Imidazole derivatives

Abstract

The present invention relates to a compound represented by general formula (I) or a pharmacologically acceptable salt thereof. The compound of the present invention has an excellent epinephrine alpha 1A receptor agonist activity, and is useful as a prophylactic or therapeutic agent for erect hypotension, intrinsic hypotension, acute hypotension associated with various diseases or conditions, and urinary incontinence. (In the formula, R1 represents a hydrogen atom or a C1-C3 alkyl group; z is selected from a group consisting of substituted phenyl amino, substituted phenyl oxy, substituted phenyl sulfenyl, substituted thienyl amino and the like. > # imgabs0 #

Description

Technical Field

[0001] The present invention relates to imidazole derivatives and their medical uses. Background Art

[0002] Epinephrine and norepinephrine are a class of neurotransmitters collectively referred to as catecholamines, which are mainly secreted by the adrenal medulla and sympathetic nerve endings and participate in the information transmission of sympathetic nerves. The adrenergic receptors involved in the expression of these effects are roughly divided into α receptors and β receptors, and there are two subtypes of α1 and α2 in α receptors. Among them, α1 receptors further have three subtypes, α1A receptors, α1B receptors, and α1D receptors, all of which are related to smooth muscle contraction. It is reported that the activation of α1A receptors is significantly related to increased blood pressure (Non-patent Documents 1 and 2).

[0003] Since the stimulation of α1 receptors causes the contraction of vascular smooth muscle, α1 receptor agonists are clinically used as pressor drugs. Currently, as α1 receptor agonists used clinically, known ones include midodrine, etilefrine, phenylephrine, etc., and their types are limited.

[0004] As α1 receptor agonists, N-((1H-imidazol-4-yl)methyl)-2-(oxazol-5-yl)aniline and 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)isoxazole have been reported (Non-Patent Document 3). Although these compounds have α1A agonist effects, they are structurally different from the compounds of the present invention that do not have an oxazole ring or an isoxazole ring in the biaryl structure.

[0005] Prior art literature

[0006] Non-patent literature

[0007] Non-patent literature 1: Circulation 100 2336-2343 1999

[0008] Non-patent document 2: J Pharmacol Exp Ther 274 97-103 1995

[0009] Non-patent document 3: Bioorg Med Chem Lett 12 3449-3452 2002 Summary of the invention

[0010] Problem that the invention aims to solve

[0011] Activation of α1A receptor plays an important role in elevated blood pressure, and therefore the present invention aims to provide a novel compound that can be used as a pressor and that exhibits a strong agonist effect on α1A receptor. In other words, the present invention aims to provide a compound that can be an excellent therapeutic or preventive drug for orthostatic hypotension, essential hypotension, acute hypotension associated with various diseases or conditions, and urinary incontinence based on activation of α1A receptor.

[0012] Solutions for solving problems

[0013] The present inventors have repeatedly studied to develop an adrenaline α1A receptor agonist having a novel structure in order to solve the above problems. As a result, they have found that the compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof have very excellent adrenaline α1A receptor agonist activity, thereby completing the present invention.

[0014] According to the present invention, a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof is provided. In this specification, these compounds and pharmacologically acceptable salts thereof are referred to as "compounds of the present invention". The present invention can be represented by the following embodiments (1) to (18).

[0015] (1) A compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof.

[0016] [Chemical formula 1]

[0017]

[0018] 〔In the formula, R 1 It represents a hydrogen atom or a C1-C3 alkyl group.

[0019] Z is selected from the group consisting of the following formulae.

[0020] [Chemical formula 2]

[0021]

[0022] R 2 It represents a hydrogen atom, a fluorine atom or a C1-C3 alkyl group.

[0023] R 3 Select from the group consisting of the following formulae.

[0024] [Chemical formula 3]

[0025]

[0026] Y represents an oxygen atom or a sulfur atom.

[0027] R 4 Each independently represents a hydrogen atom or a C1-C3 alkoxy group.

[0028] R 5 It represents a hydrogen atom, a fluorine atom, a C1-C3 alkyl group or a C1-C3 alkoxy group.

[0029] R 6 It represents a hydrogen atom, a fluorine atom or a C1-C3 alkoxy group.

[0030] R 7 It represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyclopropyl group.

[0031] R 8 It represents a hydrogen atom or a C1-C3 alkoxy group.

[0032] R 9 It represents a hydrogen atom or a C1-C3 alkyl group.

[0033] R 10 It represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyano group.

[0034] It should be noted that R 6 When it is C1-C3 alkoxy, R 7 and R 8 is a hydrogen atom; R 8 When it is C1-C3 alkoxy, R 6 is a hydrogen atom or a fluorine atom, R 7 is a hydrogen atom.

[0035] (2) A compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof.

[0036] [Chemical formula 4]

[0037]

[0038] 〔In the formula, R 1 It represents a hydrogen atom or a C1-C3 alkyl group.

[0039] Z is selected from the group consisting of the following formulae.

[0040] [Chemical formula 5]

[0041]

[0042] R 2 It represents a hydrogen atom, a fluorine atom or a C1-C3 alkyl group.

[0043] R 3 Select from the group consisting of the following formulae.

[0044] [Chemical formula 6]

[0045]

[0046] Y represents an oxygen atom or a sulfur atom.

[0047] R 4 Each independently represents a hydrogen atom or a C1-C3 alkoxy group.

[0048] R 5 It represents a hydrogen atom, a fluorine atom, a C1-C3 alkyl group or a C1-C3 alkoxy group.

[0049] R 6 It represents a hydrogen atom, a fluorine atom or a C1-C3 alkoxy group.

[0050] R 7 It represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyclopropyl group.

[0051] R 8 It represents a hydrogen atom or a C1-C3 alkoxy group.

[0052] R 9 It represents a hydrogen atom or a C1-C3 alkyl group.

[0053] R 10 It represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyano group.

[0054] It should be noted that R 6 When it is C1-C3 alkoxy, R 7 and R 8 is a hydrogen atom; R 8 When it is C1-C3 alkoxy, R 6 is a hydrogen atom or a fluorine atom, R 7 A hydrogen atom.

[0055] Among them, Z is

[0056] [Chemical formula 7]

[0057] ,

[0058] R 2 When it is a hydrogen atom, R 3 It is not 3-fluoropyridine bonded at the 2-position;

[0059] In addition, Z is

[0060] [Chemical formula 8]

[0061] ,

[0062] R 2 When it is a hydrogen atom, R 3It is not any of unsubstituted pyridine bonded at the 2-position, unsubstituted pyrazole bonded at the 3-position, or 3-methoxypyrazole bonded at the 4-position;

[0063] In addition, Z is

[0064] [Chemical formula 9]

[0065] ,

[0066] R 2 When it is a hydrogen atom, R 3 It is not an unsubstituted furan bonded at the 2-position;

[0067] In addition, Z is

[0068] [Chemical formula 10]

[0069] ,

[0070] R 1 is a C1-C3 alkyl group and R 2 When it is a hydrogen atom, R 3 It is not an unsubstituted pyrazole bonded at the 4-position;

[0071] In addition, Z is

[0072] [Chemical formula 11]

[0073]

[0074] When R 3 It is not an unsubstituted thiazole bonded at the 5-position.

[0075] It should be noted that R 1 When the alkyl group is C1-C3, the enantiomers produced are those whose α1A agonism is weaker than that of 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole.

[0076] (3) The compound according to (2) or a pharmacologically acceptable salt thereof, wherein R 3 Select from the group consisting of:

[0077] [Chemical formula 12]

[0078]

[0079] [In the formula, Y represents an oxygen atom or a sulfur atom.

[0080] R 4 Each independently represents a hydrogen atom or a C1-C3 alkoxy group.

[0081] R 5It represents a hydrogen atom, a fluorine atom or a C1-C3 alkoxy group.

[0082] R 6 It represents a hydrogen atom, a fluorine atom or a C1-C3 alkoxy group.

[0083] R 7 It represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyclopropyl group.

[0084] R 8 It represents a hydrogen atom or a C1-C3 alkoxy group.

[0085] R 9 It represents a hydrogen atom or a C1-C3 alkyl group.

[0086] R 10 It represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyano group.

[0087] It should be noted that R 6 When it is C1-C3 alkoxy, R 7 and R 8 is a hydrogen atom; R 8 When it is C1-C3 alkoxy, R 6 is a hydrogen atom or a fluorine atom, R 7 A hydrogen atom.

[0088] Among them, Z is

[0089] [Chemical formula 13]

[0090]

[0091] When R 3 Not bonded at position 4 and position 3 is R 9 Any one of substituted thiophene, pyridine bonded at the 3-position and substituted by a C1-C3 alkyl group at the 4-position, or unsubstituted pyrazole bonded at the 4-position;

[0092] In addition, Z is

[0093] [Chemical formula 14]

[0094]

[0095] When R 3 Not bonded at position 4 and position 3 is R 9 Any one of substituted thiophene, pyridine bonded at the 3-position and substituted by a C1-C3 alkyl group at the 4-position, unsubstituted pyrazole bonded at the 4-position, unsubstituted pyrimidine bonded at the 5-position, or pyrimidine bonded at the 5-position and substituted by a C1-C3 alkyl group at the 4-position;

[0096] In addition, Z is

[0097] [Chemical formula 15]

[0098] ,

[0099] R 2 When it is C1~C3 alkyl, R 3 Not bonded at position 4 and position 3 is R 9 Any one of substituted thiophene, unsubstituted pyrimidine bonded at the 5-position, or pyrimidine bonded at the 5-position and substituted at the 4-position by a C1-C3 alkyl group;

[0100] In addition, Z is the same as above, R 2 When it is a hydrogen atom, R 3 It is not pyridine bonded at the 3-position and substituted by a C1-C3 alkyl group at the 4-position, or unsubstituted pyrazole bonded at the 4-position;

[0101] In addition, Z is the same as above, R 1 is a C1-C3 alkyl group and R 2 When it is a hydrogen atom, R 3 It is not 4-cyclopropylpyridine bonded at the 3-position or unsubstituted pyrimidine bonded at the 5-position;

[0102] In addition, Z is

[0103] [Chemical formula 16]

[0104]

[0105] When R 3 Not bonded at position 4 and position 3 is R 9 Any one of substituted thiophene, pyridine bonded at the 3-position and substituted by a C1-C3 alkyl group at the 4-position, unsubstituted pyrazole bonded at the 4-position, unsubstituted pyrimidine bonded at the 5-position, or pyrimidine bonded at the 5-position and substituted by a C1-C3 alkyl group at the 4-position. ).

[0106] (4) The compound according to (3) or a pharmacologically acceptable salt thereof, wherein R 3 Select from the group consisting of:

[0107] [Chemical formula 17]

[0108]

[0109] [In the formula, Y represents an oxygen atom or a sulfur atom.

[0110] R 4 Each independently represents a hydrogen atom or a C1-C3 alkoxy group.

[0111] R 5 It represents a hydrogen atom, a fluorine atom or a C1-C3 alkoxy group.

[0112] R 6 It represents a hydrogen atom, a fluorine atom or a C1-C3 alkoxy group.

[0113] R 7a It represents a hydrogen atom, a C1-C3 alkoxy group or a cyclopropyl group.

[0114] R 7b It represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyclopropyl group.

[0115] R 8 It represents a hydrogen atom or a C1-C3 alkoxy group.

[0116] R 9 It represents a hydrogen atom or a C1-C3 alkyl group.

[0117] R 10 It represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyano group.

[0118] It should be noted that R 6 When it is C1-C3 alkoxy, R 7 and R 8 is a hydrogen atom; R 8 When it is C1-C3 alkoxy, R 6 is a hydrogen atom or a fluorine atom, R 7 A hydrogen atom.

[0119] Among them, Z is

[0120] [Chemical formula 18]

[0121]

[0122] When R 3 It is not any of pyridine bonded at the 2-position and substituted by a C1-C3 alkoxy group at the 3-position, and pyridine bonded at the 5-position and substituted by a C1-C3 alkoxy group at the 3-position. 〕.

[0123] (5) The compound according to (4) or a pharmacologically acceptable salt thereof, wherein R 3 Select from the group consisting of:

[0124] [Chemical formula 19]

[0125]

[0126] 〔In the formula, R 4 Each independently represents a hydrogen atom or a methoxy group.

[0127] R 5 represents a hydrogen atom, a fluorine atom or a methoxy group.

[0128] R6 represents a hydrogen atom, a fluorine atom or a methoxy group.

[0129] R 7a represents a hydrogen atom, a methoxy group or a cyclopropyl group.

[0130] R 7b represents a hydrogen atom, a methyl group or a methoxy group.

[0131] R 8 represents a hydrogen atom or a methoxy group.

[0132] R 9 represents a hydrogen atom or a methyl group.

[0133] R 10 It represents a hydrogen atom, a methyl group, a methoxy group or a cyano group.

[0134] It should be noted that R 6 When it is methoxy, R 7a and R 8 is a hydrogen atom; R 6 When it is a fluorine atom, R 8 is a hydrogen atom; R 8 When it is methoxy, R 6 is a hydrogen atom or a fluorine atom, R 7a is a hydrogen atom.

[0135] Among them, Z is

[0136] [Chemical formula 20]

[0137]

[0138] When R 3 It is not 3-methylpyrazole bonded at the 4-position;

[0139] In addition, Z is

[0140] [Chemical formula 21]

[0141]

[0142] When R 3 is not any of unsubstituted pyridine bonded at the 3-position, 3-methylpyrazole bonded at the 4-position, 2-methoxypyridine bonded at the 3-position, 4-methoxypyridine bonded at the 3-position, or unsubstituted thiophene bonded at the 2-position;

[0143] In addition, Z is

[0144] [Chemical formula 22]

[0145]

[0146] When R 3It is not any of unsubstituted pyrimidine bonded at the 5-position, 3-methylpyrazole bonded at the 4-position, 2-methoxypyridine bonded at the 3-position, 4-methoxypyridine bonded at the 3-position, or unsubstituted thiophene bonded at the 2-position;

[0147] In addition, Z is

[0148] [Chemical formula 23]

[0149] ,

[0150] R 2 When it is methyl, R 3 is not any of unsubstituted pyridine bonded at the 3-position, 2-methoxypyridine bonded at the 3-position, 4-methoxypyridine bonded at the 3-position, or unsubstituted thiophene bonded at the 2-position;

[0151] In addition, Z is the same as above, R 2 When it is a hydrogen atom, R 3 It is not any of unsubstituted pyridine bonded at the 3-position, 3-methylpyrazole bonded at the 4-position, or unsubstituted thiophene bonded at the 2-position;

[0152] In addition, Z is the same as above, R 2 When it is a fluorine atom, R 3 is not any of unsubstituted pyridine bonded at the 3-position, 4-methylpyrimidine bonded at the 5-position, 2-methoxypyridine bonded at the 3-position, or unsubstituted thiophene bonded at the 2-position;

[0153] In addition, Z is

[0154] [Chemical formula 24]

[0155]

[0156] When R 3 It is not any of unsubstituted pyridine bonded at the 3-position, 3-methylpyrazole bonded at the 4-position, 2-methoxypyridine bonded at the 3-position, 4-methoxypyridine bonded at the 3-position, or unsubstituted thiophene bonded at the 2-position. 〕.

[0157] (6) The compound according to (5) or a pharmacologically acceptable salt thereof, wherein R 3 Select from the group consisting of:

[0158] [Chemical formula 25]

[0159]

[0160] 〔In the formula, R 4 Each independently represents a hydrogen atom or a methoxy group.

[0161] R5 represents a hydrogen atom, a fluorine atom or a methoxy group.

[0162] R 6 represents a hydrogen atom, a fluorine atom or a methoxy group.

[0163] R 7a represents a hydrogen atom, a methoxy group or a cyclopropyl group.

[0164] R 7b Represents methoxy.

[0165] R 8 represents a hydrogen atom or a methoxy group.

[0166] R 9 represents a hydrogen atom or a methyl group.

[0167] It should be noted that R 6 When it is methoxy, R 7a and R 8 is a hydrogen atom; R 6 When it is a fluorine atom, R 8 is a hydrogen atom; R 7a When it is methoxy, R 6 is a fluorine atom, R 8 A hydrogen atom.

[0168] Among them, Z is

[0169] [Chemical formula 26]

[0170]

[0171] When R 3 It is not an unsubstituted pyridine bonded at the 3-position. 〕

[0172] (7) The compound or pharmacologically acceptable salt thereof according to any one of (2) to (6), wherein in the above general formula (I), Z is selected from the group consisting of the following formulae:

[0173] [Chemical formula 27]

[0174]

[0175] (8) The compound or pharmacologically acceptable salt thereof according to any one of (2) to (6), wherein in the above general formula (I), Z is selected from the group consisting of the following formulae:

[0176] [Chemical formula 28]

[0177]

[0178] (9) The compound or pharmacologically acceptable salt thereof according to (7), wherein in the above general formula (I), Z is the following formula:

[0179] [Chemical formula 29]

[0180]

[0181] 〔In the formula, R 2 represents a hydrogen atom, a methyl group or a fluorine atom. ],

[0182] R 3 Select from the group consisting of:

[0183] [Chemical formula 30]

[0184]

[0185] 〔In the formula, R 4 represents a hydrogen atom or a methoxy group. 〕

[0186] (10) The compound or pharmacologically acceptable salt thereof according to (8), wherein, in the above general formula (I), Z is the following formula:

[0187] [Chemical formula 31]

[0188]

[0189] R 3 Select from the group consisting of:

[0190] [Chemical formula 32]

[0191]

[0192] 〔In the formula, R 4 represents a hydrogen atom or a methoxy group.

[0193] R 6 represents a hydrogen atom or a fluorine atom.

[0194] R 7a represents a hydrogen atom, a methyl group, a methoxy group or a cyclopropyl group.

[0195] R 7b It represents a hydrogen atom, a methyl group, or a methoxy group.

[0196] It should be noted that R 6 When it is a hydrogen atom, R 7a represents methoxy or cyclopropyl; R 7a When it is methyl, R 6 is a fluorine atom; R 7a When it is cyclopropyl, R 6 is a hydrogen atom. 〕

[0197] (11) The compound according to (2) or a pharmacologically acceptable salt thereof, which is selected from the group consisting of the following compounds:

[0198] N-((1H-imidazol-4-yl)methyl)-[2,3'-bithiophene]-4'-amine;

[0199] N-((1H-imidazol-4-yl)methyl)-[2,2'-bithiophene]-3-amine;

[0200] N-((1H-imidazol-4-yl)methyl)-4-(pyridin-3-yl)thiophen-3-amine;

[0201] N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-3-yl)thiophen-3-amine;

[0202] N-((1H-imidazol-4-yl)methyl)-4-(5-methoxypyridin-3-yl)thiophen-3-amine;

[0203] N-((1H-imidazol-4-yl)methyl)-4-(5-fluoropyridin-3-yl)thiophen-3-amine;

[0204] N-((1H-imidazol-4-yl)methyl)-2-(pyridin-3-yl)thiophen-3-amine;

[0205] N-((1H-imidazol-4-yl)methyl)-4-(1H-pyrazol-5-yl)thiophen-3-amine;

[0206] N-((1H-imidazol-4-yl)methyl)-2-(pyridin-3-yl)aniline;

[0207] N-((1H-imidazol-4-yl)methyl)-2-(pyrimidin-5-yl)aniline;

[0208] N-((1H-imidazol-4-yl)methyl)-2-(thiazol-5-yl)aniline;

[0209] N-((1H-imidazol-4-yl)methyl)-4-(thiazol-2-yl)thiophen-3-amine;

[0210] N-((1H-imidazol-4-yl)methyl)-4-(pyrazin-2-yl)thiophen-3-amine;

[0211] N-((1H-imidazol-4-yl)methyl)-4-(thiazol-4-yl)thiophen-3-amine;

[0212] N-((1H-imidazol-4-yl)methyl)-2-(thiazol-4-yl)aniline;

[0213] N-((1H-imidazol-4-yl)methyl)-4-(3-methylpyridin-2-yl)thiophen-3-amine;

[0214] N-((1H-imidazol-4-yl)methyl)-4-(3-methoxypyridin-2-yl)thiophen-3-amine;

[0215] N-((1H-imidazol-4-yl)methyl)-4-(4-methylthiazol-5-yl)thiophen-3-amine;

[0216] N-((1H-imidazol-4-yl)methyl)-2-(4-methylpyrimidin-5-yl)aniline;

[0217] N-((1H-imidazol-4-yl)methyl)-5-methyl-2-(4-methylpyrimidin-5-yl)aniline;

[0218] N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-2-yl)thiophen-3-amine;

[0219] N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyridin-2-yl)thiophen-3-amine;

[0220] N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyrimidin-5-yl)thiophen-3-amine;

[0221] N-((1H-imidazol-4-yl)methyl)-4-(5-methylthiazol-4-yl)thiophen-3-amine;

[0222] N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(4-methylpyrimidin-5-yl)aniline;

[0223] N-((1H-imidazol-4-yl)methyl)-2-(pyrazin-2-yl)aniline;

[0224] N-((1H-imidazol-4-yl)methyl)-2-(pyridin-2-yl)aniline;

[0225] N-((1H-imidazol-4-yl)methyl)-2-(3-methoxypyridin-2-yl)aniline;

[0226] N-((1H-imidazol-4-yl)methyl)-4-(3-fluoropyridin-2-yl)thiophen-3-amine;

[0227] N-((1H-imidazol-4-yl)methyl)-4-(pyridin-2-yl)thiophen-3-amine;

[0228] N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyrazin-2-yl)thiophen-3-amine;

[0229] N-((1H-imidazol-4-yl)methyl)-2-(6-methoxypyridin-2-yl)aniline;

[0230] N-((1H-imidazol-4-yl)methyl)-2-(3-methoxy-1H-pyrazol-4-yl)-5-methylaniline;

[0231] N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(3-methoxy-1H-pyrazol-4-yl)aniline;

[0232] (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(pyridin-3-yl)aniline;

[0233] (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(6-methoxypyridin-2-yl)aniline;

[0234] (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(thiazol-4-yl)aniline;

[0235] N-((1H-imidazol-4-yl)methyl)-4-(furan-3-yl)thiophen-3-amine;

[0236] N-((1H-imidazol-4-yl)methyl)-4-(pyrimidin-5-yl)thiophen-3-amine;

[0237] N-((1H-imidazol-4-yl)methyl)-4-(2-methoxypyridin-3-yl)thiophen-3-amine;

[0238] 4-((2-(Thien-3-yl)phenoxy)methyl)-1H-imidazole;

[0239] 4-((2-(Furan-2-yl)phenoxy)methyl)-1H-imidazole;

[0240] 4-((2-(Thien-2-yl)phenoxy)methyl)-1H-imidazole;

[0241] 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole;

[0242] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyridine;

[0243] 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-3-methyl-1H-pyrazole;

[0244] 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole-3-carbonitrile;

[0245] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoropyridine;

[0246] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-2-methoxypyridine;

[0247] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-methoxypyridine;

[0248] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyridine;

[0249] 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole;

[0250] 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole-3-carbonitrile;

[0251] 3-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-4-methylpyridine;

[0252] 4-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-3-methyl-1H-pyrazole;

[0253] 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-3-methyl-1H-pyrazole;

[0254] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methylpyridine;

[0255] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-2-methoxypyridine;

[0256] 3-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-4-methoxypyridine;

[0257] 3-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-4-methoxypyridine;

[0258] 5-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-4-methylpyrimidine;

[0259] 5-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-4-methylpyrimidine;

[0260] 2-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)pyrazine;

[0261] 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole;

[0262] 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrazine;

[0263] 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrimidine;

[0264] 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole;

[0265] 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole;

[0266] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methylpyridine;

[0267] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-cyclopropylpyridine;

[0268] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methoxypyridine;

[0269] 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyrimidine;

[0270] 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methylpyrimidine;

[0271] 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)-6-methoxypyrazine;

[0272] (+)-4-(1-(2-(thiophen-2-yl)phenoxy)ethyl)-1H-imidazole;

[0273] 3-(2-(((1H-imidazol-4-yl)methyl)thio)phenyl)pyridine;

[0274] 4-(2-(((1H-imidazol-4-yl)methyl)thio)phenyl)-1H-pyrazole; and

[0275] 4-(((2-(Thien-3-yl)phenyl)thio)methyl)-1H-imidazole.

[0276] (12) The compound according to (4) or a pharmacologically acceptable salt thereof, which is selected from the group consisting of the following compounds:

[0277] N-((1H-imidazol-4-yl)methyl)-[2,3'-bithiophene]-4'-amine;

[0278] N-((1H-imidazol-4-yl)methyl)-[2,2'-bithiophene]-3-amine;

[0279] N-((1H-imidazol-4-yl)methyl)-4-(pyridin-3-yl)thiophen-3-amine;

[0280] N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-3-yl)thiophen-3-amine;

[0281] N-((1H-imidazol-4-yl)methyl)-4-(5-methoxypyridin-3-yl)thiophen-3-amine;

[0282] N-((1H-imidazol-4-yl)methyl)-4-(5-fluoropyridin-3-yl)thiophen-3-amine;

[0283] N-((1H-imidazol-4-yl)methyl)-2-(pyridin-3-yl)thiophen-3-amine;

[0284] N-((1H-imidazol-4-yl)methyl)-4-(1H-pyrazol-5-yl)thiophen-3-amine;

[0285] N-((1H-imidazol-4-yl)methyl)-2-(pyridin-3-yl)aniline;

[0286] N-((1H-imidazol-4-yl)methyl)-2-(pyrimidin-5-yl)aniline;

[0287] N-((1H-imidazol-4-yl)methyl)-2-(thiazol-5-yl)aniline;

[0288] N-((1H-imidazol-4-yl)methyl)-4-(thiazol-2-yl)thiophen-3-amine;

[0289] N-((1H-imidazol-4-yl)methyl)-4-(pyrazin-2-yl)thiophen-3-amine;

[0290] N-((1H-imidazol-4-yl)methyl)-4-(thiazol-4-yl)thiophen-3-amine;

[0291] N-((1H-imidazol-4-yl)methyl)-2-(thiazol-4-yl)aniline;

[0292] N-((1H-imidazol-4-yl)methyl)-4-(3-methoxypyridin-2-yl)thiophen-3-amine;

[0293] N-((1H-imidazol-4-yl)methyl)-4-(4-methylthiazol-5-yl)thiophen-3-amine;

[0294] N-((1H-imidazol-4-yl)methyl)-2-(4-methylpyrimidin-5-yl)aniline;

[0295] N-((1H-imidazol-4-yl)methyl)-5-methyl-2-(4-methylpyrimidin-5-yl)aniline;

[0296] N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-2-yl)thiophen-3-amine;

[0297] N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyridin-2-yl)thiophen-3-amine;

[0298] N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyrimidin-5-yl)thiophen-3-amine;

[0299] N-((1H-imidazol-4-yl)methyl)-4-(5-methylthiazol-4-yl)thiophen-3-amine;

[0300] N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(4-methylpyrimidin-5-yl)aniline;

[0301] N-((1H-imidazol-4-yl)methyl)-2-(pyrazin-2-yl)aniline;

[0302] N-((1H-imidazol-4-yl)methyl)-2-(pyridin-2-yl)aniline;

[0303] N-((1H-imidazol-4-yl)methyl)-4-(3-fluoropyridin-2-yl)thiophen-3-amine;

[0304] N-((1H-imidazol-4-yl)methyl)-4-(pyridin-2-yl)thiophen-3-amine;

[0305] N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyrazin-2-yl)thiophen-3-amine;

[0306] N-((1H-imidazol-4-yl)methyl)-2-(6-methoxypyridin-2-yl)aniline;

[0307] N-((1H-imidazol-4-yl)methyl)-2-(3-methoxy-1H-pyrazol-4-yl)-5-methylaniline;

[0308] N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(3-methoxy-1H-pyrazol-4-yl)aniline;

[0309] (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(pyridin-3-yl)aniline;

[0310] (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(6-methoxypyridin-2-yl)aniline;

[0311] (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(thiazol-4-yl)aniline;

[0312] N-((1H-imidazol-4-yl)methyl)-4-(furan-3-yl)thiophen-3-amine;

[0313] N-((1H-imidazol-4-yl)methyl)-4-(2-methoxypyridin-3-yl)thiophen-3-amine;

[0314] 4-((2-(Thien-3-yl)phenoxy)methyl)-1H-imidazole;

[0315] 4-((2-(Thien-2-yl)phenoxy)methyl)-1H-imidazole;

[0316] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyridine;

[0317] 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-3-methyl-1H-pyrazole;

[0318] 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole-3-carbonitrile;

[0319] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoropyridine;

[0320] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-2-methoxypyridine;

[0321] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyridine;

[0322] 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole;

[0323] 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole-3-carbonitrile;

[0324] 4-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-3-methyl-1H-pyrazole;

[0325] 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-3-methyl-1H-pyrazole;

[0326] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methylpyridine;

[0327] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-2-methoxypyridine;

[0328] 3-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-4-methoxypyridine;

[0329] 3-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-4-methoxypyridine;

[0330] 5-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-4-methylpyrimidine;

[0331] 2-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)pyrazine;

[0332] 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole;

[0333] 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrazine;

[0334] 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrimidine;

[0335] 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole;

[0336] 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole;

[0337] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-cyclopropylpyridine;

[0338] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methoxypyridine;

[0339] 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyrimidine;

[0340] 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methylpyrimidine;

[0341] 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)-6-methoxypyrazine;

[0342] (+)-4-(1-(2-(thiophen-2-yl)phenoxy)ethyl)-1H-imidazole; and

[0343] 3-(2-(((1H-imidazol-4-yl)methyl)sulfanyl)phenyl)pyridine.

[0344] (13) The compound according to (5) or a pharmacologically acceptable salt thereof, which is selected from the group consisting of the following compounds:

[0345] N-((1H-imidazol-4-yl)methyl)-[2,3'-bithiophene]-4'-amine;

[0346] N-((1H-imidazol-4-yl)methyl)-[2,2'-bithiophene]-3-amine;

[0347] N-((1H-imidazol-4-yl)methyl)-4-(pyridin-3-yl)thiophen-3-amine;

[0348] N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-3-yl)thiophen-3-amine;

[0349] N-((1H-imidazol-4-yl)methyl)-4-(5-methoxypyridin-3-yl)thiophen-3-amine;

[0350] N-((1H-imidazol-4-yl)methyl)-4-(5-fluoropyridin-3-yl)thiophen-3-amine;

[0351] N-((1H-imidazol-4-yl)methyl)-4-(1H-pyrazol-5-yl)thiophen-3-amine;

[0352] N-((1H-imidazol-4-yl)methyl)-2-(pyridin-3-yl)aniline;

[0353] N-((1H-imidazol-4-yl)methyl)-2-(thiazol-5-yl)aniline;

[0354] N-((1H-imidazol-4-yl)methyl)-4-(thiazol-2-yl)thiophen-3-amine;

[0355] N-((1H-imidazol-4-yl)methyl)-4-(pyrazin-2-yl)thiophen-3-amine;

[0356] N-((1H-imidazol-4-yl)methyl)-4-(thiazol-4-yl)thiophen-3-amine;

[0357] N-((1H-imidazol-4-yl)methyl)-2-(thiazol-4-yl)aniline;

[0358] N-((1H-imidazol-4-yl)methyl)-4-(3-methoxypyridin-2-yl)thiophen-3-amine;

[0359] N-((1H-imidazol-4-yl)methyl)-5-methyl-2-(4-methylpyrimidin-5-yl)aniline;

[0360] N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-2-yl)thiophen-3-amine;

[0361] N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyridin-2-yl)thiophen-3-amine;

[0362] N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyrimidin-5-yl)thiophen-3-amine;

[0363] N-((1H-imidazol-4-yl)methyl)-4-(5-methylthiazol-4-yl)thiophen-3-amine;

[0364] N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(4-methylpyrimidin-5-yl)aniline;

[0365] N-((1H-imidazol-4-yl)methyl)-2-(pyrazin-2-yl)aniline;

[0366] N-((1H-imidazol-4-yl)methyl)-2-(pyridin-2-yl)aniline;

[0367] N-((1H-imidazol-4-yl)methyl)-4-(3-fluoropyridin-2-yl)thiophen-3-amine;

[0368] N-((1H-imidazol-4-yl)methyl)-4-(pyridin-2-yl)thiophen-3-amine;

[0369] N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyrazin-2-yl)thiophen-3-amine;

[0370] N-((1H-imidazol-4-yl)methyl)-2-(6-methoxypyridin-2-yl)aniline;

[0371] N-((1H-imidazol-4-yl)methyl)-2-(3-methoxy-1H-pyrazol-4-yl)-5-methylaniline;

[0372] N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(3-methoxy-1H-pyrazol-4-yl)aniline;

[0373] (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(pyridin-3-yl)aniline;

[0374] (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(6-methoxypyridin-2-yl)aniline;

[0375] (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(thiazol-4-yl)aniline;

[0376] N-((1H-imidazol-4-yl)methyl)-4-(2-methoxypyridin-3-yl)thiophen-3-amine;

[0377] 4-((2-(Thien-3-yl)phenoxy)methyl)-1H-imidazole;

[0378] 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole-3-carbonitrile;

[0379] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoropyridine;

[0380] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyridine;

[0381] 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole;

[0382] 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole-3-carbonitrile;

[0383] 4-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-3-methyl-1H-pyrazole;

[0384] 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-3-methyl-1H-pyrazole;

[0385] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methylpyridine;

[0386] 3-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-4-methoxypyridine;

[0387] 2-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)pyrazine;

[0388] 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole;

[0389] 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrazine;

[0390] 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrimidine;

[0391] 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole;

[0392] 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole;

[0393] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-cyclopropylpyridine;

[0394] 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methoxypyridine;

[0395] 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyrimidine;

[0396] 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methylpyrimidine; and

[0397] 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)-6-methoxypyrazine.

[0398] (14) A pharmaceutical composition comprising the compound according to any one of (1) to (13) or a pharmacologically acceptable salt thereof as an active ingredient.

[0399] (15) The pharmaceutical composition according to (14), which is used for preventing or treating a disease selected from the group consisting of orthostatic hypotension, essential hypotension, acute hypotension associated with various diseases or conditions, and urinary incontinence.

[0400] (16) The compound according to any one of (1) to (13) or a pharmacologically acceptable salt thereof, which is used for preventing or treating a disease selected from the group consisting of orthostatic hypotension, essential hypotension, acute hypotension associated with various diseases or conditions, and urinary incontinence.

[0401] (17) Use of the compound described in any one of (1) to (13) or a pharmacologically acceptable salt thereof in the manufacture of a medicament for preventing or treating a disease selected from the group consisting of orthostatic hypotension, essential hypotension, acute hypotension associated with various diseases or conditions, and urinary incontinence.

[0402] (18) A method for preventing or treating a disease selected from the group consisting of orthostatic hypotension, essential hypotension, acute hypotension associated with various diseases or conditions, and urinary incontinence, comprising administering a therapeutically effective amount of the compound or pharmacologically acceptable salt thereof described in any one of (1) to (13) to a subject in need thereof.

[0403] Effects of the Invention

[0404] The compound of the present invention has an excellent adrenaline α1A receptor agonist activity and is useful as a preventive or therapeutic drug for orthostatic hypotension, essential hypotension, acute hypotension associated with various diseases or conditions, and urinary incontinence. DETAILED DESCRIPTION

[0405] In the present specification, each term is defined as follows.

[0406] The "C1-C3 alkyl group" refers to a linear or branched alkyl group consisting of 1 to 3 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, and isopropyl.

[0407] The "C1-C3 alkoxy group" specifically refers to an -O-(C1-C3 alkyl) group, and examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy and the like.

[0408] The "C1-C6 alkyl group" refers to a linear alkyl group consisting of 1 to 6 carbon atoms.

[0409] The compounds of the present invention are described below.

[0410] [Chemical formula 33]

[0411]

[0412] The compound of the present invention is a compound represented by the above general formula (I) wherein R 1 and Z is a compound as defined below or a pharmacologically acceptable salt thereof.

[0413] R 1 It is a hydrogen atom or a C1-C3 alkyl group.

[0414] Z is selected from the group consisting of the following formulae.

[0415] [Chemical formula 34]

[0416]

[0417] 〔In the formula, R 2 It represents a hydrogen atom, a fluorine atom or a C1-C3 alkyl group.

[0418] R 3 Select from the group consisting of the following formulae.

[0419] [Chemical formula 35]

[0420]

[0421] Y represents an oxygen atom or a sulfur atom.

[0422] R 4 Each independently represents a hydrogen atom or a C1-C3 alkoxy group.

[0423] R 5 It represents a hydrogen atom, a fluorine atom, a C1-C3 alkyl group or a C1-C3 alkoxy group.

[0424] R 6 It represents a hydrogen atom, a fluorine atom or a C1-C3 alkoxy group.

[0425] R 7 It represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyclopropyl group.

[0426] R 8 It represents a hydrogen atom or a C1-C3 alkoxy group.

[0427] R 9 It represents a hydrogen atom or a C1-C3 alkyl group.

[0428] R 10 It represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyano group.

[0429] It should be noted that R 6 When it is C1-C3 alkoxy, R 7 and R 8 is a hydrogen atom; R 8 When it is C1-C3 alkoxy, R 6 is a hydrogen atom or a fluorine atom, R 7 is a hydrogen atom.

[0430] Preferably, when Z is

[0431] [Chemical formula 36]

[0432] ,

[0433] R 2 When it is a hydrogen atom, R 3 It is not 3-fluoropyridine bonded at the 2-position;

[0434] In addition, Z is

[0435] [Chemical formula 37]

[0436]

[0437] , R 2 When it is a hydrogen atom, R 3 It is not any of unsubstituted pyridine bonded at the 2-position, unsubstituted pyrazole bonded at the 3-position, or 3-methoxypyrazole bonded at the 4-position;

[0438] In addition, Z is

[0439] [Chemical formula 38]

[0440] ,

[0441] R 2 When it is a hydrogen atom, R 3 It is not an unsubstituted furan bonded at the 2-position;

[0442] In addition, Z is

[0443] [Chemical formula 39]

[0444] ,

[0445] R 1 is C1~C3 alkyl and R 2 When it is a hydrogen atom, R 3 It is not an unsubstituted pyrazole bonded at the 4-position;

[0446] In addition, Z is

[0447] [Chemical formula 40]

[0448]

[0449] When R 3 It is not an unsubstituted thiazole bonded at the 5-position.

[0450] In the present invention, in the above R 3 Among them, a group selected from the group consisting of the following formulae is preferred.

[0451] [Chemical formula 41]

[0452]

[0453] [In the formula, Y represents an oxygen atom or a sulfur atom.

[0454] R 4 Each independently represents a hydrogen atom or a C1-C3 alkoxy group.

[0455] R 5 It represents a hydrogen atom, a fluorine atom or a C1-C3 alkoxy group.

[0456] R 6 It represents a hydrogen atom, a fluorine atom or a C1-C3 alkoxy group.

[0457] R 7 It represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyclopropyl group.

[0458] R 8 It represents a hydrogen atom or a C1-C3 alkoxy group.

[0459] R 9 It represents a hydrogen atom or a C1-C3 alkyl group.

[0460] R 10 It represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyano group.

[0461] It should be noted that R 6 When it is C1-C3 alkoxy, R 7 and R 8 is a hydrogen atom; R 8 When it is C1-C3 alkoxy, R 6 is a hydrogen atom or a fluorine atom, R 7 A hydrogen atom.

[0462] Among them, Z is

[0463] [Chemical formula 42]

[0464]

[0465] When R 3 Not bonded at position 4 and position 3 is R 9 Any one of substituted thiophene, pyridine bonded at the 3-position and substituted by a C1-C3 alkyl group at the 4-position, or unsubstituted pyrazole bonded at the 4-position;

[0466] In addition, Z is

[0467] [Chemical formula 43]

[0468]

[0469] When R 3 Not bonded at position 4 and position 3 is R 9 Any one of substituted thiophene, pyridine bonded at the 3-position and substituted by a C1-C3 alkyl group at the 4-position, unsubstituted pyrazole bonded at the 4-position, unsubstituted pyrimidine bonded at the 5-position, or pyrimidine bonded at the 5-position and substituted by a C1-C3 alkyl group at the 4-position;

[0470] In addition, Z is

[0471] [Chemical formula 44]

[0472] ,

[0473] R 2 When it is C1~C3 alkyl, R 3 Not bonded at position 4 and position 3 is R 9 Any one of substituted thiophene, unsubstituted pyrimidine bonded at the 5-position, or pyrimidine bonded at the 5-position and substituted at the 4-position by a C1-C3 alkyl group;

[0474] In addition, Z is the same as above, R 2 When it is a hydrogen atom, R 3 It is not pyridine bonded at the 3-position and substituted by a C1-C3 alkyl group at the 4-position, or unsubstituted pyrazole bonded at the 4-position;

[0475] In addition, Z is the same as above, R 1 is C1~C3 alkyl and R 2 When it is a hydrogen atom, R 3 It is not 4-cyclopropylpyridine bonded at the 3-position or unsubstituted pyrimidine bonded at the 5-position;

[0476] In addition, Z is

[0477] [Chemical formula 45]

[0478]

[0479] When R 3 Not bonded at position 4 and position 3 is R 9 Any one of substituted thiophene, pyridine bonded at the 3-position and substituted by a C1-C3 alkyl group at the 4-position, unsubstituted pyrazole bonded at the 4-position, unsubstituted pyrimidine bonded at the 5-position, or pyrimidine bonded at the 5-position and substituted by a C1-C3 alkyl group at the 4-position.

[0480] In the present invention, in the above R 3 Among them, a group selected from the group consisting of the following formulae is more preferred.

[0481] [Chemical formula 46]

[0482]

[0483] [In the formula, Y represents an oxygen atom or a sulfur atom.

[0484] R 4 Each independently represents a hydrogen atom or a C1-C3 alkoxy group.

[0485] R 5 It represents a hydrogen atom, a fluorine atom or a C1-C3 alkoxy group.

[0486] R 6 It represents a hydrogen atom, a fluorine atom or a C1-C3 alkoxy group.

[0487] R 7a It represents a hydrogen atom, a C1-C3 alkoxy group or a cyclopropyl group.

[0488] R 7b It represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyclopropyl group.

[0489] R 8It represents a hydrogen atom or a C1-C3 alkoxy group.

[0490] R 9 It represents a hydrogen atom or a C1-C3 alkyl group.

[0491] R 10 It represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyano group.

[0492] It should be noted that R 6 When it is C1-C3 alkoxy, R 7 and R 8 is a hydrogen atom; R 8 When it is C1-C3 alkoxy, R 6 is a hydrogen atom or a fluorine atom, R 7 A hydrogen atom.

[0493] Among them, Z is

[0494] [Chemical formula 47]

[0495]

[0496] When R 3 It is not any of pyridine bonded at the 2-position and substituted by a C1-C3 alkoxy group at the 3-position, or pyridine bonded at the 5-position and substituted by a C1-C3 alkoxy group at the 3-position.

[0497] In the present invention, further, in the above R 3 Among them, a group selected from the group consisting of the following formulae is more preferred.

[0498] [Chemical formula 48]

[0499]

[0500] 〔In the formula, R 4 Each independently represents a hydrogen atom or a methoxy group.

[0501] R 5 represents a hydrogen atom, a fluorine atom or a methoxy group.

[0502] R 6 represents a hydrogen atom, a fluorine atom or a methoxy group.

[0503] R 7a represents a hydrogen atom, a methoxy group or a cyclopropyl group.

[0504] R 7b represents a hydrogen atom, a methyl group or a methoxy group.

[0505] R 8 represents a hydrogen atom or a methoxy group.

[0506] R9 represents a hydrogen atom or a methyl group.

[0507] R 10 It represents a hydrogen atom, a methyl group, a methoxy group or a cyano group.

[0508] It should be noted that R 6 When it is methoxy, R 7a and R 8 is a hydrogen atom; R 6 When it is a fluorine atom, R 8 is a hydrogen atom; R 8 When it is methoxy, R 6 is a hydrogen atom or a fluorine atom, R 7a A hydrogen atom.

[0509] Among them, Z is

[0510] [Chemical formula 49]

[0511]

[0512] When R 3 It is not 3-methylpyrazole bonded at the 4-position;

[0513] In addition, Z is

[0514] [Chemical formula 50]

[0515]

[0516] When R 3 is not any of unsubstituted pyridine bonded at the 3-position, 3-methylpyrazole bonded at the 4-position, 2-methoxypyridine bonded at the 3-position, 4-methoxypyridine bonded at the 3-position, or unsubstituted thiophene bonded at the 2-position;

[0517] In addition, Z is

[0518] [Chemical formula 51]

[0519]

[0520] When R 3 is not any of unsubstituted pyrimidine bonded at the 5-position, 3-methylpyrazole bonded at the 4-position, 2-methoxypyridine bonded at the 3-position, 4-methoxypyridine bonded at the 3-position, or unsubstituted thiophene bonded at the 2-position;

[0521] In addition, Z is

[0522] [Chemical formula 52]

[0523] ,

[0524] R2 When it is methyl, R 3 is not any of unsubstituted pyridine bonded at the 3-position, 2-methoxypyridine bonded at the 3-position, 4-methoxypyridine bonded at the 3-position, or unsubstituted thiophene bonded at the 2-position;

[0525] In addition, Z is the same as above, R 2 When it is a hydrogen atom, R 3 It is not any of unsubstituted pyridine bonded at the 3-position, 3-methylpyrazole bonded at the 4-position, or unsubstituted thiophene bonded at the 2-position;

[0526] In addition, Z is the same as above, R 2 When it is a fluorine atom, R 3 is not any of unsubstituted pyridine bonded at the 3-position, 4-methylpyrimidine bonded at the 5-position, 2-methoxypyridine bonded at the 3-position, or unsubstituted thiophene bonded at the 2-position;

[0527] In addition, Z is

[0528] [Chemical formula 53]

[0529]

[0530] When R 3 It is not any of unsubstituted pyridine bonded at the 3-position, 3-methylpyrazole bonded at the 4-position, 2-methoxypyridine bonded at the 3-position, 4-methoxypyridine bonded at the 3-position, or unsubstituted thiophene bonded at the 2-position.

[0531] In the present invention, in the above R 3 Among them, groups selected from the group consisting of the following formulae are particularly preferred.

[0532] [Chemical formula 54]

[0533]

[0534] 〔In the formula, R 4 Each independently represents a hydrogen atom or a methoxy group.

[0535] R 5 represents a hydrogen atom, a fluorine atom or a methoxy group.

[0536] R 6 represents a hydrogen atom, a fluorine atom or a methoxy group.

[0537] R 7a represents a hydrogen atom, a methoxy group or a cyclopropyl group.

[0538] R 7b Represents methoxy.

[0539] R8 represents a hydrogen atom or a methoxy group.

[0540] R 9 represents a hydrogen atom or a methyl group.

[0541] It should be noted that R 6 When it is methoxy, R 7a and R 8 is a hydrogen atom; R 6 When it is a fluorine atom, R 8 is a hydrogen atom; R 7a When it is methoxy, R 6 is a fluorine atom, R 8 A hydrogen atom.

[0542] Among them, Z is

[0543] [Chemical formula 55]

[0544]

[0545] When R 3 It is not an unsubstituted pyridine bonded at the 3-position. ]

[0546] In one embodiment of the present invention, Z is a structure selected from the group consisting of the following formulae:

[0547] [Chemical formula 56]

[0548]

[0549] Among them, the structure of the following formula is preferred.

[0550] [Chemical formula 57]

[0551]

[0552] Here, R 2 It represents a hydrogen atom, a fluorine atom or a C1-C3 alkyl group.

[0553] In addition, R 3 Preferred are groups selected from the group consisting of the following formulae.

[0554] [Chemical formula 58]

[0555]

[0556] 〔In the formula, R 4 represents a hydrogen atom or a methoxy group. ]

[0557] In another embodiment of the present invention, Z is the following formula.

[0558] [Chemical formula 59]

[0559]

[0560] Here, R 3 Preferred are groups selected from the group consisting of the following formulae.

[0561] [Chemical formula 60]

[0562]

[0563] 〔In the formula, R 4 represents a hydrogen atom or a methoxy group.

[0564] R 6 represents a hydrogen atom or a fluorine atom.

[0565] R 7a represents a hydrogen atom, a methyl group, a methoxy group or a cyclopropyl group.

[0566] R 7b represents a hydrogen atom, a methyl group or a methoxy group.

[0567] It should be noted that R 6 When it is a hydrogen atom, R 7a represents methoxy or cyclopropyl; R 7a When it is methyl, R 6 is a fluorine atom; R 7a When it is cyclopropyl, R 6 is a hydrogen atom.

[0568] In the present invention, compounds with strong α1A agonist activity are preferred. 3 , compounds with strong α1A agonist effect can be obtained.

[0569] In addition, R is excluded from the scope of the present invention. 1 The enantiomer of the two enantiomers produced when the alkyl group is C1 to C3 is the enantiomer with weaker α1A agonism than 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole (Example 47). The enantiomer with weaker α1A agonism than 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole (Example 47) is, for example, the enantiomer with weaker α1A agonism than 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole (Example 47) in the test of the pharmacological test examples of this specification. 50 In a preferred embodiment of the present invention, excluding R 1 When the alkyl group is C1-C3, the enantiomer with the weaker α1A agonism is the one produced. It should be noted that the enantiomer with an optical rotation of (+) usually has a stronger α1A agonism than the enantiomer with an optical rotation of (-). That is, in a preferred embodiment of the present invention, R 1Of the two enantiomers produced when the group is a C1-C3 alkyl group, the enantiomer with an optical rotation of (+) is included in the present invention, while the enantiomer with an optical rotation of (-) is not included in the present invention.

[0570] The pharmacologically acceptable salts of the compounds of the present invention shown in general formula (I) are included in the scope of the present invention. As pharmacologically acceptable salts, salts with amino acids (e.g., salts with aspartic acid, glutamic acid, etc.), salts with inorganic acids (e.g., salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, etc.), salts with organic acids (e.g., salts with formic acid, acetic acid, trifluoroacetic acid, etc.), etc. can be cited. The formation reaction of these salts can be carried out according to conventional methods.

[0571] Compounds that are converted to compounds represented by the general formula (I) by reactions such as enzymes and gastric acid under physiological conditions in vivo are within the scope of the present invention. Examples include compounds represented by the general formula (I) in which the imidazole group is amidated (e.g., acetamidate).

[0572] The compound represented by the general formula (I) of the compound of the present invention can be manufactured by the method represented by the following reaction steps formula I to IX, the method described in the examples, or the method combining the known methods. It should be noted that the compound used as the starting material or reagent necessary for manufacturing the compound of the present invention without clearly describing the manufacturing method can be obtained as a commercial product or can be manufactured with reference to the known methods.

[0573] Reaction step formula I is R of general formula (I) 1 A method for producing a compound (4) wherein Z is a hydrogen atom and is bonded via a nitrogen atom.

[0574] [Reaction Step Formula I]

[0575] [Chemical formula 61]

[0576]

[0577] In the formula, ring A represents a ring selected from the group consisting of the following formulae.

[0578] [Chemical formula 62]

[0579]

[0580] 〔In the formula, R 2 represents a hydrogen atom, a fluorine atom or a C1-C3 alkyl group. ]

[0581] In addition, the ring B in the above formula represents a ring selected from the group consisting of the following formulae.

[0582] [Chemical formula 63]

[0583]

[0584] [In the formula, Y represents an oxygen atom or a sulfur atom.

[0585] R 4 Each independently represents a hydrogen atom or a C1-C3 alkoxy group.

[0586] R 5 It represents a hydrogen atom, a fluorine atom, a C1-C3 alkyl group or a C1-C3 alkoxy group.

[0587] R 6 It represents a hydrogen atom, a fluorine atom or a C1-C3 alkoxy group.

[0588] R 7 It represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyclopropyl group.

[0589] R 8 It represents a hydrogen atom or a C1-C3 alkoxy group.

[0590] R 9 It represents a hydrogen atom or a C1-C3 alkyl group.

[0591] R 10 It represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyano group.

[0592] It should be noted that R 6 When it is C1-C3 alkoxy, R 7 and R 8 is a hydrogen atom; R 8 When it is C1-C3 alkoxy, R 6 is a hydrogen atom or a fluorine atom, R 7 is a hydrogen atom.

[0593] [Step I-1]

[0594] The compound represented by the general formula (1) is reacted with 4-formyl imidazole (2) in a suitable solvent (such as N,N-dimethylacetamide, methanol, tetrahydrofuran, toluene, dichloromethane or a mixed solvent thereof) using an additive (such as acetic acid, triethylamine, tetraisopropyl titanate, etc.) to obtain a compound represented by the general formula (3). The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[0595] [Step I-2]

[0596] The compound of general formula (3) is reacted in a suitable solvent (e.g., N,N-dimethylacetamide, methanol, tetrahydrofuran, toluene, dichloromethane or a mixed solvent thereof) using a reducing agent (e.g., sodium borohydride, sodium triacetoxyborohydride, etc.) to obtain a compound represented by general formula (4). The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours. It should be noted that step I-1 and step I-2 can be carried out continuously without separation and purification after step I-1, or the reaction can be carried out in a one-pot manner.

[0597] Reaction step II is R of general formula (I) 1 A method for producing a compound (9) in which a C1-C3 alkyl group is bonded to Z via a nitrogen atom.

[0598] [Reaction Step Formula II]

[0599] [Chemical formula 64]

[0600]

[0601] [In the formula, ring A and ring B represent the same rings as those in reaction step formula I.

[0602] PG 1 It represents a protecting group for imidazolyl.

[0603] R 1 It represents a C1-C3 alkyl group.

[0604] X 1 represents a bromine atom or a chlorine atom. ]

[0605] [Step II-1]

[0606] The compound represented by the general formula (1) is reacted with the compound represented by the general formula (5) in a suitable solvent (such as N,N-dimethylacetamide, methanol, tetrahydrofuran, toluene, dichloromethane or a mixed solvent thereof) using an additive (such as acetic acid, p-toluenesulfonic acid, triethylamine, tetraisopropyl titanate, molecular sieves, etc.) to obtain the compound represented by the general formula (6). The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[0607] [Step II-2]

[0608] The compound represented by the general formula (6) is reacted with a Grignard reagent (such as methylmagnesium bromide) (7) in a suitable solvent (such as tetrahydrofuran) to obtain a compound represented by the general formula (8). The reaction temperature is 0°C to the boiling point of the solvent and the reaction time is 30 minutes to 24 hours.

[0609] [Step II-3]

[0610] The protecting group of the compound represented by the general formula (8) is removed by referring to the method described in "Protecting Groups in Organic Synthesis, 5th Edition, Wiley (2014)", thereby obtaining the compound represented by the general formula (9).

[0611] The compound represented by the general formula (1) used as the starting material in reaction steps I and II can be produced by the method represented by the following reaction step III, the method described in the reference examples, or a method combining known methods.

[0612] [Reaction Step Formula III]

[0613] [Chemical formula 65]

[0614]

[0615] 〔In the formula, PG 2 It represents a protecting group for an amino group or a hydrogen atom.

[0616] Ring A and ring B represent the same rings as those in reaction step formula I.

[0617] M 1 Indicates -B(OH)2 or

[0618] [Chemical formula 66]

[0619]

[0620] M 2 It represents a tri-C1-C6 alkyltin group.

[0621] X 2 represents a bromine atom or an iodine atom. ]

[0622] It should be noted that PG 2 When it is a hydrogen atom, compound (1) can be obtained without going through the compound represented by general formula (13) and step III-5.

[0623] [Step III-1]

[0624] The compound represented by the general formula (10) and the compound represented by the general formula (11) are reacted in a suitable solvent (e.g., dioxane, water, a mixed solvent of dioxane and water, etc.) in the presence of a base (e.g., potassium carbonate, sodium carbonate, potassium phosphate, etc.) using a palladium catalyst (e.g., palladium acetate, palladium chloride, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, tetrakis(triphenylphosphine)palladium, 1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium, etc.), thereby obtaining a compound represented by the general formula (13). The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[0625] [Step III-2]

[0626] The compound represented by the general formula (10) is reacted with the compound represented by the general formula (12) in a suitable solvent (e.g., dioxane, toluene, etc.) using a palladium catalyst (e.g., tetrakis(triphenylphosphine)palladium, etc.) in the presence or absence of an additive (e.g., potassium fluoride, etc.), thereby obtaining the compound represented by the general formula (13). The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[0627] [Step III-3]

[0628] The compound represented by the general formula (10) is reacted with bis(pinacolato)diboron (14) in a suitable solvent (e.g. dioxane) in the presence of a base (e.g. potassium acetate) using a palladium catalyst (e.g. tetrakis(triphenylphosphine)palladium, etc.) to obtain a compound represented by the general formula (15). The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[0629] [Step III-4]

[0630] The compound represented by the general formula (15) and the compound represented by the general formula (16) are reacted in a suitable solvent (e.g., dioxane, water, a mixed solvent of dioxane and water, etc.) in the presence of a base (e.g., potassium carbonate, sodium carbonate, potassium phosphate, etc.) using a palladium catalyst (e.g., palladium acetate, palladium chloride, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, tetrakis(triphenylphosphine)palladium, 1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium, etc.), thereby obtaining the compound represented by the general formula (13). The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[0631] [Step III-5]

[0632] PG of the compound represented by general formula (13) 2In the case of a protecting group for an amino group, the protecting group is removed by referring to the method described in "Protecting Groups in Organic Synthesis, 5th Edition, Wiley (2014)" to obtain a compound of the general formula (1).

[0633] Reaction step IV is R of general formula (I) 1 The method for producing the compound (4) wherein Z is a hydrogen atom and is bonded via a nitrogen atom is another preparation method of the reaction step formula I.

[0634] [Reaction Step Formula IV]

[0635] [Chemical formula 67]

[0636]

[0637] [In the formula, ring A and ring B represent the same rings as those in reaction step formula I.

[0638] M 1 represents the same group as in reaction step formula III.]

[0639] [Step IV-1]

[0640] The compound represented by the general formula (17) is reacted with 4-formyl imidazole (2) in a suitable solvent (e.g., N,N-dimethylacetamide, methanol, tetrahydrofuran, toluene, dichloromethane or a mixed solvent thereof) using an additive (e.g., acetic acid, triethylamine, tetraisopropyl titanate, etc.) to obtain a compound represented by the general formula (18). The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[0641] [Step IV-2]

[0642] The compound of general formula (18) is reacted in a suitable solvent (e.g., N,N-dimethylacetamide, methanol, tetrahydrofuran, toluene, dichloromethane or a mixed solvent thereof) using a reducing agent (e.g., sodium borohydride, sodium triacetoxyborohydride, etc.) to obtain a compound represented by general formula (19). The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours. It should be noted that step IV-1 and step IV-2 can be carried out continuously without separation and purification after step IV-1, or the reaction can be carried out in a one-pot manner.

[0643] [Step IV-3]

[0644] The compound represented by the general formula (19) and the compound represented by the general formula (11) are reacted in a suitable solvent (e.g., dioxane, water, a mixed solvent of dioxane and water, etc.) in the presence of a base (e.g., potassium carbonate, sodium carbonate, potassium phosphate, etc.) using a palladium catalyst (e.g., palladium acetate, palladium chloride, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, tetrakis(triphenylphosphine)palladium, 1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium, etc.), thereby obtaining the compound represented by the general formula (4). The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[0645] Reaction step formula V is R of general formula (I) 1 A method for producing a compound (25) wherein Z is bonded to a hydrogen atom via an oxygen atom.

[0646] [Reaction Step Formula V]

[0647] [Chemical formula 68]

[0648]

[0649] 〔In the formula, PG 1 represents the same group as in reaction step formula II.

[0650] X 2 represents the same group as in reaction step formula III.

[0651] R 2 represents the same group as in reaction step formula I.

[0652] Ring B represents the same ring as in reaction step formula I.

[0653] M 1 and M 2 represents the same group as in reaction step formula III.]

[0654] [Step V-1]

[0655] The compound represented by the general formula (20) is reacted with the compound represented by the general formula (21) using a Mitsunobu reaction reagent (e.g., diisopropyl azodicarboxylate, etc.) in a suitable solvent (e.g., tetrahydrofuran, etc.) in the presence of an additive (e.g., triphenylphosphine, etc.), thereby obtaining the compound represented by the general formula (22). The reaction temperature is 0° C. to the boiling point of the solvent, and the reaction time is 30 minutes to 48 hours.

[0656] [Step V-2]

[0657] The compound represented by the general formula (23) is reacted with the compound represented by the general formula (21) using a base (such as potassium carbonate, sodium carbonate, etc.) in a suitable solvent (such as N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.) in the presence or absence of an additive (such as potassium iodide, etc.), thereby obtaining the compound represented by the general formula (22). The reaction temperature is 0°C to the boiling point of the solvent, and the reaction time is 30 minutes to 48 hours.

[0658] [Step V-3]

[0659] The compound represented by the general formula (22) and the compound represented by the general formula (11) are reacted in a suitable solvent (e.g., dioxane, water, a mixed solvent of dioxane and water, etc.) in the presence of a base (e.g., potassium carbonate, sodium carbonate, potassium phosphate, etc.) using a palladium catalyst (e.g., palladium acetate, palladium chloride, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, tetrakis(triphenylphosphine)palladium, 1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium, etc.), thereby obtaining a compound represented by the general formula (24). The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[0660] [Step V-4]

[0661] The compound represented by the general formula (22) is reacted with the compound represented by the general formula (12) in a suitable solvent (e.g., dioxane, toluene, etc.) using a palladium catalyst (e.g., tetrakis(triphenylphosphine)palladium, etc.) in the presence or absence of an additive (e.g., potassium fluoride, etc.), thereby obtaining the compound represented by the general formula (24). The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[0662] [Step V-5]

[0663] The protecting group of the compound represented by the general formula (24) is removed by referring to the method described in "Protecting Groups in Organic Synthesis, 5th Edition, Wiley (2014)", thereby obtaining the compound represented by the general formula (25).

[0664] Reaction step formula VI is R of general formula (I) 1 The method for producing the compound (25) wherein Z is a hydrogen atom and is bonded via an oxygen atom is another production method of the reaction step formula V.

[0665] [Reaction Step Formula VI]

[0666] [Chemical formula 69]

[0667]

[0668] [In the formula, ring B represents the same ring as that in reaction step formula I.

[0669] R 2 represents the same group as in reaction step formula I.

[0670] PG 1 represents the same group as in reaction step formula II.]

[0671] [Step VI-1]

[0672] The compound represented by the general formula (26) is reacted with the compound represented by the general formula (20) in a suitable solvent (such as tetrahydrofuran) in the presence of an additive (such as triphenylphosphine) using a Mitsunobu reaction reagent (such as diisopropyl azodicarboxylate, etc.) to obtain a compound represented by the general formula (24). The reaction temperature is 0°C to the boiling point of the solvent, and the reaction time is 30 minutes to 48 hours.

[0673] [Step VI-2]

[0674] The protecting group of the compound represented by the general formula (24) is removed by referring to the method described in "Protecting Groups in Organic Synthesis, 5th Edition, Wiley (2014)", thereby obtaining the compound represented by the general formula (25).

[0675] Reaction step formula VII is R of general formula (I) 1 A method for producing a compound (30) in which a C1-C3 alkyl group is bonded to Z via an oxygen atom.

[0676] [Reaction Step Formula VII]

[0677] [Chemical formula 70]

[0678]

[0679] 〔In the formula, PG 1 , X 1 and R 1 represents the same group as in reaction step formula II.

[0680] R 2 represents the same group as in reaction step formula I.

[0681] Ring B represents the same ring as in reaction step formula I.]

[0682] [Step VII-1]

[0683] The compound represented by the general formula (5) is reacted with a Grignard reagent (e.g., methylmagnesium bromide) (7) in a suitable solvent (e.g., tetrahydrofuran) to obtain a compound represented by the general formula (27). The reaction temperature is from 0°C to the boiling point of the solvent, and the reaction time is from 30 minutes to 24 hours.

[0684] [Step VII-2]

[0685] The compound represented by the general formula (27) is reacted with a chlorinating agent (e.g., methanesulfonyl chloride) in a suitable solvent (e.g., chloroform) in the presence or absence of an additive (e.g., triethylamine) to obtain a compound represented by the general formula (28). The reaction temperature is from 0°C to the boiling point of the solvent, and the reaction time is from 30 minutes to 24 hours.

[0686] [Step VII-3]

[0687] The compound represented by the general formula (28) is reacted with the compound represented by the general formula (26) in a suitable solvent (such as N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.) using a base (such as potassium carbonate, sodium carbonate, etc.) in the presence or absence of an additive (such as potassium iodide, etc.), thereby obtaining a compound represented by the general formula (29). The reaction temperature is 0°C to the boiling point of the solvent, and the reaction time is 30 minutes to 48 hours.

[0688] [Step VII-4]

[0689] The protecting group of the compound represented by the general formula (29) is removed by referring to the method described in "Protecting Groups in Organic Synthesis, 5th Edition, Wiley (2014)", thereby obtaining the compound represented by the general formula (30).

[0690] The compound represented by the general formula (26) used as a raw material in reaction steps VI and VII can be produced by the method represented by the following reaction step VIII, the method described in the reference examples, or a method combining known methods.

[0691] [Reaction Step Scheme VIII]

[0692] [Chemical formula 71]

[0693]

[0694] 〔In the formula, M 1 represents the same group as in reaction step formula III.

[0695] Ring B represents the same ring as in reaction step formula I.

[0696] X 2represents the same group as in reaction step formula III.]

[0697] [Step VIII-1]

[0698] The compound represented by the general formula (31) and the compound represented by the general formula (16) are reacted in a suitable solvent (e.g., dioxane, water, a mixed solvent of dioxane and water, etc.) in the presence of a base (e.g., potassium carbonate, sodium carbonate, potassium phosphate, etc.) using a palladium catalyst (e.g., palladium acetate, palladium chloride, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, tetrakis(triphenylphosphine)palladium, 1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium, etc.), thereby obtaining the compound represented by the general formula (26). The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[0699] Reaction step formula IX is R of general formula (I) 1 A method for producing a compound (36) wherein Z is bonded to a hydrogen atom via a sulfur atom.

[0700] [Reaction Step Formula IX]

[0701] [Chemical formula 72]

[0702]

[0703] 〔In the formula, PG 1 represents the same group as in reaction step formula II.

[0704] R 2 represents the same group as in reaction step formula I.

[0705] Ring B represents the same ring as in reaction step formula I.

[0706] M 1 and X 2 represents the same group as in reaction step formula III.]

[0707] [Step IX-1]

[0708] The compound represented by the general formula (32) is reacted with the compound represented by the general formula (33) in a suitable solvent (such as N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.) using a base (such as potassium carbonate, sodium carbonate, etc.) in the presence or absence of an additive (such as potassium iodide, etc.), thereby obtaining the compound represented by the general formula (34). The reaction temperature is 0°C to the boiling point of the solvent, and the reaction time is 30 minutes to 48 hours.

[0709] [Step IX-2]

[0710] The compound represented by the general formula (34) and the compound represented by the general formula (11) are reacted in a suitable solvent (e.g., dioxane, water, a mixed solvent of dioxane and water, etc.) in the presence of a base (e.g., potassium carbonate, sodium carbonate, potassium phosphate, etc.) using a palladium catalyst (e.g., palladium acetate, palladium chloride, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, tetrakis(triphenylphosphine)palladium, 1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium, etc.), thereby obtaining a compound represented by the general formula (35). The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[0711] [Step IX-3]

[0712] The protecting group of the compound represented by the general formula (35) is removed by referring to the method described in "Protecting Groups in Organic Synthesis, 5th Edition, Wiley (2014)" to obtain the compound represented by the general formula (36).

[0713] With regard to the substituents (e.g., hydroxyl, amino, carboxyl, etc.) contained in the compounds of the present invention and the compounds used to produce the compounds, it is sometimes effective for producing the compounds to introduce suitable protecting groups into the substituents in advance at the raw material stage or the intermediate stage. The protecting groups described in the above-mentioned "Protecting Groups in Organic Synthesis, 5th Edition, Wiley (2014)" can be appropriately selected and used as needed.

[0714] In order to separate and purify the compounds of the present invention and the compounds used to manufacture the compounds from the reaction solution, the commonly used methods can be used. For example, solvent extraction, ion exchange resins, column chromatography using silica gel or alumina as a carrier, high performance liquid chromatography (HPLC) preparation, thin layer chromatography, scavenger resin, recrystallization, etc. can be used, and these separation methods and purification methods can be carried out alone or in combination. Separation and purification can be carried out at each reaction, or can be implemented after several reactions are completed.

[0715] When the compound in this specification has an asymmetric carbon and optical isomers exist, these optical isomers can be resolved by conventional optical resolution methods for racemic compounds, such as a method of forming a diastereomeric salt with a conventional optically active compound and performing recrystallization, or a conventional method of forming diastereoisomers by reaction with a conventional optically active compound and providing them for chromatography. In addition, each optical isomer can also be resolved by high performance liquid chromatography (HPLC) preparation using a column for separation of optically active substances.

[0716] The compound of the present invention thus produced acts as an adrenaline α1A receptor agonist and can therefore be used as a therapeutic agent for orthostatic hypotension, essential hypotension, acute hypotension associated with various diseases or conditions, and urinary incontinence.

[0717] In order to prevent or treat a disease selected from the group consisting of orthostatic hypotension, intrinsic hypotension, acute hypotension associated with various diseases or states, and urinary incontinence, a therapeutically effective amount of the compound of the present invention can be administered to a subject in need thereof. As the subject, for example, humans, non-human mammals, etc. can be cited, preferably humans.

[0718] The administration mode of the pharmaceutical composition containing the compound of the present invention can be selected from oral mode or non-oral mode, and various modes of administration can be selected according to the purpose. For example, as an oral administration mode, tablets, capsules, powders and granules can be listed, and as a non-oral administration mode, patches, coatings and ointments can be listed. When formed into a more convenient tablet form, the components that can be orally ingested used in the field can be appropriately selected. For example, excipients, adhesives, disintegrants, lubricants, flavoring agents and anti-aggregating agents can be listed.

[0719] The dosage of the drug containing the compound of the present invention as an active ingredient is not particularly limited and can be appropriately selected. The dosage of the drug containing the compound of the present invention can be appropriately determined according to its mode of administration, usage, age, gender and other conditions of the patient, and the degree of the disease. In the case of oral administration, the daily amount of the compound of the present invention is within the range of about 0.1 μg to 100 mg relative to 1 kg of body weight, and the amount can be divided into 1 to 4 times a day for appropriate administration. However, the dosage and the number of administrations can be determined according to relevant conditions including the degree of the symptoms to be treated, the choice of the compound to be administered and the selected route of administration, so the above-mentioned dosage and the range of the number of administrations do not limit the scope of the present invention.

[0720] Example

[0721] The present invention will be described in further detail below with reference to Examples, Reference Examples and Pharmacological Test Examples, but the technical scope of the present invention is not limited to the contents described therein.

[0722] [NMR Spectrum]

[0723] The following examples and reference examples are subjected to nuclear magnetic resonance ( 1H-NMR) spectra were measured using Agilent 400MR and Bruker AVANCE NEO 400, with tetramethylsilane as the internal standard, and chemical shift values ​​were recorded as δ values ​​(ppm). In the splitting mode, "s" represents a singlet, "d" represents a doublet, "t" represents a triplet, "q" represents a quartet, "quint" represents a quintet, "m" represents a multiplet, and "br" represents a broad peak.

[0724] Mass spectrometry analysis was performed by electrospray ionization (ESI) under any of the following measurement conditions A to D.

[0725] [Measurement Condition A]

[0726] Measurement device: Waters ACQUITY UPLC / SQD system

[0727] Column: ACQUITY UPLC BEH C18 (1.7μm, 2.1mm×50mm)

[0728] Column temperature: 50°C

[0729] Flow rate: 1.5mL / min

[0730] UV detection wavelength: 210-400nm

[0731] Mobile phase: [A] water / acetonitrile / formic acid = 97 / 3 / 0.1, [B] water / acetonitrile / formic acid = 5 / 95 / 0.1

[0732] Gradient: [A] / [B] = 95 / 5 to 1 / 99 (linear gradient for 1 minute)

[0733] [Measurement Condition B]

[0734] Measurement device: Agilent LC / MSD 1200 series

[0735] Column: Xbridge-C18 (1.7 μm, 2.1 mm × 50 mm)

[0736] Column temperature: 30°C

[0737] Flow rate: 1.5mL / min

[0738] UV detection wavelength: 214 or 254nm

[0739] Mobile phase: [A] aqueous solution containing 0.1% trifluoroacetic acid, [B] acetonitrile

[0740] Gradient: [A] / [B] = 95 / 5 to 5 / 95 (linear gradient for 2.5 minutes)

[0741] [Measurement Condition C]

[0742] Measurement device: Agilent LC / MSD 1200 series

[0743] Column: Xbridge-C18 (1.7 μm, 2.1 mm × 50 mm)

[0744] Column temperature: 30°C

[0745] Flow rate: 1.5mL / min

[0746] UV detection wavelength: 214 or 254nm

[0747] Mobile phase: [A] 0.1% ammonium bicarbonate aqueous solution, [B] acetonitrile

[0748] Gradient: [A] / [B] = 95 / 5 to 5 / 95 (linear gradient for 2.5 minutes)

[0749] In the table, “Me” represents a methyl group, “Et” represents an ethyl group, “Pr” represents a propyl group, “Bu” represents a butyl group, “Trt” represents a trityl group, “Boc” represents a tert-butyloxycarbonyl group, “Ac” represents an acetyl group, “DMA” represents N,N-dimethylacetamide, “THF” represents tetrahydrofuran, “TFA” represents trifluoroacetic acid, “dppf” represents 1,1'-bis(diphenylphosphino)ferrocene, and “dtbpf” represents 1,1'-bis(di-tert-butylphosphino)ferrocene.

[0750] <Production of the compound of the present invention in which the biaryl moiety and the imidazole moiety are bonded via a nitrogen atom>

[0751] Preparation of Biarylamine 1 Step III-1 (Reference Examples 1 to 11)

[0752] [Reference Example 1]

[0753] tert-Butyl [2,3'-bithiophene]-4'-ylcarbamate

[0754] [Chemical formula 73]

[0755]

[0756] Tert-butyl (4-bromothiophene-3-yl)carbamate (210 mg) was dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (2.5 mL), 2-thiopheneboric acid (290 mg), tetrakis(triphenylphosphine)palladium (43.6 mg), and potassium carbonate (41.7 mg) were added, and the reaction vessel was replaced with argon, and stirred at 90°C for 4 hours. The reaction solution was filtered through celite, washed with ethyl acetate, and the filtrate and the washing solution were combined and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 0 to 4 / 1) to obtain the title compound (211 mg).

[0757] ESI / MS (m / z) 282 (M+H) +

[0758] The method of Reference Example 1 was used as a reference, and the compound was synthesized according to the following reaction formula. The synthesized compound and data are shown in Table 1.

[0759] [Chemical formula 74]

[0760]

[0761] [Table 1]

[0762]

[0763] Preparation of biarylamine 2 Step III-2 (Reference Examples 12 to 15)

[0764] [Reference Example 12]

[0765] tert-Butyl (4-(thiazol-2-yl)thiophen-3-yl)carbamate

[0766] [Chemical formula 75]

[0767]

[0768] Tert-butyl (4-bromothiophen-3-yl)carbamate (1.1 g) and 2-(tributyltin)thiazole (3.0 g) were dissolved in toluene (30 mL), tetrakis(triphenylphosphine)palladium (464 mg) was added, and the reaction container was replaced with nitrogen, and stirred overnight at 110° C. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (pentane / ethyl acetate=20 / 1) to obtain the title compound (451 mg).

[0769] ESI / MS (m / z) 283 (M+H) + .

[0770] The method of Reference Example 12 was used as a reference, and the compound was synthesized according to the following reaction formula. The synthesized compound and data are shown in Table 2.

[0771] [Chemical formula 76]

[0772]

[0773] [Table 2]

[0774]

[0775] Preparation of Biarylamine 3 Steps III-3 and 4 (Reference Examples 16 to 36)

[0776] [Reference Example 16]

[0777] (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )thiophene-3- tert-Butyl)carbamate

[0778] [Chemical formula 77]

[0779]

[0780] Tert-butyl (4-bromothiophen-3-yl)carbamate (3 g) and potassium acetate (3.17 g) were dissolved in 1,4-dioxane (30 mL), and bis(pinacolato)diboron (5.5 g) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (395 mg) were added, and the reaction container was replaced with nitrogen, and stirred at 100° C. overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (pentane / ethyl acetate=10 / 1) to obtain the title compound (3.2 g).

[0781] ESI / MS (m / z) 326 (M+H) + .

[0782] [Reference Example 17]

[0783] (4-(3-Methylpyridin-2-yl)thiophen-3-yl)amino Tert-butyl ester

[0784] [Chemical formula 78]

[0785]

[0786] Tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl)carbamate (Reference Example 16, 325 mg) was dissolved in a mixed solvent of 1,4-dioxane (30 mL) and water (3 mL), potassium carbonate (552 mg), 2-bromo-3-methylpyridine (345 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (395 mg) were added, and the reaction container was replaced with nitrogen, and stirred at 100° C. overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (pentane / ethyl acetate=10 / 1) to obtain the title compound (250 mg).

[0787] ESI / MS (m / z) 291 (M+H) + .

[0788] [Reference Example 18]

[0789] tert-Butyl 4-iodo-5-methoxy-1H-pyrazole-1-carboxylate

[0790] [Chemical formula 79]

[0791]

[0792] 4-iodo-3-methoxy-1H-pyrazole (1 g) and 4-dimethylaminopyridine (109 mg) were dissolved in dichloromethane (20 mL), di-tert-butyl dicarbonate (1.46 g) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (pentane / ethyl acetate = 20 / 1 to 10 / 1) to obtain the title compound (1.2 g).

[0793] ESI / MS (m / z) 225 (M+H-boc) + .

[0794] The method of Reference Example 17 was used as a reference, and the compound was synthesized according to the following reaction formula. The synthesized compound and data are shown in Table 3.

[0795] [Chemical formula 80]

[0796]

[0797] [Table 3-1]

[0798]

[0799] [Table 3-2]

[0800]

[0801] Preparation of Biarylamine 4 Step III-5 (Reference Examples 37 to 56)

[0802] [Reference Example 37]

[0803] [2,3'-Bithiophene]-4'-amine

[0804] [Chemical formula 81]

[0805]

[0806] Dissolve [2,3'-bithiophene]-4'-ylcarbamic acid tert-butyl ester (Reference Example 1, 211 mg) in chloroform (4 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, made alkaline with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering out anhydrous sodium sulfate, it was washed with ethyl acetate. The filtrate and the washing solution were combined and concentrated under reduced pressure to obtain the title compound (137 mg).

[0807] ESI / MS (m / z) 182 (M+H) + .

[0808] The method of Reference Example 37 was used as a reference, and the compound was synthesized according to the following reaction formula. The synthesized compound and data are shown in Table 4.

[0809] [Chemical formula 82]

[0810]

[0811] [Table 4-1]

[0812]

[0813] [Table 4-2]

[0814]

[0815] Preparation steps I-1 and 2 of the compounds of the present invention (Examples 1 to 34)

[0816] [Example 1]

[0817] N-((1H-imidazol-4-yl)methyl)[2,3'-bithiophene]-4'-amine

[0818] [Chemical formula 83]

[0819]

[0820] [2,3'-bithiophene]-4'-amine (Reference Example 37, 20.0 mg) and 4-formyl imidazole (21.2 mg) were dissolved in N,N-dimethylformamide (550 μL) and stirred at 70°C overnight. After cooling to room temperature, methanol (550 μL) and sodium borohydride (10.5 mg) were added and stirred at room temperature for 30 minutes. Water was added to the reaction solution, stirred for 30 minutes, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering out anhydrous sodium sulfate, it was washed with ethyl acetate. The filtrate and the washing liquid were combined and concentrated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (NH silica; chloroform / methanol = 10 / 1) to obtain the title compound (13.7 mg).

[0821] 1 H-NMR (400MHz, CD3OD) δ7.61(d,J=1.2Hz,1H),7.35(dd,J=5.2,1.1Hz,1H),7.27(d,J=3.3Hz,1H),7.22 (dd,J=3.5,1..1Hz,1H),7.08(dd,J=5.2,3.5Hz,1H),7.01(brs,1H)6.21(d,J=3.3Hz,1H),4.24(s,2H).

[0822] ESI / MS (m / z) 262 (M+H) + .

[0823] The method of Example 1 was used as a reference, and the compounds were synthesized according to the following reaction formula. The synthesized compounds are shown in Table 5, and the data are shown in Table 6.

[0824] [Chemical formula 84]

[0825]

[0826] [Table 5-1]

[0827]

[0828] [Table 5-2]

[0829]

[0830] [Table 5-3]

[0831]

[0832] [Table 6-1]

[0833]

[0834] [Table 6-2]

[0835]

[0836] [Table 6-3]

[0837]

[0838] [Example 33]

[0839] N-((1H-imidazol-4-yl)methyl)-2-(3-methoxy- 1H-pyrazole-4- 2-Methyl-5-aniline

[0840] [Chemical formula 85]

[0841]

[0842] Tert-butyl 4-(2-amino-4-methylphenyl)-5-methoxy-1H-pyrazole-1-carboxylate (Reference Example 35, 117 mg), 4-formyl imidazole (111 mg), and acetic acid (0.1 mL) were dissolved in methanol (8 mL) and stirred at 50°C for 48 hours. After cooling to room temperature, sodium cyanoborohydride (109 mg) was added and stirred at 50°C for 16 hours. The reaction solution was concentrated under reduced pressure, water was added, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtering out anhydrous sodium sulfate, it was washed with ethyl acetate. The filtrate and the washing solution were combined and concentrated under reduced pressure, and the obtained residue was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, and stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, the obtained residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate water / acetonitrile = 80 / 20 to 30 / 70) to obtain the title compound (16 mg).

[0843] 1 H-NMR (400MHz, CD3OD) δ7.60 (s, 1H), 7.53 (s, 1H), 6.99 (d, J = 7.2Hz, 1H), 6.95 (s ,1H),6.59(s,1H),6.51(d,J=7.6Hz,1H),4.25(s,2H),3.85(s,3H),2.26(s,3H).

[0844] ESI / MS (m / z) 284 (M+H) + .

[0845] The compound was synthesized according to the following reaction formula using the method of Example 33 as a reference. The data are shown in Table 7.

[0846] [Chemical formula 86]

[0847]

[0848] [Table 7]

[0849]

[0850] Preparation steps II-1 to 3 of the compounds of the present invention (Examples 35 to 40, Reference Examples 57 to 59)

[0851] [Example 35]

[0852] N-(1-(1H-imidazol-4-yl)ethyl}-2-(pyridine-3 -yl)aniline

[0853] [Chemical formula 87]

[0854]

[0855] Suspend 2-(pyridin-3-yl)aniline (Reference Example 9, 34 mg), 1-trityl-1H-imidazole-4-carboxaldehyde (81 mg) and molecular sieve 3A (90 mg) in toluene (2 mL) and heat under reflux for 1 day. Filter the reaction solution while hot and wash the residue with toluene. Combine the filtrate and the washing solution, concentrate under reduced pressure, and dissolve the residue obtained in tetrahydrofuran (2 mL). Cool to -78°C, add 1M methylmagnesium bromide tetrahydrofuran solution (500 μL) dropwise, and warm to room temperature. After stirring for 1 hour, add saturated aqueous ammonium chloride solution and extract with ethyl acetate. Wash the organic layer with water and saturated brine, and dry over anhydrous sodium sulfate. After filtering off anhydrous sodium sulfate, the mixture was washed with ethyl acetate, and the filtrate and the washing solution were combined and concentrated under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (hexane / ethyl acetate = 1 / 1) to give 2-(pyridin-3-yl)-N-(1-(1-trityl-1H-imidazol-4-yl)ethyl)aniline (52 mg).

[0856] ESI / MS (m / z) 507 (M+H) + .

[0857] 2-(Pyridin-3-yl)-N-(1-(1-trityl-1H-imidazol-4-yl)ethyl)aniline (52 mg) obtained above was dissolved in formic acid (2 mL) and stirred at room temperature overnight. The reaction solution was washed with hexane, concentrated under reduced pressure, and then azeotroped with chloroform. The obtained residue was dissolved in tetrahydrofuran (2 mL), potassium carbonate (200 mg) was added, and stirred at room temperature for 30 minutes. After filtering out the potassium carbonate, it was washed with tetrahydrofuran. The filtrate and the washing solution were combined, concentrated under reduced pressure, and the obtained residue was purified by preparative thin layer chromatography (methanol / chloroform = 1 / 9) to obtain the title compound (20 mg).

[0858] 1H-NMR(400MHz,DMSO-d6)δ11.82(s,1H),8.58(s,1H),8.55(dd,J=4.8,1.6Hz, 1H),7.86(dt,J=7.9,1.2Hz,1H),7.51(s,1H),7.49(ddd,J=7.9,4.8,1.2Hz,1 H),7.16(t,J=7.1Hz,1H),7.00(dd,J=7.1,1.5Hz,1H),6.91(s,1H),6.77(d,J =8.1Hz,1H),6.69(t,J=7.1Hz,1H),4.56-4.52(m,2H),1.34(d,J=5.0Hz,3H).

[0859] ESI / MS (m / z) 265 (M+H) + .

[0860] [Example 36]

[0861] (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-( Pyridin-3-yl) aniline, and

[0862] [Reference Example 57]

[0863] (-)-N-(1-(1H-imidazol-4-yl)ethyl)-2-( Pyridin-3-yl) aniline

[0864] The compound prepared in Example 35 (N-(1-(1H-imidazol-4-yl)ethyl)-2-(pyridin-3-yl)aniline) was optically resolved by high performance liquid chromatography (CHIRALPAC IC; hexane / ethanol / diethylamine = 900 / 100 / 1) to give the title compound.

[0865] Embodiment 36: 1 H-NMR (400MHz, CD3OD) δ8.57 (dd, J=2.2, 0.9Hz, 1H), 8.51 (dd, J=5.0, 1.6Hz, 1 H),7.93(ddd,J=7.9,2.2,1.6Hz,1H),7.56(d,J=1.2Hz,1H),7.51(ddd,J=7.9, 5.0,0.9Hz,1H),7.17(ddd,J=8.2,7.4,1.6Hz,1H),7.02(dd,J=7.4,1.6Hz,1H) ,6.87(s,1H),6.80-6.72(m,2H),4.61(q,J=6.7Hz,1H),1.43(d,J=6.7Hz,3H).

[0866] ESI / MS (m / z) 265 (M+H) +.

[0867] Reference Example 57: 1 H-NMR (400MHz, CD3OD) δ8.57 (dd, J=2.3, 0.9Hz, 1H), 8.51 (dd, J=4.9, 1.7Hz, 1 H),7.93(ddd,J=7.9,2.3,1.7Hz,1H),7.56(d,J=1.2Hz,1H),7.51(ddd,J=7.9, 4.9,0.9Hz,1H),7.17(ddd,J=8.3,7.4,1.6Hz,1H),7.02(dd,J=7.4,1.6Hz,1H) ,6.87(s,1H),6.81-6.71(m,2H),4.61(q,J=6.7Hz,1H),1.43(d,J=6.7Hz,3H).

[0868] ESI / MS (m / z) 265 (M+H) + .

[0869] The method of Example 35 was used as a reference, and the compounds were synthesized according to the following reaction formula. The synthesized compounds are shown in Table 8, and the data are shown in Table 9.

[0870] [Chemical formula 88]

[0871]

[0872] [Table 8]

[0873]

[0874] [Table 9]

[0875]

[0876] [Example 39]

[0877] (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-( 6-Methoxypyridine Pyridin-2-yl)aniline, and

[0878] [Reference Example 58]

[0879] (-)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(6 -Methoxypyridine 2-pyridin-2-yl)aniline

[0880] The compound prepared in Example 37 (N-(1-(1H-imidazol-4-yl)ethyl)-2-(6-methoxypyridin-2-yl)aniline) was optically resolved by high performance liquid chromatography (CHIRALPAK IA; hexane / ethanol / diethylamine = 950 / 50 / 1) to give the title compound.

[0881] Embodiment 39: 1 H-NMR (400MHz, CDCl3) δ9.55 (brs, 1H), 7.98 (d, J = 6.4Hz, 1H), 7.66 (dd, J = 8.3 ,7.6Hz,1H),7.51-7.47(m,2H),7.26(s,1H),7.23(dd,J=7.6,0.7Hz,1H),7.1 7(ddd,J=8.3,7.3,1.6Hz,1H),6.86(s,1H),6.73-6.68(m,2H),6.65(dd,J=8. 3,0.7Hz,1H),4.76(quint,J=6.5Hz,1H),3.65(s,3H),1.60(d,J=6.6Hz,3H).

[0882] ESI / MS (m / z) 295 (M+H) + .

[0883] Reference Example 58: 1 H-NMR (400MHz, CDCl3) δ9.55 (brs, 1H), 7.98 (d, J = 6.4Hz, 1H), 7.66 (dd, J = 8.3 ,7.6Hz,1H),7.51-7.47(m,2H),7.26(s,1H),7.23(dd,J=7.6,0.7Hz,1H),7.1 7(ddd,J=8.3,7.3,1.6Hz,1H),6.86(s,1H),6.73-6.68(m,2H),6.65(dd,J=8. 3,0.7Hz,1H),4.76(quint,J=6.5Hz,1H),3.65(s,3H),1.60(d,J=6.6Hz,3H).

[0884] ESI / MS (m / z) 295 (M+H) + .

[0885] [Example 40]

[0886] (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-( Thiazol-4-yl )aniline, and

[0887] [Reference Example 59]

[0888] (-)-N-(1-(1H-imidazol-4-yl)ethyl)-2-( Thiazol-4-yl )aniline

[0889] The compound prepared in Example 38 (N-(1-(1H-imidazol-4-yl)ethyl)-2-(thiazol-4-yl)aniline) was optically resolved by high performance liquid chromatography (CHIRALPAK IA; hexane / ethanol / diethylamine = 950 / 50 / 1) to give the title compound.

[0890] Embodiment 40: 1 H-NMR (400MHz, CDCl3) δ8.89 (d, J = 2.0Hz, 1H), 7.50 (d, J = 1.1Hz, 1H), 7.48-7.45 (m, 2H), 7.26 (s, 1H), 7.19-7.11(m,1H),6.88(s,1H),6.75-6.67(m,2H),4.75(quint,J=6.7Hz,1H),1.60(d,J=6.7Hz,3H).

[0891] ESI / MS (m / z) 271 (M+H) + .

[0892] Reference Example 59: 1 H-NMR (400MHz, CDCl3) δ8.89 (d, J = 2.0Hz, 1H), 7.50 (d, J = 1.1Hz, 1H), 7.48-7.45 (m, 2H), 7.26 (s, 1H), 7.19-7.11(m,1H),6.88(s,1H),6.75-6.67(m,2H),4.75(quint,J=6.7Hz,1H),1.60(d,J=6.7Hz,3H).

[0893] ESI / MS (m / z) 271 (M+H) + .

[0894] Preparation steps IV-1 and 2 of imidazolylmethylaminoaryl (reference example 60)

[0895] [Reference Example 60]

[0896] N-((1H-imidazol-4-yl)methyl)-4-bromothiophen-3-amine

[0897] [Chemical formula 89]

[0898]

[0899] 4-Bromothiophene-3-amine hydrochloride (50.0 mg) and 4-formyl imidazole (44.8 mg) were dissolved in N,N-dimethylformamide (500 μL), sodium triacetoxyborohydride (49.4 mg) was added, and the mixture was stirred at 70°C for 11 hours. Sodium triacetoxyborohydride (49.4 mg) was further added, and the mixture was stirred at 70°C for 5 hours. Water and saturated sodium bicarbonate were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered out and washed with ethyl acetate. The filtrate and the washing solution were combined, concentrated under reduced pressure, and the obtained residue was purified by preparative thin layer chromatography (NH silica; chloroform / methanol = 10 / 1) to obtain the title compound (3.9 mg).

[0900] ESI / MS (m / z) 258, 260 (M+H) + .

[0901] Preparation Step IV-3 of the Compound of the Present Invention (Examples 41 to 43)

[0902] [Example 41]

[0903] N-((1H-imidazol-4-yl)methyl)-4-(furan-3-yl) )Thiophene-3-amine

[0904] [Chemical formula 90]

[0905]

[0906] N-((1H-imidazol-4-yl)methyl)-4-bromothiophene-3-amine (Reference Example 60, 3.9 mg) was dissolved in a mixed solvent of 1,4-dioxane (100 μL) and water (50 μL), 2-furanboric acid (5.1 mg), tetrakis(triphenylphosphine)palladium (0.9 mg), and potassium carbonate (8.3 mg) were added, and the reaction vessel was replaced with argon, and stirred at 100°C overnight. The reaction solution was filtered through celite and washed with ethyl acetate. The filtrate and the washing solution were combined and concentrated under reduced pressure, and the obtained residue was purified by preparative thin layer chromatography (NH silica; chloroform / methanol = 20 / 1) to obtain the title compound (0..3 mg).

[0907] 1 H-NMR (400MHz, CD3OD) δ7.78(dd,J=1.7,0.8Hz,1H),7.62(s,1H),7.53(t,J=1.7Hz,1H),7.22(d ,J=3.3Hz,1H),7.01(brs,1H),6.68(dd,J=1.9,0.8Hz,1H),6.19(d,J=3.3Hz,1H),4.23(s,2H).

[0908] ESI / MS (m / z) 246 (M+H) + .

[0909] The method of Example 41 was used as a reference, and the compounds were synthesized according to the following reaction formula. The synthesized compounds are shown in Table 10, and the data are shown in Table 11.

[0910] [Chemical formula 91]

[0911]

[0912] [Table 10]

[0913]

[0914] [Table 11]

[0915]

[0916] <Production of the compound of the present invention in which the biaryl moiety and the imidazole moiety are bonded via an oxygen atom>

[0917] Preparation of Imidazolylmethoxyaryl Group 1 Step V-1 (Reference Example 61)

[0918] [Reference Example 61]

[0919] 4-((2-iodophenoxy)methyl)-N,N-dimethyl-1H- Imidazole-1-sulfonamide

[0920] [Chemical formula 92]

[0921]

[0922] 4-(Hydroxymethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (307 mg), 2-iodophenol (363 mg), and triphenylphosphine (471 mg) were suspended in tetrahydrofuran (4 mL), and diisopropyl azodicarboxylate (441 μL) was added, and stirred at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, the obtained residue was purified by amino silica gel column chromatography (hexane / ethyl acetate = 2 / 3) and silica gel column chromatography (hexane / ethyl acetate = 1 / 2) in this order to obtain the title compound (350 mg).

[0923] ESI / MS (m / z) 408 (M+H) + .

[0924] Preparation of Imidazolylmethoxyaryl Group 2 Step V-2 (Reference Examples 62 to 64)

[0925] [Reference Example 62]

[0926] 4-((2-bromophenoxy)methyl)-N,N-dimethyl-1H- Imidazole-1-sulfonamide

[0927] [Chemical formula 93]

[0928]

[0929] 2-Bromophenol (8.7 g) and potassium carbonate (13.8 g) were suspended in dimethyl sulfoxide (100 mL), 4-(chloromethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (11.2 g) was added, and the mixture was stirred at 100°C for 12 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After filtering out anhydrous sodium sulfate, the mixture was washed with ethyl acetate. The filtrate and the washing solution were combined, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (pentane / ethyl acetate = 5 / 1 to 2 / 1) to obtain the title compound (15.1 g).

[0930] ESI / MS (m / z) 360, 362 (M+H) + .

[0931] The method of Reference Example 62 was used as a reference, and the compound was synthesized according to the following reaction formula. The synthesized compound and data are shown in Table 12.

[0932] [Chemical formula 94]

[0933]

[0934] [Table 12]

[0935]

[0936] Preparation steps V-3 and 5 of the compounds of the present invention (Examples 44 to 65)

[0937] [Example 44]

[0938] 4-((2-(Thien-3-yl)phenoxy)methyl)-1H-imidazole

[0939] [Chemical formula 95]

[0940]

[0941] 4-((2-iodophenoxy)methyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Reference Example 61, 61 mg) was dissolved in a mixed solvent of 1,4-dioxane (1 mL) and water (0.5 mL), 3-thiopheneboric acid (21 mg), tetrakis(triphenylphosphine)palladium (17 mg), and potassium carbonate (62 mg) were added, and then stirred at 90°C for 2.5 hours. The reaction solution was filtered through celite and washed with ethyl acetate. The filtrate and the washing solution were combined and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 2) to obtain N,N-dimethyl-4-((2-(thiophen-3-yl)phenoxy)methyl)-1H-imidazole-1-sulfonamide (42 mg).

[0942] ESI / MS (m / z) 364 (M+H) + .

[0943] N,N-dimethyl-4-((2-(thiophen-3-yl)phenoxy)methyl)-1H-imidazole-1-sulfonamide (42 mg) obtained above was dissolved in methanol (1 mL), 2M hydrochloric acid methanol solution (1 mL) was added, and the mixture was stirred at 70° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (NH silica; chloroform / methanol=10 / 1) to obtain the title compound (27 mg).

[0944] 1 H-NMR (400MHz, CD3OD) δ7.70(d,J=0.9Hz,1H),7.66(dd,J=3.0,1.3Hz,1H),7.53(dd,J=7.5,1.7Hz,1H),7.46(dd,J=5.1,1.3Hz,1H),7.36(d d,J=5.1,,3.0Hz,1H),7.28(ddd,J=8.3,7.5,1.7Hz,1H),7.20(dd,J=8.3,1.3Hz,1H),7.13(s,1H),7.02(td,J=7.5,1.3Hz,1H),5.09(s,2H).

[0945] ESI / MS (m / z) 257 (M+H) + .

[0946] The method of Example 44 was used as a reference, and the compounds were synthesized according to the following reaction formula. The synthesized compounds are shown in Table 13, and the data are shown in Table 14.

[0947] [Chemical formula 96]

[0948]

[0949] [Table 13-1]

[0950]

[0951] [Table 13-2]

[0952]

[0953] [Table 14-1]

[0954]

[0955] [Table 14-2]

[0956]

[0957] Preparation steps V-4 and 5 of the compound of the present invention (Example 66)

[0958] [Example 66]

[0959] 2-(2-((1H-imidazol-4-yl)methoxy)-4-methylbenzene pyrazine

[0960] [Chemical formula 97]

[0961]

[0962] 4-((2-bromo-5-methylphenoxy)methyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Reference Example 63, 38 mg), 2-(tributyltin)pyrazine (56 mg), and tetrakis(triphenylphosphine)palladium (17 mg) were suspended in toluene (0.7 mL) and stirred overnight at 100°C. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate, using silica with potassium carbonate added as a pre-column). The obtained compound was dissolved in methanol (1 mL), 2M hydrochloric acid methanol solution (1 mL) was added, and stirred at 70°C for 4 hours. After the reaction solution was concentrated under reduced pressure, the obtained residue was purified by thin layer chromatography (NH silica; chloroform / methanol = 10 / 1) to obtain the title compound (9 mg).

[0963] 1 H-NMR(400MHz,CD3OD)δ9.15-9.05(m,1H),8.64-8.56(m,1H),8.41-8.35(m,1H), 7.74-7.62(m,2H),7.19-7.09(m,2H)6.98-6.91(m,1H),5.13(s,2H),2.42(s,3H).

[0964] ESI / MS (m / z) 267 (M+H) + .

[0965] Production process of bisallylphenol VIII-1 (reference examples 65 to 75)

[0966] [Reference Example 65]

[0967] 2-(Thiazol-4-yl)phenol

[0968] [Chemical formula 98]

[0969]

[0970] 2-Hydroxyphenylboronic acid (200 mg), 4-bromothiazole (250 mg), tetrakis(triphenylphosphine)palladium (81 mg), and potassium carbonate (606 mg) were suspended in a mixed solvent of 1,4-dioxane (10 mL) and water (5 mL), and stirred at 90°C for 4.5 hours. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering out anhydrous sodium sulfate, it was washed with ethyl acetate. The filtrate and the washing solution were combined, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4 / 1) to obtain the title compound (195 mg).

[0971] ESI / MS (m / z) 178 (M+H) + .

[0972] The method of Reference Example 65 was used as a reference, and the compound was synthesized according to the following reaction formula. The synthesized compound and data are shown in Table 15.

[0973] [Chemical formula 99]

[0974]

[0975] [Table 15]

[0976]

[0977] Preparation steps of the compounds of the present invention VI-1 and 2 (Examples 67 to 77)

[0978] [Example 67]

[0979] 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole

[0980] [Chemical formula 100]

[0981]

[0982] 2-(Thiazol-4-yl)phenol (Reference Example 65, 24.3 mg), 4-(hydroxymethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (33.7 mg), and triphenylphosphine (46 mg) were dissolved in tetrahydrofuran (2 mL), and diisopropyl azodicarboxylate (35 μL) was added, and stirred at room temperature for 19 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography (hexane / ethyl acetate = 1 / 1) to obtain N,N-dimethyl-4-((2-(thiazol-4-yl)phenoxy)methyl)-1H-imidazole-1-sulfonamide (24.1 mg).

[0983] ESI / MS (m / z) 365 (M+H) + .

[0984] The N,N-dimethyl-4-((2-(thiazol-4-yl)phenoxy)methyl)-1H-imidazole-1-sulfonamide (18.2 mg) obtained above was dissolved in methanol (1 mL), and a 2M hydrochloric acid methanol solution (1 mL) was added, and stirred at 70°C for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with chloroform, washed with a saturated sodium bicarbonate aqueous solution and saturated brine, and dried over anhydrous sodium sulfate. After filtering out anhydrous sodium sulfate, it was washed with chloroform. The filtrate and the washing solution were combined, concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (NH silica; chloroform / methanol=20 / 1) to obtain the title compound (12.9 mg).

[0985] 1 H-NMR(400MHz, CDCl3)δ9.44(brs,1H),8.84(s,1H),8.18(brs,1H),8.01(brs,1H),7 .68-7.65(m,1H),7.31(ddd,J=8.3,7.3,1.8Hz,1H),7.18-7.01(m,3H),,5.23(s,2H).

[0986] ESI / MS (m / z) 258 (M+H) + .

[0987] The method of Example 67 was used as a reference, and the compounds were synthesized according to the following reaction formula. The synthesized compounds are shown in Table 16, and the data are shown in Table 17.

[0988] [Chemical Formula 101]

[0989]

[0990] [Table 16]

[0991]

[0992] [Table 17]

[0993]

[0994] Preparation of Imidazolylmethoxyaryl 3 Steps VII-1 and 2 (Reference Examples 76-77)

[0995] [Reference Example 76]

[0996] 4-(1-Hydroxyethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide

[0997] [Chemical formula 102]

[0998]

[0999] 4-Formyl-N,N-dimethyl-1H-imidazole-1-sulfonamide (500 mg) was dissolved in tetrahydrofuran (25 mL), and 1M methylmagnesium bromide tetrahydrofuran solution (2.5 mL) was added under ice cooling, and stirred at room temperature for 20 hours. Under ice cooling, saturated aqueous ammonium chloride solution and water were added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering out anhydrous sodium sulfate, it was washed with ethyl acetate. The filtrate and the washing liquid were combined, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol=12 / 1) to obtain the title compound (540 mg).

[1000] ESI / MS (m / z) 220 (M+H) +

[1001] [Reference Example 77]

[1002] 4-(1-Chloroethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide

[1003] [Chemical formula 103]

[1004]

[1005] 4-(1-Hydroxyethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Reference Example 76, 45 mg) was dissolved in chloroform (2.5 mL), triethylamine (47 μL) and methanesulfonyl chloride (21 μL) were added under ice cooling, and stirred for 1.5 hours under ice cooling. Water was added to the reaction solution and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering out anhydrous sodium sulfate, it was washed with chloroform. The filtrate and the washing solution were combined and concentrated under reduced pressure to obtain the title compound (38 mg).

[1006] ESI / MS (m / z) 238 (M+H) + .

[1007] [Reference Example 78]

[1008] 2-(Thiophen-2-yl)phenol

[1009] [Chemical formula 104]

[1010]

[1011] 2-Hydroxyphenylboronic acid (1.00 g), tetrakis(triphenylphosphine)palladium (418 mg), and potassium carbonate (3.00 g) were suspended in a mixed solvent of 1,4-dioxane (24 mL) and water (12 mL), 2-bromothiophene (930 μL) was added, and the mixture was stirred at 90°C for 4 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering out anhydrous sodium sulfate, it was washed with ethyl acetate. The filtrate and the washing solution were combined, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1) to obtain the title compound (909 mg).

[1012] ESI / MS (m / z) 177 (M+H) + .

[1013] Preparation Steps VII-3 and 4 of the Compounds of the Present Invention (Examples 78 to 79, Reference Example 79)

[1014] [Example 78]

[1015] 4-(1-(2-(Thien-2-yl)phenoxy)ethyl)-1H-imidazole

[1016] [Chemical formula 105]

[1017]

[1018] 2-(Thien-2-yl)phenol (Reference Example 78, 50 mg) was dissolved in N,N-dimethylformamide (2 mL), potassium carbonate (65 mg) and 4-(1-chloroethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Reference Example 77, 36 mg) were added, and the mixture was stirred at room temperature for 1 hour. Potassium iodide (56 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour, then heated to 50°C and stirred for 21 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered out and washed with ethyl acetate. The filtrate and the washing solution were combined and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 2) to obtain N,N-dimethyl-4-(1-(2-(thien-2-yl)phenoxy)ethyl)-1H-imidazole-1-sulfonamide (24 mg).

[1019] ESI / MS (m / z) 378 (M+H)+ .

[1020] N,N-dimethyl-4-(1-(2-(thiophen-2-yl)phenoxy)ethyl)-1H-imidazole-1-sulfonamide (23 mg) obtained above was dissolved in methanol (600 μL), 2M hydrochloric acid methanol solution (600 μL) was added, and the mixture was stirred at 70°C for 19 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (NH silica; chloroform / methanol = 50 / 1) and thin layer chromatography (chloroform / methanol = 12 / 1) in this order to obtain the title compound (7.2 mg).

[1021] 1 H-NMR (400MHz, CD3OD) δ7.64-7.60(m,2H),7.52(dd,J=3.7,1.2Hz,1H),7.36(dd,J=5.2,1.2Hz,1H),7.14(dd d,J=8.8,7.2,1.7Hz,1H),7.09-7.01(m,2H),6.98-6.91(m,2H),5.56(q,J=6.4Hz,1H),1.72(d,J=6.4Hz,3H).

[1022] ESI / MS (m / z) 271 (M+H) + .

[1023] [Example 79]

[1024] (+)-4-(1-(2-(thiophen-2-yl)phenoxy)ethyl yl)-1H-imidazole and

[1025] [Reference Example 79]

[1026] (-)-4-(1-(2-(thiophen-2-yl)phenoxy)ethyl 1H-imidazole

[1027] The compound (4-(1-(2-(thiophen-2-yl)phenoxy)ethyl)-1H-imidazole) prepared in Example 78 was optically resolved by high performance liquid chromatography (CHIRALPAK IC; hexane / isopropanol / diethylamine = 950 / 50 / 1) to give the title compound.

[1028] Embodiment 79: 1H-NMR (400MHz, CDCl3) δ7.67(dd,J=7.7,1.7Hz,1H),7.61(d,J=1.1Hz,1H),7.55(dd,J=3.7,1.1Hz,1H),7.35(dd,J=5.1,1.1Hz,1H),7.18(dd d,J=8.4,7.7,1.7Hz,1H),7.12(dd,J=5.1,3.7Hz,1H),7.05(d,J=7.7Hz,1H),7.01-6.95(m,2H),5.63(q,J=6.4Hz,1H),1.80(d,J=6.4Hz,3H).

[1029] ESI / MS (m / z) 271 (M+H) + .

[1030] Reference Example 79: 1 H-NMR (400MHz, CDCl3) δ9.07(brs,1H),7.67(dd,J=7.7,1.6Hz,1H),7.60(s,1H),7.54(s,1H),7.38-7.34(m,1H),7.18(t,J=7 .2Hz,1H),7.12(dd,J=5.1,3.7Hz,1H),7.06(d,J=7.7Hz,1H),7.01-6.95(m,2H),5.63(q,J=6.4Hz,1H),1.80(d,J=6.4Hz,3H).

[1031] ESI / MS (m / z) 271 (M+H) + .

[1032] <Production of the compound of the present invention in which the biaryl moiety and the imidazole moiety are bonded via a sulfur atom>

[1033] Preparation Step IX-1 of Imidazolylmethylthioaryl (Reference Example 80)

[1034] [Reference Example 80]

[1035] 4-(((2-bromophenyl)thio)methyl)-N,N-dimethyl -1H-imidazole- 1-Sulfonamide

[1036] [Chemical formula 106]

[1037]

[1038] N,N-dimethylformamide (2.5 mL) and 2-bromobenzenethiol (31 μL) were added to 4-(chloromethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide hydrochloride (100 mg), potassium iodide (4.2 mg) and potassium carbonate (106.1 mg), and the mixture was stirred at room temperature for 15 hours and at 60°C for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtering out anhydrous sodium sulfate, the mixture was washed with ethyl acetate. The filtrate and the washing solution were combined and concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (hexane / ethyl acetate = 1 / 1), and then purified by thin layer chromatography (chloroform / ethyl acetate = 9 / 1) to obtain the title compound (82.1 mg).

[1039] ESI / MS (m / z) 377 (M+H) + .

[1040] Preparation steps IX-2 and 3 of the compounds of the present invention (Examples 80 to 82)

[1041] [Example 80]

[1042] 3-(2-(((1H-imidazol-4-yl)methyl)thio)benzene 1-(2-amino-4-pyridine)

[1043] [Chemical formula 107]

[1044]

[1045] 1,4-dioxane (1.5 mL) and water (0.3 mL) were added to 4-(((2-bromophenyl)thio)methyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Reference Example 80, 20 mg), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (16.4 mg), tetrakis(triphenylphosphine)palladium (6.1 mg), and potassium carbonate (22.1 mg), and the mixture was stirred at 90°C for 15 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered out and then washed with ethyl acetate. The filtrate and the washings were combined and concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (hexane / ethyl acetate = 1 / 2) to obtain N,N-dimethyl-4-(((2-(pyridin-3-yl)phenyl)thio)methyl)-1H-imidazole-1-sulfonamide (25.2 mg).

[1046] ESI / MS (m / z) 375 (M+H) + .

[1047] Methanol (0.5 mL) and 2M methanol solution of hydrochloric acid (0.5 mL) were added to N,N-dimethyl-4-(((2-(pyridin-3-yl)phenyl)thio)methyl)-1H-imidazole-1-sulfonamide (25.2 mg) obtained above, and the mixture was stirred at 70° C. for 10 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (chloroform / methanol=20 / 1) to obtain the title compound (6.3 mg).

[1048] 1 H-NMR (400MHz, CD3OD) δ8.49 (dd, J=4.8, 1.6Hz, 1H), 8.42 (dd, J=2.4, 0.8Hz, 1H) ,7.77(ddd,J=8.0,2.4,1.6Hz,1H),7.56(dd,J=7.6,1.2Hz,1H),7.52(d,J=1.2H z,1H),7.46(ddd,J=8.0,4.8,0.8Hz,1H),7.38(ddd,J=7.6,7.6,1.6Hz,1H),7.3 2(ddd,J=7.6,7.6,1.2Hz,1H),7.25(m,1H),6.69(s,1H),3.96(d,J=0.8Hz,2H).

[1049] ESI / MS (m / z) 268 (M+H) +

[1050] The method of Example 80 was used as a reference, and the compounds were synthesized according to the following reaction formula. The synthesized compounds are shown in Table 18, and the data are shown in Table 19.

[1051] [Chemical formula 108]

[1052]

[1053] [Table 18]

[1054]

[1055] [Table 19]

[1056]

[1057] <Pharmacological test examples>

[1058] (1) Cultivation of cells expressing human α1A adrenergic receptor

[1059] CHO-K1 cells highly expressing human α1A adrenergic receptor were purchased from ThermoFisher (GeneBLAzer TMADRA1A-NFAT-bla CHO-K1 Cells) were cultured according to the instruction manual.

[1060] (2) Ca in human α1A adrenergic receptor expressing cells 2+ Mobilization test

[1061] The cultured human α1A adrenergic receptor expressing cells were washed with D-PBS and replaced with loading buffer (DMEM (high-glucose) containing 2 μmol / L Fluo-4 / AM, 1x PowerLoad, 2.5 mmol / L Probenecid), and incubated at 37°C in a 5% CO2 incubator for 60 minutes. The cells were detached with 0.05% trypsin-EDTA solution and suspended with assay buffer (1.15 mol / L NaCl, 0.054 mol / L KCl, 1.8 mmol / L CaCl2, 1 mmoll / L MgSO4, 0.11 mol / L Glucose, 0.01 mol / L NaH2PO4·2H2O, 0.25 mol / L HEPES, pH 7.3) to give 500,000 cells / mL.

[1062] The test compound was dissolved in dimethyl sulfoxide and diluted with a test buffer containing 0.3% BSA. The final concentration of the test compound was set to a range of 0.1 nmol / L to 10 μmol / L. As a reference compound, norepinephrine was set to a final concentration of 0.01 nmol / L to 100 μmol / L.

[1063] The cell suspension solution (20,000 cells / well) was dispensed in 40 μL portions on a 384-well clear-bottom black plate (Corning) coated with poly-D-lysine and allowed to stand for 10 minutes. The plate was transferred to a fluorescent imaging microplate reader (FDSS7000, Hamamatsu Photonics) and the measurement was started. One minute after the start of the measurement, 20 μL of the test compound solution or norepinephrine solution (total 60 μL / well) (final concentration: 0.1% BSA, 0.1% dimethyl sulfoxide) was added to each well of the plate, and the fluorescence intensity of Fluo-4 was measured over time (Ex 480nm / Em 540nm) for another 5 minutes.

[1064] (3) Emax value and EC 50 Calculation of values

[1065] The maximum fluorescence value of the fluorescence intensity change caused by the test compound and norepinephrine was obtained, and the maximum fluorescence value of the well without the test compound was set to 0% and the maximum fluorescence value at 100 μmol / L norepinephrine was set to 100% to normalize the value. The normalized value (%Activation) was used in subsequent analysis.

[1066] About Emax value and EC 50 The concentration-response curve of the test compound was prepared by 4-parameter logistic regression using XLFit, and the Emax value was calculated as the %Activation when the test compound concentration was 10 μmol / L on the curve. The EC was calculated as the concentration that showed 50% response of the Emax value. 50 The results are shown in Table 20.

[1067] As a result, it was found that all the Example compounds tested this time have a high α1A receptor agonist activity.

[1068] [Table 20-1]

[1069]

[1070] [Table 20-2]

[1071]

[1072] Comparative compound 1 is compound 14 (N-((1H-imidazol-4-yl)methyl)-2-(oxazol-5-yl)aniline) described in Non-Patent Document 3 (Bioorg Med Chem Lett 12 3449-3452 2002).

[1073] The compound of the present invention has a superior adrenaline α1A receptor agonist effect compared with comparative compound 1.

[1074] Industrial Applicability

[1075] The compound of the present invention has an excellent adrenergic α1A receptor agonist activity and is therefore useful as a preventive or therapeutic drug for orthostatic hypotension, essential hypotension, acute hypotension associated with various diseases or conditions, and urinary incontinence.

Claims

1. A compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof, [Chemical formula 1] In the formula, R 1 represents a hydrogen atom or a C1-C3 alkyl group, Z is selected from the group consisting of the following formulas, [Chemical formula 2] R 2 represents a hydrogen atom, a fluorine atom or a C1-C3 alkyl group, R 3 Select from the group consisting of the following formulas, [Chemical formula 3] Y represents an oxygen atom or a sulfur atom, R 4 each independently represents a hydrogen atom or a C1-C3 alkoxy group, R 5 represents a hydrogen atom, a fluorine atom, a C1-C3 alkyl group or a C1-C3 alkoxy group, R 6 represents a hydrogen atom, a fluorine atom or a C1-C3 alkoxy group, R 7 represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyclopropyl group, R 8 represents a hydrogen atom or a C1-C3 alkoxy group, R 9 represents a hydrogen atom or a C1-C3 alkyl group, R 10 represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyano group, It should be noted that R 6 When it is C1-C3 alkoxy, R 7 and R 8 is a hydrogen atom; R 8 When it is C1-C3 alkoxy, R 6 is a hydrogen atom or a fluorine atom, R 7 A hydrogen atom.

2. A compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof, [Chemical formula 4] In the formula, R 1 represents a hydrogen atom or a C1-C3 alkyl group, Z is selected from the group consisting of the following formulas, [Chemical formula 5] R 2 represents a hydrogen atom, a fluorine atom or a C1-C3 alkyl group, R 3 Select from the group consisting of the following formulas, [Chemical formula 6] Y represents an oxygen atom or a sulfur atom, R 4 each independently represents a hydrogen atom or a C1-C3 alkoxy group, R 5 represents a hydrogen atom, a fluorine atom, a C1-C3 alkyl group or a C1-C3 alkoxy group, R 6 represents a hydrogen atom, a fluorine atom or a C1-C3 alkoxy group, R 7 represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyclopropyl group, R 8 represents a hydrogen atom or a C1-C3 alkoxy group, R 9 represents a hydrogen atom or a C1-C3 alkyl group, R 10 represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyano group, It should be noted that R 6 When it is C1-C3 alkoxy, R 7 and R 8 is a hydrogen atom; R 8 When it is C1-C3 alkoxy, R 6 is a hydrogen atom or a fluorine atom, R 7 is a hydrogen atom, in, Z is [Chemical Formula 7] 、 R 2 When it is a hydrogen atom, R 3 It is not 3-fluoropyridine bonded at the 2-position; In addition, Z is [Chemical Formula 8] 、 R 2 When it is a hydrogen atom, R 3 It is not any of unsubstituted pyridine bonded at the 2-position, unsubstituted pyrazole bonded at the 3-position, or 3-methoxypyrazole bonded at the 4-position; In addition, Z is [Chemical Formula 9] 、 R 2 When it is a hydrogen atom, R 3 It is not an unsubstituted furan bonded at the 2-position; In addition, Z is [Chemical Formula 10] 、 R 1 is a C1-C3 alkyl group and R 2 When it is a hydrogen atom, R 3 It is not an unsubstituted pyrazole bonded at the 4-position; In addition, Z is [Chemical Formula 11] When R 3 is not an unsubstituted thiazole bonded at the 5-position, It should be noted that R 1 When the alkyl group is C1-C3, the enantiomers produced are those whose α1A agonist activity is weaker than that of 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole.

3. The compound according to claim 2 or a pharmacologically acceptable salt thereof, wherein, R 3 Select from the group consisting of: [Chemical formula 12] In the formula, Y represents an oxygen atom or a sulfur atom, R 4 each independently represents a hydrogen atom or a C1-C3 alkoxy group, R 5 represents a hydrogen atom, a fluorine atom or a C1-C3 alkoxy group, R 6 represents a hydrogen atom, a fluorine atom or a C1-C3 alkoxy group, R 7 represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyclopropyl group, R 8 represents a hydrogen atom or a C1-C3 alkoxy group, R 9 represents a hydrogen atom or a C1-C3 alkyl group, R 10 represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyano group, It should be noted that R 6 When it is C1-C3 alkoxy, R 7 and R 8 is a hydrogen atom; R 8 When it is C1-C3 alkoxy, R 6 is a hydrogen atom or a fluorine atom, R 7 is a hydrogen atom, in, Z is [Chemical Formula 13] When R 3 Not bonded at position 4 and position 3 is R 9 Any one of substituted thiophene, pyridine bonded at the 3-position and substituted by a C1-C3 alkyl group at the 4-position, or unsubstituted pyrazole bonded at the 4-position; In addition, Z is [Chemical Formula 14] When R 3 Not bonded at position 4 and position 3 is R 9 Any one of substituted thiophene, pyridine bonded at the 3-position and substituted by a C1-C3 alkyl group at the 4-position, unsubstituted pyrazole bonded at the 4-position, unsubstituted pyrimidine bonded at the 5-position, or pyrimidine bonded at the 5-position and substituted by a C1-C3 alkyl group at the 4-position; In addition, Z is [Chemical Formula 15] 、 R 2 When it is C1~C3 alkyl, R 3 Not bonded at position 4 and position 3 is R 9 any one of substituted thiophene, unsubstituted pyrimidine bonded at the 5-position, or pyrimidine bonded at the 5-position and substituted at the 4-position by a C1-C3 alkyl group, In addition, Z is the same as above, R 2 When it is a hydrogen atom, R 3 Not bonded at position 3 and position 4 is C 11 Any one of pyridine substituted with a C3-alkyl group or unsubstituted pyrazole bonded at the 4-position, In addition, Z is the same as above, R 1 is a C1-C3 alkyl group and R 2 When it is a hydrogen atom, R 3 It is not 4-cyclopropylpyridine bonded at the 3-position, or unsubstituted pyrimidine bonded at the 5-position; In addition, Z is [Chemical Formula 16] When R 3 Not bonded at position 4 and position 3 is R 9 Any one of substituted thiophene, pyridine bonded at the 3-position and substituted by a C1-C3 alkyl group at the 4-position, unsubstituted pyrazole bonded at the 4-position, unsubstituted pyrimidine bonded at the 5-position, or pyrimidine bonded at the 5-position and substituted by a C1-C3 alkyl group at the 4-position.

4. The compound according to claim 3 or a pharmacologically acceptable salt thereof, wherein, R 3 Select from the group consisting of: [Chemical formula 17] In the formula, Y represents an oxygen atom or a sulfur atom, R 4 each independently represents a hydrogen atom or a C1-C3 alkoxy group, R 5 represents a hydrogen atom, a fluorine atom or a C1-C3 alkoxy group, R 6 represents a hydrogen atom, a fluorine atom or a C1-C3 alkoxy group, R 7a represents a hydrogen atom, a C1-C3 alkoxy group or a cyclopropyl group, R 7b represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyclopropyl group, R 8 represents a hydrogen atom or a C1-C3 alkoxy group, R 9 represents a hydrogen atom or a C1-C3 alkyl group, R 10 represents a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy group or a cyano group, It should be noted that R 6 When it is C1-C3 alkoxy, R 7 and R 8 is a hydrogen atom; R 8 When it is C1-C3 alkoxy, R 6 is a hydrogen atom or a fluorine atom, R 7 is a hydrogen atom, in, Z is [Chemical Formula 18] When R 3 It is not any of pyridine bonded at the 2-position and substituted by a C1-C3 alkoxy group at the 3-position, and pyridine bonded at the 5-position and substituted by a C1-C3 alkoxy group at the 3-position.

5. The compound according to claim 4 or a pharmacologically acceptable salt thereof, wherein, R 3 Select from the group consisting of: [Chemical formula 19] In the formula, R 4 each independently represents a hydrogen atom or a methoxy group, R 5 represents a hydrogen atom, a fluorine atom or a methoxy group, R 6 represents a hydrogen atom, a fluorine atom or a methoxy group, R 7a represents a hydrogen atom, a methoxy group or a cyclopropyl group, R 7b represents a hydrogen atom, a methyl group or a methoxy group, R 8 represents a hydrogen atom or a methoxy group, R 9 represents a hydrogen atom or a methyl group, R 10 represents a hydrogen atom, a methyl group, a methoxy group or a cyano group, It should be noted that R 6 When it is methoxy, R 7a and R 8 is a hydrogen atom; R 6 When it is a fluorine atom, R 8 is a hydrogen atom; R 8 When it is methoxy, R 6 is a hydrogen atom or a fluorine atom, R 7a is a hydrogen atom, in, Z is [Chemical Formula 20] When R 3 It is not 3-methylpyrazole bonded at the 4-position; In addition, Z is [Chemical Formula 21] When R 3 is not any of unsubstituted pyridine bonded at the 3-position, 3-methylpyrazole bonded at the 4-position, 2-methoxypyridine bonded at the 3-position, 4-methoxypyridine bonded at the 3-position, or unsubstituted thiophene bonded at the 2-position; In addition, Z is [Chemical Formula 22] When R 3 is not any of unsubstituted pyrimidine bonded at the 5-position, 3-methylpyrazole bonded at the 4-position, 2-methoxypyridine bonded at the 3-position, 4-methoxypyridine bonded at the 3-position, or unsubstituted thiophene bonded at the 2-position; In addition, Z is [Chemical Formula 23] 、 R 2 When it is methyl, R 3 is not any of unsubstituted pyridine bonded at the 3-position, 2-methoxypyridine bonded at the 3-position, 4-methoxypyridine bonded at the 3-position, or unsubstituted thiophene bonded at the 2-position, In addition, Z is the same as above, R 2 When it is a hydrogen atom, R 3 is not any of unsubstituted pyridine bonded at the 3-position, 3-methylpyrazole bonded at the 4-position, or unsubstituted thiophene bonded at the 2-position, In addition, Z is the same as above, R 2 When it is a fluorine atom, R 3 is not any of unsubstituted pyridine bonded at the 3-position, 4-methylpyrimidine bonded at the 5-position, 2-methoxypyridine bonded at the 3-position, or unsubstituted thiophene bonded at the 2-position; In addition, Z is [Chemical Formula 24] When R 3 It is not any of unsubstituted pyridine bonded at the 3-position, 3-methylpyrazole bonded at the 4-position, 2-methoxypyridine bonded at the 3-position, 4-methoxypyridine bonded at the 3-position, or unsubstituted thiophene bonded at the 2-position.

6. The compound according to claim 5 or a pharmacologically acceptable salt thereof, wherein, R 3 Select from the group consisting of: [Chemical formula 25] In the formula, R 4 each independently represents a hydrogen atom or a methoxy group, R 5 represents a hydrogen atom, a fluorine atom or a methoxy group, R 6 represents a hydrogen atom, a fluorine atom or a methoxy group, R 7a represents a hydrogen atom, a methoxy group or a cyclopropyl group, R 7b represents methoxy, R 8 represents a hydrogen atom or a methoxy group, R 9 represents a hydrogen atom or a methyl group, It should be noted that R 6 When it is methoxy, R 7a and R 8 is a hydrogen atom; R 6 When it is a fluorine atom, R 8 is a hydrogen atom; R 7a When it is methoxy, R 6 is a fluorine atom, R 8 is a hydrogen atom, in, Z is [Chemical Formula 26] When R 3 It is not an unsubstituted pyridine bonded at the 3-position.

7. The compound or pharmacologically acceptable salt thereof according to any one of claims 2 to 6, wherein In the general formula (I), Z is selected from the group consisting of the following formulae: [Chemical formula 27] 8. The compound or pharmacologically acceptable salt thereof according to any one of claims 2 to 6, wherein In the general formula (I), Z is selected from the group consisting of the following formulae: [Chemical formula 28] 9. The compound according to claim 7 or a pharmacologically acceptable salt thereof, wherein In the general formula (I), Z is the following formula: [Chemical formula 29] In the formula, R 2 represents a hydrogen atom, a methyl group or a fluorine atom, R 3 Select from the group consisting of: [Chemical formula 30] In the formula, R 4 represents a hydrogen atom or a methoxy group.

10. The compound according to claim 8 or a pharmacologically acceptable salt thereof, wherein In the general formula (I), Z is the following formula: [Chemical formula 31] R 3 Select from the group consisting of: [Chemical formula 32] In the formula, R 4 represents a hydrogen atom or a methoxy group, R 6 represents a hydrogen atom or a fluorine atom, R 7a represents a hydrogen atom, a methyl group, a methoxy group or a cyclopropyl group, R 7b represents a hydrogen atom, a methyl group, or a methoxy group, It should be noted that R 6 When it is a hydrogen atom, R 7a represents methoxy or cyclopropyl; R 7a When it is methyl, R 6 is a fluorine atom; R 7a When it is cyclopropyl, R 6 A hydrogen atom.

11. The compound according to claim 2 or a pharmacologically acceptable salt thereof, which is selected from the group consisting of the following compounds: N-((1H-imidazol-4-yl)methyl)-[2,3'-bithiophene]-4'-amine; N-((1H-imidazol-4-yl)methyl)-[2,2'-bithiophene]-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-methoxypyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-fluoropyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(1H-pyrazol-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-3-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(thiazol-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(thiazol-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyrazin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(thiazol-4-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(thiazol-4-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(3-methylpyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(3-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methylthiazol-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-5-methyl-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyrimidin-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-methylthiazol-4-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyrazin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(3-methoxypyridin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(3-fluoropyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyrazin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(6-methoxypyridin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(3-methoxy-1H-pyrazol-4-yl)-5-methylaniline; N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(3-methoxy-1H-pyrazol-4-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(pyridin-3-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(6-methoxypyridin-2-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(thiazol-4-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(furan-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyrimidin-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(2-methoxypyridin-3-yl)thiophen-3-amine; 4-((2-(thiophen-3-yl)phenoxy)methyl)-1H-imidazole; 4-((2-(Furan-2-yl)phenoxy)methyl)-1H-imidazole; 4-((2-(Thien-2-yl)phenoxy)methyl)-1H-imidazole; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyridine; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-3-methyl-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole-3-carbonitrile; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoropyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-2-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyridine; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole-3-carbonitrile; 3-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-4-methylpyridine; 4-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-3-methyl-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-3-methyl-1H-pyrazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-2-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-4-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-4-methoxypyridine; 5-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-4-methylpyrimidine; 5-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-4-methylpyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)pyrazine; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrazine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-cyclopropylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methoxypyridine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyrimidine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methylpyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)-6-methoxypyrazine; (+)-4-(1-(2-(thiophen-2-yl)phenoxy)ethyl)-1H-imidazole; 3-(2-(((1H-imidazol-4-yl)methyl)thio)phenyl)pyridine; 4-(2-(((1H-imidazol-4-yl)methyl)thio)phenyl)-1H-pyrazole; and 4-(((2-(Thien-3-yl)phenyl)thio)methyl)-1H-imidazole.

12. The compound according to claim 4 or a pharmacologically acceptable salt thereof, which is selected from the group consisting of the following compounds: N-((1H-imidazol-4-yl)methyl)-[2,3'-bithiophene]-4'-amine; N-((1H-imidazol-4-yl)methyl)-[2,2'-bithiophene]-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-methoxypyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-fluoropyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(1H-pyrazol-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-3-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(thiazol-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(thiazol-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyrazin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(thiazol-4-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(thiazol-4-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(3-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methylthiazol-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-5-methyl-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyrimidin-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-methylthiazol-4-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyrazin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(3-fluoropyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyrazin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(6-methoxypyridin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(3-methoxy-1H-pyrazol-4-yl)-5-methylaniline; N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(3-methoxy-1H-pyrazol-4-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(pyridin-3-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(6-methoxypyridin-2-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(thiazol-4-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(furan-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(2-methoxypyridin-3-yl)thiophen-3-amine; 4-((2-(Thien-3-yl)phenoxy)methyl)-1H-imidazole; 4-((2-(Thien-2-yl)phenoxy)methyl)-1H-imidazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyridine; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-3-methyl-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole-3-carbonitrile; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoropyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-2-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyridine; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole-3-carbonitrile; 4-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-3-methyl-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-3-methyl-1H-pyrazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-2-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-4-methoxypyridine; 3-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-4-methoxypyridine; 5-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-4-methylpyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)pyrazine; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrazine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-cyclopropylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methoxypyridine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyrimidine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methylpyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)-6-methoxypyrazine; (+)-4-(1-(2-(thiophen-2-yl)phenoxy)ethyl)-1H-imidazole; and 3-(2-(((1H-imidazol-4-yl)methyl)sulfanyl)phenyl)pyridine.

13. The compound according to claim 5 or a pharmacologically acceptable salt thereof, which is selected from the group consisting of the following compounds: N-((1H-imidazol-4-yl)methyl)-[2,3'-bithiophene]-4'-amine; N-((1H-imidazol-4-yl)methyl)-[2,2'-bithiophene]-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-methoxypyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-fluoropyridin-3-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(1H-pyrazol-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-3-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(thiazol-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(thiazol-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyrazin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(thiazol-4-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(thiazol-4-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(3-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-5-methyl-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(4-methoxypyrimidin-5-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(5-methylthiazol-4-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(4-methylpyrimidin-5-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyrazin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(pyridin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(3-fluoropyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(pyridin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-4-(6-methoxypyrazin-2-yl)thiophen-3-amine; N-((1H-imidazol-4-yl)methyl)-2-(6-methoxypyridin-2-yl)aniline; N-((1H-imidazol-4-yl)methyl)-2-(3-methoxy-1H-pyrazol-4-yl)-5-methylaniline; N-((1H-imidazol-4-yl)methyl)-5-fluoro-2-(3-methoxy-1H-pyrazol-4-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(pyridin-3-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(6-methoxypyridin-2-yl)aniline; (+)-N-(1-(1H-imidazol-4-yl)ethyl)-2-(thiazol-4-yl)aniline; N-((1H-imidazol-4-yl)methyl)-4-(2-methoxypyridin-3-yl)thiophen-3-amine; 4-((2-(Thien-3-yl)phenoxy)methyl)-1H-imidazole; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)-1H-pyrazole-3-carbonitrile; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoropyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyridine; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-1H-pyrazole-3-carbonitrile; 4-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-3-methyl-1H-pyrazole; 4-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)-3-methyl-1H-pyrazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)-4-fluorophenyl)-4-methoxypyridine; 2-(2-((1H-imidazol-4-yl)methoxy)-4-methylphenyl)pyrazine; 4-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrazine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)pyrimidine; 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)thiazole; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-cyclopropylpyridine; 3-(2-((1H-imidazol-4-yl)methoxy)phenyl)-5-fluoro-4-methoxypyridine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methoxypyrimidine; 5-(2-((1H-imidazol-4-yl)methoxy)phenyl)-4-methylpyrimidine; and 2-(2-((1H-imidazol-4-yl)methoxy)phenyl)-6-methoxypyrazine. 14 . A pharmaceutical composition comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.

15. The pharmaceutical composition according to claim 14, which is used for preventing or treating a disease selected from the group consisting of orthostatic hypotension, essential hypotension, acute hypotension associated with various diseases or conditions, and urinary incontinence.

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