TW201114425A - Iminopyridine derivatives and use thereof - Google Patents

Abstract

The present invention aims to provide a compound having a superior selective α 1D adrenergic receptor antagonistic action and useful as an agent for the prophylaxis or treatment of a lower urinary tract disease and the like. The present invention provides a compound represented by the formula (I) wherein each symbol is as defined in the specification, or a salt thereof.

Description

201114425 VI. Description of the invention: [Technical field to which the invention pertains] The present invention relates to antagonism of superior aiD adrenergic receptor (hereinafter also referred to as a] D receptor) and prevention of diseases such as lower urinary tract Or an imine pyridine derivative of a therapeutic agent. [Prior Art] The adrenergic receptor (hereinafter also referred to as α1 receptor) is widely distributed in the cardiovascular system, the lower urinary tract, etc. and involves sympathetic nerve activity. Since it has been proposed to be associated with lesions such as hyperglycemia, cardiac hypertrophy, and dysuria, there has been a period of time that the αι receptor has attracted attention, and many attempts have been made to develop therapeutic drugs. In recent years, the industry has been effective in urinating difficulties associated with benign digestive adenocarcinoma (BPH); it has once again attracted widespread attention in combination with its market (non-patent document). . The scorpion receptor gene was selected from the late 198s to the early 1970s, and three subtypes of aiA, aiB and αι〇 were identified. Among them, e1 only a1D corpus callosum in some tissues such as blood vessels and brain The hair, the spinal cord, the digestive tract, the bladder, the kidney, etc. Although the aiD receptor d has not yet been used, due to its wide range of localization, the sputum receptor antagonist may be used as a therapeutic drug for various diseases. It has been confirmed that the a]D receptor is more distributed in the parasympathetic nucleus of the bladder and sacrai C〇rd than other subtypes (Non-Patent Documents 2 and 3), thus suggesting that it strongly relates to urine storage. product. In fact, it has been reported that the bladder capacity and single urine output are significantly increased in the Μ gene knockout mice (Non-Patent Document 4). Recent reports have shown that the expression of oc1D receptor mRNA is increased in bladders of patients with ΒρΗ and 321556 4 201114425 (Non-Patent Documents 5 and 6), and bladder muscles isolated from BPH patients are subject to a1D. The body may show an increase in the contraction function (Non-Patent Document 7), etc., thus suggesting that the a1D receptor expressed in the bladder may be involved in the pathology of BPH. From the above, the a1D receptor antagonist is promising as a prophylactic or therapeutic agent for lower urinary tract diseases and the like. Examples of compounds showing selective a1D receptor antagonism are as follows: See the compounds shown by the following formula in Non-Patent Document 8:

See the compounds shown in the formula below:

CN P is described in the compound of the formula:

See the compound shown in the following formula 3: 5 321556 201114425

And the compounds shown in the following formula of Non-Patent Document 9

Further, those known in Patent Documents 4 to 7 and Non-Patent Documents 10 to 32 are known imine derivatives. Patent Document 8 describes compounds shown by the following formulas

Citation Document Table Patent Document Patent Document 1: WO00/04012 Patent Document 2: US3997666 Patent Document 3: WO00/04027 Patent Document 4: DD 263759 Patent Document 5: ΕΡ47977 6 321556 201114425 Patent Document 6: DD106377 Patent Document 7: JP-B -48-40544 Patent Document 8: W008/050732 Non-Patent Document Non-Patent Document 1: Yakugaku Zasshi 126, 187-198, 2006 Non-Patent Document 2: Molecular Brain Research 63, 254-261, 1999 Non-Patent Document 3: J. Urol. 160: 937-943., 1998 Non-Patent Document 4: J. Urol. 174: 370-4·, 2005 Non-Patent Document 5: J. Urol. 170: 649-653., 2003 Non-Patent Document 6: J · Urol. 167: 1513-1521., 2002 Non-Patent Document 7: J. Urol 173: 657-61., 2005 Non-Patent Document 8: Eur. J. Pharmacol., 272, (1995), R5-R6 Non Patent Document 9: Eur. J_ Pharmacol., 445, (2002), 21-29 Non-Patent Document 10: Heteroatom Chemistry (2004), 15(4), 293-299 Non-Patent Document 11: Latvijas Kimijas Zurnals (1995), (3-4), 109-113 Non-Patent Document 12: Arzneimittel-Forschung (1995), 45(9), 957-62 Non-Patent Document 13: Journal of the Ch Inese Chemical Society (Taipei, Taiwan) (1993), 40(2), 181-7 Non-Patent Document 14: Zhurnal Strukturnoi Khimii (1988), 29(5), 169-72 7 321556 201114425 Non-Patent Document 15: Latvijas PSR Zinatnu Akademijas Vestis, Kimijas Serija (1986), (4), 471-8 Non-Patent Document 16: Latvijas PSR Zinatnu Akademijas Vestis, Kimijas Serija (1985), (3), 351-8 Non-Patent Document 17: Latvijas PSR Zinatnu Akademijas Vestis, Kimijas Serija (1985), (2), 200-5 Non-Patent Document 18: Tetrahedron (1980), 36(6), 785-9 Non-Patent Document 19: Zeitschrift fuer Naturforschung, Teil B: Anorganische Chemie, Organische Chemie (1980), 35B(4), 490-3 Non-Patent Document 20: Tetrahedron (1979), 35(21), 2591-3 Non-Patent Document 21: Fette, Seifen, Anstrichmittel (1980), 82(2), 82 -6 Non-Patent Document 22: Tetrahedron (1979), 35(6), 809-12 Non-Patent Document 23: Journal of Chemical Society of Japan (1978), (5), 730-6 Non-Patent Document 24: Tetrahedron Letters ( 1977), (15), 1333-6 Non-Patent Document 25: Journal fuer Praktische Chemie (Leipzig) (1976), 318 (5) ), 705-30 Non-Patent Document 26: Zeitschrift fuer Chemie (1973), 13(9), 342-3 Non-Patent Document 27: Journal of Chemical Society [Section] C: Organic (1971), (10), 1892- 5 8 321556 201114425 Non-Patent Document 28: Angewandte Chemie, International ' Edition in English (1971), 10(1), 68-70 Non-Patent Document 29: Chemical & Pharmaceutical Bulletin (1969), 17(11), 2209- 16 Non-Patent Document 30: Chemical & Pharmaceutical Bulletin (1966), 14(8), 861-6 Non-Patent Document 31: Doklady Akademii Nauk SSSR (1949), 66, 647-50 Non-Patent Document 32: Ann. (1925 SUMMARY OF THE INVENTION PROBLEM TO BE SOLVED BY THE INVENTION The present invention is intended to provide a compound as a prophylactic or therapeutic agent for diseases such as lower urinary tract. Means for Solving the Problems The inventors of the present invention have conducted intensive studies in view of the above circumstances, and have found a compound of the following formula (hereinafter abbreviated as Compound (1)) or a salt thereof,

In the formula,

It is necessary to have one or more substituents, 321556 9 201114425 R1 is a methyl group, or R1 and A ring may be bonded as needed to form a fused ring group having one or more substituents as needed, and R2 is a hydrogen atom or a methyl group, or R1 and R2 are bonded together with an adjacent carbon atom to form a cycloalkane ring, and R3 is a hydrogen atom, a halogen atom, a cyano group, optionally a hydrocarbon group having one or more substituents, a mercapto group, and optionally one or more substitutions. a heterocyclic group, an amine group having one or more substituents as needed, a hydroxyl group optionally having a substituent or a thiol group optionally having a substituent; having a1D adrenergic receptor antagonism according to a specific chemical structure thereof . Based on this finding, the inventors completed the present invention. Therefore, the present invention relates to a compound represented by the following formula [1] or a salt thereof,

Wherein the A ring is a phenyl group, a cycloalkyl group or a 5 or 6 membered aromatic heterocyclic group, each having one or more substituents as needed, R1 is a methyl group, or R) and A are optionally bonded to form a ring. A fused ring group having one or more substituents is required, R2 is a hydrogen atom or a methyl group, or R1 and R2 are bonded together with an adjacent carbon atom to form a cycloalkane ring and 10 321556 201114425. The scorpion, the cyano group, the fluorenyl group, the fluorene group, the A's soil, the ugly group, the heterocyclic group having a plurality of substituents, if necessary, the amine group having - or a plurality of substituents , if necessary, a substituent having a substituent or an optionally substituted thiol group; except for the following compounds: 5-gas-1-(2,3·dihydro-indenyl)-based 2-iodido-3 -Metformamide, 疋5·Ga-2-iminyl]_〇•Phenylethyl-dihydrotin _3_Methyl-1-yl)-1,2-dihydro The compound of the above [1] or a salt thereof, wherein the a ring is optionally required to have a ring of the above-mentioned [1] or a salt thereof. One or more substituents of phenyl hydrazine [3] The compound of the above [1] or a salt thereof, wherein r3 is a halogen ; Compound [4] [1] or a salt thereof of, wherein the moiety of formula ⑴ FIG junction σ

The group represented by the following formula: wherein the ring A is as defined in the above [i], and the salt of the compound of the above [4], wherein the ring a (1) has a selected from (a) Drawing the atom, (b) cyano and (c) alkylsulfonyl i to 3 substituents 321556 11 201114425 phenyl '(2) optionally having one or more substituents, or The compound of the above [4] or a salt thereof, wherein the ring A is (1) has a halogen atom selected from (a), (b) cyanide, and (b) a phenyl '(2)« than a dimethyl group of (i) to 3 substituents of (c) Cl. 6 alkylsulfonyl, or (3) an epoxy group; [7] a compound of the above [4] or a salt thereof, wherein the ring A is (?) a phenyl '(2)«»-pyridinium having 2 to 3 substituents selected from the group consisting of (4) a halogen atom, (b) a cyano group and a (4) Cl. 6 alkylsulfonyl group. The compound of the above [4] or a salt thereof, wherein the ring A is a benzene having a substituent selected from the group consisting of a (4) functional group and a (8) cyano group to two substituents. a group, and R is a halogen atom; wherein, a part of the structure of the formula (I) [9] the compound of the above [1] or a salt thereof, The group

a fused ring group represented by the following formula

R4 is the same as or different from K and each is selected from the group consisting of a radical, a functional atom and a ruthenium. In the formula, r6 is a pyridyl group, and P is an integer from 〇 to 2) 321556 12 201114425 代基, m is An integer of 0 to 3, and η is an integer of 0 to 4; [10] The compound of the above [9] or a salt thereof, wherein R4 is a hydroxyl group, and R is selected from a halogen atom 'cyano group and -S(0) a substituent of p-R6 (wherein r6 is an alkyl group, p is an integer of 0 to 2), and m'l or 2' are the same or different and each is 〇 or } [11] a compound or a salt thereof, wherein R3 is a tooth atom and R4 is a meridine group,

η are the same or different and each is 〇 or R5 is selected from a halogen atom, an alkyl group, ? a substituent m+n==l or 2, or 1; a salt of the compound [9] or a salt thereof, wherein R is a argon atom, R5 is a tooth atom, and m is 〇, and η is 1; [1·3] The compound of the above [1] or the salt thereof is represented by the formula 1 wherein the moiety of the formula (I)

A fused ring group as shown in the following formula 321556 13 201114425

Wherein the substituents of R41 and R5i, cyano and -S(0)p, -: R6I integer) are the same or different and each is (wherein R61 is an alkyl group selected from a hydroxyl group, a halogenogen' P 'X of 0 to 2 is S, so or s〇2, m' is an integer of 0 to 3, and η is an integer of 0 to 4; Π4] The compound of the above [13] or a salt thereof, wherein R is a tooth atom, R is a tooth atom, m' is 0, and η' is 0 or 1; [15] The compound of the above [13] or a salt thereof, wherein R3 is a _ atom, R51 is a halogen atom, and X is a so-called And m' is 0, and η' is 1; [16] The compound of the above [1] or a salt thereof, wherein a moiety of the formula (I) of the formula is represented by R2-

321556 14 201114425

A group represented by the formula: ch2-- wherein q is an integer from 0 to 4, and ring A is as defined in the above oxime]; [17] 5-chlorochlorophenyl)ethyl]-2-imine Base-1,2-dihydrogen. Pyridin-3-carbamide or a salt thereof; [18] 5-chlorosuccinate (6-chloro-2,3-dihydro-1Η-indol-1-yl)-2-imino-1,2- Dihydropyridin-3-indolylamine or a salt thereof; [19] 5-chlorofluorophenyl)ethyl;|_2_imino", dihydropyridin-3-indoleamine or a salt thereof; [20] 5-Chloro-1-[(1 ft)_11_(3,5-difluorophenyl)ethyl]_2-imino-1,2-diaza ratio ° 曱 曱 胺 amine or its salt [21] 5-Chloro-1-[(1trans)_1_(3-cyanophenyl)ethyl]_2imino12·dihydropyridine-3-carboxamide or a salt thereof; [22] 5 · Chlorine gas ten 1-dioxy ion-3,4_dihydro-2Η-sulfur bitrate; ene-4-yl)-2-imino-1,2_dihydro η than 唆_3_ amide Or a salt thereof; [23] a compound of the above-mentioned compound]; [24] - a drug comprising the compound of the above [1] or a precursor thereof; [25] The pharmaceutical agent of the above [24], a [D] adrenergic receptor antagonist; [26] above: 4 [24] of the drug, for the prevention or treatment of lower urinary tract diseases;, between - for the prevention or treatment of lower urinary tract diseases in mammals Method / method for the preparation of the above-mentioned compound [1] 321556 15 201114425 or its prodrug [] - The use of the above compound [1] or its prodrug, for the manufacture of a prophylactic or therapeutic agent for lower urinary tract diseases, etc. No effect [Invention] The compound (I) of the present invention has superior selectivity aiD The adrenaline antagonism is an agent for the prophylaxis or treatment of diseases such as the lower urinary tract. [Embodiment] The present invention will be described in detail below, without otherwise referring to the sun and the moon, otherwise "Southern atom" means gas atom in the present specification. , chaotic atoms, > stinky atoms or moth atoms. In the formula (I), the ring A is a phenyl group, a cycloalkyl group or a 5- or 6-membered aromatic heterocyclic group each having one or more substituents as necessary. Examples of the "cycloalkyl group" include a C3.8 cyclodecyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like. "5 or 6 membered aromatic heterocyclic group," examples include, in addition to a carbon atom, a 5- or 6-membered aromatic heterocyclic group derived from a nitrogen atom, a sulfur atom and an oxygen atom; "Famyl, fluorenyl, oxime, money-loving, hetero-isolation, (tetra)-based, hetero-radical, imipenyl, fluorenyl, oxadiazolyl 1,2,4-, diazolyl, u, 4, oxazolyl 'furanyl, ruthenium-based, ^ red, u, 4m tris-s, a 'seat-sit-base, B-bite, thiophene-based Biting bases " than wells, triterpenoids, etc.) "Phenyl, cyclofilament or 5 or 6 贞 秘 "" Examples of substituents as needed include 321556 】 6 201114425 (I) Halogen atoms (for example, Fluorine atom, gas atom, desert atom, moth atom*, etc.), '(2) nitro, _(3) cyano, (4) hydroxy, (5) 1 to 3 halogen atoms as needed (for example, fluorine An alkoxy group of an atom, a gas atom, a bromine atom or an iodine atom (for example, a decyloxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a second butoxy group, Pentyloxy, hexyloxy, fluorodecyloxy, etc.), (6) C6 _14 aryloxy (eg, phenoxy, naphthyloxy, etc.), (7) C7_16 aralkyloxy (eg, benzyloxy, phenethyloxy, dipyridyloxy, 1-naphthylmethoxy) , 2-naphthylmethoxy, 2,2-diphenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, etc.), (8) Sulfhydryl, (9) an alkylthio group (preferably a Cw alkylthio group) having 1 to 3 halogen atoms (for example, a fluorine atom, a gas atom, a bromine atom, or an iodine atom) as needed (for example, a thiol group, Difluorosulfonylthio, trifluorosulfonylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc. ), (1〇) C6_14 arylthio (eg, phenylthio, naphthylthio, etc.), (II) C7-16 arylsulfuryl (eg, benzylthio, phenethylthio, diphenylmethylsulfide) Base, 1-naphthylsulfonylthio, 2-naphthylsulfonylthio, 2,2-diphenylethylthio, 3-phenylpropylthio, 4-phenylbutylthio, 5-phenylpentyl Thio group, etc., (12) amine group, (13) mono-Cw alkylamino group (for example, methylamino group, ethylamino group, etc.), 17 321556 201114425 (14) mono-C6_14 arylamino group (for example, anilino group) 1-naphthylamino, 2-naphthylamino, etc.), (15) mono-C7-I6 aralkylamino (eg, benzylamino, etc.), (16) di-Cw alkylamine (eg, decylamine) a group, a diethylamino group, etc.), (17) a di-C6_14 arylamino group (for example, a diphenylamino group, etc.), (18) a second <7_16 aralkylamino group (for example, a dibenzylamino group, etc.), (19) Carbenyl, (20) Cu alkyl-carbonyl (eg, ethyl, propyl, etc.), (21) C6_14 aryl-carbonyl (eg, benzinyl, 1-naphthyl, 2-naphthalene) (2) a carboxyl group, (23) a Ck6 alkoxy-carbonyl group (for example, an anthraceneoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a third butoxycarbonyl group, etc.), (24) a C6_14 aryloxy group- Carbonyl (e.g., phenoxycarbonyl, etc.), (25) amine indenyl, (26) amine (thiomethyl), (27) mono-Cw alkyl-amine thiol (e.g., methylamine oxime) Base, ethylamine sulfhydryl, etc., (28) di-CV6 alkyl-amine sulfhydryl (eg, dimethylamine carbaryl, diethylamine carbhydryl, ethyl decylamine hydrazine) (29) C6_14 aryl-amine fluorenyl (for example, phenylamine fluorenyl, 1-naphthylamino fluorenyl, 2-naphthylamine fluorenyl, etc.), _ (30) An alkylsulfonyl group having 1 to 3 halogen atoms (for example, a fluorine atom, a gas atom, a bromine atom, or an iodine atom) as needed (preferably CK6 alkylsulfonyl 18 321556 201114425 *> (eg, fluorenylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl, etc.), '(31) C6_14 arylsulfonyl (eg, phenylsulfonyl, 1-naphthylsulfonate)醯• base, 2-nene-based, etc.), (32) alkylsulfinyl (preferably (^.6 alkylsulfinyl)) (eg, fluorenylsulfinyl, ethyl) Sulfosyl group, etc., (33) C6.]4 arylsulfinyl (for example, phenylsulfinylene, 1-naphthylsulfinyl, 2-naphthylsulfinyl, etc.), (34) mercaptoamine group, (35) C]_6 alkyl-carbonylamino group (for example, ethenylamino group, etc.), (36) C6_14 aryl-carbonylamino group (for example, benzhydrylamino group) , a naphthylamino group, etc.), (37) a Cw alkoxy-carbonylamino group (for example, an anthraceneoxycarbonylamino group, an ethoxycarbonylamino group, a propoxycarbonylamino group, a butoxycarbonylamino group, etc.), 38) Acryl group-based amine group (for example, 5 fluorenyl yellow amine group, ethyl fluorescens amine group, etc.) (39) C6_]4 arylsulfonylamino group (for example, phenylsulfonylamino group, 2-nyl sulfonic acid amine group, 1-methyl sulfhydrylamino group, etc.), (40) alkane a carbonyloxy group (for example, an ethoxylated group, a propyloxy group, etc.), (41) a C6.]4 arylcarbonyloxy group (for example, a benzyloxy group, a naphthylcarbonyloxy group, etc.), (42) a Cu6 alkoxy group. Carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propyloxycarbonyloxy, butoxycarbonyloxy, etc.), (43) mono-C!-6 alkyl-amine decyloxy ( For example, mercaptoaminocarbonyl, ethylamine decyloxy, etc., 19 321556 201114425 (44) Di-C^alkyl-amine decyloxy (eg, dimethylamine formazan) (Alkyloxy, diethylamine, mercaptooxy, etc.), (45) C6_I4 aryl-amine mercaptooxy (for example, phenylamine mercaptooxy, naphthylamine, mercaptooxy, etc.) And (46) a 5- to 7-membered saturated cyclic amine group having one or two kinds of one to four hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, as needed, in addition to a carbon atom and a nitrogen atom (for example, ° ° ° D each -1 - group, N-hexahydrogen. Specificity, hexahydropyridin-1-yl, N-morpholinyl, thio N-morpholinyl, hexahydroindol-1-yl, etc., (47) In addition to carbon atoms, one or two a 5 to 10 membered aromatic heterocyclic group selected from the group consisting of a nitrogen atom, a sulfur atom and 1 to 4 hetero atoms of an oxygen atom (for example, 2-β-sepeno group, 3-1·sepeno group, 2-° ratio) °定定, 3-° ratio °定定, 4-D ratio °定基, 2-啥啥基, 3-啥琳基, 4-噎你基, 5-喧琳基, 8-啥琳基, 1-异Anthracene, phenyl, 3-isoquinolinyl, 4-isoindolyl, 5-isoindolinyl, 1-D fluorenyl, 2-indenyl, 3-indolyl, 2-benzothiazole , 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl, etc., (48) 0^3 An alkylenedioxy group (for example, a methylenedioxy group, an ethylenedioxy group, etc.), (49) a C3_7 cycloalkyl group (for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group). And (50) optionally having a Cw alkyl group selected from an il atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom) and a hydroxyl group of 1 to 3 substituents (for example, an anthracenyl group, an ethyl group, or the like). N-propyl, isopropyl, n-Butyl, isobutyl, t-butyl, tert-butyl, n-pentyl, second amyl, isopentyl, neopentyl, 20 321556 201114425 n-hexyl, isohexyl, etc.), sub, i: Requires: C2·6 dilute group having 1 to 3 halogen atoms (for example, fluorine atom, gas atom) (for example, dilute propyl, isopropyl diisopropyl, 2-pentyl, 2-hexenyl Etc.), I) ^2-6 blocks (eg 'block propyl, 2 τ k 3. pentynyl, 3. hexyl, etc.), butyl group, 3 · butyl group, (b) a base group, an amine methyl group (for example, cyclopropylamine methyl sulfonyl group, % butylamine methyl fluorenyl group, etc.), a hydrazine carbon atom 'containing - or two kinds selected from a nitrogen atom, a sulphur atom, an oxygen atom i to 4 heteroatoms 5 to 1 G M heterocyclic group 峨 体 吗 琳 琳 琳 琳 琳 琳 琳 琳 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ^ ^ Preferably, it is a thiol group, a south atom, a cyano group and a hexagram 6 (wherein R is an alkyl group of 'P is an integer of 〇 to 2), more preferably a thiol group, a tooth atom, a cyano group and a oxime group (wherein r6) For Q 6 alkyl, p is 〇 to an integer of 2), and more preferably (tetra), cyano and s (〇vr6 (in the formula c" , P is an integer of 〇6 to 2)' is particularly preferably a (tetra) or a cyano group, and most preferably an alkyl group which is not a halogen atom, preferably an alkyl group such as methyl, ethyl or n-propyl. Base, isopropyl, n-butyl, isobutyl, t-butyl, third; base, n-pentyl, second pentyl, isopentyl, neopentyl, n-hexyl, isohexyl The A ring is preferably a phenyl group, a c36 cyclofilament or a 5 or 6 M aromatic heterocyclic group (preferably a furyl group, a thienyl group, a pyridyl group), each having a — or a oxime substituent, as needed. Preferably, it is a phenyl group, a thienyl group or a pi-pyridyl group, each having 321556 21 201114425 having - or a plurality of substituents; particularly preferably having - or a plurality of phenyl groups as needed. Specifically, the A ring is preferably a phenyl-cycloalkyl group or a 5- or 6-membered aromatic heterocyclic group (preferably, a thiol group, an anthracenyl group, a fluorenyl group) (preferably a phenyl group, a porphinyl group). , ^ particularly preferred is phenyl) 'each of which has a substituent selected from the group consisting of a radical and -S(〇)〆 (wherein R6 is a burning group, and P is an integer from 〇 to 2); 1 to = gui is: base, C erki or 5 or 6 members of the fangs, heart H wire) (the remaining silk base (, ^ (four) silk base (four) to face with silk" than 疋 与, W (wherein "Cl ritual, p is the original whole" I to 3 substituents; 'the integer' is more preferably phenyl, C3_6 cycloalkyl or 5 or $=_yl, (tetra), 1 to phenyl, C 3 · 6 cycloalkyl or 5 or 6 aryl is a thiol group, 嗟 ) ) 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳An acyl group, preferably a heterobasic group (preferably a base group, particularly preferably a phenyl group), each of which depends on a base/butter to 3 (preferably 13 ge 2) substituents; South atom and cyano! The best is phenyl, C3.6 ring wire ^ for butterfly, Naji (:: 321556 22 201114425 base, especially good for phenyl), each as needed 1 to 3 (preferably 1) halogen atom. * ' In another embodiment, the ring A preferably has (1) having a halogen atom selected from (a), (b) a cyano group and (c) an alkane. a phenyl group having 1 to 3 substituents of the sulfonyl group, (2) a pyridyl group having one or more substituents as necessary, or (3) a thienyl group having one or more substituents as needed; more preferably And (1) a phenyl group having 1 to 3 substituents selected from the group consisting of (a) a halogen atom, (b) a cyano group and (c) an alkylsulfonyl group, (2 units of pyridyl, or (3) thiophene Particularly preferred is a phenyl group having 1 to 2 substituents selected from the group consisting of (a) ii atoms and (b) cyano groups. R1 is a fluorenyl group, or R and A are optionally bonded to form one or more a fused ring group of a substituent. When R1 is a fluorenyl group, the group represented by the following structural formula:

A preferred specific example is a group represented by the following formula

Wherein ring A is as defined above (but R2 is a hydrogen atom). In this embodiment, the ring A is preferably a phenyl group, a fluorene 3-6 cycloalkyl group or a 5 or 6 membered aromatic heterocyclic group (preferably a furyl group, a thienyl group, an acridinyl group) (preferably a stupid group, a thienyl group, a pyridyl group, particularly preferably a phenyl group, each optionally having a hydroxyl group, a halogen atom, a cyanogen 23 321556 201114425 group and -S(〇)p-R6 (wherein R6 is an alkyl group 3) Substituent; P is, 〇 to an integer of 2) to more preferably stupid, C3 6 net p and + c is butterfly, pheno, ring-based, especially good for stupid), each as needed ) 基 基 、, material = 0 VR (in the formula ~ (four) base, β. to 2 integer): 1 to 3 substituents; positive 弑) is preferably fluorenyl, C3 · 6 Wei Ke or 5 or 6 Μ aromatic heterocyclic group (wider: soil phenanthrene, 0 to 0 base) (preferably phenyl, porphin, mouth ratio ° bauxite, especially phenyl), each as needed ( Wherein R6 is C16 calcined, ρ Α has; ^ atom, cyano group and 3 substituents; !·6 seam integer)! To = gui, phenyl, C3.6 cyclofilament or 5 or 6-membered aromatic heterocyclic group after the bite % base "sembranyl K group" (better silk base " thiophene) than bite base More preferably, it is a phenyl group. ' Each of them may have from 3 to 3 (preferably 1 or 2) substituents selected from a halogen atom and a nitrogen group; most preferably a phenyl group, (: 3-6 cycloalkyl group) Or a 5- or 6-membered aromatic heterocyclic group (preferably a fluorenyl group, an age group, a "base") ((a) a silk group, a (tetra) group", a bite base, and a particularly good base), each having as needed! Up to 3 (preferably a halogen atom. In another embodiment, the ring A is preferably (1) having 1 to 3 substituents selected from the group consisting of a (4) functional atom, (b) a cyano group, and a (4) alkyl group. a phenyl group, (2) a thiopyridyl group having one or more substituents as necessary, or (3) a thienyl group having one or more substituents as necessary; / 321556 24 201114425 . * more preferably (1) having a selected from (8) ii atom, (8) cyano group and (c) c] _6. The phenyl group of 1 to 3 substituents of the fluorene group, (7) a thiol group, or (7) an oxenyl group; particularly preferably having a halogen atom selected from (4) And (b) a phenyl group having 1 to 2 substituents of a cyano group. When required to have one or more substituents of the rings is slightly group, a group represented by the following partial structural formula:

A preferred specific example of R2- is a slightly cyclic group selected from the groups shown below.

The substituent R4 which is selected from the group consisting of a hydroxyl group, a halogen atom and a cyanide P which is an integer of 0 to 2) is the same as or different from R5 and the respective groups are -S(0)p-R6 (wherein R6 is an alkyl group, a group, m is 〇 An integer up to 3, and η is an integer from 〇 to 4 (except that R2 is a hydrogen atom). The fused ring group may be the same or improper, and each m may be an integer of 2 or more (ie, a position of substitution) When there are two or more R4), 321556 25 201114425 , in addition, when η is an integer of 2 or more (that is, the fused ring group may have 2 or more R 5 in place of the substitution) Each R5 may be the same or different. R4 is a substituent present on the ring bonded to the ring, and r5 is a substituent appearing on the other ring. The above-mentioned thick: %: in the group, as shown below a fused ring group is preferred

The symbols in the formula are as defined above. In this specific example, preferred embodiments are shown below. Μ and: are preferably the same or different and each is a substituent selected from the group consisting of pW (wherein rUc) 6^^ integer). R4 of 芏2 is more preferably a warp group. R5 is more preferably a substituent selected from a tooth atom, a cyano group and a _s (〇vr6 (an integer in the formula), particularly preferably a ruthenium atom: 乂 and ^m+n=1 or 2 (but also the same or Each of which is 0 or "; preferably m is (^ is a ^ or 'When 11] and octacyclic is required to have a plurality of substituent fused ring groups, the following partial structure. Another preferred embodiment of the R1 group The slightly closed ring base shown in the following formula 321556 26 201114425

(R41)/, X' \^' (R51W wherein me is the same or different and each is selected from the group consisting of cyano and -S(0)p, -R61 (wherein R61 is an alkyl substituent, P is 〇 to an integer of 2) X is S, SO or so2, m' is an integer from 0 to 3, and η' is an integer from 0 to 4 (only R2 is a hydrogen atom). Examples of "burning group" represented by R61 include And R6 is as shown in R6, wherein C is preferably a methyl group, particularly preferably a methyl group. The soil M is similar, and in the specific example, a preferred embodiment is preferably S2 as follows. Preferably, the hydrazine is the same or different and each is a substituent of the sub-nitro group and the _, wherein (r6 in the formula is: an integer of the earth =). P. to R. 2 is more preferably a trans-group. :r Dimercapto is selected from the group consisting of 'atoms, cyano and s(〇)-r6i (wherein P' is an integer from ° to 2), especially good. U and m are m, +n, =1 or 2 (only work: and each is...) '一为.,... or::: R2 is a hydrogen atom or a group, or R】2 〃 is to be combined with the adjacent carbon atom 321556 27 201114425 to form Cycloalkane Rings Examples of cycloalkane rings include Cp cycloalkane rings (eg, cyclopropyl, cyclobutyl, cyclopentyl, ring) Base, cycloheptyl, etc.). In this case: lower = partial structural formula: V..... r1 .k_y '···〆 The following formula is expressed (ci-y^cH2 v_y) q is an integer of 0 to 4, and the a ring is as defined above. In this specific example, ring A, preferably phenyl, C3-6 cycloalkyl or 5 or 6 membered aromatic heterocyclic group (preferably A furyl group, a thienyl group, a pyridyl group (preferably a phenyl group, a thienyl group, a pyridyl group) is optionally selected from the group consisting of (4), a picture atom, a cyano group and a -S(〇)p. -R6 (wherein R6 is an alkyl group, p is an integer from 〇 to 2) to 3 substituents; more preferably phenyl, C: 3·6 cycloalkyl or 5 or 6 membered aromatic heterocyclic ring a base (preferably a thiol group, a gram group, a "base" (preferably a silk base group, a ringing base, particularly preferably a phenyl group)" each optionally having a hydroxyl group, a functional atom, and a cyanide a group having 1 to 3 substituents of S(0)PR (wherein R6 is C.6 alkyl, p is an integer from 〇 to 2); more preferably phenyl, C3-6 cycloalkyl or 5 or 6 member(s): a heterocyclic group (preferably a furyl group, a thienyl group, a pyridyl group) (preferably a phenyl group, a thienyl group, a pyridyl group), particularly preferred It is a phenyl group, each of which has a choice from (4), a nitrogen group and 321556 28 201114425 -S(0)p-R6 (wherein the ruler 6 is a Ci-6 base, and p is a 〇 to 2 climb). Pairs, 3 substituents; and helmet numbers 1 to » ' When R1 and R2 are as desired with adjacent carbon atoms, R1 is preferably not A- &person#& + forming a decane ring group A fused ring group; 'the next substitution ^ is preferably an integer from G to 3, particularly preferably an integer from G to 2. K is a hydrogen atom, a tooth atom, a cyano group, a hydrocarbyl group of a fluorenyl group, a fluorenyl group, or a plurality of heterocyclic groups having n or more substituents, and an amino group of A carpet base having a substituent or a thiol group having a substituent as needed. Examples of the tooth atoms shown include fluorine atoms, gas atoms, and hard atomic disks. Preferably, the "smoke group" which does not "require a hydrocarbon group having - or a plurality of substituents" as needed includes a chain or cyclic hydrocarbon group (for example, 'silk, alkenyl group, cycloalkyl group, aryl group, An aromatic filament or the like; wherein, the linear group has 1 to 16 carbon atoms or the like. Examples of the above alkyl group include C 6 alkyl (for example, mercapto, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, t-butyl: yl, hexyl, etc.) Wait. Examples of the above alkenyl group include a C2-6 alkenyl group (e.g., a vinyl group, an allyl group, an isopropyl group, a 1 butanyl group, a 2-butanyl group, a 3'-group, a 2·methacryl group, and 1). _Methyl-2-propenyl, 2-methyl-hydrazine-propenyl, etc.). Examples of the above-mentioned block base include a C2·6 block (e.g., an ethyl group, a propyl group, a 1-butynyl group, a 2-butynyl group, a 3-butynyl group, a hexynyl group, etc.). 321556 29 201114425 Examples of the above cycloalkyl group include a c3-7 cycloalkyl group (for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, etc.) and the like. Examples of the above aryl group include a C6-14 aryl group (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-indenyl, etc.), etc. . Examples of the above aralkyl group include a C7-]6 aralkyl group (e.g., phenyl_C]-6 alkyl group such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 5-benzene. A pentyl group or the like; a naphthyl-Cw alkyl group such as a 1-naphthylfluorenyl group, a 2-naphthylfluorenyl group or the like; a diphenyl-Cm alkyl group such as a diphenylfluorenyl group and a 2,2-diphenylethyl group; and many more. When the "hydrocarbyl group" is an alkyl group, an alkenyl group or an alkynyl group, it is optionally substituted with one or three substituents selected below (1) a halogen atom (for example, a halogen atom, a chlorine atom, a bromine atom, a moth atom). Etc.), (2) nitro, (3) cyano, (4) hydroxy, (5) choline having 1 to 3 halogen atoms (for example, fluorine atom, gas atom, bromine atom 'iodine atom) as needed An oxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, second butoxy, pentyloxy, hexyloxy, fluoromethoxy, etc.) ), (6) C6-i4 aryloxy (eg, phenoxy, naphthyloxy, etc.), (7) 匚7.16 aralkyloxy (eg, benzyloxy, phenylethoxy, diphenylanthracene) Oxy, 1-naphthylmethoxy, 2-naphthyloxy, 2,2-diphenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenyl Pentyloxy, etc., (8) fluorenyl, 30 321556 201114425 (9) If necessary, have 1 to 3 halogen atoms (for example, fluorine atom, gas atom, bromine atom, iodine atom) (^_6 alkylthio group ( For example, methylthio, difluorosulfonylthio, trifluorosulfonylthio, ethylthio, propylthio Isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc., (1〇) C6_14 arylthio (eg, phenylthio, naphthylthio, etc.) (11) C7_16 aralkylthio (for example, benzylthio, phenethylthio, diphenylsulfonylthio, 1-naphthylsulfonylthio, 2-naphthylsulfonylthio, 2,2-di Phenylethylthio, 3-phenylpropylthio, 4-phenylbutylthio, 5-phenylpentylthio, etc.), (12) Amino, (13) Mono-C]-6 alkylamine ( For example, amidino, ethylamine, etc.), (14) mono-C6_14 arylamino (for example, anilino, 1-naphthylamino, 2-naphthylamino, etc.), (15) mono-C7_]6 An alkylamino group (for example, a benzylamino group, etc.), (16) a di-C-6-6-amino group (for example, 'dimethylamino group, diethylamino group, etc.), (17) a di-C6_14 arylamino group ( For example, diphenylamine or the like), (18) di-C7-]6 aralkylamino (eg, dibenzylamino, etc.), (19) indolyl, (20) CN6 alkyl-carbonyl (eg, B) Mercapto, propyl, etc.), (21) C6_M aryl-carbonyl (eg, benzinyl, 1-naphthylquinone, 2-naphthylquinone, etc.), (22) carboxyl, (23) CV6 alkoxy- Carbonyl (eg, methoxycarbonyl, ethoxycarbonyl) Base, propoxycarbonyl, tert-butoxycarbonyl, etc.), (24) C6_14 aryloxy-carbonyl (eg, phenoxycarbonyl, etc.), 31 321556 201114425 (25) Aminomethyl sulfhydryl, (26) Amine (Thionine) ), (27) mono-C!·6 alkyl-amine sulfhydryl (eg, mercapto amidino, ethylamine thiol, etc.), (28) di-C!·6 alkyl- Amine group (for example, dimethylamino group, diethylamine fluorenyl group, ethyl decyl fluorenyl group, etc.), (29) Ce-H aryl-amine fluorenyl group (for example, Phenylamine fluorenyl, oxalylamine fluorenyl, 2-naphthylamine fluorenyl, etc., (30) (^-6 alkylsulfonyl (for example, mercaptosulfonyl, ethyl sulfonate)醯基等), (31) C6"4 aryl hydrazino group (for example, phenyl fluorenyl, i_naphthyl; e-xanthene, 2·nyl continuation, etc.), (32) C _ _6 A sulfhydryl group (for example, a hydrazino group, an ethyl sulfinyl group, etc.), (33) a C6-H aryl group (for example, a phenyl phenyl group, a 1-naphthyl group) Sulfhydrazinyl, 2-naphthylsulfinyl, etc.), (34) mercaptoamine, (35) 0^6 alkyl-carbonylamino (eg, ethylamino), (36) C6_14 aryl-carbonyl Amino group (for example, benzhydrylamino group, naphthylmethylamino group, etc.), (37) Cw alkoxy-carbonylamino group (for example, methoxycarbonylamino group, ethoxycarbonylamino group, propoxy group) a carbonylamino group, a butoxycarbonylamino group, etc., (38) a CN6 alkylsulfonylamino group (for example, a methylsulfonylamino group, an ethylsulfonylamino group, etc.), 32 321556 201114425 (39) CVm aryl arylamino group (for example, phenyl aryl amine group, • 2-naphthylsulfonylamino group, 1-naphthyl sulfonylamino group, etc.), (40) Ci·6 Alkyl-oxyl (e.g., 'acetoxy, propyloxy, etc.) ' (41) arylcarbonyloxy (e.g., benzhydryloxy, naphthyloxy, etc.), (42) C]-6-oxo-aryloxy (for example, methoxyloxy, ethoxy Ik-oxy, propyl-lactoyloxy, butoxyoxy), (43) Early-C]_6 alkyl-amine-mercaptooxy (for example, methylamine-mercaptooxy, ethylamine-methylcarbonyloxy, etc.), (44) di-C]-6 alkyl-amine Mercaptooxy (for example, dimethylamine-mercaptooxy, diethylamine-mercaptooxy, etc.), (45) C6_M aryl-amine a mercaptooxy group (for example, a phenylamine-mercaptooxy group, a naphthylamine anthraceneoxy group, etc.), (46) in addition to a carbon atom and a nitrogen atom, optionally containing a bite selected from nitrogen 5 to 7 membered saturated cyclic amine groups of an atom, a sulfur atom and an oxygen atom to 4 hetero atoms (for example, pyrrolidinium-fluorenyl group, N-hexahydropyridyl group, hexahydropyridinium); N_morpholinyl, thioindole·morpholinyl, hexahydroanthracene, etc.), (6) In addition to a carbon atom, contains - or two kinds of i to 4 heteroatoms selected from a nitrogen source / _ and an oxygen atom a 5 to 1 G member aromatic heterocyclic group (for example, 2·thienyl, 3_thienyl, 2-pyridyl, 3-pyridyl, decidinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolinyl, 8-quinoline, bisolinyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, b (tetra)yl, , 3, phenyl, 2, benzoxazole, benzoxanthene 321556 33 201114425, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo [b]furanyl, etc.), (48) CN3 alkylenedioxy (for example, methylenedioxy, ethylenedioxy, etc.), (49) C3_7 cycloalkyl E.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like) and the like. Further, when the above "hydrocarbon group" is a cycloalkyl group, an aryl group or an aralkyl group, it is optionally substituted with 1 to 5 (preferably 1 to 3) substituents selected from the following (1) halogen atom. (for example, fluorine atom, gas atom, bromine atom, iodine atom, etc.), (2) schlossyl, (3) cyano group, (4) hydroxy group, (5) having 1 to 3 halogen atoms as needed (for example, fluorine atom) a Cu alkoxy group of a gas atom, a bromine atom or an iodine atom (for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a second butoxy group, (pentyloxy, hexyloxy, fluoromethoxy, etc.), (6) C6-]4 aryloxy (for example, phenoxy, naphthyloxy, etc.) ' (7) <: 7.16 aralkyloxy ( For example, benzyloxy, phenylethoxy, diphenylmethoxy, 1-naphthylmethoxy, 2-naphthylmethoxy, 2,2-diphenylethoxy, 3-phenyl Propyloxy, 4-phenylbutoxy, 5-phenylpentyloxy, etc.), (8) fluorenyl, (9) 1 to 3 halogen atoms as needed (for example, fluorine atom, gas atom 34 321556 201114425 • Cu, alkyl, and iodine atoms) (eg, thiol, difluoro) Antimonythio, trifluorosulfonylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc., &quot (10) c6_14 arylthio (eg, phenylthio, naphthylthio, etc.), (11) C7-] 6 arylsulfanyl (eg, sulfhydryl, phenylethylthio, diphenylsulfonylthio) , 1-naphthylsulfonylthio, 2-naphthylsulfonylthio, 2,2-diphenylethylthio, 3-phenylpropylthio, 4-phenylbutylthio, 5-phenylpentanesulfur (12) Amine, (13) mono-CK6 alkylamino (eg, guanylamino, ethylamino, etc.), (14) mono-C6_14 arylamine (eg, anilino, 1-naphthalene) Amino, 2-naphthylamino, etc.), (15) mono-indenyl-7-yl 6-aralkylamino (for example, benzylamino), (16) di-Cw alkylamino (for example, diamylamine) , diethylamino group, etc.), (17) di-C6-I4 arylamino group (for example, diphenylamino group, etc.), (18) di-<:7_16 aralkylamine group (for example, dibenzylamine group, etc.) , (19) fluorenyl, (20) CK6 alkyl-carbonyl (eg, ethyl, propyl, etc.), (21) C6-H aryl-carbonyl (eg, benzhydryl, 1-naphthoquinone) Base, 2-naphthalene, etc.), (22) carboxyl group, (23) Ci-6 alkoxy-carbonyl (for example, decyloxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), (24) C6_14 aryloxy-carbonyl (for example, oxy Alkylcarbonyl, etc.), (25) Aminyl, 35 321556 201114425 (26) Amine (thioformamidine), • (27) Mono-C]·6 alkyl-amine sulfhydryl (eg, methylamine) Sulfhydryl, ethylamine fluorenyl, etc.), (28) di-C]·6-indolyl-carbamic acid group (for example, dinonylaminocarbamyl, diethylamine, mercapto, ethyl (amino)carboxamidine, etc., (29) C6-M aryl-amine fluorenyl (for example, phenylamine fluorenyl, phthalylamine fluorenyl, 2-naphthylamine fluorenyl, etc.), (30) A Cu alkylsulfonyl group having 1 to 3 atoms (for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom) (for example, a mercaptosulfonyl group, an ethylsulfonyl group, or a third) Fluorinylsulfonyl, etc., (31) C6_M arylsulfonyl (for example, phenylsulfonyl, fluorenylnaphthylsulfonyl, 2-naphthylsulfonyl, etc.), (32) C] _6 alkylsulfinyl (for example, mercaptosulfinyl, ethylsulfinyl, etc.), (33) C6_M arylsulfinyl (e.g., phenylsulfinyl, 丨-naphthylsulfinyl, 2-naphthyl fluorenyl, etc.), (34) mercaptoamine, (35) C!·6, carbonylamino (e.g., anthranylamino group, etc.), (36) C6_H aryl-truncylamino group (e.g., benzhydrylamino group, naphthylmethylamino group, etc.), (37) Cw alkoxycarbonylamino group ( For example, a decyloxycarbonylamino group, an ethoxycarbonylamino group, a propoxycarbonylamino group, a butoxycarbonylamino group, etc.), (38) a ketone group, and a gas group amine group (for example, a thiol group) Amino group, ethyl sulphate, etc.), 321556 36 201114425 (39) 〇ν] 4 aryl decylamino group (for example, phenyl hydroxyalkyl, 2-naphthylsulfonylamine a base of 'naphthylsulfonylamino group, etc.), (40) ci_6, a keto-carbonyloxy group (for example, an ethoxylated group, a propyloxy group, etc.), (41) a CM4 aryl group-based oxy group (for example, Benzyloxy, naphthalenecarbonyl, etc.), -(42)C6·6 alkoxy-carbonyloxy (for example, methoxycarbonyloxy, ethoxyoxy, propoxyoxyloxy) , T oxycarbonyloxy, etc.), ^ (43) mono-Cl-6 alkyl-amine decyloxy (eg, decylamine hydrazine) Mercaptooxy, ethylamine, mercaptooxy, etc.), _(44)-C]-6 alkyl-aminocarbonyl (for example, dimethylaminocarboxylic acid oxy, diethylamine hydrazine) a mercaptooxy group, etc., (45) a C6-m aryl-amine mercaptooxy group (for example, a strepylamine decyloxy group, a naphthylamine decyloxy group, etc.), (46) in addition to carbon In addition to an atom and a nitrogen atom, it may optionally contain one or two 5- to 7-membered saturated cyclic amine groups selected from a nitrogen atom, a sulfur atom and an oxygen atom to 4 hetero atoms (for example, pyrrolidinyl group, N_6) Hydropyridyl, hexahydropyridin-1-yl, N. morpholinyl, thio N-morpholinyl, hexahydropurine, etc. (47) In addition to a carbon atom, one or two selected from the group consisting of a 5 to 1 G member aromatic heterocyclic group having 1 to 4 hetero atoms of a nitrogen atom, a sulfur atom and an oxygen atom (for example, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4• Pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolinyl, 8-quinolinyl, ^isoquinolinyl, 3-isoquinolinyl, 4-isoquinoline Olinyl, 5-isoquinolyl, indole, 2-fyl, 3-, indenyl, 2-benzoxazolyl, 2-benzo[b] 321556 37 201114425 base, 3-benzo-Benyl, 2-phenylene-attached B-based, 3-phenylene-affinated, etc.), (48)0^-3destenanedioxy (for example, Methylene-2) An oxy group, an ethylenedioxy(49)C3-7 cycloalkyl group (e.g., hexyl, cycloheptyl, etc.), a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a ring (50) optionally have an anthracene selected from 3 alkyl groups from atomic _, (four), gas atom, desert atom, ruthenium atom and i to 3 substituents of the radical (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl) Base, isobutyl, t-butyl, tert-butyl, n-pentyl, second pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, etc.), (51) should have 1 to a C26 base group of three halogen atoms (for example, a fluorine atom, a gas atom, a desert material, or a broken atom) (for example, isopropyl group, isopropenyl isobutenyl group, 1-methyl propyl group, 2·pentanyl group, 2 • hexyl, etc.), (52) C2.6 block (eg, propyl, 2-butan, butyl, 3-pentynyl, 3-hexynyl, etc.), (53 a single _C3-7 cycloalkylamino amidino group (for example, cyclopropylamine methyl, butyl butyl carbamate, etc.), (54) In addition to a carbon atom, one or two selected from a nitrogen atom, a sulfur atom and an oxygen atom to 5 hetero atoms, 5 to a heterocyclic group, etc. (for example, 4-N-morpholinyl group) Carbonyl group, etc.). R3 shows "county, examples of which include those derived from Qianlin" to the sulfhydryl group of the atom; preferred examples thereof include c]7 alkyl fluorenyl (for example, fluorenyl, C -6 alkyl-carbonyl such as Ethyl, propyl, butyl, dicene 321556 38 201114425

Anthracenyl, pentylene, hexyl, fluorenyl, etc., C6 i4 arylbenzylidene, naphthalenecarbonyl, etc.), C -6 alkoxy-carbonyl (eg, g aralkyloxy-carbonyl ( For example, a silyl-Cm alkyloxycarbonyl group such as a benzyloxycarbonyl group, etc., a 5 or 6 membered heterocyclyl-carbonyl group or a fused heterocyclic group thereof - a carbonyl group (eg, 'containing a nitrogen atom selected from the group 5 or 6 members of a heterocyclic group - 1 or a heterocyclic group of 1 to 4 hetero atoms such as an oxidizing atom, an oxygen atom or a sulfur atom (optionally mono- or di-oxidative), such as a pyrrolylcarbonyl group such as 2- or 3-pyrrole a carbonyl group or the like; n is more than a thiol group such as 3-'4- or 5------------------------------- 2,3-triazol-4-yl-yl, 1,2,4-triazol-3-ylcarbonyl, etc.; tetrazolylcarbonyl such as 1 Η- or 2 Η-tetrazole _5-ylcarbonyl, etc.; a base such as 2- or 3-hexanyl or the like; a fluorenyl group; a carbon group such as a 2- or 3-thienylcarbonyl group; an oxazolylcarbonyl group such as a 2-, 4- or 5-cyanocarbonyl group; Etoxazolylcarbonyl such as 3, 4- or 5-isoxazolylcarbonyl, etc.; oxadiazolylcarbonyl such as 1,2,3-oxadiazole-4- or 5-carbonyl, 1 , 2,4-Π, etc. Diterpene•3- or 5-quinolyl, 1,2,5-卩萼2° sitting-3- or 4-based carrier, 1,3,4-卩, etc. a -2-ylcarbonyl group or the like; a thiazolylcarbonyl group such as a 2-, 4- or 5-thiazolylcarbonyl group; an isothiazolylcarbonyl group such as a 3-, 4- or 5-isothiazolylcarbonyl group; a thiadiazolylcarbyl group; Such as 1,2,3-thiadiazole-4- or 5-carbonylcarbonyl 1,2,4-thiadiazol-3- or 5-carbonyl, 1,2,5-thiadiazole-3- or 4-ylcarbonyl, 1,3,4·thiadiazol-2-yloxyl 39 321556 201114425, etc., D-pyridylcarbonyl such as 2- or 3-pyrrolidinylcarbonyl; pyridylcarbonyl such as 2-' a 3- or 4-pyridylcarbonyl group; a pyridyl group in which a nitrogen atom is oxidized such as a 2-, 3- or 4-pyridyloxycarbonylcarbonyl group; a mercaptocarbonyl group such as a 3- or 4-mercapto group; a carbonyl group or the like; wherein one or two nitrogen atoms are oxidized by a group of 13 groups such as 3, 4, 5, or 6-transyl-n-oxyl yl group; pyrimidinylcarbonyl such as 2 , 4- or 5-pyrimidinylcarbonyl, etc.; a pyrimidinylcarbonyl group in which one or two nitrogen atoms are oxidized, such as a 2, 4, 5 or 6-pyrimidinyl_N_oxy ion group; Pentylcarbonyl; hexahydropyridylcarbonyl such as 2_, 3 _ or 4-hexahydropyridylcarbonyl, etc.; hexahydropyridinyl carbonyl; fluorenylcarbonyl such as 3Η-吲哚-2- or 3-ylcarbonyl; etc.; pyranylcarbonyl such as 2-3- or pyridinium a bromocarbonyl group or the like; a thiocarbonyl group such as a 2-, 3- or 4-thiocarbonyl group; a quinolylcarbonyl group such as a 3-, 4-, 5-, 6-, 7- or 8-quinolinylcarbonyl group; Isoquinolylcarbyl; pyrido[2,3-d]pyrimidinylcarbonyl (for example, pyrido[2,3-d]pyrimidine. a nal-2-yl group; a naphthyridinyl group such as a., a s-, a s, a 2, 6 or a 2,7-n-hexylcarbonyl group (for example, anthracene, a naphthyridine_2_ or 3_ylcarbonyl), etc.; thieno[2,3-d]pyridylcarbonyl (for example, thieno[,pyridinyl-3-ylcarbonyl]) ° 哄 quinolinylcarbonyl (for example, η than 哄And [2,3_b]quinoline·2-carbonyl), bite: alkenylcarbonyl (for example, 2 fluorene-2-ene or 3-carbonyl), etc., 5 or 6 membered fluorenyl-ethene a group (for example, a 5- or 6-membered heterocyclic group-B containing from i to 4 heteroatoms selected from a nitrogen atom (optionally oxidized), an oxygen atom, a sulfur atom (optionally mono- or di-oxidized), etc. A mercapto group, for example, a 2-pyrrolidinoyl group, a 3-imidazolylethane group, an oxazolylamino group such as a 5-isoindole, or the like). As for the substituent of the fluorenyl group, for example, when "mercapto group, which is Cl. alkanoyl group or C] _6 oxo-severyl group, it is selected from the following 1 to 3 as needed. 321556 201114425 Substituent substitution: a sulfur-burning group (for example, a Cm-burning sulfur group such as a methylthio group, an ethyl sulfonyl group, a n-propylthio group, an isopropylthio group, etc.), a halogen atom (for example, fluorine, gas, desert, hydrazine) ), • alkoxy (for example, c -6 alkoxy such as decyloxy, ethoxy, n-propoxy, • third butoxy, n-hexyloxy, etc.), nitro, alkoxy _ A carbonyl group (for example, a methoxy-carbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, a n-propoxycarbonyl group, an isopropoxycarbonyl group, a n-butoxycarbonyl group, an isobutoxycarbonyl group, a second butoxycarbonyl group; , a third butoxycarbonyl group, etc.), an alkylamino group (for example, mono- or di-c)-6 alkylamino group such as amidino, ethylamine, n-propylamine, n-butylamine, tert-butylamine Base, n-pentylamino, n-hexylamino, dimethylamino, diethylamino, methylethylamino, bis-(n-propyl)amine, di-(n-butyl)amine, etc., Alkoxyimino group (eg, 'oxyl imine Such as methoxyimino, ethoxyimido, n-propoxyimino, tert-butoxyimido, n-hexyloxy-imino, etc.), hydroxyimino group, etc. The group is C6^4 aryl-yl, Ce·!4 aryloxy-carboyl, C*7-l9 aralkyl-carbonyl, c^9 aralkyloxycarbonyl, 5 or 6-membered heterocyclic ring a carbonyl group or a 5 or 6 membered heterocyclyl-ethenyl group, which is optionally substituted with from 1 to 5 (preferably 1 to 3) substituents: an alkyl group (for example, a thiol group) Such as fluorenyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tert-butyl, n-pentyl, second pentyl, isopentyl, neodecyl, An n-hexylisohexyl group or the like, a ruthenium 3·6 cycloalkyl group such as a cyclohexyl group, etc.), a base group (for example, a C 2_6 alkenyl group such as an allyl group, an isopropenyl group, an isobutenyl group, a benzyl group, a 2-pentenyl group, 2. hexenyl, etc.), fast radicals (eg, c2-6 blocks such as block propyl, 2-butyl block, 3-butyl block, 3-pentynyl, 3-hexyl, etc.) , alkoxy groups (eg '(:] _6 垸 oxy group such as methoxy, ethoxy, n-propoxy, 41 321556 201114425 third butoxy Base, n-hexyloxy, etc.), fluorenyl [for example, c]-7 alkylene such as methyl, ethyl, propyl, butyl, isobutyl, pentylene, hexyl, gamma, etc. ; c6_]4 aryl-carbonyl such as benzhydryl, naphthalenecarbonyl, etc.; Q-6 alkoxy-carbonyl such as decyloxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy Carbonyl group, isobutoxycarbonyl group, second butoxycarbonyl group, tert-butoxycarbonyl group, etc.; c6_14 aryloxy-carbonyl group such as phenoxycarbonyl group, etc.; c7.19 aralkyl-carbonyl group such as phenyl-Cm alkane a carbonyl group (for example, benzylcarbonyl, phenethylcarbonyl, phenylpropylcarbonyl, etc.), etc.; C7.19 aralkyloxy-carbonyl such as phenyl-Cm alkoxy-carbonyl (for example, benzyloxy) Base, etc.), nitro, amine, trans, cyano, amine, sulfhydryl, halogen (for example, fluorine, chlorine, bromine, iodine), alkylthio (Cm alkylthio) For example, sulfonylthio group, ethylthio group, n-propylthio group, isobutylthio group, etc.) and the like. Examples of the "heterocyclic group" represented by R3 as the "heterocyclic group having one or more substituents as necessary" include those selected from a nitrogen atom (optionally oxidized), an oxygen atom, and a sulfur atom (optional via a single- Or a 2- to 8-membered heterocyclic group of 1 to 4 hetero atoms (preferably a 5- or 6-membered heterocyclic group); and a derivatized freely selected from a nitrogen atom (optionally oxidized), oxygen a 3 to 8 membered heterocyclic ring (preferably a 5 or 6 membered heterocyclic ring) having 1 to 4 hetero atoms of an atom, a sulfur atom (optionally mono- or di-oxidized, etc.) and a benzene ring or containing a nitrogen atom selected from the group consisting of Forming a 3 to 8 membered heterocyclic ring (preferably a 5 or 6 membered heterocyclic ring) of 1 to 4 hetero atoms such as an oxygen atom (optionally oxidized), an oxygen atom, or a sulfur atom (optionally mono- or di-oxidized) a group of a fused ring; preferably a derivative containing from 1 to 4 heteroatoms selected from a nitrogen atom (optionally oxidized), an oxygen atom, a sparing atom (optionally mono- or di-oxidized, etc.) a 3 to 8 membered heterocyclic ring (preferably 5 or 6 42 321 556 201114425 . beheicyclic ring) and a fused ring group formed by a stupid ring. • Specific examples include. C. Base (for example, azirinyl (for example, or 2), such as 2-, 3- or 'azepine), bamboo bite such as nitrogen thiol 2- Or Kenting. All, hydrogen (for example, u, 2 =, for example, Bu Hu), perhydrooctanoyl (for example, b, 孓, 3 / or 屯 吖 吖 基 ( ( (for example, !., 2• or 3·对4; or all hydrogen. 丫辛1-, 3-, 4_ or 5·0 is more than spyryl), i-saltyl (such as 'diyl), Tris-salt (eg, u, 3 · trisal, its 4-, 5- or 5-oxazol-1-, 3-, 4- or 5-yl), tetras-salt (eg, tetrasa 1 U, 4-dibasic group (for example, 2 or 3·), "sequenyl (e.g., ϊ2 =· group), base), wherein "子·魏化之(四)细如·· 嗟 二 dioxide) , Butterfly, for example, 2 • Beauty: Kei U-*'3-...Different,...22==Ice or 5-base, a azole! 3 4 0- - . 5, base, i, 2, 5, Diazole j base, = kibswow group (for example, 2·, ... • sitting base), inner: plug::=, 4 cut:,, -m base), 0 ratio „each. Determining (for example, Bu 2_ or p is more than a cyclyl group (for example, 2 to 3 or 4" than a bite group), wherein the atomic atom is via a thiol group (for example, 2, 3, or 4° pyridine group) Ν_oxide), 嗒卩 well f: 4_° 八 ) )), wherein - or two nitrogen atoms are / are oxidized by oxygen (for example, 3 - 4 ·, 5 - or "荅哄Ν·Ν.oxide), pyridinite (for example, 2-, 4· or 5-radyl), wherein one or two nitrogen atoms are oxidized by /321556 43 201114425. dense. Base (for example, 2·, 4· '5· or 6 · shot I oxide), Talks, hexahydro group (for example, Bu 2·, 3 _ or hexahydro* base), Liu Feng ° More than a thiol group (for example, or 2-hexahydroindenyl), ten bases (for example, 3Η·吲哚-2-, 3-, 4_, s----, 6- or 7-yl) a group (for example, 2_, 3· or a mercapto group) "semeyl (for example, 2_, 3 or 4 (tetra) group), a thiol group in which a sulfur atom is oxidized (for example, 2_, 3• or 4_thiopyranyl^•dioxide), morphinyl (eg '2., 3_ or 4·leninyl), thiotropin, 啥 基 base (example 1 '2-, 3- , 4-, 弋c ι-t ^ ·, 7- or 8- 啥 基 )), 啥 啥 基 、, 比 比 [ 0 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 密密咬·2_基卜蔡咬基 such as 1,5-, 1,6-, ι,7·, W· ' 2,6_ or 2,7-cacilidine, etc. (for example, 1,5-na Bite -2- or 3 · base) " sputum [2,3_d]. than bite base (for example, " sputum [2, 3 flank ratio _3_ base), ° 哄 啥 啥 啥Base (for example, 哄[2,3-dMolin-2-yl), sprayed (for example, 2H-propene-2- or 3-yl), 2-benzo[b]喔 ^ , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Examples include the same as the above-mentioned "hydrocarbyl group which is optionally substituted," which is a hydrocarbon group which is optionally substituted with a cycloalkyl group, an aryl group or a aryl group; the number of substituents is ^ Up to 5, preferably 1 to 3. R3 represents "an amine group having one or more substituents as needed, and examples include the formula -NRV (wherein R and r8 are each a hydrogen atom, optionally having a group represented by a hydrocarbon group of one or more substituents, optionally having a heterocyclic group or a fluorenyl group having one or more substituents. R or R8 represents a hydrocarbon group having one or more substituents as required, 321556 44 201114425 Examples include the above-mentioned "hydrocarbon group having one or more substituents as necessary" as shown by R3. Examples of "heterocyclic group having one or more substituents as necessary" represented by R7 or R8 Examples include the above-mentioned "heterocyclic group having one or more substituents as necessary" as indicated by R3. Examples of "mercapto group" represented by R7 or R8 include and R3 The above-mentioned "mercapto group" is similar. Examples of the "hydroxy group having a substituent as necessary" represented by R3 include the formula -OR9 (wherein R9 is a hydrogen atom, optionally a hydrocarbon group having one or more substituents, if necessary a group represented by a heterocyclic group or a fluorenyl group of one or more substituents. Examples of the "hydrocarbon group having one or more substituents as necessary" as indicated by R9 include the above-mentioned "on the A hydrocarbon group of a plurality of substituents is similar. Examples of the "heterocyclic group having one or more substituents as necessary" represented by R9 include those similar to the above-mentioned "heterocyclic group having one or more substituents as necessary" represented by R3. Examples of the "mercapto" shown by R9 include those similar to the above-mentioned "mercapto" shown by R3. Examples of the "thiol group having a substituent as necessary" represented by R3 include a formula -SR1Q (wherein R)() is a hydrogen atom, optionally a hydrocarbon group having one or more substituents, optionally having one or more substituents a group represented by a heterocyclic group or a fluorenyl group. R]G is an example of "hydrocarbyl group having one or more substituents as needed". 45 321556 201114425 or a hydrocarbon group of a plurality of substituents, including the above-mentioned "as needed" similar to R3. R does not need to have one or more substituents. The general example includes the above-mentioned "When necessary, there are - or a plurality of substituents; base = base, similar. The substituent is a chowder. Examples of the base include R3 which is preferably a halogen atom similar to the above "county" shown by r3. Preferred specific examples of the compound (1) of the present invention are shown below. (1) In the compound: 'The group represented by the structural formula below

R2-- L.. R1 is a group represented by the following formula

Η--ch3 where a ring is phenyl, c3 8 cycloalkyl or 5 or 6 members (preferably furanyl, pyrenyl, pyridyl) (relative, " fenyl bristo, horse base, n寞It is preferably 0. Base, especially phenyl), each of which is as old as 6', and is selected from the group consisting of a thiol group, a halogen group, a cyano group and a -S(0)p-R6 (wherein r6 is an alkyl group). a country atom, to three substituents; and R3 is a halogen atom. Aromatic heterocyclic group (preferably in the compound, preferably ring A is phenyl, CVS cycloalkyl or 5 or 6 321556 46 201114425, It is t green, He κ κ) (preferably, the silk group.f is preferably a phenyl group). Each one optionally has a group selected from the group consisting of: a base group:::sub =. group and W (wherein R6 is a Ci 6 silk) Atomic rat. 1 to 3 substituents; and to 2 integers) R3 is a halogen atom; more preferably 5^6Ά 巧天录塞% η than bite base) (preferably stupid base, especially good benzene) Each of the groups optionally has a base selected from the group consisting of: -S(〇)p-R6 (wherein R6 is c俨', a thiol group and three substituents), and "silk, p is an integer of (1) (6) to R3 are a halogen atom; more preferably a di- or 5- or 6-membered aromatic heterocyclic group (preferably 喃 & & quot 塞 塞 塞 、 The base (preferably stupid, stetyl, t-t', particularly preferably phenyl)' each has a substituent selected from a halogen atom to 3 (preferably 1 or 2). And R3 is a halogen atom; particularly preferably, the ring A is a phenyl group, a cycloalkyl group or a 5- or 6-membered aromatic heterocyclic group (preferably a thiol group, a (tetra) group, a decyl group) (preferably a benzene group). The base group, the fluorenyl group, and the yl group are particularly preferably a phenyl group, each of which has 1 to 3 as needed (a healthy i halogen atom, and R3 is a ii atom. 321556 47 201114425 In another specific example, Preferably, ring A is (1) a phenyl group having 1 to 3 substituents selected from the group consisting of (a) ii atom, (b) cyano group and (c) alkyl sulfonyl group, and (2) optionally having one Or a pyridyl group of a plurality of substituents, or (3) a thienyl group having one or more substituents as necessary, and R3 is a halogen atom; more preferably, the A ring is (1) the phenyl group has a halogen (a) selected from (a) 1 to 3 substituents of the atom, (b) cyano group and (c) alkylsulfonyl group, (2) pyridyl group, or (3) thienyl group, and R·3 is a halogen atom; particularly preferably A ring Is a phenyl group having one or two substituents selected from the group consisting of (a) _ atoms and (b) cyano groups; R3 is a halogen atom. (2) In the compound: a group represented by the following structural formula:

Is a fused ring group selected from the following groups 48 321556 201114425

Wherein R and R are the same or different and each group is -S(0)p-R6 (wherein 1 is from a hydroxyl group, a tooth atom, a guest group, m is a number of from 0 to 3, and an integer of from ΛΡ40 to 2) And the number of the atomic atoms I is an integer of 0 to 4, and in the compound, preferably the group shown below

system

The symbols in the formula are as defined above. Further, in the compound, R4 and R5 are the same or different and each is a selected group and 5(0)ρ-Ι16 (wherein R6) Is a CU6 alkyl group, a substituent, and m and η are, m+n=l or 2 (only m蛊^, the same or different and 321556 49 201114425 are each 〇 or 1) (preferably m is 〇, η is 】), and R3 is a halogen atom; more preferably R4 is a hydroxyl group, R5 is selected from the group consisting of # atom, cyano and -s(o)p-R6 (wherein R6 is a Ci6 alkyl group, and P is an integer of 0 to 2) a substituent (preferably a halogen atom), m and 11 are, m+n=l or 2 (only m and η are the same or different and each is 0 or U (preferably m is 〇, η is 1) And R3 is a south atom. (3) In the compound: a group represented by the following structural formula

R

The condensation shown in the following formula

In the cyclic group formula, R41 is the same as or different from R51 and each is cyano and -S(0)p, -R6i (formula, ", from a hydroxyl group, a tooth atom, a substituent, X is S, is a burnt group' P , is an integer from 0 to 2) an integer from 0 to 4, and S 2 ' m' is an integer from 0 to 3, and η is a halogen atom. In the compound, 'X is S〇2, 321556 50 201114425 is the same or different and each is selected from the group consisting of hydroxyl, halogenogen # base and -s(o)p, -R6] (wherein R6) is a Cl_6 alkyl group, and ρ is a 〇 to 2' effect = Base, positive number) ...Um ten!! One 1驭" (only m' and η, Xiangmin is 0 or 1) (preferably m' is 〇, η' is 〇 or 1), and R3 is a tooth atom; More preferably, X is S〇, and R 1 is a trans group, and R51 is selected from a halogen atom, a cyano group, and _S(〇)p, _R61 (in the formula r6)

The substitute base of the hospital base 'p' is an integer from G to 2) (preferably _ atom) 7 W is '1 or 2 (only ", same as or n; and each is 0 or I) Preferably, m is 〇, n is 0 or 丨), and R3 is a halogen atom. (4) Among the compounds, the groups shown in the following structural formulas

Based on the formula

An integer of the group 2 i 4 'A ring is a phenyl group, a c3_s cycloalkyl group or a 5 or 6 Γ::; a base is a coughyl group, a phenyl group, a hydrazine group is preferably a phenyl group, particularly preferably a phenyl group) 'Each one as needed has a radical selected from 321556 51 201114425, a sulfonyl group, a cyano group, and an integer of Vr6 to 2) to 3 substituents, and wherein R is an alkyl group and P is 0 R3 is a tooth. Atom; preferably an anthracene ring is a phenyl group, a ring record or a 5 or 6 is a bite wire "sequenyl, % group) (more preferably than a read heterocyclic group (preferably base 'excellent tears) From == ^-s(〇)p.R6(,tRUCi6^>p^ 1 to 3 substituents, ^^^number) q is an integer from 0 to 3, and R3 is ii atom; more preferably Is a benzyl group, a C3·8 ring filament or a 5 or 6 membered aromatic heterocyclic group (preferably, a thiol group), preferably a phenyl group, a thiophene group. ; than the bite base 'excellently phenyl) 'each of which is optionally selected from a tooth atom, a cyano group and -S(0)p-R6 (wherein R6 is a Ci 6 alkyl group, and p is an integer from 〇 to 2) ^ to 3 substituents, q is an integer from 0 to 3, and R3 is ii atom. In compound (I), particularly preferred is 5-gas-l-[l-(3-phenylphenyl) Base]_2_ Amino, 1,2-dihydroacridine, 3 decylamine (Example 1), 5-gas-1-(6-gas-2,3-dihydro-1Η-indol-1-yl)-2 -imino 1}2 hydrogen 0 to ° -3 - an amine (Example 2), 321556 52 201114425 5-Ga-2-iminyl 4-(1 (°Cet-3-yl) Ethyl)-1,2-dihydropyridinium-3-decylamine (Example 5), 5-Gas-H(iR)-l-helium phenyl)ethyl]-2-imino -1,2·Dihydropyridinium-3-decylamine (Example 12), 5-Gas-1-[(1R)-H3,5-difluorophenyl)ethyl]-2-imine Base-1,2-dihydropyridine-3-carboxamide (Example haiku, 5-gas-2-imino-H1·phenylcyclopropyl)-1,2-dihydropyridine-3- Indoleamine (Example 15), 5-gas-1-(6-cyano-2,3-dihydro-1Η-indol-1-yl)-2-imido-1,2-dihydropyridine -3-decylamine (Example 19), 5-oxo-l-[(lR)-l-(4-fluorophenyl)ethyl]-2-imino] 1,2-diargon. Bis-pyridine-3-carbamide (Example 22), 5-gas-1-[(1R)-1_(3-cyanophenyl)ethyl]-2-imino-1,2-dihydroanthracene Pyridin-3-indoleamine (Example 23), 5-gas-1-(6-chloro-1,1-dioxyindol·3,4-dihydro-2H-thiopenten-4-yl) · 2 · imino-I, 2-dihydropyrazine _3 · decylamine (Example 30) and its salts and the like; wherein, particularly preferred is 5-gas-1-[1-(3- Esteryl)ethyl]_2-imino-1,2-dihydropyridine-3-indoleamine (Example 1), 5-gas-1-(6·Gas-2,3-dihydro dH -Indol-1-yl)-2-imino-1,2-dihydroacridin-3-indenylamine (Example 2), 5-chlorofluorophenyl)ethylimino-I,2 Dihydro 0-pyridin-3-indoleamine (Example 12), 321556 53 201114425 5-Phenyldifluorophenyl)ethyl]-2-imino-1,2-dihydropyridine-3-indole Indoleamine (Example 14), 5-gas-1-[(1R)-H3-cyanophenyl)ethyl]-2-imino-1,2-dihydropyridin-3-indoleamine ( Example 23), 5-air small (6-chloro-1,1-dioxoindol-3,4-dihydro-2-indole-thiodecen-4-yl)-2-imino-1,2 -dihydropyridin-3-indoleamine (Example 30) and its salts, etc. 5-Gas-1-(2,3-dihydro-111-indol-1-yl)-2-imino-1 ,2- Hydropyridine-3-guanamine, 5-gas-2-imino-1-(1-phenylethyl)-1,2-dihydropyridine-3-decylamine and 5-chloro-2- Imino-1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1,2-dihydropyridine-3-decylamine is not included in the compound (I). Chloro-1-(2,3-dihydro-111-indol-1-yl)-2-imino-1,2-dihydropyridine-3-carboxamide, 5-fluoro-l-[ (lR)-2,3-dihydro-1H-indole-buyl]-2-imino-1,2-dihydropyridin-3-indoleamine and 5·gas-l-[(lS)- 2,3-Dihydro-1H-indol-1-yl]-2-imino-1,2-dihydropyridin-3-indoleamine is also not included in the compound (I). Similarly to "5-chloro-2-imino-1((p-phenylethyl)hydropyridine·3.methanamine), 5-chloro-2-imino--:[[is) -l·Phenylethyl;^,^dihydropyridine-3-carboxamide and 5_gas·2·imino group; stupidyl ethyl]^·dihydropyridine-3-decylamine It is contained in the compound (1). When the compound (I) is a salt, examples of such salts include salts with inorganic bases, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and basic or acidic amino acids. Salt and so on. Preferred examples of the salt with the inorganic test include sodium salt, potassium salt and the like metal 321556 54 201114425 salt; calcium salt, magnesium salt, barium salt and other alkaline earth metal salts; aluminum salt and the like. Preferable examples of the salt with an organic base include tridecylamine, triethylamine, pyridine, mercaptopyridine, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, and the like. The salt formed. Preferred example salts with salts of inorganic acids include those formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred examples of the salt with an organic acid include tannic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, sulfonic acid, benzene. a salt formed of a sulfonic acid, p-toluenesulfonic acid or the like. The salt with a basic or amino acid preferably includes a salt formed with arginine, lysine, ornithine. Preferable examples of the salt with an acidic amino acid include salts formed from aspartic acid, glutamic acid and the like. Among them, a pharmaceutically acceptable salt is preferred. Solvates such as hydrates are also encompassed within the scope of the compound (I). The compound (I) can be labeled with an isotope (for example, 3H, ]4C, 35S, 1251, etc.) or the like. The compound (I) may also be a hydrazine conversion type. When the compound (I) has an asymmetric center, an isomer such as a mirror image isomer or a non-image isomer will appear. Such isomers and mixtures thereof are intended to be within the scope of the invention. Such isomers and mixtures thereof are also encompassed within the scope of the compound (I) of the present invention when there are isomers due to the configuration. The method for producing the compound (I) of the present invention or a salt thereof will be described below. 55 321556 201114425 The compound represented by the compound σ) (wherein the symbols in the formula are as defined above) can be according to the following method A (J: ν wu, i " 八 is a halogen atom, and the remaining symbols are as defined above) Or, class: 乂 method manufacturing. The starting material compounds in the various steps of the mashing process may be used, and such examples include those similar to the salt of the compound (1). Further, the product obtained by the following method Φ can be in the form of a salt which does not adversely affect the reaction. Formula:: Compound (I_A) (hereinafter abbreviated as Compound (I) wherein R is a halogen atom. D, I; Method A] NGw^nh2 (II) Less X 〇 (HI) Ο Step 1

3© Step 2

Ο W) HO

NH, V nh • Construction (VI)

V 3

XtV;nh2 <Ι·Α) Step 4 o R:

N^m (l> Wuzhongyi is _atomic' and the rest is said as defined above. As a starting material for the method, the compound represented by the following formula is abbreviated as (10) • the compound (v) is represented by the following formula (hereinafter) The compound (which is a commercially available product, which can be used as it is or after being isolated and used, or can be produced according to a method known per se or the like, 4 is used as a starting material for the method (III) The disk shown (hereinafter referred to as compound (III)) can be carried out according to a method known per se or the like, as described in J. Am. Chem. Soc., 1953, 75, 1909 and the like. Process, 321556 56 201114425. (Step 1) This step is a step of reacting compound (II) with compound (III) in the presence of a base to produce compound (IV) of the following formula (hereinafter abbreviated as compound (IV)) This reaction can be usually carried out by reacting the compound (II) with the compound (III) in the presence of a base in a solvent inert to the reaction. Examples of the reaction used in the reaction include metal salts such as moxibustion of potassium hydroxide, sodium carbonate, and carbonic acid. Nano, carbonated, etc.; amines such as ° ratio. Indoleamine, hydrazine, hydrazine-dimercaptoaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc.; metal alkoxides such as sodium decylate, sodium ethoxide, third butyl A potassium hydride or the like; a metal hydride such as sodium hydride, potassium hydride, etc. The amount of the base used per 1 mole of the compound (II) is usually from about 1 to about 20 mol, particularly preferably from about 1 to about 3 mol. The amount of the compound (III) to be used in the compound (II) is usually, for example, about 1 to about 5 mol, preferably about 1 to about 3 mol. The solvent used in the reaction is not particularly limited as long as the reaction is continued; Including aromatic hydrocarbons such as benzene, toluene, diphenylbenzene, etc.; ethers such as tetrahydrofuran, dimethoxyethane, dioxane, diethyl ether, etc.; guanamines such as hydrazine, decyl-didecyl decylamine (DMF) , N,N-dimercaptoacetamide (DMA), 1-decyl-2-pyrrolidone, etc.; alcohols such as decyl alcohol, ethanol, propanol, tert-butanol, decyl alcohol, etc.; sulfoxide Such as disulfoxide (DMSO), etc.; water; and mixed solvents thereof. The reaction is usually carried out at a temperature of from about -50 ° C to about 200 ° C, preferably from about -10 ° C to about 100 ° C; Usually about 0.5 hours to about 60 hours. 7 321556 201114425 The compound (ιν) thus obtained can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc. (Step 2) This step is a cyclization reaction of the compound (IV) with an amine represented by the formula (V) (hereinafter abbreviated as the compound (V)) in the presence of a base in an inert solvent to give the compound (VI) of the following formula ( Hereinafter, the procedure of the compound (VI)) is abbreviated. The amount of the compound (V) to be used per 1 mol of the compound (IV) is usually, for example, about 1 to about 10 mol, preferably about 1 to about 3 mol. Examples of tests for this reaction include the detection of metal salts such as hydroxide to remove sodium hydroxide, sodium carbonate, potassium carbonate, etc.; amines such as pyridine, tridecylamine, triethylamine, N,N-didecylaniline, 1,8 -diazabicyclo[5.4.0]undec-7-ene (DBU) or the like; metal alkoxides such as sodium decoxide, sodium ethoxide, potassium t-butoxide, etc.; organometallics such as n-butyl lithium, lithium diisopropylamide (LDA) or the like; a metal hydride such as sodium hydride, potassium hydride or the like. The amount of the base used per 1 mol of the compound (IV) is usually from about 1 to about 10 mol, preferably from about 1 to about 3 mol. The solvent used in the reaction is not particularly limited as long as the reaction is continued; examples thereof include aromatic hydrocarbons such as benzene, methyl benzene, diphenylbenzene, etc.; ethers such as tetrahydrofuran, dimethoxyethane, dioxane, diethyl ether, etc.; Amines such as N,N-dimercaptodecylamine (DMF), dimercaptoacetamide (DMA), 1-decyl-2-pyrrolidone, and the like; alcohols such as decyl alcohol, ethanol, propanol, Third butanol, methoxyethanol, etc.; ketones such as acetone; nitriles such as acetonitrile; sulfoxides such as disulfoxide (DMSO); and mixed solvents thereof. 58 321556 201114425 This reaction is usually carried out at a temperature of from about -50 ° C to about 200 ° C, preferably from about -10 ° C to about 100 ° C; the reaction time is usually from about 0.1 hour to about 60 hours. The compound (VI) thus obtained can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Further, the compound (VI) can be used in the form of a reaction mixture in the next step (step 3) without isolation and purification. (Step 3) This step is a step of subjecting the compound (VI) to a decarboxylation reaction to give a compound (Ι-A). For the decarboxylation reaction, a known decarboxylation reaction can be used; for example, a method such as heating, using an acid or a test under heating can be used. The solvent used in the reaction is not particularly limited as long as the reaction is continued; examples thereof include aromatic hydrocarbons such as benzene, toluene, diphenylbenzene, etc.; ethers such as tetrahydrofuran, dioxyl oxide, dioxane, diethyl ether, etc.; Such as N,N-dimercaptodecylamine (DMF), N,N-dimercaptoacetamide (DMA), 1-mercapto-2-pyrrolidone, etc.; alcohols such as methanol, ethanol, C Alcohol, tert-butanol, methoxyethanol, etc.; sulfoxides such as diterpenoid (DMSO); nitriles such as acetonitrile; organic acids such as acetic acid, trifluoroacetic acid, etc.; water; and mixed solvents thereof. Examples of the base used in the reaction include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate and the like; amines such as pyridine, tridecylamine, N,N-didecylaniline, 1,8-diaza Heterobicyclo[5.4.0]undec-7-ene (DBU) or the like; metal alkoxides such as sodium decoxide, sodium ethoxide, potassium butoxide, etc.; metal hydrides such as sodium hydride, potassium hydride, and the like. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, and the like; organic acids such as acetic acid, trifluoroacetic acid, and the like. 59 321556 201114425 The amount of the base or acid used per 1 mol of the compound (VI) is usually, for example, from about 1 to about 100 mo, preferably from about} to about 1 mol, and the reaction is usually from about -5 ° C to about 200. The hydrazine is preferably carried out at a temperature of from about -10 ° C to about 100 ° C; the reaction time is usually from about 1 hour to about 60 hours. The compound (I_A) thus obtained can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. (Step 4) This step is a step of producing a compound (I) by subjecting the compound (I-A) to a known displacement reaction. Examples of the displacement reaction include the use of one of a transition metal catalyst, a carbon oxide insertion reaction, a Suzuki coupling reaction, a cyanidation reaction using cyanide, and the like. In this step, a compound protected by a conventional protecting group (Ι-A) can be used as needed. In this case, the protecting group can be removed after the reaction as needed to obtain the target compound. The reaction using a transition metal catalyst can be carried out according to a method known per se [e.g., Chemical Reviews, 1995, vol. 95, page 2457, etc.] or the like. For example, the reaction can be carried out in the presence of a transition metal catalyst and a base in a solvent which does not adversely affect the reaction. Examples of transition metal catalysts used include palladium catalysts (e.g., acetic acid | bar (II), ginseng (dibenzylideneacetone) gemini (0), chlorinated | bar (H), bismuth (triphenylphosphine). (〇), etc.), nickel catalyst (such as 'vaporized nickel, etc.). When necessary, a ligand (e.g., diphenylphosphine, di-second butylphosphine, etc.) may be added, and a metal oxide (e.g., copper oxide, silver oxide, etc.) may be used as a co-catalyst. 321556 60 201114425 Every 1 mol] The amount of the catalyst used for the compound (I-A) varies depending on the type of the catalyst, but is usually from about 0.0001 to about i m〇I, preferably from about 〇1 to about 5 mo. The amount of the ligand used per 1 m of the oxime I compound is usually from about 〇 to about 4 mol, preferably from about 〇.01 to about 2 m〇i; the amount of the cocatalyst used is usually from about 0.0001 to about 4 mol, preferably. It is from about 0.01 to about 2 m〇1. Examples of the base to be used include organic amines (for example, tridecylamine, triethylamine, diisopropylamine, N-methylmorphine, ;,8-diazabicyclo[5 4〇]11·7·grilled , pyridinium, hydrazine, hydrazine-dimethylaniline, etc.) 'alkali metal salts (for example, sodium bicarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, carbonic acid, Wei sodium, linolenic acid, sodium hydroxide, Potassium hydroxide, etc.), metal hydride (eg, hydrogenation clock, sodium nitride, etc.), alkali metal alkoxide (eg, sodium decoxide, sodium ethoxide, third butanol =, second butanol), metallurgy a di-Wulminide (for example, a saponin, a di-sulphide, a diamine, a diamine), and the like; wherein, a metal salt such as potassium carbonate, carbonic acid, sodium phosphate, potassium phosphate, etc.; A metal alkoxide such as sodium t-butoxide, potassium r-butyric anhydride or the like, and an organic amine such as triethylamine or monoisopropylamine is preferred. The amount of the compound (j_A) used is usually from about 1 to about 1 〇m 〇, preferably from about 1 to about 5 m 〇h. There is no particular limitation on the solvent used as long as there is no adverse effect on the reaction. Examples include hydrocarbons (for example, stupid, toluene, dioxane, etc.), halogenated fumes (such as chaotic, one-air e-sinter, etc.), nitriles (for example, acetonitrile, etc.), ethers (such as oxyethylene tetrahydrofuran, etc.), Alcohols (for example, sterols, ethanol f such as N, N dimethyl ketone, dimethyl hydrazine, fluorenyl (tetra) _, water, mixtures thereof, etc. The reaction temperature is usually 321556 6] 201114425 about 1 〇 to Approximately 200 ° C ' is preferably from about 0 to about 15 mc. The reaction time is usually from about 0.5 to about 48 hours, preferably from about 0.5 to about 16 hours. Examples of cyanation reactions include methods known per se [eg, Synth Commmi" 24. 6. 1994. 887-890, etc.] or a similar method. The reaction may, for example, be added to the presence of a transition metal catalyst and a base in a solvent which does not adversely affect the reaction. Examples of the cyanating agent used include zinc cyanide, copper cyanide, sodium cyanide, potassium cyanide, and trimethyldecyl cyanide. The amount of cyanating agent used per compound (Ι·Α) varies depending on the type of the nucleating agent, but is usually from about 1 to about 10 μm, preferably from about J to about 5 m. Examples of transition metal catalysts used. Including palladium catalysts (eg, acetic acid! (II)? (diphenylidene acetonide) dipalladium (ruthenium), vaporized palladium (8) ruthenium (triphenylphosphine ginger (0) homing)' nickel catalyst (eg, chlorine) The amount of the catalyst used per 1 mol of the compound (I_A) is usually from about 〇 to about 1 (four) 1 , preferably about 0. (H to about 〇.5 _, depending on the type of the catalyst. 'Examples of organic amines (for example, tridecylamine, triethylamine-isopropylamine N-methyl-methionine, j-diazabi-tetrafene 4〇) ten...7·sparse of sorghum, Ν _ _Methyl aniline, etc., metal salts (for example, sodium bicarbonate, cesium hydrogen hydride, sodium citrate, potassium carbonate, carbonic acid planer, sodium phosphate, potassium phosphate, nitrous oxide, potassium hydroxide, etc.), metal hydrogenation a metal alkoxide (for example, potassium hydride, sodium, etc.) (for example, sodium methoxide, sodium ethoxide, potassium tributyl ketone, etc.), an alkali metal dioxane amide (for example, diamine light amination) Sodium decane amination, potassium aluminide, etc.) Wherein, the metal of the age is, for example, potassium carbonate, carbonic acid planing, sodium phosphate, potassium phosphate, etc.; alkali metal 62 321556 201114425 alkoxide such as sodium butoxide, potassium butoxide, etc.; organic amines such as triethylamine, Diisopropylamine or the like is preferred. 'The amount of the base used per 1 mol of the compound (Ϊ-A) is usually from about 〇丨 to about (7) mol', preferably from about 1 to about 5 mol. The solvent to be used is not particularly limited as long as it is The reaction may be carried out without adverse effects; examples thereof include hydrocarbons (for example, benzene, methyl benzene, xylene, etc.), halogenated hydrocarbons (for example, gas, 1,2-dichloroethane, etc.), nitriles (for example, acetonitrile, etc.) ), ethers (eg, 'monooxyethylene bromide' tetrahydrofuran, etc.), alcohols (eg, decyl alcohol, hydrazine ethoxide), aprotic polar solvents (eg, N,N-dimethylformamide' dioxin Bismuth, hexamethylenephosphonamide, etc.), water, and mixtures thereof. The reaction temperature is usually from about -10 to about 200 ° C, preferably from about 〇 to about 15 Torr. <:. The reaction time is usually from about 0.5 to about 48 hours, preferably from about 〇5 to about 16 hours. The compound (I) thus obtained can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. In the respective reactions for synthesizing the target compound and the starting material, when the starting compound has an amino group, a carboxyl group or a hydroxy substituent, these groups can be protected using a protecting group generally used in peptide chemistry or the like. In this case, if necessary, these protecting groups can be removed after the reaction to obtain the target compound. Such protecting groups include, for example, those described in Wiley-Interscience, Theodara W. Greene, and Peter G. M. Wuts, "Protective Groups in Organic Synthesis, 3rd Ed. (1999)". 63 321556 201114425 Amine = shouting materials include Jiaxian, ksi (four) Γ =: Γ基, etc., stupid county, c-calcinyl oxy-hydrogen column / ethoxy pottery), aryloxy pottery, Stupid base rebellion 4),% looking for base sales (for example, f oxygen county, etc.), soil conservation, a sputum base, two awkward base, brewing base, etc., each of which can be substituted for the sub-package (4) Atoms (for example, gas atom, chlorine atom, r-dise), c]-6-alkyl group, carbonyl group (for example, ethyl thiol, propyl ketone group: butyl-f-group 4), nitro group, etc.; number of substituents It is 1 to 3. Examples of the carboxy protecting group include c] 6 fen (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, etc.), stupid, tri, shi xi lai, each There may be substituents; the substituents of these substituents - (4) atoms (gas atom, gas atom, desert atom, germanium atom), carbenyl group, alkyl group - several groups (for example, ethyl, propyl, propyl, Butyl County, etc., Shi Xiaoji, etc.; the number of substituents is 1 to 3. Examples of the trans-protecting group include c]_6 (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, etc.), phenyl, 〜. An aralkyl group (e.g., a group or the like), a fluorenyl group, a c6 group, a group (for example, an ethyl group, a propyl group, etc.), an aryloxy group (for example, a phenoxy group, etc.), ~ . Each of the arylalkyl-carbonyl group (e.g., 'oxycarbonyl group, etc.), pyridyl group, furyl group, decyl group, etc. may have a substituent; examples of such substituents include a tooth atom (a gas atom, a gas atom, a desert) Atom, moth atom), Ci 6 alkyl group, phenyl group, c7.] anthracene aralkyl group, nitro group, etc.; the number of substituents is from 4 to 4. Such protecting groups may utilize known methods or are described in

Published by Wiley-Interscience, Theodara W. Greene, Peter G. M. 321556 64 201114425

The method of "Protective Groups in Organic Synthesis, 3rd Ed. (1999)" edited by Wuts or the like is removed. For example, a method of treating with acid, alkali, reduction, ultraviolet irradiation, hydrazine, phenylhydrazine, sodium N-mercaptodithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like can be used. In the above method, when the compound (I) which is a free compound is obtained, it can be, for example, a mineral acid (for example, hydrochloric acid, sulfuric acid, hydrogen oxalic acid, etc.), an organic acid (for example, A). Tannic acid, benzenesulfonic acid, toluene acid, oxalic acid, fumaric acid, maleic acid, tartaric acid, etc.), inorganic base (for example, metal such as nano, needle, etc., soil test metal such as: i bow, Magnesium, etc., or organic bases (eg, tridecylamine, triethylamine, pyridine, mercaptopyridine, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, hydrazine, Ν'-dibenzyl phenyl) A diamine or the like is formed to form a salt; when the compound (I) in the form of a salt is obtained, it can be converted into a free compound or other salt according to a conventional method. Further, when the starting compound forms a salt in each of the above reactions, the compound may be used in the form of a salt. These salts include, for example, those exemplified in the salt of the compound (I). The compound (I) prepared by these methods can be isolated and purified by a typical separation method such as recrystallization, steaming, chromatography or the like. When the compound (I) contains optical isomers, stereoisomers, stereoisomers and rotamers, they are also within the scope of the compound (I), and can be synthesized and isolated according to the nature. Methods (eg, concentration, solvent extraction, column chromatography, recrystallization, etc.) are prepared as a single product. For example, when the compound (I) has an optical isomer, an optical isomer which is isolated from the compound is also encompassed in the compound (I). 65 321556 201114425 Optical isomers can be prepared by methods known per se. In particular, optically active synthetic intermediates are used, or the final racemic product is optically resolved to obtain optical isomers according to conventional methods. The optical resolution method can be a method known per se, such as fractional recrystallization, a palm-column method, a non-mirrored isomer method, and the like. 1) Fractional recrystallization method In this method, an optically active compound is formed (for example, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+) small styrene a racemic salt of an amine, (-)-1-phenethylamine, cinchonacin, (-)-cinchonadine, strychnine, etc., which is separated by fractional recrystallization, and used when necessary The neutralization step produces free optical isomers. 2) For the column method In this method, the racemate or its salt is applied to the column for optical isomer separation (on the column) to separate it. In the case of liquid chromatography, for example, a mixture of optical isomers is applied to a pair of caps such as ENANTIO-OVM (manufactured by Tosoh Corporation), to palms, J (Daicel Chemical Industry Co., Ltd.), and the like. Expanded with water, various buffers (eg, phosphate buffer), and organic solvents (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) alone or in admixture to The optical isomers are separated. In the case of gas chromatography, for example, separation is carried out using a cap column such as CP-Chirasil-DeX CB (manufactured by GL Sciences). 3) Non-image isomer method 66 321556 201114425 In this method, a racemic mixture is prepared as a mixture of non-image isomers by chemical reaction with an optically active reagent, using a typical separation method (for example, fractional recrystallization, layer The optical isomer is prepared by separating it into a single substance, and performing a chemical treatment such as hydrolysis or the like to separate the optically active reagent portion. For example, when the compound (I) contains a trans group or a primary or secondary amine group in the molecule, the compound is made with an optically active organic acid (for example, ΜΤΡΑ[α-methoxy-α-(trifluoromethane) The condensation reaction is carried out by phenylacetic acid], (-)-monoxyacetic acid, etc., to obtain a non-image isomer of the ester compound or the guanamine compound, respectively. When the compound (I) has a carboxylic acid group, the compound is subjected to a condensation reaction with an optically active amine or an alcohol reagent to obtain a non-image isomer of the guanamine compound or the ester compound, respectively. The isolated non-image isomer is converted to the optical isomer of the original compound by acid hydrolysis or base hydrolysis. Compound (I) may be in a crystalline form. The crystallization of the compound (I) can be carried out by crystallizing the compound (I) by a crystallization method known per se. Examples of the crystallization method include solution crystallization, steam crystallization, and melt crystallization. The "solution crystallization method" is typically a method of converting an unsaturated state into an oversaturated state by various factors which change the solubility (solvent composition, pH, temperature, ionic strength, redox state, etc.) of the compound or the amount of the solvent. More specifically, for example, a concentration method, a slow cooling method, a reaction method (diffusion method, electrolysis method), a hydrothermal crystal growth method, a melting method, and the like can be mentioned. Examples of the solvent to be used include aromatic hydrocarbons (for example, benzene, toluene, diphenylbenzene, etc.), halogenated hydrocarbons (for example, dioxins, chloroform, etc.), saturated hydrocarbons (for example, hexane, hept 67 321556 201114425: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ( ( ( ( ( ( ( ( ( ( ( ( ( Sub-classes (for example, dimethyl sulphate, etc.), awake amines (eg, dimethyl dimethyl carbamide, etc.), _ column, ethyl acetate, etc., ... Ν methyl methyl mss For example, methanol, B (4), ... water, etc.. They may also be used when they are dissolved alone or at an appropriate ratio. "Steam crystallization" is, for example, 笈 .., BC; ^ Bursting method (closed tube method, air flow method), 虱 phase reaction method, chemical transport method, etc. 1 = crystallization method is 'for example' positive f; east knot method (CZGehralski method, ldgman method), area glare method (region Leveling method and floating zone. Special day and day method (VLS method and liquid phase epitaxy method), etc. Preferred examples of the crystallization method include adding temperature to (10) the right agent (example) , the alcohol (such as A, 7 '-, B.) dissolved the compound (I), and then the cold liquid to a temperature not higher than the dissolution temperature (for example, 0 S 50. 匸, preferably 0 to 20 The method of the sputum, etc. - The crystallization of the invention of the present invention can be utilized, for example, by filtration, etc. The analysis method of the crystallographic analysis method of the obtained crystal diffraction is usually used. The calendering powder is used. In addition, the crystal orientation measurement method described above is a crystal of the compound (1) obtained in the above production method (hereinafter referred to as ''this month's crystal)) having high purity, high quality, and low hygroscopicity. Even after long-term storage under normal conditions, it does not change, and has excellent stability. 321556 68 201114425 These crystals also have superior biological properties (for example, in vivo dynamic properties • (absorbed, distributed) "Sexual, metabolic, secretory", efficacy, etc.), is a very useful pharmaceutical agent. In the present specification, the melting point means the use, for example, a micro-melting device (Yanako, MP-500D) or DSC. (Minor Scanning Calorimeter) Prepared by SEIKO (EXSTAR 6000), etc. Compound drug (I) is a compound that is converted into a compound of Compound (1) by reaction with an enzyme, gastric acid, etc. in vivo or under physiological conditions; that is, using a compound which is converted into a compound (1) by an enzyme oxidation, an original, a hydrolysis or the like; or a compound which is converted into the compound (1) by a hydrolysis reaction with gastric acid or the like. The compound (I) is a precursor compound which is an amine group in the compound (1). a compound obtained by a thiolation, alkylation or phosphonylation reaction (for example, subjecting an amine group in the compound (I) to peanut thiolation, propylamine thiolation, pentylamine carbonylation, (5-fluorenyl) 2-keto-1,3-dioxol-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidinylmethylation, trimethylacetoxymethylation, a compound obtained by a reaction such as a third butylation reaction; a compound obtained by subjecting a hydroxyl group in the compound (1) to a thiolation, alkylation, phosphonylation or boration, etc. (for example, by subjecting a base group in the compound (1) Ethylation, palmitoylation, propionation, three Methylacetylation, a compound obtained by perrylation, anti-butylation, arylation, propylamine methylation or dimethylaminomethylation reaction; and the like (I) A compound obtained by a reaction such as esterification or guanidation by a slow-acting group (for example, the thiol group, the benzene vinegar, the thiol group, and the bismuth amide group in the compound (1) , tridecyl ethoxylated oxime esterification, ethoxycarbonyloxyethyl esterification, ugly esterification, (5-mercapto-2-69 321556 201114425 keto-1,3-dioxole a compound obtained by a reaction such as a methyl esterification, a cyclohexyloxycarbonylethylation or a methyl hydrazide reaction, or the like. Any of these compounds can be prepared from compound (I) by a method known per se. The compound (I) prodrug may also be converted under physiological conditions as described in, for example, IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol. 7, Design of Molecules, p. 163-198, 1990, published by HIROKAWA SHOTEN. It is a compound (I). The compound (I), a salt thereof and a precursor thereof are hereinafter abbreviated as "the compound of the present invention". The compounds of the invention have superior adrenergic receptor antagonistic effects. In particular, the compounds of the invention have selective a1D adrenergic receptor antagonism. The compound of the present invention is preferably a compound having selective a1D adrenergic receptor antagonism. Here, the selective a]D adrenergic receptor antagonism means that at least 1 to 10 times or more of the a1A adrenergic receptor is present and at least 10 times or more than the a]B adrenergic receptor. Antagonistic activity. Since the compound of the present invention has selective a1D adrenergic receptor antagonism, it is thought that the blood pressure lowering action which is considered to be based on the antagonism of the a1A receptor or the a1B receptor can be reduced. Therefore, the compounds of the present invention are considered to provide pharmaceutical agents with less side effects. Furthermore, since the compounds of the present invention have low toxicity (for example, 'cardiotoxicity (for example, 'human etheng0_g0 related gene (HERG) inhibitory activity), phospholipidosis (slipester metabolic disease) (PLsis), acute toxicity, chronic toxicity, genotoxicity, reproduction Toxicity) 'drug interaction, carcinogenicity, phototoxicity, etc.' can therefore be administered to mammals (eg, mice, rats, hamsters, rabbits, tracing, 70 321556 201114425 dogs, cattle, sheep, monkeys, Humans, etc.). Further, the compound of the present invention has superior drug absorption, scavenging properties, etc.). ', motility (for example, mammals (for example, small: 乍: 乍) 'The compounds of the invention can be used in monkeys, humans as any aiD, or, anti- or therapeutic agents, such as: ...pre-related diseases =) lower urinary tract diseases [including all diseases with the following: for example, win a, urinary tract symptomatic bladder $ r ° disease, benign prostate hypertrophy, interstitial, etc., storage symptoms (daytime Frequent urinary, nighttime frequency loss of Hr stress urinary incontinence, acute urinary incontinence, 'Luohe 1 $ 4 urinary dysfunction, nocturnal bedwetting, continuous urinary incontinence, other urinary dysfunction, enhanced bladder, decreased or eliminated ginseng, , , : m 'Xiao Xiao searched, urinary symptoms (urinary weakness (or urine ^ again), urinary W segment (or segmental urinary flow), sputum urine, interruption of urinary flow (or intermittent urinary flow), urinary effort ( Or difficulty urinating), - private - 'prepared, east - leaf; special force (or hard) when urinating, shirt (or hide) #), post-lin symptoms (residual urinary, post-urine drip temple), sexual father Caused by peak pain, vaginal dryness, urinary incontinence, etc.), symptoms caused by pelvic (four) prolapse (foreign body , low back pain, etc.), fresh official pain or lower urinary tract pain (bladder pain, urethral pain, genital pain, vaginal pain, scrotal pain, perineal pain, pelvic pain, etc.), reproductive organs or urinary tract pain syndrome (bladder pain syndrome, Urethral pain syndrome, genital pain syndrome, vaginal syndrome, scrotal pain syndrome, perineal pain syndrome, pelvic pain syndrome, etc.), suggesting symptomatic symptoms of urinary tract dysfunction (overactive bladder, suggesting urinary bladder obstruction under capillaries 321556 71 201114425 symptoms, etc.), polyuria, urinary calculi (urethral, urethra, etc.); (2) metabolic diseases [eg, diabetes (insulin-dependent diabetes mellitus, diabetic complications, diabetic retinopathy, diabetic small blood vessels) Lesions, diabetic neuropathy, etc., impaired glucose tolerance, obesity, benign prostatic hypertrophy, sexual dysfunction, etc.; (3) central nervous system diseases [eg, neurodegenerative diseases (eg, AIDS) Haimo's disease, Down's disease, Parkinson's disease Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis (ALS), Huntington's chorea, diabetic neuropathy, multiple sclerosis, etc., mental illness (eg, schizophrenia) Symptoms, sorrow, arrogance, anxiety neurosis, obsessive-compulsive disorder, panic disorder, epilepsy, alcohol addiction, drug addiction, anxiety, anxiety, emotional abnormalities, circulatory affective disorders, neurological excitability , autism, fainting, sputum, low libido, etc.), central nervous system and peripheral nerve disorders (eg, head trauma, spinal injury, cerebral edema, sensory dysfunction, sensory dysfunction, autonomic dysfunction, autonomic nervous function) Abnormalities, whip-type injuries, etc.), memory disorders (eg, Alzheimer's disease, amnesia, cerebrovascular dementia, etc.), cerebral vascular disorders (eg, cerebral hemorrhage, cerebral infarction, etc. and its sequelae or complications, asymptomatic Cerebrovascular accident, transient ischemic attack, hypertensive brain disease, blood-brain barrier disorder, etc.), recurrence of cerebral vascular disorders and sequelae (for example, Symptoms, psychological symptoms, subjective symptoms, disorders of daily living, etc.), insufficient central function after cerebrovascular obstruction, dysregulation or abnormality of cerebral circulation or renal circulation, and sleep disorders; (4) genital dysfunction [eg , male erectile dysfunction, 72 321556 201114425 ejaculation disorders, female genital dysfunction, etc.; (5) digestive tract diseases [eg, intestinal tract, inflammatory bowel disease, ulcerative colitis, Crohn's disease, by urease-positive Spiral Gram-negative bacteria (eg, Helicobacter pylori (ifWcokcier j^/orz·), etc.) caused abnormalities (eg, gastritis, gastric ulcer, etc.), gastric cancer, postoperative gastrostomy disorders, dyspepsia, esophageal ulcers, pancreas Visceritis, colon polyps, gallstones, pruritus, peptic ulcer, situational ileitis, bulimia, constipation, diarrhea, belching, etc.; (6) inflammatory or allergic diseases [eg, allergic rhinitis, conjunctivitis , Gastrointestinal allergy, hay fever, allergic reactions, dermatitis, herpes, psoriasis, bronchitis, cough, retinopathy, inflammation after surgery and after injury Regression of puffiness, pharyngitis, cystitis, meningitis, inflammatory eye disease, etc.; (7) bone and joint disease [eg rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, osteoporosis, Abnormal cell growth, fracture, bone refolding, rickets, osteopenia, Behcet's disease, ankylosing myelitis, joint tissue damage due to knee deformation and similar diseases, (8) Breathing Sexual diseases [eg cold, pneumonia, asthma, pulmonary hypertension, pulmonary embolism / pulmonary occlusion, pulmonary sarcoma, tuberculosis, interstitial pneumonia, silicosis, adult respiratory syndrome, chronic obstructive pulmonary disease, cough嗷, etc.; (9) Infectious diseases [HIV infectious diseases, viral infections due to cytomegalovirus, influenza virus, vesicular virus, etc., rickettsial infectious diseases, bacterial infectious diseases, sexual Infectious diseases, Pneumocystis pneumonia, 73 321556 201114425 Helicobacter pylori infectious diseases, systemic fungal infectious diseases, tuberculosis, invasive staphylococcal infectious diseases, acute diseases Encephalitis, acute sputum meningitis, AIDS encephalitis, septicemia, sepsis, sepsis gravis, septic shock, endotoxic shock, toxic shock syndrome, etc. (10) Cancer [eg, primary, metastatic or recurrent breast cancer, prostate cancer, pancreatic cancer, stomach cancer, lung cancer, colorectal cancer (colon cancer, rectal cancer, anal cancer), esophageal cancer, duodenum) Cancer, head and neck cancer (tonal cancer, pharyngeal cancer, laryngeal cancer), brain tumor, schwannoma, non-small cell lung cancer, small cell lung cancer, liver cancer, kidney cancer, biliary tract cancer, uterine cancer (uteral cancer) , cervical cancer), ovarian cancer, bladder cancer, skin cancer, hemangioma, malignant lymphoma 'malignant melanoma, verrucous adenocarcinoma, osteoma, angiofibroma, retinal sarcoma' Yin! Cancer, juvenile solid cancer, Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, upper sinus tumor, fibroblastoma, uterine muscle tumor, rhabdomyosarcoma, adipose sarcoma, uterine fibroid tumor , osteoblastoma, osteosarcoma, chondrosarcoma, cancerous mesothelioma, tumors such as leukemia, Hodgkin's disease; (11) circulatory diseases [eg 'acute coronary syndrome (eg, acute) Myocardial infarction, unstable angina, etc.), peripheral arterial occlusion, Raynaud's disease, Buerger's disease, coronary interventional therapy (coronary balloon dilatation (PTCA), directional coronary atheroma) ^ Resection (DCA), placement of stents, etc., restenosis, restenosis after coronary bypass surgery, other peripheral arterial interventions (vascular repair, atherectomy, placement of stents, etc.) or after bypass surgery Restenosis, ischemic heart disease 321556 74 201114425 Disease (eg, myocardial infarction, ventricular sulcus cerebral infarction, arterial stiffness =,), myocarditis 'intermittent claudication, dirty failure (emergency Heart failure, sputum such as 'atherosclerosis, etc., heart failure, arteriosclerosis called = chronic congestion (10) failure), rhythmic pressure tinnitus, low blood count]; exhibition, thrombosis, hypertension, high blood (12 Pain [eg, headache, pain, including bladder pain, etc.]; migraine, neuralgia, and pelvic organ pain (13) autoimmune disease [eg, collagen] systemic erythematous wolf: scleroderma, polyarteritis 1 myasthenia gravis, multiple sclerosis, Sjogren's syndrome, Bezi's disease, etc. p (14) Liver [eg, hepatitis (including chronic hepatitis), cirrhosis, interstitial liver disease, etc.]; 05) Dysentery [eg, visceral inflammation (including chronic pancreatitis), etc.] ((9) Kidney disease [eg 'nephritis, glomerulonephritis, glomerulonephritis, renal failure, thrombotic microangiopathy, washed poetry Symptoms, organ disorders include nephropathy due to radiation, diabetic nephropathy, etc.; (17) Endocrine diseases [eg, Addis〇n, Cushing syndrome, melanoma, primary cortisol Ketotoxicity, etc.]; (18) Other diseases such as (a) transplant platoon [eg 'rejection after transplantation, post-transplantation erythrocytosis, blood pressure, organ imbalance and/or vascular hypertrophy, graft versus host disease, etc.], (b) abnormal blood and/or blood component characteristics [eg, increased platelet aggregation] Red blood cell deformability abnormality, white blood cell adhesion increased, blood viscosity increased 321556 75 201114425 plus, erythrocytosis, vascular purpura, autoimmune hemolytic anemia, generalized intravascular coagulation syndrome (DIC), multiple spinal cord lesions, etc. ], (c) Gynecological diseases [eg, menopausal disorders, gestational toxicity, endometriosis, uterine fibroids, ovarian disease, breast disease, premenstrual syndrome, etc.], pelvic organ prolapse (eg, vaginal anterior wall) Prolapse, vaginal prolapse, vaginal posterior wall prolapse, uterine ptosis, etc.), other diseases in which the organ is prolapsed from the normal position due to weakening of the pelvic floor muscles (eg, rectal prolapse, etc.), (d) skin disease [eg, tumors, hemangioma, psoriasis, itching, etc.], (e) ophthalmic diseases [eg glaucoma, ocular hypertension, etc.], (1) ENT diseases [eg, Menuel (Menuel) Syndrome, tinnitus, taste disorder, dizziness, imbalance, difficulty swallowing, etc., (g) Diseases due to environmental and/or occupational factors (eg, radiation disorders, disorders due to ultraviolet rays, infrared rays, laser light, mountains) Symptoms, (h) ataxia, stiffness, SI shaking, sports injuries, motor insufficiency, (1) chronic fatigue syndrome, (1) sudden infant death syndrome, (k) snoring' (l) causing palpitations, dizziness, heartburn, etc. The disease. Among the diseases, the compound of the present invention is particularly useful as a prophylactic agent for lower urinary tract diseases such as overactive bladder, stress urinary incontinence, prostate hypertrophy, and the like for preventing or treating urinary tract diseases. The preparation containing the compound of the present invention may be any solid preparation such as a powder, a granule, a tablet, a capsule, an orally disintegrating film, and the like, and a liquid such as a sugar, an emulsion, an injection or the like. 76 321556 201114425 The prophylactic or therapeutic agent of the invention may be blended, kneaded, granulated, made into a bond, two ‘, 礼化, etc. in the form of any of the preparations. For the purpose of manufacturing such pharmaceutical preparations, for example, • Two:: Two Pharmacopoeia Pharmacy Preparations - General principles of each item. In addition, the present invention is capable of riding the active ingredient and the biodegradable polymerized heart paste (4). The formula of the compound of the present invention can be determined according to the formula, and the content of the compound of the present invention is determined according to the form of the preparation. For the entire formulation, it is usually from 〇〇ι to (10), 5 . The weight %, more preferably 〇 5 to 2. weight%. t = followed by (d), which can be used alone to make = two: a form of agent (for example, powder, lactose, Yan sugar 'Qing Jingyi fiber agent (for example, Dian powder, gum arabic, ^ methyl cellulose, each =; , crystalline cellulose, seaweed, gelatin, polyethylene. Ratio = search = slip agent (for example, stearic acid 'hard agent (for example, water for injection, raw ==, thinner (for example, An, 丨艮 brine temple) 'and when needed, with the addition of such as female mites, preservatives, colorants, fragrances, dissolution aids = chemicals, buffers, isotonic agents, etc.), etc.: _ such as powder, called = = preparations such as injections, etc., and can be administered orally or parenterally = intramuscular injection; may also be administered by topical administration (4), eg, Yilu or (4) injections; 321556 77 201114425 Formulations such as implants, granules, powders, etc., liquids such as suspensions, ointments, etc., etc. For example, when an injection is to be produced, the compound of the present invention and a dispersing agent (for example, a surfactant such as Tween) 80, HCO-60, etc., polysaccharides such as carboxymethyl cellulose, sodium alginate, hyaluronic acid, etc., polysorbate, etc.) Preservatives (for example, decyl hydroxybenzoate, propyl p-hydroxybenzoate, etc.), isotonic agents (for example, sodium chloride, mannitol, sorbitol, glucose, etc.), buffers (for example, A carbonated dance, etc., a pH adjuster (for example, sodium sulphate, potassium sulphate, etc.), etc. are prepared together as an aqueous suspension to obtain an actual preparation for injection. Further, the compound (I) is provided with a phospholipid such as lecithin. A vegetable oil such as sesame oil, corn oil or the like or a mixture thereof, or a medium chain fatty acid triglyceride (for example, miglyol 812 or the like) is dispersed together to obtain an oily suspension for actual injection. The prophylactic or therapeutic agent of the present invention may also be used. Used together with other pharmaceutical agents. The drug mixed or combined with the compound of the present invention (hereinafter referred to as a combination drug) includes the following drugs: (1) Diabetes therapeutic agent insulin preparation (for example, an animal insulin preparation extracted from bovine or porcine pancreas) Human insulin preparation synthesized by genetic engineering using E. coli or yeast; zinc zinc; protamine zinc insulin; insulin fragment or derivative For example, INS-1, etc.), insulin-sensitive enhancers (for example, pioglitazone hydrochloride, troglitazone, rosiglitazone or its cisplatin Dilute acid salt, JTT-501, 78 321556 201114425 MCC-555, ΥΜ-440, GI-262570, KRP-297, FK_614, CS-011 temple), a- Portuguese word sugar transfer inhibitor (for example, Peixin (VOgiib〇se), acarbose, miglito I, emiglitate, etc., bifidos (eg, phenformin, diterpene, diterpene) Etc.), sulphate urea (for example, toluene yellow butazone, glyburide, methyl bicyclic urea, chlorpropamide, sulfonylurea, sulfacyclohexylurea, glyclopyramide) , giimepi (HimepieHde), and other insulin secretagogues (such as 'repaglinide, senaglinide, mitiglinide or its calcium salt, GLP small Natlinide, etc., dipeptidyl peptidase IV inhibitors (eg, NVP-DPP-728, PT-100, P32/98, etc.), 3 agonists (eg, CL-316243, SR-5861 1-A, UL-TG-307, AJ-9677, ΑΖ40140, etc.), amyloid agonists (eg, pramlintide) ), etc.), phosphotyrosine phosphatase inhibitors (eg, vanadic acid), inhibitors of glucose production (eg, glycoglucosidase inhibitors, glucose-6-cansin inhibitors, pancreatic hyperglycemia) Hormone antagonists, etc.), SGLT (sodium-glucose co-transporter) inhibitors (eg, T_1095, etc.), etc.; (2) Diabetic complication therapeutics aldose reductase inhibitors (eg, torista (t〇 Lrestat), epalrestat, zenarestat 'zopolrestat, fidarestat (SNK-860), minarrestat (ARI-509) ), CT-112, etc., neurotrophic factors (eg, NGF, NT-3, etc.), AGE inhibitors (eg, ALT-945, pimagedine, pyratoxathine, Desertification N-benzene with 曱79 321556 201114425 thiophene (ALT-766), EXO-226, etc., active oxygen scavenger (for example, lipoic acid, etc.) a cerebral vasodilator (for example, tiapuride, etc.); (3) a statin compound that inhibits cholesterol synthesis by a hyperlipemia agent (for example, pravastatin, simvastatin) Simvastatin), lovastatin, acevastatin, atorvastatin, fluvastatin, fluvastatin, cerivastatin or a salt thereof (eg, sodium salt, etc.) a squalene synthetase inhibitor or a fibrate compound having a triglyceride lowering action (for example, bezafibrate, clofibrate, bismuth octanoate) (simfibrate), clinofibrate, etc.; (4) hypotensive agents angiotensin converting enzyme inhibitors (eg, captopril, enalapril, de Radipril, etc., angiotensin II inhibitors (eg, losartan, candesartan cilexetil, etc.), calcium antagonists (eg, manidipine) 'Nifedipine, Anlo Amlodipine, efenidipine, nicardipine, etc., clonidine (c) onidine, etc.; (5) weight-loss drugs acting on the central nervous system (such as 'ground Dexfenfluramine, fenfiuramine, phentermine, sibutramine, amfepramone, dexamphetamine, benzene Flavor, 321556 80 201114425 0 (mazindol), stupid propanolamine, clobenzorex, etc., pancreatic lipase inhibitors (eg, orlistat, etc.), β3 agonists (eg CL-316243, SR-58611-A, UL-TG-307, AJ-9677, AZ40140, etc.), an appetite-suppressing peptide (for example, leptin, CNTF (ciliary neurotrophic factor), etc.), Cholecystokinin agonist (eg, lintitript, FPL-15849, etc.), serotonin 2C receptor agonist (eg, APD-356 > SCA-136 'ATHX-105 ' WAY-163909 > YM-348) et al; (6) diuretic xanthine derivatives (for example, cocoa succinate, cocoa lauric acid 1 bow ), thiazide preparations (eg, acetylated oxime, cyclopentanthene, trichlorosulfonium thioate, hydrochlorothiazide, hydrofluoroquinone thiocyanate, benzyl dihydrochlorothiophenate) Phthalate, pentafluorothroated, polythiazide, xenon thiocyanate, anti-aldosterone formulations (eg, spironolactone, triamine, etc.), carbonate dehydratase inhibitors (eg, B Oxazolamide, etc., chlorobenzenesulfonamide preparation (for example, chlorthalidone, mefruside, indapamide), azosemide, isosorbide, uric acid, skin Piretanide, butyl phenoxy acid, diuretic sulfonamide, etc.; (7) chemotherapeutic alkylating agents (eg, cyclophosphamide, ifosamide, etc.), metabolic antagonists (eg, Aminoguanidine, 5-fluorouracil, etc.), anti-tumor antibiotics (such as 'mitomycin, ariamycin, etc.), plant-derived anti-tumor agents (eg 'Changchun new test, vindesine (vindesine) , paclitaxel, etc., cis start ingot 'carboplatin, etoposide (etopos Ide) 83 321556 201114425, etc.; among them, 5-fluorourine-series derivatives such as Furtulon and Neo-Furtulon are preferred; (8) immunotherapeutic microorganisms or bacteria Derivatives (eg, muramy 1 dipeptide derivative, Picibanil, etc.), immunopotentiating polysaccharides (eg, mushroom sugar, schizophyllum polysaccharide, proteoglycan ( Krestin), genetically engineered interleukins (eg, interferon, interleukin (IL), etc.), community stimulating factors (eg, 'granulocyte community stimulating factor, erythropoietin, etc.); Preferably, IL-1, IL-2, IL-12, etc.; (9) Progesterone derivatives (e.g., megestrol acetate) which are identified in animal models or clinical practice to improve cachexia [J〇urnal] 〇f

Clinical Oncology, ν〇1·12, ρρ· 213-225, 1994], metoclopramide medicine, tetrahydrocannabinol medicine (the above reference is used herein), fat metabolism improving agent (for example) , 廿 廿 廿 ) [British Journal of Cancer, vol. 68, ρρ· 314-318, 1993], growth hormone, IGF·1, and cachexia-inducing factors such as TNF-α, LIF, IL-6 and tumor Μ Antibodies; (10) Anti-inflammatory agents steroids (eg, dexamethasone, etc.), sodium hyaluronate, epoxidase inhibitors (eg, indomethacin, ketoprofen, lesoprost) Loxoprofen, meloxicam (me) 〇xicam), ampiroxicam, cdec〇xib, rofecoxib (r〇fec〇xib), etc.; (11) Other 321556 201114425 Inhibitors of saccharification (eg 'ALT-711, etc.), nerve regeneration promoting agents (eg 'Y-128, VX853, prosaptide, etc.), drugs acting on the central nervous system (eg Antidepressants such as desipramine, amitriptyline, and propylidene (i Mipramine), fluoxetine, paroxetine, doxepin, etc., anticonvulsants (eg, lamotrigine, carbamazepine), antiarrhythmia Drugs (eg, mexiletine), acetaminophen receptor ligands (eg, ABT-594), endothelin receptor antagonists (eg, ABT-627), monoamine uptake inhibitors (eg, Tramadol) Monoamine uptake inhibitors (eg, Fluoride 1; D, Paroxetine), narcotic analgesics (eg, tons), GABA receptor agonists (eg, gabapentin) )), GABA uptake inhibitors (eg, B tiagabine), alpha 2 receptor agonists (eg, clonidine), topical analgesics (eg, capsaicin), protein kinase C inhibitors (eg, LY-333531), anxiolytics (eg, benzodiazepines), phosphodiesterase inhibitors (eg, sildenafil), dopamine receptor agonists (eg, A Park morphine), a dopamine receptor antagonist (eg, halopyridinone (hal Operidol)), a serotonin receptor agonist (eg, tandospirone citrate, sumatryptan), a serotonin receptor antagonist (eg, cyproheptadine) , ondansetron (ondansetron), serotonin uptake inhibitors (eg, fluvoxamine maleate, fluoxetine, paroxetine, butyl), hypnotic drugs (eg 'three ° Sitting on triazolam, zolpidem, anti-cholinergic agents, receptor blockers (eg 'Tanlo 83 321556 201114425 new (tamsulosin), muscle relaxants (eg, baclofen (baclofen) ), etc., unloading channel openers (eg, nicorandil), channel blockers (eg 'nifedipine'), Alzheimer's disease prevention and/or therapeutic agents (eg , more than dopezil, rivastigmine, galanthamine, Parkinson's treatment (eg, levodopa (L-dopa)), multiple Sclerosis prophylaxis or therapeutic agents (eg, beta-la interferon), histamine Η! Inhibitors (e.g., isoproterenol hydrochloride, coax (Promethazine)), proton pump inhibitors (e.g., lansoprazole. Sitting (lansoprazole), Omera. Omegaprazole, antithrombotic agents (eg, aspirin, cilostazol), NK-2 receptor antagonists, HIV infection therapeutics (saquinavir, Zidov) Zidovudine, lamivudine, nevirapine, chronic obstructive pulmonary disease therapeutics (salmeterol, thiotropium bromide, cilorami) Cilomilast)); anti-biliary energy testers include, for example, atropine 'guanamine, homatropine, tropicamide, cyclopentolate, bromobutyl Indoleamine, propantheline, methylbenactyzium, mepenzolate, flavoxate, pirenzepine, ipratropium bromide (ipratropium bromide), trihexyphenidyl, oxybutynin, propiverine, darifenacin, tolterodine, timvirine Temiverine), trosium chloride (trospium 84 321556 201114425 chloride Or a salt thereof (for example, atropine sulfate, strontium hydrobromide & / post-acidomarine, cyclopentolate hydrochloride, flavone hydrochloride, salt', now taking Xiping, trihexyphenidate, gas Oxybutynin, tolterodine tartrate, etc., etc., 浐佳为, oxybutynin, propiverine, dafinacin, tolterodine, telvirin, tromethamine or its salt For example, oxybutynin, tolterodine tartrate, etc.; in addition, 'acetylcholinesterase inhibitors (eg, distigmine, etc.), etc. may be used; NK-2 receptor antagonists include 'For example, alpha melon. Derivatives such as GR159897, GR149861, SR48968 (saredutant), SR144190, YM35375, YM38336, ZD7944, L-743986, MDL105212A, ZD6021, MDL105172A, SCH205528, SCH62373, R-113281, etc., all hydrogen. A ruthenium derivative such as RPR-106145 or the like, a quinoline derivative such as SB-414240 or the like, a pyrrolidine derivative such as ZM-253270 or the like, a pseudopeptide derivative such as MEN11420 (nepadutant), SCH217048, L -659877 'PD-147714 (CAM-2291) > MEN10376 'S16474 and the like, and others such as GR100679, DNK333, GR94800, UK-224671, MEN10376, MEN10627, or a salt thereof. When used in combination, the administration time of the compound of the present invention and a concomitant drug is not limited, and the compound of the present invention or a pharmaceutical composition thereof and the accompanying drug or a pharmaceutical composition thereof can be simultaneously administered to a subject. Or may be cast at different times. The dose of the accompanying drug can be determined according to the clinical dose, and can be appropriately selected depending on the subject to be administered, the route of administration, the disease, the combination, and the like. 85 321556 201114425 八二随,, the method of administration of the substance is not specifically limited, and only the combination of the δ substance of the present invention and the ik drug is required to be administered. Examples of such administration methods include: treating a compound of the present invention or a pharmaceutical composition thereof with J:):r" and attaching (2) via the same administration route, simultaneously administering a bifithamine compound or its ## group Silk and two kinds of preparations accompanying the medicine or its medical treatment; (3) In a staggered manner, the separately manufactured eight-piece Mu Li Dian, the Xiangmen and the 迓 戋 。. Or a two-form preparation of a blushing composition and a medicinal compound 1; (4) a compound of the present invention produced separately; two preparations from _ or a pharmaceutical composition thereof; (7) in a staggered manner: The inventive compound or the (four) composition thereof is then administered in the same order and administered in the reverse order, via the different two = or its pharmaceutical composition and attached: as in the present invention, the present invention The content of the compound is usually _2; π heavy material 5 〇% by weight, and further preferably about 〇.5 to the same dose 'according to the content of the drug _ _ For the preparation, it is usually about _ to ι 〇〇 weight: ..., 0·1 to 50 weight 0/0, and the step is preferably about 0.5 to 20 heavy dam. Inventive combination shot, the addition is as _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The compound of the present invention is similar in content to the accompanying drug. The moon/lower, can be taken, depending on the type of the compound of the present invention or a pharmaceutically acceptable salt thereof, the dosage, the age of the private symptom patient, etc.; In the case of an adult patient with urinary incontinence, " gram (four) / kg _ weight / day, preferably about 〇〇 5 to day" is exemplified by the compound of the present invention, preferably eight^7 days, more preferably about G .2 to 4 grams / kg body weight / large ' can be divided into about 1 to 3 times. When the pharmaceutical composition of the present invention is a sustained-release preparation, the type and content of the compound, the dosage form, and the medicine __= visual = = movement: the subject (for example, 'mammal such as human, rat 'mouse') Dog two 'two; the difference: for example, for the parenteral mg of the compound of the invention / month and the self-sufficiency and the bribery about ο1 to about 100 drug double and sensitivity, the time of administration and Special f-species rainbow type, active ingredient type, etc., different blending and dosage-passing...: Weight 'in terms of combination medicine, gram to 2000 mg' is preferably about 500 millimeters a day: about .... milligrams忒大刀—to four doses. 321556 87 201114425 When the combination drug of the present invention is administered, the compound of the present invention and the combination drug may be administered simultaneously, or the combination drug may be administered prior to administration of the compound of the present invention, and vice versa. In the case of staggered casts, the time interval is different depending on the active ingredient's formulation and the route of administration. For example, if the combination drug is administered first, the compound of the present invention can be administered to the combination. 1 minute to 3 days after the agent, preferably 1 minute to 1 day. More preferably, it is administered for 15 minutes to 1 hour. If the compound of the present invention is administered first, the combination drug may be administered from 1 minute to 1 day after administration of the compound of the present invention, preferably 10 minutes to 6 hours, more preferably 15 minutes. The pharmaceutical composition of the present invention has a low sputum property and can be used as a female. Specifically, since the compound of the example shown below is excellent in oral absorption, it can be advantageously used as an oral preparation. EXAMPLES The present invention will be further described in detail with reference to the following Reference Examples, Examples, Preparation Examples and Experimental Examples; however, the above examples are not intended to limit the invention, and may be modified without departing from the scope of the invention. Measurement conditions) In the following examples, HPLC-mass spectrometry (LC-MS) was measured under the following conditions: Measurement apparatus: Quattr〇Micro manufactured by Micromass; HP1100 manufactured by Agilent Technologies; or high-speed liquid layer manufactured by ASHIMADZU Corporation Mass spectrometer LCMS-2010; or MUX system manufactured by Waters (Micromass ZQ) column: Capcelpak Cl8 88 321556 201114425 UG-120, 1.5 X 35 (mm) manufactured by Shiseido Co., Ltd.; Made from Nonuira Chemical Co., Ltd., Develosil Combi-RP-5, 2.00 x 35 mm. Solvent: Solution A: 5 (mM) ammonium acetate/2% acetonitrile/water; Solution B: 5 mM ammonium acetate/ 95% acetonitrile/water gradient cycle: 0.00 minutes (solution A 100%), 2.00 minutes (solution B 100%), 3.00 minutes (solution B 100%), 3.01 minutes (solution A 100%), 3.80 minutes (solution A 100 %) Flow rate: 0.5 ml/min Detection method: UV 220 nm (nm) Ionization method: Electron Impact Ionization (ESI) (Preparative HPLC conditions) In the following examples, under the following conditions Purification was carried out using preparative HPLC. Instrument: High throughput purification system manufactured by Gilson Inc. Pipe column: Capcelpak C18 UG-120 manufactured by Shiseido Co., Ltd., S-5 μΜ, 20 x 50 mm; or Combi Prep Hydrosphere C18 HS-340-CC manufactured by YMC, S-5 μΜ, 20 x 50 mm Solvent: Solution A: 0.1 ° /. Aqueous trifluoroacetic acid;

Solution B: 0.1% acetonitrile-containing trifluoroacetic acid gradient cycle: 0.00 minutes (solution A / solution B = 95/5), 1.10 minutes (solution A / solution B = 95/5), 5.00 minutes (solution A / solution B 89 321556 201114425 =0/100) ' 6'40 minutes (solution A / solution B = 〇 / l 〇〇), 6.50 minutes (solution A / solution B = 95/5) Flow rate: 20 ml / min Detection method: UV 220 nm (other conditions) i-NMR spectrum was measured using AV-400M (400 MHz), AVANCE 300 (300 MHz) or AVANCE II 300 (300 MHz) manufactured by Bruker or VNMRS-400 (400 MHz) manufactured by Varin, and All four delta values are expressed in ppm using tetrakid stone as an internal standard. Unless otherwise indicated, the value indicated by the mixed solvent is the volume mixing ratio of the individual solvents. Unless otherwise indicated, 'other' means weight. /. . The room temperature (normal temperature) in the present specification is from about 10 ° C to about 35. (: Unless otherwise specified, in the Reference Examples and Examples, the elution of the column chromatography was carried out by TLC (Thin Layer Chromatography) under observation. In this TLC observation, it was manufactured by Merck. 60F254 or TLC (NH) manufactured by FUJI SILYSIA as a TLC plate, and a solvent using a solvent as a solvent for column chromatography. The UV detector is used for the detection. The silicone 60 manufactured by Merck is used. 70 to 230 mesh) as a silica gel for column chromatography, and using CHROMATOREX NH manufactured by FUJI SILYSIA as an alkaline silicone. Other abbreviations used in this specification mean the following meanings: s : single peak d: doublet t: triplet 90 321556 201114425 q : quartet dd: doublet br: broad peak J: coupling constant Hz: Hertz CDCI3: liquefied chloroform H NMR . Proton nuclear magnetic resonance reference example 1 2 _2-(3,4_二气-5_§同基_2,5-dihydrofuranyl) ethanoamine makes chloric acid (15.1 g (g)) and 2-cyanoethylidene (7 53 g) Dissolve in decyl alcohol (53.6 ml), add 25N aqueous sodium hydroxide solution (53.6 ml) dropwise with ice cooling and stirring. The mixture was stirred at room temperature for further 3 hours. The reaction mixture was poured into EtOAc EtOAc. The title compound (3.74 g) was obtained eluted eluted eluted eluted eluted eluted eluted eluted with J = 3.2 Hz) 5 91 (1 H, d, J = 4.0 Hz), 7.85 (1 H, br. s.), 8.03 (1 H, br. s.). Example 1 5-chlorochlorobenzene Ethyl]-2-imino-i,2-dihydropyridine_3_decylamine, under ice cooling, on 2-cyano-2-(3,4-dichloro-5-keto) _2,5-dihydrofuran-2-yl)acetamidamine (0.5 g) in tetrahydrofuran (10), added 321556 91 201114425 1-(3_methanol)ethylamine hydrochloride (0.62 g The suspension (3 ml) with triethylamine (0.64 g) in tetrahydrofuran was allowed to warm to room temperature and was stirred for 18 hours. The reaction mixture was concentrated and the crystals were collected by filtration. Add the resulting crystals to a mixture of bismuth (5 ml)-water (5 ml), which mixes you............... at 80. (: Stirring the small dices.) The agglutination reaction mixture was purified by chromatography on silica gel to give the title compound (40 mg (mg)). HPLC purity 97% MS m/z 310 (M+H+) H NMR (400 MHz, CDC13) δ ppm 1.78 (3 only 5.32 (1 H, br. s·), 5.79 (1 H, br· s.), 6 > 35' ' J==6*8 Hz) , (1 H. br. s.): 7.08-7.12 (1 H,m), 7.19 (1 H, d, J=2.4 H7, ), /.22 gate tr, 7.33-7.38 (2 H, m) , 8.16 (1 H, br. s.), 10.94 n , WH, s), - U br s, Example 2 · S·) ° 5 - gas-1-(6-gas-2,3-second wind -1H-member-1-yl)-2-indol was -3-decylamine, -, dihydropyridine. According to the method of Example 1, 2-cyano-2,5-dihydrofuran-2 was obtained. The acetamide is reacted with 6-chloro-2,3-dihydro-1H, acid salt to give the title compound. HPLC purity 96% MS m/z 322 (M+H+) 丨H NMR (400 MHz, CDC13) δ ppm 2.06, 2 & 2.68-2.81 (1 H, m), 2.95-3.16 (2 H, m), 5 6l 5.85 (1 H, br. s.), 6.53 (1 H, br. s.), 6.77 (1 HH, s), 7.32 (1 H, d, J=8.0 Hz), 7.35-7.39 (1 H, chloro, 5-ketoguanamine salt (1 H, m), (1, br. s.), br • S'), 7.18 (1 m)' 8.14 (1 H, 321556 92 201114425 br. s.), 11.07 (1 H, br. s.). Example 3 5-Gas-1-(7-chloro-1,2,3,4-tetrahydronaphthalene-1-yl)_2-imino-1,2-dihydrogen 11 ratio biting-3- formazan Amine according to the method of Example 1, 2-cyano-2-(3,4-dichloro-5-keto-2,5-dihydrofuran-2-yl)acetamide and 7-chloro-m The tetrahydronaphthalene·amine hydrochloride is reacted to synthesize the title compound. HPLC purity 94% MS m/z 336 (M+H+) ]H NMR (400 MHz, CDC13) δ ppm 1.89 (2H, m), 2.01-2.21 (2H, m), 2.79-2.97 (2H, m), 5.39 (1 H, d, J = 4.6 Hz), 5.82 (1 H, br. s.), 6.72 (1 H, s), 6.84 (1 H, br. s.), 6.97 (1 H ,d, J=1.7

Hz), 7.16-7.20 (1 H, m), 8.14 (1 H, d, J=2.4 Hz), 10.65 (1 H, br. s.). Example 4 5-Gas-l-[l-(3-fluorophenyl)ethyl]_2-iminoamine·ι,2-dihydro-n-bital amine hydrochloride at room temperature, at room temperature Acetyl 2-(3,4-dioxa-5-keto-2,5-dihydrofuran-2-yl)acetamide (0.5 g) in ethanol (1 〇 solution, added with stirring 1- (3-fluorophenyl)ethylamine hydrochloride (〇·75 g) and triethylamine (0 85 g), the mixture was allowed to warm to room temperature and stirred at 50 ° C for 18 hours. The mixture was stirred at 80 ° C for 2 hours. The reaction mixture was concentrated and the residue was purified eluting with EtOAc EtOAc. The title compound (45 mg) was obtained by filtration. The title compound (45 mg) was obtained. ipl NMR (400 MHz DTVTSri Η, 、, ιιηζ, UMSO-d6) δ ppm 1.90 (3 H> ^ J=6 6 Hz), 6.25 (1 H, q, J=6.4 Hz), 7.22-7.31 (2 H, m), 7.39 (1 H, d, 1 = 10.3 Hz), 7.45-7.55 (1 H, m), 8.24 (1 H, s), 8.43 (1 H, d, J=2.0 Hz), 8.63 (1 H, d J=2 0 H7, s /1 tt v 5 zu 6.73 (1 H, S), 9.88 (2 H, br. s.) ° Example 5 5' Nitrogen_2_ The amine group is called tesselin _3_yl)ethyl H,2_diazepamidine hydrochloride at room temperature at 2_cyano-2·(3,4_二气_5_g同基· 2,5-dioxane-2-yl)acetamide (0.5 g) in a sterol (5 ml) suspension, adding bis(thiophene-3-yl)ethylamine hydrochloride (1.06 g) and To a solution of triethylamine (0.65 g) in MeOH (3 mL), EtOAc (EtOAc m. The residue was partitioned between EtOAc and EtOAc (EtOAc m. The precipitated crystals were recrystallized to give the title compound (23 mg).]H NMR (300 MHz, DMSO-d6) δ ppm 1.83-1.93 (3H, m), 6.00-6.20 (1H, m), 7.13- 7.25 (1H, m)5 7.64-7.71 (1H, m), 7.73-7.79 (1H, m), 8.22 (1H, s), 8.24-8.32 (1H, m), 8.51-8.58 (1H, m), 8.62 (1H, s), 9.65-9.87 (2H, m). Example 6 5-Chloro-2-imino-indole [ι_(2,4,5-trifluorophenyl)ethyl]-1,2-dihydro. Pyridine 94 321556 201114425 -3-decylamine hydrochloride (Step 1) 1-(2,4,5-trifluorophenyl)ethanone (5.0 g) in pyridine (20 ml) at room temperature And (aminooxy) decane hydrochloride (2.88 g) for 3 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid and saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. Tetrahydrofuran-borane (90 ml, 1 M tetrahydrofuran solution) was added to a solution of the obtained residue in tetrahydrofuran (50 ml). After heating the reaction mixture for 4 hours under reflux, the reaction was quenched with ice and 1N hydrochloric acid (150 ml). This mixture was stirred at 90 ° C for 2 hours, and ethyl acetate was added to the reaction mixture. The separated aqueous layer was basified with 8N sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. After the residue was dissolved in decyl alcohol, 4N hydrogen chloride-ethyl acetate solution (10 ml) was added, and the obtained precipitate was collected by filtration and washed with ethyl acetate to give 1-(2,4,5-trifluorophenyl). Ethylamine hydrochloride (3.81 g). ]H NMR (300 MHz, DMSO-d6) δ ppm 1.52 (3 Η, d, J=6.78 Hz), 4.49-4.68 (1 H, m), 7.60-7.74 (1 H, m), 7.84-8.02 ( 1 H, m), 8.76 (3 H, s). (Step 2) According to the method of Example 5, 2-cyano-2-(3,4-dichloro-5-keto-2,5-dihydrofuran-2-yl)acetamide was subjected to Step 1 The obtained 1-(2,4,5-trifluorophenyl)ethylamine hydrochloride was reacted to give the title compound. Towel NMR (300 MHz, DMSO-d6) δ ppm 1.78-1.90 (3H, m), 6.27-6.43 (1H, m), 7.61-7.75 (1H, m)5 7.82-7.96 (1H, m), 8.24 ( 2H, d, J = 2.3 Hz), 8.58 (1H, d, J = 2.3 Hz), 8.70 (1H, s), 9.97 (2H, s). 95 321556 201114425 Example 7 5-Chloro-l-[l-(3,5-difluorophenyl)ethyl]-2-imino-1,2-dihydropyridine·3-decylamine hydrochloride Salt according to the method of Example 5, 2-methyl-2-(3,4-dioxa-5-mercapto-2,5-dihydrofuran-2-yl)acetamide and 1-(3) , 5-Difluorophenyl)ethylamine hydrochloride reaction 'synthesis of the title compound. *H NMR (300 MHz, DMSO-d6) δ ppm 1.83-1.95 (3Η, m), 6.16-6.32 (1H, m), 7.20-7.39 (3H, m), 8.22 (1H, s), 8.40-8.45 (1H, m), 8.60-8.65 (1H, m), 8.71 (1H, s), 9.78-9.99 (2H, m). Example 8 5-Gas-1-(6-murine-2,3-dioxa-1H-Ip-1-yl)-2-imido-1,2-diazepine ratio. Benzene-3-amine hydrochloride salt according to the method of Example 5, 2-cyano-2-(3,4-dichloro-5-keto-2,5-dihydrofuran-2-yl) The acetamide was reacted with 6-fluoro-2,3-dihydro-1H-phenanthrene-1-amine hydrochloride to give the title compound. NMR (300 MHz, DMSO-d6) δ ppm 2.18-2.36 (1H, m)s 2.77-3.00 (2H, m), 3.03-3.19 (1H, m), 6.23 (1H, t, J = 6.6 Hz), 7.22-7.34 (2H, m), 7.44-7.53 (1H, m), 7.73 (1H, s), 8.23 (1H, s), 8.57 (1H, s), 8.67 (1H, s), 9.83 (2H, Br.s). Example 9 5-Chloro-l-indole (4-fluorophenyl)ethyl]-2-imino-1,2-dihydroacridin-3-indole hydrochloride The method according to Example 5 To make 2-cyano-2-(3,4-dioxa-5-keto 96 321556 201114425 •2,5-dihydro-hydrocarbyl-Nan-2-yl)-ethylamine and 1-(4-dun The title compound was synthesized by reaction of ethylamine hydrochloride. ]H NMR (300 MHz, DMSO-d6) δ ppm 1.89 (3Η, d, J= 6.8 Hz), 6.05-6.19 (1H, m), 7.23-7.37 (2H, m), 7.51 (2H, dd5 J= 8.7, 5.3 Hz), 8.21 (1H, s), 8.36 (1H, d, J = 1.9 Hz), 8.49-8.67 (2H, m), 9.60-9.83 (2H, m). Example 10 5-Chloro-l-[l-(2,5-diphenyl)ethyl]-2-imino-l,2-dihydro. Specific biting_3_methantamine hydrochloride according to the method of Example 5, 2-cyano-2-(3,4-dichloro-5-keto-2,5-diarhydrofluorene The ethylamine was reacted with 1-(2,5-difluorophenyl)ethylamine hydrochloride to give the title compound. NMR (300 MHz, DMSO-d6) δ ppm 1.87 (3H, d, J = 6.4 Hz), 6.31 (1H, q, J = 6.4 Hz), 7.29-7.46 (2H, m), 7.54-7.64 (1H, m), 8.20-8.29 (2H, m), 8.55 (1H, d, J = 2.3 Hz), 8.65 (1H, s), 9.89 (2H, br.s). Example 11 5-Chloro-l-[l-(3-cyanophenyl)ethyl]-2-imino-1,2-dihydro. Than _3_methantamine hydrochloride according to the method of Example 5, 2-cyano-2-(3,4-dichloro-5-keto-2,5-dihydrod-fol-2 Reaction of the amine-acetic acid amine with 3-(1-aminoethyl)benzonitrile nitrate to synthesize the title compound. [H NMR (300 MHz, DMSO-d6) δ ppm 1.92 (3H, d} J = 6.7 Hz), 6.19 (1H, q, J = 6.7 Hz), 7.61-7.69 (1H, m), 7.71-7.79 321556 97 201114425 (1H, m), 7.89 (1H5 d, J= 7.6 Hz), 7.97 (1H, s)5 8.22 (1H, s), 8.43 (1H, d, J= 2.3 Hz), 8.59 (1H, d , J = 2.3 Hz), 8.65 (1H, s), 9.79 (2H, br.s). Example 12 5-Gas-l-[(lR)-l-(3-fluorophenyl)ethyl]_2-imino-indole-dihydrogen. Bipyridin-3_carbamide hydrochloride at room temperature in 2-cyano-2-(3,4-dichloro-5-keto-2,5-dihydrofuran-2-yl)acetamide (1. 〇g) sterol (1 〇) suspension of (iR)-i-(3-fluorophenyl)ethylamine (1·78 g) and triethylamine (131 g) sterol (5 ml) solution, the mixture was heated to 5 (rc, stirred overnight. The reaction mixture was concentrated, EtOAc (10 ml) was added, and the mixture was stirred at 8 hr. (: stirring for 2 hours. The solvent was evaporated under reduced pressure and the residue was partitioned to acetic acid. Ethyl acetate and water, the organic layer was dried (MgSO4jjjjjjjjjjjjj 4N Hydrogen chloride-ethyl acetate solution was added to the yellow oil, and the crystals which crystallised were collected and recrystallized to give the title compound (3 g 8 mg). 'H NMR (300 MHz, DMSO-d6) δ ppm 1.90 (3H, d5 .T= 6.4 Hz), 6.19 (1H, s), 7.20-7.30 (2H, m), 7.33-7.42 (1H, m), 7·43-7.55 (1H, m), 8.22 (1H, s), 8.41 (1H, d, J = 2.3 Hz), 8.55-8.74 (2H, m), 9.80 (2H, br.s). [α]25〇 = +128.1 (c 0.5, MeOH). Example 13 5- Gas-l-[i _(4_Cyanophenyl)ethyl]_2_imino-indole 孓 dihydro ton 唆 _3• 曱 胺 amine 321556 98 201114425 According to the method of Example 5, 2 cyano _ The title compound was synthesized by the reaction of 2-(3,4-dichlorol-l-2,5-dihydrofuran-2-yl)acetamide with 4-(1-aminoethyl)benzonitrile hydrochloride. NMR (300 MHz, DMS〇-d6) δ ppm 1.93 (3Η, d J= 5 4

Hz), 6.14-6.41 (1H, m), 7.60 (2H, d, 8.0 Hz), 7.93 (2H d J= 8.7 Hz), 8.22 (1H, s), 8.46 (1H, d, J= 1.9 Hz) , 8.56-8 78 (2H, m), 9.67-9.97 (2H, m). Example 14 5-Chloro-l-[(lR)-l-(3,5-difluorophenyl)ethyl]_2-imino-1,2-dihydrogen. Bis-pyridine-3-carbamide hydrochloride at room temperature in 2-cyano-2-(3,4-dichloro-5-keto-2,5-dihydrofuran-2-yl)acetamidine Add (lR)-l-(3,5-difluorophenyl)ethylamine (2.01 g) and triethylamine (1 31 g) to a suspension of the amine (i_〇g) in methanol (1 ml) The decyl alcohol (5 ml) solution was heated to 5 〇〇c and stirred overnight. The reaction mixture was concentrated, DMSO (10 ml) was added, and the mixture was stirred at 80 ° C for 3 hours. The solvent was evaporated under reduced pressure. The residue was partitioned from ethyl acetate and water. The solvent was evaporated under reduced pressure. The residue was purified by basic EtOAc (EtOAc:EtOAc:EtOAc). 4N Hydrogen chloride·ethyl acetate solution was added to the obtained yellow oil at room temperature, and the crystals which precipitated were collected by filtration and recrystallized to give the title compound (338 mg). ]H NMR (300 MHz, DMSO-d6) δ ppm 1.89 (3H, d, J= 6 8

Hz), 6.12-6.28 (1H, m), 7.21-7.38 (3H, m), 8·22 (1H, s), 8.39-8.45 (1H, m), 8.58-8.64 (1H, m), 8.69 ( 1H, s), 9 87 (2H, br.s). 321556 99 201114425 [α] 2'〇= +108.3 (c 1.0, MeOH). Example 15 5-Gas-2-Imino-p-propylcyclopropyl•dihydropyridine _3_methalamine at room temperature In a suspension of 2-cyano-2-(3,4-dione, 2,5-dihydrofuran-2-yl)acetamide (0.5 g) in methanol (10 ml) A solution of the cyclopropylamine hydrochloride (1.1 g) and triethylamine (0.89 mi) in methanol (5 mi) was stirred at 50 ° C overnight. The solvent was evaporated under reduced pressure, acetic acid (5 ml) was added, and the mixture was stirred at 50 ° C for 2 hours. The solvent was evaporated under reduced pressure. EtOAc (EtOAc m. The solvent was evaporated under reduced pressure. The residue was purified by alkaline blasting and column chromatography (ethyl acetate hexanes: hexane). The obtained yellow oil was purified by preparative EtOAc (EtOAc) (EtOAc) H NMR (300 MHz, CDC13) δ ppm 1.03-2.15 (4 H, m), 5.86 (1 H, br. s.), 6.92 (2 H, d, J=7.2 Hz), 7.29-7.50 (4 H , m), 8.26 (1 H, d, J = 2.7 Hz), 10.98 (1 H, br. s.). Example 16 5·Ga-2-imido-l-{l-[3-(methylsulfonyl)phenyl]ethylidene, 2•dihydropyridine-3-decylamine hydrochloride Salt (Step 1) at 0 ° C in 1-[3-(indolylsulfonyl)phenyl]ethanol (22 〇g), diphenylphosphine (43.2 g) and quinone imine (24.3 g) To a solution of tetrahydrofuran (440 mL) / broth, azo-hyd-acid diisopropylacetate (32 ml) was added and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between di-hexane and 2N hydrochloric acid. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. . The residue was dissolved in ether (25 〇

(Step 2) 2·{1·[3-(methylsulfonyl)phenyl]ethyl}-1Η-isoindole·ι,3(2Η)_dione (21) obtained in the step 1 at room temperature To the ethanol solution (30〇1111) of 〇g), hydrazine monohydrate (27 2 1111) was added to reflux the mixture for 1 hour. The solvent was evaporated under reduced pressure and the residue was partitioned from dichloromethane and water. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in diethyl ether (3 mL). EtOAc was evaporated. The precipitated solid was collected by filtration to give ([((((()))). !H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (3 Η, d, J=6.82

Hz), 3.25 (3 H, s), 4.57 (1 H, m), 7.73 (1 H, t, J = 7.8 Hz), 7.89 (1 H, d, J = 7.6 Hz), 7.95 (1 H, d, J = 8.0 Hz), 8.12 (1 H, s), 8.58 (3 H, br_s.). (Step 3) at room temperature under 2-cyano-2-(3,4-dichloro-5-keto-2,5-dihydrofuran-2-yl)acetamide (丨〇g) To the solution of potassium carbonate (1 8 g) in ethanol (1 ml), 1-[3-(indolylsulfonyl)phenyl]ethylamine salt obtained in Step 2 101 321556 201114425 acid salt (2.1 g) The mixture was stirred at 7 °C overnight. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc. The title compound (3 50 mg) was obtained by adding 4N hydrogenation-ethyl acetate solution (1 ml), and the crystals were crystallized to give the title compound (3 50 mg). MHz, DMSO-d6) δ ppm 1.95 (3 Η, d Τ=6 6 Hz), 3.27 (3 Η, s), 6.31 (1 Η, q), 7.63-7.79 (2 Η m) 7.88-8.02 (1 Η, m), 8.05 (1 Η, br. s.), 8.23 (1 H, br. s.), 8 48 (1 H, d, J=2.1 Hz), 8.62 (1 H, d, J= 2.3 Hz), 8.71 (1 H, br s ) 9.88 (2H, br. s.) Example 17 5-Gas-l-[l-(2-fluorophenyl)ethyl]-2-imino -i, 2_dihydropyridine _3_ decylamine hydrochloride at 7 ° C in ethanol (30 ml) Stirring 2-cyano-2-(3,4-dioxa-5-keto-2,5-dihydrofuran-2-yl)acetamide (2. g), fluorophenyl)ethylamine ( 1.42 g) with potassium carbonate (1.76 g) for 12 hours. The reaction mixture was quenched with 1N hydrochloric acid and partitioned with ethyl acetate. The aqueous layer was basified with 8N sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (3m) was added, and the mixture was crystallized from ethyl acetate. The crystals which precipitated were collected by filtration and recrystallized to give the title compound (60 mg). 'H NMR (300 MHz, DMSO-d6) δ ppm 1.89 (3 H, d, J=6.78

Hz), 6.22-6.42 (1 H, m), 7.22-7.45 (2 H, m), 7.49-7.61 (1 H, 321556 102 201114425 m), 7.65-7.76 (1 H, m), 8.18 (1 H , d, J = 2.26 Hz), 8.25 (1 h, s), 8.55 (1 H, d, J = 2.26 Hz), 8.66 (1 H, s), 9.88 (2 H, s). Example 18 5-Gas-2-Imino-l-[6-(methylindenyl)_2,3-dihydro-1H-segmentyl]-1,2-dihydropyridine-3-T Indoleamine hydrochloride (Step 1) 6-(methyl sulphate)-2,3-dihydro-1H-inden-1-one (17.2 g) was suspended in methanol (250 ml) at room temperature. The mixture was slowly added with boron hydride steel (1.99 g). After the mixture was stirred for 1 hour, the reaction was terminated with propionium (1 〇mi). The solvent was evaporated under reduced pressure. The residue was partitioned between chloroform and 2N hydrochloric acid. The organic layer was washed with aqueous sodium hydrogen carbonate and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give 6-(methylsulfonyl)-2,3-dihydro-1H-indole-1-ol (15.6 g) as white crystals. H NMR (400 MHz, CDC13) δ ppm 1.98-2.09 (1 Η, m)5 2.12 (1 Η, d5 J=6.4 Hz), 2.53-2.64 (1 H, m), 2.85-2.96 (1 H, m ), 3.06 (3 H, s), 3.14 (1 H, ddd, J = 16.8, 8.6, 4.4 Hz), 5.32 (1 H, q, J=6.4 Hz), 7.43 (1 H, d, J=7.6 Hz), 7.84 (1 H, dd, J=7.8, 1.8 Hz), 7.99 (1 H, s). (Step 2) 6〇〇(Methylsulfonyl)_2,3_monohydro-1H-indol-1-ol (15.6 g), triphenylphosphine (28 8 g) and hydrazine obtained in the step 〇〇C To a solution of the imine (16 2 g) in tetrahydrofuran (340 ml), diisopropyl azodicarboxylate (21.4 ml) was added and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure and the residue was partitioned between di-hexane and 2N hydrochloric acid. The organic layer was washed with sodium bicarbonate broth and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was suspended in a mixed solvent of ethyl acetate (5 ml), isopropyl ether (25 ml) 321556 103 201114425 and hexane (300 ml), and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and washed with isopropyl ether. The resulting solid was suspended in ethyl acetate (100 ml). The suspension was stirred at 50 ° C for 1 hour and allowed to cool to &gt; pho. After the solid was collected, the washing was carried out to obtain the white solid 2-[6-(indolylsulfonyl)-2,3-dihydro-1H-indol-1-yl]_1H_ Π-to-1,3(2Η)-dione (13.0 g). Η NMR (400 MHz, CDC13) δ ppm 2.58 (2 Η, m), 3.00 (3 Η, s), 3.02-3.14 (1 Η, m), 3.45 (1 Η, ddd, J=16.8, 9.2, 4.8 Hz), 5.88-5.95 (1 H, t, J=8.0 Hz), 7.49 (1 H, d, J=8.0 Hz), 7.67 (1 H, s), 7.72-7.78 (2 H, m), 7.80-7.88 (3 H, m) 〇 (Step 3) 2_[6_(methylsulfonyl)-2,3-dihydro-1H-indol-1-yl]-1H obtained in step 2 at room temperature To a suspension of isoindole-l,3(2H)-dione (13.0 g) in ethanol (260 ml) was added hydrazine monohydrate (15 3 ml) and the mixture was heated under reflux for 1 hour. The solvent was evaporated under reduced pressure and the residue was partitioned between dioxane and water. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in a dioxane, and 4N hydrochloric acid-1,4-dioxane (9.54 ml) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration to give 6-(methylsulfonyl)-2,3-dihydro-1H-indole-1-amine hydrochloride (8.42 g) as a white solid. JH NMR (400 MHz, DMSO-d6) δ ppm 1.99-2.13 (1 H, m), 2·54 Ο H, dd, J=6.76, 3.59 Hz), 2.92-3.04 (1 H, m), 3.11- 3.19 (1 h, m), 3.20 (3 H, s), 4.81 (1 H, t, J = 6.8 Hz), 7.61 (1 H, d5 J=8.0 Hz), 7.91 (1 H, dd, J= 8.0, 1.6 Hz), 8.20 (1 H, s), 8·53 (3 H, s). 321556 104 201114425 (Step 4) 2-Cyano-2-(3,4-dichloro-5-keto-2,5-dihydrofuran-2-yl)acetamide (0.5) obtained in Step 3 at room temperature. §) Add potassium carbonate (0.88 g) to a suspension of 6_(decylsulfonyl)-2,3-diar-1H-indole-1.amine hydrochloride (0.69 g) in ethanol (1 ml) ), the mixture is at 7 〇. (: Stirring overnight. The reaction mixture was filtered through a pad of Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate············ Hydrogen and ethyl acetate solution (1 ml), and the crystals which were crystallized and recrystallized to give the title compound (161 mg). H NMR (300 MHz, DMSO-d6) δ ppm 2.16-2.39 (1 Η, m), 2.80-3.12 (2 Η, m), 3.12-3.30 (1 Η, m), 3.19 (3 Η, s), 6.39 (1 Η, br. s.), 7.71 (1 Η, d, J =8.1 Hz), 7,88 (1 Η, br. s.), 7.99 (1 H, s), 7.96 (1 H, d, J=1.7 Hz), 8.24 (1 H, br. s.), 8.61 (1 H, br. s.), 8.73 (1 H, br. s.), 9.97 (2H, br. s.). Example 19 5- ox-1-(6- oxy-2, 3-anthracene-fluorene-fp-l-yl)-2-imino-i,2-dihydron-pyridin-3-carboxamide hydrochloride to warm, 2-meryl-2- (3,4-digas-5_S homo--2,5-dihydro-sodium Nan-2-yl) acetamide (1.0 g) and potassium carbonate (〇·88 g) in ethanol (1〇mi) suspension 3-Amino-2,3-dihydro-1H-indole-5-indole nitrile hydrochloride (0.99 g) was added to the mixture, and the mixture was stirred at 70. The reaction mixture was quenched with 1N hydrochloric acid. The mixture was washed with ethyl acetate. The aqueous layer was basified with aqueous sodium hydroxide and then extracted with isopropyl ether. The extract was washed with saturated brine and evaporated. Purification by column chromatography (ethyl acetate: hexane = 7:3 -1: hydrazine). 4N hydrogenation-acetic acid B 105 321556 201114425 ester solution (1 ml) was added to the obtained yellow oil. The crystals were recrystallized to give the title compound (122 mg). <H NMR (300 MHz, DMSO-d6) δ ppm 2.16-2.37 (1 H, m)? 2.79-3.12 (2 H, m), 3.19 -3.29 (1 H, m), 6.25-6.44 (1 H, m) 7.65 (1 H,d,J=7.6 Hz), 7.84-7.94 (3 H, m), 8.24 (1 H,br. s. 8.60 (1 H, br. s.), 8.73 (1 H, br. s·), 9.93 (2 H, br. s.). Example 20 5-Gas-l-[(lR)-l-(2-fluorophenyl)ethyl]-2-imino-1,2-dihydropyrryl. Stabilize 2-cyano-2-(3,4-dichloro-5-keto-2,5-dihydrogen in ethanol (30 ml) at 〇3_carbamide hydrochloride at 7 °C Furan-2-yl)acetamide (2.81 g), fluorophenyl)ethylamine (2.0 g) and potassium carbonate (2.48 g) for 8 hours. The reaction of the reaction mixture was quenched with a sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic EtOAc (EtOAc) chromatography. The residue was dissolved in EtOAc, EtOAc (EtOAc) (EtOAc) The precipitated crystals were collected by filtration and recrystallized to give the title compound (1.80 g). JH NMR (300 MHz, DMSO-d6) δ ppm 1.89 (3 H, d, 1 = 6.78 Hz), 6.30-6.36 (1 H, m), 7.23-7.33 (1 H, m), 7.34-7.44 (1 H, m), 7.48-7.61 (1 H, m), 7.70 (1 H, t5 J=7.63 Hz), 8.18 (1 H, d, J=2.〇7 Hz), 8.24 (1 H, s) , 8.56 (1 H, dd, J = 3.39, 2.07 Hz), 8.67 (1 H, s), 9·89 (2 H, s). [α]20〇= +188.7 (c 0.50, MeOH). 321556 106 201114425 Example 21 5-Gas-l-[(lR)-l-(2,4-difluorophenyl)ethyl]·2- Imino-i,2-dihydro-bipyridyl_3_carbamide hydrochloride at 70 ° C in ethanol (30 mi), stirring 2 - cyano 2 - (3, 4 - two gas - 5-keto-2,5-dihydrofuran-2-yl)acetamide (2.49 g), (1R)-1_(2,4-difluorophenyl)ethylamine (2.0 g) and potassium carbonate ( 2.2 g) 18 hours. The reaction mixture was quenched with sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The residue was dissolved in MeOH <RTI ID=0.0>(M </ </RTI> </RTI> <RTIgt; This was recrystallized to give the title compound (2.35 g). NMR (300 MHz, DMSO-d6) δ ppm 1.87 (3 Η, d, J = 6.59 Hz), 6.33 (1 H, s), 7.22-7.44 (2 H, m), 7.70-7.84 (1 H, m), 8.19 (1 H, d, 1 = 2.26 Hz), 8.25 (1 H, s), 8.53-8.61 (1 H, m), 8.69 (1 H ,s),9.93 (2 H, s) [a] 20D = +153.6 (c 0.43, MeOH). Example 22 5-chloro-l-[(lR)-l-(4-fluorophenyl)ethyl]-2-imine Base_1,2-dihydrogen 0 to bite·3_methanamine hydrochloride, stirred at 70 ° C in ethanol (30 ml), 2-cyano-2-(3,4-dichloro-5-oxime) Homo- 2,5-dibenzopyran-2-yl)ethinamine (2.81 g), (]^)_ι·(4·gasphenyl)ethylamine (2.0 g) and potassium carbonate (2.48 g) The reaction of the reaction mixture was quenched with sodium hydroxide in &lt;s&gt; sulphate &lt;s&gt; solution, and extracted with ethyl acetate. Organic &gt; 321556 107 201114425 After washing with saturated brine, dried over magnesium sulfate. Purified by alkaline oxime column chromatography (ethyl acetate). The obtained residue was dissolved in decyl alcohol, 4N hydrogen hydride-ethyl acetate solution (1) was added, and the mixture was crystallized from ethyl acetate. The precipitated crystals were collected by filtration and recrystallized to give the title compound (1.60 g). ???H NMR (300 MHz, DMSO-d6) δ ppm 1.89 (3H, d, J=6.78 Hz), 6.25 (1 H , s), 7.23-7.38 (2 H, m), 7.45-7.63 (2 H, m)5 8.22 (1 H, s)5 8.37 (1 H, d, J=2.07 Hz), 8.61 (1 H, d, J=6.03

Hz), 8.72 (1 H, d, J = 6.03 Hz), 9.88 (2 H, s). [a] 20 D = +127.6 (c 0.45, MeOH). Example 23 5- gas-l-[(lR)-l-(3-cyanophenyl)ethyl]-2-iminyl-indole, 2_Dihydroacridine-3-carboxamide hydrochloride to temperature, in 2-cyano-2-(3,4-dichloro-5-keto-2,5-dihydrofuran-2- Addition of GR)-l-(3-cyanophenyl)ethylamine (〇·45 g) and triethylamine (0 58) in the suspension of acetamidine (0.49 g). A solution of methanol (5 ml) was stirred at 50 overnight. The solvent was evaporated under reduced pressure. EtOAc (EtOAc m. Drying over sodium sulfate, the solvent was evaporated under reduced pressure. EtOAcjjjjjjjjjjjjjj Hydrogen · ethyl acetate solution (1 ml), and the mixture was crystallized from ethyl acetate. The crystals which precipitated were collected by filtration and recrystallized. 6 (rc, crystallized in n-heptane, stirring 321556 108 201114425 3 hours later Filtration and drying gave the title compound ( 〇················································ , 7.65 (1 H, t, J = 7.76 Hz), 7.71-7.79 (1 H, m), 7.89 (1 H, d, J = 7.57 Hz), 7.97 (1 H, s), 8.22 (1 H, s), 8.43 (1 H, d, J = 2.27 Hz), 8.59 (1 H, d, J = 1.89 Hz), 8.65 (1 H, s), 9.78 (2 H, s). [a] 2〇 D = +146.8 (c 0.45, MeOH). Example 24 5 gas-1-[1-(3-murly-5-murine)ethyl]-2 -imino _i,2_diazo π ratio sigma -3-carboxamide hydrochloride

(Step 1) In a solution of 3-bromo-5-fluorobenzonitrile (1 〇.〇g) in tetrahydrofuran (50 ml) at 0 ° C under nitrogen atmosphere, adding bismuth bromide magnesium (5 〇〇 ml) , 3 〇M diethyl ether solution). After the mixture was allowed to warm to room temperature, it was stirred for 15 hours and then cooled to 0 C. Hydrogenated cockroach (5.69 g) was added, and after the mixture was stirred for 1 Torr, the reaction was quenched with water and partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to afford (3 bromo-5-fluorophenyl)ethylamine (5.23 g). ]H NMR (400 MHz, CDC13) δ ppm 1.36 (3 H) d, J=6.8 Hz) 4.10 (1 H, q, J=6.8 Hz), 7.03 (1 H, dt, J=9.65 1.6 Hz), H, dt, J = 8.0, 2.2 Hz), 7.30 (1 H, s). (Step 2) (Under rc, in the step of the sputum, get rid of sulphur, sulphur, ethylamine (5.23 g), dichloromethane (3 〇 ml) solution towel, add diacetate dibutyl vinegar (5.23g) and Triethylamine (6.69 ml). The mixture was stirred at room temperature for 2 hours, 321556 109, 201114425, and the solvent was evaporated under reduced pressure. The residue was partitioned between methylene chloride and water. The solvent was evaporated, and the residue was purified mjjjjjjjjjjjjjj Tert-butyl carboxylic acid (71 〇g) H NMR (400 MHz, CDC13) δ ppm 1.37 (3 Η, s), 1.42 (9 Η, s), 4.73 (1 Η, br. s.)5 4.79 (1 H, br. s.), 6.95 (1 H, d, J=9.2

Hz), 7.12 (1 H, dt, J = 8.0, 2.0 Hz), 7.23 (1 H, s). (Step 3) Adding a solution of the butyl hydroxy)ethyl]aminocarbamic acid tert-butyl ester (5.2 g) obtained in the second step at room temperature to a solution of hydrazine-dimethylacetamide (3 〇mL). Zinc cyanide (0.89 g), ginseng (dibenzylideneacetone)-di-palladium (〇) (0.600 g) and U'_bis(diphenylphosphino)ferrocene (〇73 phantom. Under nitrogen atmosphere, 12 (TC stirred the solution for 3 hours, evaporated the solvent under reduced pressure. The residue was washed with decyl alcohol. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography. Purified to give a white solid (3·Cyanofluorophenyl)ethyl]amino decanoic acid tert-butyl ester (3.20 g). H NMR (400 MHz, CDC13) δ ppm 1.43 (9 H, s) , 1.44 (3 H, d: J 6.8 Hz), 4.81 (1 H, br. s.), 4.86 (1 H, br. s.), 7.23-7.29 (2 H. m), 7.41 (1 H, s). 4) 〇C under '[H3-Cyano-5-fluorophenyl)ethyl]aminocarbamic acid obtained in step 3, second butyl (3.9 () in the solution of dichlorocarbyl (10) 4N gasification hydrogen _!, 4• 曙 曙 溶液 solution (2mi). The mixture was allowed to be allowed to stand at room temperature for 18 hours, and the solid was collected by hydrazine to give 3-(1-aminoethyl) as white JU- 5- Fluorobenzene T-nitrile hydrochloride (2.20 g). 321556 110 201114425 !H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (3 H, d, J=6 g Hz), 4.52 (1 H, q, J =6.8 Hz), 7.85-7.93 (3 H, m), 8.67 (BH br. s.) (Step 5) at room temperature on 2-cyano-2-(3,4-dichloro-5- Addition of 3-(1-Aminoethyl)·5·Fluor obtained in Step 4 to a suspension of keto 2,5-dihydrofuran-2-yl)acetamide (0.5 g) in methanol (1 mL) A solution of phenylhydrazine nitrile hydrochloride (〇.7 g) and triethylamine (1.2 ml) in methanol (5 ml), and the mixture was stirred overnight at 50 ° C. The solvent was evaporated under reduced pressure and acetic acid (5 ml) The mixture was stirred at 5 ° C for 2 hours. The solvent was evaporated, evaporated, evaporated, evaporated, evaporated The product was purified by EtOAc (EtOAc: EtOAc = EtOAc:EtOAc: This was recrystallized to give the title compound (310 mg). NMR (300 MHz, DMSO-d6) δ ppm 1.91 (3 H, d, J= 6.6

Hz), 6.17 (1 H, q), 7.76 (1 H, dd, J=l〇.i, h4 Hz), 7 83 (1 H, b, s.) 5 7.89-7.97 (1 H, m) , 8.20 (lH,b,s.)5 8.41 (lH5b,s.), 8.57 (1 H,br. s.),8.65 (1 H, br. s.), 9.79 (2 H, br. s. ). Example 25 5-Chlorochloro-5-cyanophenyl)ethyl]_2-iminoindole • Diazo n-pyridin-3-indoleamine hydrochloride (Step 1) G ° C 'under nitrogen atmosphere In the solution of 315•qiqi carbonitrile (15.0 g) in tetrahydrofuran, a solution of methylmagnesium (10) μ was added. . Μ 验 test solution). After the mixture was allowed to warm to room temperature, _i5 hours, then 321556 111 201114425 was cooled to 〇.氢化 Add hydrogenated chain (5.69 g)' to stir the mixture for 1 Torr, quench the reaction with water and partition it with dioxane and water. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) NMR NMR (400 MHz, CDC13) δ ppm 1.35 (3 Η, d, J=6.8 Hz), 4.07 (1 H, q, J=6.8 Hz), 7.29 (1 H, t, J=1.6 Hz), 7.37 (1 H, t! J=1.8 Hz), 7.41 (1 H, m). , (Step 2) Add a solution of [(ns succinyl) ethylamine (5.6 g) in dichloromethane (30 ml) at 0 ° C, then add ditributyl dicarbonate (6.8) g) with triethylamine (6.7 ml). The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated under reduced pressure. The residue was partitioned between dichloromethane and water. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7:1) to afford white crystals of ([---bromo-5- Butyl ester (6 〇 8 phantom. JH NMR (400 MHz, CDC13) δ ppm 1.40 (9 H, s), 1.42 (3 Η, s), 4.71 (1 H, br. s.), 4.79 (1 H, Br. s.)5 7.22 (1 H, t, J=1 A Hz), 7.32 (1 H, t, J=1.4 Hz), 7.39 (1 H, t, J=1.8 Hz) 〇 (Step 3)室温, Ν-dimercapto &amp; decylamine (30 mL) in a solution of the second vinegar (6.08 g) obtained in the second step at room temperature, Add zinc cyanide (0.99 g), ginseng (diphenylidene acetonide) _ dipalladium (〇) (0.67 g) and 1,1'-bis(diphenylphosphino)ferrocene (〇81. Under nitrogen atmosphere The solution was stirred at 120 C for 3 hours, and the solvent was evaporated under reduced pressure. After the residue was evaporated, the mixture was washed with methanol, and the filtrate was concentrated under reduced pressure. The residue was purified by hexanes column chromatography 321556 112 201114425 (hexane: ethyl acetate = Purification by 7:1) gave butyl cyano-5-chlorophenyl)ethyl]amino decanoate (3.9 g) as a white solid. !H NMR (400 MHz, CDC13) δ ppm 1.42 (9 Η, s), 1 44 (3 Η s), 4.75 (1 Η, br. s.), 4.83 (1 H, br. s.), 7.49 (1 H, s), 7.52 (2 H, m). ' (Step 4) (T-butyl 3-(3-cyano-5-chlorophenyl)ethyl]amino decanoate (3.90 g) in dichloromethane (2 〇 ml) obtained in step 3 under TC To the solution, 4N hydrogen chloride-1,4-dioxane solution (2 ml) was added, and the θ compound was collected for 18 hours, and the solid was collected by filtration to give the ethyl group as a white solid. Benzomidil hydrochloride (2.39 g). H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (3 H,d, J=7 0

Hz), 4.50 (1 H, q, J=7.0 Hz), 8.03 (2 H, d, J=2.〇Hz), 8.10 (1 H,t,J=1.6 Hz), 8.58 (3 H, br .s.). (Step 5) 2_Cyano·2·(3,4·Dichloro·5-keto-2,5-monohydroindol-2-yl) obtained from the step 4 at room temperature (〇6S) Add 3-(1-Aminoethyl)-5-chlorobenzonitrile hydrochloride (1 〇 与 and triethylamine (1:5 ml) of methanol (5) in a suspension of methanol (ι〇1) (ml) solution. The mixture was quenched at 5 ° C overnight, and the solvent was evaporated under reduced pressure. Acetic acid (5 ml) was added and the mixture was stirred for 5 hrs for 2 hr. The aqueous solution of sodium hydrogencarbonate is dissolved in 1N hydrogen hydroxide. The organic layer is dried under sodium sulfate. The solvent is evaporated under reduced pressure. The residue is purified by column chromatography (acetic acid ethyl acetate: hex = 7:3 -1) The residue was purified by chromatography. (300 MHz, DMSO-d6) δ p_ 1.91 (3 H,d,j=6.6

Hz), 6.18 (1 H, q), 7.94 (2 H, d5 J=1.5 Hz), 8.Π (1 H, t, J-1.7 Hz), 8.22 (1 H, br· s.), 8.44 (1 H, d, J = 2.3 Hz), 8.61 (1 H, d, J = 1.9 Hz), 8.68 (1 H, br. s·), 9_84 (2 H, br. s ). 'Example 26 5-Chloro. 2-imino-1-(1 decyl-3-yl)ethyl)_u·diqixin _3·carbamamine dihydrochloride 〇°C, In ethanol (10 ml), stir 2·cyano·2·(3,4-dichloro-5-keto-2,5-diarfuran-2-yl)acetamide (1,00 g), hydrazine _(Pyridinyl)ethylamine (0.68 g) and potassium carbonate (1.18 g) overnight. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. The residue was purified by basic column chromatography (ethyl acetate:hexane = 7:3 - 1 : EtOAc). A chlorohydrin-ethyl acetate solution (1 ml) was added to the obtained white oil. H NMR (300 M Hz, DMSO-d6) δ ppm 1·98 (3H,d, J=6 4

Hz),6_52 (1H,q,J=6.7 Hz), 7.91 (1H,dd,J=8.3,' 5·'3 Hz), 8.25 (1H, s), 8.42 (1H, d, J=8.3 Hz ), 8.54 (1H, d, J-2.3 Hz) 8.71 (1H, d, J = 1.9 Hz), 8.84 (2H, d, J = 5.3 Hz), 9.00 (1H s) 10.12 (2H, br. s. ). ' ' Example 27 5 · Chlorine small (1,1-dioxy ion 3,4_ dihydro 2H-sulfur spray-cardiyl imido-1,2-dihydro 0 to 0--3 - Benzylamine hydrochloride (Step 1) at room temperature in pyridine (3〇1111), stirring 2,3_dihydro-4 thioglycon-4-one (13.0 g) with 〇-methyl Hydroxylamine hydrochloride (7% phantom 4 hours. 321556 114 201114425 The reaction solution was poured into water' mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate and filtered. Tetrahydrofuran-borane (200 ml, 1 M tetrahydrofuran solution) was added to the resulting residue in tetrahydrofuran (15 mL). The reaction mixture was stirred at 90 ° C for 3 hours and then quenched with ice. The reaction was carried out, and the salt was added (300 ml). After mixing the mixture for 2 hours at 90 ° C, ethyl acetate was added thereto. The separated aqueous layer was alkalized with 8 N sodium hydroxide solution to give acetic acid. Ethyl acetate extraction. The extract was washed with saturated brine, dried over magnesium sulfate, and filtered, and evaporated. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol. Solution (20 ml), The resulting precipitate was collected by filtration, washed with ethyl acetate to give 3,4_ dihydro _2H_ thiopental dilute hydrochloride (6.16 g).

H NMR (300 M Hz, DMSO-d6) δ ppm 2.12-2.27 (13⁄4 2.36-2.48 (1H, m) 2.96-3.29 (2H, m) 4.52 (1H, d, J=3.4l Hz) 7.09-7.31 ( 3H,m) 7·53 (1H,d,J=7.95 Hz) 8.66 (3H, s).Z (Step 2) at room temperature '3,4_Dihydro_2H•Sulphur thinning obtained in step i 4-Aminohydrochloride (5.3 g) and triethylamine (5.85 g) in tetrahydrofuran (2 μμ), and a solution of the second solution, dibutyl succinate (6.88 g) was added. The mixture was stirred for 3 hours. The reaction solution was poured into water, and the mixture was extracted with hexyl hexanoate. The extract was washed with 1N hydrochloric acid and saturated brine, and the mixture was treated with 尨 丨 丨 丨 Μ Μ Μ And filtered. Evaporate the solvent under reduced pressure. The residue obtained was dissolved in ethyl acetate (200 ml).

Wako Pure Chemical Industries, Ltd.). After the reaction mixture was stirred for 6 hours, it was washed with an aqueous solution of sodium hydrogencarbonate and water, 321556 115 201114425 dried under magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic celite column chromatography (ethyl acetate: hexane). The obtained residue was dissolved in decyl alcohol (30 ml), 4N vaporized gas ethyl acetate solution (15 (6)) was added, and the mixture was stirred for 5 hours at rc. The reaction mixture was concentrated under reduced pressure and filtered. After collection, it was washed with ethyl acetate to give 3,4-dihydro-2H-thiopenten-4-amine 1,1-dioxide hydrochloride (5 illus. NMR (300 M Hz, DMSO-d6) δ ppm 2.60-2.80 (2H, m) 3.66-3.86 (2H, m) 4.79 (1H, s) 7.64-7.90 (4H, m) 8.98 (3H, s) 〇 (Step 3) at 70 ° C, In ethanol (i〇ml), 3,4-dihydro-2H-thiopentene-4-amine 1,1 -dioxide hydrochloride (2 〇g), 2_cyano-2- obtained by stirring step 2 (3,4-dioxa-5-keto-2,5-dihydrofuran-2-yl)acetamide (ί ο g) and potassium carbonate (1.18 g) overnight. The reaction mixture was filtered through celite. The solvent was evaporated under reduced pressure. The residue was purified by preparative EtOAc. 〇H NMR (300 M Hz, DMSO-d6) δ ppm 2.69-2.89 (1H, m) 2.91-3.07 (1H, m) 3.68-3.83 (1H, m) 3.84-3.98 (1H, m) 6.44 (1H, dd, J= 4.5, 9.1 Hz) 7.17-7.28 (1H, m) 7.60-7.77 (2H, m) 7.98 (1H, dd, J= 1.5, 7.6 Hz) 8.26 (2H5 s) 8.60 (1H, d, 1.9 Hz) 8.68 (1H, s) 9.83-10.25 (2H, m) Example 28 5-Gas-2-imino-1-(1-(» ratio Bite-2-yl)ethyl)-1,2-dihydro. Ratio. -3 - indigoamine dihydrochloride 116 321556 201114425 70 ° C, in ethanol (ίο ml), stirring 2· Cyano-2-(3,4-dichloro-5-keto-2,5-dihydrofuran-2-yl)acetamide (1〇g), ^(pyridine-2-yl)ethylamine (0.77 g) With potassium carbonate (L18 g) overnight. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc. The title compound (61 mg) was obtained from EtOAc. H NMR (300 M Hz, DMSO-d6) δ ppm 1.95 (3H, d, J=6.8

Hz), 6.37 (1H, q), 7.42 (1H, dd, J=6.4, 4.9 Hz), 7.75 (1H, d, J-7.6 Hz), 7.94 (1H, td, J=7.8, 1.9 Hz), 8.21 (1H, s), 8.55 (1H, d, J=4.2 Hz), 8.59 (1H, d, J=2.3 Hz), 8.66 (1H, d, J=1.9

Hz), 8.75 (1H, br. s.), 9.79 (2H, br. s.). Example 29 5-Chloro-2-imino-1-(1 medium-to-ice base) ethyl M,2-dihydropyr. Stabilize 2-cyanoguanidine dihydrochloride at 7 ° C under stirring in ethanol (10 mi) with 2-cyano-2_(3, dichloro-5,yl-2,5-dihydrobitate Acetylamine (1 〇g), hexadecidinyl-cardiamine) Ethylamine dihydrochloride (1.08 g) and potassium carbonate (1.76 g). The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. The residue was purified by an alkaline hexane column chromatography (ethyl acetate:hexane = 7:3 -1: EtOAc). 4N Hydrogen chloride-ethyl acetate solution (1 m) was added to the obtained yellow oil, and the crystals precipitated were collected and recrystallized to give the title compound (16 〇m illus.) H NMR (300 M Hz, DMSO-d6) δ ppm 1.97 (3H, d, J=6 6 Hz), 6.37 (1H, d), 7.57 - 7.88 (2H, m), 8.25 (1H, br. s.)3 8 5 1 321556 117 201114425

(1H,d, J=2_l Hz), 8.68 (1H, s), 8.71 - 8.78 (1H, m), 8.81 (2H d, J=4.7 Hz), 9.93 (2H, br. s.) 〇Example 3 0 5-Chloro-1-(6-aero-1,1-dioxyindol-3,4·dihydro-2H-thiopenten-4-yl)imino-1,2-dihydro. Bis-pyridine-3-decylamine hydrochloride (step 1) at room temperature in pyridine (50 ml), stirring 6-gas-2,3-dihydro-4H-thiopenten-4-one (1 〇 〇g) and 〇_mercaptohydroxylamine hydrochloride (5 47 16 hours. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated brine and dried over magnesium sulfate. Filtration. The solvent was evaporated under reduced pressure. (THF, THF, EtOAc (EtOAc, EtOAc) Stop the reaction with ice '1N hydrochloric acid (200 ml) was added. After the reaction mixture was stirred at 7 (TC for 2 hours τ, ethyl acetate was added thereto. After the separated aqueous layer was basified with 8 N sodium hydroxide solution, The mixture was extracted with EtOAc. EtOAc (EtOAc) The obtained precipitate was collected by filtration and washed with ethyl acetate to give 6-gas- 3,4-dihydro-2H-thiodecen-4-amine hydrochloride (3.86). g).H NMR (300 M Hz, DMSO-d6) δ ppm 2.05-2.44 (2H, m) 2-89-3.28 (2H, m) 4.56 (1H, s) 7.16-7.26 (1H, m) 7.28 -7.37 (out, m) 7.62 (1H,S) 8.58 (3H,S). (Step 2) 6 ° gas _3,4_ diar argon-2H_thiopentene-4 obtained in step} at room temperature -amine hydrochloride (3.8 g) and triethylamine (3 26 g) in tetrahydrofuran (1〇〇118 321556 201114425 called solution in the addition of diacetate dibutyl vinegar (4 57 core mixture in the same, stir In an hour, the reaction solution was poured into hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine (4), dried over sulfuric acid, and then evaporated. The solvent was evaporated under reduced pressure. 200 ml) and add m-benzoic acid at room temperature (9 w, water: wak〇 Pure Chemical Ind her milk, (10)). The mixture was mixed at the same temperature, and then the sodium thiosulfate solution was used. The reaction was terminated. The organic layer was washed with sodium bicarbonate (4) and the mixture was washed, (4) dried, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic column chromatography (ethyl acetate: hexane Dissolve the residue obtained Methanol (9) mi ten added 4 Ν hydrogen chloride-ethyl acetate solution (10 ml) 'The mixture was stirred at 6 Torr for 1 hour. The reaction mixture was depressurized, and the residue was solidified with methanol-acetic acid ethyl acetate to give a compound. Mountain dioxide salt (3.54 g). 4 Dirty (M Hz, D hidden... Peng 2 56 2 84 (2H, (9) 3.65-3.92 (2H, m) 4.81 (lH, b, s.) 7.76 (lHj d J=8 48 Hz) 7.92 (1H, d , J=8.48 Hz) 8.03 (iH, s) 8.94 (3H, br. s.) 〇 (Step 3) At 80 C, in the acetic acid gate 2 ^ Ά η Λ - - C ' (7 ml), Stirring step 2, yield, 5_-furfuryl) acetamamine (0.70 g 1 , H sulfur gamma 4 amine U.: oxide hydrochloric acid correction. 6 g) and potassium ana sulphate (0.83 g) After 3 hours, the reaction solution was filtered through a soil, and the solvent was evaporated under reduced pressure. Residues: ssssssssssssssssssssssssssssssssssssssssssssssssssss Add 4N hydrogenation-acetic acid ethyl acetate solution (1 ml) to the low-water &amp; and the top-grade oil to collect the precipitated crystals to make the crystals again, 321556 119 201114425 to obtain the title compound (54 mg) . 'H NMR (300 M Hz, DMSO-d6) δ ppm 2.67-3.03 (2Η, m) 3.68-3.99 (2H,m) 6.39-6.51 (1H,m) 7.55 (1H,d, 1.5 Hz) 7.77 (1H , dd, J= 2.1, 8.5 Hz) 7.99 (lH, d, J= 8.7 Hz) 8.20-8.33 (2H, m) 8.53-8.62 (1H, m) 8.67 (1H, s) 9.95-10 23 (2H, m). Example 31 5-Chloro-1-(6-fluoro-1,1-dioxyindol-3,4-dihydro-2fj_thiopentene_4_yl)_2_imino-1,2-di Hydrogen acetophenone-3-carboxamide hydrochloride (step 1) at room temperature in a ratio of bite (5 〇mi), 6-fluoro-2,3_dihydro-4H-thiopentene-4 - ketone (10.0 g) and hydrazine-methylhydroxylamine hydrochloride (55 phantoms 16% by weight. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated brine and then magnesium sulfate The mixture was dried and filtered. The solvent was evaporated under reduced pressure. Toluene (yield: 137 (6), tetrachlorite. After the reaction mixture was stirred for 4 hours, the reaction was quenched with ice and 1N hydrochloric acid (250 ml). 7 (rc mixed mixture for 2 hours, and added acetic acid s to the reaction mixture. The separated aqueous layer was tested with 8n sodium oxide solution, and then extracted with acetic acid. The extract was washed with saturated brine. The sulfuric acid was dried and filtered. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol. Sue, 6_ gas from -~ hydrogen-2H-sulfur sprayed 4-amine hydrochloride (4,52 g). lH NMR (3〇° M HZ^ DMS〇·^) δ ppm 2.07-2.44 ( 2H, m) 321556 120 201114425 2.96-3.28 (2H,m) 4.54 (1H,s) 7·(Π-7·30 (2H, m) 7.47 (1H, d, J=10.22 Hz) 8.66 (3H,s (Step 2) 6_Fluoro-3,4-dihydro-2H-thiopentene-4-amine hydrochloride (4·4 g) obtained in step 1 at 〇 °c and triethylamine (4.05) g) Di-tert-butyl dicarbonate (5.68 g) was added to a solution of tetrahydrofuran (1 〇〇ml). The mixture was stirred at room temperature for 14 hours, and the reaction solution was poured into 1N hydrochloric acid and extracted with ethyl acetate. The mixture was washed with saturated brine, dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate (200 ml), and m-chloroperbenzoic acid (10.86 g,

Wako Pure Chemical Industries, Ltd.). After the mixture was stirred at room temperature for 4 hours, the reaction mixture was quenched with aqueous sodium thiosulfate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic column chromatography (ethyl acetate:hexane = 1:1). The residue was dissolved in methanol (100 ml). EtOAc (EtOAc) The reaction mixture was concentrated under reduced pressure to give 6-----3,4-dihydro-2H-thiopentene-4-amine 1,1-dioxide hydrochloride (4.35 g). lB NMR (300 M Hz, DMSO-d6) δ ppm 2.55-2.84 (2H, m) 3.61-3.91 (2H, m) 4.81 (1H, s) 7.43-7.64 (1H, m) 7.79 (1H, s) 7 · 99 (1H, dd, J = 8.85, 5.65 Hz) 8.95 (3H, s). (Step 3) Using the same procedure as in Example 3, Step 3, using 2-cyano-2-(3,4-dichloro-5-keto-2,5-dihydrofuran-2-yl)acetamidine The amine and the 6-fluoro-3,4-dihydro-2H-sulfan-4-amine 1,1-dioxide hydrochloride 121 321556 201114425 salt obtained in Step 2 gave the title compound. 'H NMR (300 M Hz, DMSO-d6) δ ppm 2.68-3.04 (2H, m) 3.69-3.98 (2H, m) 6.41-6.54 (1H, m) 7.33 (1H, dd, J= 2.3, 9.8 Hz ) 7.56 (1H, td, J= 2.7, 8.5 Hz) 8.06 (1H, dd, J= 5.5, 8.9

Hz) 8.24 (1H, s) 8.31 (1H, s) 8.59 (1H, d, J = 1.9 Hz) 8.67 (1H, br.s.) 9.91-10.25 (2H, m). Example 32 5-Chloro-l-[(lR)-l-(3-cyanophenyl)ethyl]_2-imino-1,2-dihydropyridine-3-indolyl L-tartrate 5-V-l-[(lR)-l-(3-cyanophenyl)ethyl]-2-imino-1,2-dihydropyridine _3_曱醯 obtained in Example 23 The amine hydrochloride (1.2 g) was dissolved in a mixed solvent of ethyl acetate and ethyl acetate, and sodium hydroxide (30 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. L-(+)-tartaric acid (〇.i3 g) was added to the residue (〇.25 g), and the mixture was stirred overnight at room temperature in a solvent mixture of ethanol (4 and water). The precipitated crystals were collected by chromatography, crystallised from ethyl ether, ethyl ether, ethyl acetate 4 NHVtR (3〇〇M Hz, DMSO-d6) δ ppm I.84 (3H,d,J= Μ Hz) 3.94 (2H, s) 6.14 (1H,q,J= 6.9 Hz) 7.55-7.74 (2H , m) 7.78-7.99 (3H, m) 8.11-8.23 (2H, m) 8.38-8.67 (1H, m). Example 33 5-Gas-1-[(1R)_H3·cyanophenyl)ethyl]_2-imino], 2-dihydropyridin-3-amine sulfate 321556 122 201114425 Example 23-Chloro-l-[(lR)-l-(3-cyanophenyl)ethyl]-2-imino-1,2-dihydropyridine-3-carboxamide hydrochloride (0.75 g) was dissolved in water, saturated sodium bicarbonate (50 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (10 ml). The crystals which crystallized were collected by filtration, and crystallised from ethyl acetate, water and ethyl acetate to give the title compound (0.81 g). !H NMR (300 M Hz, DMSO-d6) δ ppm 1.93 (3H, d, J = 6.8 Hz) 6.06 (1H, q, J = 6.8 Hz) 7.58-7.78 (2H, m) 7.85-7.97 (2H, m) 8.22 (1H, s) 8.43 (1H, d, J = 2.3 Hz) 8.50-8.64 (2H, m) 9.42-9.86 (3H, m). Example 34 5-Chloro-l-[(lS,2S)-2-hydroxy-2,3-dihydro-1H-member-1-yl]-2-imino-1,2-dihydropyridine- 3-Chloramine hydrochloride was stirred at 70 ° C with 2-cyano-2-(3,4-dichloro-5-keto-2,5-dihydrofuran-2-yl)acetamide ( 0.79 g), (1S,2S)-1-Amino-2,3-dihydro-1H-indol-2-ol (0.5 g) and diisopropylethylamine (1.7 ml) in ethanol (5 ml) The solution was overnight. The reaction mixture was poured into a 1N sodium hydroxide solution and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography. The resulting residue was dissolved in ethanol, and a 4N hydrogenated-ethyl acetate solution was added. The crystals which crystallized were collected by filtration and crystallised from ethyl acetate and ethyl acetate to give the title compound (114 mg). 123 321556 201114425 'H NMR (300 Μ Hz, DMSO-d6) δ ppm 2.87 (1H, dd, J= 7.2, 15.4 Hz) 3.30 (1H, dd, J= 7.2, 15.4 Hz) 4.81 (1H, q, J = 7.0 Hz) 6.03-6.31 (2H, m) 7.19-7.26 (1H, m) 7.27-7.36 (1H, m) 7.36-7.46 (2H, m) 8.03 (1H, br.s.) 8.26 (1H, s 8.74 (1H, br.s.) 9.60-10.15 (2H, m). The structural formulas of the compounds in the examples are shown in Table 1. 124 321556 201114425 Table 1

Example fi Example 7 X 矻 Example B Example 9 Example 10 C, YY^nh2 c 丨丫γΊ 〇, ΤΤ^ΝΗ2 CSj^Y^NH2 C, VV^nh2 ^cc; ^rr^NH A&gt;f ^aF ^aF ΗΠ HfM HfM WCA hcm Example π Example 12 Caution Example 13 Solid spore Example 14 Example 1R Cl^Y^V^NHa ^ΪΪΓ^ΝΗ Λό^ Ο c 丨丫Υ^Νη2 ^aF . &quot;〇6 CI'^^V^nh2, into 5NH ^yF cls^T^T^NH2 ^ΙνΓ^ΝΗ HCl ΗΠ HCl 矻 real example lfi example] 7 example Ifl capital running example 18 Example 20 〇Ι*Ύ^Τ^ΝΗ2 lUH\f °*&quot;γΊ^ΝΗ2 ^ΊνΤ^ΝΗ CVY^nhj ά〇Ρ&quot; α,γΝ^ΝΗ2 ^N^NH ώ5^ aYY^NH2 吣N^SlH HCl ΗΠ HCl HCl HCl will be applied! η 资 例 22 Example 2 Example 24 Example CVT^NH2 ^aF CV^Anh2 ^n^nh ^aF C, YY^nh2 ^N^NH ^XXCN.丫Y^nh2 Anh ΛητΝ CkVX,!V^NH2, human NH ΗΠ HCl HCl HCl HC】 125 321556 201114425

Experimental Example 1 Measurement of 0CID adrenergic receptor binding inhibitory activity The following gene manipulation method was carried out according to the method described in Maniatis et al., Molecular Cloning, Cold Spring Harbor Laboratory, 1989, and the experimental procedure attached to the reagent. (1) Preparation of human a1D adrenergic receptor expressing plastids The a1D adrenergic receptor gene was selected from human liver cDNA by a PCR method. The PCR reaction was carried out by Gene Amp PCR System 9700 (Applied Biosystems) using the a1D adrenergic receptor gene assay described in DEBRA A. et al. (J, Pharamacol. Exp. Ter., 272, 134-142 (1995)). Primer set 5,-CCGACGGCCGCTAGCGAGATGACTTTCCGCGATCTC CTGAGCGTC-3, [SEQ ID NO: 1] and 5,-GCTCTGGGTACCTTAAATATCGGTCTCCCGTAGGTTG C-3' [SEQ ID NO: 2] 50 ng each human hippocampus cDNA library (Takara Shuzo Co_, Ltd.) as a template and TaKaRa 126 321556 201114425 LA-Taq DNA polymerase (Takara Shuzo Co., Ltd.) (Reaction conditions: 94 ° C for 15 seconds, 68 ° C for 3.5 minutes, 45 cycles) . The PCR fragment prepared above was decomposed with a restriction enzyme Nhel (Takara Shuzo Co., Ltd.) and Kpn I (Takara Shuzo Co., Ltd.), and a gel electrophoresis method was applied to recover a DNA fragment. The DNA fragments were ligated with the animal cell pcDNA3.1/Zeo (Invitrogen) decomposed by Nhel and Κρη I, and subjected to Escherichia coli JM109 by DNA Ligation Kit Ver. 2 (Takara Shuzo Co., Ltd.). Competent cell transformation, obtaining plastid pcDNA3.1/Zeo-Adrea1D. (ii) Introducing human a1D adrenergic receptor expressing plastids into CHO-K1 cells and preparing membrane fragments in a 150 square centimeter (cm2) culture flask (Corning Coaster) using 0.5 g/L trypsin-0.2 g/L EDTA (Invitrogen) CHO-K1 cells subcultured in HamF12 medium (Invitrogen) containing 10% fetal bovine serum (TRACE SCIENCETIFIC) were separated, and the cells were washed with D-PBS (I) (Invitrogen) and centrifuged (1〇〇〇) Rpm, 5 min). Next, DNA was introduced into the cells using GenePulserll (BioRad) under the following conditions. In a 4 cm gap phototube (BioRad), lxlO7 cells were suspended in D-PBS(-) (700 ml), 10 pg of pcDNA3.1/Zeo-Adrea1D was added, and at 0.25 kV, 960 pF Under the capacitor 'electroporation method. The cells were cultured in HamF12 medium containing 10% fetal bovine serum and 250 μg (pg)/mL Zeocin (Invitrogen), and a Zeocin-resistant transgenic strain was selected. A plurality of Zeocin resistant transgenic plants were selected and cultured in a cell culture flask (150 cm2) 127 321556 201114425 to a semiconfluent, and cell membrane fragments were prepared as follows. The semi-clustered cells were separated by 〇.〇2% EDTA containing D-PBS (I) and recovered by centrifugation. The cells were suspended in membrane preparation buffer (] mM mM NaHC03 pH 7.4 'Protease Inhibitor Cocktail (Roche)) at a speed of 20,000 (rpm) per minute on a p〇lytron homogenizer (m〇del PT-3100, KINEMATICAAG) was treated for 20 seconds for a total of three times to disrupt the cells. Then, the cells were centrifuged at 2000 rpm for 10 minutes to obtain a supernatant containing membrane fragments. Using a super high speed centrifuge (Model L8-70M, rotor 70 Ti, Beckman apparatus), the supernatant was centrifuged at 30,000 rpm for 1 hour to obtain a precipitate containing film fragments. The membrane fragments obtained from each of the transgenic plants were subjected to the binding experiments shown below. Diluted membrane fragments (20 pg/well) with [3H]-»» as a ligand by binding assay buffer (50 mM Tris-HCl, 10 mM MgCl2, 0.5% BSA, protease inhibitor cocktail pH 7.5) Prazosin (2.5 nM, PerkinElmer Lifescience) » was added to a 96-well microplate and allowed to react at room temperature for 1 hour. For non-specific binding assays, further phentolamine (Sigma) was added to become 10 μΜ. Next, the reaction mixture was filtered, and transferred to a single filter membrane type GF/C (PerkinElmer Lifescience) using a cell harvester (PerkinElmer Lifescience). The filter was washed 3 times with ice-cold 50 mM Tris buffer (pH 7.5). After drying the filter, MicroScinti 0 (PerkinElmer Lifescience) was added to the filter, and radioactivity was measured by TopCount (PerkinElmer Lifescience). The film for compound evaluation shown below was prepared in a similar manner to the above method using the strain showing the most superior S/B value (total binding radioactivity/non-specific 128 321556 201114425 sex-binding radioactivity) in the binding assay using membrane fragments. Fragmentation. (iii) Evaluation of the Example Compounds After diluting the membrane fragments (20 pg/well) in combination with the assay buffer, the compound and the melon (2.5 nM 'PerkinElmer Lifescience), adding to the 96-well microplate and allowing the mixture to be in the chamber The temperature was reacted for 1 hour. For non-specific binding assays, further add fentanyl (Sigma) as a cold ligand to 1 〇 μΜ. Then, the 'transition reaction mixture was transferred to a single membrane type GF/C (PerkinElmer 1^65 (^1106) using a cell harvester (PerkinElmer Lifescience). The cooled 5〇111]^1'145 buffer (卩117.5) The batter was washed 3 times. After the filter was dried, MicroScinti 0 (PerkinElmer Lifescience) was added to the filter, and radioactivity was measured by TopCount (PerkinElmer Lifescience). Reduction was calculated using GlaphPad Prism Ver3.2 (GlaphPad Software) [3H] - The concentration of the compound required to bind the membrane fragment to 50% (IC50). The measurement results of the above method (a1D adrenergic receptor binding inhibition rate at 1 micromolar concentration (μΜ)) are shown in Table 2. 129 321556 201114425 Table 2 Test compound binding inhibition rate (%) (Example No.) _ 1 100.1 2 101.5 5 79.4 12 97.0 14 100.0 15 62.0 19 94.8 22 96.1 23 100.0 30 96.9 Formulation Example 1 (1) Example 1 Compound 10 Mg (2) Lactose 60 mg (3) Corn starch 35 mg (4) Hydroxypropyl methylcellulose 3 mg (5) Magnesium stearate 2 mg Compound obtained in Example 1 (10 mg), lactose (60 mg ) with a mixture of corn starch (35 mg) at 10 Aqueous hydroxypropyl methylcellulose solution (0.03 m Bu 3 mg of hydroxypropyl decyl cellulose) was granulated, dried at 40 ° C, and sieved. The obtained granules and magnesium stearate (2 mg) Mix and compress 130 321556 201114425 mixture. The suspicion is coated with sugar coating (sucrose, titanium dioxide, talc and acacia in water). The coated tablets are polished with beeswax to obtain • coated tablets. Formulation Example 2 (1) Compound of Example 1 10 mg (2) Lactose 70 mg (3) Corn starch 50 mg (4) Soluble starch 7 mg (5) Magnesium stearate 3 mg Compound obtained in Example 1 (10 mg And granulated with magnesium stearate (3 mg) in a soluble aqueous solution of starch (0.07 ml, 7 mg of soluble powder), dried, and mixed with lactose (70 mg) and corn starch (50 mg). Industrial Applicability The compound of the present invention has superior selectivity to a1D adrenergic receptor antagonism and is effective as a prophylactic or therapeutic agent for diseases such as lower urinary tract. [Simple description of the diagram] None. [Description of main component symbols] None 0 131 321556 201114425 Sequence Listing &lt;110&gt; Takeda Pharmaceutical Co., Ltd. &lt;120&gt; Iminopyridine derivative and use thereof &lt;130&gt;&lt;160&gt; 2 &lt;170&gt; Patentln version 3.3 &lt;210&gt; 1 &lt;211&gt; 45 &lt;212&gt; DNA &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Selection of human aDL adrenergic receptor gene &lt;400&gt; 1 ccgacggcog ctagcgagat gactttccgc gatctcctga Gcgtc 45 &lt;210&gt; 2 &lt;211&gt; 38 &lt;212&gt; DNA &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Selection of human a ID adrenergic receptor gene primer &lt;400&gt; 2 gctctgggta Ccttaaatat cggtctcccg taggttgo 38 (1)

Claims (1)

201114425 VII. Patent application scope: 1. A compound of the following formula (I) or a salt thereof, Wherein the A ring is a phenyl group, a (tetra) group or a 5 or 6 membered aromatic heterocyclic group, each having one or more substituents as needed, R 1 is a methyl group, or R 1 and A are optionally bonded to form a ring as needed. a fused ring group of one or more substituents, R 2 is a hydrogen atom or a methyl group, or a cycloalkyl ring is bonded together with a _ carbon atom, and R is a hydrogen atom, a halogen atom, a cyano group, If desired, a hydrocarbyl group having one or more substituents, a mercapto group, a heterocyclic group having one or more substituents as necessary, an amine group having one or more substituents, and optionally a substituent a radical or a substituent having a substituent; ', except for the following compounds: 5 gas-1_(2,3·dihydro_1H-indol-1-yl)-2-imino-1 2- Hydropyridine-3-indenylamine, a 1 15 gas imino group - Η 1-phenylethyl)-1,2-dihydro &quot; ratio. Ding_3_carbamamine and 5-mil-2-imine are small (1,2,3,4_tetrazane-cai-diyldiazepine 321556 132 201114425 bite 3-carboxamide. Ring is 2. If applied A compound of the first aspect of the invention, or a salt thereof, which optionally has a phenyl group having one or more substituents, and an AR is a halogen. 3. A compound of the formula: or a salt thereof, an atom. T, R R - R a group CH as shown in the following formula, In the formula H-, the ring A is as defined in the scope of the patent application. 5. The compound of claim 4 or a salt thereof, wherein the ring A is (1) having i to 3 selected from the group consisting of (a) a halogen atom, (b) a cyano group and (c) an alkylsulfonyl group. a stupid group of substituents, (2) a thiol group having one or more substituents as desired, or (3) an fluorenyl group having one or more substituents as needed. 6. The compound of claim 4 or a salt thereof, wherein the ring A is (1) having one selected from the group consisting of (a) a halogen atom, (b) a cyano group and (c) a Cl-6 alkylsulfonyl group. a phenyl group of 3 substituents, (2) pyridyl group, or (3) thienyl group. 7. The compound of claim 4 or a salt thereof, wherein the ring A is (1) having one selected from the group consisting of (a) a halogen atom, (b) a cyano group and (c) a Cl 6 alkylsulfonyl group. a phenyl group, a pyridyl group, or a thienyl group of three substituents, and R is a halogen atom. 133 321556 201114425 8. The compound of claim 4 or a salt thereof, wherein A % is a stupid group having a substituent selected from the group consisting of (8) a tooth atom and (9) an aryl group, and Z is a _ atom. 9. For example, please refer to the compound of the scope of patent patent or its salt. The group shown in the formula, x () a fused ring group as shown by the following formula Or group And R are the same or different and each sub, mouse and -s (〇Vr6 (wherein, r6, self = base, Nanyuan integer) substituent, is an alkyl group, P is 0 to 2, m is 〇 to An integer of 3, and an integer of 0 to 4, 如. The scope of the patent is 经, a compound or a salt thereof, wherein 4 is from a south atom, a cyano group and a Ci-6 alkyl group, ρ For Λ 1 ) PR (where R6 is an integer of p), m+n=l is long or 1. —'The calendar and the crucible are the same or different and each is 〇321556 134 201114425 11. The compound of claim 9 or a salt thereof, R3 is a tooth atom, R4 is a hydroxyl group, and R is selected from a halogen atom, a cyano group and a substituent of _S (〇w ci-6 alkyl, p is an integer from 〇 to 2), and XR is either broad or (four) or 2, but * is the same or different and each is C 12. As claimed in the patent application A compound of 9 or a salt thereof, wherein R3 is a halogen atom, R5 is an atom, m is ruthenium, and η is 1. a salt, wherein, the formula (I) 13. The compound of the formula or the partial structural formula thereof a fused ring group represented by the following formula Wherein R41 and R51 are the same or different and each are deuterium from a hydroxyl group, a halogen atom, a cyano group and -S(〇)p, -R6i (wherein R01 is an alkyl group, ?, an integer from 〇 to 2) The substituent, X is S, so or so2, 135 321556 201114425 m ' is an integer from 0 to 3, and η' is an integer from 0 to 4. The compound of claim 13 or a salt thereof, wherein R is an atom, R51 is a halogen atom, m' is 0, and η' is 0 or 1. The compound according to claim 13 or a salt thereof, wherein R3 is a halogen atom, R51 is a halogen atom, X is S02, m' is 0, and η' is 1. a group represented by a part of the structural formula 16. The compound of the first aspect of the patent application or a salt thereof, wherein, the formula (1) a group represented by the following formula Wherein q is an integer from 0 to 4, and the anthracene ring is as defined in item 1 of the scope of the patent application. 17. A compound which is 5-a-l-[l-(3-indolyl)ethyl]_2-imino-1,2-dihydro σ than 0-1,3-carbamide or Its salt. 321556 136 201114425 18. A compound which is 5-chloro-1-(6-gas-2,3-dihydro-1 Η-indol-1-yl)-2-imino-1,2-dihydro Pyridine-3-carbamamine or a salt thereof. 19. A compound which is 5-chloro-[[111]-1-(3-fluorophenyl)ethyl]-2-imino-1,2-dihydrogen-tolerant Or its salt. 20. A compound which is 5-chloro-l-[(lR)-l-(3,5-difluorophenyl)ethyl]-2-imino-1,2-dihydropyridine-3 - guanamine or its salt. 21. A compound which is 5-chlorocyanophenyl)ethyl]_2-imino-1,2-dihydropyridine-3-carboxamide or a salt thereof. 22. A compound which is 5_gas dioxy ionyl 3,4_dihydro-2H-thiosulphonic acid 4-yl)_2-imino-1,2-dihydro" bite_3 _ Brewing amine or its salt. 23 — A compound pre-drug that is applied for in the scope of the patent application. 24. A pharmaceutical agent comprising a compound of claim j or a prodrug thereof. ^ &amp; A pharmaceutical agent according to claim 24, which is (10) an adrenergic receptor antagonist. A. For example, the pharmaceutical prophylactic or therapeutic agent of claim 24 of the patent application. , a compound that promotes or treats a mammalian lower urinary tract disease or a precursor drug thereof. Shen — 丨 — \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ 范围 \ \ \ \ 范围 \ 范围 \ \ 范围321556 137 201114425 ’ IV. Designated representative map: - (1) The representative representative of the case is: None. • (2) A brief description of the symbol of the representative figure: None. ._ There is no schema in this case. 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 3 321556