TW201236682A - Substance capable of inhibiting glycine transporter - Google Patents

Abstract

The present invention relates to a novel compound represented by formula [I] or a pharmaceutically acceptable salt thereof. This compound is useful for the prevention or treatment of diseases 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, a specific phobia, acute stress disorder, and the like), depression, drug dependence, convulsion, tremor, pain, Parkinson's disease, attention deficit/hyperactivity disorder, bipolar disorder, eating disorder, sleep disorder and the like, of which the action relies on an inhibitory activity on the intake of glycine.

Description

201236682 VI. Description of the Invention [Technical Field of the Invention] The present invention relates to an inhibitory compound having a glycine transporter. [Prior Art] The NMDA receptor system, one of the glutamate receptors, is present on the cell membrane of the brain and is associated with neurophysiological phenomena such as neuroplasticity, cognition, concentration, and memory. There is a complex (allosteric) bond site on the NMD A receptor, and the glycine linkage site is also (the NMDA receptor complex glycine bond site). It has been reported that the NMDA receptor complex glycine linkage site is associated with NMDA receptor (Non-Patent Document 1). Glycine is released at the synaptic cleft when glycine-acting presynaptic nerve endings are at an active potential. After the released glycine is bonded to the posterior receptor, the transporter protein of the glycine acid is removed from the synaptic cleft by the transporter to regulate the function of the glycine acid in the extracellular fluid to regulate the function of the NMDA receptor. Glycine transporter (GlyT) is a protein associated with cellular uptake of extracellular glycine. To date, GlyTl and GlyT2 subtypes are known to exist. GlyTl is mainly expressed in the cerebral cortex, hippocampus and inferior's report that it is associated with dysregulation, Alzheimer's disease, dysfunction, dementia, anxiety (overall anxiety, panic disorder, social disorder) One of the various ectopic nerves used in phobia, post-traumatic stress, and specific fear, the life reaches the synapse. The two visceral cognition, the strong disease, the -5-201236682 acute compression, etc. It is associated with diseases such as depression, drug dependence, convulsions, tremors, pain, Parkinson's disease, deficient defects, hyperactivity disorder, bipolar disorder, eating disorder, and sleep disorders (Non-Patent Documents 2 to 4). In the following documents, a compound having a GlyTl inhibitory action and having an amidine-2-one structure is reported (Patent Documents 1 and 2). The compounds described in Patent Documents 1 and 2 are compounds characterized by an aryl bond via a guanamine or a carbonyl group in a ring nitrogen atom of one of the imidazole groups [Prior Art Document] [ [Patent Document 1] WO2008092878 [Patent Document 2] WO2009034062 [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), 30, 1963-1985 [Non-Patent Document 4] Expert Opinion on Therapeutic Patents (2004) 14 (2) 201-214 [Summary of the Invention] [The invention is to be solved Problem] The present invention provides a -6-.201236682 integration disorder, Alzheimer's disease, cognitive dysfunction, dementia, general anxiety disorder, panic disorder caused by glycine acid intake inhibition Disorders, obsessive-compulsive disorder, social phobia, post-traumatic stress, specific phobia, acute stress, etc.), depression, drug dependence, paralysis, tremor, pain, Parkinson's disease, lack of focus A novel compound or a pharmaceutically acceptable salt thereof which is useful for the prevention or treatment of diseases such as hyperactivity disorder, bipolar disorder, eating disorder or sleep disorder. [Means for Solving the Problem] The inventors of the present invention have further examined the compounds of GlyTl, which are hindered by the novel skeleton, and found that the compound represented by the following formula is a ring of imidazole. In the case of an internal nitrogen atom, an aryl group is a compound which is not bonded through a guanamine or a carbonyl group, and is an excellent GlyTl hindrance substance, and the present invention has been completed. The present invention will be described in detail below. The aspect of the present invention (hereinafter referred to as "the compound of the present invention") is as follows. (1) a compound of the formula [I] or a pharmaceutically acceptable salt thereof,

(wherein R 1 represents phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or pyridinyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and pyridone 201236682 1 to 3 substituents which may be selected from the substituent group 1 are substituted, and the substituent group 1 represents an alkyl group (the C, -6 alkyl group may be formed by a hydroxyl group, a Cu oxime group, and a group represented by the formula -NR7R8). 1 to 3 substituents selected by the group are substituted, R7 and R8 may be the same or different, and represent a hydrogen atom or a Cm-based group, a halogenated Cl-6 alkyl group, a Cm alkoxy group, a halogenated Cu alkoxy group, a C2 group. .7 alkoxycarbonyl, cyano, halogen atom, heteroaryl group of 5 or 6 members (the heteroaryl group of 5 or 6 members may be substituted by 1 or 2 C, -6 alkyl groups), C, · 6-alkyl fluorenyl and formula _NR9R1G (R9 and R1G may be the same or different, meaning a hydrogen atom or a Ch6 alkyl group ' or R9 and riq together with a bonded nitrogen atom to form a saturated heterocyclic ring of 4 to 6 members a group of 4 to 6 membered saturated heterocyclic rings which may be substituted by a pendant oxy group), and R 2 represents a phenyl group which may be substituted with 1 to 3 substituents selected from the substituent group 2, or Substituent group 2 a monocyclic or bicyclic heteroaryl group substituted with 1 to 3 substituents, and the substituent group 2 represents a phenyl group (the phenyl group may be formed by an alkyl group, a C.6 alkoxy group, and a halogen atom) Substituted by a group of 丨~3 substituents substituted, Cm alkyl (the Cu alkyl group may be (^.6 alkoxy, phenyl, 〇3-6 cycloalkyl, halogenated C, _6 alkoxy) , halogenated (: 3-6 cycloalkyl and 3-methyl propylene oxide-3-yl group selected by the group of 1 to 3 substituents substituted), _Ci-6 courtyard, Ci-6 alkoxy (The Ci-6 alkoxy group may be one to three substituents selected from the group consisting of a Ci-6 alkoxy group, a hydroxyl group, a c3-6 cycloalkyl group, and a 3-methyl propylene oxide-3-yl group. Substituted), hydroxy, benzyloxy, halogenated Cu alkoxy, c3-6 cycloalkyl, c3.6 cycloalkoxy, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, tetrahydropyran Base oxygen-8 - 201236682 base 'C2-7 compound oxygen ore group, cyano group, halogen atom, 5- or 6-membered heteroaryl (the 5- or 6-membered heteroaryl group can be derived from Ci.6 alkyl , a halogen atom, and a group of 1 or 2 substituents selected by a group of Ci_6 alkoxy groups), Cu alkane The formula -NRUR^R11 and R12 may be the same or different and represent a hydrogen atom or an alkyl group, or R11 and R12 together with a bonded nitrogen atom form a saturated heterocyclic ring of 4 to 6 members, which is 4 to 6 The saturated heterocyclic ring of the member may be substituted with a pendant oxy group) and the formula -CONR13R14 (r13 and R14 may be the same or different, and represent a hydrogen atom or a Ci-6 substituent, or R, 3 and R14 and a bond. a group in which a nitrogen atom of a knot is formed to form a saturated heterocyclic ring of 4 to 6 members, and a saturated heterocyclic ring of 4 to 6 members may be substituted by a pendant oxy group, and R3 and R4 may be the same or different. , represents a hydrogen atom, an alkyl group, a C 3 ·6 cycloalkyl group, a phenyl group or a benzyl group, or R 3 and R 4 together with a bonded carbon atom to form a C 3-7 cycloalkane ring, a tetrahydrofuran ring, or a tetra Hydroquinone ring (except where R3 and R4 are simultaneously a hydrogen atom), R5 and R6 may be the same or different, and represent a hydrogen atom, Ci.6 alkyl) (only 'R1 is selected from substituent group 1) When a phenyl group is substituted with 1 to 3 substituents, R2 is a monocyclic or bicyclic heteroaryl group which may be substituted by 1 to 3 substituents selected from the substituent group 2) (2) as (1) ) On the permitted or a pharmaceutically acceptable salt of the compound, wherein, R5 and R6 are both hydrogen atoms. (3) A compound as described in (1) or (2) or a pharmaceutically acceptable salt thereof, wherein R3 and R4 together with a bonded carbon atom form a C3-7 cycloalkane ring. -9-201236682 (4) A salt as claimed in any one of (1) to (3) or a salt thereof, wherein R2 is a group of 丨~3 substituted by substituent group 2 A monocyclic heteroaryl group substituted with a phenyl group substituted with a group or a 丨~3 substituent which may be selected from the substituent group 2. (5) The compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof, wherein R2 is a benzene which may be substituted with 丨~3 substituents selected from the substituent group 3 a monocyclic heteroaryl group substituted with 1 to 3 substituents which may be selected from the substituent group 4, and the substituent group 3 is a C, -6 alkoxy group, a halogenated q-6 alkoxy group and 5 The group consisting of a heteroaryl group and a substituent group 4 is a phenyl group (the phenyl group may be one to three substituents selected from the group consisting of a CU6 alkyl group, a C|.6 alkoxy group, and a halogen atom). Substituted), (^.6 alkoxy, halogenated C, _6 alkoxy and a heteroaryl group of 5 or 6 members. (6) As in any of (1) to (3) A compound or a pharmaceutically acceptable salt thereof, wherein R2 is a phenyl group which may be substituted with 1 to 3 substituents selected from the substituent group 3, and 1 to 2 substituents which may be selected from the substituent group 4. a oxazolazole group substituted with a substituent, a oxadiazolyl group which may be substituted by one substituent selected from the substituent group 4, and a triazole which may be substituted with 1 to 2 substituents selected from the substituent group 4. a group selected from the group of substituents 4 a pyrazolyl group substituted with 1 to 3 substituents or a pyridyl group which may be substituted with 1 to 3 substituents selected from the substituent group 4. (7) As in (1) to (3) A compound or a pharmaceutically acceptable salt thereof, wherein R2 is substituted by a 5-membered heteroaryl group -10-201236682 phenyl group, 1 to 2 substituents which may be selected from the substituent group 4 a pyrazolyl group substituted with a group, a pyrazolyl group which may be substituted with 1 to 3 substituents selected from the substituent group 4, or a pyridyl group which may be substituted with 丨~3 substituents selected from the substituent group 4. (8) A compound according to any one of (1) to (7) or a pharmaceutically acceptable salt thereof, wherein 'R1 is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or pyridinyl The pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group and pyridone group may be substituted by 1 to 3 substituents selected from the substituent group 1. (9) As in (1) to (7) A compound according to the item 1 or a pharmaceutically acceptable salt thereof, wherein R1 is a phenyl group, a pyridyl group, a pyrimidinyl group or a pyrazinyl group, and the phenyl group, pyridyl group, pyrimidinyl group and pyrazinyl group It may be substituted by 1 to 3 substituents selected from the substituent group 5, which is a C.6 alkyl group, a Cm alkyl group, a Cm alkoxy group, a halogenated C, -6 alkoxy group, (10) A compound according to any one of (1) to (7) or a pharmaceutically acceptable salt thereof, wherein R1 is selected by the substituent group 5 a pyridyl group substituted with -3 substituents or a pyrimidyl group substituted with 1 to 3 substituents selected by the substituent group 5. (1 1) A pharmaceutical composition containing (1) to (1) The compound described in any one of the above, or a pharmaceutically acceptable salt thereof, is used as an active ingredient. (12) - Integral disorders 'Alzheimer's disease, cognitive dysfunction, dementia, anxiety, depression, drug dependence, paralysis, tremor, pain-11 - 201236682 Pain, Parkinson's disease, focus on defects A prophylactic or therapeutic agent for a disease of a hyperactive disorder, a bipolar disorder, an eating disorder or a sleep disorder, which comprises the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof As an active ingredient. [Effects of the Invention] The compound of the present invention has a glycine transporter (GlyTl) inhibitory activity. [Embodiment] [Formation for Carrying Out the Invention] "Cx-y (x and y represents a natural number)" used in the present specification means that the number of carbon atoms is X to y. The "(^_6 alkyl group)" used in the present specification means a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group. , isobutyl, tert-butyl, pentyl, isopentyl, hexyl. "C3.6 cycloalkyl" as used in the specification means a cycloalkyl group of cyclohexane having 3 to 6 carbon atoms. Cyclobutyl, cyclopentyl, cyclohexyl. The "C3.7 naphthenic ring" as used in the specification means a cycloalkane ring of a 3 to 7 carbon atoms, a cyclobutane ring, a cyclobutane ring, and a cyclopentane. Ring, cyclohexane ring, cycloheptane ring. "CL6 alkoxy group" used in the present specification means a linear or branched alkoxy group having 1 to 6 carbon atoms, and may, for example, be a methoxy group. , ethoxy-12-201236682, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, hexyloxy. "C3_6 cycloalkoxy" as used in this specification The term "base" means a cycloalkyloxy group having 3 to 6 carbon atoms and is a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group or a cyclohexyloxy group. "Halogen (halogenated)" is used in the present specification. , chlorine, bromine, indeed. The "(^.6 alkyl fluorenyl group)" used herein represents a chain or branched chain of 1 to 6 carbon alkyl groups, and examples thereof include a methyl group, an ethyl group, a propyl group, a butyl group, a butyl group, and a trimethyl group. The "methylene-6 methoxy group" used in the present specification means a chain or branched chain alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl methoxy group and a a mercaptooxy group, a propyl fluorenyloxy group, a butyl fluorenyloxy group, a trimethyl ethinyloxy group. The "halogenated C, .6 alkyl group" used in the present specification means a linear chain substituted by a halogen atom or The chain-like alkyl group having 1 to 6 carbon atoms and preferably having 1 to 3 halogen atoms is fluoromethyl, difluoromethyl, trifluoromethyl or trichloromethyl. The "halogenated α-6 alkoxy group" used in the present specification means a linear or branched chain alkoxy group having 1 to 6 carbon atoms which is substituted by a halogen atom, and a preferred substitution number of the halogen atom is 1 to 3, for example, a fluoromethoxy group, a difluoromethoxy group, or a trifluoromethoxy group. The "halogenated C3-6 cycloalkyl group" used in the specification means a carbon number 3 substituted by a halogen atom. The cycloalkyl group of 6 and the halogen atom preferably have a '1 -13-201236682 algebra of 1 to 3, and may, for example, be a fluorocyclopropyl group or a difluorocyclopropyl group. R9 and R1Q, RH and R12 of the present specification Examples of the "saturated heterocyclic ring of 4 to 6 members which are bonded together with the bonded nitrogen atom" in R13 and R14 include a trimethylene ring, a pyrrolidine ring, and an acridine ring. a ring structure in which a hetero atom is contained in a ring like a porphyrin ring or a thiomorpholine ring. The "monocyclic or bicyclic heteroaryl group" used in the present specification means that at least one nitrogen atom is contained in the ring. A monocyclic or bicyclic heteroaryl group of an atom selected from the group consisting of an oxygen atom and a sulfur atom. When a nitrogen atom is present in the ring, the nitrogen atom may be an N-oxide. Monocyclic heteroaryl. Preferred as a heteroaryl group of 5 or 6 members, which may, for example, be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, iso Oxazolyl, stilbene, triazolyl, oxadiazolyl. Further, the "divalent monocyclic heteroaryl group" used in the present specification may, for example, be a group obtained by removing any hydrogen atom of each of the above groups. The bicyclic heteroaryl group is preferably a heteroaryl group of 9 or 10 members, and examples thereof include an anthracenyl group, a benzofuranyl group, a benzimidazolyl group, an imidazopyridyl group, a quinolyl group, and an isoquinolyl group. The "C2-7 oxyalkylene group" used in the present specification means a group in which a hydroxy group is substituted by a carbonyl group, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxycarbonyl group. In the specification, the term "salt allowed in medicine" means an acid addition salt which is acceptable in the pharmaceutical agent, and examples of the acid to be used include inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid and phosphoric acid, or acetic acid. Oxalic acid, lactic acid, -14- 201236682 Citric acid, malic acid, gluconic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and P-toluenesulfonic acid Etc. Organic acids. The transition from the free body to the salt can be carried out by a conventional method. Preferred embodiments of the compounds of the present invention are listed below. a compound wherein R1 is a phenyl group, a pyridyl group, a pyrimidinyl group or a pyrazinyl group, and the phenyl group, pyridyl group, pyrimidinyl group and pyrazinyl group may be substituted with 1 to 3 substituents selected from the substituent group 5; The compound obtained by substituting a pyridyl group substituted with 1 to 3 substituents selected from the substituent group 5 of R1 or a pyrimidyl group substituted with 1 to 3 substituents selected by the substituent group 5 is more preferable. R 2 is a phenyl group substituted with 1 to 3 substituents which may be selected from the substituent group 3, and an isoxazolyl group which may be substituted by 1 to 2 substituents selected from the substituent group 4, may be substituted by a substituent The oxadiazolyl group substituted by one substituent selected from the group 4., the triazolyl group which may be substituted by 1 to 2 substituents selected from the substituent group 4, and 1 to 1 which may be selected from the substituent group 4. A pyrazolyl group substituted with three substituents or a pyridyl group which may be substituted with 1 to 3 substituents selected from the substituent group 4 is preferred; and R2 is a 5-membered heteroaryl group. a substituted phenyl group, an isoxazolyl group which may be substituted with 1 to 2 substituents selected from the substituent group 4, a pyrazolyl group which may be substituted with 1 to 3 substituents selected from the substituent group 4, Further, a compound obtained by a pyridyl group substituted with 1 to 3 substituents selected from the substituent group 4 is more preferable. Preferably, a compound in which R3 and R4 are bonded to a carbon atom to form a C3-7 cycloalkane ring is preferred. -15- 201236682 It is preferred that a compound in which R5 and R6 are simultaneously a hydrogen atom. The compounds of the invention may contain a plurality of asymmetric centers. Therefore, the above compounds are not only optically active, but also racemates thereof, and even plural non-image isomers. All of the foregoing forms are included within the scope of the invention. Various isomers can be obtained by known methods, such as the use of optically active starting materials or intermediates, optically selective or non-image selective reactions used in the manufacture of intermediates or final products, or the use of Separation or the like by chromatography used in the production of an intermediate or a final product. Further, when the compound of the present invention forms a hydrate or a solvent, these are also included in the scope of the present invention. Likewise, pharmaceutically acceptable salts of the hydrates or solvents of the compounds of the invention are also included within the scope of the invention. The compound of the present invention can be administered orally or parenterally. The dosage form can be a tablet, a capsule, a granule, a powder, a powder, a tablet, an ointment, a cream, an emulsion, a suspension, an anal suppository, an injection, etc., and can be prepared by a conventional preparation technique. (For example, the 15th edition, the method specified in the Pharmacy, etc.) is manufactured. Such dosage forms can be appropriately selected depending on the patient's condition, age, and purpose of treatment. Such preparations may be formulated with a pharmacologically acceptable carrier, i.e., an excipient (e.g., crystalline cellulose, starch, lactose, mannitol), a binding agent, in a composition containing the compound of the present invention. (eg hydroxypropylcellulose, polyvinylpyrrolidone), slip agents (eg magnesium stearate, talc), breakers (eg carboxymethylcellulose calcium), other pharmacologically acceptable Additives to make. -16- 201236682 Further, the compound of the present invention can be used with one or more other therapeutic agents, various antipsychotics, antidepressants, such as 5HT3 antagonists, 5HT2 antagonists, serotonin promoters, NK-1. Antagonist, selective serotonin reuptake obstruction (SSRI), serotonin norepinephrine reuptake inhibitor (SNRI), tricyclic antidepressant, dopamine antidepressant 'H3 antagonist, 5HT1A Antagonists, 5HT1B antagonists, 5HT1D antagonists, D1 promoters, M1 promoters, anticonvulsants, cognitive function enhancers, and other psychoactive drugs are used. Other therapeutic agents which can be used in combination with the compounds of the present invention are exemplified by, for example, ondansetron, granisetron, metoclopramide, sumatriptan (sumatriptan). ), rauvolscine, yohimbine, metoclopramide, fluoxetine, citalopram, escitalopram, non Femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine, venlafaxine , reboxetine, milnacipran, duloxetine, imipramine, amitriptiline, chlomipramine, nortripte Nortriptiline, bupropion, amineptine, divalproex, carbamazepine, diazepam-17- 201236682 (diazepam) 'lipe Ketone (risperidone), olanzapine (olan Zapine), ziprasidone, aripiprazole, quetiapine, perospirone, clozapine, haloperidol, pimo Pimozide, droperidol, chlorpromazine, thioridazine, mesoridazine, trifluoperazine, warp chloropropyl ( Perphenazine), fluphenazine, thiflupromazine, prochlorperazine, acetophenazine, thiothixene, chlorprothixene , lamotrigine, loxapine, molindone, and the like. These combinations can be administered simultaneously (same medical prescription or different medical prescription), individually or continuously. In terms of the advantages associated with the use and treatment of the combination of the compounds of the present invention, it can be mentioned that the administration amount of each component is generally equal or more improved with less dosage than the usual administration. . It is also expected to be more effective in the treatment of positive symptoms and/or negative symptoms and/or cognitive dysfunction of mental disorders. The use and treatment of the combination of the present invention is advantageous for the treatment of patients who are not well treated or resistant to certain neuromuscular drugs. The administration amount of the compound of the present invention is 1 to 2 mg mg per day in the treatment of an adult, and this administration can be carried out once or several times a day. The dose can be appropriately increased or decreased depending on the age, weight and symptoms of the patient. The compound of the formula 制造 can be produced by various synthetic methods. The following -18-201236682 method is an illustration of the production method of the compound of the present invention, and is not limited thereto. In the general production method, the "inert solvent" may, for example, be an alcohol such as methanol, ethanol, isopropanol, η-butanol or ethylene glycol, diethyl ether, t-butyl methyl ether or diisopropyl ether. , ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, hydrocarbons such as pentane, hexane, heptane, toluene, benzene, xylene, etc., ethyl acetate An ester such as ethyl formate, a ketone such as acetone or methyl ethyl ketone, a halogenated carbon-based solvent such as chloroform or dichloromethane, dimethylformamide or N-methylpyrrolidone. Amidoxime, acetonitrile, dimethylhydrazine, water or a mixed solvent thereof. The "alkali" is a hydride of an alkali metal or an alkaline earth metal such as lithium hydride, sodium hydride, potassium hydride or calcium hydride; lithium decylamine, sodium decylamine, lithium diisopropyl decylamine, lithium dicyclohexyl hydrazine; An alkali metal or an alkaline earth metal amide such as an amine, lithium hexamethyldiazine nitride, sodium hexamethyldiazine nitride or potassium hexamethyldifluoride; sodium methoxide, sodium ethoxylate, a lower alkoxide of an alkali metal or an alkaline earth metal such as potassium tert-butyl oxide; an alkyl lithium such as butyl lithium, sec-butyl lithium, tert-butyl lithium or methyl lithium; sodium hydroxide or hydrogen a hydroxide of an alkali metal or an alkaline earth metal such as potassium oxide, lithium hydroxide or barium hydroxide; a carbonate of an alkali metal or an alkaline earth metal such as sodium carbonate, potassium carbonate or carbonic acid; sodium hydrogencarbonate or potassium hydrogencarbonate; Hydrocarbonate of an alkali metal or alkaline earth metal; triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4·0 Η--carbon-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), anthracene, fluorene-dimethylaniline, etc.; pyridine, imidazole ,2 , a basic heterocyclic compound such as 6-lutidine or the like. These bases can be suitably selected according to the respective reaction conditions of -19 - 201236682 which are well known to those skilled in the art. The "acid" includes inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as P-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, acetic acid, acetic acid, citric acid, and oxalic acid. These acid groups can be appropriately selected in accordance with various reaction conditions known to those skilled in the art. In a general production method, X1 and X4 represent a halogen atom or a hydroxyl group; X2 represents a chlorine atom, a bromine atom, an iodine atom or a trifluoromethanesulfonyloxy group; and X3 represents a halogen atom or a trifluoromethanesulfonyloxy group. ; P1 represents a protecting group for a nitrogen atom such as tert-butoxycarbonyl or benzyloxycarbonyl (refer to Theodora W. Green, Peter GMWuts, "Green's Protect iye Groups in Organic Synthesis," Forth Edition)"; Wiley Interscience); P2 is a protecting group for vinegar, benzyl, etc. (see above); p3 is benzyl, P-methoxybenzyl, etc. The protecting group of the amine group: P4 represents a protecting group of a nitrogen atom of a pyrazole such as 2-(trimethylsulfonyl)ethoxymethyl group (refer to the above reference); Ra represents a 1~ which can be selected from the substituent group 2 a phenyl group substituted with two substituents, or a monocyclic or bicyclic heteroaryl group which may be substituted by 1 to 2 substituents selected from the substituent group 2; Rb represents a phenyl group (the phenyl group may be C, 1 to 3 substitutions selected from groups consisting of -6 alkyl, C|-6 alkoxy and halogen atoms Substituted), Ci6 alkyl (the alkyl group may be composed of Cu alkoxy, phenyl, c3-6 cycloalkyl, halogenated Ci 6 alkoxy, _Cie ring and 3-methyl propylene oxide-3 Substituted by a group of 1 to 3 substituents selected, a halogenated Ci6 alkyl group, a c36 cycloalkyl group, a tetrahydrofuranyl 'tetrahydropyranyl group or a 5- or 6-membered heteroaryl group (the-20 - 201236682 The heteroaryl group of 5 or 6 members may be substituted by 1 or 2 substituents selected from the group consisting of a Cu alkyl group, a halogen atom and an electrophilic group; R° represents Cl. 6 alkyl (this Cu The alkyl group may be substituted by 1 to 3 substituents selected from the group consisting of Cm alkoxy, hydroxy, C 3-6 cycloalkyl, 3-methyl propylene oxide-3-yl, halogen atom and phenyl group), or C3.6 cycloalkyl; Rd and Re are the same or different, and represent a hydrogen atom or a Ci-6 compound, or a Rd&Re system and a bonded nitrogen atom together form a saturated heterocyclic ring of 4 to 6 members ( The 4 to 6 membered saturated heterocyclic ring may be substituted with a pendant oxy group or a 5-membered heteroaryl ring, and the other is synonymous with the foregoing. General Manufacturing Method 1 [Chemical 2] 0 Person HN Ν-κ

R3V (2) Steps (1) R2 r54—x1 R6

Step i: The compound [1] of the present invention is obtained by reacting the compound (1) with a compound (2) wherein X1 is a halogen atom in an inert solvent in the presence or absence of a base. Alternatively, the compound (1) and the compound (1) wherein X1 is a hydroxyl group in an inert solvent in the presence or absence of a base, by using an organic phosphorus compound and an azo compound or a phosphorus-containing alkylene The compounding reaction [I] of the compound of the present invention can be carried out. Here, examples of the organophosphorus compound include triphenylphosphine and tributylphosphine; and examples of the azo compound include diethyl azodicarboxylate diisopropyl azodicarboxylate and azo. The diter butyl ester of dicarboxylic acid or the like; and the reagent of the phosphorus-containing alkylene compound may, for example, be cyano-21 - 201236682 methylene tributylphosphane or the like. General manufacturing method

Step 2: Compound (3) and compound (4) are carried out in an inert solvent in the presence or absence of a base using a palladium catalyst or a copper catalyst and optionally a ligand of the metal catalyst thereof. The reaction gives the compound [I] of the present invention. Here, examples of the palladium catalyst include Pd(OAc) 2 and Pd2(dba)3 'Pd(PPh3)4, and examples of the copper catalyst include Cul and CuBr. Examples of the ligand of the palladium catalyst include triphenylphosphine, Xantphos, BINAP (registered trademark), and the like, and the ligand of the copper catalyst may, for example, be N,N'-dimethylethylenediamine. 1,2-cyclohexanediamine, phenanthroline, quinonecarboxylic acid, and the like. General manufacturing method 3 [Chemical 4]

Step 3: The compound (5) is cyclized using a reagent such as triphosgene, phosgene or carbonyldiimidazole in an inert solvent in the presence or absence of a base to give the compound [I] of the present invention. The above compound (1) is produced by the following method. General Manufacturing Method 4 -22- 201236682 [Chemical 5] Step 4 Ρ1 h2n-r1 (8).

Ρ1-χ> (6) R3^〇 (7) Step 6

(10) Step 7 Step 5

Step 4: In an inert solvent, the compound (7) can be obtained by a general oxidation reaction from an alcohol to an aldehyde using an oxidizing agent. Here, the oxidation reaction may be carried out by a method using an oxidizing agent such as IBX, TEMPO, PCC or PDC, or Swern oxidation. Step 5: Compound (9) can be obtained by supplying compound (7) and compound (8) to a reductive amination reaction using a reducing agent in an inert solvent in the presence or absence of an acid. Examples of the term "reducing agent" include hydrogenated sodium triethoxyborohydride, sodium cyanoborohydride, sodium borohydride and the like. Step 6: Deprotection reaction as described in Theodora W. Green, Peter GMWuts, "G ree η 's P Rotective G roupsi η Organic Synthesis, Forth Edition", to obtain a compound ( 1 0) ^ Step 7: The compound (10) can be converted into the compound (1) by the same method as the step 3 in the general production method 3. The compound (1) can also be produced by the following method. General Manufacturing Method 5 -23- 201236682 [Chem. 6]

H2N R

(11) R1

O

O Λ Ri

- ► HN NK Step 10 (1) Step 8: In an inert solvent, in the presence or absence of a base, for example, a compound (1 2)-like isocyanate can be reacted with compound (1 1) to form a urea structure, The compound (13) was obtained. Step 9: Compound (14) can be stirred by heating in an inert solvent in the presence or absence of a base to give compound (14). Step 10: Compound (14) can be reacted with a reducing agent in an inert solvent to obtain compound (1). Here, the reducing agent may, for example, be lithium aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride or the like. Further, it may be heated or stirred or aluminum trichloride may be used as needed. The above compound (1) can also be produced by the following method. General Manufacturing Method 6 [Chem. 7] K〇H (15) OCN-R1 (12)

°Y Step 11 R1 ΝΗ

Step 12 Ο ΗΝ person NTR1

r3V Step 11: Compound (15) can be converted into a compound (ϊ6) by the same method as Step 8 in General Manufacturing Method 5 « -24- 201236682 Step 12: According to Journal of Organic Chemistry (1999, 64, The compound (1) can be obtained from the compound (16) by the method described in 294 1 - 2943). The above compound (1) can also be produced by the following method. [Chemical 8] 0 r3^r4 (17) Step 13 0X HN NH R3Vb Step 14 (18) 0X HN NHR3V (19) X2- R1 (4) Step 15

HN Ο Λ Ri N^r R3V (1) Step 1 3: Compound (17) with ammonium carbonate, potassium cyanide or trimethyl sulfonium cyanide in an inert solvent in the presence or absence of a base The cyanolation reagent 'is heated as needed to give the compound (18). Step 14: Compound (18) can be converted into Compound (19) by the same method as Step 1 in General Manufacturing Method 5. Step 15: Compound (19) can be converted into compound (1) by the same method as in Step 2 of the general production method 2. The above compound (10) can also be produced by the following method. General Manufacturing Method 8 【化9】Ρΐ.>ί〇Η h2n-r1 (8) (2〇> Step 16 VVR1 —^ R R H Step 17 (21)

, R1 Step 18 R3 R4 (10) , R1 -25- 201236682 Step 16: The indoleamine can be carried out by using the compound (8) for the compound (20) in an inert solvent in the presence or absence of a base. The reaction is carried out to give the compound (2 1). Here, the guanidation reaction can be carried out by most standard methods well known to those skilled in the art, for example, using ethyl chlorocarbonate, isobutyl chlorocarbonate, trimethylethyl sulfonium chloride or the like via a mixed acid anhydride. The imidization performed is either using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDOHC1), 1,3-dicyclohexylcarbazide Imine (DCC), diphenylphosphoryl azide (DPPA), diethyl cyanophosphate, carbonyl diimidazole (CDI), 0-(7-azabenzotriazol-1-yl) -N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or benzotriazol-1-yloxy ginseng (dimethylamino)scale hexafluorophosphonate (BOP reagent) And the condensing agent such as hydrazide. Here, an additive such as 1-hydroxybenzotriazole (HOBt) or hydroxyammonia imine (HOSu) may be used as needed in the case of using a hydrazine amidation reaction. Step 17: Compound (21) can be converted into Compound (22) by the same method as Step 6 in General Production Method 4. Step 18: In an inert solvent, the compound (10) can be obtained by reacting a reducing agent with the compound (22). Here, the reducing agent is a reagent which can reduce the indoleamine and convert it into an amine, and examples thereof include lithium aluminum hydride, borane, sodium bis(2-methoxyethoxy)aluminum hydride, diisobutylaluminum hydride, and the like. . The above compound (3) can also be produced by the following method. General Manufacturing Method 9 -26- 201236682 [Chemical 1 0] h2n-p3 § (23) R3 person f 'R4 (17) Step 19 P3 HN CN R3XR4 (24) Step 20 NH NH, (25)

PK

P3, NH HN-p1

H2N HNR3V R2 r5^-x2 R2, a pi R6 or CHO —(28)__(29) Step 21 (26) Step 22 (27) Step 23

Step 19: Compound (I7) can be reacted with an inorganic cyanating reagent or an organic cyanating reagent in the presence of an acid (23) in an inert solvent in the presence or absence of an acid to obtain a compound ( twenty four). Here, the inorganic cyanation reagent may, for example, be potassium cyanide or sodium cyanide, and the organic cyanation reagent may, for example, be trimethyldecyl cyanide. Step 20: Compound (25) can be obtained by subjecting compound (24) to a reduction reaction in an inert solvent. Here, the reduction reaction refers to a method of reducing a cyano group to a first-order amine, and examples thereof include a method of using a reducing agent such as lithium aluminum hydride in an inert solvent, or a catalyst such as palladium carbon in a hydrogen atmosphere. Contact hydrogenation reaction, etc. Step 21: According to the protection reaction of the amine described in Theodora W. Green, Peter G. M. Wuts, "Gre en's Protective Groups in Organic Synthesis' Forth Edition", it can be obtained from the compound (25). Compound (26). -27-201236682 Step 22: Compound (26) can be converted into Compound (27) by the same method as Step 6 in General Manufacturing Method 4. Step 23: Compound (28) can be obtained by reacting compound (28) with compound (27) in an inert solvent in the presence or absence of a base to give compound (30). Further, in an inert solvent, the compound (2*7) and the compound (29) can be subjected to a reductive amination reaction in the same manner as in the general method 4 in the production method 4 in the presence or absence of an acid. And a compound (30) in which both R5 and R6 are a hydrogen atom. Step 24: Compound (30) can be converted into Compound (31) by the same method as Step 6 in General Production Method 4. Step 25: Compound (31) can be converted into Compound (3) by the same method as Step 3 in General Production Method 3. The above compound (5) can also be produced by the following method. General manufacturing method 10

Step 26: Compound (5) can be obtained by reacting compound (31) with compound (32) in an inert solvent in the presence or absence of a base. Further, when X3 is a chlorine atom, a bromine atom, an iodine atom or a trifluoromethanesulfonyl-28-201236682 oxy group, it is used in an inert solvent in the presence or absence of a base, even if it is used and a general production method. The palladium catalyst and the optional ligand described in the second step of 2 may also be converted into the compound (5). Step 27: Compound (10) can be converted into Compound (5) by the same method as Step 23 in General Manufacturing Method 9. However, when compound (29) is used, R5 and R6 are both a hydrogen atom. General manufacturing method Π 【化1 2】

Step 28: Compound (34) can be obtained from Compound (1) and Compound (33) by the same procedure as in Step 1 in the General Production Method 1. Step 29: reacting the compound (3) with a palladium catalyst and optionally a ligand in an inert solvent in the presence or absence of a base in the presence or absence of a compound (34) wherein X4 is a halogen atom. The compound of the present invention [12] is obtained. Here, examples of the palladium catalyst include Pd(OAc) 2, Pd2(dba)3, and Pd(PPh3)4, and examples of the ligand include triphenylphosphine, Xantphos, and BINAP (registered trademark). Wait. Further, the compound (35) represents an organic -29 - 201236682 metal reagent, and examples thereof include a Grignard reactant such as RbMgCl, a zinc reactant such as RbZnCl, a boron reactant formed by bonding Rb with boric acid or a boric acid ester, or a boron reactant such as RbSnBu3. Tin reactants, etc. Step 30: For the compound (34) wherein X4 is a halogen atom, the compound [13] of the present invention can be obtained by reacting the compound (36) in an inert solvent in the presence or absence of a base. In this step, a palladium catalyst, a copper catalyst, and various ligands as given in the second step of the general production method 2 may be used as needed. Step 31: The compound (3 4) wherein X4 is a halogen atom can be obtained by reacting a compound (37) wherein X is a hydroxyl group in the presence or absence of a base in an inert solvent. Inventive compound [14]. Further, the compound (3 4)' wherein X4 is a hydroxyl group can also be obtained by reacting a compound (37) wherein X1 is a halogen atom in the presence or absence of a base in an inert solvent. 14 ]. General manufacturing method 12 [Chemical 1 3]

-30- [15] 201236682 Step 32: The compound (39) can be obtained from the compound (1) and the compound (38) by the same method as in the step 1 of the general production method. Step 33: Compound (39) can be converted into Compound (40) by the same method as Step 6 in General Production Method 4. Step 34: The compound (41) can be reacted with the compound (40) in an inert solvent in the presence or absence of a base to give the compound [15] of the present invention. Further, when Rb is a phenyl group which may be substituted or a heteroaryl group which may be substituted, the compound (41) of the present invention can be obtained by reacting the compound (41) with a copper catalyst and, if necessary, a ligand. Here, examples of the copper catalyst include Cul and CuBr, and examples of the ligand include N,N'-dimethylethylenediamine, 1,2-cyclohexanediamine, phenanthroline, and anthracene. Carboxylic acid and the like. [Examples] Hereinafter, the present invention will be described in more detail by way of Production Examples, Examples and Test Examples, but the present invention is not limited to the Examples. The microwave reaction apparatus used in the following Production Examples and Examples is Biotage's Initiator. In the following production examples and examples, Biotage (registered trademark) SNAPCartridge KP-NH and "Secondary Oxide Colloidal Sleeve Dialyser" were used in the "NH2 ruthenium colloidal sleeve dialysis device" for purification by column chromatography. Use Biotage (registered trademark) SNAPCartridge KP-Sil or HP-Sil in j. M0RITEX (registered trademark) Purif-Pack ODS is used in "reverse phase cerium oxide colloidal sleeve dialysis machine". In the following production examples and examples, the "NH2 cerium oxide colloid" used in the purification by fractional thin layer chromatography (PTLC) -31 - 201236682 is used, and the light, NH2 cerium oxide colloid 60F254 Plate-Wako 20cmx20cm, In the "cerium oxide colloid", in the production examples and examples using Merck, cerium oxide colloid 60F2 54 and 20 cm x 20 cm 〇, the purification by fractional high-speed liquid chromatography (HP LC) 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 for obtaining a free body is carried out. Machinery: Gilson preparative HPLC system Column: Shiseido Capcelpak Cl 8 MGII 5μπι 2〇χ 1 50mm Solvent: A solution; 0.1% trifluoroacetic acid-containing water, B solution; 0.1% trifluoroacetic acid-containing acetonitrile gradient condition 1: 〇分(A liquid / B liquid = 90/10), 22 points (A liquid / B liquid = 20/80), 25 points (A liquid / B liquid = 10/90) Gradient condition 2: 0 points (A liquid /B liquid = 8 0/20), 20 minutes (A liquid / B liquid = 5/ 95), 25 points (A liquid / B liquid = 1 / 99) Flow rate: 20mL / min, detection method: UV 254nm or less In the production examples and examples, the mass spectrum (MS) was measured under the following conditions.

MS spectrum: Shimadzu LCMS-2010EV or micromass Platform LC The following fabrication examples and structures were confirmed using nuclear magnetic resonance spectroscopy (NMR). Nuclear magnetic resonance spectroscopy (NMR) was measured under the following conditions. NMR spectrum: [1 H-NMR] 600 MHz: JNM-EC A600 (Nippon Electric-32-201236682), 500 MHz: JNM-ECA500 (Japan Electronics), 300 MHz: UNITY NOVA3 00 (Varian Inc.) > 200 MHz: GEMINI 2000/200 (Varian Inc.) In the following production examples and examples, the compound names are named according to ACD/N ame (ACD/Labs 12.01, Advanced Chemistry Development Inc.). Production Example 1 3-[6-(three Fluoromethyl)pyridin-3-yl]-1,3-diazaspiro[4.5]decane-2-one [Chemical 1 4]

(1) 2-Dioxyiodobenzoic acid (1.2 g) was added to a solution of [1-(hydroxymethyl)cyclohexyl]carbamic acid tert-butyl ester (0.82 g) in DMSO (10 mL). Stir for one night. Water, ethyl acetate, and insoluble matter were filtered off with diatomaceous earth. The filtrate was extracted with ethyl acetate. The mash layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. After concentrating the filtrate under reduced pressure, the residue was dissolved in chloroform (1 mL), and 2-trifluoromethyl-5-aminopyridine (0.7 g) and hydrogenated sodium triacetoxyborate (1.1 g) were added. Stir at room temperature for one night. After adding a saturated aqueous solution of sodium hydrogencarbonate and extracting with chloroform, it was dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solution was filtered and concentrated under reduced pressure 201236682. The residue was purified by column chromatography (cerium oxide colloidal dialyzer, hexane / ethyl acetate) to give Π-({[6-(trifluoromethyl)pyridin-3-yl]amino} Methyl)cyclohexyl]carbamic acid t ert-butyl ester (0.63 g). 1H NMR (600 MHz > C HLOROFORM-d) d ppm 1.17 -2.11 (m, 19 H), 3.66 (s, 1 H), 4.28 - 4.64 (m, 2 H), 6.86 - 6.95 (m, l H ), 7.41 (d, J = 8.3 Hz, 1 H), 8.04 (d, J = 3.2 Hz, l H) (ESI pos.) m/z : 3 96([M + Na] + ) (2) Add 4M hydrochloric acid to a solution of [l-({[6-(trifluoromethyl)pyridin-3-yl]amino}methyl)cyclohexyl]carbamic acid tert-butyl ester (600 mg) in ethanol (8 mL) /ethyl acetate (4 mL), stirred for one night. The reaction mixture was concentrated under reduced pressure. The organic layer was dried over anhydrous sodium sulfate, and then filtered and evaporated. Ν-[(1·Aminocyclohexyl)methyl]-6-(trifluoromethyl)pyridine-3-amine (300 mg) 〇 (ESI pos.) m/z: 274 ([M + H] +) (3) 1'1^ (10〇11〇 solution) of N-[(1-aminocyclohexyl)methyl]-6-(trifluoromethyl)pyridin-3-amine (3 001^) Triethylamine (0.71111 〇) was added, and the mixture was cooled to dryness. EtOAc (EtOAc) was evaporated. 'The desiccant was filtered off, and the filtrate was evaporated.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Hz,2 H) > 1.5 7 - 1.67 (m,3 H) > 1.67 - 1.7 9 (m,5 -34- 201236682 Η) ' 3.69 (s,2 Η) ' 5.52 (br. s.,l Η) ' 7.64 (d, J = 8.7 Hz H), 8.36 (s, l H), 8.69 (d, J = 2.8 Hz, l H) (ESI pos.) m/z : 3 00 ([M + H ]+) (ESI neg.) m/z : 298 ([MH]-) The following compound was synthesized in the same manner: 3-(5-methoxypyridin-2-yl)-1,3-diazide Heterospiro[4.5]decane-2-ketone (ESI pos.) m/z 2 62([M + H] + ) 4- ( 2-sided oxy-1,3-diazaspiro[4.5]indol-3-yl)benzoic acid methyl vinegar (ESI pos.) m/z : 289 ([M + H] + ) 3-(6- Methoxypyridin-3-yl)-1,3-diazaspiro[4.4]nonan-2-one (ESI pos.) m/z : 248 ([M + H] + ) 3-(6-chloro Pyridin-3-yl)-1,3-diazaspiro[4.5]decane-2-one (ESI pos.) m/z : 266 ([M + H] + ) 3-(6-methoxy Pyridin-3-yl)-1,3-diazaspiro[4.5]decane_2_嗣(ESI pos.) m/z : 262([M + H]+) 3-(卩比陡-3 -yl)-1,3-diazaspiro[4.5]valer-2-one (ESI pos.) m/z : 23 2([M + H] + ) 3-(2,4-difluorobenzene ))-1,3-diazaspiro[4.5]decane-2-ketone (ESI pos.) m/z : 267 ([M + H]+) 3-(4-fluoro-3-methoxy Phenyl)-1,3-diazaspiro[4.5] brothel_2_嗣(ESI pos.) m/z : 279([M + H] + ) 3-(5-chloropyridin-2-yl - 1,3-diazaspiro[4-5]decane oxime (ESI pos.) m/z : 266 ([M + H] + ) 3-(5-fluoropyridin-2-yl)-1, 3-diazaspiro[4.5]decane-2 ketone-35- 201236682 (ESI pos.) m/z : 250([M + H] + ) 3-(6-methylpyridin-3-yl) -1,3-diazaspiro[4.5]decane-2-one (ESI pos.) m/z : 246 ([M + H] + ) 3-(2-methoxypyridin-4-yl) -1 ,3-diazaspiro[4.5]decane-2-one (ESI pos.) m/z 262([M + H] + ) 3-(4-methylphenyl)-1,3-diazepine Heterospiro[4 ·5]nonan-2-one (ESI pos.) m/z : 245 ([M + H] + ) 3- (4-ethylphenyl)-1,3-diaza snail [4..5] decane-2-one (ESI pos.) m/z : 259 ([M + H] + ) 4- (2-methylpropyl)-1-[6-(trifluoromethyl) Pyridin-3-yl]imidazole [1 _2 (ESI pos.) m/z : 28 8 ([M + H] + ) 4-(propyl phenyl-2-yl)·1-[6-( Dimethyl group) 卩 陡 steep-3· base] miso _2 (ESI pos.) m/z : 274 ([M + H]+) 3-(6-bromopyridine-3-yl)-1 ,3-diazaspiro[4.5]decane-2-one (ESI pos.) m/z : 3 10([Μ + Η]+) 3-(5-methoxypyridin-3-yl)- 1,3-diazaspiro[4.5]decane-2 ketone (ESI pos.) m/z : 262 ([M + H]+) 3-(5-fluoropyridin-3-yl)-1, 3-diazaspiro[4.5]nonan-2-one (ESI pos.) m/z : 250([M + H]+) 3-(5-methylpyridin-3-yl)-1,3 -diazaspiro[4.5]decane-2-ketone (ESI pos ·) m/z : 246([M + H] + ) 3-(6-fluoropyridin-3-yl)-1,3-di Azaspiro[4.5]decane-2-one-36- 201236682 (ESI pos.) m/z : 250([M + H]+) 4-(butan-2-yl)-l-[6- (trifluoromethyl)pyridine-3 Imidazopyridine 2-(ESI pos.) m/z : 2 8 8([M + H]+) 3-(4-methoxyphenyl)_ι,3-diazaspiro[4.5]癸Alkan-2-one (ESI pos.) m/z : 26 1 ([M + H]+) 3-(6-ethoxypyridin-3-yl)-1,3-diazaspiro[4.5]癸 -2- ketone (ESI pos.) m/z : 276 ([M + H] + ) l-(4-methoxyphenyl)-4-propylimidazolidin-2-one (ESI pos. m/z : 2 5 7 ([M + Na] + ) Production Example 2 3-(4-fluorophenyl)_i,3-diazaspiro[45]decane-2-ketone [Chemical 1 5] H2N C02Me (1)

(1) In a solution of hydrazine-aminocyclohexanecarboxylic acid methyl hydrochloride (1.23 g) in ethanol (13 mL), triethylamine (27 mL), 4-fluorophenylisocyanate (0.87 mL) Under ' stirring at i5 ° °c for 15 minutes. A total of 3 sets of 'all together' were subjected to the same operation and concentrated under reduced pressure. Water (10 mL) was added and stirred at room temperature for 10 minutes and then filtered. The solid was washed with water and ethyl acetate to give 3-(4-fluorophenyl)-1,3-diazaspiro[4.5]decane-2,4-dione (3.77 ru). (ESI pos.) m/z : 263 ([M + H]+) (2) Under a nitrogen atmosphere '3-(4-fluorophenyl)_i,3-diazaspiro[4.5] 201236682 decane- 2'4-dione (3.68) 1'}^(7〇1111〇 solution was added with hydrogenated bis(2-methoxyethoxy)aluminum sodium (70%/toluene solution, 19.7 g), and heated to reflux 4 After ice-cooling, a 2M aqueous solution of potassium hydroxide (100 mL) was added, and ethyl acetate was evaporated. After drying over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. Purification of the ruthenium dioxide colloid, hexane/ethyl acetate = 70: 30 to 60: 40) to give the title compound (2.5 g) (ESI pos.) m/z 249 ([M + H] + ) Example 3 4-(2-Sideoxy-1,3-diazaspiro[4.5]indol-3-yl)benzyl ester of acetic acid [Chemical 1 6]

(1) A solution of 4-(2-oxo-oxy-1,3-diazaspiro[4.5]indol-3-yl)benzoic acid methyl ester (25 mg) in THF (5 mL) was ice-cooled, and aluminum hydride was added. Lithium (66 mg) 'Stirring for 2 hours. 1 〇% aqueous sodium hydroxide solution (1 mL) was added dropwise, and the mixture was stirred at room temperature for 30 minutes, then anhydrous magnesium sulfate was added. The desiccant was filtered off, and the filtrate was dried under reduced pressure to give 3-[4-(hydroxymethyl)phenyl]-indole, <RTI ID=0.0>> 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.40 - 1.78 (m,10 Η) > 3.65 (s,2 Η) « 4.65 (s,2 Η) » 4.84 - 4.93 (m,l Η) * 7.31 - 7.39 (m,2 Η) > 7.52 - 7.5 7 (m,2 Η) -38- 201236682 (ESI pos·) m/z : 261([M + H]+) (2) 3-[4 -(Hydroxymethyl)phenyl]-1,3-diazaspiro[4.5]decane-2-one (〇.2g) was dissolved in chloroform (5 mL), triethylamine (0.22 mL) and anhydrous Acetic acid (0.11 mL) was stirred at room temperature for 30 min. After adding a saturated aqueous solution of sodium hydrogencarbonate, the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was evaporated. 1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.25 -1.78 (m, 10 H), 2.06 (s, 3 H), 3.62 (s, 2 H), 4.95 - 5.11 (m, 3 H), 7.26 - 7.3 9 (m, 2 H), 7.47 - 7.61 (m, 2 H) (ESI pos.) m/z : 325 ([M + Na] + ) Preparation Example 4 3-(6-methoxypyridine-3 -yl)-8-oxa-1,3-diazaspiro[4.5]decane-2-one [Chemical 1 7]

(1) Diisopropyl B was added to a solution of 4-{[(benzyloxy)carbonyl]amino}tetrahydro-2H-furan-4-carboxylic acid (〇.85 g) in chloroform (15 mL) Base amine (0.571111〇, 11 八1'1; (1.25 8) and 5-amino-2-methoxypyridine (〇.418), stirred at room temperature for one night. Add saturated aqueous sodium hydrogencarbonate to chloroform Extracted -39- 201236682, dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (cluster colloidal dialysis, chloroform / methanol). 4-[(6-Methoxypyridin-3-yl)aminemethanyl]tetrahydro-2H-indol-4-yl}carbamic acid benzyl ester (465 mg). 1H NMR (600 MHz, CHLOROFORM -d) d ppm 1.98 - 2.08 (m,2 H) * 2.28 - 2.39 (m,2 H) > 3.61 - 3.73 (m,2 H) > 3.82 - 3.8 8 (m,2 H) » 3.91 ( s,3 H)> 5.03 (s,l H)» 5.13 (s,2 H), 6.70 (d, J = 9.2 Hz, l H), 7.28 - 7.43 (m, 5 H), 7.66 - 7.88 ( m,l H),8.13 (br. s.,l H),8.88 (br. s.,l H) (ESI pos.) m/z 3 8 6 ([M + H] + ) • (2) {4-[(6-Methoxypyridin-3-yl)aminemethanyl]tetrahydro-2H-indol-4-yl}amine Add 5% palladium on carbon (3 Omg) to a solution of benzylic acid (3 〇〇mg) in ethanol (5 mL). After the system was replaced with hydrogen, stir-night. Palladium-carbon was removed. The filtrate was concentrated under reduced pressure. 4-Amino-N-(6-methoxy D-pyridin-3-yl)tetrahydro-211-nonan-4-carboxamide (19〇1118). 1H NMR (600 MHz, CHLOR〇) FORM-d) d ppm 1.31 - 1.41 (m,2 Η)' 1.65 (br. s.,2 Η)' 2.36 - 2.47 (m,2 Η), 3.60 - 3.70 (m,2 Η) ' 3.91 (s , 3 Η), 3.94 - 4.01 (m, 2 Η), 6.73 (d, J = 8.7 Ηζ, Ι H) - 8.00 - 8.07 (m, l H) . 8.20 (d, J = 2.3 Ηζ, Ι H) > 9.80 (br. s., 1 H) (ESI pos.) m/z : 252([M + H] + ) (3) 4-Amino-N-(6-methoxypyridine_3 A solution of tetrahydro-2H-purpurin-4_carboxamide (18 mg) in THF (6 mL) was evaporated. After ice-cooling, 1% by weight of nitrogen-40-201236682 sodium hydroxide aqueous solution (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. After drying over anhydrous magnesium sulfate and filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (cerium oxide colloidal dialyzer, chloroform/methanol) to give N-[(4-aminotetrahydro-2H-indol-4-yl)methyl]-6- Methoxypyridin-3-amine (1 65 mg) 〇1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.43 - 1.49 (m, 2H) '1.70 - 1.80 (m, 2H), 2.97 (s, 2H), 3.71-3.78 (m,4 Η), 3.86 (s,3 Η), 6.61 (d, J = 9.2 Hz, 1 Η), 6.99 - 7.06 (m, l H), 7.60 (d, J = 3.2 Hz, l H) (ESI pos.) m/z : 23 8 ([M + H] + ) (4) In the same manner as in Production Example 1 (3), from N-[(4-aminotetrafluoro_ 2H - The title compound (7 3 mg) was obtained from yt. 1H NMR (600 MHz, CHLOROFORM-d) d ppm i .79 . 1_91 (m, 4 H), 3.70 (s, 2 H), 3.71 - 3.80 (m, 4 H), 3.91 (s, 3 H) ' 5_25 (br. s.,l H) ' 6.75 (d, J = 9.6 Hz, 1 H), 8.03 (d, J = 2.3 Hz, l H), 8.06 - 8.14 (m, l H) (ESI pos. m/z : 264 ([M + H] + ) Example 5 4-Cyclohexyl-1-(4-methoxyphenyl)imidazolidine-2-one [Chem. 1 5 8]

-41 - 201236682 (1) 4-methoxyphenyl isocyanate (〇.25 mL) was added dropwise to a solution of 2-amino-2-cyclohexylethanol (300 mg) in THF (10 mL). After concentrating the reaction mixture under reduced pressure, the solid was washed with diethyl ether to give 1-(1-cyclohexyl-2-hydroxyethyl)-3-(4-methoxyphenyl) urea (0.56 g) ). 1 H NMR (200 MHz, CHLOROFORM-d) d ppm 0.85 - 1.87 (m, ll H) > 2.93 - 3.11 (m, l H)> 3.56 - 3.70 (m, 2 H), 3.81 (s, 3 H) > 4.82 - 4.96 (m, IH), 6 · 4 8 (b r. s, 1 H), 6.81 - 6.96 (m, 2 H), 7.16 - 7.31 (m, 2 H) (ESI pos. m/z : 293([M + H] + ) (2) Under ice-cooling, l-(i-cyclohexyl-2-hydroxyethyl)-3-(4-methoxyphenyl)urea (〇) To a solution of THF (10 mL) in THF (10 mL) was added to a solution of EtOAc (3 mL). After stirring for 30 minutes under ice-cooling, water was added, and ethyl acetate was evaporated and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography chromatography chromatography chromatography chromatography 1H NMR (200 MHz, CHLOROFORM-d) d ppm 0.83 -1.91 (m,ll Η) - 3.40 - 3.65 (m,2 Η) > 3.77 (s,3 Η) > 3.82 -3.96 (m,l Η > 4.73 (br. s.,1 H) > 6.71 - 6.93 (m,2 H) > 7.35 - 7.48 (m,2 H) (ESI pos.) m/z : 275([M + H ] + ) In the same manner, the following compound was synthesized. 4-Benzyl-1-(4-methoxyphenyl)imidazolidin-2-one (ESI pos.) m/z : 283 ([M + H]+) -42- 201236682 4-(2,2-Dimethylpropylmethoxyphenyl)imidazolidine-2-one (ESI pos.) m/z : 263 ([M + H] + ) 1-(4-Methoxyphenyl)-4-phenylimidazolidine-2-one (ESI pos.) m/z: 269 ([M + H]+). -2-yl)-1,3-diazaspiro[4.5]decane-2-one [Chemical 19]

1,3-diazaspiro[4_5]nonan-2-one (100 mg), 5-chloro-2-iodopyranidine D, P d 2 (db a) 3 (3 4 m g) under a nitrogen atmosphere A solution of Xantphos (38 mg) and tert-butoxy sodium (94 mg) in toluene (4 mL) was stirred at 100 ° C for 2 h. The reaction solution was diluted with chloroform, and then a mixture of NH. This was purified by column chromatography (silica silica gel, chloroform/methanol) to give the title compound (1 2 3 mg). (ESI pos.) m/z : 267 ([M + H] + ) 1H NMR (600 MHz, CHLOROFORM-d) d ppm χ Z1 1.76 (m, 10 H), 3.85 (s, 2 H), 5.13 ( Br. s., l H), 8.55 (s 2 H) In the same manner, the following compounds were synthesized. 3-[6-(Trifluoromethyl)pyridin-3-yl]-1,3-diazaspiro[4.61 + C~carban-2-one (ESI pos.) m/z : 3 14 ([ M + H] + ) -43- 201236682 4 -Methyl-4-(propylidene-2-yl)-1-[6-(trifluoromethyl)卩仕卩定-3-基]咪哇症- 2-ketone (ESI pos.) m/z : 288 ([M + H]+) 3-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]-1,3-diaza Snail [4.5] 癸院-2 -嗣(ESI pos.) m/z : 3 1 8([M + H] + ) 3-[5-(trifluoromethyl)indole-2-yl]-1 , 3-diazaspiro[4.5] brothel - 2-ketone (ESI pos.) m/z : 301 ([M + H] + ) Production Example 7 3-[.6-(Difluoromethyl) shame Pyridin-3-yl]-1,3-diazaspiro[4.5]癸

(1) DMF-methanol (2:1, 8 mL·) in 3-(6-bromopyridin-3-yl)-1,3-diazaspiro[4.5]nonan-2-one (520 mg) Potassium carbonate (348 mg) and Pd(PPh3) 4 (194 mg) were added to the solution, and the reaction system was replaced with carbon monoxide gas, followed by stirring at 80 ° C for 2 hours. After adding a saturated aqueous solution of sodium hydrogencarbonate and extracting with ethyl acetate, the organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then filtered to remove the desiccant, and then concentrated under reduced pressure to dissolve -44 - 201236682. The residue was washed with a mixed solvent of hexane and ethyl acetate (5:1) to give 5-(2-oxo-1,3-diazaspiro[4·5]indol-3-yl)pyridine. 2-carboxylic acid methyl ester (3 89 mg). 1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.40 -1.90 (m, 10 Η), 3.71 (s, 2 Η), 4.01 (s, 3 Η), 5.65 (br. s, l H), 8.06 - 8.19 (m, l H), 8.26 - 8.3 8 (m, l H), 8_74 (d, J = 2.2 Hz, l H) (2) at 5-(2-oxo-1,3-diazepine To a solution of succinyl [4.5] indol-3-yl)pyridine-2-carboxylic acid methyl ester (380 mg) in THF (15 mL). After adding a saturated aqueous solution of sodium hydrogencarbonate and extracting with ethyl acetate, the organic layer was washed with water and saturated brine. After drying with anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO (10 mL), and 2-dioxyiodobenzoic acid (yield: 74 g) was added and stirred for 2 hours. Water and ethyl acetate were added to the reaction mixture, and the insoluble matter was filtered off, and then the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure to give 5-(2- s-[sup.]- 1,3-diazaspiro[4.5]indol-3-yl)pyridin-2-ylaldehyde (3 62 mg). 1H NMR (200 MHz, CHLOR 〇FORM-d) d ppm 1.42 -1.84 (m, 10 H), 3.71 (s, 2 H), 5 _ 6 3 (b rs, l H), 7.94 (d, J = 7.9 Hz, l H), 8.20 - 8.36 (m, l H), 8.7 7 - 8.87 (m, l H), 9.99 (s, l H) (3) Let 5-(2-side oxygen-1,3 -Diazaspiro[4_5]indol-3-ylpyridin-2-carboxaldehyde (3 62 mg) was dissolved in chloroform, and after ice-cooling, bis(2-methoxyethyl)-45-201236682 amine sulfur was added. Trifluoride (0.96 mL) was stirred at room temperature for 30 min. After adding a saturated aqueous solution of sodium hydrogencarbonate, the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (yield of silica gel, chloroform/methanol) to give the title compound (1 95 mg). 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.43 - 1.79 (m, 10 H) > 3.67 (s, 3 H) > 5.42 (br. s., 1 H) > 6.46 -6.78 (m, l H) > 7.59 (d, J = 8.7 Ηζ, Ι H) > 8.21 - 8.35 (m, l H) > 8.65 (d, J = 2.3 Ηζ, Ι H) (ESI pos.) m/z : 280 ([MH]-) Production Example 8 [3-(6-Methoxypyridin-3-yl)-2-oxo-1,3-1,3-diazaspiro[4.5]indol-1-yl]acetic acid [Chem. 2 1]

(1) A solution of 3-(6-methoxypyridin-3-yl)-1,3-diazaspiro[4.5]nonan-2-one (1-4 g) in DMF (20 mL) Sodium (2 66 mg), stirred for 30 minutes. Ethyl bromoacetate (0.74 mL) was added and stirred at room temperature overnight. After adding a saturated aqueous solution of sodium hydrogencarbonate and extracting with ethyl acetate, the organic layer was washed with water and saturated brine. After drying with anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (cerium oxide colloidal dialyzer, hexane/ethyl acetate = 75: 25 -46 - 201236682 to 60: 40) to give [3-(6-methoxypyridine). -3-yl)-2-oxo-1,3-diazaspiro[4.5]dec-1-yl]acetic acid ethyl ester (1.05 g). 1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.0 1 - 1.92 (m, 10 H), 1.24 - 1.37 (m, 3 H), 3.68 (s, 2 H), 3.93 (s, 3H), 3.97 ( s, 2H), 4.22 (q, J = 7.0 Hz, 2H), 6.64-6.82 (m, l H), 8.06 (d, J = 3.1 Hz, l H), 8.15 - 8·26 (m, l H (ESI pos.) m/z : 3 48 ([M + H]+) (2) in [3-(6-methoxypyridin-3-yl)-2-oxo-1,3-di Add a solution of water (5 mL) and sodium hydroxide (140 mg) to a solution of methanol (l〇m L) of azaspiro[4.5] dec-1-yl]acetate (ethyl ester). one night. After distilling off the solvent under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate was added and ethyl acetate was evaporated. The aqueous layer was made neutral with 1N hydrochloric acid, extracted with chloroform and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was evaporated. 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.09 -1.20 (m,l Η) > 1.30 - 1.41 (m,2 Η) > 1.47 - 1.60 (m,2 Η) * 1.66 - 1.90 (m, 5 Η) » 3.68 (s,2 Η) > 3.91 (s,3 Η) > 3.97 (s,2 Η) > 6.74 (d,J = 9.6 Ηζ,Ι Η) > 8.02 - 8.17 (m , 2 Η) (ESI pos.) m/z : 3 20 ([M + H]+) The following compounds were synthesized in the same manner. {2-Sideoxy-3-[6-(trifluoromethyl)pyridin-3-yl]-1,3-diazaspiro[4.5] 癸-l-yl}acetic acid (ESI pos.) m/z : 3 58([M + H] + ) [3 - (6-chloropyridin-3-yl)-2 - oxo-1,3-diazaspiro[4 · 5 ] 癸-1 -yl] - 47-201236682 (ESI pos.) m/z : 324 ([M + H] + ) Production Example 9 Propoxy-1,2-oxazol-5-yl)methyl]-1,3·diaza Snail [4.5] decane-2-one _ [Chemical 2 2]

-48- 201236682 A desiccant, and the filtrate was concentrated under reduced pressure to give 1-(aminomethyl)-N-phenylmethylcyclohexaneamine (1 g). (ESI pos.) m/z : 2 1 9 ([ M + H ] +) (3) Dissolving 1-(aminomethyl)-N-benzylcyclohexylamine (i〇.7g) in THF (150 mL) 'A solution of di-1 er t-butyl dicarbonate (1 0.9 g) in THF (50 mL) was evaporated. After stirring for 2 hours, dimethylamine (im/THF solution, 20 mL) was added and stirred for 1 minute. After concentrating the reaction mixture under reduced pressure, the residue was purified by column chromatography (c. s. s., hexane/ethyl acetate) to give {[1-(phenylmethylamino)cyclohexyl] Methyl}tert-butyl ester amide (11.6 g). (ESI pos.) m/z : 3 19([M + H]+) (4) tert-butyl ester of {[1-(benzylamino)cyclohexyl]methyl}carbamate (6.6) g) A solution of methanol (100 mL) was added with 10% palladium on carbon (i. 5 g), and the reaction system was replaced with hydrogen, followed by stirring for 3 days. After the palladium carbon was filtered off, the filtrate was concentrated under reduced pressure to give <RTI ID=0.0>> (ESI pos.) m/z: 229 ([M + H] + ) (5) DMF (lOmL) of [(1-aminocyclohexyl)methyl]carbamic acid tert-butyl ester (0.55 g) A solution of potassium carbonate (0.4 g) and 3-propyloxy-5-bromomethylisoxazole (0.55 g) in DMF (2 mL) was added to the solution and stirred overnight. After adding a saturated aqueous solution of sodium hydrogencarbonate and extracting with ethyl acetate, the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was removed, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (cerium dioxide colloidal sleeve dialysis apparatus, hexane/ethyl acetate) to obtain [n_U(3-propoxy-49-201236682-based-1,2-oxazole-5-) Methyl]amino]cyclohexyl)methyl]carbamic acid tert-butyl ester (〇.62g). (ESI pos.) m/z : 3 68 ([M + H]+) (6) In the same manner as in Production Example 1 (2), from [(l-{[(3-propoxy-1), Tert-butyl ester of 2-oxazol-5-yl)methyl]amino}cyclohexyl)methyl]carbamate (0.55 g) gives 1-(aminomethyl)-N-[(3-propane) The crude product (0.42 g) of oxy-1,2-oxazol-5-yl)methyl]cyclohexaneamine. (ESI pos.) m/z : 268 ([M + H] + ) (7) In the same manner as in Production Example 1 (3), 1-(aminomethyl)-N-[(3-propoxy) Base-1,2-oxazol-5-yl)methyl]cyclohexaneamine (.42g, mp. 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.00 (t, J = 7.6 Hz, 3 H) > 1.07 - 1.84 (m, 12 H) « 3.27 - 3.31 (m, 2 H) > 4.16 (t , J = 6.6 Hz, 2 H) > 4.30 (s, 2 H) - 5.86 (s, l H) (ESI pos.) m/z : 3 1 6([M + Na] + ) In the same way The following compounds were synthesized. 1-[(6-propoxypyridin-3-yl)methyl]-1,3-diazaspiro[4.5]decane-2-one. (ESI pos.) m/z : 3 04 ([ M + H] + ) Production Example 10 [3-(Proton-2-yloxy)-1,2-oxazol-5-yl]methanol-50-201236682 [Chem. 2 3]

(1) Potassium carbonate (5.8 g) and 2-iodopropane (3.2 mL) were added to a solution of 3-hydroxy-1,2-oxazole-5-carboxylic acid methyl ester (3.0 g) in DMF (80 mL). , Stir at 70 ° C for 3 hours. A saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give 3-(propan-2-yloxy)-1,2-oxazol-5-carboxylic acid methyl ester (3.35 g). 1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.40 (d, J = 6.2 Hz, 6 H) - 3.95 (s, 3 H) > 4.96 (spt, J = 6.2 Hz, l H) > 6.50 ( s,l H) (2) A solution of 3-(propan-2-yloxy)-1,2-oxazole-5-carboxylic acid methyl ester (3.35 g) in THF (80 mL) Aluminum lithium (0.6 8 g), stirred for 30 minutes. A 10% aqueous sodium hydroxide solution (4 mL) was added dropwise, and stirred at room temperature for 1 hour. After drying over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (yield of silica gel, hexane, ethyl acetate) to afford the title compound (1.33 g). (ESI pos.) m/z : 158 ([M + H]+) The following compound was synthesized in the same manner. (3-Ethoxy-1,2-oxazol-5-yl)methanol (ESI pos.) m/z: 166 ([M + Na] + ) .3 -51 - 201236682 (3-propoxy- 1,2-oxazol-5-yl)methanol (ESI pos.) m/z : 158 ([M + H] + ) (3-butoxy·1,2-oxazol-5-yl)methanol ( ESI pos.) m/z : 1 94 ([M + Na] + ) [3-(cyclopropylmethoxy)-1,2-oxazol-5-yl]methanol (ESI pos.) m/z : 1 70([M + H] + ) [3-(2,2,2-Trifluoroethoxy)-1,2-oxazol-5-yl]methanol (ESI pos.) m/z : 1 98([M + H]+) [3-(3,3,3-trifluoropropoxy)-1,2-oxazol-5-yl]methanol (ESI pos.) m/z : 2 1 2 ([M + H]+) [3-(3-Fluoropropoxy)-1,2-oxazol-5-yl.]methanol (ESI pos.) m/z : 1 7 6 ([ M + H ] +) [3-( Butan-2-yloxy)-1,2-oxazol-5-yl]methanol (ESI pos.) m/z : 1 72 ([M + H]+) {3 -[(2R)-butane-2-yloxy]-1,2-oxazol-5-yl}methanol (ESI pos.) m/z : 1 72 ([M + H] + ) {3- [(2S)-butan-2-yloxy]-1,2-oxazol-5-yl}methanol (ESI pos.) m/z : 1 72 ([M + H]+) [3- (2-methoxyethoxy)-1,2-oxazol-5-yl]methanol (ESI pos.) m/z : 1 74 ([M + H] + ) [3-(2-{[ 44-butyl(dimethyl)indenyl]oxy} Ethoxy)-1,2-oxazol-5-yl]methanol (ESI pos.) m/z : 274 ([M + H] + ) (3-{[(2S)-l,l,l- Trifluoropropan-2-yl]oxydi 1,2-oxazol-5-yl) -52- 201236682 Methanol (ESI pos.) m/z : 2 12 ([M + H]+) [3-( 2-methylpropoxy)-1,2-oxazol-5-yl]methanol (ESI pos.) m/z : 1 72 ([M + H] + ) (5-propoxypyridine-3- Methanol) (ESI pos.) m/z : 168 ([M + H] + ) [3-(3-{[41^-butyl(dimethyl)indolyl]oxy}propoxy)- 1,2-oxazol-5-yl]methanol (ESI pos.) m/z : 2 88 ([M + H] + ) [3-(2-fluoroethoxy)-1,2-oxazole- 5-yl]methanol (ESI pos.) m/z : 162 ([M + H] + ) [3-(2,2-difluoroethoxy)-1,2-oxazol-5-yl]methanol (ESI pos.) m/z : 1 80 ([M + H]+) [3-(cyclobutylmethoxy)-1,2-oxazol-5-yl]methanol (ESI pos.) m/z: 1 84([M + H] + ) [3-(2-Fluoropropyloxy)-1,2-oxazol-5-yl]methanol (ESI pos.) m/z : 1 76 ([M + H ])) Production Example 11 5-(Bromomethyl)-3-propoxy-1,2-oxazole [Chemical 1 6]

Triphenylphosphine (8 52 mg) and carbon tetrabromide (1.04 g) were added to a solution of (3-propoxy-1,2-oxazol-5-yl)methanol (450 mg) in THF (5 mL). Stir at room temperature -53 - 201236682 for 2 hours. After adding chloroform and silica sand colloid, the solvent was saturated under reduced pressure. The residue was purified by column chromatography (yield of silica gel, hexanes, hexanes, ethyl acetate = 98/2 to 80/20) to give the title compound (4 9 ό mg) ESI (ESI pos.) m/z 220 ([M + H] + ) The following compound was synthesized in the same manner. 5-(Bromomethyl)-3-ethoxy-1,2-oxazole (ESI pos.) m/z 206([M + H] + ) 5-(bromomethyl)-3-(propane- 2-yloxy)-1,2-oxazole (ESI pos.) m/z : 220([M + H] + ) 5-(bromomethyl)-3-butoxy-1,2- Oxazole (ESI pos.) m/z : 234 ([M + H]+) 5·(bromomethyl)-3-(cyclopropylmethoxy)-1,2-oxazole (ESI pos.) m /z : 23 2([M + H] + ) 5-(Bromomethyl)-3-(2,2,2-trifluoroethoxy)-l,2-oxazole 1H NMR (600 MHz, CHLOROFORM -d) d ppm 4.36 (s, 2 H), 4.64 (q, J = 8.3 Hz, 2 H), 6.08 (s, 1 H) 5-(bromomethyl)-3-(3,3,3- Trifluoropropoxy)-1,2-oxazole (ESI pos.) m/z : 274 ([M + H] + ) 5 · (Methyl)-3-(3-propoxy)- 1,2-D oxime (ESI pos.) m/z : 23 8 ([M + H] + ) 5-(bromomethyl)-3-(butan-2-yloxy)-1,2 - oxazole (ESI pos.) m/z : 234 ([M + H]+) 5-(bromomethyl)-3-[(2R)-butane-2-yloxyindole]-1,2- Oxazole-54- 201236682 (ESI pos.) m/z : 234([M + H] + ) 5-(bromomethyl)-3-[(2S)-butan-2-yloxy]-1 , 2-oxazole (ESI pos.) m/z : 234([M + H]+) 5-(bromomethyl)-3-(2-methoxyethoxy)-1,2-oxazole (ESI p Os.) m/z : 23 6([M + H] + ) 5-(bromomethyl)-3-(2-{[tert-butyl(dimethyl)indenyl]oxy}ethoxy -1,2-oxazole (ESI pos.) m/z : 3 3 6 ([M + H]+) 5-(bromomethyl)-3-{[(2S)-l,l,l- Trifluoropropan-2-yl]oxy}-l,2-H caesium (ESI pos.) m/z : 274 ([M+.H]+) 5-(bromomethyl)-3-(2- Methylpropoxy)-1,2-oxazole (ESI pos.) m/z : 234 ([M + H] + ) 5-(bromomethyl)-2-ethoxypyridine (ESI pos.) m/z : 2 16([M + H]+) 5-(bromomethyl)-2-propoxypyridine (ESI pos.) m/z : 2 3 0 ([M + H]+) 3- (Bromomethyl)-1-methyl-5-propoxy-1H-pyrazole (ESI pos.) m/z : 2 3 3 ([M + H]+) 2-(bromomethyl)-5 -(propan-2-yloxy)pyridine 1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.36 (d, J = 6.2 Hz, 6 H) > 4.47 (s, 2 H) > 5.31 (spt, J = 6.2 Ηζ, Ι H) > 6.68 (d, J = 8.8 Hz, 1 H) - 7.49 - 7.69 (m, 1 H), 8.15 (d, J = 2.2 Ηζ, Ι H) -55- 201236682 2 -(bromomethyl)-5-propoxypyridine (t, j= Hz, 2 (m, 1 (d, J = 6.66 (d, J: yl) - 2.01 H), 1H NMR (200 MHz, CHLOROFORM -d) d ppm 1.06 7.3 Hz, 3 H) > 1.85 (sxt, J = 7.0 Hz, 2 H) > 3.99 (t, J = 6.6 H) > 4.56 (s, 2 H) > 7.09 - 7.25 (m, l H) > 7.30 - 7.41 H) - 8.27 (d, J = 2.6 Ηζ , Ι H) 4-(Bromomethyl)-5-methyl-1-phenyl-1H-1,2,3-triazole (ESI pos.) m/z : 2 5 2 ([M + H] + ) 5-(Bromomethyl)-2-(propan-2-yloxy)pyridine 1 Η NMR (600 MHz, CHLOROFORM-d) d ppm 1.3 3 6.4 Hz, 6 H) > 4.45 (s, 2 H), 5.19 - 5.34 (m,1 H), (d,J = 8.7 Ηζ,Ι H) > 7.59 (dd, J = 8.7,2.8 Hz, 1 H), 8.13 2.8 Ηζ,Ι H) 5- (Bromomethyl)-3-(3-{[tert-butyl(dimethyl)indenyl]oxy}propoxy 1,2-oxazole (ESI pos.) m/z : 350 ([M + H]+) 5-(Bromomethyl)-3-(2-fluoroethoxy)-1,2-oxazole (ESI pos.) m/z : 224 ([M + H] + ) 5-( Bromomethyl)-3-(2,2-difluoroethoxy)-1,2-oxazole (ESI pos.) m/z : 242 ([M + H]+) 5-(bromomethyl) -3-(cyclobutylmethoxy)-1,2-oxazole 1 H NMR (600 MHz, CHL0R0F0RM-d) d ppm 1.77 - (m, 4 H), 2.07 - 2.17 (m, 2 H), 2.76 ( Spt, J = 7.4 Ηζ, Ι 4.20 (d, J = 6.6 Hz, 2 H), 4.33 (s, 2 H), 5.94 (s, l H) 5-(bromomethyl)-3-(2-fluoro Propoxy)-1,2-oxazole-5 6-201236682 (ESI pos.) m/z : 23 8 ([M + H] + ) Production Example 12 2-bromo-5-(bromomethyl)pyrazine [Chem. 1 7]

Add N-bromosuccinimide (774 mg) and 2,2,-azobis(2-methyl) to a solution of 2-bromo-5-methyloxime (500 mg) in carbon tetrachloride (15 mL). Propionitrile) (48 mg) was stirred at 80 ° C overnight. After filtration through celite, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc EtOAc EtOAc EtOAc (EtOAc) , 2 Η) ' 8.48 (d, J = l_3 Ηζ, Ι Η), 8.65 (d, J = 1.3 Hz, l Η) In the same manner, the following compounds were synthesized. 5-(bromomethyl)-4-methyl-3-propoxy-1,2-oxazole 4-(bromomethyl)-5-methyl-3-propoxy-1,2-oxazole The above 2 compounds are a mixture. 5-(Bromomethyl)-4-fluoro-3-propoxy-1,2-oxazole (ESI p〇s.) m/z : 23 8 ([M + H] + ) 5-(bromo 1,1,2-oxazole-3-carboxylic acid ethyl ester 1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.36 -1.48 (m,3 H) > 4.34 - 4.55 (m,4 H) &gt 6.74 (s, l H) Production Example 13 (l-{[2-(Trimethyldecyl)ethoxy]methyl}-lH-pyrazole-4-201236682))Methanol [Chem. 1 8]

(1) Potassium carbonate (17.8 g) and 2-(trimethylsilyl)ethoxymethyl chloride (13.6) were added to a solution of 4-pyrazolecarboxylic acid ethyl ester (9.0 g) in DMF (100 mL). m L), stirred at room temperature for one night. After dilution with diethyl ether, 'water was added. After concentrating the organic layer under reduced pressure, the residue was purified by column chromatography (salt silica colloidal dialyzer, hexane/ethyl acetate) to obtain 丨··^2·(trimethyldecyl)B. Ethyl]methyl}-1 Η-pyrazole·4-carboxylic acid ethyl ester (12.4 g). 1H NMR (200 MHz, CHLOROFORM-d) d ppm -0.0 1 (s, 9 Η), 0.86 - 0.98 (m, 2 Η), 1.36 (t, J = 7.3 Hz, 3 Η), 3.51 - 3.65 (m , 2 Η), 4·32 (q, J = 7.0 Hz, 2 H), 5.44 (s, 2 H), 7.95 (s, l H), 8.06 (s, l H) (2) will l-{ A solution of [2-(trimethylsulfonyl)ethoxy]methyl}-lH-pyrazole-4-carboxylic acid ethyl ester (12.4 g) in THF (250 mL) Base aluminum (1.0 M toluene solution, 136 mL). After stirring at room temperature for 2 hours, an aqueous solution of sodium potassium tartrate was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After extracting with chloroform, the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography chromatography chromatography chromatography chromatography (ESI pos.) m/z : 229([M + H]+) 1H NMR (200 MHz, CHLOROFORM-d) d ppm -0.0 1 -58- 201236682 (s,9 Η), 0.82 - 0.99 (m, 2 Η), 3.48 - 3.6 8 (m, 2 Η), 4.62 (s, 2 Η), 5.41 (s, 2 Η), 7.5 3 - 7.62 (m, 2 Η) Manufacturing Example 14 1-(1H-Pyridin Zin-4-ylmethyl)-3_[6-(trifluoromethyl)pyridine-3-yl]-1,3-diazaspiro[4.5]decane-2-one [Chem.

(1) 3-[6-(Trifluoromethyl)pyridin-3-ylindole, 3-diazaspiro[4.5]decane-2-one (52 0 mg), (1-{[2- (Trimethylhydrazino)ethoxy]methyl}_ 1H-pyrazol-4-yl)methanol (590 mg) and decylmethylenetri-n-butylphosphane (830 mg) in toluene (5 mL) The solution was stirred at 150 ° C for 4 hours. The reaction solution was purified by column chromatography (cerium oxide colloidal dialyzer, hexane/ethyl acetate) to give 3-[6-(trifluoromethyl)pyridin-3-yl]-i-[ (i-{[2-(Trimethyldecyl)ethoxy]methyl}-1Η-pyrazol-4-yl)methyl]-1,3-diazaspiro[4.5]decane-2 - Ketone (820 mg). (ESI pos.) m/z : 5 10([Μ + Η]+) (2) in 3-[6-(trifluoromethyl)pyridin-3-yl]-l-[(l-{[2 -(Trimethyldecyl)ethoxy]methyl}_1H-pyrazol-4-yl)methyl]-1,3-diazaspiro[4.5]decane-2-one (8 2 0 mg) 2M hydrochloric acid (40 mL) was added to a solution of ethanol (20 mL). After stirring at room temperature for 1 hour, the mixture was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (NH sleeve dialysis apparatus, Purification of the title compound -59-201236682 (5 3 Omg) 〇(ESI pos.) m/z : 380 ([M + H] + ) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.12 - 1.23 (m,l H), 1.33 - 1.44 (m,2 H), 1.58 - 1·90 (m,7 H), 3.66 (s,2 H)> 4.36 (s , 2 H) > 7.57 - 7.69 (m, 4 H) > 8.34 - 8.43 (m, l H) > 8.67 - 8.75 (m, l H) Production Example 15 2-(Chloromethyl)-1- (tetrahydro-2H-indol-2-yl)_1H-benzopyrim [chemical 2 0]

Add 3,4-dihydro-2H-furan (0.82 mL) and 10-camphorsulfonic acid (4l8 mg) to a solution of 2-chloromethylbenzimidazole (1.0 g in THF (10 mL). hour. An aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform, and the organic layer was washed with brine. After drying over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexane /EtOAc) (ESI pos.) m/z: 251 ([M + H] + ) Example 1 3-(6-methoxypyridin-3-yl)-1-[(3-phenyl-1,2- Azole-5-yl)methyl]-1,3-diazaspiro[4.5]decane-2-one-60- 201236682 [Chem. 2 1]

σ Under nitrogen atmosphere, 3-(6-methoxypyridin-3-yl)-indole, 3-diazaspiro[4.5]decane-2-one (1〇〇11^) 01^(21111 The hydrazine solution was ice-cooled, and sodium hydride (23 mg) was added. After stirring for 30 minutes, 5-(chloromethyl)-3-phenyl-1,2-oxazole (1 l 〇mg) was added and stirred at room temperature overnight. After adding a saturated aqueous sodium carbonate solution and extracting with ethyl acetate, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. Purification by chromatography (chromium dioxide colloidal sleeve dialysis apparatus, hexane / ethyl acetate = 80: 20 to 70: 30) gave the title compound (1,09 mg) 〇 Example 2 1-{[3-(3- Methoxyphenyl)-1,2,4-oxadiazol-5-yl]methyl}· 3-(6-methoxypyridin-3-yl)-1,3-diazaspiro[4.5 ] decane-2-one hydrochloride [Chemical 2 2]

-61 - 201236682 DMA solution of [3-(6-methoxypyridin-3-yl)-2_sideoxy-1>3-diazaspiro[45]dec-1-yl]acetic acid (50 mg) EDC.HCl (46 mg), H0BT.H20 (37 mg), n, hydroxy-3 methoxybenzoquinone (40 mg) were added and stirred at room temperature overnight. This was heated to 1 1 Torr and stirred for 5 hours. After adding a saturated aqueous solution of sodium hydrogencarbonate and extracting ethyl acetate, the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc (EtOAc/EtOAc (EtOAc) This was dissolved in ethyl acetate / isopropanol' to a 4M hydrochloric acid / ethyl acetate solution. The resulting solid was filtered to give the title compound (34 mg). Example 3 3-(6-Methoxypyridine-3-yl)-l-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]-1,3-di Azaspiro[4.5]decane-2-one [Chemical 2 3]

A solution of [3-(6-methoxypyridin-3-yl)-2-oxo-1,3-diazaspiro[4.5]indol-1-yl]acetic acid (100 mg) in chloroform (3 mL) After ice cooling, CDI (53 mg) was added and stirred for 30 minutes. Benzopyrene (44 mg) was added, and after further stirring for 1 hour, triphenylphosphine (163 mg) and carbon tetrabromide (206 mg) were added and stirred at room temperature overnight. The reaction mixture was purified by column chromatography (yield: hexane, hexane, ethyl acetate = EtOAc: EtOAc: EtOAc: Example 4 3-{4-[(Dimethylamino)methyl]phenyl}-1-[(3-phenyl-1,2-oxazol-5-yl)methyl]·1,3 -diazaspiro[4.5]decane-2-one [Chemical 2 4]

(1) 4-{2-Phenoxyphenyl-1,2-oxazole-5-yl)methyl]-1,3-diazaspiro[4.5]indol-3-yl}benzyl Water (imL) and sodium hydroxide (20 mg) were added to a solution of EtOAc (2 mL). Methanol (2 nlL) was added and stirred for another 2 hours. The reaction mixture was concentrated under reduced EtOAc. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (cerium oxide colloidal dialyzer, hexane / ethyl acetate = 75: 25 to 50: 50) to give 3-[4-(hydroxymethyl)phenyl] Phenyl-indole, 2-oxazol-5-yl)methyl]-1,3-azaspiro[4.5] oxacin-2-one (91111 §). (2) 3-[4-(Hydroxymethyl)phenyl]-l-[(3-phenyl-1,2-oxazole-5-yl)methyl]-1,3-diazaspiro [4.5] Chloroform (2 mL) of decane-2-one (100 mg) was added triethylamine (〇·〇 4 mL) and methanesulfonyl chloride (0.02 mL). A saturated aqueous sodium hydrogencarbonate solution was added and the mixture was extracted with chloroform. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (2 mL), and dimethylamine-63-201236682 hydrochloride (39 mg) <RTIgt;</RTI> The organic layer was washed with water and a saturated aqueous After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc (6.Methoxypyridine-3-yl)-2-oxo-1,3-diazaspiro[4.5]dec-1-yl]methyl b N,N-dimethylbenzimidimimine Hydrochloride [Chemical 2 5]

(1) 4-{[3-(6-Methoxypyridin-3-yl)-2-oxo-1,3-diazaspiro[4.5]indol-1-yl]methyl}benzoic acid Water (2 mL) and sodium hydroxide (92 mg) were added to a solution of methyl ester (34 mg) in methanol (4 mL) and stirred at room temperature overnight. The reaction mixture was neutralized with 1 mL of EtOAc. After filtering off the desiccant, the filtrate was concentrated under reduced pressure to give 4-{[3-(6-methoxypyridin-3-yl)-2-oxoxy-1,3,diazaspiro[4.5]癸- 1-yl]methyl}benzoic acid (331 mg). (ESI pos.) m/z : 3 96([M + H] + ) (2) 4-{[3-(6-methoxypyridin-3-yl)-2-oxanoxy-1,3 -Diazaspiro[4.5]dec-1-yl]methyl}benzoic acid (50 mg) in DMF (1 mL) solution • 64-201236682 EDC.HCl (30 mg), H0BT.H20 (24 mg), A 50% aqueous solution of dimethylamine (0.03 m) was stirred at room temperature overnight. After adding a saturated aqueous solution of sodium hydrogencarbonate to ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified with PTLC (ethyl acetate) to afford a coloured oil. This was dissolved in ethyl acetate, and 4M hydrochloric acid / ethyl acetate was evaporated. Example 6 1-(4-Ethoxybenzyl)-3-(6-methoxypyridin-3-yl)-1,3-diazaspiro[4.5]decane-2-one hydrochloride Salt [6 2]

(1) 1-[4-(Benzyloxy)benzyl]-3-(6-methoxypyridin-3-yl)-1,3-diazaspiro[4.5]decane- To the methanol of 2-ketone (1.238) (10% palladium on carbon (0.1 2 g) was added to the 151111 hydrazine solution. The reaction system was replaced with hydrogen. After stirring at room temperature for 6 hours, palladium carbon was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (cerium oxide colloidal dialyzer, hexane/ethyl acetate = 70: 30 to 50: 50) to give 1-(4-hydroxybenzyl)-3. -methoxypyridin-3-yl)-1,3-diazaspiro[4.5]nonan-2-one (0.93 g). (2) in 1-(4-hydroxybenzyl)-3- (6-methoxypyridine-3-yl-in-diazaspiro[4.5]decane-2-one (50 mg) in DMF solution was added with carbonic acid planer-65-201236682 (88 mg), ethyl bromide (〇_〇) 2 mL), sodium iodide (2 mg), stirred under microwave irradiation for 25 minutes at 160 ° C. After stirring at 180 ° C for 10 minutes, the insoluble matter was filtered off. The filtrate was purified by fractional HPLC. The oil was dissolved in isopropyl alcohol (1 mL), EtOAc (EtOAc)EtOAc. 5-{2·Side Oxygen- l-[(3-Phenyl-1,2-oxazol-5-yl)methyl]-1,3·diazaspiro[4.5]indol-3-yl}pyridine -2-carbonitrile [Chemical 2 7]

3-(6-Chloropyridin-3-yl)-1 -[(3-benzoquinone-1,2-oxazol-5-yl)methyl]-1,3-diazaspiro[4.5]癸Alkyl-2-ketone (10〇11^) 〇]^(1.51111〇 solution in which zinc cyanide (17mg), Pd2(dba)3 (7.5mg),

Xantphos (8.3 mg), N,N,N,,N,-tetramethylethylenediamine (0.1 mL) was stirred at 180 ° C for 30 minutes under microwave irradiation. After adding a saturated aqueous solution of sodium hydrogencarbonate, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. Example 8 1-[4-(1Η-imidazol-1-yl)benzyl]_3·[6-(trifluoromethyl)pyridin-3-yl]-1,3-diazaspiro[4.5]癸Alkan-2-one-66- 201236682 [Chem. 2 8]

(Τ 1-(4-Iodophenylmethyl)-3-[6-(trifluoromethyl)pyridin-3-yl]-1,3-diazaspiro[4.5]nonan-2-one ( 70 mg), imidazole (14 mg), 3,4,7,8-tetramethyl-1,10-morpholine (13 mg), copper (I) iodide (5 mg) and potassium carbonate (56 mg) in DMSO (1 mL) The solution was stirred for 3 hours at 10 ° C. After adding a saturated aqueous solution of sodium hydrogencarbonate to extract ethyl acetate, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc) Methyl}-3-[6-(trifluoromethyl)pyridin-3-yl]-i,3-diazaspiro[4.5]decane-2-one [Chemical 2 9]

丨- to 6-bromopyridin-3-yl)methyl]-3-[6-(trifluoromethyl)pyridin-3-yl]-1,3-one gas snail [4.5] 癸院-2 - Ketone (70mg), 1-methyl-5-(4,4,5' 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-iH-pyrazole (37mg) Pd(PPh3)4 (17 mg), potassium carbonate (31 mg) in DMF/ethanol (2:1, 1 mL) -67-201236682 The solution was stirred at 150 ° C for 15 minutes under microwave irradiation. Dilute with ethyl acetate and add NH ruthenium colloid to stir. After filtration over celite, EtOAc (EtOAc)EtOAc. Example 10 Cyclohexyloxy)pyridin-3-yl]methyl}-3-[6-(trifluoromethyl)pyridin-3-yl]-1,3-diazaspiro[4.5]decane- 2-ketone [chemical 3 0]

Sodium hydride (10 mg) was added to a solution of cyclohexanol (26 mg) in NMP (1 mL). Add]-[(6-bromopyridin-3-yl)methyl]-3-[6-(trifluoromethyl)pyridin-3-yl]-1,3-diazaspiro[4.5]decane 2-ketone (60 mg) was stirred at 200 ° C for 20 minutes under microwave irradiation. After adding a saturated aqueous solution of sodium hydrogencarbonate and extracting ethyl acetate, the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (yield of silica gel, hexane/ethyl acetate) to give the title compound (40 mg). Amino)pyridin-3-yl]methyl}-3-[6-(trifluoromethyl)pyridin-3-yl]-1,3-diazaspiro[4.5]decane-2-one-68 - 201236682 【化3 1】

1-[(6-Bromopyridin-3-yl)methyl]-3-[6-(trifluoromethyl)pyridin-3-yl]-1,3-diazaspiro[4.5]decane- 2-ketone (100 mg), isopropylamine (1 9 mg) 'Pd2(dba)3 (llmg), Xantphos (19 mg) and sodium tert-butoxide (31 mg) in toluene (2 mL), under microwave irradiation Stir at 170 ° C for 20 minutes. After diluting with chloroform, it was washed with a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted with chloroform, and the organic layer was washed with water. After concentrating the organic layer under reduced pressure, the residue was subjected to column chromatography (cruise colloidal sulphide, hexane/ethyl acetate) and PTLC (NH flat chromatographic plate, hexane/ethyl acetate) Purification to give the title compound (3 2 mg). Example 12 3-[6-(morpholine-4-yl)pyridin-3-yl]-l-{[6-(propan-2-yloxy)pyridin-3-yl]methyl}-1 , 3-diazaspiro[4·5]nonan-2-one [Chemical 3 2]

3-(6-Fluoropyridin-3-yl)-1-{[6-(propan-2-yloxy)pyridin-3-yl]methyl}-1,3-diazaspiro[4.5] To a solution of decane-2-one (46 mg) in DMSO (0.5 mL) was added to a solution of <RTI ID=0.0>> Add morphine (i〇〇mg) to 200. (: 201236682, stirring for 30 minutes. The reaction mixture was diluted with EtOAc EtOAc (m.) 1-{[6-(propan-2-yloxy)pyridin-3-yl]methyldoxime, 3-diazaspiro[4.5]decane-2-ketone [Chemical 3 3]

(1) 3-(6-Bromopyridin-3-yl)-1-{[6-(propan-2-yloxy)pyridin-3-yl]methyl}-1,3-diazaspiro [4.5] Pd(PPh3)4 (100mg) and potassium carbonate (180 mg) were added to a solution of decane-2-one (400 mg) in DMF-ethanol (2:1, 5 mL) to make carbon monoxide in the reaction system. The gas was replaced and stirred at i〇0〇C for 3 hours. After adding water and extracting with ethyl acetate, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (cerium oxide colloidal dialyser, hexane/ethyl acetate) to give 5-(2-oxo-1-{[6-(propane-2-yloxy) Peptidyl-3-yl]methyl}-1,3-diazaspiro[4.5]indol-3-yl)pyridine-2-carboxylic acid methyl ester (3 75 mg). (2) 5-(2-Sideoxy-1-{[6-(propan-2-yloxy)pyridin-3-yl]-methyl-70-201236682 base 1,3-diazaspiro[4] A solution of 5: indol-3-yl)pyridine-2-carboxylic acid methyl ester (89 mg) in THF (2 mL) was ice-cooled, and lithium aluminum hydride (8 mg) was added and stirred for 1 hour. Add 1 〇% aqueous sodium hydroxide solution (〇 · 5 m L) and stir at room temperature for 1 hour. After drying over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by fractional HPLC to give 3-[6-(hydroxymethyl)pyridin-3-yl]-1-{[6-(propan-2-yloxy)pyridin-3-yl]methyl} -1,3-diazaspiro[4.5]decane-2-one (241^). (ESI pos.) m/z : 4 11 ([M + H] + ) (3) in 3-[6-(hydroxymethyl)pyridin-3-yl]-l-{[6-(propane-2 -Baseoxy)indole is added to a solution of 2-amino-3-methyl}-1,3-diazaspiro[4.5] oxan-2-one (13〇111§) in DMSO (2 mL) Dioxyiodobenzoic acid (i.08 mg) was stirred at room temperature for 2 hours. 2-Dioxyiodobenzoic acid (80 mg) was added and stirred for additional 2 hours. Water and ethyl acetate were added, and the insoluble matter was filtered off with diatomaceous earth. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform (2 mL) and bis(2-methoxyethyl)aminothiotrifluorobenzene ( </ RTI> After stirring at room temperature for 2 hours, water was added to extract from chloroform. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was evaporated,jjjjjjjjjjjj Example 14 3-[6-(Fluoromethyl)pyridin-3-yl]-1-{[6-(propan-2-yloxy)pyridin-3-yl]methyl}-1,3 -di Azaspiro[4.5]decane-2-one-71 - 201236682 lit 3 4]

5-(2-Sideoxy-1-{[6-(propan-2-yloxy)pyridin-3-yl]methyl}-1,3-diazaspiro[4.5]indol-3-yl To a solution of pyridine-2-carboxylic acid methyl ester (15 mg) in THF (2 mL), A saturated aqueous ammonium chloride solution was added, and the mixture was stirred at room temperature for 1 hour. After extracting with ethyl acetate, the mixture was washed with saturated aqueous sodium hydrogen carbonate and brine and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform (3 mL). EtOAc (EtOAc m. After adding a saturated aqueous solution of sodium hydrogencarbonate, the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc) Example 15 3-[6-(1,1-Difluoroethyl)pyridin-3-yl]-1-{[6-(propan-2-yloxy)pyridin-3-yl]methyl}- 1,3-diazaspiro[4.5]decane-2-one-72- 201236682 [Chemical 3 5]

(1) 3-(6-Bromopyridin-3-yl)-1-{[6-(propan-2-yloxy)pyridin-3-yl]methyl}-1,3-diazaspiro [4.5] decane-2-one (20〇11^), tributyl(1-ethoxyvinyl)tin (186mg), PdCl2(PPh3)2 (30tng) and copper (I) iodide (8mg) A solution of acetonitrile (2 mL) was stirred at 150 ° C for 20 minutes under microwave irradiation. After adding a saturated aqueous solution of sodium hydrogencarbonate and extracting with ethyl acetate, it was washed with water and saturated brine. After drying over anhydrous magnesium sulfate and filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (yield of silica gel, hexane/ethyl acetate) to afford a yellow oil. This was dissolved in 1,4-dioxane (2 mL), and 1 M hydrochloric acid (2 mL) was added and stirred overnight. After adding a saturated aqueous solution of sodium hydrogencarbonate and extracting with chloroform, dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by fractional HPLC to give 3-(6-ethylpyridin-3-yl)-1-{[6.(propan-2-yloxy)pyridin-3-yl]methyl}-1. 3-diazaspiro[4.5]nonan-2-one (1011^). (2) 3-(6-Ethylpyridin-3-yl)-1-{[6-(propan-2-yloxy)pyridin-3-yl]methyl}-1,3-diazepine A solution of the snail [4.5] decane-2-one (90 ml) in chloroform (2 mL) was ice-cooled, and bis(2-methoxyethyl)amine sulphur trifluoride (0.15 mL) was added and stirred at room temperature 2 hours. Diethylaminosulfur trifluoride (0.1 lmL) was added and stirred for 1 hour. Heat to 6 〇t and stir for another 4 hours. Water was added and the mixture was extracted with chloroform to dry with anhydrous magnesium sulfate. After filtering off the dry-73-201236682 desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Example 16 3-[6-(mono-methoxy)disgust-3-yl]propanol-2-yloxy)pyridin-3-yl]methyl}-1,3-diazaspiro[4.5 ] decane-2·one and 3_[1-(dioxymethyl)-6-sideoxy-1,6-dihydro D ratio steep-3-yl]_ι_{[6·(丙院_2·基Oxy)pyrene-deep-3-yl]methyl}-1,3-diazaspiro[4.5]valer-2-one [chemical 3 6]

(1) Add 30% to a solution of 3-(6-methoxypyridin-3-yl)-1,3-diazaspiro[4.5]nonan-2-one (1.25 g) in acetic acid (5 mL) A hydrogen bromide/acetic acid solution (10 mL) was stirred at 100 ° C for 2 hours. A hydrogen bromide/acetic acid solution (10 mL) was added, followed by stirring at 100 ° C for 1 hour. The mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure and azeotroped with toluene to give 3-(6-s-oxy-1,6-dihydropyridin-3-yl)-1,3-diazaspiro[4.5] Decan-2-one (1, 09g). (ESI pos.) m/z : 248 ([M + H] + ) (2) in 3-(6-oxo-oxy-1,6-dihydropyridin-3-yl)-1,3-diaza Sodium-74-201236682 [4.5] DMF/water mixed solution (10:1, 5 mL) of decane-2-one (200 mg) was added potassium carbonate and sodium chlorodifluoroacetate (0.24 g), and stirred at room temperature. After adding water, it was extracted with chloroform, and then concentrated under reduced pressure. The residue was purified by column chromatography (yield of silica gel, chloroform/methanol) to afford colourless solid (49mg). This is a mixture of two types of compounds. (3) The mixture obtained in the above (2) was dissolved in DMF (2 mL), and sodium hydride (10 mg) was added and stirred at room temperature. 5-(Bromomethyl)-2-(propan-2-yloxy)pyridine (70 mg) was added, and stirred at room temperature for 2 days. After adding a saturated aqueous solution of sodium hydrogencarbonate and extracting with chloroform, it was dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was dried under reduced pressure. The residue was purified by fractional HPLC to give 3-[6-(difluoromethoxy)pyridin-3-yl]-1-{[6-(propan-2-yloxy)pyridin-3-yl]- }-1,3-diazaspiro[4.5]decane-2-one (38 mg) and 3-[1-(difluoromethyl)-6-oxo-oxy-1,6-dihydropyridine-3 -yl]-l-{[6-(propan-2-yloxy)pyridin-3-yl]methyl}-1,3-diazaspiro[4.5]decane-2-one (2.3 mg) . Example 17 1-[(5-propoxypyridin-3-yl)formamidine]-3-[6-(trifluoromethyl)pyridin-3-yl]-1,3-diazaspiro[4.5 ] decane-2-one hydrochloride [Chemical 3 7]

(1) 2-Dioxyiodobenzoic acid (260 m) was added to a solution of (5-propoxypyridin-3-yl)methanol (130 mg) in DMSO (5 mL) and stirred for 3 hr. Water and ethyl acetate were added and stirred, and the insoluble matter was filtered off. The filtrate was extracted with ethyl acetate-75-201236682 ester, and the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform (3 mL), and N-[(l-aminocyclohexyl)methyl]-6-(trifluoromethyl)pyridin-3-amine (200 mg). (I65 mg), stirred at room temperature for 1 hour. Additional sodium triethoxyborohydride (200 mg) was added and stirred for another night. A saturated aqueous solution of sodium hydrogencarbonate was added, and the organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (cluster colloidal dialysis, hexane/ethyl acetate) to give N-[(l-{[(5) -propoxypyridin-3-yl)methyl]amino}cyclohexyl)methyl]-6-(trifluoromethyl)pyridin-3-amine (1 85 mg). (ESI pos.) m/z : 423 ([M + H] + ) (2) on N-[(l-{[(5-propoxypyridin-3-yl)methyl]amino}cyclohexyl) To a solution of methyl]-6-(trifluoromethyl)pyridin-3-amine (150 mg) in THF (3 mL), triethylamine (0.2 mL). After stirring for 1 hour, a saturated aqueous solution of sodium hydrogencarbonate was added and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (yield of silica gel, hexane/ethyl acetate) to give an oil. This was dissolved in ethyl acetate, and 4M hydrochloric acid / ethyl acetate was evaporated. Example 18 3-(5-chloropyrimidin-2-yl)-1-[(3·propoxy-indole, 2-oxazol-5-yl)methyl]-1,3-diazaspiro[ 4.5] decane-2-one-76- 201236682 [Chemical 3 8]

Will [(3-propoxy-1,2-oxazol-5-yl)methyl]-1,3-diazaspiro[4.5] oxacin-2-one (5〇mg) and 2 - A solution of -5-chloropyrimidine (6 1 mg), Pd2 (dba) 3 (16 mg), Xantphos (17 mg), sodium tert-butoxide (5 mg) in toluene (1 mL) under microwave irradiation at 18 ( The mixture was stirred for 1 (1 min), purified by column chromatography (chromium dioxide colloidal sleeve dialyzer, hexane/ethyl acetate) and fractional HPLC to give the title compound (1). Omg). Example 19 1-[(1-Methyl-2-phenyl-1H-imidazol-4-yl)methyl]-3-[6-(trifluoromethyl)pyridin-3-yl]- 1,3-diazaspiro[4.5]decane-2-one [Chemical 3 9]

3-[6-(Trifluoromethyl)pyridin-3-yl]-1,3-diazaspiro[4.5]decane-2-one (10 Omg), (1-methyl-2-benzene) A solution of ketone-1H-imidazol-4-yl)methanol (170 mg) and cyanomethylenetris-n-butylphosphane (130 mg) in toluene (2 mL) was stirred in vacuo. The reaction mixture was purified by column chromatography chromatography chromatography chromatography eluting eluting . -77- 201236682 Example 20 1-{[1-(Π 陡 steep-2-yl)-1 Η-Π ratio I -4-yl]methyl}-3-[6 (difluoromethyl) fluorene ratio Strepto-3-yl]-1,3-diazaspiro[4.5]valer-2-one [chemical 4 0] Q.

1-(1H-pyrazole·4ylmethyl)-3_[6·(trifluoromethyl)pyridin-3-yl]·1,3-diazaspiro[4.5]decane-2-one (50 mg), 2-bromopyridine (31 mg), trans-1,2-bis(methylamino)cyclohexane (3 mg), copper iodide (1) (3 in g) and carbonic acid (65 mg), 4 - The brothel (lmL) solution was placed in a closed tube at 12 Torr. Stir for 1 hour. The reaction mixture was purified with EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 3_[6_(difluoromethyl)disorder-3-yl]-1,3-diazaspiro[4.5]valer-2-one [chemical 4 1]

To pyrazol-4-ylmethyl)-3-[6-(trifluoromethyl)pyridin-3-yl]- 1,3 -azaspiro[4.5]nonan-2-one (50 mg) Sodium hydride (7 mg) was added to a solution of DMF (1 mL) and stirred at room temperature for 5 min. Add 2-Iodine two hospitals 201236682 (35mg) 'stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and purified to purified crystal crystal crystal crystal crystal crystal crystal crystal Example 22 1-{[6-(Ethoxymethyl)pyridin-3-yl]methyl}-3-[6-(trifluoromethyl)pyridin-3-yl]-1,3-diazepine Heterospiro[4.5]decane-2-one [Chemical 4 2]

(1) 5-({2-Sideoxy·3-[6-(trifluoromethyl)pyridin-3-yl]-1,3-diazaspiro[4.5]indole-l-yl}methyl To a solution of pyridine-2-carboxylic acid methyl ester (170 mg) in THF (3 mL). After adding saturated ammonium chloride and extracting with ethyl acetate, the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (cerium chloride colloidal dialyzer, hexane/ethyl acetate-chloroform/methanol) to give (hydroxymethyl)pyridin-3-yl]methyl}-3-[ 6-(Trifluoromethyl)pyridin-3-yl]-1,3-diazaspiro[4.5]decane-2-one (88 mg). (ESI pos.) m/z : 443 ([M + Na]+) (2) in 1-{[6-(hydroxymethyl)pyridin-3-yl]methyl}-3-[6-(three Add hydride (12 mg) to a solution of fluoromethyl)pyridin-3-yl]-1,3-diazaspiro[4.5]nonan-2-one (8 Omg) in DMF (2 mL). 10 minutes. Ethyl iodide (〇.〇3m L) was added and stirred at room temperature for 2 hours. It was diluted with ethyl acetate -79-201236682, washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc m. Example 23 Benzimidazol-2-ylmethyl)-3-[6-(trifluoromethyl)pyridin-3-yl]-1,3-diazaspiro[4.5]decane-2·one 4 3]

CF, in 3-[6-(trifluoromethyl)pyridin-3-yl]-1,3-diazaspiro[4.5]decane-2-one (10〇1112), 0^^(51111〇 Sodium hydride (60%, 4 〇mg) was added to the solution and stirred for 30 minutes. Forced into 2-(chloromethyl)-1-(tetrahydro-2H-indol-2-yl)-1 Η-benzimidazole (126 mg), the mixture was stirred for 2 hours. After adding water and extracting with chloroform, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol. (5 mL), p-toluenesulfonic acid monohydrate (100 mg) was added, and the mixture was stirred at night at 10 ° C. After adding water and extracting with chloroform, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After that, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (yield of silica gel, hexane/ethyl acetate) to give the title compound (37 m). 24 1-[(1-Oxo-5-propoxypyridine-2-yl)methyl]-3-[6-(tri-80-201236682 fluoromethyl)pyridin-3-yl]-1,3 -diazaspiro[4.5]decane-2-one [4 4]

1-[(5-propoxypyridin-2-yl)methyl]-3-[6-(trifluoromethyl)pyridin-3-yl]-1,3-diazaspiro[4.5]癸To the chloroform (2 m L) solution of the alkan-2-one (50 mg) was added m-chloroperbenzoic acid (70%, 36 mg), and stirred at room temperature for 16 hours. An aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform, and the organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj Example 25 l-{[3-(2-Hydroxyethoxy)-l,2-oxazol-5-yl]methyl}-3-[6-(trifluoromethyl)pyridine-3-yl] _丨,3_diazaspiro[45]decane-2·one

CFa is i-{[3-(2-{[tert-butyl(dimethyl)indenyl)oxy}ethoxy)·1,2-oxazol-5-yl]methyl}·3_[ Add 6-(trifluoromethyl)pyridine...-yldiazaspiro[4.5]decane-2-one (3911^) to 1^(11111〇 solution was added tetrabutylammonium fluoride (1.0M/THF) Solution, 〇_〇 8mL), stir for about 3 days at room temperature. After the solvent is saturated under reduced pressure, the residue is chromatographed with column chromatography (cerium oxide colloidal sleeve -81 - 201236682 cartridge dialyzer, 3 帛 / acetic acid Base vinegar) pure π, obtained (30mg) · Example 26丨-(1)...yi-difluoropropoxy 啰哩·5•yl]methyl) 3-[6-(trifluoromethyl)妣 steep_3_ Base μι, 3_: azaspiro[4 5]decane-2-one [4 6]

(1) By the same operation as in Example 25, from butyl (dimethyl) decyl] oxy} propoxy oxime, 2-oxazole _5-yl] methyl b 3 [6- (Trifluoromethyl)pyridin-3-ylpyridinium-diazaspiro[45]decane·factory ketone (112 mg) gives 1-{[3-(3-hydroxypropoxy)-indole, 2-π Ester-5-yl]methyl 3-[6-(trifluoromethyl)pyridin-3-yl]-1,3-diazaspiro[4·5] 癸院·2-ketone (87 mg). (ESI pos.) m/z : 45 5 ([M + H]+) 1H NMR (500 MHz, CHLOROFORM-d) d ppm li〇_ 1.24 (m, l H), 1.3 2 - 1.47 (m, 2 H), 1.61 - 1.92 (m, 7 h), 1.97 - 2_04 (m, 2 H), 3.71 (s, 2 H) ' 3.74 - 3.81 (m, 2 H), 4.38 (t, J = 6.1 Hz, 2 H) - 4.42 (s, 2 H) - 5.91 (s, l H) » 7.64 (d, J = 8.8 Hz, l H), 8.30 - 8.41 (m, l H), 8.65 - 8.7 5 (m, l H) -82- 201236682 (2) By the same procedure as in the step (3) of Example 13, l-{[3-(3-hydroxypropoxy)-1,2-oxazolyl] The title compound (3.7 mg) was obtained from mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The structural formulas of the compounds shown in Examples 1 to 26 and the compounds synthesized in the same manner and the instrumental data are shown in Table 1-1, Table 1-2 and Tables 2-1 to 2-24. The numbers in the columns of the examples in the Tables indicate that the compounds are synthesized in the same manner as in any of the above Examples 1 to 26. Further, the compound in which the salt column is blank is not a free form. -83- 201236682 [Table 1 - 1] Compound S Example Construction Salt (ES! pos.) m/z (ESI neg. > m/z 1H-NMR 1 1 C\^r, 1HCI 405 ([M+H ]+) 2 1 1HCI 421([M+H]+) 3 1 459([M+Na]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.90 (d, J=6.0 Hz. 3 H) 0.99 (d. J=6.4 Hz. 3 H), 1.35 (d. J=BO Hz. 6 H), 1.40 - 1.50 (m, 1 H). 1.62 - 1.79 (m. 2 H), 3.48 (dd J=8.7, 6.9 Hz. 1 H). 3.57 - 3.71 (m. 1 H). 3.93 (t, J=8.7 Hz. 1 H), 4.07 (d. J=15,1 Hz. 1 Η). 4.B0 (d. J=15.1 Hz. 1 H), 5.18 - 5.36 (m. 1 H), 6.68 (d, J=8.7 Hz. 1 H), 7.51 - 7.59 Cm. 1 H). 7.64 (d J=8.7 Hz, 1 H). 8.07 (d. J=2.3 Hz. 1 H). 8.39 (dd, J=8.7, 2.3 Hz, 1 H), 8.64 - 8.74 (m. 1 H) 4 1 423 ([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.84 (d. J=6.9 Hz, 3 H). 0.95 (d. J=7.3 Hz. 3 H). 1.31 -1.39 ( m. 6 H), 2.12 - 2.24 (m, 1 H). 3.46 - 3.63 &lt;m. 2 H). 3.68 - 3.77 (m. 1 H). 3.98 (d, J=15.1 Hz. 1 H). 4.67 (d. J = 15.6 Hz. 1 H), 5.20 - 5.34 (m. 1 H), 6.67 (d, J = 8.3 Hz. 1 H), 7.52 - 7.60 (m, 1 H). 7.63 (d. J=8.7 Hz. 1 H). 8.05 (d. J=2.3 Hz. 1 H). 8 .41 (dd. J=8.7, 2.3 Hz. 1 H). 8.70 (d. J=2.8 Hz, 1 H) 5 1 437([M+H]+) 6 1 449([M+Na]+) -84-201236682 [Table 1 - 2 . Compound Example Construction Salt (ESI pos.) m/z (ESI nee.) m/z 1H-NMR 7 1 414 ([M+Na]+) 8 1 414 ([ M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.96 -1.37 (m. 5 H), 1.51 - 1.64 (m. 2 H), 1.68 - 1.89 Cm, 6 H). 3.47 - 3.73 (m, 3 H). 4.10 (d, J=16.5 Hz, 1 H), 4.14 - 4.23 (m. 2 H). 4.81 (d, J=16.5 Hz, 1 H), 5.88 (s. 1 H) , 6.82 - 6.91 (m, 2 H). 7.41 - 7.47 (m. 2H) 9 1 6 422([M+H]+) 10 1 -/Γ 402([M+H]+) 11 1 408([ M+H]+) 12 1 453([M+H]+) 1H NMR (6QQ MHz, CHLOROFORM-d) d ppm 0.99 (t. J=7.3 Hz. 3 H), 1.39 - 1.55 (m. 2 H 1.60 - 1.84 (m. 10 H). 1.87 - 2.00 (m, 2 H), 3.65 (s. 2 H). 4.10 (t J=6.6 Hz. 2 H). 4.45 (s. 2 H). 5.91 (s, 1 H). 7.63 (d, J=8.7 Hz, 1 H), 8.27 - 8.41 (m, 1 H). 8.63 - 8.7t (m. 1 H) 13 1 427 ([M+H] +) The compound 14 to 3 02 is a compound having a structure represented by the following formula [II]. -85-201236682 201236682 [Table 2 - 1] Compound Example R R1 Salt (E曰poaj m/i (ESI negj m/z 1H-NMR 14 2 F &lt; K 456t[M+H]+) 1H NMR ( 600 MHz. CHLOROFORM-d) d ppm 1.10 -1.23 On, 1 H). 1.34 - 1.47 (m. 2 H), 1.51 - 1.65 (nv 2 H). 1.69 - 1.75 (m. 1 H). 1.78 - 1.89 (m. 4 H). 3.72 (s. 2 H), 3.92 (s. 3 H). 4.74 (s. 2 H), 6.76 (d. J=9.2 Hz. 1 H). 6.90 - 6.99 (m. 1 H). 7.57 - 7.66 (m. 2 H). 8.09 (d, J=Z8 Hz. 1 H). 8.16 (dd. J=9.2.2.8 H*. 1 H) 15 2 420UM+H]” 1H NMR (600 MHz. CHLOROFQRKHd) d ppm 1.10 -1,22 (mj Ηλ 1.33 - M7 (π\ 2 Ηλ 1.57 - 1.64 On 2 Η), 1.66 - 1.75 (m. 1 HX 1.76 - 1.89 (rrv 4 Η), 3.71 (β. 2 Ηλ 3.93 (s. 3 Η). 4.76 (s. 2 Η). 6.76 (d. J=8.2 Hz. 1 Η). 7.43 - 7.55 (m, 3 ΗΧ 8.02 - 8.12 (m. 3 Η). 8.18 (dd. J=9.2, 2.0 Hz. 1 Η) 16 1 F ^〇-°\ 436([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.04 -t .16 (m, 1 H). 1.29 - 1.40 (m. 2 H). 1.48 - 1.64 (m. 4 H). 1.63 - t.72 (m. 1 H). 1.72 - 1.Θ1 (m. 2 H). 3.63 (». 2 HX 3.92 (8, 3 H). 4.45 (e. 2 Η), β.75 Cd, J=9.2 H*. 1 H). 7.04 - 7.13 (m. 1 H). 7.18 (*. 1 Η). Ί2Ί - 7J7 (m. 2 H). 8.06 (d. Hz. 1 H}. 8.19 ( Dd. J=8.7, 2.8 Hz. 1 H) 17 3 &lt;K 420( [M+H]*) 1H NMR (600 MHz. CHLOROFORU-d) d ppm 1.10 · U3 (m. 1 H). 1.30 - 1.45 (m, 2 H). 1.65 - 1.73 (m. 5 H). 1.75 - 1.86 (m. 2 H). 3.67 (t, 2 H). 3.93 (e. 3 H\ 4.79 (s. 2 H) 6.78 (d, J=0.9 Hz. 1 H). 7.43 - 7.59 (m. 3 H).8.0t -8.19(m.4H) 18 1 Cu 339([M+H}+) 19 1 o-&lt ;x ._hO~°\ 1HCI 420([M+H]+) 20 1 ^o~°\ 429([M+H]+) 21 1 419([MtH]+) 1H NMR (600 MHz. CHLOROFORM- d) d ppm U1 -t.25 (m. 1 H), U1 - 1.44 (m. 2 H). 1.63 - 1.7B (m. 5 H). 1.78 - J.90 On. 2 H). 3.65 ( %, 2 Ηλ 3.92 (e. 3 H), 4.56 (s. 2 H). 6.61 (·. 1 Η). Θ.76 (d. J^e.3 Hz. 1 H\ 7.38 - 7.48 (m. 3 H). 7.73 - 7.B3 (m. 2 H). a.07 (d. J=2.8 Hz. 1 H), 6.)5 {66. J=8.9, 3.0 Η*. \ H) 22 1 &lt;K 435([M+H]+) 23 2 &lt;K 426([M+H]+) 24 1 (V XJU 429([M+H» 1H NMR (600 MHz. CHLOROFORM-d) d Ppm 1.11 -1.20 (m. t H). 1.29-1.41 (m. 2 H). 1.57- 1.83 (m, 7 H). 3.66 (t. 2 H) 3.92 (s. 3 H). 4.63 (s. 2 H), 6.76 (d. J=9^ Hi, 1 H). 7.36 - 7.42 (m. 1 H). 7.44 - 7.49 (m. 2 H) 1.52 (d. J=8.3 Ht 1 H), 7.55 - 7.59 (m. 2 H). 7.83 (dd. J=7.8. 2.3 Hz. 1 H). 8.05 - 8.13 (m. t H). 8.22 ( Dd. J=8.9, 3.0 Hz. 1 H). 8.69 &gt; 8.80 (m. 1 H) 25 2 &lt;K 1HCI 438([M+H]+) -87- 201236682 [Table 2 - 2 R R1 Salt (ESI potj m/t (ESI net.) m/z 1H-NMR 26 2 &lt; κ 1HCI 438 ([M+H]+&gt; 27 2 &lt;κ 1HC) 450([M+H]+) 28 2 〇, 〇Λ 1HCI 450([M+H]+) 1H NMR (600 MHz. OMSO-d6) d ppm 1.09 - t.18 (m. 1 HX 1.39 - 1.50 (m. 2 H). 1.55 - 1.75 (m. 7 H). 3.80 (s. 2 H). 3.6t («, 3 H). 3.83 (%, 3 H). 4.62 («, 2 H). 6.82 (d. J=8.3 Ht. 1 H). 7.14 - 7.19 (nv 1 HX 7.45 - 7.51 (m. 2 H). 7.54 - 7.61 {m. 1 H). 8.03 - 8.12 (m. t H). 6^8 (d. J»2.8 Hz 1 H) 29 2 _fO~°\ 1HCI 450〇H]+) 1H NMR (600 MHz. DMS&^6) d ppm 1.09 - 1.20 (m. 1 H), MO - 12 H). 1.60 U Jsll* 7 H). 3.80 {%. 2 Η). 3.B3 (t, 3 H). 3.86 (t. 3 Η). 4.Θ2 (s. 2 H). β.β« (4 J=8.7 Ht t HX 7.11(d #15.1 Hi* f Η)· 7Λ4 ( *. 1 HX 7.50 - 7.61 (m. 1 H). 7.77 - 7.85 (m. 1 Ηλ Β·0β 8.15 1 Η). β·30 (d J=2.B 1 H&gt; 30 2 &lt;κ 1HC) 39B([M*H» 31 2 1HCI 4I2([M+H» 32 2 ~^cy°\ 1HCI 400([M*H» 33 2 F 1HC1 34 2 〇Λ tHCI 434 ([M+H]+) 35 2 〇Λ 1HCI 454([M+H]*〇36 1 fO_〇\ 4t9([M«H]«) 1H NMR &lt;600 MHz. CHLOROFORM-d) d ppm 1.11 · 1.23 (m. 1 H 1.40 - 1.53 (m. 2 H). 1.63 - t.85 (m, 7 H). 3.84 (t. 3 H). 3.92 (t. 2 H). 4.56 (». 2 H). 6.60 ( %, 1 H). 7.23 - 7.30 (m, 1 H). 7.38 - 7.4B (m. 3 H). 7.74 -7.82 (m. 2 H). 7.89 (d. J=3.7 Hi. 1 H). 8.24 (d. J=9.2 Hz.tH) 37 1 ο\ 446([M+Hjf&gt; 1H NMR (600 MHs. CHLOROFORM-d) d ppm 1.16 -1.26 (m. 1 H). 1.35- 1.47 (m, 2 H). 1.65- 1.93 (m. 7 H). 3.72 (*. 2 H), 3.81 (e. 3 H). 4.59 (*. 2 H). 6.63 (». 1 H). 7.38 - 7.47 ( m. 3 H). 7.63 - 7.71 (m. 2 H), 7.76 -7.84 (rrv 2 H). 7.99 · 8.07 (m. 2 H) -88- 201236682 [Table 2 — 3] Chemical hybrids R R1 salt (ESI posj m/z (ESI nex.) m/z 1H-NMR 38 1 ^cy°\ 436 ([M+H]+) 39 4 &lt;y0H 418([M +H]+) 1H NMR (600 MHz, CHLOROFORM-t〇d ppm U3 · 1.25 (m. 1 H), 1.32 - 1.45 Cm. 2 H). 1.65 - 1.75 (m. 5 H). t .77 - 1.86 (m. 2 H), 3.68 (s, 2 H). 4.56 (s. 2 H). 4.65 (s, 2 H). 6.61 (long 1 H). 7.35 (d. on 8.3 Hi 2 Ηλ 7.40 - 7.45 (m. 3 H). 7.55 - 7.60 (m. 2 H). 7.75 - 7.80 40 1 CC ~^y°\ 1HCI 382([M+H]+) 41 1 &quot;XX ^cy°\ 1HCI 382 ([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.02 -1.1Θ (m. 1 H). 1.27 - 1.43 (m. 2 H). 1.48 - 1.85 {m. 7 H) 3.58 (c. 2 H), 3.79 (s. 3 H). 4.33 (s. 3 H). 4.39 (s, 2 Η). 6.78 - 6.92 (m. 2 H). 7.12 (d. J=9.6 H*. t H). 7^0 -7.29 (m. 2 H), 7.83 (br. e., 1 H), 9.30 - 9.46 (m. 1 H) 42 1 0 &lt;y 460([M+ H]+) 43 1 1HCI 449 ([M+H]·*-) 1H NMR (600 MHz. OMSO-dS) d ppm 1.10 - 1.20 (m. 1 H). 1.37 - 1.49 (m. 2 H). 1.54 - 1.64 (m. 3 H), 1.66 -1.75 (m. 4 H). 3.74 (s. 2 H). 3.69 (e. 3 H). 3.85 (s. 3 H). 4.59 (8, 2 H 6.76 (·. t H). 6.84 (d. J=9.6 Hz. 1 H). 7.04 (td. Js7.e, 0.9 Hz, 1 H). 7.18 (d. J=7.8 Hz. 1 H) , 7.42 - 7.51 (m. 1 H). 7.72 (dd. J=7.8, 1.8 Hz. 1 H). 8.10 (dd. 2.8 Hz. 1 H). 8.29 (d. Hz. 1 H) 44 1 KK 1HCI 382UM+H» 45 1 '(X ^o^°\ 1HCI 352([M+H] +) 4B 4 CHX \ &lt;y^ 445([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.15 -1.24 (m. 1 HX 1.35 - 1.45 &lt; m, 2 H). 1.64 - 1.88 Cm. 7 H). 2.24 (8. β H). 3.41 (br. u 2 Η). 3.6Θ (e. 2 H), 4.57 (*. 2 H). 6.62 ($, 1 H) , 7.29 (d. J=8.3 Hz. 2 H), 7.3S -7.46 (m, 3 H), 7.54 (d. J=8.7 Hz. 2 H). 7.76 - 7.81 (m. 2 H) 47 1 Ί &lt;K 410C[M+H]+) 48 1 &lt;K 1HCI 436([M+H]+) 49 5 Λχ, ^0~〇\ 1HCI 423([M+H]+) 1H NMR (600 MHt CHLOROFORM-d) d ppm 1.05 -U7 (m. 1 H). 1.29 - 1.4J (m, 2 H). 1.50 - 1.84 (m. 7 Η). 2.M - 3.16 (m. 6 H). 3 .S4 (e. 2 H). 4.09 (s. 3 H). 4.48 (s. 2 H). 6.86 - 6.96 (m. 1 H). 7.32 - 7.40 (m. 4 H). 8.02 (br. 1 H). 8.65 (br. 1 H) -89- 201236682 [Table 2 - 4 Compound Example R R1 Salt (ESI pos.) m/z (ESI ner) »n/z 1H-NMR 50 5 &lt;y \ 1HCI 449([M+H]f) 51 1 &lt;y\ 428([M*H]+) 52 1' CHa. 423([M+H)+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.15 -1.26 (m. 1 H). 1.33 - 1.46 (m, 2 H). 1.68 - 1.79 (m. 5 H). 1.81 - 1.90 (m, 2 Η). 3.6Θ (e. 2 H). 4.58 (e. 2 H), 6.61 (a, \ H). 7.29 (d. J=8.7 Hi. 1 H), 7.39 - 7.4B (m, 3 H). 7.73 - 7.85 (m. 2 H). 8.24 - B.31 (m, 1 Η). B.35 (d. J=2.8 Hz. 1 H) 53 1 &lt;K 420C[M+H]+) 54 1 CHX. ./=NF 479(tM+Na]+&gt; 1H NMR (600 MHz. CHLOROFORhHl) d ppm 1.13 -1.27 (m. 1 H). 1.40 (qt J=13.3, 3.7 H*. 2 H), 1.64 -1.7Θ Cm. 5 Η). 1.Θ1 - 1.92 (m. 2 H) 3.72 (e. 2 H). 4.59 (e. 2 H), 6.61U. 1 Η), 7·38 _ 7.4B (m, 3 H&gt;. 7 M (d. J=0.7 Hz. 1 H) 7.74 - 7.83 (m. 2 H). 8.36 (dd, J=8.7. 2.8 Hz. 1 H). 8.73 (d. J=2.B Hz. 1 H) 55 1 〇389CCM+H]*) 56 1 ^G^°\ 480([M+N8]+) 57 6 HOxx 390([M+Na&gt;) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.02 -1J6(m. 1 H). 1.22- 1.40 (m, 2 H). 1.48- 1.60 (m. 7 H). 3.60 (e. 2 H). 3.91 (8. 3 H). 4.36 (e. 2 H). 5.77 {·. 1 H). 6.66 - 6.79 (m. 3 H). 7.11 - 7.20 (m. 2 H). 8.05 (d. J=2.B Hz. 1 Η). Θ.19 (dd. J=8.9. 3.0 Hz. 1 H ) 58 1 XJU &lt;K 1HCI 383([M+H]+&gt; 59 6 ^〇XX, &lt;K 1HCI 396([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.07 -1.17 (m. 1 H). 1.30-1.3B (m. 2 H). 1.41 (t J=7.1 Hl 3 H). 1.52 - 1.84 (m, 7 Η). 3.6t (br. e. 2 H). 4.02 (q. J=7.0 Hr. 2 H). 4.32 (br. 8.. 3 H). 4.40 ( s. 2 H). 6.84 (d, J=8.3 Hz. 2 H). 7.10 (br. 1 H). 7.24 (d. J=8.3 Hz, 2 H), 7.88 (br. b, 1 H). 0.32 (br. 1 H) 60 6 ～Xu &lt; K 1HCI 410 &lt;[M+H]·*·) 1H NMR (600 MHz. DMSO-d6) d ppm 0.96 (t. J»7.6 Hz, 3 H) 1.08 (q. J=12.8 Hr. 1 H). 1.31 - 1.49 (m. 4 H). 1.51 - 1.65 (m, 5 H). 1.66 - 1.75 (m. 2 H). 3.67 {*. 2 H 3.81 (s. 3 H). 3.87 (t J=6.4 Hz. 2 H). 4.30 (e. 2 H). 6.77 - 6.B8 (m. 3 H). 7_24 (d. J=8.7 Hi_ 2 H). BU (dd· J=8.7, 2.8 Hr* 1 H). 8.27 (d· J=2.8 Hi« 1 H) 61 6 &lt;K 1HCI 1H NMR (600 MHz. DMS0-d6) d ppm 1.03 · 1.15 (m, 1 H). 1.24 (d. J=6.0 Hi. 6 H), 1.32 - 1.68 (m, 9 H). 3.68 (s. 2 H), 3.83 (8. 3 H), 4.30 ( e. 2 H&gt;. 4,52 - 4.59 (m. \ Η). 6.7Θ - 6.87 (m. 3 H). 7.24 (d. J=8.7 Hz. 2 H). 8.08 -8.16 (m. 1 Η ). 8.2Θ (d. J=3.2 Hz. 1 H) -90 - 201236682 [Table 2-5] Compounds Salts (ESI posj m/z (ESI negj m/z

424 ([M+H]+) 1H NMR (600 MHz. OMSO-d6) d ppm 0.92 (t. J»7.3 Hz. 3 H). 1.01 - 1.13 (m, 1 H). 1.30 - 1.47 (m. 6 H). 1.49 - 1.71 (m. 7 H). 3.67 (*. 2 H). 3.81 (e. 3 H). 3.91 (t, J=6.6 Hi. 2 H). 4.30 (*, 2 H) 6.77 - 6.87 (m. 3 H). 72A (d. J=8.7 Hz. 2 H). 8.06 - 8.15 (m, 1 HX 8^7 (d. &gt;2.8 Hi. 1 H) 63

1HCI 422([M+H]+)

450([Μ·*^]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.04 -t.te (m. t HI t.28- 1.42 (nv 2 H). t.48- t.82 (m. 7 H). 3.61 (s. 2 H). 3.92 (s. 3 H). 4.33 (q. J^8.3 Hz. 2 H). 4.40 (a. 2 H). 6.76 (d. J= 8.7 Hz. 1 H). 6.84 - 6.92 (m. 2 H). 7.28 - 7.35 (m. 2 H). 8.06 (β. 1 H). 8^1 (dd. J=8.7. 2.6 Hz. 1 H )

1H NMR (600 MHz. CHLOROFORM-d) d ppm t.02 (d. J=6.4 Hz. β H). 1.06 - U7 (m. 1 H). 1.27 - 1.40 (m, 2 H), 1.56 - U7 (m. 7 H). 2.04 - 2.Ϊ3 (m, 1 H). 3.59 (e. 2 H), 3.70 (d, «1=6.4 Hz. 2 H). 3^2 (s. 3 H) 4.39 (s. 2 H). 8.75 (d, J=8.7 Hi. 1 H). 6.81 - 6.85 (m. 2 H). 7.25 -7.28 (m. 2 H). 7.99 - 8.08 (m. 1 Ηλ 8.18 - 8.26 (m. 1 H)

3B3([M+H]+)

452 (CM+H]+)

426([M+H]+)

400([Μ4Ή]+) 1H NMR (600 MHz. OMSO-d6) d ppm 1.02 - U7 (m, 1 H). 1.29 - 1.71 (m. 9 H). 3.69 (s. 2 H). 3.80 (s 3 H). 3.62 (s. 3 H). 4.32 (s. 2 H). 6.82 (d, J^9.2 Hz. 1 H). 7.03 - 7.23 (m. 3 Η). Θ.06 - 8.14 ( m, 1 Η). Θ.25 - 8.30 Cm, 1 H)

/=NF 488([M+H]f) 1H NMR (600 MHz. CHLOROFORM&gt;d) d ppm 1.09 1.22 (m. 1 H). 1.36 - 1.69 (m. 4 H). 1.71 - 1.92 &lt;m, · H). 3.79 (e. 2 H). 3.97 (s. 3 H). 4.80 (e. 2 H). 7.00 -7.U (m, 2 H&gt;. 1.43 - 7.5&gt; (m. \ H&gt ;, 7.66 (d. Hz. 1 H). 7.96 - 8.04 (m. 1 H), 8.37 - 8.46 (m. t H). 8.74 (d. J=2.3 Ηϊ. \ H) 73 454 ([M+ H]+) 1H NMR (600 MHz. CHLOROFORM~d) d ppm 1.08 -\ .22 (m. \ H). 1.35 - \A1 (m. 2 H&gt;. 1.58 - 1.6? (m, 2 H). 1.70 - 1.91 (m. 5 H). 3.73 (s. 2 H). 3.97 (s. 3 H). 4.78 (s. 2 H). 7.00 - 7.11 (m. 2 H). 7.30 (d. J= 9.6 Hz. 1 H). 7.48 (ddd J=8.3. 7.3. t.fi Hz. 1 H), 7.99 (dd. J*7.6. t.6 H2. 1 H). 0.27 - 8.37 (m, 2 H ) -91 201236682 [Table 2 - 6 Compound 9 Example R R1 Salt (ESI pos.) m/x (ESI nee.) m/z 1H-NMR 74 1 丫Ou &lt;K 411([M-*H] +) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.07 · 1.19 (m. 1 H). 1.29-1.41 (m. 8 H). 1.55 - 1.64 (m. 4 H&gt;. 1.66 - 1.72 (nv 丨H). 1.75 - 1.M (n% 2 H). 3.60 (». 2 H). 3.92 (e. 3 H). 4.36 (*. 2 H). 5.19 · 5.31 (m. 1 H). 6.63 (d. J=8.7 Hz, 1 H) 6.75 (d. J=9.2 Hz. 1 H), 7.64 (dd. J=8.5, 2.5 Hz. 1 H), 8.05 (d. J=2.8 Hi, 1 H). 0.08 (d. J=2.3 Hz . 1 H). 8.16 - 8.20 (m. 1 H) 75 1 41Θ([Μ*Η]·*-) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.06 * t.18 (m. 1 H) 1.29 - 1.39 (m. 2 H). 1.55 - 1.63 (m. AH). 1.65 - 1.71 (m. 1 H). 1.74 - 1.79 (m. 2 H). 3.63 (». 2 Η). Θ2 (s. 3 H), 4.48 (s. 2 H). 6.45 - 6.47 (m. 1 H). β.7β (d. J=9,2 Hz. 1 H). 7.44 (d. J=8.7 Hz. 2 H). 7.60 -7.66 (m. 2 H). 7.72 (s. \ H). 7.91 (e. 1 H). 8.08 (e. 1 H). 8.21 (dd. J=9.2. 2.8 Hz . 1 H) 76 1 /==N 419([M+H]+) 77 1 丫. Ou 44Θ([Μ+Η]+) 1H NMR (600 MHz. CHLOROFORM-&lt;〇d ppm U1 -1.20 (m. \ H). 1.34 (d, J=6.0 Hr. 6 H). 1.35 - 1.42 ( m. 2 Hi, 1.57 - t.77 (m. 5 H). 1.78 - 1.87 (m. 2 H). 3.68 (b, 2 H), 4.39 (t, 2 H). 5.19 - 5.35 (m. 1 H). 6.64 (d. J=8.7 Hz. 1 H). 7.57 - 7.68 (m. 2 H). 6.09 (*. 1 Η). Θ.35 -8.44 (m. 1 H), 8.71 (d, J=2.3 Hz. 1 H) 78 1 &lt;y- 415([M*H]+) 1H NMR (600 MHz. CHLOROPORM-d) d ppm 1.08 -1.19 (m. 1 H). 1.33 (d, J =6.4 Hr. 6 H). 1.34 - 1.40 (m. 2 H), 1.56 - 1.74 (m. 5 H). 1.76 - 1.83 (m. 2 H). 3.61 (*. 2 H). 4.36 (e. 2 H). 5.21 - 5.30 (m. 1 H), 6.63 (d. J=8.7 Hr. 1 H). 7.26 - 7.2Θ (m. 1 H). 7.61 (dd. J=8.5.15 Hz. 1 H). 8.07 (8.1 H). 8.26 - 8.33 (m, 2 H) 79 1 /^=NF ΚΙλ^τ 457([M*»H]+) 1H NMR (600 MHz. CHL0R0F0RM&gt;d) d ppm 1.22 -1.32 (m. 1 H). 1.33 - 1.45 (m, 2 H). 1.60 - 1.67 (m. 2 H). 1.70 - 1.78 (m, 1 H). 1.03 - 1.88 (m, 4 H&gt;, 3.69 (e. 2 H). 4.62 (*. 2 H). 7.39 - 7.46 (m. 1 Hi, 7.47 - 7.56 (m. 2 H). 7.84 (*. 1 H). 7.70 - 7.77 (m. 2 Η ), β.15 (e. 1 H). 8.32 (dd. J=8.7. 2.8 Hr. 1 H). 8.77 (&lt;t J=2.3 Ht. 1 H) BO 7 o^xo— 414([M+H]+) 1H NMR (600 MHz. CHLOROFORM- d) d ppm 1.16 -1.27 (m. 1 H). 1.35 - 1.46 (m. 2 H). t.87 - 1.81 (m. 5 H). t.84 - 1.94 (m. 2 H). 3.73 ( e, 2 H). 4.60 (e. 2 H). 6.M (. 1 H). 7.40 - 7.48 (m· 3 HX 7.66 (4 J*8.7 Ht 1 H). 7.76 - 7.Θ3 (m. 2 H). 8.29 - 8.37 (m. t H). 8.76 (d. Js2.3 Ht 1 H) 81 1 &lt;K 408([M+H]+) 82 1 &lt;y- 422([M+ H]+) 1H NMR (600 MHz. CHLOROFORMS) d ppm 1.08 &gt; U7 (m. 1 H). 1.31 - 1.42 (m. 2 Ηλ 1.59 - 1.68 (m. 4 H). t.67 - 1.74 (m 1 H). 1.76 - 1.82 (m. 2 H). 3.65 (*. 2 H). 4.50 (». 2 H). 6.43 - 6.49 (m. \ H). 7.30 (d. J=8.7 Hi. 1 H). 7.43 (d. J=8.3 Hz. 2 H). 7.64 (d. J=8.7 Hi. 2 H). 7.72 (e. 1 H). 7.9! (». 1 H). 8.30 - 8.38 (m. 2 H) 83 1 COu O-' 423([M+H]+) 1H NMR (600 MHz. CHLOROFORMS) d ppm 1.09 -1.20 (m, t H). 1.31 - 1.44 (m. 2 H) 1.59 - 1.8S (m, 7 H). 3.66 (s. 2 H). 4.49 (*. 2 Η), β.44 - 6.4Θ (m, 1 H). 7.30 (d. J=8.7 Ht 1 H), 7.71 - 7.75 Cm. 1 H), 7.86 (dd. J=8.7. 2.3 Hz. 1 H). 7.94 (d. J=B.3 Hi, 1 H). 8.28 - 8.35 (m. 2 H). 8.37 - 8.41 (m. 1 H). 8.54 (d. J=2.B Hi. 1 H) 84 6 /=NF 456([M+H]+) 85 8 /=NF 473([M^H]+) -92- 201236682 [Table 2-7] Compound Example R Salt (ESI poe. m/z (ES! necJ m/z 1H-NMR 66 1 /==NF 457 ([M+H3+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.05 -U3 (m. 1 H). 1.33 - 1.48 (m. 2 H), 1.60 - l.flO (n\ 7 H). 3.74 (s. 2 H). 4.55 (b. 2 H). 7.52 (d. J=8.7 Hz. 2 H), 7.68 (d. J=8.7 Hz. 1 H). 7.68 - 7.73 (m, 2 Η). 7Λ5 (*. 1 H). 7.94 - 8.01 (m. 1 H). 8.35 - 8.47 (m. 1 H) 8.71 -8^0 (m. 1 H) 87 1 423([M+H]+) 88 2 ο— /==NF fO~tF 506([M+H]+) 1H NMR (600 MHz. CHLOROFORM -d) d ppm 1.12 -U3 (mj Ηλ U8 · 1.49 (nv 2 H). 1.59 - 1.6B (n% 2 H). 1.71 - 1.93 (m, S Η), 3.Θ0 Cs. 2 H). 3.9S (». 3 H). 4.79 (s. 2 H). 6.99 (dd. J=9.2, 4.1 Hz. 1 H). 7.13 - 7.21 (m. 1 H). 7.$6 (d. J= 8.7 Hz. t H). 7.7S (dd. J=8.7. 3.2 Hz. 1 H). 6.38 - 8.45 (m. 1 H). 8.74 (d, J=2.B Hz, 1 H) 89 2 0 494([M+N»]*) !H NMR (600 MHz. CHLOROFORM-d) d ppm 1.11 -\22 (m. 1 H), 1.35 - 1.49 (m. 2 H). 1.57 - 1.67 (m. 2 H). 1.69 - 1.91 On. 5 H). 3.74 (e. 2 HX 3.95 (b. 3 Ηλ 4.77 (e. 2 Η). 6Λ5 (dd, J=8.9, 4.4 Hz. 1 H). 7.14 - 7.21 (m. 1 H). 7.30 (d. J=8.7 Hz, 1 H). 7.74 ( Dd. J=8.7, Z2 Hz. 1 H). 8.29 - Θ.38 (m. 2 H) 90 1 丫Ou ~i^y~F 1HCI 398([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.11 -1.21 (jn. 1 H). V30 - 1.«0 (m. 2 HX 1.54 - 1.65 (m. 4 H). 1.67 &lt; 1.87 (m, 3 H). 3.63 ( e. 2 H). 4.38 (e. 2 H). 5.38 - 5.4Θ (m, 1 Η). 6.Θ1 - 6.94 (m. 1 H). 7.00 - 7.10 (m. 2 H). 7.45 - 7.5 Fi (m. 2 H), 8.07 (br. 8, 1 H). 8.21 (br. e. 1 H) 91 1 丫Xu ^y)~FF 1HCI 4t6([M+H]+) 92 1 νχχ, 0—1HCI 428([M+H]+) 93 \ 丫l 1HCI 399UM+H3+) 94 1 丫Xu IHCi 415([M+H]+) 95 1 (^X /=NF 475([M+H) +) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.21 &gt; 1.30 (m. 1 H), 1.33 - t.44 (m. 2 H). 1.60 - 1.96 (m. 7 Η). 3.6B ( $. 2 H). 4.63 (*. 2 H). 7^6 - 7.33 (m. 2 h\ 7.38 - 7.49 (m. 1 H). 7.62 (d. J=9.2 Hi. 1 H). 7.85 - 7.97 (m. 1 H). 8.15 - 8.23 (m. 1 H). 8 .29 - 8.39 (m. 1 H). 8.6S - 8.82 (m. 1 H) 96 1 ~^C)~ 2HCI 395ί[Μ+Η]+) 97 1 丫. Ou 2HCI 4U([M+H3*) -93- 201236682 [Table 2 - 8 Compound 贲 Example R R1 Salt (ESI pos.) m/z (ESI ner) m/z 1H-NMR 9S 丫l 1HCI 394 ( [M+H]+&gt; tH NMR (600 MHz. CHLOROFORM-d) d ppm 1.09 -1.23 &lt;m, 1 H). U0 - 1.42 (m_ 2 H&gt;, Μβ (d. J=S.5 Ht 6 H). 1.53 - 1.05 (m. 7 H), 2.32 (·. 3 H). 3.64 («. 2 H). 4.38 (e. 2 H). 5.39 - 5.51 (m. 1 H), 6.85 - 6.95 (m. 1 H). 7.16 (d. J=8.3 Hi. 3 H). 7.44 (d. J=fl.7 Hi. 2 H). 8.14 (br. 8. 1 Η). B.22 ( Br. 8. 1 H) 99 ^O-7 1HCI 408([M-&lt;H]^) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.10 -1.19 (m. 1 H). t.22 ( t J=7.6 H*. 3 H). 1.30- 1.40(m. 2 H). 1.44 (d. J=6.0 Hz. 6 H). 1.53 - 1.63 (m. 4 Η). 1.6β -U3 (m . 1 H), !.75 - 1.B3 (m, 2 H). 2.62 (q. J=7.3 Hi. 2 H). 3.64 (e. 2 H). 4.38 (e. 2 H). 5.34 - 5.48 (m. 1 H). 6.80 - 6.90 (m. 1 H), 7.18 (d. J=8.7 Hi, 2 Η). 7.4β (d. J=8.7 Hi, 2 Η). Θ.07 (br . 8, 1 H), 8.20 (br. st 1 H) 100 1 ^0^tF 457([M-*H]+) 1H NMR (600 MHz. CHLOROFORM&gt;d) d ppm 1.12 -1.21 (m. 1 H). 1.34 - 1.44 (m. 2 H). 1.60 - 1.6B (m. 4 H). 1.70 - 1.86 (m. 3 H). 3.72 («. 2 H). 4.51 (e. 2 H). 6.45 - 6.4B (m. 1 H). 7.66 (d. J=8.7 Hi. 1 H). 7.72 -7.75 (m. 1 H). 7.86 (dd. J=8.7. 2.3 Hz. 1 H). 7.95 (d. J=8.3 Hi. 1 H). 8.38 - 8.43 (m. 2 H ), 8.54 (d. J=2.8 Hi. 1 H). 8.74 (d. J=2.8 Hi. 1 H) 101 1 y=NF KLh^ 435([M^H]+) 1H NMR ¢600 MHt CHLOROFORM- d) d ppm U0 -1.21 (m. 1 HX 1.32 - 1.41 (m, 2 Η). 1.3Θ (t J=7.t Hz. 3 H). 1.57 - 1.76 (m. 5 H). 1.77 - 1 .B5 (m. 2 H). 3.67 (e, 2 H). 4.30 - 4.37 (m. 2 H). 4.40 (s. 2 H). 6.68 (d. J=8.7 Hr. 1 H). 7.61 - 7.65 (m. 2 H). 8.05 - 8.11 (m. t H). 8.39 (dd. J=8.7. 2.8 Hi. 1 Η). Θ.71 (d. J=2.3 Hz. 1 H) 102 1 ~ XL· /=NF ΚΙ&gt;~^ 449([M+H]+&gt; 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.02 (t J=7.3 Hi. 3 H). 1.08 - 1.20 (m. 1 H), 1.31 - 1.42 (m, 2 H). 1.55 - 1.86 (m. 9 H). 3.67 ($, 2 Ηλ 4.22 (t J=8.6 Hz. 2 H). 4.40 (e. 2 H). 6.69 (d. J=8.7 Ht. 1 H). 7.60 -7.67 (m. 2 H). 8.09 (d. Js2.3 Hz. 1 Η). Β.3Θ (dd. J:8.7. 2.Θ Hz. 1 H). 8.71 (d, J=2.3 Hi. 1 H) 103 t F y=NF Kj^ 475([ M+H]+) IHNMFUeOOMH^CHLOROFORM-cOdppmUa-1.31 (m. 1 H). 1.32 - 1.42 (m, 2 Ηλ 1.50 - 1.65 (m. 2 H). 1.71 - 1.76 (m. 1 H). 1.83 - 1.95 (m. 4 H). 3.68 (e, 2 H). 4.60 (e. 2 H). 7.10 - 7.16 (m. 1 H). 7.43 - 7.5β (m. 3 H). 7.63 (d. J =8.7 Hz. 1 H). 8.14 (a. 1 H). 8.31 (dd* ϋ=8·7· 2·3 1 Ηλ 8.75 (4 &gt;2.8 Hi* 1 H&gt; 104 y /=NF Kj^f An({M*H]*) 1H NMR (600 MHz. CHLOROFORM-&lt;f) d ppm 1.23 · 1.32 (m« 1 H). 1.33 · 1.46 (m« 2 H&gt;. 1.60 - 1.6β (rru 2 H). 1.71 - 1.78 (m. 1 H). 1.83 - 1.99 (m. 4 H), 3.69 (e, 2 H). 4.61 (·. 2 H). 7.16 - 7.24 (m. 2 H). 7.64 (d. J=9.2 Hz. 1 H). 7.69 - 7.75 (m. 2 H). 8.11 (», 1 Η). ΘΛ6 -8.34 (m. 1 H). 8.77 (d, J=2.3 Hi. 1 H) 105 9 471 ([M+H]*) 106 7 /=NF 41β〇Η]+) 107 θ /=NF 4S7([M+H]O 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.05 -1.19 {m, 1 H). 1.30 - 1.45 (m. 2 H). 1.58 - 1.84 (m. 7 H). 3.71 (e. 2 H). 4.53 (·. 2 H). 7.46 (d. J =8.7 Hi. 2 H). 7.65 (d. J=8.7 Hz. 1 H). 7.80 (s. 2 H). 7.98 - Θ.06 (m, 2 H), 8.39 - 8.46 (m. 1 H) . 8 .73 (d. J=2.8 Hz. 1 H) 108 °xx /=s=NF 478([M+Na]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm U0 -1.1Θ (m, 1 H). 1.32 - 1.42 (m. 2 H). 1.58 - 1.6S (m, 4 H). 1.69 - 1.75 (m. 1 H). 1.76 - 1.85 (m. 2 H). 3.71 (e. 2 H 4.52 (s. 2 H). 6.45 - 6.48 (m. 1 H). 7.44 (d. J=8.7 Hi. 2 H). 7.63 - 7.69 (m. 3 H). 7.72 (β. 1 Η) , 7.Θ1 (*. 1 H). 8.43 (dd. J=8.7. 2.8 Hi. 1 Η). Θ.74 (d. J=2.8 Hr. 1 H) 109 1 丫l o- 459i[M+ H]+) 1H NMR (600 MHi. CHLOROFORM-d) d ppm 1.07 -1.18 (m. 1 H). 1.33 (d. J=6.4 Hz. β H), 1.34 - ^.40 (m. 2 H) 1.6 - 1.67 (m. 1 H). 1.76 - 1.83 (m. 2 H). 3.60 (a. 2 H). 4.36 (s. 2 H), 5.20 - 5.30 (m. \ H). 6.63 (d, J=8.7 Hi. 1 H). 7.41 &lt;d. J=8.7 Hz. 1 H). 7.61 (dd. J=8.5. 2.5 Hi. 1 H). 8.07 (d, J=2.3 Hz, 1 Η). 8.t8 - 8.23 (m. 1 H). 8.30 (d. J=2.8 Hi, t H) -94- 201236682 [Table 2-9] Compound 笪Example R R1 salt (ESI posJ m/z (ESI nee.) m/z 1H*NMR 110 1 o—41t([M+H]+) 111 t 丫Xu V 399UWl+H)+) 112 1 丫Xu 395( [M+H]+) 113 8 丫Ou 446([ M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.10 -t.20 (m. \ H). 1.34 (d. J=6.0 Hz. 6 H&gt;. t.35 - 1.42 (m 2 H). 1.56 - 1.85 (m. 7 H). 3.67 (e. 2 H), 4.39 (s, 2 HX 5.21 - 5.33 (m. 1 H), 6.43 &gt; 6.49 (m. 1 H). 6.65 (d. J=8.7 Hz. 1 H), 7.66 (dd. J=8.5. 2.5 Hz. 1 HX 7.70 -7.74 (m. 1 H). 7.95 (d. J=8.7 Ht. 1 H), 8.09 (d, J=iB Hz, 1 Η). 8.2B - 8.30 (m. 1 Η), β.50 (dd. J=9.4. 2.5 Hz. 2H&gt; 114 8 丫Ou 463(EM+H]+) 115 1 YOU M9([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.12 -U1 (m. 1 H). 1.34 (d, J=6.4 Hz. 6 H). 1.36 - 1.43 (m. 2 H), 1.58 - 1.77 (m. 5 H). t.78 - 1.87 (m. 2 Η), 3.ββ (e. 2 H). 4.39. (e. 2 H). 5.22 - S.31 (m. 1 H). 6.64 (d. J=8J Hi, 1 H). 7.59 - 7.67 (m. 2 H). 8.06 - Θ.11 (m. 1 H). 8.37 - Θ.43 Cm. 1 Η), B.71 (d. J=2J Hz. t H) 116 2 506([M+H)+) 117 2 cy&lt;^ /=N 472&lt;[M+H]+&gt; 118 10 CJOu /=^i F 489([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.07 -2.05 (m. 20 H), 3.67 (#, 2 H), 4.39 (s, 2 H), 4.9S - 5.04 (m, 1 H). 6.66 (d. J=8.7 Hz. 1 H 7.59 - 7.66 (m. 2 H). fi.Od (d. J=2.8 Hz. 1 H). 8.36 · 8.43 (m. 1 H). 8.71 (d. J=2.3 Hi. 1 H) 119 1 丫t ^0~f 399([M+H]+) 120 10 cr°tu 1HCI 475([M+H]+) 121 10 °σ°ΧΧ, /=NF 477([M+H]+) -95-201236682 [Table 2 - 1 0] Compound Example R R1 Salt (ESI posj m/z (ES! nec.) m/z 1H-NMR 122 10 /=NF 461 ([Μ·^Η]·* ·) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.08 · 1.19 (m. 1 H). 1.30 - 1.42 (m. 2 H). 1.48 - 1.75 (m. 7 H). 1.77 - 1.86 (m. 2 H). 2.08 - 2.10 (m. 2 H). 2.39 -2.48 (m. 2 H), 3.66 (%, 2 Η). 4.3Θ (». 2 H). 5.13 (quin, J=7.5 Hz. 1 H). 6.64 (d. J=8.7 Hr. 1 H). 7.60 - 7.67 (m. 2 H). 8.07 (d. J=2.3 Hz. 1 H). 8.39 (dd. J=8.7, 2.8 Hi 1 H). 8.70 (d, J=2.3 Hi. 1 H) 123 11 44β([Μ 屮K) 1H NMR (Q00 MHz. CHLOROFORM-d) d ppm 0.60 -1.87 (m. 16 H). 3.65 ( a. 2 H). 3.81 - 3.92 (m. 1 H). 4.33 (*. 2 H). 4.40 (br. 1 H). 6.33 (d. J=8.3 Ht 1 H). 7.48 -7.56 (m. 1 H). 7.64 (d. &gt;1=8.7 Hz. 1 H), 8.01 (d. J=2.3 Ht 1 H). 8.37 - 8.44 (m. 1 H). 8.71 (d. J=2.8 Hz. t H) 124 11 Vtx, 4Β2([Μ·ι·Η]+) 125 8 丫. Ou 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.13 -U9 (m. 1 H). 1.34 (d. J=6.0 Hz. 6 H). 1.36 - 1.44 (m. 2 H). 1.58 - 1.86 ( m. 7 H). 3.68 (e. 2 H). 4.39 (s. 2 H). 5^2 - 5.32 (m. 1 H). 6.65 (d. J=8.7 Ht 1 H). 7.64 -7.74 ( m, 3 H). 7.75 - 7.80 (m. 2 H). 7.85 (a. 1 H). 7.94 -7Λ8 (m. 1 H). 8.08 - 8.12 (m. 1 H) 12Θ 8 丫447 ([M屮) ♦) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.06 - 1.19 (m. 1 H). 1.33 (d. J=6.0 Hz. 6 H). 1.35 - 1.44 (m. 2 H). 1 , 60 - 1.84 (m, 7 H). 3.67 (e. 2 H), 4.37 (e. 2 H). 5.19 - 5.31 (m. 1 H), 6.63 (d. J=8.7 Hz. 1 H), 7.66 (dd. J=8.5. 2.5 Hz, 1 H). 7.69 - 7.74 (m. 2 H). 7.78 (*. 2 H). 8.00 - 8.05 (m. 2 H), 8.06 · Θ.14 (nv 1 H) 127 B 447([Μ·*Η]+) 128 9 丫129 11 °XX, 474(CM*H]^) 130 11 /=NF KLht 476([M,HH 131 7 丫L o- 406 ({M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.24 -1.32 (m. 1 Η), Μβ (d_ J=eO β H). 1.47 - U55 (nv 2 Η), 1.6 Θ - 1.89 (m, 5 H). 1.92 - 1.98 (m. 2 H). 3.79 (e. 2 H). 4.51 (e. 2 H). 5.35 - 5,42 (m. 1 Η). 7β ( d. J=8.3 Ht 1 H). 7.72 - 7.75 (m. 1 H), 7.77 (d. J=8.7 Hz. 1 H). 8.21 (d. J=2.3 Hz. 1 H). 8.47 (dd. J=8.7. 2.8 Hz. t H). 8.66 (d. J=2.8 Hz. 1 H) 132 12 丫l &lt;K&gt; 466([M4H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.05 &gt; 1.16 (m. 1 H). 1.27 - 1.39 (m. θ H). 1.57 - 1.81 (m. 7 H). 3.39 - 3.4B (m. 4 H). 3.58 (e. 2 H). 3.79 - 3.Θ6 (m. 4 H). 4.34 (s. 2 H). 5.21 - 5.29 (m. 1 H). 6.62 (d. J=8.3 Hi, 1 H). 6.67 (d. J=9.6 Hz. 1 H), 7.59 - 7.67 (m. 1 H). 8.04 - 8.17 (m. 3 H) 133 9 /=NF ^Jr^; 471([M*H]+) 1H NMR (600 MHz. CHLOROFORM -d) d ppm 1.U -1.23 (m. 1 H), 1.34 - 1.45 (m. 2 H). 1.61 - 1.69 (m. 4 H). 1.71 - t.78 (m. 1 H). 1.80 - 1.B8 (m. 2 H). 3.73 (e. 2 H). 4.22 (s. 3 H). 4.5t (s. 2 H). 6.56 (d, J=Y.6 Hz. t H) 7.49 (d. d=2.3 Hz. 1 H). 7.53 (d. J^8.3 Hi. 1 H). 7.65 (d. J=8.7 Hz. 1 H). 7.75 - 7.81 (m. t H). 8.36 - Θ.42 (m. 1 H). 8.61 - 8.66 (m. 1 H). 8.74 (d. J = 2.8 Hz, 1 H) -96- 201236682 [Table 2 - 1 1] Compound Example R R1 Salt (ESI posj m/x (ESI nec.) m/z 1H-NMR 134 9 丫l H j^s. / 461([M+H]+) 135 12 436([M+H]+) 136 12 450([M+H]+) 137 12 丫l Pu 464([Mm]+) 138 12 丫. Ou 424([M+H]+) 139 1 乂 439 ([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.13 -1.24 (m, 1 H). 1.31 - t.46 (m, BH). 1.63 - 1.78 (m, 5 H), 1.82 - 1.92 (m. 2 H). 3.71 (e. 2 H), 4.42 (e. 2 H). 4.85 (spt. J=6.1 Hju 1 H). 5.87 (β, \ H). 7.W (d. J=S.7 Ηϊ. 1 H). 8.33 - 8.41 (m, 1 H). 8.71 (d, J=2.3 Hi. 1 H 140 13 丫Xu 439([M+H]+) 1H NMR (600 MHz. CKLOROFORM-d) d ppm 1.09 -U9 (m. 1 H). 1.34 (d, J=6.0 Hz. 6 H). U6 - 1.44 (m. 2 H), 1.58 - 1.85 On. 7 Ηλ 3.69 (e. 2 H). 4.00 («. 3 H). 4.39 (s. 2 H), 5.19 - 5.31 (m. t H). 6.64 (d. J=S.3 Hz. 1 H), 7.60 - 7.68 Cm. 1 H&gt;. 8.0B - 8.15 (m. 2 H), 8.30 -8.36 (m. 1 H). 8.76 (d. J ^2.8 Hz. 1 H) 141 1 Ί 47 47l ([M+Na]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.13 · 1.22 (m. t H), 1.35 (d. J=8.0 Hz 6 H). 1.37 - 1.43 (m. 2 H). 1.6t - 1.75 (m. 5 H). 1.79 - 1.90 (m. 2 H). 3.63 (e. 2 H). 4.38 (*, 2 H ) 4.80 - 4.Θ7 (m. 1 Η). 5.B4 (e. 1 HX 7.41 (d. J=8.7 Hz. 1 H), 8.13 - 8.t9 (m, 1 H). 8.3t ( d, J=3.2 Hi. 1 H) 142 7 418([M+Nb]+) 143 1 /=NF 425([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.15 -1.25 (m. 1 H). 1.34 - 1.46 (m. 5 H). t.65 - 1.72 Cm. 4 H). 1.72 - 1.79 (m. 1 H). 1.83 - 1.91 (m. 2 H). 3.71 (e. 2 H). 4.27 (a J=7.3 Hi. 2 H). 4.42 (e. 2 H). 5.90 (s, 1 H). 7.64 (d. J=8.7 Hz. 1 Η). 8.33 - 8.39 (m. 1 H). 8.71 (d. J=2.8 Hi, 1 H) 144 1 Also /=N . F _hCh^f 439([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm f.00 (t, J=1.8 Hz. 3 H). 1.13 - 1.26 (m 1 H). 1.35 - 1.45 (m. 2 H). 1.65 - 1.71 (m. 4 H). t.72 - 1.82 (m. 3 H). 1.83 -t.91 (m. 2 H), 3.71 (s. 2 H). 4.16 (t. J=8.4 Hz. 2 H), 4.42 (s. 2 H). 5.91 (s. 1 H). 7.64 (d. J=9.2 Hi, 1 H). 8.34 - 8.40 (m. 1 H). 8.71 (d. &gt;2.8 Hz. 1 H) 145 t /=NF 453([M+HJ+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.94 (t, J =7.3 Hz. 3 H). 1.14 - 1.24 (m, 1 H). 1.32 - 1.47 (m, 4 H), 1.65 - 1.78 (m. 7 H). t.81 - 1.89 (m. 2 H). 3.70 (*. 2 H). 4.19 (t, J=6.6 Hi, 2 H). 4.41 (3. 2 H), 5.89 (·, 1 H). 7.63 (d. J=8.7 Hz. 1 H). 8.31 - 8.38 (m. 1 H). 8.70 (d, J=2.8 Hz. 1 H) Γ' Ο -97- 2012 36682 [Table 2 — 1 2] Compound «Examples Salt (ESI pos.) m/z (ESI nen.) m/i

-N F 470([M+H)+)

431 ([ΜπΉ]·*·) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.10 · .19 (m. t H). U3 (d. J=6.4 Hz. 6 H). 1.34 - t.41 (m. 2 H). 1.57 - 1.74 (m, 5 H). 1.76 - 1.85 (m. 2 H). 3.60 (*, H), 4.38 (s. 2 H). S.22 - 5.29 (m. 1 H), 6.48 - 6.74 (m. 2 H). 7.56 - 7.65 (m. 2 H), 8.05 - 8.09 (m, 1 H), Θ.32 (dd. Js8.7. 2.Θ Hz. 1 Η). Θ.6Θ (d. Js2.8 Hz. 1 K) 413{[Μ·&lt;·Η]+) 1H NMR (600 MHz. CHLOROFORM&gt;d) d ppm 1.10 -.19 (m. \ H 1.34 (d. J=6.4 Hi. 6 H). 1.35 - 1.42 (m. 2 H). 1.58 - 1.75 (m. 5 H). 1.77 - 1.83 (m. 2 H). 3.66 (e. 2 H), 4.38 (s. 2 H). 5.22 · 5.30 (m. 1 H). 5.38 - 5.52 (m. 2 H). 6.64 (d. J=8.7 Hz. 1 H). 7.43 (d. J= 8.7 Hr. 1 H). 7.62 - 7.66 (m. 1 H), 8.06 - 8.10 (m. ί Η). Θ.23 -8.28 (m. 1 H). 6.63 (d. J=2.3 Hz. 1 H )

445([Μ+Νβ]·〇150 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.30 -0.36 (m. 2 H). 0.SB - 0.65 (m. 2 H). 1.13 · 1.23 (m. 1 H). U3 - 1.31 (m. 1 H). 1.39 (td. J=8.7. 4.1 Hi. 2 H), 1.64 - 1.77 (m. 5 Η). 1.B2 - 1.90 (m, 2 H) , 3.70 (e. 2 H). 4.02 (d. J=7.3 Ht 2 H). 4.41 (e. 2 H). 5.91 {·. 1 H). 7.63 (d, J=8.7 Hz. 1 H). 8.31 &gt; 8.38 (m, 1 Η). Θ.70 (d. J=2.8 Hz. 1 H) 丫.

445([MH]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.09 -.19 (m. 1 H), 1.29 - 1.40 (m. 8 HX 1.56 - 1.84 (m. 7 H). 2.00 ( t J=1B.6 Hz. 3 H). 3.65 (e. 2 H). 4.37 (s. 2 H). 5.21 - 5.31 (m. 1 H). 6.63 (d. J=8.3 Hi. 1 Η) 7.5Θ -7.86 (m. 2 H). 8.05 - 8.10 (m. ! H). 8.24 - Θ.28 (m. 1 H). 6.66 (d. &gt;2.3 Hz. 1 H)

447 ([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.08 -.19 (m. 1 H). 1.29 - 1.40 (m. 8 H). 1.58 - 1.74 (m. 5 H ), t.75 - 1.86 (m. 2 Η). 3.Θ1 (e. 2 HX 4.37 (b, 2 H). 5.20 - S.32 (m, 1 H)r 6.64 (d. J-8.7 Hz . 1 H), 6.90 (d. J=9.2 Hi. 1 H). 7.36 - 7.54 (m. 1 H). 7.60 - 7.65 (m, Ϊ H). 8.04 - 8.10 (m. t H). 8.13 ( d. J=2.8 Hi. 1 H). 8.29 -8.35 (m.) H) 153

447([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.07 -1.18 (m. 1 H). 1.29 - 1.40 (m, 8 H). 1.56 - 1.84 (m. 7 Η) 3.4Θ (e. 2 H). 4.32 (e, 2 H). 5.20 - 5.32 (m. 1 h). 6.57 (d. J=10.1 Hr. 1 H). 6.64 (d. J=a.3 Hi. 1 H). 7.27 -7.31 (m. 1 H), 7.59 - 7.63 (m. 1 H). 7.70 - 7.83 (m. 1 Η). Θ.05 - 8.0S (m. 1 H). 8 .t0 - B.14 (m. 1 H)

501 ([Μ·&lt;·Ν〇]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm U3 -1.25 (rrv 丨H&gt;. 1.35 - M7 (m· 2 H)· 1.61 - 1.72 (m. 4 H). 1.73 - 1.78 (m, 1 H). 1.81 - 1.91 (m. 2 H). 3.71 ($, 2 H). 4.44 (s. 2 H). 4.S6 (q. J^8.3 Hz 2 H). 6.02 (e. 1 H), 7.64 (d. J=8.7 H*. 1 H). 8.35 (dd. J=8.7, 2.3 Hz. 1 H). 8.71 (d. J=2.3 Hr . 1 H) Λ

453 ([M+H]+&gt; 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.95 (t J=7.3 Hi. 3 H). 1.16 - t.24 (m. JH), 1.33 (d. J =6.0 Hz. H). t.36 - 1.45 (m. 2 H). t.58 - 1.79 (m. 7 Η), 1.B4 -1.92 (m. 2 H), 3.71 (e. 2 H) 4.41 (s. 2 Ηλ 4.60 · 4.70 (m, \ Η). 5.B8 (*. 1 H). 7.64 (d. J=8.7 Hi, 1 H). 8.33 -8.39 (m. 1 H). 8.71 (d. J=2.8 Hz. 1 H)

453([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.01 (t J=7.6 Hz. 3 H). 1.13 - 1.25 (m. 1 H), 1.34 - 1.45 (m. 2 H). 1.57 - 1.90 (m, 9 H). 1.96 (·. 3 H). 3.69 (*. 2 H), 4.16 - 4.21 (m. 2 H). 4.40 (s. 2 H). 7.60 - 7.65 (m. 1 H). 8.32 - 6.40 (m. 1 Η). Θ.65 - 8.72 (m. 1 H) 157

443([M&gt;Na]·»-) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.00 (t. J=7.3 Hz. 3 H). U6 - 1.29 (m. 1 H). 1.39 (ddd. J=13.5. 6.0. 3.4 Hz. 2 H), 1.63 - 1.92 (m. 9 H). 3.70 (*. 2 H). 4.16 (t. J=6.6 Hz. 2 H). 4.42 (s. 2 H 5.91 (s. 1 H). 6.49 -B.78 (m. 1 H), 7.61 (d. J=8.7 Hz. 1 H). 0.25 - 8.34 (m. H). 8.69 (d. J= 2.3 Hz. 1 H) -98 - 201236682 [Table 2 - 1 3] Compound Example R R1 Salt (ESI posj m/z (ESI nec.) m/z 1H-NMR 158 1 /=NF 453 (tM+ H]+) 1H NMR (600 MHr* CHLOROFORM-tO d ppm 1.03 (t J=7.3 Hz. 3 H). 1.10 - 1.22 (m. IH), 1.31 - 1.89 (m, 11 H), 2.42 (8l 3 H). 3.63 (s. 2 H). 4.17 (», 2 H). 4.23 {t J=6.6 Hz. 2 H). 7.63 (d. J=B.7 Hz. 1 H). 8 J2 - 8.39 (m. 1 H). 8.69 (d, J«2.3 Hz, 1 H) 159 1 457 ([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.98 -1.05 (nv 3 HX 1 ·1β - 1.26 (m* t Η>· 1.3β _ 1.47 (m* 2 H). 1,63 - 1.93 (m. 9 H). 3.71 (s. 2 H). 4.23 (t. J=6.6 Hz 2 H). 4.49 (d. J=1.8 Hz. 2 H). 7.63 (d. J^8.7 Hz. 1 H), 8.36 - 8.44 (m. 1 H). 8.64 - B.73 (m. 1 H) 160 1 452 ( [M+H3+) 161 1 453{[M-^H3+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.94 (t J=7.3 Hz. 3 H). U3 - 1.23 (m. 1 H). 1.32 (d. J=6.0 Hz. 3 H). t.35 - 1.45 (m. 2 H), 1.57 - 1.79 (m, 7 H). 1.8i -t.92 (m. 2 H). 3J0 (» 2 H), 4.40 (s. 2 H). 4.5fl - 4.68 (mj H). 5.87 (*. 1 H), 7.63 (d. J=8.7 Hz·〗H). 8.36 (dd. J=8.7 2.6 Hz. 1 H). 8.70 (d. J=2.8 Hz. 1 H) 162 1 /=NF 453([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.94 (t J =7.3 Hz. 3 H). 1.13 - 1.24 (m. 1 H). 1.32 (d, J=6.4 Hz. 3 H), 1.35 - 1.45 (m. 2 H). 1.58 - 1.78 (m. 7 H) U0 -1.91 (m. 2 H). 3.70 (s. 2 H). 4.40 (e. 2 H). 4.58 - 4.69 (m, 1 H&gt;. 5.86 (e. 1 H), 7.63 (d, J =8.7 Hi. \ H). B.3t -8.3Θ (m. 1 Η), β.70 (d. J=2.B Hz. 1 H) 163 16 丫'T\ 47B([M+H] +) r 164 1 —0 /=NF 455l[M+H]+) 165 25 HO 441{[M+H]+) 166 1 (X &lt;Λ;390([M+H]+&gt; 167 1 Cy /=UF ~KLh^ 404([M+H]+) 168 16 丫l N=v F «9([Μ^]+Ϊ 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.07 1.1Θ (m , 1 H). 1.34 (d. J=6.0 Hz. 6 H), 1.44 (q, J=13.6 Hz. 2 H). 1.56 - 1.81 (m. 7 H), 3.91 (e. 2 H), 4.39 (s, 2 H). 5.24 - 5.3t (m. 1 H). 6.64 &lt;d, J=8.7 Hz . H). 7.61 -7.65 (rrv 1 H). 7.81 - 7.84 (m. 1 H). 8.08 - 8.11 (m. 1 H), 8.48 (d. J=9.2 Hz. 1 H). 8.52 - 8.56 (m. 1 H) 169 10 /=NF ΉΙλ^ρ 449([M+H]+) \H NMR (600 MHi. CHLOROFORM-d) d ppm 1.01 (t. J=7.6 3 H). 1_08 - 1.19 (n\ 1 H). 1.31 - M4 (m. 2 H). 1.56 - 1.87 (m. 8 H), 3.73 ($. 2 H). 4.22 (t J=6.6 Hz. 2 H). 4.40 (s 2 H), 6.60 (s. 1 H). 6.79 - 6.B6 (m. 1 H). 7.64 &lt;d, J=8.7 Hz. 1 H). 8.07 (d. J=5.5 Hi. t H 8.36 - Θ.43 (m. 1 H). 8.73 (d. J=2.8 Hi. 1 H) -99- 201236682 [Table 2 - 1 4] Compound lean example R R1 salt (ESI ponj m/z (ESI neic.) m/z 1H-NMR 170 17 /^=NF 1HCI 449([M*H)+) 171 18 385ttM+H]+) t72 18 ^〇A 401([M+H]+) 173 10 _hQ~^f 463([M+H]+) 174 18 400(tM^H)+) 175 18 405([M&gt;H)+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.ΘΘ (t. J=7.8 Hi. 3 H). 1.11 - 1.21 (m. 1 H). 1.39 - 1.52 (m. 2 Ηλ 1.5Θ - 1.66 (m. 9 H). 3.88 (s. 2 H), 4.16 (t. J=6.6 Hz 2 H). 4.40 (8. 2 H). 5.89 (β. 1 H). 7.54 - 7.63 (m. t H). 6.20 - 8.25 (m. ) H). 8.28 (d. J=9.2 Ht 1 H) 17β 18 4〇3([M+H]+) 177 13 〇Jxx /=NF 449([M+hi]O 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.09 -1.21 (m. 1 H ), 1.32 - 1.4β (m. 2 H). 1.58 - t.66 (m. 4 Ηλ 1.70 - 1.77 (m. 1 H), 1.78 - 1.88 (m. 2 H). 3.73 (e. 2 H) 4.01 (e. 3 Η). 4.5Θ («. 2 H). 7.66 (d. J=8.7 Hi, 1 H). 7.85 - 7.95 (m. 1 H). 8.10 (d. J=7.B Hz. 1 H). 8.38 (dd. J=8.7. 2.Θ Hz. 1 H). 8.69 - 6.76 (m. 2 H) 178 10 /=NF KLh^f 450(CM+H]+) 179 10 406([Μ+Η]+Ϊ 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.98 (t. J=7.3 Hz. 3 H). t.12 - 1.22 (m. 1 H). 1.36 - 1.46 ( m. 2 H). 1.62 - 1.Θ5 (m. 9 Η). 3.B5 (s. 2 H). 4.14 (t. J=6.6 Hz. 2 H). 4.40 (e. 2 H). S .96 (β. 1 H). 8.54 (e. 2 H) 180 1Β o- 386([M^H]+) 161 22 XXX /=HF ~KLht 449((M^H)+) 1H NMR (600 (M. 1 H). 1.28 (t, J=7.1 Hi. 3 H). H). 1.69 - t.75 (m. 1 H). 1.77 -1.86 (m. 2 H). 3.63 (q. J: 6.9 Hz. 2 H). 3.69 (s. 2 H). 4.48 (β. 2 H). 4.61 (*. 2 H). 7.41 (d. J=7.fl Ht 1 H) 7.64 (d. J=9.2 Hz. 1 H). 7.72 - 7.77 (m. 1 H). 8.36 -8.42 (m, 1 H). 8.49 - 8.53 (m. 1 H). 8.73 (d. J= 2.3 Hz. 1 H) -100- 201236682 [Table 2 - 15] Compound Example R R1 Salt (ESI posj m/z (ESI neit) m/z IH-NMR 182 22 rr^ 439 ([M+H} +) 183 ia 390([M+H3+) 184 t ^cy~F 3B9(CM+H]+) 185 22 493([M+H3+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.14 -1.25 ( m. t H), 1.34 - 1.46 (m. 2 H). 1.61 - 1.79 (m. 5 H). 1.81 - 1.92 (m. 2 H), 3.72 (a. 2 H), 3.85 (q. J= «.4 Hz. 2 H). 4.55 (e. 2 H). 4.70 ($, 2 Ηλ β.36 (e. 1 H). 7.64 Cd. J=8.7 Hz, 1 H). 8.33 - 8.3Θ ( m. 1 H). 8.69 - B.74 (m. 1 H) 18Θ 18 386&lt;(M+H3+) 187 18 F 423([M+H]+) 1H NMR (600 MHz. CHLOROFORMS) d ppm 0.99 ( t J=7.6 Hz. 3 H). U1 - 1.22 (m. t H), 1.31 - 1.43 (m. 2 H). V59 - 1.»0 On. 9 H). 3.83 {%, 2 Η), 4.3 (0. 2 H). 5.89 (e. 1 H). 7.40 - 7.53 (m. 1 H). B.10-8.18(m, 1 H) 1Β8 18 440 (CM+H] +) 1H NMR (600 MHz. OMSCHJ6) d ppm 0.94 (t Js7.6 Hz. 3 H). 1.09 - 1.79 &lt;m. 12 H). 3.89 (e, 2 H). 4.t0 (t. J =6.4 Hz. 2 H). 4.54 (e. 2 H)r 6.24 (s. 1 Η). Β.ΘΘ (», 1 H). 9.58 (s. 1 H) 189 18 4~^y~ F 403 (CM+H]+) 190 18 ^〇KBr 471(CM+Ne]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.99 (t. J=7.6 Hz. 3 H), 1.09 - t.21 (m. 1 H), 1.38 - 1.52 (m. 2 H). 1.57 - t.90 (m, 9 H). 3.67 (s. 2 HX 4.16 (t J=6.4 Hz. 2 H). 4.40 (e 2 H). 5.89 (e. 1 H). 7.66 - 7.75 (m. 1 H). 8.24 (d. J=9.2 Hz. 1 Η). Θ.30 - 6.35 (m. 1 H) 191 18 N ==\ 450(CM+H3+) 1H NMR (600 MHz. CHLOROFORMS) d ppm 0.Θ9 (t J=7.3 Hz. 3 H). 1.12 - 1.24 (m, 1 H). 1.35 - 1.49 (m. 2 H), 1.61 - 1.89 (m, 9 H). 3.85 (s. 2 H). 4.15 (t J=6.6 Hz« 2 H). 4,41(8. 2 H). 5.97 (s, t H) 8.63 &lt;8, 2 H) ^92 7 418([M+Na» 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.00 (t. J=7.6 Hz, 3 H). 1.t2 - 1.23 Cm 1 H), 1.39 - 1.51 (m. 2 H). 1.61 - 1.8Θ (m, 9 H). 3.92 (s, 2 H), 4.16 (t, J=6.6 Ht 2 H), 4.42 (». 2 H). 5.90 (*. 1 H). 7.33 &lt;dd. J=3.9. 2. 1 Hz. 1 H). 8.45 (d. J=8.7 H*. 1 H). 8.55 - B.5fl (m. 1 H) 193 7 419([M+Na)+) ν· ο -101 201236682 [ Table 2 - 16 6 Compound Example R R1 Salt (ESI posj m/z (ESI nex.) m/z 1H-NMR 194 23 /==NF ^0~^τ 430{[M+H)+) 195 1 /=N f 449([M*H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.03 (t. J=7.6 Ht· 3 H&gt;. 1.10 - 1.21 (n\ 1 H). 1.27 Called .40 (m, 2 Η). 1.4B - 1.57 (m. 2 H). 1.62 - 1.72 (m, 3 H), 1.74 -1.88 (m, 4 H). 3.68 (s. 2 H). 3.94 (t J=6.4 Hz. 2 H). 4.55 (e, 2 H), 7.08 - 7.18 {m. 1 H). 7.34 (d. J=8.3 Hz. 1 H). 7.63 (d. J=9.2 Hz 1 H). 8.18 (d. J=2.8 Hz. 1 H). 8.3S - Θ.43 (m. 1 H). 8.72 (d. J»2.8 Hz. 1 H) 196 18 416 ([M+ T〇+) 197 1Θ N==NF 440([M*H]+) 198 18 439([M+H]&lt;〇189 18 % 439([M+M3·*·) 200 1Θ N^=\ F ^KjT^ 439 ([M+H]*〇201 18 454([MfH]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.Θ8 (t. J=7.6 Hz. 3 H). 1.12 · 1.21 (m, 1 H). 1.31 - 1.42 (m, 2 H). 1.59 - 1.87 (m. 9 H). 3.63 (*. 2 H). 4.05 - 4.18 (m. 2 H). 4.38 Cs. 2 H), 5.88 (s. 1 H). 7.14 - 7.22 (m. 2 H). 7.52 - 7.64 (m. 2 H) 202 1. Helium 400 ([M+H]+) 1H NMR (GOO MHz, CHLOROFORM-d) d ρρπ 0 .Θ5 -1.01 (m, 3 H). U2 - 1.20 (m. 1 H), 1.29-1.41 (m, 2 H). t.57 - 1.70 (m. 5 H). 1.72 - 1.85 (m. 4 H). 3.61 (s. 2 H). 3.78 (*. 3 H). 4.14 (t. J=6.6 Hz. 2 H). 4.37 (b. 2 H). 5.80 (8. 1 Η). 6. B0 - 6.96 (m. 2 H). 7.39 - 7.50 (m. 2 H) 203 1 〇Λ 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.9B (t. J=7.6 Ht. 3 H). U1 - 1.21 (m. 1 H). 1.31 - 1.40 (m. 2 H). 1.60 - 1.73 (m. 5 H). 1.74 - 1.85 (m. AH). 3.6t (#. 2 Η). 3.90 (t 3 H). 4.14 (t J^6.6 Hz. 2 H). 4.38 (s. 2 Η). 5.8Θ (·. 1 H). 6.73 (d. J=9.2 Hz. 1 H). 8.04 (d J=2.8 Hs. 1 H). 8.08-8.16 (m. 1 H) 204 &lt;κ_ 415([M+H)+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.99 (t J=7.3 Hz. 3 H). 1.13 - 1.22 (m. 1 H), 1.31 - 1.42 (m. 5 H). 1.60 - t.74 (m. 5 H), 1.74 - 1.87 (m, 4 H). 3.62 ( *. 2 Ηλ 4.16 (t J=8.4 2 H). 4_32 (q. J=6.9 Hz» 2 H). 4.38 (». 2 H). 5.89 (*. 1 H). 6.72 (d. J=8.7 Hi. 1 H). 8.04 (d. J-2.8 Hz. 1 H). 8.09 - B.17 (m. 1 H) 205 1 /=NF 457([M-*-H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.16 -1.24 (m. 1 Ηλ 1.33 - 1.44 (m 2 H). 1.59 - 1.67 (m, 2 H). 1.69 - 1.88 (m. 5 H). 3.70 (e. 2 H), 4.62 (e. 2 H). 7.30 - 7.37 (m. 1 H) 7.44 - 7.49 (m. 2 H). 7.64 (d. J=8.7 H). 7.82 (s· 1 H). 8.00 - 8.05 (m, 2 H)· 8.38 ·* 8.43 (m. 1 H). 8.72 (d. J=2.0 Hi. ! H) -102- 201236682 [Table 2 - 1 7] it^} 寅Example R R1 Salt (E Tian poe·) m/z (ESI ηβό m/x 1H-NMR 206 1 423 ([ΜΗ〇·〇1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.05 -U7 (m. 1 H). 1.33 - 1.46 (m. 2 H). 1.57 - 1.62 (m, 4 H) 1.65 - 1.70 (m. 1 H). 1.71 - 1.79 {m. 2 H). 3.86 (·. 2 HX 4.53 (e. 2 H). 6.44 - 6.47 (m. 1 H). 7.46 - 7.52 (m , 2 H), 7.S9 - 7.66 (m. 2 H). 7.70 - 7.73 (nv 1 H). 7.88 - 7.92 (m. 1 H), fi.56 (e. 2 H) 207 18 455{[ M+H]+) 208 1 /=NF 456([M+H]+) 1H NMR (600 MHz. CHLOROFORM-^) d ppm 1.15 -U5 (m. 1 H). 1.33 - 1.45 (m. 2 Ηλ 1.62 - 1.69 {m. 2 H). 1.71 - U9 (m. 3 H). 1.81 - 1.B9 (m. 2 H). 3.66 (e. 2 H)..4.37 (s. 2 H). 7 . 22 - 7.29 (m, 1 H). 7.39 - 7.48 (m. 2 H), 7.59 - 7.68 On. 4 H). 7.99 (*. t Η), Θ JS -8.41 (m. 1 H), 8.71 ( d. J=2.8 Hz. 1 H) 209 1 (1)X 471([M+H]+) 210 19 /=NF &quot;ΚΙλ~^ 470([M+H]*J 1H NMR (600 MHz. CHLOROFORM-d d ppm 1.17 -U5 (m, t HX.1.32 - 1.44 (m. 2 H), 1.61 - 1.74 (m. 3 H). 1.79 - 1.95 (m. 4 H). 3.67 (s. 3 H), 3.67 (*. 2 H). 4.44 (*. 2 H). 7.00 (». 1 H). 7.36 - 7.47 (m. 3 H). 7i5 -7.65 (m, 3 H). 8.37 - Θ.43 ( m, 1 H), 8.73 (d. J=2.3 Hz. 1 H) 211 1 /=s=NF 459&lt;[Μ+Ή]·〇212 1 Br 469(CM+H]+) 213 19 4S8([ M+H]+) 214 1 534([M+H]+) 215 1 /==NF 456([M+H]+) 216 1 F 44β([Μ+Η]*) ΐΗ NMR (600 MHz. CHLOROFORM-d) d ppm 1.Ί2 -1.23 (m, 1 H). 1.38 - 1.49 (m. 2 H). 1.61 - 1.77 (m. 5 Η). 1.7Θ - t.87 (m. 2 H) 3.88 (*. 2 Ηλ 4.44 (e. 2 H). 4.58 (q. J=8.1 Hz. 2 H). 6.09 (e. 1 H). 8.55 (e, 2 H) 217 1 eve, 0 /° Ό^ η·- 420([M+H]+) NMR (600 MH^ CHLOROFORM-d) d ppm 0_94 {t J=7.6 Hz. 3 H). 1.11 - 1.23 (m. 1 H), t.33 (d. J=6.0 Hz. 3 H). 1.37 - 1 .47 (m. 2 H). 1.59 - 1.79 (m. 7 H). 1.79 -1.87 (m, 2 H), 3.87 (s, 2 H). 4.41 (s. 2 H). 4.63 (ext. J =6.1 Hz, 1 H). 5.94 (s. 1 H). 8.55 (e. 2 H) -103- 201236682 [Table 2 — 1 8] Compound cargo R R1 salt (ES! poej m/z (ESI Nee·]m/z 1H-NMR 218 20 /=NF 457([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.15 -1.24 (m. 1 H). 1.34 - 1.45 (m , 2 H), 1.65 - t.70 (m. 2 H). 1.71 - 1.79 (m, 3 H). 1.80 - 1.89 (m. 2 Η). 3.6B (e. 2 H). 4.41 (. 2 H). 7.15 - 7.21 (m. 1 H). 7.61 - 7.67 (m. 1 H). 7.74 (*. \ H). 7.77 - 7.84 (m, \ H). 7.92 -7.97 (m. 1 H ), 8.36 - 8.45 (m, 2 Η). Θ.54 (e. 1 Η). B.71 (d. J=2.8 Hz. 1 H) 219 21 YH0^r fO^F 422 ([M+H ]+) 220 21 /=NF 436([M+H]+) 1H NMR (600 MHz. CHLOROFORM&lt;d} d ppm 0.93 (t, Js7.6 Hz. 3 H). 1.15 - 1.24 (m. 1 H 1.26 - 1.45 (m. 4 H). 1.60 - 1.66 (m. 2 H). 1.68 - 1.78 (m. 3 H). 1.79 -1.89 (m. 4 H). 3.65 (*. 2 H). 4.07 (t, J=7.3 Hz. 2 H), 4.30 (e. 2 H). 7.41 - 7.48 (m. 2 H). 7.64 (d. J»8.7 Hz. 1 H). 8.35 - 8.42 (m. 1 H), 8.71 (d, J=2.3 Hz, 1 H) 221 20 /=NF KZ/~tF 457([M+H]+) 1H NMR (600 MHz. CHLOROFORM'd) d ppm 1.17 -1.28 (m. 1 H). 1.36 - 1.47 (m. 2 H). 1.63 - 1.80 (m. 5 H), 1.83 - 1.91 (m. 2 H). 3.69 (s. 2 H). 4.39 (s. 2 H). 7.3Θ (dd. J=8.5. 4.8 Hr. 1 H 7.65 (d, J=a.7 1 H). 7.73 (*· 1 H). 7.99 - 8.03 (m&lt; 1 Ηλ β.Μ &lt;8.丨Ηλ 8.39 (dd. J=8.7. 2.3 H *. 1 H). 8.51 - 8.57 (m. 1 H), 8.72 (d. J=2.8 Hz. 1 H). 8.98 (d. J=2.3 Hi. 1 H) 222 20 458 ([M+H] +) 223 20 /=NF 458([M*H]+) 224 20 γΗχ, /=NF 45Θ([Μ^Η]+) 225 1 CM -H&gt; 423([M+H]f) 1H NMR ( 600 MHz. CHLOROFORM-d) d ppm 1.14 -1.24 (m. 1 H). 1.38 - 1.50 (m. 2 Ηλ 1.61 - 1.68 (m. 2 H). 1.68 - 1.76 (m. 3 H). 1.77 - t .86 (m. 2 H). 3.84 (e. 2 H), 4.37 (*. 2 H). 7.20 - 7.29 Cm. 1 H), 7.39 - 7.45 (m. 2 H). 7.63 - 7.71 (m. 3 HX 8.11 (β. 1 Η), Θ.55 (e. 2 H) 226 1 420 ([M,H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.Θ3 (t J=7.6 Hi. 3 H). 1.10 - 1.22 (m, 1 H). 1.32 (d. J=6.0 Hi. 3 H). 1.36 - 1.47 (m. 2 H). 1.57 - 1.78 (m. 7 Η). 1.7 - -1.65 (m. 2 H). 3.86 (t. 2 H). 4.39 (s. 2 H). 4.62 (sxt. J=6.1 Hz. 1 H), 5.93 U. 1 H). 8.54 (s. 2 H) 227 18 Leaf F 440 ([M—“] ♦) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.9Θ (t J=7.3 Hi. 3 H). 1.16 - 1.25 (m. 1 H). 1.33 - 1.45 ( m. 2 H). 1.65 - 1.82 (m. 7 H). 1.83 - 1.93 (m. 2 H). 3.69 (s. 2 H). 4.15 (t J=6.6 Hz. 2 H), 4.42 ($. 2 H). 5.91 (e. t H). 9.HU. 2H&gt; 228 18 N=\ FF 457([M+H)+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.00 (t, J =7.3 Ht 3 H). 1.13 - 1.23 (m. 1 H). 1.32 - 1.« (m. 2 H). 1.60 - I.8B (m. 9 H). 3.89 (s, 2 H). 4 .t6 (t J=6.6 Ht 2 H). 4.41 (8l 2 Η). 5.Θ0 (s. 1 H). 7.68 (dd. J=9.6. 1.8 Hz. 1 H). 8.44 (s. 1 H 229 1 424([M+H]+) 1H NMR (600 MHz. CHLOROPORM&gt;d) d ppm 1.16 · 1.27 (m. 1 H). 1.37 - 1.49 (m, 2 H). 1.64 - 1.76 (m. 5 H). 1.79 - 1.90 (m. 2 H). 3.89 (·. 2 H). 4.59 (t, 2 H). 6.71 (». t H). 7.38 - 7.51 (m. 3 H), 7.74 - 7.84 (m. 2 Η). Θ.56 (s. 2 H) -104- 201236682 [Table 2 - 1 9] Compound K Example R R1 Salt (ESI posj m/z (ESI necJ m/z 1H-NMR 230 19 fO'^r 503([M+H]+) IH NMR (600 MHz. CHLOROFORM-d) d ppm 1.11 &gt; \.Z\ Cm. \ H).\2Z - \AZ (m, 2 H). 1.47 (d. J=6.4 Hz. 3 H). 1.57 - 1.88 (m. 7 H). 3.68 (e. 2 H). 4.38 - 4.44 (m, 2 H). 5,70 - 5.79 (m. 1 H). 6.76 (d. J=8.3 Hz. 1 H). 7.63 (d. J=8.7 Hz. 1 H). 7.67 - 7.71 (m. 1 H). 8.03 - B.13 (m. 1 H). 8.38 (dd J=8.7. ZB Hz. t H). 8.7t (d. J=2.8 Hi. 1 H) 231 19 α-α, 456(fM+H]+) 232 19 424{[Μ+Η]·0 IH NMR (600 MHz. CHLOROFORM-d) d ppm 1.19 -1.29 (m. 1 Ηλ 1.34- 1.50 (m. 2 H). 1.56 - 1.61 (m. 2 H), 1.66 - 1.74 &lt;m. 1 H) US - 2 H). VB6 -1.95 (m. 2 H), 3.54 (s. 2 H). 4.60 (s. 2 H). 7.36 - 7.45 (m. 1 H). 7.46 - 7.53 (m. 2 H), 7.70 - 7.76 (m. 2 H). 8.27 (s.1 H). 8.54 (8. 2 H) 233 19 p-Ow F 442([M+H]+) IH NMR (600 MHz, CHLOROFORM -d) d ppm 1.19 -1.31 (m. t H). 1.36 - t.4fl (m, 2 H). 1.58 - 1.64 (m. 2 H). 1.68 - t.75 (m. 1 H). t .80 - 1.97 (m. 4 Η). 3.Θ5 (e. 2 H). 4.60 (s, 2 H), 7.08 - 7.18 {m, IH). 7.42 - 7.5S (m, 3 H), 8.29 (β. 1 Ηλ 6.55 (e, 2 H) 234 21 ~^cy^Fr 408([M+H]+) 235 21 422([M+H]+) 236 21 / 438([M+H]+) 237 20 \ cWx /=NF KLh^ 4B8([M+H» 1H NMR (600 MHz. CHLOROFORM-d) d Ppm 1.15 -1.24 (nv 1 H). 1.34 - 1.43 (m. 2 H), 1.64 - 1.69 (m. 2 H), 1.72 - 1.80 (m. 3 H). 1.82 - 1.B7 (m. 2 H 3.65 (e. 2 H). 3.88 (e. 3 H). 4.39 (e. 2 H). 7.00 - 7.0S (m. 2 H). 7.26 - 7J0 (m. 1 H). 7.62 (d J=8.7 Hz. 1 H), 7.66 -7,69 (m. 2 Ηλ B.05 (s. 1 H&gt;. 8.39 (dd« J=8.7. JL3 Hr» 1 H). 8.71 (d. J =2.8 Hz. 1 H) 238 20 486([M+Hj+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.23 -t.28 (m. 1 H). 1.34 - 1.43 (m. 2 H), 1.63 - 1.68 (m. 2 H). 1.71 - 1.77 (m. 3 H). 1.81 - 1.87 (m. 2 H). 3.66 (s. 2 H). 3.85 (e. 3 H). 4.37 (s. 2 H). 6.81 (dd. J=8.3, 1.8 Hz. \ Η), 7.1B - 7.21 (m. 1 H). 7J26 - 7.28 (m. 1 H&gt;. 7.29 - 7.33 (m. 1 H). 7.63 (d. J=8.7 Hz. 1 Η). 7.6Θ (e, 1 H), 7.97 (e. 1 H). 8.38 (dd. J=8.7. 2.8 Hi. 1 H). 8.71 (d. J =2.3 Hz. 1 H) 239 20 /. 486 pin 486([M+H]+) IH NMR (600 MHz. CHLOROFORM-d) d ppm 1.23 -1.30 (m. 1 H). 1.32 - 1.45 (m. 2 H). 1.62 - 1.68 (m. 2 H). 1.70 - 1.79 (m. 3 H). 1.80 - 1.89 (m. 2 H). 3.66 (s. 2 H). 3.83 (8. 3 H). 4.36 (e. 2 H). 6.88 - 7.00 (m. 2 H). 7.51 - 7.58 (m. 2 H). 7.60 - 7.67 (m. 2 H), 7.90 (s. 1 H). 8.34 - 8.41 (m. 1 H), 8.71 (d. J=2.3 Hz. 1 H) 240 1 /=NF ^0~^f 458([M+H]+) IH NMR (600 MHz. CHLOROFORM-d) d ppm 1.17 -1.30 (tn. 1 H). 1.36 - 1.40 (m. 2 H). 1.68 - 1.81 (m, 5 H). 1.85 - 1.95 (m. 2 H), 3.75 (e, 2 H). 4.62 (s, 2 H). 6.67 (s. 1 H). 7.35 - 7.44 (m. 1 H), 7.66 (d. J=9.2 Hz, 1 H). 8.07 - 8.16 (m. 1 H). 8.33 - 8.41 (m, 1 H). 8.65 -8.71 ( m. 1 H). 8.74 (d. J=13 Hz. 1 Η). Θ.98 - 9.04 (m. 1 H) 241 21 ^o~tp 434([M+H]+) IH NMR (600 MHz CHLOROFORIvHi) d ppm 0.30 -0.41 Cm. 2 H). 0.58 - 0.67 On, 2 H), 1.10 - t.30 (m. 2 H). 1.32 - t.47 (m. 2 H), 1.61 - 1.78 (m, 5 H). 1.80 -1.89 (m. 2 H). 3.65 (s, 2 Η). 3.A4 (d. J=6.9 Hi. 2 H). 4.31 (s. 2 H). 7.45 ( s. 1 H). 7.55 (s. 1 H). 7.63 (d. J=8.7 Hz. 1 H). 8.38 (dd. J=8.7. 2.3 Hz, 1 H). 8.71 (d. J=2.3 Hz. t H) -105- 201236682 [Table 2 - 2 0] Compound Example R R1 Salt (ESI posj m/z (ESI nen.) m/z 1H-NMR 242 21 /=NF ~KLh-f 448([M*K]+&gt; 1H NMR (600 MHr. CHLOROFORM-d) d ppm 1.15 - 1.25 (m. 1 H). 1.31 - 1.43 (m. 2 H). 1.58 - 1.76 (m. 7 Η). 1.7Θ - 1.90 (m. 4 H). 1.91 - 2.03 (m. 2 H). 2.08 -2.17 (m. 2 H). 3.63 (s. 2 H). 4.28 (s. 2 H). 4.58 (quin. J=7.2 Hi. 1 H). 7.42 (e. 1 H). 7.48 {·. 1 H). 7.62 (d. J=8.7 Hz. 1 H). 8.33 - 8.39 (m. 1 H). 8.70 (d. J=2.8 Hr. 1 H) 243 20 /=NF Kj^f 474([ M+H]+) 1H NMR (600 MHz. CHLOROFORM-d).d ppm 1.13 -1.2B(m, 1 H). 1.31 -1.46 (m. 2 H). 1.63- t.80 (m. 5 H ), 1.80 - 1.89 (m. 2 H). 3.67 (e. 2 H). 4.39 (s. 2 H), 7.14 - 7.28 (m. 3 H). 7.63 (d. J=8.7 Hz. 1 H) 7.71 (s. \ H). 7.81 - 7.89 (m. \ H). 7.S9 - 8.06 (m. t Η). B.37 -8.45 (m. YH). 8.69 Cd. J=2.3 Hz. 1 H) 244 20 F 474([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.17 -1.26 (m. 1 H). 1.35 - 1.46 (m. 2 H). 1.64 - 1.80 (m. 5 H). 1.83 - 1.90 (m. 2 Η). 3.6B (e, 2 H). 4.37 (e. 2 H). 6.92 - 7.01 (m. 1 H). 7.36 - 7.4t (m, 1 H). 7.42 - 7.48 ( m. 2 H). 7.65 (d. J=8.7 Hz. 1 H). 7.68 (β. \ H). 7.99 (». 1 HX 8.39 (dd, sJ=8.7. 2.8 Hz. 1 H). 8.72 ( d. J=2.8 Hz. 1 H) 245 20 /=NF 474{[M+H]+) YH NMR (600 MHz. CHLOROFORM-d) d ppm U5 -1.31 (m. 1 H), 1.35 - 1.4Θ (m. 2 H). 1.62 - 1.82 (πχ 5 H). 1.83 - 1.91 (m. 2 H). 3.68 (·. 2 H). 4.37 (». 2 H). 7.08 - 7.17 (m. 2 H 7.59 - 7.68 (m, 4 H), 7.95 (β. 1 Η). Θ.38 (dd. J=8.7. 2.3 Hz. 1 H), 8.73 (d. J=2.3 Hz. 1 H) 246 1 &quot;Cu /^=NF 516([M+H]+) 247 1 Br&lt;x, /=NF ^0~tF 469([M*H]+) 24Θ 21 &gt;〇. /=NF 450( [MH^·*·) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.74 (t J=7.6 Hz. 6 H). 1.11 - 1.23 (m, 1 H). 1.30 - 1.42 (m. 2 H) 1.57 - 1.92 (m. 11 H). 3.64 (e. 2 H). 3.79 - 3.87 (m. \ H). 4.33 (s. 2 H), 7.42 (e. 1 H). 7.46 (*, 1 H), 7.64 (d. J=8.7 H*. 1 H). 8.34 - 8.41 (m. 1 H). 8.70 - 8.75 (m. t H) 249 21 450(tM+H]+) 250 \ 454( [M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm U4 -1.28 (m. 1 H). 1.36 - 1.48 (m. 2 Η). 1.M - 1.78 (m. 5 H). 1.80 - 1.87 (m. 2 H). 3.88 (e. 2 H 3.88 (e. 3 H). 4.61 (e. 2 H). 6.85 (e. 1 H). 6.86 - 7.05 (m, 2 H). 7.36 -7.43 (m. 1 H). 7.82 - 7.8Θ (m. 1 H). 8.55 (e. 2 H) 251 1 &gt; /=NF _fO_^F 4fi3([M+H]+) 1H NMR (500 MHz, CHLOROFORM-d) d ppm 1.17 -1.30 (m , 1 H), 1.34 - 1.48 (m. 2 H). 1,62 - 1.80 (m. 5 H). 1.82 - 1.93 (m. 2 H). 2.55 - 2.69 (m. 2 H). 3.72 (s , 2 H). 4.39 - 4.50 (m. AH). 5.94 Ce. 1 H). 7.65 (d. J=0.4 Hz. 1 H). 8.32 - 8.40 (m, 1 Η). B.72 (d, J=2.3 Hz. 1 H) 252 1 &gt; 460([Μ·*Ή)+) 253 18 N=\ ^ 440([Μί·Η]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.99 (t. J=7.3 3 H&gt;. U4 - 1.24 (rrv 1 Ηλ 1.36 - 1.40 (m. 2 H). 1.62 - 1.87 (m. 9 H). 3.93 ($. 2 H). 4.15 (t J= 6.6 Hz. 2 H), 4.43 (e. 2 H). 5.98 (s. 1 H). 6.82 (s, 2 H) -106- 201236682 [Table 2 - 2 1] Compound 苡 Example R R1 Salt (ESI Poej m/z (ESI nec.) m/z 1H-NMR 254 18 402([M+H]+) 255 20 475([M+H]+) 1H NMR (500 MHz. CHLOROFORM-d) d ppm 1.1 6 -1.27 (m« 1 H).U4 · 1.47 (take 2 H). 1.64 - 1.79 (m_ 5 Η). 1.81 * 1.90 (m. 2 H). 3.68 (s. 2 H), 4.42 («. 2 Ηλ 7.24 - 7.29 (m. 1 H). 7.59 - 7.6δ (m. 2 H). 7.82 (*, 1 H). 8.29 - 8.32 (〇% 1 Η). B.36 (s. 1 H) 8.39 - 8.45 (m. 1 H). 8.71 (d. J=2.3 Hz. 1 H) 256 1 N=\ 425(tM+H]+) 257 20 /=NF 475([M+H]+) 1H NMR (500 MHz. CHLOROFORM-d) d ppm 1.17 -1.30 (m. 1 H). 1.35 - 1.48 (m, 2 H). 1.65 - t.B1 (m. 5 H). 1.83 - 1.92 (m. 2 Ηλ 3.70 (s, 2 H). 4.38 (s. 2 H). 7.65 (d. J=8.8 Hz. 1 H). 7.74 (β. \ H). 7.80 - 7.86 (m. 1 H). 8.05 (e. 1 H). 8.3S - 8.42 (m. 2 H). 8.70 - 8.74 (m, \ H). 8.78 - 8.8t (m. 1 H) 258 20 475([M+H]+) 259 19 /=NF 470([M+H1+) 1H NMR (500 MHz. CHLOROFORM&gt;d) d ppm t.09 · 1.19 (nv 1 H).丨.32 - 1.44 〇rv 2 H). 1.59 · 1.87 &lt; Ra 7 H). 3.69 (8. 2 H). 3.73 (e. 3 H). 4.66 (e, 2 H). 7.10 (·. 1 H). 7.40 - 7.50 (m. 3 H), 7.58 - 7.62 (m. 2 H). 7.66 (d, J=8.0 Hi. 1 H), 8.3t - 8.40 Cm. 1 H). 8.74 - 8.78 (m. 1 H) 260 19 430 ([M+H» 261 20 /=NF 457([M+ H]+) 1H NMR (500 MHz, CHLOROFORM-d) d ppm 1.14 -1.27 (m. 1 H). 1.32 - 1.46 (m. 2 H), i.61 - 1.80 (m. SH). 1.82 - 1.91 (m, 2 H). 3.63 (s. 2 Ηλ 4.36 (e. 2 H). 7.56 - 7.67 (m. 3 H). 7.72 (*, 1 H). 8.10 (*. 1 H). 8.32 -8 ^8 (m. 1 H). 8.60 - 8.65 (m. 2 H). 8.69 - 8.75 (m. 1 H) 262 20 0 &quot;^O〈ff 407([M+H]+) 1H NMR (500 MHz. CHLOROFORM-d) d ppm 1.12 -1.30 (m. t H), t^2 - A.47 (m, 2 H). 1.62- 1.8Θ (m. 7 H&gt;. 3.66 {». 2 H) 4.05 (e. 3 H), 4.39 (e. 2 Η). 7Λ0 (dd. J=7.6. 5.0 Hz. 1 H). 7.62 (d. J=8.4 Hi. 1 H). 7.69 (». 1 H). 8.04 - 8.15 (m. 2 H). 8.23 (s. t H). 8.33 - 8.45 (m, 1 H), 8.7t (d. J=2.7 Hi, 1 H) 263 20 c,^x 491([M+H]+) 1H NMR (500 MHz. CHLOROFORM-d) d ppm 1.17 -1.29 (m. 1 H). U4 - 1.48 (m. 2 H). 1.64 - 1.92 (m, 7 H 3.70 (8. 2 H). 4.38 (s, 2 H). 7.65 (d, J=0.8 Hz. 1 H). 7.74 (8,1 Η). Θ.03 (s, 1 H). 8.05 - Θ.10 (m. 1 H), 8.38 -8.43 (m, 1 Η), Θ.45 - 8.50 (m. 1 Η), Θ.69 - 8.74 (m. 1 H). 8.81 - 8.87 (m . 1 H) 264 20 475([M+H]+) 1H NMR (500 MHz. CHLOROFORM-*d) d ppm 1.14 -1.30 (m. t H), 1.34 - 1.47 (m. 2 H). 1.64 - 1.96 (m. 7 H). 3.69 (*, 2 H). 4.40 (*. 2 H). 7.30 - 7.37 &lt;m. \ H). 7.65 (d. J=8.8 Hz. 1 H). 7.77 (e. 1 H). 8.09 - 8.14 (m. 2 H). 8.32 - 8.47 (m. 2 H). 8.68 - 8.73 (m. 1 H) 265 20 =NF ^0~^ρ 487([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.04 -U6 (m. ί HX 1.20 - 1.35 (m. 2 H), 1.53 - 1.78 (m. 7 H). 3.56 (s. 2 H). 3.83 (s. 3 H). 4.31 (*. 2 H). 7.12 -7.20 (m. 1 H) 7.25 - 7.32 (m. 1 H). 7.53 (d, J=8.7 Hz. 1 H). 7.66 (*. IH). 8.02 - 8.10 (m. t H). 8.16 (e. t H). 8.24 - 8.32 (m. 1 H). 8.59 - 8.66 (m. 1 H) -107- 201236682 [Table 2 — 2 2] Compound cargo salt (ESI potj m/t (ESI neiJ m/t

464([M+H.V) 267

1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.13 -1.23 (m, 1 H). 1.34- 1.45 (m. 2 H). 1.64- 1.79 (m. 5 H). 1.82 - 1.92 (m. 2 H 2.09 - 2.23 (m. 2 H). 3.71 (s. 2 H), 4.35 (t J=6.0 Hz. 2 H). 4.42 (». 2 H). 4.49 - 4.ββ (m. 2 H 5.92 (s. 1 H), 7.64 (d. J^8.7 Hz. 1 H). 8.36 (dd &gt;8.7, 2.5 1 H)·Θ.71 (d_ #2_5 Hz· 1 H) 475([ M+H:J+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.16 · Ml (m. 1 H). 1.35 - 1.47 (m. 3 H). 1.62 - 1.93 (m. 7 H). 2.25 - 2.38 (m. 2 H). 3.72 (e. 2 H). 4.39 (t. J=6.0 Ht 2 H). 4.43 (e. 2 H). 5.88 - 6.12 (m. 2 H). 7.64 (d. J=8.7 Η*. 1 H). 8.32 - 8.39 (m, 1 H). 8.70 - 8.75 (m, \ H) Λ

471([M+H]+) 1H NMR (600 MHt. CHLOROFORM-d) d ppm 0.95 (t. J=7.4 Hi. 3 H). t.16 - 1.2! (m. 1 H). 1.33 (d J=6.2 Ht 3 H). 1.35 - 1.45 (m. 2 H). 1.58 - Ϊ.89 (m, 9 H), 3.90 (s. 2 H). 4.40 (s. 2 H), 4.57 - 4.69 (m. 1 H). 5.87 (β. 1 H), 7.63 - 7.73 (nv 1 H), 8.44 (». IH) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.94 (t. J=7.4 Hz , 3 H), 1.16 - 1.21 (m. 1 H). 1.33 (d. ϋ=β.2 Ht, 3 H). 1.35 - 1.46 (m. 2 H). 1.57 - 1.88 (m. 9 H). 3.89 (β. 2 H). 4.40 (*, 2 H). 4.57 - 4.70 (m. 1 H). 5.87 (β. 1 H), 7.61 - 7.70 (m, ί H). 8.44 (*. 1 H FO*ρ4λ &lt;y 493 ([Μ+Η» 1H NMR (600 MHz. CHLOROFORM-d) d ppm U2 -1.28 (m. 1 H). 1.34 - 1.47 (m. 2 Η), Ϊ.63 - 1.94 (m. 7 H). 3.72 (e. 2 H). 4.30 - 4.49 (m. 2 H), 5.1 \ - 5.20 (m. H). 5.98 (β. 1 H). 7.6S (d, ^ Θ.7 Hz. 1 H). 8.32 - 8.41 (m. 1 H). 6.66 - 8.75 (m. 1 H) 272

453([Μ·*Ή]+) tH NMR (600 MHz. CHLOROFORM-d) d ppm 0.98 (d. J=6.6 Hi. 6 H). 1.15 - 1.26 (m. \ H). 1.33 - 1.45 Cm. 2 H). 1.65 - 1.77 (m. 5 H). 1.82 - 1.91 (m. 2 H), 2.02 -2.t2 (m. 1 H). 3.70 (e. 2 H). 3.97 (d. J= 6.6 Hi. 2 H). 4.42 (s. 2 H). 5.91 (s. 1 H). 7.64 (d. J=8.7 Hi. 1 H), 6.33 - 8.40 (m. 1 Η). 8.6Θ - 8.74 (m. 1 H)

430(CM*H]+) 20 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.16 -1.2B Cm. 1 H), 1.34 - 1.48 (m. 2 HX 1.64 - 1.91 (m, 7 H). 3.67 (·. 2 H). 3.93 - 3.88 (m. 3 H). 4.39 (s. 2 H), 6.96 Cd. J=5.8 Hz. 1 H), 7.63 (d. J=8.7 Hz. IH). 7.70 (e. 1 H). 6.04 (8.1 H). 8.29 - Θ.40 (m. 1 H). 8.46 (d. J=5.4 Hz. 1 H). 6.70 - Θ.78 (m. 1 H), 8.84 (s. 1 H) 275

471([M+H]+) IHNMR^OOMHLCHLOROFORM-cOdppml.n· 1.30 Cm. 1 H). 1.32 - 1.47 (m. 2 H), 1.64 - 1.90 (m, 7 H), 2.41 (s. 3 Η ), 3.6Θ (t. 2 H). 4.39 (&gt;. 2 H). 7.65 (d. J=8.7 Hz. 1 H). 7.72 (β. 1 H). 7.85 (β. 1 H). 8.02 (8. \ H). 0.33 - 6.42 (m. 2 H). 6.69 - 8.74 (m. 1 H). 8.75 -8.Θ1 (m. 1 H)

487([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.16 . 1.28 (m. 1 H). 1.33 - 1.46 (m, 2 H). 1.63 - 1.92 (m, 7 H) , 3.69 (s. 2 H), 3.92 (s. 3 H). 4.38 (s. 2 H). 7.57 -7.61 (m. 1 H). 7.64 (d. J=8.7 Hz. 1 H). 7.72 ( β. 1 H), 6.02 (s. 1 H). 8.20 - 6.27 (m. 1 H). 8.35 · 8.43 (m. f H). 8.48 - B.55 (m. 1 H). 8.69 - 8.74 ( m. 1 H) 277

1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.08 -1.23 (m. ) H). 1.29 - 1.41 (m. 2 H). 1.54- t.62 (m. 2 H). 1.63 - 1.75 (m. 5 H). 1.77 - 1.92 (m. 4 H). 1.96 -2.07 (m. 2 H). 2.70 - 2.82 (m, 1 H). 3.61 (e. 2 H). 4.04 (d. J*7.0 Hz 2 H). 4.26 (s. 2 H). 7.34 - 7.44 (m, 2 H). 7.60 (d. J=8.7 Hz. 1 H). 8.30 - 8.39 (m. 1 H). 8.66 -8.71 ( m. t H) -108- 201236682 [Table 2-2 3 Compound Example Salt (ESI posj m/z (ESI negj m/z &lt;y 462([M+H)+)

280

464([M+H]+) 281

• Θ8 (d 420([M+H]+) 1H NMR (600 MHz. CHLOROFORM-&lt;〇d ppm 0.Θ J=6.6 Hz, 6 H). 1.10 - 1.22 (m. 1 H), 1.35 - 1.48 (i H). 1.62 - 1.89 (m. 7 H), 2.02 - 2.t3 (m, 1 H). 3.87 (e. 2 H). 3.96 (d, J=6.6 Hz. 2 H). 4.41 (s. 2 H), 5.98 (s. 1 H). 8.55 (s. 2 H)

/=N F 470([M+H]+) 283

476([M-^]+) 1H NMR (600 Mhlz. CHLOROFORM-d) d ppm U4 -\2A (nv 1 H). \.33 - 1.45 (m. 2 H). 1.56 - 1.B9 (m , 7 H). 2.65 &gt; 2.78 (m. 2 H). 3.65 (s. 2 H). 4.25 - 4.35 (m. 4 H). 7.46 - 7.50 (m. 2 H). 7.64 (d. J= Fi.7 Hz. 1 Η). B.34 -8.40 (m. 1 H). 8.68 - 8.74 (m. 1 H)

450UM+H» 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.02 (t. J=7.4 Hz. 3 H). 1.09 - 1.20 (m, 1 H), U3 - 1.47 (m. 2 H). t .51 - 1.85 &lt;m. 9 H). 3.89 &lt;·. 2 H). 4.22 &lt;X. J=6.B ^ 2 HM.42 (8. 2 H). 8.69 (d, Q.7 1 H). 7.76 (dd, ^8.7, 2.5 Hz. 1 Η). Θ.09 (d. J*2.5 Hz. 1 H). 8.82 (s, 2H)

2BS

424((M+H)+) 286

425([M+H]+) 287

480([M+H]+) tH NMR (600 MHz, CHLOROFORM-d) d ppm 1.11 &gt; 1.27 (mj H). U7 - 1.S0 On· 2 Ηλ 1.60 · 1.92 (m« 7 Η). 3 .Θ4 (e. 2 H). 4.46 U, 2 H). 4.53 - 4.67 (m. 2 H). 6.10(8. 1 H), 8.83 (s.2H) 286

454([M+H]+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.94 (t. J=7.4 Hz, 3 H). U4 - 1.24 (m, 1 H), 1.33 (d. J= 6.2 Hz. 3 H). 1.38 - 1.50 Cm. 2 H). 1.58 - 1.91 (m. 9 H). 3.93 (a. 2 Η). 4.A2 (e. 2 H). 4.59 - 4.6fi (m . H). 5.95 (s. \ H). 8.82 (m. 2 H) 269

454([M+H]+) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.93 (t J=7.4 Hi. 3 H). U3 * 1.25 (m. 1 H). 1.32 (d. J=6.2 H). 1.35 - 1.47 (m. 2 H), 1.57 - 1.89 (m. θ H). 3.92 (e. 2 H). 4.41 (s, 2 H). 4.56 - 4.67 (m. 1 H) , 5.94 (s, \ H). 8.61 (s. 2 H) -109- .-3⁄4 201236682 [Table 2 - 2 4] Compound 贲 Application salt (ESI posj m/z (ES negJ m/x 290

465([M+Hh)

/=NF 443([M+H]〇292 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.16 · t.24 (m, 1 H). 1.36 - 1.47 (m. 2 H). 1.62 - 1. B1 (m. 5 H). 1.82 - 1.93 (m. 2 H), 3.72 (s. 2 K). 4.37 - 4.48 (m. 4 Ηλ 5.97 - 6.21 (m. 2 H), 7.65 (d. J= 8.7 Hi. t H). 0.33 &gt; 8^9 (m, 1 H), 8.68 · B.74 (m, 1 H) 2»3

471 ((M+H)+) 1H NMR (600 MHz. CHLOROFORMS d ppm 1.24 -2.07 (m. 10 H). 145 (e. 3 H&gt;. 3.6S (e. 2 H). 4.60 (e. 2 H). 7.40 - 7.65 (m. 6 H). 8.28 - 8.38 (m, t H). 8.67 -8.77 (m. 1 H)

405([M*H)+) 295

/—NF 459([M+H:|+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.09 * ί.23 (m.1 H). U2- 1.45 (m. 2 H). 1.57 - 1.67 (m. 4 HX 1.6Θ - 1.BB (m. d H). 3.73 (s. 2 K). 4.53 (s, 2 Ηλ 7.61 - 7.67 (m. 2 Η), 7.Θ8 - 7.95 (m. 1 H), 8.32 - 8.39 (m. 1 H). 8.67 - 8.75 (m. 2 H) 296

425([M+H]+) 29? 454([M+H]^) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 0.98 (d. J=8.6 Ht. 6 H). 1.16 - 1.27 (m 1 H). 1.35 - 1.49 (m. 2 H). 1.62 - 1.92 (m, 7 H). 2.03 - 2.12 (m. 1 H). 3.93 ($. H). 3.96 (d, J=6.6 Hi . 2 H). 4.43 (*. 2 H), 5.99 (β. 1 Η). Θ.82 (s. 2 H) 299

-K&gt;f 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.0Θ -1.17 (m. 1 H). 1.33 - 1.46 (m. 2 H). 1.56 - 1.83 (m. 7 H). 3.92 (s , 2 H). 4.5S (s. 2 Η), Θ.44 - 6.49 (m. 1 H), 7.40 - 7.53 (m. 2 H). 7.60 - 7.67 (m. 2 H). 7.68 - 7.74 ( m. 1 Ηλ 7.88 - 7.Θ4 (m. 1 H). 8.84 (s. 2 H) 299

463([MH〇+) 1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.02 (t J=7.4 Hi, 3 H). 1.08 - 1.19 (m, 1 H). 1.28 - 1.43 (m, 2 H) 1.54 - 1.88 (m. 9 H). 2.16 («. 3 H). 3.66 (e. 2 H). 4.24 (t. J=fi.6 Hz. 2 H). 4.38 (». 2 H). 7^9 - 7.46 (m. 1 H). 7.63 (d. J=8.7 Hr. \ H). 7.86 - 7.93 (m. 1 Η). 8Λ4 -8.42 (m, 1 HX 8.66 · 8.76 (m, 1 H) &lt;x

/=NF 465([M+H]*) 1H NMR (600 MHz. CHLOROFORU-d) d ppm 1.17 -1.26 (m. \ H). 1.34 - 1.46 (m. 2 H). 1.62 - 2.02 (m. 11 H). 2.06 - 2.16 (m, 2 H). 2.69 - 2.B0 (m. 1 H). 3.71 Ce. 2 H). 4.17 (d. J=7.0 Hz. 2 H). 4.42 (e. 2 H). 5.91 (β. 1 -8.4! (n H). 7.64 (d. J=fi.7 Ηϊ. 1 H). 8.33 8.74 (m. 1 H) &gt;.1 H). 8.68-

1H NMR (600 MHz. CHLOROFORM-d) d ppm US · 1.27 (m, 1 H), 1.32 - 1.47 (m. 5 H). 1.61 - 1.95 (m, 7 H). 3.71 (e. 2 H). 4.20 - 4.37 (m. 2 H), 4.43 (e. 2 H). 4.69 - 5.09 (m. 1 H). S.96 (β. 1 H). 7.64 (d. J=6.7 Hz. H). 8.37 (dd. J=8.7. 2.5 Hi, 1 H). 8.71 (d. J=2.5 Hi. 1 H) 30?

1H NMR (600 MHz. CHLOROFORM-d) d ppm 1.10 -1.24 (m. 1 H). 1.36 - 1.47 (m. 2 H), 1.56 - 1.78 (m. 7 H), 1.78 - 1.91 (m. 4 H ), 1.94 - 2.02 (m, 2 H). 2.08 -2.19 (m. 2 H). 3.86 (·. 2 H). 4.30 (e. 2 H). 4.57 (qu^ J=7.2 Hz, 1 H) 7.44 (*. t H), 7.60 (β. 1 H), 8.81 (s. 2 H) -110- 201236682 Test Example 1 [Glycine uptake inhibition test] Glycine intake test was performed by Neuron , the method disclosed in 8, 927-935, 1992. Glioma T98G cells expressing human type 1 glycine transporter (GlyTl) were used. T98G cells were seeded on a 96-well culture dish at 2·〇χ1 04 cells/well, and cultured overnight in a carbon dioxide gas culture incubator. After the test substance was dissolved in a 1% DMSO solution, it was dissolved in 10 mM HEPES 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. Buffer (pH 7.4). After the culture medium for cell culture is removed, the test substance is pretreated for 1 minute. Thereafter, the test substance and [3H]glycine (final concentration: 250 nM) were added to the cells, and allowed to react at room temperature for 15 minutes. After the completion of the reaction, the manifold was aspirated to remove the extracellular fluid, and the excess glycine acid present outside the cells was removed, and then the cells were lysed with a 0.5 M aqueous sodium hydroxide solution. The amount of glycine present in the cells is determined by measuring the radioactivity in the cell lysate by a liquid flash counter. The glycine intake in the presence of 1〇μΜ of ALX5407 is used as a non-specific uptake, and the specific intake minus the non-specific intake from the total presence of 1〇μΜ of ALX5407 is used as specificity. intake. In addition, the glycine acid uptake inhibitory activity (IC 5 〇値) is calculated from the test substance in the ΐ9Γ(ΐ5Μΐ concentration inhibition curve. In addition, ALX5407 is N-[(3R)-3-([ l, lbiphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine HC1 salt. The compounds of the examples of the invention have IC5G 小于 all less than 1 Specifically, the IC5G値 of the compound 3 is 〇.23μΜ, the IC5G値 of the compound-111 - 201236682 18 is 2.3 μΜ, the IC5G値 of the compound 29 is 0.087 μΜ, and the IC5Q値 of the compound 100 is 〇.〇. 62μΜ, IC5〇値 of compound 134 is 0.43μΜ, IC5G値 of compound 194 is 1.8μΜ, IC5〇値 of compound 240 is 0.091μΜ, IC5〇値 of compound 248 is 0.13μΜ, and IC5G値 of compound 253 is 〇.〇 65 μΜ, the IC5〇値 of the compound 257 is 0·057 μΜ, and the IC5〇値 of the compound 297 is 0.038 μΜ. [Industrial Applicability] The compound of the present invention has a glycine transporter (GlyTl) inhibitory activity, and therefore, It is effective in the prevention or treatment of diseases associated with glycine transporters, specifically, integrative disorders , Alzheimer's disease, cognitive dysfunction, dementia, anxiety (overall anxiety, panic disorder, obsessive-compulsive disorder, social phobia, post-traumatic stress, specific phobia, acute compression, etc.), depression Symptoms, drug dependence, squatting, tremors, pain, Parkinson's disease, deficient defects, hyperactivity disorder, bipolar disorder, eating disorder or sleep disorders, etc. -112-

Claims (1)

201236682 VII. Patent application scope 1. A compound represented by the formula [π or its pharmaceutically acceptable salt, [Chem. 4 8] (wherein R1 represents a phenyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group or a pyridone group, and the phenyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group and pyridone group can be used. 1 to 3 substituents selected from the substituent group 1 are substituted, and the substituent group 1 represents an alkyl group (the C6 alkyl group may be formed by a hydroxyl group, a Ci. 6 alkyl alkoxy group, and a group represented by the formula -NR7R8). 1 to 3 substituents selected by the group are substituted, R7 and R8 may be the same or different, and represent a hydrogen atom or a ci-6 alkyl group, a halogenated Cm alkyl group, a Cu alkoxy group, a halogenated d_6 alkoxy group, or a C2- 7-yard oxycarbonyl, cyano 'halogen atom, 5 or 6 membered heteroaryl (the 5 or 6-membered heteroaryl can be substituted by 1 or 2 Ci_6), Cu alkyl thiol and -NR9R1Q (R9 and R1Q may be the same or different, indicating a hydrogen atom or a Cl_6 yard group' or R9 and RiQ and a bonded nitrogen atom may form a saturated heterocyclic ring of 4 to 6 members, which is 4 to 6 members. a group in which a saturated heterocyclic ring may be substituted with a pendant oxy group), R 2 represents a phenyl group which may be substituted with 1 to 3 substituents selected from the substituent group 2, or may be selected from the substituent group 2 of a monocyclic or bicyclic heteroaryl group substituted with 1 to 3 substituents, -113-201236682 The substituent group 2 represents a phenyl group (the phenyl group may be represented by (:, .6 alkyl, Q-6 alkoxy) Substituted by a group of halogen atoms to be substituted with 丨~3 substituents), C^6 alkyl (the C, .6 alkyl group may be C, -6 alkoxy, phenyl, C3-6 ring a group of 1 to 3 substituents selected from the group consisting of an alkyl group, a halogenated c, a 6 alkoxy group, a halogenated C3.6 cycloalkyl group, and a 3-methyl propylene oxide-3-yl group), halogenated (^_6) An alkyl group, a Ci.6 alkoxy group (the Cu alkoxy group may be selected from the group consisting of an alkoxy group, a hydroxyl group, a c3.6 cycloalkyl group, and a 3-methyl propylene oxide-3 group). Substituted by a substituent), hydroxy, benzyloxy, halogenated Cu alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, tetrahydrofuranyl, tetrahydrofuranyloxy, tetrahydropyranyl, Tetrahydropyranyloxy, C2.7 alkoxycarbonyl, cyano, halogen atom, heteroaryl group of 5 or 6 members (the 5- or 6-membered heteroaryl group may be a G-6 alkyl group, a halogen atom and a group of one or two substituents selected from a group of alkoxy groups), CU6 alkyl fluorenyl group, The formula -NRHR^R11 and R12 may be the same or different and represent a hydrogen atom or a C..6 alkyl group, or R11 and R12 together with a bonded nitrogen atom to form a saturated heterocyclic ring of 4 to 6 members. a 6-membered saturated heterocyclic ring may be substituted with a pendant oxy group) and a formula -CONR13R14 (Ri3 and R14 may be the same or different and represent a hydrogen atom or a Ci_6 alkyl group, or R13 and R14 may be bonded to each other. a group in which a nitrogen atom is formed to form a saturated heterocyclic ring of 4 to 6 members, and a saturated heterocyclic ring of 4 to 6 members may be substituted by a pendant oxy group, and R3 and R4 may be the same or different, and a hydrogen atom, an alkyl group, a C3.6 cycloalkyl group, a phenyl group or a benzyl group, or R3 and R4 together with a bonded carbon atom to form a C3-7 cycloalkane ring, a tetrahydrofuran ring, or a tetrahydroanthracene- 114- 201236682 Anthracene (except where R3 and R4 are simultaneously a hydrogen atom), R5 and R6 may be the same or different and represent a hydrogen atom, C, .6 alkyl) (except that R1 is a group of substituents) When a phenyl group substituted with 1 to 3 substituents is selected, R2 is a monocyclic or bicyclic heteroaryl group which may be substituted by 1 to 3 substituents selected from the substituent group 2. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are simultaneously a hydrogen atom. 3. A compound as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are taken together with a bonded carbon atom to form a C3-7 ring. 4. The compound according to any one of claims 1 to 3, wherein the R2 is a phenyl group which may be substituted by 1 to 3 substituents selected from the substituent group 2, or a pharmaceutically acceptable salt thereof; A monocyclic heteroaryl group which may be substituted by 1 to 3 substituents selected from the substituent group 2. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R2 is a phenyl group which may be substituted with 1 to 3 substituents selected from the substituent group 3 or a monocyclic heteroaryl group which may be substituted by i to 3 substituents selected from the substituent group 4, and the substituent group 3 is composed of a Cm alkoxy group, a halogenated Cu methoxy group and a 5-membered heteroaryl group. The group and the substituent group 4 are composed of a phenyl group (the phenyl group may be substituted by 1 to 3 substituents selected from the group consisting of a group of a compound, a Ci6 alkoxy group, and a halogen atom), C!·6. a compound of the oxy group, the halogenated Ci-6, and the 5- or 6-negative heteroaryl group. -115- 201236682 6. The compound according to any one of claims 1 to 3 or a pharmaceutical thereof The salt to be tolerated, wherein R2 is a phenyl group which may be substituted with 1 to 3 substituents selected from the substituent group 3, and an isoxazole which may be substituted with 1 to 2 substituents selected from the substituent group 4. a oxadiazole group which may be substituted by one substituent selected from the substituent group 4, a triazolyl group which may be substituted by 1 to 2 substituents selected from the substituent group 4, may be substituted a pyrazolyl group substituted with 1 to 3 substituents selected from Group 4, or a pyridyl group which may be substituted with 1 to 3 substituents selected from Substituent Group 4. 7. Any one of claims 1 to 3 The compound described or a pharmaceutically acceptable salt thereof, wherein R2 is a phenyl group which may be substituted with one 5-membered heteroaryl group, and may be substituted by 1 to 2 substituents selected from the substituent group 4. An isoxazolyl group, a pyrazolyl group which may be substituted with 1 to 3 substituents selected from the substituent group 4, or a pyridyl group which may be substituted with 1 to 3 substituents selected from the substituent group 4. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R1 is a pyridyl group, a pyridazinylpyrimidinyl group, a muscarinyl group or a pyridone group, and the pyridyl group or the fluorene group The azine group, the pyrimidinyl group, the pyrazinyl group, and the pyridone group may be substituted by 1 to 3 substituents selected from the substituent group 1. The compound according to any one of claims 1 to 7 or a pharmaceutical thereof Permissible salts, wherein 'R1 is phenyl, pyridyl, pyrimidinyl or fluorenyl * phenyl, pyridyl, pyrimidinyl and pyrazinyl Substituted by 1 to 3 substituents selected from the substituent group 5, -116-201236682 The substituent group 5 is composed of a Cu alkyl group, a halogenated C丨-6 alkyl group, a C丨-6 alkoxy group, a halogenated Ci- The compound of any one of the above-mentioned items 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R1 is selected by the substituent group 5 a pyridyl group substituted with ～3 substituents or a pyrimidyl group substituted with 1 to 3 substituents selected by the substituent group 5. Π·- a pharmaceutical composition, which is contained in claims 1 to 1 0 The compound described in any one of the above or a pharmaceutically acceptable salt thereof is used as an active ingredient. 12. A combination disorder, Alzheimer's disease, cognitive dysfunction, dementia 'anxiety disorder, depression, drug dependence, paralysis, tremors, pain, Parkinson's disease, deficient defects. Hyperactivity disorder, double A prophylactic or therapeutic agent for a disease of a disorder of a disorder, an eating disorder, or a sleep disorder, which comprises the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof as an active ingredient. 117- 201236682 Four designated representative maps: (1) The representative representative of the case is: No (2) The symbol of the representative figure is simple: No 201236682 If there is a chemical formula in the case, please disclose the chemical formula that best shows the characteristics of the invention: 1 【化1】 [I]