulfonic acid 2,2-difluoro-2-{[2'-fluoro-5'-({[(1-methyl-1H-imidazol-4-yl)carbonyl)]]propane-2- Aminomethyl}methyl)biphenyl-3-yloxy}ethyl (ESI pos.) m/z : 602 ( [M + H]+) « Manufacturing Example 11 Trifluoromethanesulfonic acid 2'- Fluor-5'-( { [(1-methyl-1H-imidazol-4-yl)carbonyl](tetrahydro-2H-pyran-4-yl)amino}methyl)biphenyl-3-yl [ 1 6]

1^-[(6-Fluoro1-3'-carbylbiphenyl-3-yl)methyl]-1-methyl->^-(tetrahydro-2H-pyran-4-yl)- To a solution of 1H-imidazol-4-aminecarboxamide (296 mg) in chloroform (5.0 ml), pyridine (1 14 mg) was added, and anhydrous trifluoromethanesulfonate (244 mg) was added dropwise to an ice bath, and stirred at room temperature for 1 hour. . 10% hydrochloric acid and diethyl ether were added to the reaction mixture, and the organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate and brine. After concentrating under reduced pressure, the residue was purified by EtOAc EtOAc (EtOAc: EtOAc (EtOAc) (ESI p〇s.) m/z : 542 ( [M + H] + ) Manufactured Example 12 N- { [6-fluoro-2,-(hydroxymethyl)biphenyl-3-yl]methyl} 1-methyl-N-(tetrahydro-2H.pyran-4-yl)-1H-imidazol-4-aminecaramidine [Chemical 1 7]

Ν-{[2'-( {[Tertiarybutyl(dimethyl)indenyl)oxy}methyl)-6-fluorobiphenyl-3-yl]methyl}-1-methyl-oxime To a solution of (tetrahydro-2Η-pyran-4-yl)-1Η-imidazol-4-aminecarboxamide (175 mg) in dioxane (3.0 ml), Stirring was carried out for 2 hours at room temperature. An aqueous sodium hydroxide solution was added to the reaction mixture, followed by extraction with chloroform. After concentrating under reduced pressure, the residue was purified by EtOAc EtOAc EtOAc EtOAc /z : 424 ( [M + H]+ ) Production Example 13 N-(3-bromo-4-fluorobenzyl)-1, methyl_N_(tetrahydro-2H-pyran-4-yl)- 1H-1,2,4-triazolyl-3.aminecaramidine-46- 201225956 [Chem. 1 8]

N-(3-bromo-4-fluorophenylmethyl)-N-(tetrahydro-2H-D-pyranyl-4-yl)-1H-1,2,4-'triazolyl-3-aminecarboxamidine (6.76 g) of a solution of N,N-dimethylformamide (20 ml) was added 55% sodium hydride (530 mg) and stirred at room temperature for 10 min. Methyl iodide (2 - 25 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The residue was purified by column chromatography (hexanes, hexanes / ethyl acetate = 50: 50 to 0: 100 to chloroform / methanol = 100: 〇~ 95: 5) to give the title compound (2. 〇〇g ). (ESI pos.) m/z: 3 97 ([M + H] + ) The following compounds were synthesized in the same manner. N-(3-Bromo-4-fluorobenzyl)-N-cyclohexyl-1-methyl-1H-1,2,4-triazolyl-3-aminecarboxamide (ESI pos.) m/z : 395 ( [M + H]+ ) N-(3-Bromo-4-fluorobenzyl)-1-methyl-N-(propan-2-yl)-1Η· 1,2,4-triazole Benzene-3-amine formazan (ESI pos.) m/z : 3 5 5 ([M + H]+ ) Production Example 14 1\1-{[6-Fluoro-3,-(hydroxymethyl)biphenyl -3-yl]methyl} -1_methyl_N-(propan-2-yl)_ih-1,2,4-triazolyl-3-aminecarbamidine-47- 201225956 【化1 9】

5'-({Cyclohexyl[(1-methyl-1H-1,2,4-triazolyl-3-yl)carbonyl]amino}methyl)-2'-fluorobiphenyl-3-carboxylate A mixture of acid methyl (4 08 mg), sodium borohydride (1.3 g) and ethanol (18 ml) was stirred at room temperature for 2 days under reflux. After adding acetone and water to the reaction mixture and extracting with chloroform, the mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (yield: chloroform/methanol = MeOH: EtOAc: EtOAc: (ESI pos.) m/z : 423 ( [M + H] + ) The following compounds were synthesized in the same manner. N- { [6-fluoro-3'-(hydroxymethyl)biphenyl-3-yl]methyl}-1-methyl-N-(propan-2-yl)-1H-1,2,4- Triazolyl-3-aminecarboxamidine (ESI pos.) m/z : 3 8 3 ( [M + H]+) N-{[6-fluoro-4'-(hydroxymethyl)biphenyl-3- Methyl}-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-1,2,4-triazolyl-3-aminecarboxamide (ESI pos.) m /z : 425 ( [M + H]+) N-{[6-fluoro-3'-(hydroxymethyl)biphenyl-3-yl]methyl}-1-methyl-N-(tetrahydro- 2H-pyran-4-yl)-1H-1,2,4-triazolyl-3-aminecarboxamidine (ESI pos.) m/z : 425 ( [M + H]+ ) Manufactured Example 15 > 1-{[3,-(bromomethyl)-6-fluorobiphenyl-3-yl]methyl}-N-cyclohexyl-1-methyl-1H-1,2,4-triazolyl-3 -Aminoguanidine

S -48 - 201225956 【化2 0】

To N-{[6-fluoro-3'-(hydroxymethyl)biphenyl-3-yl]methyl}-1-methyl-N-(propan-2-yl)-1H-1,2,4 To a solution of triazolyl-3-amine formazan (136 mg) in chloroform (3.2 ml), N-bromosuccinimide (86 mg) and triphenylphosphine (12 6 mg) were added and stirred at room temperature for 30 min. . Water and chloroform were added to the reaction mixture, and the organic layer was separated and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate = EtOAc: EtOAc: EtOAc: EtOAc: /z : 485 ( [M + H]+ ) The following compounds were synthesized in the same manner. N-{[3'-(Bromomethyl)-6-fluorobiphenyl-3-yl]methyl}-1-methyl-N-(propan-2-yl)-1H-1,2,4- Triazolyl-3-aminecarboxamidine (ESI pos.) m/z : 445 ( [M + H]+ ) N- { [4'-(bromomethyl)-6-fluorobiphenyl-3-yl] Methyl}-1-methyl·N-(tetrahydro-2H-pyran-4-yl)-1H-1,2,4-triazolyl-3-aminecarboxamide (ESI pos.) m/z : 487 ( [M + H] + ) N-{[3'-(Bromomethyl)-6-fluorobiphenyl-3-yl]methyl} -1-methyl-N-(tetrahydro-2H- Pyran-4-yl)-1H-1,2,4-triazolyl-3-aminecarboxamidine (ESI pos.) m/z : 487 ( [M + H]+ ) Manufacturing Example 16 Ν·( { 3'-[2-(3-{[Third butyl(dimethyl)oxime-49- 201225956 yl)oxy}azetidin-1yl)ethyl]-6-fluorobiphenyl-3 -yl}methyl)-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-aminecaramidine [Chemical 2 1]

2-[2'-Fluoro-5'-({[(1-methyl-1H-imidazol-4-yl)carbonyl)]]]]] Methyl)biphenyl-3-yl]ethyl (200 mg), 3-((t-butyldimethylmethyl)oxy)azetidine (370 mg), N-ethyl-N-(propane A mixture of -2 -yl)propane-2.amine (500 mg) and acetonitrile (3.0 ml) was stirred at 85 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure. (ESI pos.) m/z : 607 ( [M + H] + ) The following compounds were synthesized in the same manner. N-( {3'-[3-(3-{[T-butyl(dimethyl)indenyl)oxy}azetidin-1-yl)propyl]-6-fluorobiphenyl-3 -yl}methyl)-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-aminecarboxamidine (ESI pos.) m/z : 6 2 1 ( [M + H] + ) N-( {3'-[2-(3-{[T-butyl(dimethyl)indenyl)oxy}azetidin-1-yl)ethyl]- 6-fluorobiphenyl-3-yl}methyl)-N-(l,4-dioxaspiro[4.5]dec-8-yl)-1-methyl-111-imidazol-4-aminecarboxamide ESI pos.) m/z : 663 ( [M + H]+ ) -50- 201225956 Example 1 N-( {6 -Fluoro-3'-[2-(Measlavin-1-yl)ethyl] Biphenyl·3·yl}methyl)-1-methyl-N-(propyl-2-yl)-1H-miso-4-amine methyl 2-hydrochloride [Chemical 2 2]

2-[2'-Fluoro-5'-({[1-methyl-1H-imidazol-4-yl)carbonyl](propan-2-yl)amino}methyl)biphenyl-methanesulfonate- Pyrrolidine (242 mg) was added to a solution of 3-yl]ethyl (208 mg) in toluene (1.7 ml), and stirred at 100 ° C for 1.5 hours. After concentration under reduced pressure, the residue was purified by EtOAc EtOAc EtOAc. It was dissolved in ethyl acetate (2.1 ml), and then a solution (4.06 ml) The reaction mixture was concentrated under reduced pressure to give the title compound (155 mg). Example 2 N-( {6-Chrysanthemum (-3'-[2-(3-]-based heterocyclobutan-1-yl)ethyl]biphenyl-3-yl}methyl)-1-methyl -N-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-amineformamidine 2 hydrochloride [Chemical 2 3]

N-( {3'-[2-(3-{[T-butyl(dimethyl)indolyl)oxyindole azetidinyl)ethyl]-6-fluorobiphenyl_3 ·Methyl-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-aminecarboxamide (l〇〇mg β 201225956 ) in tetrahydrofuran (1.0ml) i.OM tetra-n-butylammonium fluoride/tetrahydrofuran solution (〇.16 ml) was stirred at room temperature for 2 hours. After adding water to the reaction mixture and extracting with chloroform, the mixture was concentrated under reduced pressure. After the residue was purified by HPLC, EtOAc (methanol) was evaporated and evaporated to give the title compound (20 m). Example 3 N-({ 6-Fluoro-3'-[2-(3-hydroxyazetidinyl)ethyl]biphenyl-3-yl}methyl)-N-(4-hydroxyl ring Hexyl)-1-methyl-1H-imidazole-4-amine formazan [Chemical 2 4]

N-( {6-Fluoro-3'-[2-(3-hydroxyazetidin-1-yl)ethyl]biphenyl-3-yl}methyl)-1-methyl-N-( A solution of 4-oxocyclohexyl)-1H-imidazole-4-amine-formamide (646 mg) in tetrahydrofuran (13 ml) was added with aq. After stirring for 15 minutes, the mixture was stirred at room temperature for 1 day. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was extracted with chloroform. After concentrating under reduced pressure, the residue was purified EtOAc EtOAcjjjjjj Example 4 N-( { 3'-[2-(azetidin-1-yl)ethoxy]-6-fluorobiphenyl-3-yl}methyl)-1-methyl-N-( Tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-amineformamidine 2 hydrochloride

S -52- 201225956 [Chem. 2 5]

N-{[6-Fluoro-3 '-(2-Sideoxyethoxy)biphenyl-3-yl]methyl}-1-methyl-N-(tetrahydro-2H-pyran-4 Add azacyclobutane (23 mg) to a solution of -1H-imidazol-4-aminecarboxamide (153 mg) in chloroform (2.0 ml), stir at room temperature for 30 minutes, then add triethoxyboron Sodium hydride (10 8 mg) was stirred for 1 day. A 6.0 M aqueous sodium hydroxide solution was added to the reaction mixture, followed by extraction with chloroform. After concentration under reduced pressure, the residue was purified by HPLC and purified using PTLC ( NH chloroform chloroform / methanol = 97 / 3 ). After dissolving in methanol (3. 〇ml), a 4.0 M hydrochloric acid / ethyl acetate solution (0.11 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The title compound (78 mg) was obtained after concentration under reduced pressure. Example 5 N-( { 6-Fluoro-3'-[2·(3-hydroxyazetidin-1-yl)ethyl]biphenyl-3-yl}methyl)-bumethyl-indole-(propane -2-yl)-1Η-imidazole-4-amine formazan [Chemical 2 6]

Heart [4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzyl]-1-methyl-indole-( Propane-2-yl)-1 Η-imidazol-4-aminecarboxamide (176 mg), bis(3-bromophenethyl)azetidin-3-ol (75 mg), hydrazine (triphenylphosphine)palladium ( A mixture of 35 mg), potassium carbonate (80 mg), N,N-dimethyl 201225956 carbamide (1.0 ml) and ethanol (0.5 ml) was reacted in a microwave (150 ° C, 15 min). Water was added to the reaction mixture, and the mixture was extracted with chloroform and concentrated under reduced pressure. The residue was purified by column chromatography (NH.sub.2 g. . Example 6 N-( {3'-[3-(Dimethylamino)propoxy]-6-fluorobiphenyl-3-yl}methyl)-1-methyl-N-(tetrahydro- 2H-pyran-4-yl)-1H-imidazol-4-amine formamidine 2 hydrochloride [Chem. 2 7]

N-[(6-Gas-3'-yl-based-3-yl)methyl]-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazole- a mixture of 4-aminoformamidine (I50mg), 3-(dimethylamino)propan-1-ol (112mg), cyanide methyltri-n-butylthiocyclophosphine (106mg) and tetrahydrofuran (2.0ml) Stir for 1.5 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The residue was purified by column chromatography (NH.sub.2, chloroform/methanol = </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 98: 2) and purified by HPLC. Purification was further carried out with PTLC (NH-ethyl acetate). After dissolving in methanol (4.0 ml), a solution of 4·〇Μ hydrochloric acid/ethyl acetate (12 ml) was added, and the mixture was stirred at room temperature for 30 minutes. Concentration under reduced pressure gave the title compound (99 mg). -54- 201225956 Example 7 N-( { 4'-[l,l-difluoro-2-(pyrrolidin-1-yl)ethoxy]-6-fluorobiphenyl-3-yl}methyl) -1-methyl-N-(propan-2-yl)-1H-imidol-4-amine formazan [Chemical 2 8]

2,2-difluoro-2-{[2'-fluoro-5'·( {[(1-methyl-1Η-imidazol-4-yl)carbonyl) 4-propanesulfonic acid] A mixture of -amino)methyl}methyl)biphenyl-4-yloxy}ethyl (200 mg) and pyrrolidine (2.0 ml) was reacted in a microwave (150 ° C, 1 hour). After the reaction mixture was concentrated under reduced pressure, the residue was purified by HPLC to give the title compound (45 m). Example 8 4-[2'-Fluoro-5'-({[(1-methyl-111-imidazol-4-yl)carbonyl](tetrahydro-2H-pyran-4-yl)amino} Biphenyl-3-yl]-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl [Chemical 2 9]

2'-Fluoro-5'-({[(1-methyl-1H-imidazol-4-yl)carbonyl)](trihydro-2H-pyran-4-yl)amino} Biphenyl-3-yl (239 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-5,6-dihydropyridine -1 ( 2H )-carboxylic acid tert-butyl (150 mg), hydrazine (triphenylphosphine) palladium (51 mg), carbonic acid planer (215 mg), toluene (1.5 ml), -55- • prison 201225956 ethanol (1.5 ml The mixture of water and water (1.0 ml) was stirred at 10 ° C for 5 hours. Water and chloroform were added to the reaction mixture, and the organic layer was separated and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc / EtOAc / EtOAc / EtOAc EtOAc EtOAc EtOAc ({[(1-Methyl-1H-imidazol-4-yl)carbonyl](tetrahydro-2H-pyran-4-yl)amino}methyl)biphenyl-3-yl]piperidine-1- Tributyl carboxylic acid [Chemical 3 0]

4-[2'-Fluoro-5,-({[1-methyl-1H-imidazol-4-yl)carbonyl](tetrahydro-2H-pyran-4-yl)amino}methyl) Adding 5% palladium on carbon (24 mg) to a solution of biphenyl-3-yl]-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl (240 mg) in methanol (3.0 ml) The mixture was stirred at room temperature for 1 day. After the diatomaceous stone was filtered, it was concentrated under reduced pressure. The residue was purified by column chromatography (yield: chloroform/methanol = 100: 0 to 95: 5) to give the title compound (130 mg). Example 10 N-{[3,-(azetidin-3-oxy)-6-fluorobiphenyl-3-yl]methyl}-1-methyl-N-(tetrahydro-2H-pyridyl) -4-4-yl)_1H_imidazole-4_amine formamidine 2 hydrochloride

S -56- 201225956 【化3 1】

3-{[2'-Fluoro-5'-({[(1-methyl-1H-imidazol-4-yl)carbonyl](tetrahydro-2-indole-pyran-4-yl)amino}methyl Biphenyl-3-yl]oxy}azetidin-1-carboxylic acid tert-butyl (202 mg), 4·0Μ hydrochloric acid/1,4-dioxane solution (1.35 ml) and methanol (2.0 The mixture of ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (NH.sub.2, chloroform/methanol = 100 : 〇~97:3). After dissolving in methanol (1.0 ml), a 4.0 M hydrochloric acid / ethyl acetate solution (0.03 ml) was added, and the mixture was stirred for 1 hour in an ice bath. After depressurization under reduced pressure, the title compound (1 9 m g) was obtained. Example 11 N-( {6-Fluoro-3,-[(1-methylazetidin-3-yl)oxy]biphenyl-3-yl}methyl)methyl-N-(tetrahydro) -2H-pyran-4-yl)-1H-imidazol-4-aminecaramidine 2 hydrochloride [Chemical 3 2]

N-{[3,-(azetidin-3-oxy)-6-fluorobiphenyl-3-yl]methyl}-1-methyl-N-(tetrahydro-2H-pyran- A mixed liquid of 4-yl)-1H-imidazol-4-aminecarboxamide (131 mg), 37% formaldehyde (58 mg), formic acid (77 mg) and water (-57-201225956 0.05 ml) was stirred at 110 Torr for 2 hours. A 6.0 M aqueous sodium hydroxide solution was added to the reaction mixture, followed by extraction with chloroform. The residue was purified by HPLC and purified using PTLC ( NH EtOAc/MeOH = 98/2). After dissolving in methanol (1.0 ml), a 4.0 M hydrochloric acid / ethyl acetate solution (0.03 ml) was added, and the mixture was stirred for 1 hour in an ice bath. The title compound (29 mg) was obtained after concentration under reduced pressure. Example 12 N-{[6-Fluoro-3'-(4-methylpiperazin-1-yl)biphenyl-3-yl]methyl}-1-methyl-N-(tetrahydro-2H- Pyran-4-yl)-1H-imidazole-4-amine formazan [Chemical 3 3]

2,-Fluoro-5'·( {[(1-methyl-1H-imidazol-4-yl)carbonyl](tetrahydro-2Η-pyran-4-yl)amino} Biphenyl-3-yl (60 mg), 1-methylpiperazine (I3 mg), palladium acetate (1.2 mg), (R)-(+)-2,2'-bis(diphenylphosphino) A mixture of -1,1,-binaphthyl (5.1 mg), carbonated (50 mg) and toluene (1.0 ml) was stirred under reflux for 1 day. After the reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure. The residue was purified by PTLC (EtOAc(MeOH) Example 13 N-({6-Fluoro-3,-[2-(pyrrolidin-1-yl)ethyl]biphenyl-3-yl}methyl)-N-[(2S)-1-hydroxypropane -2-yl]-bu methyl-1H-

S -58- 201225956 Imidazol-4-amine formamidine 2 hydrochloride

(2S) -2-[({6-fluoro-3,-[2-(pyrrolidinyl)ethyl)biphenyl-3-yl}methyl)amino]propane·1·alcohol ( 171 mg), 1-methyl-1H-imidazole-4-carboxylic acid (165 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (138 mg), A mixture of 1-hydroxybenzotriazole hydrate (110 mg), N,N-diisopropylethylamine (186 mg) and hydrazine, hydrazine-dimethylformamide (5.0 ml) was carried out at room temperature. Stir in the day. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and extracted with chloroform. After concentration under reduced pressure, the residue was purified by HPLC and purified using PTLC ( NH </ RTI> chloroform/methanol = 95/5). After dissolving in 1.0 M hydrochloric acid and lyophilizing, the title compound (63 mg) was obtained. Example 14 N-({6-Fluoro-3'-[2-(pyrrolidin-1-yl)ethoxy]biphenyl-3-yl}methyl)-1-methyl-N-(tetrahydro) - 2H-pyran-4-yl)-1H-imidazol-4-aminecaramidine 2 hydrochloride [Chemical 3 5]

N-[(6-Fluoro-3'-hydroxybiphenyl-3-yl)methyl]-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazole-4 - A solution of acetonitrile (200 mg) in acetonitrile 201225956 (4.0 ml) was added with (2-chloroethyl)pyrrolidine hydrochloride (333 mg), sodium iodide (590 mg) potassium carbonate (70 mg), and stirred under reflux 3 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was extracted with chloroform. After concentration under reduced pressure, the residue was purified with EtOAc EtOAc. After dissolving in ethyl acetate (1.0 ml), a 4.0 M hydrochloric acid / ethyl acetate solution (1.0 ml) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (16 mg). Example 15 N-cyclohexyl-N-( { 3 '-[(dimethylamino)methyl]-6-fluorobiphenyl-3-yl}methyl)-1-methyl-1H-1, 2,4-triazolyl-3-aminecarboxamidine hydrochloride [Chemical 3 6]

N-{[3'-(Bromomethyl)-6-fluorobiphenyl-3-yl]methyl}-N-cyclohexyl-1-methyl-1H-1,2,4-triazolyl- 3-Aminoguanidine (155 mg) &gt; A 50% aqueous solution of dimethylamine, potassium carbonate (221 mg) and acetonitrile (3.2 ml) was stirred at room temperature for 3 days. Water and chloroform were added to the reaction mixture, and the organic layer was separated and concentrated under reduced pressure. The residue was purified by column chromatography (NH.sub.2, hexane/ethyl acetate = 50: 50 to 0: 100). After dissolving in ethyl acetate (1.8 ml), a solution of 4·〇Μ hydrochloric acid/ethyl acetate (67 μM) was added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (1.

S-60-201225956 Example 16 N-[(6-Fluoro-3'-{2-[6-(hydroxymethyl)-3-azabicyclo[3.1.0]hex-3-yl]ethyl} Biphenyl-3-yl)methyl]-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-aminecaramidine 2 hydrochloride [Chem. 3 7]

3-{2-[2'-Fluoro-5'-({[(1-methyl-:^-imidazol-4-yl)carbonyl](tetrahydro-2H-pyran-4-yl)) 1.0M diphenyl-3-yl]ethyl}-3-azabicyclo[3.1.0]hexane-6·carboxylic acid methyl (226 mg) in tetrahydrofuran (6.0 ml) A solution of butyl aluminum hydride/toluene (1.17 ml) was added under ice bath for 30 minutes. To the reaction mixture, a saturated aqueous solution of sodium potassium tartrate was added thereto, and the mixture was stirred at room temperature for 1 hour, and then extracted with chloroform. After concentration under reduced pressure, the residue was purified by HPLC. The title compound (10 m g ) was obtained by adding 1 ·hydrochloric acid and lyophilizing. Example 17 3-[2,-Fluoro-5'-({[(1-methyl-1H-imidazol-4-yl))yl](tetrahydro-2H-pyran-4-yl)amino} Methyl)biphenyl_3_yl]azetidin-1-carboxylic acid tert-butyl [Chemical 3 8]

N-(3-Bromo-4-fluorobenzyl)_1-methyl_N-(tetrahydro-2H_^-61 - 201225956-an-4-yl)-1H-methane-4-aminecarboxamide 297 mg), 3-(3-( 4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)azetidin-1-carboxylic acid A mixture of butyl (29 6 mg), hydrazine (triphenylphosphine) palladium (87 mg), carbonic acid planer (367 mg), toluene (3.0 ml), ethanol (3_Oml) and water (2.0 ml) was carried out at i〇〇t Stir for 5 hours. Water and chloroform were added to the reaction mixture, and the organic layer was separated. After concentrating under reduced pressure, the residue was purified to purified crystals eluted eluted elution Example 18 N-( { 3 '-[2-(azetidin-1-yl)ethyl]-6-fluorobiphenyl-3-yl}methyl)-1-methyl-N-(4 -Sideoxycyclohexyl)-1H-imidazol-4-amine formazan [Chemical 3 9]

N-( {3'-[2-(azetidin-1-yl)ethyl]-6-fluorobiphenyl-3-yl}methyl)-N-(l,4-dioxaspiro a mixture of [4_5]dec-8-yl)-1-methyl-1H-imidazol-4-aminecarboxamide (220 mg), 2.0 M hydrochloric acid (2.05 ml) and tetrahydropyran (1.5 m 1 ) Stir at 70 ° C for 6 hours. 2·0 盐酸 hydrochloric acid (2.05 ml) was added and stirred at 70 ° C for 12 hours. A 6.0 Μ aqueous sodium hydroxide solution was added to the reaction mixture to make it alkaline. After extracting with chloroform, concentration was carried out under reduced pressure. The residue was purified with EtOAc (yield) to afford compound (71 mg).

S-62-201225956 The structural formulae of the compounds of Examples 1 to 18, the compounds synthesized in the same manner, and the data of these instruments are shown in Tables 1-1 to 1-1. The numbers shown in the column of the examples in the table indicate that the compound was synthesized in the same manner as in all of the examples in the above Examples 1 to 18. The compound of "-" in the column of LCMS indicates that LCMS was not measured. -63- 201225956 [Table 1 -1] Compound 结构Example Structure Salt LCMS Retension Time (ESI Pos.) m/z (ESI nee..) m/z 1 15 HCI 3.29 492 ([M+H]+) 2 15 HCI 3.08 452 ([M+H]+) 3 15 HCI 3.09 494 ([M+H]+) 4 15 HCI 3.00 452 ([M+H]+) 5 15 HCI 3.23 492 ([M+H]+ ) 6 15 P^af03 HCI 3.03 494 ([M+H]+) 7 4 2.64 451 ([M+H]+) 8 15 ρότα0^ HCI 3.32 410 ([M+H]+) 9 15 2HCI 3.78 450 ( [M+H]+) 10 14 3.22 482 ([M+H]+)

S-64 - 201225956 [Table 1-2] Compound Example Structure Salt LCMS Retension Time (ESI Pos.) m/z (ESI nee..) m/z 11 4 2.79 409 ([M+H]+) 12 4 3.16 449 ([M+H]+) 13 4 2.80 491 ([_]+) 14 4 2.65 493 ([M+H]+) 15 4 2.76 479 ([M+H]+) 16 4 3.09 437 ([ M+H]+) 17 4 〇^〇5^ 2.62 437 ([M+H]+) 18 13 2HCI 2.84 409 ([M+H]+) 19 13 /° 2HCI 2.68 425 ([_]+) 20 13 2HCI 3.05 423 ([M+H]+)

-65-201225956 [Table 1 - 3] Compound Example Structural Salt LCMS Retension Time (ESI Pos.) m/z (ESI neg..) m/z 21 13 2HCI 2.83 451 ([M+H]+) 22 4 2.91 421 ([M+H]+) 23 4 3.03 435 ([M+HJ+) 24 4 2HCI 2.65 451 ([Μ+Η» 25 4 2.74 477 ([M+H]+) 26 4 2.95 505 ([M +H]+) 27 Η 2HCI - 481 ([M+H]+) 28 Η 2HCI 2.88 507 ([M+H]+) 29 13 F 3.09 463 ([M+H]+) 30 13 3.35 463 ([ M+H]+) -66- 201225956 [Table 1-4] Compound Example Structure Salt LCMS Retension Time (ESI Pos.) m/z (ESI negj m/z 31 13 3.01 423 ([M+H]+) 32 4 2HCI 2.85 541 ([M+H]+) 33 4 ρ^α°^0 2HCI 2.72 463 ([M+H]+) 34 4 2HCI 2.90 527 ([M+H]+) 35 1 2HCI 2.79 465 ([M+_ 36 1 ^y^〇9^〇2HCI 2.94 505 ([M+H]+) 37 13 p^OC°^ 0 2.54 423 ([M+H]+) 38 13 3.12 435 ([M +H]+) 39 13 pYcc0^&quot; 2.73 407 ([M+H]+) 40 1 2HCI 2.89 507 ([M+H]+)

-67- 201225956 [Table 1 - 5] Compound Example Structural Salt LCMS Retension Time (ESI Pos.) m/z (ESI nee..) m/z 41 14 2HCI 2.81 499 ([M+H]+) 42 6 2HCI 2,88 495 ([M+H]+) 43 1 2.72 451 ([M+H]+) 44 6 oJ^afK^ 2HCI 2.90 481 ([M+H]+) 45 1 2HCI 2.83 477 ([M +H]+) 46 4 2.72 481 ([M+H]+) 47 4 2HCI 2.61 469 ([M+H]+) 48 4 2HCI 2.60 455 ([M+H]+) 49 6 2HCI 2.72 467 ([ M+H]+) 50 4 2HCI - 493 ([M 十H]+) -68- 201225956 [Table 1 - 6] Compound Example Structure Salt LCMS Retension Time (ESI Pos,) m/z (ESI nee.. ) m/z 51 13 2.81 451 ([M+H]+) 52 13 2.83 451 ([_]+) 53 6 2HCI 2.90 507 ([M+H]+) 54 4 2.77 499 ([_]+) 55 10 PJro5x〇^ 2HCI 2.76 465 ([M+H]+) 56 1 2HCI 2.94 507 ([M+H]+) 57 11 2HCI 2.79 479 ([M+H]+) 58 13 2HCI 2.60 437 ([M+ H]+) 59 13 2HCI 2.61 437 ([M+H]+) 60 1 p^of^0 2HCI 2.94 491 ([M+H]+)

-69- 201225956 [Table 1 - 7] Chemicals Example Structure Salt LCMS Retension Time (ESI Pos.) m/z (ESI nee..) m/z 61 6 2HCf 2.88 493 ([M+H]+) 62 4 2HCI 3.09 547 ([M+H]+) 63 6 p^CC°&quot;XiH - 507 ([M+H]+) 64 13 2.67 451 ([M+H]+) 65 13 2.65 437 C[M +H]+) 66 4 2HCI 2.68 451 ([M+H]+) 67 4 2HCI 2.75 465 ([M+H]Ten) 68 4 2HCI 2.74 463 ([M+H]+) 69 11 P^ofV 2.74 463 ([M+H]+) 70 6 2HCI 3.02 533 ([M+H]+) s -70- 201225956 [Table 1 - 8] Compound Example Structural Salt LCMS Retension Time (ESI Pos.) m/z ( ESI nee..) m/z 71 1 2HCI 2.99 521 ([M+H]+) 72 1 2HCI 2.85 491 ([M+H]+) 73 6 2HCI 2.79 507 ([M+H]+) 74 12 2.76 492 ([M+H]+) 75 10 2.90 477 ([M+H]+) 76 11 2.88 491 ([M+H]+) 77 1 2.73 465 ([M+H]+) 78 1 p^XX0 ^ , 〇〆 2.83 491 ([M+H]+) 79 1 Cr^CC0^ 2.74 507 ([M+H]+) 80 1 ρ^οα0^ 2.79 477 ([M+H]+)

Λ π)·: -71 - 201225956 [Table 1 _ 9] Analytical Example Structure Salt LCMS Retension Time (ESI Pos.) m/z (ESI neg..) m/z 81 6 2.69 481 ([M+H ]+) 82 6 1 ϋΥοίτ 2.79 495 ([M+H]+) 83 6 2.75 523 ([M+H]+) 84 7 3.12 501 ([_]+) 85 7 3.10 501 ([M+H]+ 86 6 ρόοα0^0 2HCI 3.01 465 ([M+H]+) 87 4 F 2HCI 2.72 495 ([M+H]+) 88 4 F 2HCI 2.76 495 ([M+H]+) 89 6 3.14 479 ( [M+H]+) 90 1 2HCI 2.88 423 ([M+H]+)

S-72-201225956 [Table 1 - 1 ο] Compound Example Structural Salt LCMS Retension Time (ESI Pos.) m/z (ESI neE,.) m/z 91 1 2HCI 3.01 449 ([M+H]+) 92 1 p^rof^Xi 2HC1 2.93 465 ([M+H]+) 93 1 ρ^τα0^ 2HCI 2.94 435 ([M+H]+) 94 1 2HCI 2.90 423 ([_]+> 95 1 ο P ^ccc 2HCI 2.90 449 ([M+H]+) 96 1 0 p^O〇y 2HCI 2.90 465 ([M+H]+) 97 1 2.79 507 ([M+H]+) 98 1 2.81 509 ([ _]+) 99 1 p^pof^O.....^ 2.87 509 ([M+H]+) 100 6 P^OC/^ 2.87 537 ([_]+) -73- 201225956 [Table 1 — 1 1] Compound Example Structural Salt LCMS Retension Time (ESI Pos.) m/z (ESI nee:..) m/z 101 6 〇3.06 521 ([M+H]+) 102 6 P^bcar 3.01 495 ( [M+H]+) 103 3.05 505 ([M+H]+) 104 1 p^O^T) 2.86 505 C[M+H]+) 105 1 2.76 507 ([M+H]+) 106 1 ϋ}ξΌ^κ^Ό- 2.76 507 ([M+H]+) 107 1 2HCI 2.95 505 ([M+H]+) 108 1 2HCI 3.21 475 ([M+H]+) 109 1 3.16 461 ([ M+H]+) 110 1 p^OCU^s 2.76 495 ([M+H]+) -74-

S 201225956 [Table 1 - 1 2] Compound Example Structure Salt LCMS Retension Time (ESI Pos.) m/z (ESI neff..) m/z 111 t P^acr^° 2082 521 ([M+H]+ ) 112 1 Ρ^χχ°^° 2.92 505 ([M+H]+) 113 5 2.87 451 ([M+H]+) 114 1 3.01 453 ([M+H]+) 115 1 3.04 467 ([M +H]+) 116 4 3.01 467 ([M+H]+) 117 4 pfJxryfK^of 2.97 467 ([M+H]+) 118 1 2.88 465 ([M+H]+) 119 1 PxcoSk^〇. ..- - 465 ([M+H]+) 120 1 〇0C〇5^ 2.98 465 ([M+H]+) -75- r- 201225956 [Table 1 - 1 3] Compound Example Structure Salt LCMS Retension Time (ESI Pos.) m/z (ESI ne&amp;.) m/z 121 1 2HCI 3.00 463 ([M+H]+) 122 1 2HCI 3.00 479 ([M+H]+) 123 1 2HCI 2.94 479 ( [M+H]+) 124 1 2HCI 3.10 493 ([M+H]+) 125 1 Ο^ΧΌ^ό 2HCI 3.07 463 ([M+H]+) 126 1 2.83 509 ([M+H]+) 127 1 Ρ^Ο°^Ό 2.96 523 ([M+H]+) 128 1 ρ}τ〇^λ^ 3.61 517 ([M+H]+) 129 1 2.83 495 ([M+H]+) 130 1 p0C〇5^Cv 0 2.90 506 ([_]+) 76- 201225956 [Table 1 - 1 4] Compound Example Structural Salt LCMS Retension Time (ESI Pos.) m/z (ESI neg. .) m/z 131 1 3.13 492 ([M+H]+) 132 1 2HCI 3.27 505 ([M+H]+) 133 2HCI 2.92 525 ([M+H]+) 134 1 〇0CO^Xi? 3.05 493 ([_]+) 135 1 ϋΥοΡ^χ)- 2HCI 2.76 525 ([M+H]+) 136 1 P^O^O...' 2.86 521 ([M+H]+) 137 1 p^CC0^0 2HCI 2.87 511 ([M+H]+) 138 1 2HCI 3.02 539 ([M+H]+) 139 1 P^iDca^cv 2HCI 2.73 548 ([M+H]+) 140 1 2HCI 2.90 535 ([M+H]+) S'. -77- 201225956 [Table 1 - 1 5] Compound Example Structure Salt LCMS Retension Time (ESI Pos.) m/z (ESI nee.) m/z 141 1 2.72 525 ([M+H]+) 142 1 〇YXXCUC3 W 3.01 533 (tM+H]+) 143 2-73 521 ([M+H]+) 144 1 Ρ^α°^χ〇Η 2HCI 2.76 535 ([M+H]+) 145 1 2.71 495 ([M+H]+) 146 3 OH 2.65 491 ([M+H]+) 147 3 OH 2.65 491 (tM+H]+) 148 1 2HCI 2.90 523 ([M+H]+) 149 1 2HCI 2.83 562 ([M+H]+) 150 1 2HCI 2.82 576 ([M+H]+)

S-78-201225956 [Table 1 - 1 6] Compound Example Structure Salt LCMS Retension Time (ESI Pos.) m/z (ESI nee:-) m/z 151 2 2HCI 2.72 493 ([M+H]+) 152 1 P^cc^^xr 2HCI 2.76 521 ([M+H]+) 153 1 2HCI 2.76 507 ([M+H]+) 154 1 pJT〇P^0 2HCI 2.79 521 ([M+H]+) 155 1 Ρ}ξΌ°-χχ^Η 2HCI 2.79 549 ([M+H]+) 156 1 2HCI 2.84 523 ([M+H]+) 157 1 2HCI 2.78 509 ([M+H]+) 158 1 ρ ^α°^ ^cr ho 2HCI 2.74 521 ([M+H]+) 159 16 oJra°^〇^OH 2HCI 2.79 533 ([_]+) 160 1 2HCI 2.75 562 ([M+H]+) -79 - 201225956 [Table 1 - 1 7] Compound Example Structural Salt LCMS Retension Time (ESI Pos,) m/z (ESI neg.,) m/z 161 2 2HCI 2.85 507 _H]+) 162 1 2HCI 2.87 547 ([ M+H]+) 163 2 2HCI 2.61 479 ([M+H]+) 164 1 2HCI - 507 ([M+H]+) 165 3 OH 2.65 507 ([M+H]+) 166 1 p^〇 5^^h 2HCI 2.61 493 ([M+H]+) 167 13 2HCI 2.90 479 ([M+H]+) 168 1 2HCI 2.76 507 ([M+H]+) 169 13 OH 2HCI 2,65 493 ( [M+H]+) 170 13 oJ) py^O 0 / 2HCI 2.94 479 ([M+H]+) s -80- 201225956 [Table 1 - 1 8] Compound Example LCMS Retension Time (ESI Pos.) m/z CESI nee..) m/z 171 13 ΡΥό^ό —0 2.88 465 ([M+H]+) 172 13 HO 2.94 479 ([M+H]+ ) 173 13 2HCI 2.83 477 ([M+H]+) 174 13 OH 2HCI - 493 ([M+H]+) 175 13 pJip〇fK^o HO 2HCt 2.61 465 ([_]+) 176 13 ^gcc^ o 2.94 505 ([M+H]+) 177 13 HO 2HCI - 465 ([M+H]+) 178 13 pf\p^T) 0, 2HCI 3.12 493 ([M+H]+) 179 13 I 2HCI 3.28 507 ([M+H]+) 1B0 13 p^pof^O HO 2HCI 2.68 451 ([M+H]+) -81 - 201225956 [Table 1 - 1 9] Analytical Example Structure Salt LCMS Retension Time ( ESI Pos.) m/z (ESI nee..) m/2 181 17 - 549 ([M+H]+) 182 1B 0 - 489 ([M+H]+) 183 18 0 - 505 ([M+ H]+) 184 6 - 587([M+Na]+) 1B5 8 - 575 ([M+H]+) 186 9 - 577 ([M+H]+) 187 1 - 575 ([Μ+Η» 188 2 w° - 549 ([M+H]+) Test Example 1 [Absorption inhibition test of glycine] The glycine absorption test was carried out in accordance with the method disclosed in Neuron, 8, 927-935, and 992. T98G cells expressing a neuroglioma of human type 1 glycine transporter (GlyTl) were used. T98G cells were seeded in a 96-well plate -82-201225956 to 2. 〇xl 04 cells/well, and cultured overnight in a carbon dioxide thermostat incubator. After the test substance was dissolved in 1% DMS solution, it was dissolved in 10 mM HEPES buffer containing 150 mM sodium chloride, 1 mM calcium chloride, 5 mM potassium chloride, 1 mM magnesium chloride, 10 mM glucose, and 0.2% bovine serum albumin ( Η7·4). After the medium for cell culture is removed, the test substance is treated for ί minutes. Thereafter, the test substance and [3η]glycine (final concentration: 250 Μ) were added to the cells, and the reaction was carried out for 15 minutes at room temperature. After the completion of the reaction, the extracellular fluid was taken up by an exhaust pipe to remove excess glycine acid present outside the cells, and then the cells were dissolved in a sodium hydroxide aqueous solution of 5 Μ. The amount of glycine present in the cells is determined by measuring the radioactivity in the cell lysate by a liquid scintillation counter. The amount of glycine extracted in the presence of XμΜ of ALX5407 was taken as a non-specific absorption, and the amount of non-specific absorption was subtracted from the total absorption in the absence of 1 〇μΜ of ALX5407 as the specific absorption. Further, the glycine acid absorption inhibiting activity (IC50 値) was calculated from the inhibition curve of the concentration of the test substance (Γ9 to 10_5Μ), and 八1^5407 was &gt;1-[(31〇-3-([1, 1'-biphenyl]-4-oxy)-3-(4-fluorophenyl)propyl]-&gt; 1-methylglycine 11 (:1 salt. Among the compounds of the present invention, compound 3, 4 IC5 of 5, 8, 19, 24, 29, 31, 37, 39, 52, 169, 178, 179. 値 is Ι.ΟμΜ Above, IC5Q 値 of other compounds is smaller than 1. ΟμΜ. IC5Q値1. Of the compounds 、μΜ, compounds 12, 14, 26, 30, 48, 62, 69, 73, 98, 99, 100, 108' 110, 115, 116, 117, 121, 125, 127, 132, 138, 139 The IC5 of 148, 150, and 175 is -83-201225956 0. 1 ΟμΜ to 丨0.050μΜ, and 1 is less than 0.050 μΜ for compounds 7, 13, 15 ' 17, 21, 22 , 23, 25, 27 ' 28 , 33 ' 3 5 '36 , 41 , 42 , 43 , 44 , 45 49 ' 50 , 5 1 '53 , 55 , 56 , 57 , 60 , 61 '63 , 6 6 , 67 , 68, 71, 72 83 ' 89 90 ' 91 , 93 , 97 , 103 , 104 , 105 , 106 , 107 , 109, 1 11 , 113 , 1 14 '118' 119 , 120 , 122 , 123 , 126 , 129 , 1 3 0 , 133 , 134 , 135 , 136 , 137 , 140 143 , 144 &gt; 145, 1 47 , 149 , 15 1 , 152 , 153 , 154 , 15 5 &gt; 156, 157 % 158, 1 59 , 160 , 16 1 '162 ' 163 , 16 4 , 165 , 166 , 168 , 170 , 1 73 , 177 ° Compound 1 9 '40 , 49 , 61 , 76 ' 11 7 , 1 2 7 , 169 Table 2 shows the specific enthalpy, and the absorption inhibition test of glycine acid was not carried out for the compound 1 8 : 1 to 188. [Table 2] Compound IC50 _) 19 1.0 40 0.22 49 0.013 61 0.021 76 0.36 117 0.058 127 0.089 169 1.2 Industrial Applicability The compound of the present invention has a glycine transporter (GlyT 1 ) hindering activity, and thus Acid transporter-related diseases, specifically schizophrenia -84 - 201225956, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder (general anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, Post-traumatic stress disorder, specific phobia, acute stress disorder Etc., depression, drug dependence, convulsions, hand shocks, pain, and sleep disorders are effective or preventive. -85-

Claims (1)

201225956 VII. Application for Patent Park: 1. A compound of the formula [I] or a pharmaceutically acceptable salt thereof wherein the formula [I] is [Chemical 1] (wherein R1 represents a hydrogen atom or a Cu alkyl group, and R2 represents a C1-6 alkyl group which may be substituted by 1 to 3 substituents selected from the substituent group 1, and may be selected from the group consisting of a hydroxyl group and a pendant oxy group 1 to 3 a C 3 · 8 cycloalkyl group substituted by a substituent (when substituted by a pendant oxy group, the carbonyl group formed by the pendant oxy group and the substituted carbon atom may be protected), and 4 having an oxygen atom in the ring a 6-membered saturated heterocyclic group, or a sulfur atom-oxidizable tetrahydrothiopyranyl substituent group 1 is a hydroxyl group, a Cu alkoxy group, a halogen atom, a c3_6 cycloalkyl group, and an oxygen atom in the ring. ~6-membered saturated heterocyclic groups are grouped, Y represents a nitrogen atom or a formula CH, and R3, and R4 represent the same or different hydrogen atoms, a halogen atom, a Cl-6 alkyl group, a halogenated Ci.6 alkyl group, a Ch6 alkane Oxy or halogenated h.6 alkoxy, R5 represents the formula W-R6, w represents a ci.6 substituent which may be substituted by 1 to 3 halogen atoms, and O-Ci which may be substituted by 1 to 3 halogen atoms -6 alkyl, oxygen atom or -86- 201225956 bond, R6 represents 1~3 substituents selected from substituent group 2 '4~8 having at least 1 nitrogen atom in the ring a heterocyclic group, an thiomorpholinyl group which may be oxidized by an amine group or a sulfur atom which may be substituted by one or two substituents selected from the substituent group 3, and a substituent group 2 is a hydroxyl group, a halogen atom, C,- 6 alkyl, halogenated Ci-6 alkyl, hydroxy Cu alkyl, Cu alkoxy Cu alkyl, Cu alkoxy, halogenated C 6 alkoxy, C 2-7 alkoxycarbonyl, c 3.6 naphthenic a Ci-6 alkoxy group, a C3_6 cycloalkyl group, a Cm alkanoyl group, a Cm alkoxyimino group, and a formula of the formula CONR7R8 (wherein R7 and R8 represent the same or different hydrogen atoms or Ci-6 alkyl groups) The group, the substituent group 3 is represented by a group consisting of C!-6 alkyl group, c3-6 cycloalkyl group, and hydroxyCl.6 alkyl group. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is a Cu alkyl group, R3 is a halogen atom, and R4 is a hydrogen atom or a halogen atom. 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2 is a Ci.6 alkyl group which may be substituted by a Ci6 alkoxy group, and a C3 which may be substituted by a hydroxyl group -8 cycloalkyl or a 5-6 membered saturated heterocyclic group having an oxygen atom in the ring. 4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein γ is a formula CH. 5. A compound according to any one of claims 1 to 4, wherein the W is a hydrazine-Ci-6 alkylene group, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R6 is a) may be selected from the group consisting of a hydroxyl group, a hydroxy Ci-6 alkyl group, And a 4- to 8-membered saturated heterocyclic group having at least one nitrogen atom in the ring, or b) may be selected from a Ci-6 alkyl group and a hydroxy group C. 6 amine groups substituted by 1 or 2 substituents. A medicine comprising a compound as claimed in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient. 8. A preventive or therapeutic agent for a disease wherein the disease is schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, drug dependence, paralysis, hand shake, pain or A sleep disorder characterized by containing a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient. S ~ 88 - 201225956 IV. Designation of representative drawings: (1) The representative representative of the case is: No (2) The symbol of the symbol of the representative figure is simple: No 201225956 V. If there is a chemical formula in this case, please reveal the characteristics that can best show the invention. Chemical formula: formula [I] -4- '· 1 S