0001]The present invention relates to pharmaceutical compositions containing substituted guanidine compound and it particularly prevented by VAP-1 inhibitor, for the treatment of alleviation and / or the disease being treated, relates to substituted guanidine compounds and pharmaceutical compositions containing them .
BACKGROUND
[0002]Type 2 diabetes is a kind of lifestyle-related diseases, the number of patients in recent years has been steadily increasing. Prolonged hyperglycemic state may gradually destroy the microvessels in the body, the eye, can lead to serious damage to various organs, including the kidney. Such severe failures are termed diabetic complications, among them diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, three as a large complications, major challenges onset prevention and suppression of progression of diabetes It has become.
[0003]
　Preventing onset and suppression of progression of diabetic complications, firstly although glycemic control is fundamental, in recent years, blood VAP-1 in diabetic patients (Vascular Adhesion Protein-1; also referred to as SSAO (Semicarbazide-Sensitive Amine Oxidase) that) the activity is increased, further it was found to be correlated with the amount in the plasma glycated hemoglobin. The enzyme that selectively localize in vascular tissue catalyzes the deamination of methylamine and aminoacetone, respectively, H 2 O 2 in addition to, ammonia, producing formaldehyde or methylglyoxal. Since they have a cytotoxic any, increase in blood VAP-1 activity it has been noted as one cause of onset of inflammatory diseases and diabetic complications (e.g., Non-Patent Documents 1 and 2 reference.).
[0004]
　This variety of VAP-1 inhibitors have so far been reported. Formula:
[Formula 1]

a compound represented by having a VAP-1 inhibitory activity, VAP-1-related diseases including various inflammatory diseases and diabetes complications, especially diabetic nephropathy or diabetic macular that are useful in the prevention and / or treatment of edema have been described (e.g., see Patent Document 1).
[0005]
　Further, the following formula:
[Formula 2]

a compound represented by having a VAP-1 inhibitory activity, VAP-1-related diseases including various inflammatory diseases and diabetes complications, especially diabetic nephropathy or diabetic that are useful in the prevention and / or treatment of sexual macular edema has been described (e.g., see Patent Document 2).
[0006]
　Meanwhile, the VAP-1 expression in the patient's liver with chronic liver disease is increasing, soluble VAP-1 concentration and VAP-1 expression in the liver of the patient serum with nonalcoholic fatty liver disease, be elevated compared to that of patients not having the non-alcoholic fatty liver disease, further soluble VAP-1 levels in serum from liver biopsies of patients with non-alcoholic fatty liver disease Toko there is a correlation severity of fibrosis has been reported (e.g., see non-Patent Document 3). Therefore, by VAP-1 inhibitor, in addition to diabetic complications mentioned above, non-alcoholic fatty liver disease, in particular the prevention of non-alcoholic steatohepatitis, relaxation and / or therapy is expected.
CITATION
Patent Document
[0007]
Patent Document 1: WO 2011/034078 Patent Publication
Patent Document 2: WO 2012/124696 Patent Publication
Non-patent literature
[0008]
Non-Patent Document 1: Diabetologia (1997) 40: 1243-1250
Non-Patent Document 2: Diabetologia (2002) 45: 1255-1262
Non-Patent Document 3: The Journal of Clinical Investigation ( 2015) 2: 501-520
Summary of the Invention
Problems that the Invention is to Solve
[0009]
　The present invention is prevented by VAP-1 inhibitor, to provide a relief and / or novel compounds useful in the treatment of the disease being treated and pharmaceutical compositions containing them.
Means for Solving the Problems
[0010]
　The present inventors have made intensive studies on compounds having VAP-1 inhibitory activity, a series of substituted guanidine compounds having a fluoro pyridine ring in place in the molecule or a salt thereof, excellent VAP-1 inhibitor have activity, prevented by VAP-1 inhibition, alleviation and / or the disease being treated, found to be particularly useful for diabetic nephropathy and treatment of non-alcoholic steatohepatitis, and completed the present invention.
[0011]
　The present invention provides the following [1] to [20].
[1] general formula (I):
[Chemical Formula 3]

(wherein,
　X is CR 1 R 2 , carbonyl group or the following formula (Ia):
[Chemical Formula 4] 　is,

R 1 and R 2 are each independently and a hydrogen atom, a halogen atom, hydroxy group, protected hydroxy group, an unsubstituted or substituted C 1 -C 6 alkyl group, or an unsubstituted or substituted C for 1 -C 6 alkoxy group, wherein " substituted ", a deuterium atom, a halogen atom, hydroxy group and C 1 -C 6 means that it is substituted with at least one substituent selected from the group consisting of alkoxy groups, 　p and q are each independently, an integer from 0 to 3, provided that p + q is 2 or more) compounds or pharmacologically acceptable salt thereof represented by.

[2] R 1 is a hydrogen atom, a halogen atom, hydroxy group, an unsubstituted or substituted C 1 -C 6 alkyl group, or an unsubstituted or substituted C for 1 -C 6 alkoxy group, R 2 is hydrogen atom, a halogen atom, or a C 1 -C 3 alkyl group, compound or pharmacologically acceptable salt thereof according to [1].
[3] R 1 is a halogen atom, hydroxy group, C 1 -C 6 alkoxy group, or at least one C are replaced with deuterium atoms 1 -C 6 alkoxy group, according to [2] compound or pharmacologically acceptable salt thereof.
[4] Salts p and q are, independently of one another, is 1 to 2 integer that is acceptable compound or a pharmacologically according to [1].
[5] the following compounds:
　2-fluoro-3- [5-fluoro-6- (3-methoxy-l-yl) pyridin-3-yl] benzyl carbamimidoyl
　carbamate, 2-fluoro-3- {5-fluoro-6- [3- (methoxy -d 3 ) azetidin-1-yl] pyridin-3-yl} benzyl carbamimidoyl
　carbamate, 3- [6- (3-ethoxy-1-yl) -5-fluoropyridine - 3-yl] -2-fluorobenzyl carbamimidoyl
　carbamate, 2-fluoro-3- {5-fluoro-6- [3- (2-fluoroethoxy) azetidin-1-yl] pyridin-3-yl} benzyl carbamimidoyl
　carbamate, 2-fluoro-3- [5-fluoro-6- (3-propoxy-1-yl) pyridin-3-yl] benzyl Luba Mimi Doyle
　carbamate, 2-fluoro-3- [5-fluoro-6- (3-isopropoxyphenyl l-yl) pyridin-3-yl] benzyl carbamimidoyl
　carbamate, 2-fluoro-3- (5-fluoro-6- {3 - [(tetrahydropyran-2-yl) oxy] azetidin-1-yl} pyridin-3-yl) benzyl carbamimidoyl
　carbamate, 2-fluoro-3- [5-fluoro 6- (3-hydroxy-l-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate,
　3- [6- (azetidin-1-yl) -5-fluoropyridin-3-yl] - 2-fluorobenzyl carbamimidoyl carbamate,
　2-fluoro-3- [5-fluoro-6- (3-fluoro-1-yl) pyridin-3-yl] benzyl carbamimidoyl
　carbamate, 3- [6- (3,3-difluoroazetidin 1-yl) -5-fluoro-3-yl] -2-fluoro - benzyl carbamimidoyl
　carbamate, 2-fluoro-3- [5-fluoro-6- (3-methyl-1-yl ) pyridin-3-yl] benzyl carbamimidoyl
　carbamate, 3- [6- (3,3-dimethyl-1-yl) -5-fluoro-3-yl] -2-fluorobenzyl carbamimidoyl
　carbamate, 2-fluoro-3- (5-fluoro-6- {3-methyl-3 - [(tetrahydropyran-2-yl) oxy] azetidin-1-yl} Pi 3-yl) benzyl carbamimidoyl
　carbamate, 2-fluoro-3- [5-fluoro-6- (3-hydroxy-3-methyl-l-yl) pyridin-3-yl] benzyl Karubamimi Doyle carbamate, or
　2-fluoro-3- [5-fluoro-6- (2-oxa-6-azaspiro [3.3] heptan-6-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate
in there, the compound or pharmacologically acceptable salt thereof according to [1].
[6] 2-fluoro-3-a [5-fluoro-6- (3-methoxy-l-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate compound according to [1] or a pharmacologically acceptable salt thereof.
[7] 2-fluoro-3- {5-fluoro-6- [3- (methoxy -d 3 is a) azetidin-1-yl] pyridin-3-yl} benzyl carbamimidoyl carbamate, in [1] compound or pharmacologically acceptable salt thereof.
[8] 2-fluoro-3-a [5-fluoro-6- (3-hydroxy-l-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate compound according to [1] or a pharmacologically acceptable salt thereof.
"9" is 2-fluoro-3- [5-fluoro-6- (3-fluoro-1-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate compound according to [1] or a pharmacologically acceptable salt thereof.
[10] 2-fluoro-3- [5-fluoro-6- (3-hydroxy-3-methyl-l-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate, in [1] compound or pharmacologically acceptable salt thereof.
[11] 2-fluoro-3- [5-fluoro-6- (2-oxa-6-azaspiro [3.3] heptan-6-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate, compound or a pharmacologically acceptable salt thereof according to [1].
[12] Salts pharmacologically acceptable salt is a salt of an organic acid, which is pharmacologically acceptable compound according to any one of [1] to [11].
[13] Salts pharmacologically acceptable salt is a salt of a dicarboxylic acid, which is pharmacologically acceptable compound according to any one of [1] to [11].
[14] [1] to [13] the compound or a pharmacologically acceptable salt thereof according to any one of, containing an additive acceptable at least one pharmacologically, pharmaceutical compositions.
[15] prevented by VAP-1 inhibitor, for the treatment of alleviation and / or the disease being treated, the pharmaceutical composition according to [14].
[16] the disease is diabetic nephropathy, the pharmaceutical composition according to [15].
[17] the disease is non-alcoholic steatohepatitis, the pharmaceutical composition according to [15].
[18] prevented by VAP-1 inhibitor, for use in the treatment of diseases which are alleviated and / or treatment, [1] a compound or a pharmacologically acceptable salt thereof according to any one of - [13].
[19] prevented by VAP-1 inhibitor, for the manufacture of a medicament for the treatment of alleviation and / or the disease being treated, acceptable compound or a pharmacologically according to any one of [1] to [13] the use of salt.
[20] A therapeutically effective amount of a compound or a pharmacologically acceptable salt thereof according to any one of [1] to [13], comprising administering to a patient in need thereof, preventing the VAP-1 inhibitor the method treatment of diseases which are alleviated and / or treatment.
Effect of the invention
[0012]
　Compound or a pharmacologically acceptable salt thereof represented by the general formula (I) of the present invention has a high VAP-1 inhibitory activity and excellent pharmacokinetic properties, preventing the VAP-1 inhibitor, alleviating and / or disease being treated, typically, non-alcoholic fatty liver disease, such as nonalcoholic steatohepatitis; atopic dermatitis, inflammatory diseases such as psoriasis; diabetic neuropathy, diabetic retinopathy (particularly, useful in the treatment of metabolic disorders such as obesity; heart diseases such as myocardial infarction; vascular disease atherosclerosis and the like; diabetic macular edema), diabetic complications such as diabetic nephropathy.
DESCRIPTION OF THE INVENTION
[0013]
　The means of terms used in the specification and claims, is described below. Unless stated otherwise, terms used in the specification and claims have the following meanings.
[0014]
　Numerical range expressed by using "to" in the specification are indicative of the range including the respective minimum and maximum values ​​of the numerical values ​​described before and after "to".
[0015]
　In the present invention, compounds of general formula (I) includes its isotope isomer. That is, in the compounds of formula (I), all or part of each atom may be replaced by the corresponding isotopes atoms. The isotopic atom refers to an atom having a different mass number and mass number found in nature. Examples of such isotopes atom, hydrogen atom ( 2 H, 3 H), carbon atoms ( 13 C, 14 C), nitrogen atom ( 15 N), oxygen atom ( 17 O, 18 include O) and the like It is. In particular, a deuterium atom ( 2 H) may be referred to as "D". In such a case, in the compound of formula (I), all of the hydrogen atoms of a particular location which is denoted by D is replaced by deuterium atom, a different molecular weight than the molecular weight calculated from the mass number found in nature.
[0016]
　The "halogen atom" or "halo", alone or in combination with other groups, means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0017]
　"C 1 -C 6 includes alkyl groups", alone or in combination with other groups, having 1-6 carbon atoms, straight-chain or branched-chain saturated aliphatic hydrocarbon monovalent It refers to the group. C 1 -C 6 Examples of alkyl groups include methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group (including various isomers). C 1 -C 6 Preferred embodiments of the alkyl groups, C 1 -C 4 alkyl group, e.g., methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec- butyl group, with tert- butyl There, a more preferred embodiment, C 1 -C 3 alkyl group.
[0018]
"C 1 -C 6 The alkoxy group", alone or in combination with other groups, '(wherein, R' is the C group -O-R 1 -C 6 is an alkyl group) means a to. C 1 -C 6 Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, butyloxy group, pentyloxy group, hexyl group (including various isomers). C 1 -C 6 a preferred embodiment of the alkoxy groups, C 1 -C 4 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, butyloxy group, isobutyl group, sec- butyloxy, tert - a butyloxy group, and more preferred embodiment, C 1 -C 3 alkoxy group.
[0019]
　The "aryl group", having 6-10 carbon atoms, means a monovalent radical of an aromatic hydrocarbon. Examples of aryl groups are phenyl, 1-naphthyl, 2-naphthyl and the like.
[0020]
"C 1 -C 7 and the acyl group", "(wherein, R" is a hydrogen atom, the C group -CO-R 1 -C 6 alkyl group or a phenyl group) means. C 1 -C 7 Examples of the acyl group, a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a hexanoyl group and a benzoyl group.
[0021]
　"Protected hydroxy" means a hydroxy group protected by any protecting group, such protecting groups, those skilled in the art known techniques, for example, Protective Groups in Organic Synthesis 4th ed., TW Greene, PGM Wuts al, John Wiley & Sons Inc. (2006 years), such as arbitrarily be chosen from the protective groups for hydroxy groups described. The protecting group of such hydroxy groups, C 1 -C 7 acyl group (e.g., formyl group, acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a hexanoyl group, a benzoyl group ) acyl type protecting groups such as, methoxymethyl, 1-ethoxyethyl group, a methylthiomethyl group, benzyloxymethyl group, acetal-type protective groups such as tetrahydropyranyl group; tri (C 1 -C 4 alkyl) silyl group ( For example, a trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, dimethylisopropylsilyl group, tert- butyldimethylsilyl group), (C 1 -C 4 alkyl) diarylsilyl groups (e.g., tert- butyldiphenylsilyl group, diphenylmethyl silyl group), triaryl Lil group (e.g., a triphenylsilyl group), a silyl based protective group such as tribenzylsilylamino; benzyl, p- methoxybenzyl, a benzyl-based protecting group such as triphenylmethyl and the like. A preferred embodiment of the protecting group, C 1-C 7 acyl group, tetrahydropyranyl group, tri (C 1 -C 4 alkyl) silyl group, a benzyl group, p- methoxybenzyl group, a triphenylmethyl group and the like. That is, a preferred embodiment of the "protected hydroxy group", C 1 -C 7 acyloxy group, tetrahydropyranyloxy group, tri (C 1 -C 4 alkyl) silyloxy group, a benzyl group, p- methoxybenzyl group a triphenylmethyl group and the like.
[0022]
　In the present invention, "substituted or unsubstituted" refers to the group, which is unsubstituted, or a given substituent group, for example, a deuterium atom, a halogen atom, hydroxy group, C 1 -C 6 alkoxy group It means that it is substituted with at least one substituent selected from the group consisting of.
[0023]
　In the present invention, "substituted or unsubstituted C for 1 -C 6 preferred embodiment of the alkyl group", (unsubstituted) C 1 -C 6 or an alkyl group, or a deuterium atom, a halogen atom, hydroxy group, and C 1 -C 6 least one is substituted with a substituent C is selected from the group consisting of alkoxy groups 1 -C 6 alkyl group. "Substituted or unsubstituted C for 1 -C 6 and more preferred embodiments of the alkyl group", (unsubstituted) C 1 -C 6 from the group consisting of either an alkyl group or a deuterium atom, a halogen atom and hydroxy group C is substituted with at least one substituent selected 1 -C 6 alkyl group. "Substituted or unsubstituted C for 1 -C 6 further preferred embodiment of the alkyl group", (unsubstituted) C 1-C 6 or an alkyl group, or at least one of which is substituted with a substituent C is selected from the group consisting of heavy hydrogen atoms and halogen atoms 1 -C 6 alkyl group. "Substituted or unsubstituted C for 1 -C 6 particularly preferred embodiment of the alkyl group", (unsubstituted) C 1 -C 6 is selected from the group consisting of either an alkyl group or a deuterium atom and a fluorine atom C substituted with at least one substituent 1 -C 6 alkyl group.
[0024]
　In the present invention, "substituted or unsubstituted C for 1 -C 6 preferred embodiment of the alkoxy group", (unsubstituted) C 1 -C 6 or an alkoxy group, or a deuterium atom, a halogen atom, hydroxy group, and C 1 -C 6 least one C is substituted with a substituent selected from the group consisting of alkoxy groups 1 -C 6 alkoxy group. "Substituted or unsubstituted C for 1 -C 6 and more preferred embodiment of the alkoxy group", (unsubstituted) C 1 -C 6 is selected from the group consisting of alkoxy group, or a deuterium atom, a halogen atom and hydroxy group C is substituted with at least one substituent 1 -C 6 alkoxy group. "Substituted or unsubstituted C for 1 -C 6 further preferred embodiment of the alkoxy group" (unsubstituted) C 1-C 6 or an alkoxy group, or at least one of which is substituted with a substituent C is selected from the group consisting of heavy hydrogen atoms and halogen atoms 1 -C 6 alkoxy group. "Substituted or unsubstituted C for 1 -C 6 particularly preferred embodiment of the alkoxy group", (unsubstituted) C 1 -C 6 is selected from the group consisting of or an alkoxy group, or a deuterium atom and a fluorine atom C substituted with at least one substituent 1 -C 6 alkoxy group.
[0025]
　General formula (I) compounds represented by the present invention, (if present) a stereoisomer thereof. Stereoisomers means isomers that differ in the arrangement of their atoms in space, diastereomers, optical isomers enantiomers such or geometrical isomers, and the like. For example, when a compound represented by the general formula (I) of the present invention have one or more chiral centers, the compounds represented by the general formula (I) of the present invention, optically pure enantiomers, racemic mixtures of enantiomers etc., optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, can be present in the form of a mixture of racemic diastereomers.
[0026]
　The pharmaceutically acceptable salts of the compounds represented by the general formula (I) of the present invention, for example, hydrochloride, hydrobromide, hydroiodide, nitrate, inorganic or sulfate or phosphate salt; or acetate, trifluoroacetate, benzoate, oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate salt, trifluoromethanesulfonate, benzenesulfonate, p- toluenesulfonate, organic acid salts such as glutamate or aspartate salts. A preferred embodiment of the organic acid salt, oxalate, malonate, succinate, maleate, fumarate, a salt of a dicarboxylic acid such as tartaric acid salt.
[0027]
　The pharmaceutically acceptable salts of the compounds represented by the general formula (I) of the present invention, other such as sodium salt, potassium salt, calcium salt or magnesium salts of metal salts: ammonium inorganic salts such as salt: or organic amine salts such as triethylamine salt or guanidine salt.
[0028]
　Compound or pharmacologically acceptable salt thereof represented by the general formula (I) of the present invention includes a solvate pharmacologically acceptable. A preferred embodiment of the solvate is a hydrate. Note hydrate may be one produced as a result of the general formula (I) compound or hygroscopicity of a pharmacologically acceptable salt thereof represented by the present invention.
[0029]
　When the compound or a pharmacologically acceptable salt thereof represented by the general formula (I) of the present invention is crystalline, it may show crystal polymorphism. Crystalline polymorph, crystal structure mean different things in the same material. Each crystal or a mixture thereof in any proportion are encompassed by the present invention.
[0030]
　Will be described in detail embodiments of the present invention are described below.
　The present invention relates to compounds of the general formula (I):
[Chemical Formula 5]

(wherein,
　X is CR 1 R 2 , carbonyl group or the following formula (Ia):
[Chemical Formula 6] 　is,

R 1 and R 2 are each independently, a hydrogen atom, a halogen atom, hydroxy group, protected hydroxy group, an unsubstituted or substituted C 1 -C 6 alkyl group, or an unsubstituted or substituted C for 1 -C 6 alkoxy group, wherein "substituted", a deuterium atom, a halogen atom, hydroxy group and C 1 -C 6 means that it is substituted with at least one substituent selected from the group consisting of alkoxy groups, 　p and q are, independently of one another, an integer from 0 to 3, provided that p + q is 2 or more) relates to compounds or a pharmacologically acceptable salt thereof.

[0031]
　In certain embodiments, the present invention, X is CR 1 R 2 is The compound or related pharmacologically acceptable salt thereof represented by the general formula (I) of the present invention. Specifically, represented by the following general formula (II).
Formula (II):
[Chemical Formula 7]

　In general formula (II), R 1 and R 2 are as defined in the general formula (I).
[0032]
　In certain embodiments, the present invention is, R 1 and R 2 are, independently of one another, a hydrogen atom, a halogen atom, hydroxy group, an unsubstituted or substituted C 1 -C 6 alkyl group, or an unsubstituted or substituted C 1 -C 6 alkoxy group, compound or related pharmacologically acceptable salt thereof represented by the general formula (I) or (II). Where "substituted C 1 -C 6 alkyl group" or "substituted C 1 -C 6 alkoxy group", a deuterium atom, a halogen atom, hydroxy group and C 1 -C 6 least selected from the group consisting of an alkoxy group is substituted with one substituent, preferably a deuterium atom, it is substituted with at least one substituent selected from the group consisting of a halogen atom and hydroxy group, more preferably a deuterium atom and a halogen atom It is substituted with at least one substituent selected from the group consisting of, more preferably substituted with at least one substituent selected from the group consisting of heavy hydrogen atom and fluorine atom.
[0033]
　In certain embodiments, the present invention is, R 1 is a hydrogen atom, a halogen atom, hydroxy group, an unsubstituted or substituted C 1 -C 6 alkyl group, or an unsubstituted or substituted C 1 -C 6 alkoxy group there, the compound or related pharmacologically acceptable salt thereof represented by the general formula (I) or (II).
[0034]
　In certain embodiments, the present invention is, R 1 is a halogen atom, hydroxy group, C 1 -C 6 alkoxy group, or at least one C are replaced with deuterium atoms 1 -C 6 is an alkoxy group the compound or related pharmacologically acceptable salt thereof represented by the general formula (I) or (II).
[0035]
　In certain embodiments, the present invention is, R 2 is a hydrogen atom, a halogen atom, or a C 1 -C 3 alkyl group, the compound or a pharmacologically represented by general formula (I) or (II) about the upper acceptable salts.
[0036]
　R 1 and R 2 in the "substituted C 1 -C 6 alkyl group" or "substituted C 1 -C 6 alkoxy group", a deuterium atom, a halogen atom, hydroxy group and C 1 -C 6 from the group consisting of an alkoxy group is substituted with at least one substituent selected, it is preferably substituted with at least one substituent selected from the group consisting of heavy hydrogen atom, a halogen atom and hydroxy group, more preferably a deuterium is substituted with at least one substituent selected from the group consisting of atoms and a halogen atom, more preferably substituted with at least one substituent selected from the group consisting of heavy hydrogen atom and fluorine atom .
[0037]
　In certain embodiments, the present invention is, R 1 is a hydrogen atom, a halogen atom, hydroxy group, an unsubstituted or substituted C 1 -C 6 alkyl group, or an unsubstituted or substituted C 1 -C 6 alkoxy group There, R 2 is a hydrogen atom, a halogen atom, or a C 1 -C 3 alkyl group, wherein "substituted C 1 -C 6 alkyl group" or "substituted C 1 -C 6 alkoxy group", deuterium and halogen atoms (preferably fluorine atom) at least one is substituted with a substituent, the compounds of general formula (I) or (II) with the indicated compound or a pharmacologically selected from the group consisting of on acceptable salt thereof.
[0038]
　In certain embodiments, the present invention is, R 1 is a halogen atom, hydroxy group, C 1 -C 6 alkoxy group, or at least one C are replaced with deuterium atoms 1 -C 6 alkoxy group , R 2 is a hydrogen atom, a halogen atom, or a C 1 -C 3 alkyl group, compound or related pharmacologically acceptable salt thereof represented by the general formula (I) or (II).
[0039]
　In certain embodiments, the present invention is, R 1 and R 2But independently of one another, a hydrogen atom; a fluorine atom, a chlorine atom, a bromine atom, an iodine atom; a hydroxy group; an acetyl group, a pivaloyloxy group, tetrahydropyran-2-yloxy group, tert- butyldimethylsilyl group, benzyloxy group, p- methoxybenzyl group, triphenylmethyl group; a methyl group, an ethyl group, an isopropyl group, a propyl group, a butyl group, a pentyl group, a hexyl group; methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, butyloxy group, pentyloxy group, hexyloxy group; deuterated methyl group; 2-fluoroethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, 3-fluoropropyl group; hydroxymethyl group , 2-hydroxyethyl group, 2-hydroxypropyl group, - hydroxypropyl, 3-hydroxy-2-methylpropyl group, 4-hydroxybutyl group, 3-hydroxy-3-methylbutyl group, 3-hydroxy-2,2-dimethyl - propyl group, 2,3-dihydroxypropyl group 3-hydroxy-2- (hydroxymethyl) - propyl group, 3-hydroxy-2- (hydroxymethyl) -2-methyl - propyl group, 3,4-dihydroxy-butyl group; methoxymethyl group, ethoxymethyl group, propoxy methyl, butyl oxymethyl group, pentyloxymethyl group, hexyloxy group, a methoxyethyl group, ethoxyethyl group, propoxyethyl group, butyl oxy ethyl group, pentyloxy ethyl group, hexyloxyethyl group, methoxypropyl group, ethoxy propyl group, propoxypropyl group, Tokishibuchiru group; 3-fluoro-2- (hydroxymethyl) propyl group, 2-fluoro-3-hydroxypropyl group; 2-hydroxy-3-methoxypropyl group, 3-hydroxy-2-methoxy propyl, 3-hydroxy - 2- (methoxymethyl) propyl group, 4-hydroxy-3-methoxybutyl group, 2-methoxy-3- (trityl) propyl group, 2-acetyloxy-3-methoxypropyl group; deuterated methoxy group; 2-fluoroethoxy group, 2,2-difluoro-ethoxy, 2,2,2-trifluoroethoxy group, 3-fluoro-propoxy group; hydroxy methoxy, 2-hydroxyethoxy group, 2-hydroxypropoxy group, 3-hydroxy propoxy, 3-hydroxy-2-methyl-propoxy group, 4-hydroxy-butoxy group, 3-hydroxy-3-methylbutoxy group, 3-hydroxy-2,2-dimethyl - propoxy group, 2,3-dihydroxy propoxy group, 3-hydroxy-2- (hydroxymethyl) - propoxy group, 3-hydroxy-2- (hydroxymethyl) -2-methyl - propoxy group, 3,4-dihydroxy-butyl group; methoxymethoxy group, ethoxymethoxy group, propoxy methoxy, butyloxy methoxy group, pentyloxy Butoxy group, hexyloxy methoxy group, methoxyethoxy group, ethoxyethoxy group, propoxyethoxy group, butyl oxy ethoxy, pentyloxy ethoxy, hexyloxy ethoxy, methoxypropoxy group, ethoxypropoxy group, propoxy propoxy group, butyl oxy butyl group; 3-fluoro-2- (hydroxymethyl) propoxy group, 2-fluoro-3-hydroxypropoxy group; or 2-hydroxy-3-methoxypropoxy group, 3-hydroxy-2-methoxypropoxy group, 3-hydroxy 2- (methoxymethyl) propoxy, 4-hydroxy-3-methoxybutyl group, 2-methoxy-3- (trityloxy) propoxy or 2-acetyloxy-3-methoxypropoxy group, the present invention General formula (I) or compound or to a pharmacologically acceptable salt thereof represented by (II).
[0040]
　In certain embodiments, the present invention is, R 1 and R 2 are, independently of one another, a hydrogen atom; a fluorine atom, a chlorine atom, a bromine atom, an iodine atom; a hydroxy group; tetrahydropyran-2-yloxy group; a methyl group , an ethyl group, an isopropyl group, a propyl group, a butyl group; a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, butyloxy group; deuterated methyl group; 2-fluoroethyl group, 2,2-difluoroethyl group, 2 , 2,2-trifluoroethyl group; hydroxymethyl group, 2-hydroxyethyl group; methoxymethyl group, a methoxyethyl group; deuterated methoxy group; 2-fluoroethoxy group, 2,2-difluoro-ethoxy, 2, 2,2-trifluoroethoxy group; hydroxy methoxy, 2-hydroxyethoxy group; or methoxymethoxy group Properly is a methoxyethoxy group, compound or to a pharmacologically acceptable salt thereof represented by the general formula (I) or (II).
[0041]
　In certain embodiments, the present invention is, R 1 and R 2 are, independently of one another, a hydrogen atom; a fluorine atom; hydroxy group; tetrahydropyran-2-yloxy group; a methyl group; methoxy group, an ethoxy group, a propoxy group , isopropoxy group; deuterated methoxy group; or 2-fluoroethoxy group, compound or to a pharmacologically acceptable salt thereof represented by the general formula (I) or (II).
[0042]
　In certain embodiments, the present invention is, R 1 is a fluorine atom; hydroxy group; methoxy group, an ethoxy group, a propoxy group, an isopropoxy group; a or deuterated methoxy group, R 2 is a hydrogen atom; a fluorine atom; or a methyl group, the compound or to a pharmacologically acceptable salt thereof represented by the general formula (I) or (II).
[0043]
　In another embodiment, the present invention, X is a carbonyl group, a compound or related pharmacologically acceptable salt thereof represented by the general formula (I) of the present invention. Specifically, the following general formula (III).
Formula (III):
[Formula 8]

[0044]
　In yet another embodiment, the present invention, X is Formula (Ia), the compound or related pharmacologically acceptable salt thereof represented by the general formula (I) of the present invention. Specifically, represented by the following general formula (IV).
Formula (IV):
[Formula 9]

　In the general formula (IV), p and q are as defined in the general formula (I).
[0045]
　In yet another embodiment, the present invention is, p and q are 1, relates to the general formula (I) or compound or a pharmacologically acceptable salt thereof represented by (IV) of the present invention.
[0046]
　In yet another embodiment, the present invention, p is 0, q is 2 (a or p is 2, q is 0), the general formula of the present invention (I) or (IV) compounds represented or to a pharmacologically acceptable salt thereof.
[0047]
　In yet another embodiment, the present invention, p is 1, q is 2 (a or p is 2, q is 1), the general formula of the present invention (I) or (IV) compounds represented or to a pharmacologically acceptable salt thereof.
[0048]
　In yet another embodiment, the present invention, p is 0, q is 3 (a or p is 3, q ​​is 0), the general formula of the present invention (I) or (IV) compounds represented or to a pharmacologically acceptable salt thereof.
[0049]
　In yet another embodiment, the present invention is, p and q is 2, relates to the general formula (I) or compound or a pharmacologically acceptable salt thereof represented by (IV) of the present invention.
[0050]
　In yet another embodiment, the present invention, p is 1, q is 3 (a or p is 3, q ​​is 1), the general formula of the present invention (I) or (IV) compounds represented or to a pharmacologically acceptable salt thereof.
[0051]
　In yet another embodiment, the present invention, p is 2, q is 3 (a or p is 3, q ​​is 2), the general formula of the present invention (I) or (IV) compounds represented or to a pharmacologically acceptable salt thereof.
[0052]
　In certain embodiments, the present invention provides the
　following: 2-fluoro-3- [5-fluoro-6- (3-methoxy-l-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate (I
　-1), 2-fluoro-3- {5-fluoro-6- [3- (methoxy -d 3 ) azetidin-1-yl] pyridin-3-yl} benzyl carbamimidoyl carbamate (I-2),
　3- [6- (3-ethoxy-1-yl) -5-fluoro-3-yl] -2-fluorobenzyl carbamimidoyl carbamate
　(I-3), 2-fluoro-3- {5 - fluoro-6- [3- (2-fluoroethoxy) azetidin-1-yl] pyridin-3-yl} benzyl carbamimidoyl carbamate
　(I-4), 2-fluoro-3- [5-fluoro -6 - ( - propoxy-1-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate
　(I-5), 2-fluoro-3- [5-fluoro-6- (3-isopropoxyphenyl azetidine-1- yl) pyridin-3-yl] benzyl carbamimidoyl carbamate
　(I-6), 3- [6- (3- butyloxy-1-yl) -5-fluoro-3-yl] -2- fluorobenzyl carbamimidoyl carbamate (I-7),
　3- {6- [3- (2,2-difluoro-ethoxy) azetidin-1-yl] -5-fluoro-3-yl} -2-fluorobenzyl carbamimidoyl carbamate (I-8),
　2-fluoro-3- {5-fluoro-6- [3- (2,2,2-trifluoroethoxy) azetidin-l-yl] - pyridin-3-yl} benzyl carbamimidoyl carbamate (I-9
　), 2-fluoro-3- {5-fluoro-6- [3- (2-hydroxyethoxy) azetidin-1-yl] - pyridin-3-yl} benzyl carbamimidoyl carbamate
　(I-10), 2 - fluoro-3- {5-fluoro-6- [3- (2-methoxyethoxy) azetidin-l-yl] - pyridin-3-yl} benzyl carbamimidoyl carbamate
　(I-11), 2-fluoro - 3- [5-fluoro-6- (3-hydroxy-l-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate
　(I-12), 3- [6- (azetidin-1-yl) - - fluoropyridin-3-yl] -2-fluorobenzyl carbamimidoyl carbamate
　(I-13), 2-fluoro-3- [5-fluoro-6- (3-fluoro-1-yl) pyridine - 3-yl] benzyl carbamimidoyl carbamate
　(I-14), 3- [6- (3-chloro-1-yl) -5-fluoro-3-yl] -2-fluorobenzyl carbamimidoyl carbamate
　(I-15), 3- [6- (3- Buromoazechijin-1-yl) -5-fluoro-3-yl] -2-fluorobenzyl carbamimidoyl carbamate (I-16),
　2-fluoro-3- [5-fluoro-6- (3-Yodoazechijin-1-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate
　(I-17), 3- [6- (3,3- difluoro-1-yl) -5-fluoro-3-yl] -2-fluoro - benzyl carbamimidoyl carbamate
　(I-18), 3- [6- (3- chloro-3-fluoroazetidine 1-yl) -5-fluoro-3-yl] -2-fluorobenzyl carbamimidoyl carbamate
　(I-19), 2-fluoro-3- [5-fluoro-6- (3-methyl-azetidines 1-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate
　(I-20), 3- [6- (3- ethyl-l-yl) -5-fluoropyridin-3-yl] - 2-fluoride Benzyl carbamimidoyl carbamate
　(I-21), 2-fluoro-3- [5-fluoro-6- (3-propyl-1-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate (I
　-22), 2-fluoro-3- [5-fluoro-6- (3-isopropyl-l-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate
　(I-23), 2-fluoro - 3- {5-fluoro-6- [3- (hydroxymethyl) azetidin-1-yl] pyridin-3-yl} benzyl carbamimidoyl carbamate (I-24),
　2-fluoro-3- {5-fluoro-6- [3- (methoxymethyl) azetidin-1-yl] pyridin-3-yl} benzyl carbamimidoyl carbamate
　(I-25), 3- [6- ( 3,3-dimethyl-1-yl) -5-fluoro-3-yl] -2-fluorobenzyl carbamimidoyl carbamate
　(I-26), 3- [6- (3- ethyl-3- methyl-1-yl) -5-fluoro-3-yl] -2-fluorobenzyl carbamimidoyl carbamate
　(I-27), 2-fluoro-3- [5-fluoro-6- (3- methoxy-3-methyl-l-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate
　(I-28), 2-fluoro-3- {5-fluoro-6- [3- (methoxy -d 3 ) -3- Chiruazechijin-1-yl] pyridin-3-yl} benzyl carbamimidoyl carbamate
　(I-29), 2-fluoro-3- [5-fluoro-6- (3-hydroxy-3-methyl azetidine-l- yl) pyridin-3-yl] benzyl carbamimidoyl carbamate
　(I-30), 3- [6- (3- ethyl-3-hydroxy-l-yl) -5-fluoro-3-yl] 2-fluorobenzyl carbamimidoyl carbamate
　(I-31), 2-fluoro-3- [5-fluoro-6- (3-fluoro-3-methyl-l-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate (I-32),
　2-fluoro-3- [5-fluoro-6- (3-oxoazetidin-1-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate
　(I-33), 3- [6- (3,3- dihydroxy-1-yl) -5-fluoro-3-yl] -2-fluorobenzyl carbamimidoyl carbamate
　(I-34), 2-fluoro-3- {5-fluoro-6- [3- hydroxy-3-methoxy-1-yl] pyridin-3-yl} benzyl carbamimidoyl carbamate
　(I-35), 3- [6- (3,3-dimethoxy-1-yl) -5 - fluoropyridin-3-yl] -2-fluorobenzyl carbamimidoyl carbamate
　(I-36), 3- [6- (3- ethoxy-3-hydroxy-l-yl) -5- Furuoropi 3-yl] -2-fluorobenzyl carbamimidoyl carbamate
　(I-37), 3- [6- (3- ethoxy-3-methoxy-1-yl) -5-fluoro-3- yl] -2-fluorobenzyl carbamimidoyl carbamate
　(I-38), 3- [6- (3,3-diethoxy-1-yl) -5-fluoro-3-yl] -2- fluorobenzyl carbamimidoyl carbamate
　(I-39), 2-fluoro-3- (5-fluoro-6- {3 - [(tetrahydropyran-2-yl) oxy] azetidin-1-yl} pyridine-3 yl) benzyl carbamimidoyl carbamate (I-40),
　2-fluoro-3- (5-fluoro-6- {3-methyl-3 - [(tetrahydropyran-2-yl) oxy] azetidin-1-yl} pyridin-3-yl) benzyl carbamimidoyl carbamate (
　I-41), 2-fluoro-3- [5-fluoro-6- (2-oxa-6-azaspiro [3.3] heptan-6-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate (
　I-42), 2-fluoro-3- [5-fluoro-6- (1-oxa-6-azaspiro [3.3] heptan-6-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate (
　I-43), 2-fluoro-3- [5-fluoro-6- (6-oxa-2-azaspiro [3.4] octane-2-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate ( I-4 4),
　2-fluoro-3- [5-fluoro-6- (5-oxa-2-azaspiro [3.4] octane-2-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate (I-
　45), 2-fluoro-3- [5-fluoro-6- (7-oxa-2-azaspiro [3.5] nonane-2-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate (I-
　46), 2-fluoro-3- [5-fluoro-6- (6-oxa-2-azaspiro [3.5] nonane-2-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate (I- 47), or
　2-fluoro-3- [5-fluoro-6- (7-oxa-2-azaspiro [3.6] decan-2-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate (I -48)
In it, the compound or to a pharmacologically acceptable salt thereof represented by the general formula (I).
[0053]
　In certain embodiments, the present invention provides the
　following: 2-fluoro-3- [5-fluoro-6- (3-methoxy-l-yl) pyridin-3-yl] benzyl carbamimidoyl
　carbamate, 2 - fluoro-3- {5-fluoro-6- [3- (methoxy -d 3 ) azetidin-1-yl] pyridin-3-yl} benzyl carbamimidoyl
　carbamate, 3- [6- (3-Etokishiazechi l-yl) -5-fluoro-3-yl] -2-fluorobenzyl carbamimidoyl
　carbamate, 2-fluoro-3- {5-fluoro-6- [3- (2-fluoroethoxy) azetidine 1-yl] pyridin-3-yl} benzyl carbamimidoyl
　carbamate, 2-fluoro-3- [5-fluoro-6- (3-propoxy-azetidine 1-yl) pyridin-3-yl] benzyl carbamimidoyl
　carbamate, 2-fluoro-3- [5-fluoro-6- (3-isopropoxyphenyl l-yl) pyridin-3-yl] benzyl carbamate Mimi Doyle
　carbamate, 2-fluoro-3- (5-fluoro-6- {3 - [(tetrahydropyran-2-yl) oxy] azetidin-1-yl} pyridin-3-yl) benzyl carbamimidoyl carbamate ,
　2-fluoro-3- [5-fluoro-6- (3-hydroxy-l-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate,
　3- [6- (azetidin-1-yl) -5-fluoro-3-yl] -2-fluorobenzyl carbamimidoyl
　carbamate, 2-fluoro-3- [5-fluoro-6- (3-fluoro azetidin-1-yl) pyridin-3-yl] benzyl carbamimidoyl
　carbamate, 3- [6- (3,3-difluoro-1-yl) -5-fluoro-3-yl] -2 - fluoro - benzyl carbamimidoyl
　carbamate, 2-fluoro-3- [5-fluoro-6- (3-methyl-l-yl) pyridin-3-yl] benzyl carbamimidoyl
　carbamate, 3- [ 6- (3,3-dimethyl-1-yl) -5-fluoro-3-yl] -2-fluorobenzyl carbamimidoyl
　carbamate, 2 - fluoro-3- (5-fluoro-6- {3-methyl-3 - [(tetrahydropyran-2-yl) oxy] azetidin-1-yl} pyridin-3-yl) benzyl carbamimidoyl
　carbamate, 2 - fluoro-3- [5-fluoro-6- (3-hydroxy-3-methyl-l-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate, or
　2-fluoro-3- [5- fluoro-6- (2-oxa-6-azaspiro [3.3] heptan-6-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate
the compound or a pharmacologically represented by the general formula (I) about the upper acceptable salts.
[0054]
　In certain embodiments, the present invention
　is 2-fluoro-3- [5-fluoro-6- (3-methoxy-l-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate, or a pharmacologically about the upper acceptable salts.
[0055]
　In certain embodiments, the present invention
　is 2-fluoro-3- {5-fluoro-6- [3- (methoxy -d 3 ) azetidin-1-yl] pyridin-3-yl} benzyl carbamimidoyl carbamate , or to a pharmacologically acceptable salt thereof.
[0056]
　In certain embodiments, the present invention
　is 2-fluoro-3- [5-fluoro-6- (3-hydroxy-l-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate, or a pharmacologically about the upper acceptable salts.
[0057]
　In certain embodiments, the present invention
　is 2-fluoro-3- [5-fluoro-6- (3-fluoro-1-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate, or a pharmacologically about the upper acceptable salts.
[0058]
　In certain embodiments, the present invention
　is 2-fluoro-3- [5-fluoro-6- (3-hydroxy-3-methyl-l-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate , or to a pharmacologically acceptable salt thereof.
[0059]
　In certain embodiments, the present invention
　is 2-fluoro-3- [5-fluoro-6- (2-oxa-6-azaspiro [3.3] heptan-6-yl) pyridin-3-yl] benzyl carbamate Mimi Doyle carbamate, or to a pharmacologically acceptable salt thereof.
[0060]
　As the compound represented by the general formula (I) of the present invention, illustrate the compounds of Table 1 to Table 4. In Formula I-1 ~ I-48, D represents a deuterium atom.
[0061]
[Table 1]

[0062]
[Table 2]

[0063]
[table 3]

[0064]
[Table 4]

[0065]
　A compound represented by the general formula (I) of the present invention or a general method for preparing a pharmacologically acceptable salt thereof are shown below. The compound or a pharmacologically acceptable salt thereof of the present invention is not limited to the prepared compound or a pharmacologically acceptable salt thereof by the following manufacturing method.
[0066]
　In the production methods shown below, or inhibit the desired reaction in the compound, or a partial structure undergo side reactions (e.g., hydroxy group) occurs, the desired by introducing a protecting group into their partial structure the reaction carried out, the desired product can be obtained by subsequently removing the protective group. METHOD introduction reaction and their removal reactions are protecting groups conventionally used in organic synthetic chemistry (for example, Protective Groups in Organic Synthesis 4th ed., TW Greene, PGM Wuts al, described in John Wiley & Sons Inc. (2006 years) and the like can be carried out in accordance with the method). Further, for each specific manufacturing method of the present invention compounds are explained in detail in the Examples below.
[0067]
(Method 1)
[of 10]

[0068]
　X is CR 1 R 2 , carbonyl group or the following formula (Ia):
[Formula 11] 　is,

R 1 and R 2 are, independently of one another, a hydrogen atom, a halogen atom, hydroxy group, protected hydroxy group , unsubstituted or substituted C 1 -C 6 alkyl group, or an unsubstituted or substituted C for 1 -C 6 alkoxy group, wherein "substituted", a deuterium atom, a halogen atom, hydroxy group and C 1 - C 6 means that it is substituted with at least one substituent selected from the group consisting of alkoxy groups, 　p and q are each independently integers of 0 to 3, provided that p + q is 2 or more it is.

[0069]
　Step 1 of Production Method 1 is in a solvent in the presence of 1,1'-carbonyldiimidazole is reacted with guanidine or salts of guanidine compounds (1) and the compound (2), represented by the general formula (I) it is a step for preparing a compound.
　Compound (1) can be produced according to Reference Example of synthesis 1 to 3 and herein will be described later.
　The guanidine salt of the compound (2), for example, guanidine hydrochloride, guanidine sulfate, guanidine carbonate, and the like.
　Compound (2) are known, for example, available from reagent suppliers such as Tokyo Chemical Industry Co., Ltd.. The amount of the acid salt of guanidine or guanidine, per 1 mol of compound (1), usually 0.9-5 times by mole, preferably 1.1 to 3 times the molar amount.
　The solvent to be used, does not inhibit the reaction, is not particularly limited as long as to be dissolved therein to a certain extent the raw materials, for example, aromatic hydrocarbons such as benzene, such as toluene or xylene; methylene chloride, chloroform or 1, halogenated aliphatic hydrocarbons such 2-dichloroethane and the like; tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane and the like; nitriles such as acetonitrile or propionitrile; N, N-dimethyl formamide, N , N- dimethylacetamide or amides such as N- methyl pyrrolidone; or any mixed solvents thereof. Preferably, N, N-dimethylformamide is used. The amount of the solvent is not particularly limited, relative to the weight of Compound (1) is generally 1 to 20 times, preferably 2 to 10 times.
　The amount of 1,1'-carbonyldiimidazole, the compound (1) with respect to 1 mole, usually 0.9 to 5 times the molar quantity, preferably 1.1 to 3 times the molar amount.
　The reaction temperature, the raw material, the type of such a solvent may vary depending the amount, in general, we find it convenient -20 ° C. ~ 0.99 ° C., preferably, 0 ℃ ~ 40 ℃.
　The reaction time varies depending on the reaction temperature and is usually from 1 minute to 48 hours, preferably from 1 hour to 24 hours.
　The reaction pressure is appropriately set as required, pressure, vacuum, may be any of atmospheric pressure, preferably at atmospheric pressure. The reaction atmosphere can be carried out in an atmosphere selected as necessary, preferably, an inert gas atmosphere such as air atmosphere, or nitrogen or argon.
[0070]
　When a protective group in compound (I) is present, it can be subjected to a deprotection step if necessary a compound (I).
　When compound (I) having at least two different protecting groups, by selecting the deprotection conditions, it is also possible to selectively remove only one protective group.
　Deprotection conditions, methods conventionally used in organic synthetic chemistry (for example, Protective Groups in Organic Synthesis 4th ed., TW Greene, PGM Wuts al, A method according to John Wiley & Sons Inc. (2006 years), etc.) or the according to example of the specification can be implemented as appropriate.
[0071]
　The above compound (1) is, for example, the following synthetic 1-3 and in accordance with the reference example or the like of the present specification, can be appropriately prepared.
(Synthesis 1)
[Chem 12]

　X are as defined above, Hal is a halogen atom.
[0072]
　Step 2 Synthesis 1, in a solvent in the presence of a base, by reacting the compound (3) with the compound (4) is a step of obtaining compound (5).
　Compound (3) it is known, available from reagent supplier. As such an example, 5-bromo-2,3-difluoro-pyridine. Alternatively, the compound (3) may be prepared according to known methods from known compounds.
　Compound (4) it is known, available from reagent supplier. As such an example, azetidine, azetidin-3-ol, 3-methyl azetidine, 3,3-dimethyl azetidine, 3-fluoro-azetidine, 3,3-difluoroazetidin, 2-oxa-6-azaspiro [3,3] heptane, or their acid salts. Alternatively, the compound (4) may be prepared according to known methods from known compounds.
　The salt of the compound (4), such as hydrochloride, sulfate, acetate, and oxalate and the like.
　The amount of the compound (4) are the compound (3) with respect to 1 mole, usually 0.9 to 5 times the molar quantity, preferably 1.1 to 3 times the molar amount.
　The solvent to be used, does not inhibit the reaction, is not particularly limited as long as to be dissolved therein to a certain extent the raw materials, for example, alcohols such as methanol, ethanol, propanol or isopropanol; benzene, aromatic such as toluene or xylene family hydrocarbons; methylene chloride, halogenated aliphatic hydrocarbons such as chloroform or 1,2-dichloroethane; ethers such as tetrahydrofuran and 1,2-dimethoxyethane or 1,4-dioxane; acetonitrile or propionitrile nitriles; N, N- dimethylformamide, N, N- dimethylacetamide or N- amides such as methylpyrrolidone; sulfoxides such as dimethyl sulfoxide; or any mixed solvents thereof. Preferably, alcohols such as ethanol, N, N- dimethylformamide, amides such as N- methylpyrrolidone, sulfoxides such as dimethyl sulfoxide is used. The amount of the solvent is not particularly limited, relative to the weight of the compound (3) is generally 1 to 50 times, preferably 5 to 20 times.
　Examples of the base used, for example, alkali metal acetates such as sodium acetate or potassium acetate; sodium carbonate, alkali metal carbonate such as potassium carbonate or cesium carbonate; organic base such as or triethylamine or diisopropylethylamine and the like, preferably, potassium carbonate, cesium carbonate, triethylamine or diisopropylethylamine. The amount of the base to be used, the compound (3) with respect to 1 mole, usually 0.9 to 10 times the molar quantity, preferably, 1 to 5 times the molar amount.
　The reaction temperature, the raw material, the type of such a solvent may vary depending the amount, in general, it finds it convenient 0 ° C. ~ 0.99 ° C., preferably, 40 ℃ ~ 120 ℃.
　The reaction time varies depending on the reaction temperature and is usually from 1 minute to 48 hours, preferably from 0.5 hours to 24 hours.
　The reaction pressure is appropriately set as required, pressure, vacuum, may be any of atmospheric pressure, preferably at atmospheric pressure. The reaction atmosphere can be carried out in an atmosphere selected as necessary, preferably, an inert gas atmosphere such as air atmosphere, or nitrogen or argon.
　The compound (5) to a functional group (e.g., halogen atom, hydroxy group, a carbonyl group) occurs, by reacting according to their functional groups into the appropriate reactants and known methods, additional desired possible compound (5) prepared (e.g., see reference examples 2-1 to 2-5,8,9,12 ~ 14).

claims

[Requested item 1]
　General formula (I):
[Chemical formula 1]

(wherein,
X is CR 1 R 2 , carbonyl group or the following formula (Ia):
[Chemical Formula 2] 　is,

R 1 and R 2 , independently of one another, a hydrogen atom, a halogen atom, hydroxy group, protected hydroxy group, an unsubstituted or substituted C 1 -C 6 alkyl group, or an unsubstituted or substituted C for 1 -C 6 alkoxy group, wherein "substituted" , a deuterium atom, a halogen atom, hydroxy group and C 1 -C 6 means that it is substituted with at least one substituent selected from the group consisting of alkoxy groups, 　p and q are, independently of each other , an integer from 0 to 3, provided that p + q is 2 or more) compounds or pharmacologically acceptable salt thereof represented by.

[Requested item 2]
　R 1 is a hydrogen atom, a halogen atom, hydroxy group, an unsubstituted or substituted C 1 -C 6 alkyl group, or an unsubstituted or substituted C for 1 -C 6 alkoxy group, R 2 is a hydrogen atom, a halogen atom, or a C 1 -C 3 alkyl group, compound or pharmacologically acceptable salt thereof according to claim 1.
[Requested item 3]
　R 1 is a halogen atom, hydroxy group, C 1 -C 6 alkoxy group, or at least one C are replaced with deuterium atoms 1 -C 6 alkoxy group, A compound according to claim 2 or pharmacologically acceptable salts.
[Requested item 4]
　p and q are, independently of one another, is 1 to 2 integer compound or a pharmacologically acceptable salt thereof according to claim 1.
[Requested item 5]
　The following
　compounds: 2-fluoro-3- [5-fluoro-6- (3-methoxy-l-yl) pyridin-3-yl] benzyl carbamimidoyl
　carbamate, 2-fluoro-3- {5- fluoro-6- [3- (methoxy -d 3 ) azetidin-1-yl] pyridin-3-yl} benzyl carbamimidoyl
　carbamate, 3- [6- (3-ethoxy-1-yl) -5 - fluoropyridin-3-yl] -2-fluorobenzyl carbamimidoyl
　carbamate, 2-fluoro-3- {5-fluoro-6- [3- (2-fluoroethoxy) azetidin-1-yl] pyridine -3 - yl} benzyl carbamimidoyl
　carbamate, 2-fluoro-3- [5-fluoro-6- (3-propoxy-1-yl) pyridine-3 Le] benzyl carbamimidoyl
　carbamate, 2-fluoro-3- [5-fluoro-6- (3-isopropoxyphenyl l-yl) pyridin-3-yl] benzyl carbamimidoyl
　carbamate, 2-fluoro 3- (5-fluoro-6- {3 - [(tetrahydropyran-2-yl) oxy] azetidin-1-yl} pyridin-3-yl) benzyl carbamimidoyl carbamate,
　2-fluoro-3- [ 5-fluoro-6- (3-hydroxy-l-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate,
　3- [6- (azetidin-1-yl) -5-fluoro-3-yl] -2-fluorobenzyl carbamimidoyl
　carbamate, 2-fluoro-3- [5-fluoro-6- (3-fluoro azetidin-1-yl) pyridin-3-yl] benzyl carbamimidoyl
　carbamate, 3- [6- (3,3-difluoro-1-yl) -5-fluoro-3-yl] -2 - fluoro - benzyl carbamimidoyl
　carbamate, 2-fluoro-3- [5-fluoro-6- (3-methyl-l-yl) pyridin-3-yl] benzyl carbamimidoyl
　carbamate, 3- [ 6- (3,3-dimethyl-1-yl) -5-fluoro-3-yl] -2-fluorobenzyl carbamimidoyl
　carbamate, 2 - fluoro-3- (5-fluoro-6- {3-methyl-3 - [(tetrahydropyran-2-yl) oxy] azetidin-1-yl} pyridin-3-yl) benzyl carbamimidoyl
　carbamate, 2 - fluoro-3- [5-fluoro-6- (3-hydroxy-3-methyl-l-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate, or
　2-fluoro-3- [5- fluoro-6- (2-oxa-6-azaspiro [3.3] heptan-6-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate
the compound or a pharmacologically acceptable according to claim 1 salt.
[Requested item 6]
　2-fluoro-3- [5-fluoro-6- (3-methoxy-l-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate compound according to claim 1 or a pharmacologically acceptable salt thereof.
[Requested item 7]
　2-fluoro-3- {5-fluoro-6- [3- (methoxy -d 3 is a) azetidin-1-yl] pyridin-3-yl} benzyl carbamimidoyl carbamate compound according to claim 1 or a pharmaceutically acceptable salt thereof.
[Requested item 8]
　2-fluoro-3- [5-fluoro-6- (3-hydroxy-l-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate compound according to claim 1 or a pharmacologically acceptable salt thereof.
[Requested item 9]
　2-fluoro-3- [5-fluoro-6- (3-fluoro-1-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate compound according to claim 1 or a pharmacologically acceptable salt thereof.
[Requested item 10]
　2-fluoro-3- [5-fluoro-6- (3-hydroxy-3-methyl-l-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate compound according to claim 1 or a pharmaceutically acceptable salt thereof.
[Requested item 11]
　2-fluoro-3- [5-fluoro-6- (2-oxa-6-azaspiro [3.3] heptan-6-yl) pyridin-3-yl] benzyl carbamimidoyl carbamate, claim 1 compound or pharmacologically acceptable salt thereof according to.
[Requested item 12]
　Salts pharmacologically acceptable salt is a salt of an organic acid, is pharmacologically acceptable compound according to any one of claims 1 to 11.
[Requested item 13]
　Salts pharmacologically acceptable salt is a salt of a dicarboxylic acid, is pharmacologically acceptable compound according to any one of claims 1 to 11.
[Requested item 14]
　A compound according to any one of claims 1 to 13 or a salt thereof pharmacologically acceptable, containing an additive acceptable at least one pharmacologically, pharmaceutical compositions.
[Requested item 15]
　Prevented by VAP-1 inhibitor, for the treatment of alleviation and / or the disease being treated, the pharmaceutical composition according to claim 14.
[Requested item 16]
　The disease is diabetic nephropathy, the pharmaceutical composition according to claim 15.
[Requested item 17]
　The disease is non-alcoholic steatohepatitis, the pharmaceutical composition according to claim 15.
[Requested item 18]
　Prevented by VAP-1 inhibitor, for use in the treatment of alleviation and / or the disease being treated, the compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 13.
[Requested item 19]
　Prevented by VAP-1 inhibition, relief and / or for the manufacture of a medicament for the treatment of the disease being treated, the use of a compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 13.
[Requested item 20]
　The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 13, a therapeutically effective amount, comprising administering to a patient in need thereof, preventing the VAP-1 inhibitor, alleviating and / or method treatment of the disease being treated.