TW201022223A - Di-substituted benzopyrane compound - Google Patents

Abstract

Disclosed is a therapeutic agent for arrhythmia. Specifically disclosed is a benzopyrane compound represented by formula (I) [wherein R1 and R2 independently represent a C1-6 alkyl group or the like; R3 represents a hydroxy group or the like; R4 represents a hydrogen atom or the like; R5 represents a hydrogen atom or the like; m represents an integer of 0 to 4; n represents an integer of 0 to 4; V represents a single bond, CR12R13, NR14 or the like; R6 represents a C6-14 aryl or the like; and R31, R32, R33 and R34 independently represent a C1-6 alkyl group, a C6-14 aryl group, a C2-9 heteroaryl group, a halogen atom, a hydroxy group, a C1-6 alkoxy group, a nitro group, a cyano group, an amino group, a C1-6 alkylcarbonylamino group, an aminocarbonyl group, a C1-6 alkylcarbonyl group, a C1-6 alkoxycarbonyl group, a carboxyl group or the like].

Description

201022223 VI. Description of the Invention: [Technical Field] The present invention relates to a benzopyran compound having a non-reaction period prolonging effect, and relates to a user who treats arrhythmia in a mammal including a human. [Prior Art] As the benzopyrene derivative, a 4-mercaptoaminobenzopyran derivative represented by Cromakalim is known (for example, Patent Document 1). Although it is known that the 4-mercaptoaminobenzopyran derivative represented by Cromakalim opens the ATP-sensitive K + channel and is effective for the treatment of hypertension or asthma, there is no mention of the heart rhythm regarding the prolongation of the non-reaction period. Incomplete treatment. In addition, as a benzopyran compound having a non-reaction period extending action, a substituted benzopyran derivative or the like is disclosed (for example, Patent Document 2 for reference). However, no specific description of the compounds described in the present invention is possible. [PRIOR ART DOCUMENT] [Patent Document 1] Japanese Laid-Open Patent Publication No. JP-A No. 2003-81961 [Patent Document 2] [Problems to be Solved by the Invention] -5 - 201022223 However, the anti-arrhythmia drugs with the main mechanism of non-reactive period prolongation (such as Vaughan Williams' anti-arrhythmia classification belonging to group 1 drug or group 3 d-Sotalol, dofetilide, etc.) are induced The role of sudden death of extremely dangerous arrhythmia, such as torsades de pointes, which is induced by prolongation of the ventricular myoelectric activity associated with the prolongation of the non-reaction period, is a therapeutic issue, and it is desired to develop a drug with fewer side effects. [Means for Solving the Problem] The present inventors have made an effort to study the results of the benzopyran compound, and surprisingly found that the compound represented by the formula (I) does not affect the non-reaction period of the ventricular muscle and the activity potential, and affects the atrium. The present invention is completed by the selective non-reaction period of the muscle. That is, the present invention is composed of the following.

❹ 【化1】 R5vM/(CH2)m-V-(CH2)n-R6

R and r2 are each independently a hydrogen atom, a Ci-6 alkyl group (the alkyl group may be a halogen atom, a Ci-6 alkoxy group (the alkoxy group may be optionally substituted by a halogen atom) 201022223 (the aryl group may be a halogen atom, (The alkyl group may be optionally substituted by a halogen atom or an atom) or the hydroxyl group may be arbitrarily taken up by a halogen atom, and may be =0, or (the alkyl group may be optionally substituted by a halogen atom or a radial group) or c6 -14 arylhydroxy, nitro, cyano, C16 alkyl Cl. 6 oxime (the alkoxy group may be optionally substituted by halogen) or Cl-6 alkoxy (the alkene) may be optionally substituted, or R1 And R2 = NR7 (R7 is a hydrogen atom, a Cl-6 alkyl group or a Ch6 alkoxy group (the alkoxy group may be optionally substituted by a halogen atom)), a hydroxyl group, a C1_6 alkoxy group (the alkoxy group may be used) Substituted by a halogen atom), C6-14 aryl, <:2_9 heteroaryl (the aryl and heteroaryl group may be substituted by R1G (R1G is a halogen atom, a hydroxyl group, a C]-6 alkyl group ( The alkyl group may be optionally substituted by a halogen atom, a hydroxyl group or a c16 alkoxy group (which may be optionally substituted by a halogen atom), a C16 alkoxy group (the alkoxy group) May be optionally substituted by a halogen atom), a nitro group, a cyano group, acyl methyl, acyl amine methyl group, a sulfo acyl group, a sulfo group, an amino group, (^ "alkyl group, an alkoxy two ^

Amino group, C!-6-based ore-based amine group, Ci 6 alkylsulfonylamino group, amine methyl sulfonyl group, C, 6 alkylaminocarbonyl group, diCi-6 alkylaminocarbonyl group, (^ ^Alkylcarbonyl, C!-6-homoyloxycarbonyl, sulfonylamino, Ci 6 alkylsulfonyl, decyl or Ce-M arylcarbonyl) optionally substituted, 〇 is an integer from i to 3, 〇 2 or 3, R1G may be the same or different)), or with the carbon atom of the bond, for 201022223 [Chemical 2] \^r(CH2\

(CH2)rG

(wherein 'j is an integer of 〇~7, k is an integer of 0 to 7' G is a single bond, CR8R9 (R8 and R9 are each independently, and are a hydrogen atom, a C.6 alkyl group (the alkyl group may be a halogen atom) , a hydroxyl group, a hydrazine: a 6 alkoxy group (the alkoxy group may be optionally substituted by a halogen atom), a c6.14 aryl group, a C2-9 heteroaryl group (the aryl group and the heteroaryl group may each be a R1Q) (R1()& 〇 has the same meaning as defined above) optionally substituted with 'Ci-6 alkylcarbonyloxy, nitro, cyano, formamyl, formamidine, amine, Ch alkylamino, two Cu alkylamino group, <^_6 alkylcarbonylamino group, <^-6 alkylsulfonylamino group, amine mercapto group, CU6 alkylaminocarbonyl group, bis(6.6 alkylamino group) Carbonyl, Cb6 alkylcarbonyl '(^-6 alkoxycarbonyl, sulfonylamino, c^6 alkylsulfonyl, carboxy or sulfonyl optionally substituted), c^M aryl, c2-9 heteroaryl a group (the aryl group and the heteroaryl group may be optionally substituted by R1() (R1() and hydrazine are in the same meaning as defined above), a hydroxyl group, and a Ci_6 alkoxy group (the oxy group may be optionally substituted by a halogen atom) ), nitro, cyano, formamidine, formamidine, sulfonylamino, azide, amine, mountain a 6-alkylamino group, a di-C!-6 alkylamino group, a Cl-6 alkylcarbonylamino group, a Q-6 alkylsulfonylamino group, an amine formazan group, a Cl. alkylamine base group, DiCl·6-yard amino-based carbon group, C!-6-yard fluorenyl group, Cl 6 alkoxycarbyl group, sulfonylamino group, Cu alkylsulfonyl group, carboxyl group, <:6·14 aryl group a carbonyl group or a c2_9 heteroarylcarbonyl group (the arylcarbonyl group and the heteroarylcarbonyl group may be optionally substituted by 0 r10 (R1G and hydrazine in the same sense as defined above), or R8 and R9 - -8- 201022223 are =0 or = s), NR11 (R11 may be a hydrogen atom, a C.6 alkyl group (the alkyl group may be a halogen atom, (^-6 alkoxy group (the alkoxy group may be optionally substituted by a halogen atom), a hydroxyl group, a C6- 14 aryl, C2.9 heteroaryl (the aryl and heteroaryl groups may be optionally substituted by R1() (R1Q and hydrazine are the same as defined above), <^.6 alkylaminocarbonyl 'Di-Cm alkylaminocarbonyl, 匕.6 1 alkylcarbonyl, C3.8 cycloalkylcarbonyl, C, -6 alkoxycarbonyl, C, -6 alkyl, sulfonyl, carboxy, C6-14 a carbonyl group or a C2.9 heteroarylcarbonyl group optionally taken as a C, 6. 6 alkylaminocarbonyl group, a di Cm alkylaminocarbonyl group, (:, -<;alkylcarbonyl, C3_8 cycloalkylcarbonyl, C,-6 alkoxycarbonyl, C^6 alkylsulfonyl, C6.14 arylsulfonyl, or C2-9 heteroarylsulfonyl (The arylsulfonyl and heteroarylsulfonyl groups may be optionally substituted by R1G (R1() and hydrazine in the same sense as above), carboxyl group, C6.14 arylcarbonyl group or c2-9 heteroaryl group. a carbonyl group (the arylcarbonyl group and the heteroarylcarbonyl group may be optionally substituted by R10 (R1Q and hydrazine in the same sense as defined above)), hydrazine, S, S0 or S02), and % R3 is a hydroxyl group or a Cu alkyl group. A carbonyloxy group, or bonded to r4, 'R4 is a hydrogen atom or bonded to R3, 'm is an integer from 0 to 4, η is an integer from 0 to 4, and V is a single bond, CR12R13 (R12 and R8 has the same meaning, r13 has the same meaning as r9), NR14 (R14 has the same meaning as R11), 〇, S, S0 or s〇2, and R5 is a hydrogen atom or a Ci-6 yard (the base can be halogen atom, Ci6). Alkoxy (the alkoxy group may be optionally substituted by a halogen atom) or optionally taken through a group of -9 - 201022223), R6 is a hydrogen atom, a Cu alkyl group (the alkyl group may be a halogen atom, a Cl. 6 alkoxy group) (The alkoxy group can be optionally a halogen atom Substituted), an amine group, a carboxyl group or a hydroxyl group optionally substituted), <: 3-8 cycloalkyl group, C3·8 cycloalkenyl group (the cycloalkyl group and the cycloalkenyl group may be a halogen atom, a C..6 alkyl group ( The alkyl group may be optionally substituted by a halogen atom, a Cl. 6-group oxy group (the oxy group may be optionally substituted by a halogen atom), an amine group, a fluorenyl group or a hydroxy group, or an alkoxy group (the alkoxy group may be a halogen atom) Any substitution), an amine group, a carboxyl group or a hydroxyl group optionally substituted), an amine group, a hospital amine group, a diC|6 alkylamino group, a c6_14#ylamino group 'c2 9 heteroarylamine group (the arylamine group) And the heteroarylamine group can be p of Rl 5 (R" and R丨. In the same sense, P has the same meaning as 〇) any substitution), C6-μ aryl, (: 2-9 heteroaryl (the aryl and heteroaryl groups can be p of R18 (with the same meaning, p and 〇 have the same meaning) Any optionally substituted or C2·9 heterocyclic group (the heterocyclic group may be a halogen atom, an alkyl group (the alkoxy group may be optionally substituted by a halogen atom), an amine group , carboxy or hydroxy optionally substituted), Cl.6 alkoxy ( ❹ ❹ ❹ ❹ ❹ ❹ 任意 ' ' ' ' ' ' ' ' ' ' ' ' Ch Ch Ch Ch Ch Ch Ch Ch Ch Ch Ch Ch Ch Ch Ch Ch Ch Ch Ch Ch Ch Ch Ch Ch r]5 (r15 has the same meaning as R10, P has the same meaning as 〇), hydroxy, nitro, cyano, decyl, carbylamino, amine, C 6 alkylamino, Alkylamino group, alkylcarbonylamino group, C1_0 alkylsulfonylamino group, amine carbenyl group, C!6 alkylaminocarbonyl group, diCl 6 alkylaminocarbonyl ' Ci 6 alkylcarbonyl group, C,-6 alkoxycarbonyl, sulfonylamino, C 6 alkylsulfonylcarboxy or C6_14 arylcarbonyl optionally substituted), -10- 201022223 R31 and R32 are each independently C, .6 alkyl, Cu alkoxy

Ci-6 alkylcarbonylamino, (6-6 alkylaminocarbonyl, bis CL6 alkylaminocarbonyl, Ch6 alkylcarbonyl, (6. alkoxycarbonyl, hydrazine:, .6 alkylsulfonyl) Base (the alkyl group, alkoxy group, alkylcarbonylamino group, (^-6 alkylaminocarbonyl, di-C)-6 alkylaminocarbonyl, alkylcarbonyl, alkoxycarbonyl and alkylsulfonyl It may be a halogen atom, a hydroxyl group, (^_6 alkoxy group (the alkoxy group may be optionally substituted by a halogen atom or a Cm alkoxy group), a c6-14 aryl group, a C2-9 heteroaryl φ group (the aryl group and the hetero group) The aryl group can be optionally substituted by q R16 (R16 and R1G have the same meaning 'q and 〇 have the same meaning), (^-6 alkylcarbonyloxy, nitro, cyano, decyl, carbenamide) , amine group, (^-6 alkylamino group, di-C!-6 alkylamino group, C!-6 alkylcarbonylamino group, ¢^.6 alkylsulfonylamino group, amine mercapto group, Cbe Alkylaminocarbonyl, diCl-6 alkylaminocarbonyl 'Cu-based carbonyl, Cu alkoxycarbonyl, sulfonylamino, (^.6 alkylsulfonate, carboxyl or sulfo optionally substituted), C6_14 aryl, C2-9 heteroaryl, ce-14 aryl carbonyl, C2-9 heteroaryl carbonyl (the aryl, heteroaryl) , φ arylcarbonyl and heteroaryl carbonyl may be optionally substituted by q R16 (R16 and q have the same meaning as defined above), halogen atom, hydroxyl group, nitro group, cyano group, formamyl group, formamidine group, a sulfonylamino group, a sulfo group, an amine group, an amine carbaryl group, a sulfonylamino group or a carboxyl group, and R33 and R34 are each independently a hydrogen atom, a Cu alkyl group, a Cu alkoxy group, a C!·6 alkylcarbonyl group. Amine, Cl 6 alkylaminocarbonyl, diCl 6 alkylaminocarbonyl, (:, .6 alkylcarbonyl, Cl 6 alkoxycarbonyl, Cl. 6 alkylsulfonyl (the alkyl, alkoxy, Alkylcarbonylamino group, CL6 alkylaminocarbonyl group, bis(^.6 alkylaminocarbonyl, alkylcarbonyl, alkoxycarbonyl and -11 - 201022223 alkylsulfonyl group may be halogen atom, hydroxyl group, Ci 6 alkoxy (the alkoxy group may be optionally substituted by a halogen atom or (^-6 alkoxy group), a c6-14 aryl group, a C2-9 heteroaryl group (the aryl group and the heteroaryl group may be q) Same as Rio, q has the same meaning as 〇) optionally substituted), (:!_6 alkylcarbonyloxy, nitro, cyano, methionyl, carbenamide, amine, Cl-6 alkylamine, one Cl·6 yard based fee , Ci_6-based sulfhydryl-based, Ci-6-based ortho-based amine, amine-mercapto, Cu alkylaminocarbonyl, diCl-6 alkylaminocarbonyl, Cu alkylcarbonyl 'Cu alkoxy a carbonyl group, a sulfonylamino group, a Cu alkanesulfonyl group, a carboxyl group or a sulfo group optionally substituted), a C6_14 aryl group, a C2-9 heteroaryl group, a c6-14 arylcarbonyl group, a c2-9 heteroarylcarbonyl group (the aryl group, The heteroaryl group, the arylcarbonyl group and the heteroarylcarbonyl group may be optionally substituted by q of R10 (R16 and q have the same meanings as defined above), a halogen atom, a hydroxyl group, a nitro group, a cyano group, a decyl group, a formamide. A sulfonylamino group, a sulfo group, an amine group, an amine carbaryl group, a sulfonylamino group or a carboxyl group. A benzopyran compound or a pharmaceutically acceptable salt thereof. 2. R1 and R2 are a benzopyran compound described in the first item in which the methyl group 'R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, VQ is a single bond, m is 2 or 3, and η is 〇. Allowable salt. 3. R1 and R2 are methyl 'R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and V is a cr12r13 (R12 is a c丨·6 alkyl group, a C丨-6 alkoxy group (the alkyl group and the alkoxy group may be A benzopyran compound according to the first aspect of the invention, wherein the halogen atom is substituted by a halogen atom or a hydroxy group, and R13 is a hydrogen atom, and m is 1 or 2, and η is 〇.

4. R1 and R2 are methyl 'R3 is a hydroxyl group, and R4 and R5 are a hydrogen atom 'V -12- 201022223 is NR14 (R14 is Ci-6, K.6. A benzopyran compound according to the first aspect, wherein the substituent is a halogen atom or a hydrogen atom, 111 is 1 or 2, and n is 0, or a pharmaceutically acceptable salt thereof. 5. R6 is a benzopyran compound of the second, third or fourth aspect of the C^-6 alkyl group or a pharmaceutically acceptable salt thereof. • 6. R6 is a benzopyran compound of the second, third or fourth aspect of the C3-8 cycloalkyl group or a pharmaceutically acceptable salt thereof. VII. R6 is a benzoxanthene compound of the 2' 3 or 4 of the Ce-i4 aryl group or a pharmaceutically acceptable salt thereof. 8. The benzene ring system containing R31, R32, R33 and R34 is represented by formula (II) [Chemical 3]

(Π) [wherein R31 and R32 are each independently, and are Cu alkyl 'Cm alkoxy, C -6 alkylcarbonylamino, alkylaminocarbonyl, diCl.6 alkylaminocarbonyl, <;^_6 alkylcarbonyl, (^-6 alkoxycarbonyl, alkylsulfonyl (the alkyl, alkoxy, alkylcarbonylamino, C, .6 alkylaminocarbonyl, dioxane The aminocarbonylcarbonyl group, the alkylcarbonyl group, the alkoxycarbonyl group and the alkylsulfonyl group may be optionally substituted by a halogen atom, a hydroxyl group or a Cl_6 alkoxy group (the alkoxy group may be optionally substituted by a halogen atom or a C..6 alkoxy group) , (6-14 aryl, C2-9 heteroaryl (the aryl and heteroaryl groups can be optionally substituted by q R16 (R16 and R10 are the same meaning -13-201022223 meaning, q and 〇 have the same meaning) ), (^-6 alkylcarbonyloxy, nitro, cyano, methionyl, carbylamino, amino, alkylamino, di-Cue, amine, C!.6 alkyl Carbonylamino group, Cl6 alkylsulfonylamino group, amine mercapto group, c!6 alkylaminocarbonyl, diCi 6 alkylaminocarbonyl, Cue fluorenyl, C!.6 alkoxy Carbonyl, sulfonylamino, Cl 6 alkyl sulfonate, residue or sulfo group optionally substituted), (6-14 aryl, C2.9 a heteroaryl group, a C^m arylcarbonyl group, a C2.9 heteroarylcarbonyl group (the aryl group, the heteroaryl group, the arylcarbonyl group and the heteroarylcarbonyl group) may be substituted by q r16 (r>6 and q with the aforementioned The same oxime, meaning) optionally substituted), halogen atom, hydroxy group, nitro group, cyano group, methionyl group; methionine group, sulfonylamino group, sulfo group, amine group, amine mercapto group, decylamine Or a carboxyl group, R3 3 and R 34 are each independently a hydrogen atom, a C 1 -6 alkyl 'C 1 -6 alkoxy group, a Ci-6 alkylcarbonylamino group, a mountain-6 alkylamino group; , C 1 -6 alkylamino group A £iti acyl group C 1 -6 ketone carbonyl, Ci-6 alkoxy γμι methoxy group 'C, -6 phenyl group thiol group (the alkyl group, alkoxy group) , alkylcarbonylamino-based C 1-6 alkylaminocarbonyl, di-Ch6 alkylaminocarbonyl, alkylcarbonyl, oxy VOJ, thiol and sulfonyl can be halogen atom, hydroxyl, Cm a group (the oxy group may be optionally substituted by a halogen atom or a C. .6 alkoxy group) C 6 - 1 - 4 aryl group, a C 2-9 heteroaryl group (the aryl group and Heteroaryl groups can be optionally substituted by q R 1 6 (R16 and R10 have the same meaning of q and 〇 have the same meaning) C 1-6 ketone carbonyloxy, nitro, cyano, formazan, formamide Amino group, amine group, C, -6-based amino group, di-C 1 i-alkylamino group, ¢^.6-based arylamino group > C 1 - 6 -based sulfonylamino group, amine formazan Base, C1_6-based aminocarbonyl, di-C 1 - 6 mercaptoamine-based Cl -6 -based group, C 1 _ 6 alkoxy ore group, extended amine group, C). 6 alkane-14 - 201022223

Arylsulfonyl, carboxy or sulfo group optionally substituted) aryl, C6-, 4 arylcarbonyl, C2-9 heteroarylcarbonyl (the aryl, heteroaryl, arylcarbonyl and heteroarylcarbonyl groups can be q Rl6 (Rl6 and q have the same meanings as defined above) are optionally substituted) 'halogen atom, trans group, nitro group, cyano group, formyl group, formamidine group, sulfonylamino group, sulfo group, amine group, amine A benzopyran compound or a pharmaceutically acceptable salt thereof, as described in items 5, 6 and 7 of the methylidene group, the sulfonylamino group or the carboxyl group. _ 9- 1131 is a _6 yard base (the alkyl group may be optionally substituted by a halogen atom, a hydroxyl group or an aristocratic group (the alkoxy group may be optionally substituted by a halogen atom or a Ci. 6 alkoxy group), a halogen atom' a hydroxyl group, a Cl_6 alkoxy group (which may be optionally substituted by a halogen atom) or a nitro group, and a 2 2 octa-R group is a Ci-6 alkyl group (the alkyl group may be a halogen atom, a hydroxyl group or a C, 1 " 6 An alkoxy group (the alkoxy group may be optionally substituted by a halogen atom or a Ci_6 alkoxy group), a peripherin atom 'hydroxyl group, a C1-6 alkoxy group (the alkoxy group may be optionally substituted by a halogen atom), a nitrate A benzopyran compound according to item 8 wherein Φ r33 and r34 are a hydrogen atom or a pharmaceutically acceptable salt thereof. - 10. The benzene ring containing R31, R32, R33 and r34 is of the formula (m) [Chemical 4]

R32 丫, R34 (ΠΙ) -15- 201022223 [wherein R31 and R32 are each independently, which is Cl_6 alkyl, Cl-6 alkoxy,

Cl. 6 alkylcarbonylamino, ¢^-6 alkylaminocarbonyl, bis(^-6alkylamino), 4 alkylcarbonyl, d-6 alkoxycarbonyl, Cl.6 alkylsulfonyl (The alkyl group, alkoxy group, alkylcarbonylamino group, Cl-6 alkylaminocarbonyl group, di-Ci-6 alkylaminocarbonyl group, alkylcarbonyl group, alkoxycarbonyl group and alkylsulfonyl group may be halogen atom , hydroxy, (^.6 alkoxy (the alkoxy group may be optionally substituted by a halogen atom or a C..6 alkoxy group), a C6_14 aryl group, a C2-9 heteroaryl group (the aryl group and the heteroaryl group are both) It can be optionally substituted by q r16 (r16 and r1g have the same meaning of 'q with the same meaning of 〇), (^-6 alkylcarbonyloxy, nitro, cyano, formazan, formamidine, Amino group, Cl-6 alkylamino group, di-Ci-6 alkylamino group, (^-6 alkylcarbonylamino group, Cl_6 alkylsulfonylamino group, amine carbaryl group, (^.6 alkylamine) Carbonyl group, diCl-6 alkylaminocarbonyl,

Ci.6 alkylcarbonyl, C^6 alkoxycarbonyl, sulfonylamino, Cl-6 alkylsulfonyl, carboxy or sulfo optionally substituted), C6.14 aryl, C2-9 heteroaryl, C6.M aryl a carbonyl group, a C2-9 heteroarylcarbonyl group (the aryl group, the heteroaryl group, the arylcarbonyl group and the heteroarylcarbonyl group may be optionally substituted by q r16 (r16 and q have the same meaning as in the above)), halogen Atom, a hydroxyl group, a nitro group, a cyano group, a decyl group, a formamidine group, a sulfonylamino group, a sulfo group, an amine group, an amine carbaryl 'sulfonylamino group or a carboxyl group, and R33 and R34 are each independently Hydrogen atom, Cu alkyl group, Cu alkoxy group (^.6 alkylcarbonylamino group, c,.6 alkylaminocarbonyl, diCl-6 alkylaminocarbonyl, C1-6 alkylcarbonyl, Cl-6 alkoxy a carbonyl group, a C.6 alkyl group (the alkyl group, an alkoxy group, an alkylcarbonylamino group, an alkylaminocarbonyl group, a bis(6-6 alkylaminocarbonyl group, an alkylcarbonyl group, an alkoxycarbonyl group) And -16- 201022223 alkylsulfonyl group can be halogen atom, hydroxyl group, Ci 6 alkoxy group (the alkoxy group can be optionally substituted by a dentate atom or a Cl-6 alkoxy group), c6-14 aryl group, c2 -9 heteroaryl (the aryl and heteroaryl groups can be q R16 (r16 has the same meaning as Rio 'q has the same meaning as 〇), Ci6 alkylcarbonyloxy, nitro 'cyano, carbaryl 'carbamoylamino, amine, Ci6 alkylamino -' Cm alkylamino group, Cm alkylcarbonylamino group, Ci 6 alkylsulfonyl group, amine group, amine carbenyl group, c, -6 alkylaminocarbonyl group, diCi6 alkylaminocarbonyl group Base, Cl.6 alkylcarbonyl, Cl.6 alkoxycarbonyl, sulfonylamino, 匕6 alkyl expanded, carboxy or sulfo optionally substituted), c6.14 aryl, C2-9 a group, a C6.M arylcarbonyl group, (: 2-9 heteroarylcarbonyl group (the aryl group, heteroaryl group, aryl group and heteroaryl group) may be n by r16 (r16 and q are the same as described above) Meaning) optionally substituted), halogen atom, hydroxyl group, nitro group, aryl group, methionyl group, formamidine group, sulfonylamino group, sulfo group, amine group, amine carbaryl group, sulfonylamino group or carboxyl group. The benzopyran compound described in items 5, 6 and 7 or a pharmaceutically acceptable salt thereof. # n· R31 is a Cl·6 alkyl group (the alkyl group may be a dentate atom, a hydroxyl group, or a Cl group). (; • alkoxy group (the alkoxy group may be halogen atom or Cl alkoxy) Any optionally substituted -) or c^6 alkylcarbonyl optionally substituted), C6_M aryl (the aryl group may be optionally substituted by q of R16 (R16 and q are the same as defined above)) 'halogen atom, hydroxy, C, -6 alkoxy (which may be optionally substituted by a halogen atom), nitro, cyano, amine, Cm alkylcarbonyl, c,-6 alkoxycarbonyl, carboxy, r32 is C1-6 alkyl ( The alkyl group may be substituted by a halogen atom, a hydroxyl group, a C-group oxy group (the alkoxy group may be optionally substituted by a halogen atom or a C1_6 alkoxy group, -17-201022223), a halogen atom, a transatom group, and a 1-6 oxo group ( The oxy group may be optionally substituted by a halogen atom or a 6 alkoxy group, a nitro group, a cyano group, an amine group, a hexamethylenecarbonylamino group or an amine carbaryl group, R33 and R34 are a hydrogen atom, and R32 is a nitrate. In the case of the base, R31 is not a benzopyran compound described in Item 10 of the amine group or a pharmaceutically acceptable salt thereof. 12. The benzene ring containing R31, R32, R33 and R34 is of the formula (IV). ❿ [Chemical 5]

Wherein R31 and R32 are each independently and are Cl-6 alkyl, Cl-6 alkoxy, C!6 alkylcarbonylamino, (^.6 alkylaminocarbonyl, di C!-6 alkylamino) Mercapto, C, -6 alkylcarbonyl, Cl-6 alkoxycarbonyl, Cl6 alkylsulfonyl (the alkyl, alkoxy, alkylcarbonylamino, C1-6 alkyl carbonyl, di C, -6 The alkoxycarbonyl group, the alkylcarbonyl group, the alkoxycarbonyl group and the alkylsulfonyl group may be optionally a halogen atom, a hydroxyl group or a C1_6 alkoxy group (the alkoxy group may be optionally a halogen atom or a C!·6 alkoxy group). Substituted), c6_14 aryl, C2_9 heteroaryl (the aryl and heteroaryl groups can be optionally substituted by q r16 (ri6 has the same meaning as Rio, q has the same meaning as 〇)), Cl-6 alkyl carbonyl oxide Base, nitro, cyano, formamyl, formamidine, amine, Ci 6 alkylamino, bis-18- 201022223 (^-6 alkylamino, (^.6 alkylcarbonylamino) 'C!-6 alkylsulfonylamino, aminemethanyl, Ci.6 alkylaminocarbonyl, diCl-6 alkylaminocarbonyl, C]-6 alkylcarbonyl, C!-6 alkoxycarbonyl , sulfonamide, (^_6 alkylsulfonyl, carboxyl or sulfo optionally substituted), C6_14 aryl, C2-9 An aryl group, a c6_14 arylcarbonyl group, a C2-9 heteroarylcarbonyl group (the aryl group, the heteroaryl group, the arylcarbonyl group and the heteroarylcarbonyl group may be optionally substituted by q of R16 (R16 and q are the same as defined above)), Halogen atom, hydroxyl group, nitro group, cyano group φ, formamyl group, formamidine group, sulfonylamino group, sulfo group, amine group, amine carbaryl group, sulfonylamino group or carboxyl group, and R33 and R34 are each independently Is a hydrogen atom, a Cl.6 alkyl group, a Cm alkoxy group, a C..6 alkylcarbonylamino group, a Cl-6 alkylaminocarbonyl group, a di C.6 alkylaminocarbonyl group, a Ci.6 alkylcarbonyl group. , Cu alkoxycarbonyl, Cu alkylsulfonyl (the alkyl group, alkoxy group, alkylcarbonylamino group, Cl 6 alkylaminocarbonyl group, di C! 6 alkylaminocarbonyl group, alkylcarbonyl group, The alkoxycarbonyl group and the alkylsulfonyl group may be a halogen atom 'hydroxy group, (^_6 alkoxy group (the alkoxy group φ may be optionally substituted by a halogen atom or a Cu alkoxy group), c6.14 aryl group, C2- 9 heteroaryl (the aryl and heteroaryl groups can be optionally substituted by q Ri6 ( Ri 6 and Ri 〇 have the same meaning 'q and 〇 have the same meaning), (^.6 alkylcarbonyloxy, nitro , cyano, carbaryl, formazan Base, amine group, Cl. 6 alkylamino group, di C!-6 alkylamino group, (:, -6 alkylcarbonylamino group, Cl_6 alkylsulfonylamino group, amine formazan group, (^ _6 alkylaminocarbonyl, di-C16 alkylaminocarbonyl, C!·6 alkylcarbonyl, C!6 alkoxycarbonyl, sulfonylamino, Cl-6 alkylsulfonyl, carboxyl or sulfo group optionally substituted ), (: 6_14 aryl, C2.9 heteroaryl, C6 — 】 4 arylcarbonyl, C 2 ·9 heteroarylcarbonyl (the aryl, heteroaryl-19- 201022223, arylcarbonyl and heteroaryl) The carbonyl group may be optionally substituted by q ri6 (r16 and the same meaning as defined above), a halogen atom, a hydroxyl group, a nitro group, a cyano group, a decyl group, a formamidine group, a sulfonylamino group, a sulfo group, an amine group. A benzopyran compound according to items 5, 6 and 7 or a pharmaceutically acceptable salt thereof, which is represented by the group 'n-carbamyl group, sulfonamide group or carboxyl group'. 13. R31 is a nitro group or an amine group, and the size 32 is a Cm alkyl group (the alkyl group may be optionally substituted by a halogen atom, a hydroxyl group or a Ci alkoxy group (the alkoxy group may be optionally substituted by a halogen atom), an amine group or A benzopyran compound of the Qth Cm alkylcarbonylamino group, wherein R33 and R34 are a hydrogen atom, or a pharmaceutically acceptable salt thereof. 14· 1- { 3-hydroxy-2,2-dimethyl-7-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-chromic (chromene -6-yl}propyl-2-one, j (3-hydroxy-2,2-dimethyl-7-nitro-4-{[2-(4-chlorophenyl)ethyl]amino } -3,4-dihydro-2H-chromen-6-yl)propan-2-one, 2,2-dimethyl-6-nitro-4·[(2-phenylethyl)amino] -3,4-dihydro-2 H-chromene-3,7-diol, 6-amino-2,2-dimethyl-4-[(2-phenylethyl)amino]-3 , 4-dihydro- ❹ 214-chromene-3,7-diol, 2,2-dimethyl-7-nitro-4-[(2-phenylethyl-)amino]-3, 4-Dihydro-211-chromene-3,6-diol, 7-bromo-6-methoxy-2,2-dimethyl-4-[(2-phenylethyl)amino] -3,4-dihydro-211-chromen-3-ol, 3-hydroxy-6-methoxy-2,2-dimethyl-4-[(2-phenylethyl)amino]- 3,4-Dihydro-2Η-chromene-7-carbonitrile, 3-hydroxy-2,2-dimethyl-6-nitro-4-[(2-phenylethyl)amino]-3 , 4-dihydro-211-chromene-7-carbonitrile, 6-amino-3-hydroxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3, 4-Dihydro-2Η-chromene-7-carbonitrile, 6-amino-3-hydroxy-2,2-dimethyl-4-[(2-phenylethyl-20-201022223)amino] -3,4-dihydro-2^1-color -7-Carboxyguanamine, 3-{3-hydroxy-2,2-dimethyl-7-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-2H -chromen-6-yl}ethyl benzoate, 2,2·dimethyl-7-nitro-6-phenyl-4-[(2-phenylethyl)amino]-3,4- Dihydro-2H-chromen-3-ol, 6-(4-methoxyphenyl)-2,2-dimethyl-7-nitro-4-[(2-phenylethyl)amino ]-3,4-Dihydro-2H-chromen-3-ol, 2,2-dimethyl-7-nitro-6-(3-nitrophenyl)-4-[(2-phenyl) Ethyl)amino]-3,4-dihydro-2H-chromen-3-ol, 3-hydroxy& base-2,2-dimethyl-7-nitro-4-[(2-benzene Ethylethyl)amino]-3,4-dihydro-2H-chromene-6-carbonitrile, 3-hydroxy-2,2-dimethyl-7-nitro-4-[(2-phenyl) Methyl)amino]-3,4-dihydro-2 H-chromene-6-carboxylic acid methyl ester, 3-hydroxy-2,2-dimethyl-7-nitro-4-[(2- Phenylethyl)amino]-3,4-dihydro-2H-chromene-6-carboxylic acid, 7-amino-3-hydroxy-2,2-dimethyl-4-[(2-benzene) Ethylethyl)amino]-3,4-dihydro-211-chromene-6-carboxylic acid methyl ester, 6-bromo-2,2,5-trimethyl-4-[(2-phenylyl) Amino]-3,4-dihydro-2H-chromen-3-ol, N- { 3-hydroxy-2,2-dimethyl-7-nitro-4-[(2-phenyl) Ethyl)amino]-3,4-diφ hydrogen-2H-color -8-yl}acetamide, 2,2-dimethyl-6-nitro-4-[(2-phenylethyl)amino]-7-(trifluoromethyl)-3,4- Dihydro-2H-chromen-3-ol, 2.2-dimethyl-6-nitro-4-[(2-phenylethyl)amino]-5-(trifluoromethyl)-3,4 -dihydro-2H-chromen-3-ol, 8-amino-2,2-dimethyl-7-nitro-4-[(2-phenylethyl)amino]-3,4- Dihydro-2H-chromen-3-ol, 6-amino-2.2-dimethyl-4-[(2-phenylethyl)amino]-7-(trifluoromethyl)-3,4 -dihydro-2H-chromen-3-ol, 6-amino-2,2-dimethyl-4-[(2-phenylethyl)amino]-5-(trifluoromethyl)- 3,4-Dihydro-2H-chromen-3-ol, 2,2-dimethyl-8-nitro-4-[(2-phenylethyl)amino]-6-(trifluoromethyl) Base)--21 - 201022223 3,4-Dihydro-211-chromen-3-ol, 5-fluoro-2,2-dimethyl-8-nitro-4-[(2-phenylethyl) Amino]-3,4-dihydro-2H-chromen-3-ol, 6-methoxy-2,2-dimethyl-8-nitro-4.[(2-phenylethyl) Amino]-3,4-dihydro-2H-chromo-3-ol, 6-bromo-2,2,8-trimethyl-4-[(2-phenylethyl)amino]_3 ,4-dihydro-2H-chromo-3-ol, 5-oxa-8-methoxy-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-color En-3-ol or 6-bromo-2,2,5,7- Methyl _4 _ permitted on the [(2-phenylethyl) amino] -3,4-dihydro-benzo -2H- chromen-pyran-3-ol of the compound or a pharmaceutically acceptable salt thereof. 15. A benzopyran compound according to any one of 1 to 14, or a pharmaceutically acceptable salt thereof, as an active ingredient. 16. The benzopyran compound according to any one of 1 to 14, or a pharmaceutically acceptable salt thereof, as an active ingredient, is a special arrhythmia therapeutic agent. [Best Mode for Carrying Out the Invention] Next, each substituent of the compound (I) of the present invention will be specifically described. In this book, "η" is positive, "i" is different, "s" is second, "t" is third, "." is ring, "〇" is adjacent, and "m" is between, "P" is a pair, "Me" is a methyl group, "Et" is an ethyl group, "Pr" is a propyl group, "Ms" is a methanesulfonyl group, "Ph" is a phenyl group, and "Ac" is an ethyl group. .

Cu alkyl, such as methyl, ethyl, η-propyl, i-propyl, η-butyl, i-butyl, s-butyl, t-butyl, 1-pentyl, 2-pentyl , 3-pentyl, i-pentyl, neopentyl, 2,2-dimethylpropyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-methyl-η-pentyl, 1,1 , 2-trimethyl-η-propyl, 1,2,2-trimethyl-201022223 η-propyl and 3,3-dimethyl-n-butyl and the like. Preferred examples of the methyl group, the ethyl group, the η-propyl i-propyl group and the η-butyl group atom include a fluorine atom, a gas atom, a bromine atom and an iodine atom. Preferred are fluorine atoms, chlorine atoms, and desert atoms. 'Cm alkoxy group, for example, methoxy 'ethoxy group, cardiopropyloxy group, .i-propoxy group, η-butoxy group, i-butoxy group, s-butoxy group, butoxy group Base, 丄_lupentyloxy, 2-pentyloxy, 3-pentyloxy, hydrazine-pentyloxy, neopentyloxy, 2,2-dimethylpropoxy, hexyloxy, 2• Hexyloxy, 3-hexyloxy, benzyl-η-pentyloxy, hydrazine, ι,2-trimethyl-n-propoxy, hydrazine, 22-trimethyl-n-propoxy and 3,3 - dimethyl-η-butoxy and the like. Preferred are methoxy, ethoxy, η-propoxy and propoxy. The C6-丨4 aryl group may, for example, be a phenyl group, a 0-biphenyl group, an m-biphenyl group, a p-biphenyl group, an α-naphthyl group, a non-naphthyl group, a fluorenyl group, a 2-indenyl group, 9-fluorenyl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl 4-phenanthrenyl and 9-phenanthryl. φ is preferably a phenyl group. a C2_9 heteroaryl group, which comprises a C2_6 monocyclic heterocyclic group which may contain an oxygen atom, a nitrogen atom, a sulfur atom of 1 to 3 atoms, or a combination of 5 to 7 membered rings, and a C5-9 condensation group constituting an atomic number of 8 to 10. Bicyclic heterocyclic group. The C2.6 monocyclic heterocyclic group of the 5- to 7-membered ring may, for example, be a 2-thienyl group, a 3-thienyl group, a 2-furyl group, a 3-furyl group, a 2-pyranyl group or a 3-pyranyl group. , 4 -pyranyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1 ·imidazolyl, 2-mercapto, 4-mowyl, 1-nutrienyl, 3-indenyl , 4 - fluorenyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazole-23- 201022223, 5-isothiazolyl, 2-oxazole , 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-1,3,4-oxadiazolyl, 2-1, 3,4-thiadiazolyl, 3-1,2,4oxadiazolyl, 5-1,2,4-oxadiazolyl, 3-1,2,4-thiadiazolyl, 5- 1,2,4-thiadiazolyl, 3-1,2,5-oxadiazolyl and 3-1,2,5-thiadiazolyl, and the like. A C5_9 condensed bicyclic heterocyclic group having an atomic number of 8 to 10, such as 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzo Furanyl, 7-benzofuranyl, 1-isobenzofuranyl, 4-isobenzofuranyl, 5-isobenzofuranyl, 2-benzothiophenyl, 3-benzothiophenyl, 4- Benzopyranyl, 5-benzothienyl, 6-benzothienyl, 7-benzothienyl, 1-isobenzothiophenyl, 4-isobenzothiophenyl, 5-isobenzothiophenyl , 2-Chloronyl, 3-benzopipetanyl, 4-benzopipetanyl, 5-benzopyranyl, 6-benzopipetanyl, 7-benzopiperine Cyclol, 8-benzopyranyl, 1-pyridazinyl, 2-pyridazinyl, 3-oxazinyl, 5-pyridazinyl, 6-pyridazinyl, 7-fluorene Azinyl, 8-oxazinyl, 1-isoindenyl, 2-isoindolyl, 4-isoindenyl, 5-isodecyl, 1-indenyl, 2-indenyl, 3-mercapto, 4-indenyl, 5-nonyl, 6-fluorenyl, 7-fluorenyl, 1-oxazolyl, 2-oxazolyl, 3-oxazolyl, 4- Carbazolyl, 5-oxazolyl, 6-oxazolyl 7-carbazolyl, 1-indenyl, 2-indenyl, 3-indenyl, 6-fluorenyl, 7-fluorenyl, 8-indenyl, 2-quinolinyl, 3-quinolinyl, 4- Quinolinyl, 5-quinolyl, 6-quinolinyl, 7-quinolyl, 8-quinolinyl, 1-isoquinolinyl, 3-isoquinoline-24-201022223, 4-isoquinoline Lolinyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolinyl, 1-benzoxazinyl, 5-benzoxazinyl, 6-benzene And pyridazinyl, 1-2, 7-π Naphthyridinyl, 3-2,7-α naphthyl, 4-2,7-α naphthyridyl, acridinyl, 3_2,6_ Acridinyl, 4_2,6.α-naphthyridyl, 2-1,8-π-naphthyridyl, 3-1,8·D-naphthyridyl, 4-1,8-αnayptyl, 2-1, 7-Acridine, 3-1,74, naphthyridyl, 4-1,7-acridinyl, 5-1,7-acridinyl, 6-1,7-α-naphthyl, 8.1, 7-d-naphthyridyl, 2-1,6-α-naphthyl, 3-1,6-〇奈_# * ' 4-1 ,6-acridinyl, 5-purine, 6-α-naphthyridyl , 7-1,6-n-naphthyridyl, 8-I,6-acridinyl, 2-1-, 5-a-naphthyridyl, 3-15-acridinyl, 4-1,5-acridinyl, 6 -1,5-acridinyl, 7·1,5-acridinyl, su-η-naphthyridyl, 2-pyridolinyl, 5-quinoline Porphyrin, 6-carbolinyl, 2-quinazolinyl, 4-quinazolinyl, 5-quinoxalinyl, 6-quinazolinyl, 7-quinoxalinyl, 8-quinoline Ortholinyl, 3-U octyllinyl, 4-carboline, 5-D octyl phenyl, 6-carbolinyl, 7-carbolinyl, 8-carboline, 2-pteridinyl, 4- butterfly Pyridyl, 6-pteridinyl and 7-pteryls. φ is preferably 2-pyridyl, 3-pyridyl and 4-pyridyl. C] 6 alkylamino group, for example, methylamino group, ethylamino group, n-propylamino group, i-propylamino group, c-propylamino group, n-butylamino group 'i -butylamino 's-butylamino, butylamino, c-butylamino' oxime-pentylamino, 2-pentylamino, 3·pentylamino, i-pentylamino , neopentylamino, t-pentylamino, c-pentylamino, 丨-hexylamino, 2-hexylamino, 3-hexylamino, c-hexylamino, 1-methyl N-pentylamino, hydrazine, ^-trimethyl-η-propylamino, i, 2,2-trimethyl-η-propylamino and 3,3-dimethyl-η-butyl Amino group and the like. Preferred examples are -25-201022223, such as a methylamino group, an ethylamino group, an η-propylamino group, an i-propylamino group, and an η-butylamino group. The di-Ci-6 alkylamino group may, for example, be a dimethylamino group, a diethylamino group, a di-n-propylamino group, a mono-i-propylamino group or a di-c-propylamino group. , di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, di-c-butylamino, di-1- Amylamino, di-2-pentylamino, dimethyl-3-pentylamino, di-i-pentylamino, di-neopentylamino, di-t-pentylamino, two -c-pentylamino, di-1-hexylamino, di-2-hexylamino, dimethyl-3-hexylamino, di-c-hexylamino, bis-(1-methyl-n- Amyl)amino, di((1,2-trimethyl-η-propyl)amino, bis-(l,2,2-trimethyl-η-propyl)amino, di- (3,3-Dimethyl-η·butyl)amino, methyl(ethyl)amino, methyl(η-propyl)amine, methyl(i-propyl)amino, methyl (c-propyl)amine, methyl(n-butyl)amine, methyl(i-butyl)amine,methyl(s-butyl)amine,methyl(t-butyl) Amino, methyl (c-butyl) amine, ethyl (η-propyl) amine, ethyl (i-propyl) amine, ethyl (c-propyl) amine , ethyl (η-butyl) amine, ethyl (i-butyl) amine, ethyl (s-butyl) amino 'ethyl (t-butyl) amine, ethyl (c- Butyl)amino, η-propyl (i-propyl)amine, η-propyl (c-propyl)amine, η-propyl(η-butyl)amine, η-propyl I-butyl)amino, η-propyl (s-butyl)amine, η-propyl (t-butyl)amine, η-propyl (c-butyl)amine, i-propyl (c-propyl)amine, i-propyl(η-butyl)amine, i-propyl(i-butyl)amine, i-propyl(s-butyl)amine, i -propyl (t-butyl)amine, i-propyl (c-butyl)amine, c-propyl(η-butyl)amine, c-propyl (i-butyl-26- 201022223 Amino group, c-propyl (S-butyl) amine group, C-propyl (t-butyl) amine group, c-propyl (c-butyl) amine group, η-butyl group (i -butyl)amino, n-butyl(s-butyl)amine, η-butyl(t-butyl)amine, η-butyl(c-butyl)amine, i-butyl (s-butyl)amine, i-butyl(t-butyl)amine, i-butyl(c-butyl)amine, s-butyl(t-butyl)amine, s- Butyl (c -butyl)amino group and t-butyl (c-butyl)amino group and the like. Preferred examples are dimethylamino group, diethylamino group, di-η-propyl sense amino group, di-i-propylamino group and di-η-butylamino group. C^-6 alkylcarbonylamino group, for example, methylcarbonylamino group, ethylcarbonylamino group, η-propylcarbonylamino group, i-propylcarbonylamino group, η-butylcarbonylamino group, i -butylcarbonylamino, s-butylcarbonylamino, t-butylcarbonylamino, fluorenyl-pentylcarbonylamino, 2-pentylcarbonylamino, 3-pentylcarbonylamino, i-pentyl Alkylcarbonylamino group, neopentylcarbonylamino group, t-pentylcarbonylamino group, 1-hexylcarbonylamino group, 2-hexylcarbonylamino group, 3-hexylcarbonylamino group and the like. Preferable examples thereof include a methylcarbonylamino group, an ethylcarbonylamino group, an η-propyl φ carbonylamino group, an i-propylcarbonylamino group, and an η-butylcarbonylamino group. • C^-6 alkylsulfonylamino group, for example, methylsulfonylamino, ethylsulfonylamino, η-propylsulfonylamino, i-propylsulfonyl Amine, η-butylsulfonylamino, i-butylsulfonylamino, s-butylsulfonylamino, t-butylsulfonylamino, 1-pentylsulfonyl Amino, 2-pentylsulfonylamino, 3-pentylsulfonylamino, pentylsulfonylamino, neopentylsulfonylamino, t-pentylsulfonylamino, 1-hexylsulfonylamino group, 2-hexylsulfonylamino group, 3-hexylsulfonylamino group and the like. Preferred are, for example, methylsulfonylamino, ethylsulfonylamino, n--27-201022223 propylsulfonylamino, i-propylsulfonylamino and η-butylsulfonate. Mercaptoamine

The Cj-6 alkylaminocarbonyl group may, for example, be methylaminocarbonyl, ethylaminocarbonyl, η-propylaminocarbonyl, i-propylaminocarbonyl, η-butylaminocarbonyl, i- Butylaminocarbonyl, s-butylaminocarbonyl, t-butylaminocarbonyl, 1-pentylaminocarbonyl, 2-pentylaminocarbonyl, 3-pentylaminocarbonyl, i-pentyl Aminocarbonyl, neopentylaminocarbonyl, t-pentylaminocarbonyl, 1-hexylaminocarbonyl, 2-hexylaminocarbonyl, 3-hexylaminocarbonyl, and the like. Preferred are, for example, a methylaminocarbonyl group, an ethylaminocarbonyl group, an η-propylaminocarbonyl group, an i-propylaminocarbonyl group, and an η-butylaminocarbonyl group. The di-Ci.6 alkylaminocarbonyl group may, for example, be dimethylaminocarbonyl, diethylaminocarbonyl, di-η-propylaminocarbonyl, di-i-propylaminocarbonyl or di-c. -propylaminocarbonyl, di-η-butylaminocarbonyl, di-i-butylaminocarbonyl, di-s-butylaminocarbonyl, di-t-butylaminocarbonyl, di-c -butylaminocarbonyl, di-1-pentylaminocarbonyl, di-2-pentylaminocarbonyl, bis-3-pentylaminocarbonyl, di-i-pentylaminocarbonyl, di-new Pentylaminocarbonyl, bis-t-pentylaminocarbonyl, di-c-pentylaminocarbonyl, di-1·hexylaminocarbonyl, di-2-hexylaminocarbonyl, and -3--3-hexylamine Alkylcarbonyl and the like. Preferred are, for example, dimethylaminocarbonyl, diethylaminocarbonyl, di-η-propylaminocarbonyl, di-i-propylaminocarbonyl, di-c-propylaminocarbonyl and - η-butylaminocarbonyl. The C!-6 alkylcarbonyl group may, for example, be methylcarbonyl, ethylcarbonyl, η-propylcarbonyl, i-propylcarbonyl, η-butylcarbonyl, i-butylcarbonyl, s-butyl 201022223 carbonyl, T-Butylcarbonyl, 1-pentylcarbonyl, 2-pentylcarbonyl, 3-pentylcarbonyl, i-pentylcarbonyl, neopentylcarbonyl, t-pentylcarbonyl, 1-hexylcarbonyl, 2-hexylcarbonyl And 3-hexylcarbonyl. Preferable examples thereof include a methylcarbonyl group, an ethylcarbonyl group, an η-propylcarbonyl group, an i-propylcarbonyl group, and an η-butylcarbonyl group. The alkoxycarbonyl group may, for example, be a methoxycarbonyl group, an ethoxycarbonyl group, a η-propoxycarbonyl group, an i-propoxycarbonyl group, an η-butoxycarbonyl group or an i-butoxycarbonyl group. , s-butoxycarbonyl, t-butoxycarbonyl, 1-pentyloxycarbonyl, 2-pentyloxycarbonyl, 3-pentyloxycarbonyl, i-pentyloxycarbonyl, neopentyloxycarbonyl, t a pentyloxycarbonyl group, a 1-hexyloxycarbonyl group, a 2-hexyloxycarbonyl group, a 3-hexyloxycarbonyl group or the like. Preferred are, for example, methoxycarbonyl, ethoxycarbonyl, η-propoxycarbonyl, i-propoxycarbonyl, η-butoxycarbonyl, i-butoxycarbonyl, s-butoxycarbonyl and T-butoxycarbonyl.

The Cj-6 alkylsulfonyl group may, for example, be a methanesulfonyl group or an ethanesulfonyl group • a C6-M arylcarbonyl group, and examples thereof include a benzamidine group, a p-methylbenzhydrazide group, and a pt. -butylbenzylidene, P-methoxybenzhydryl,? _Chlorobenzylidene, P-nitrobenzhydryl, P-cyanobenzylidene, hydrazine-biphenylcarbonyl, m-biphenylcarbonyl, P.biphenylcarbonyl, α-naphthyl Carbonyl, sulfonyl-naphthylcarbonyl, 1-fluorenylcarbonyl, 2-mercaptocarbonyl, 9-fluorenylcarbonyl, 1-phenanthrylcarbonyl, 2-phenanthrylcarbonyl, 3-phenanthrylcarbonyl, 4-phenanthrylcarbonyl and 9-phenanthrylcarbonyl. Preferred examples are a benzamidine group, a p-nitrobenzylidene group and a p-cyanobenzoyl group. -29- 201022223

The Ci-6 alkoxycarbonylamino group may, for example, be a methoxycarbonylamino group, an ethoxycarbonylamino group, a η-propoxycarbonylamino group, an i-propoxycarbonylamino group or an η-butoxy group. Carbonylamino, i-butoxycarbonylamino, s-butoxycarbonylamino, t-butoxycarbonylamino, 1-pentyloxycarbonylamino, 2-pentyloxycarbonylamino, 3 -pentyloxycarbonylamino, i-pentyloxycarbonylamino, neopentyloxycarbonylamino, t-pentyloxycarbonylamino, 1-hexyloxycarbonylamino, 2-hexyloxycarbonylamine And 3-hexyloxycarbonylamino group and the like. C6-14 arylcarbonylamino group, for example, benzhydrylamino group, p-methylbenzhydrylamino group, pt-butylbenzylideneamino group, p-methoxybenzamide Amino, P-chlorobenzhydrylamino, P-nitrobenzimidyl, P-cyanobenzamide, 0-biphenylcarbonylamino, biphenylcarbonylamine , p-biphenylcarbonylamino, α-naphthylcarbonylamino, A.naphthylcarbonylamino, 1-fluorenylcarbonylamino, 2-mercaptocarbonylamino, 9-fluorenylcarbonylamino , 1-phenanthrylcarbonylamino, 2-phenanthrylcarbonylamino, 3-phenanthrylcarbonylamino, 4-phenanthrylcarbonylamino and 9-phenanthrylcarbonylamino. The C3.8 cycloalkyl group may, for example, be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or a cyclooctyl group. Preferred are, for example, a cyclopropyl group, a cyclobutyl group and a cyclohexyl group. The C3.8 cycloalkenyl group may, for example, be 1-c-pentenyl, 2-c-pentenyl, 3-c-pentenyl, 1-methyl-2-c-pentenyl, 1-methyl Base-3-c-pentenyl, 2-methyl-1-c-pentenyl, 2-methyl-2-c-pentenyl, 2-methyl-3-C-pentenyl, 2 -Methyl-4-c-pentenyl, 2-methyl-5-c-pentenyl, 2-methylene-c-pentyl, 3-methyl-1-c-pentyl, 3 -methyl- 2-c-pentyl, 3-methyl-3-c-pentenyl, 3-methyl-4-c-pentenyl, 3-methyl-5-c-pentenyl ' 3- •30- 201022223 methylene-C-pentyl, 1-C-hexenyl, 2-C-hexenyl, 3-c-hexenyl, 1-c-heptenyl, 2- C-heptenyl, 3-c-heptenyl, 4-c-heptenyl, 1-c-octenyl, 2-c-octenyl and 3-c-octenyl, 4-c-octyl Alkenyl and the like. Preferred are, for example, 1-c-pentenyl, 2-c-pentenyl, 3-c-pentenyl, 1-c-hexenyl, 2-c-hexenyl and 3-c-hexyl Alkenyl. Preferred specific examples of the substituent of the compound used in the present invention are explained. Preferred examples of R1 and R2, such as a Cu alkyl group (which may be substituted by a _ φ 素 atom, a hydroxyl group or an alkoxy group (the alkoxy group may be optionally substituted by a halogen atom) or a bonded carbon) The atoms together are =0 or [Chemical 6] » ΛΛΛ (where j is an integer of 1 to 3, letting it be an integer of 0 to 3, 〇 is a single bond, Ο cr8R9 (R8 and R9 are each independently a hydrogen atom or Ci 6 alkyl (the alkyl group may be optionally substituted by a halogen atom, a trans group or a Ci-6 alkoxy group (which may be optionally substituted by a halogen atom)), NR11 (r11 is a nitrogen atom or

The Cl-6 base (the base of the compound may be optionally substituted by a halogen atom, a Ci 6 alkoxy group (which may be optionally substituted by a halogen atom) or a sulfhydryl group), 〇, S, so or so2). More specific examples of R1 and R2, such as a methyl group. A preferred embodiment of R3 is as hydroxy or bonded to r4~. A more preferred embodiment of R is as a base. -31 - 201022223 A preferred embodiment of R4, such as a hydrogen atom or a bond with R3. More specific examples of R4, such as a hydrogen atom. Preferred specific examples of R5 are, for example, a methyl group or a hydrogen atom. More specific examples of R5, such as a hydrogen atom. N-(CH2)mV-(CH2)n- is a combination of m and n and V, preferably V is a single bond, m is 2 or 3, η is 〇, or V is CR12R13 (R12 is C!-6) Alkyl, Q.6 alkoxy (the alkyl and alkoxy may be substituted by a halogen atom) or via a radical 'R13 is a hydrogen atom), m is 1 or 2, η is 0, or V^ is NR14 (R14) It is a Cu alkyl group, a Cy alkoxy group (the alkyl group and the alkoxy group may be substituted by a halogen atom) or a hydrogen atom), m is 1 or 2, and η is 0. ! !! Preferably, the combination of π and V is a single bond, m is 2 or 3, ^ is 0, and more preferably V is a single bond, ^! is 2, and η is 〇. A preferred specific example of R6 is as C6_14 aryl (which is unsubstituted or substituted by a halogen atom), <: 2.9 heteroaryl, Ci 6 alkyl or C3 8 cycloalkyl. More preferably, <:6·Μaryl (the aryl group is unsubstituted or substituted by a halogen atom), and more preferably a phenyl group (the phenyl group is unsubstituted or substituted by a halogen atom) ◎ 〇N_(CH2) Preferred examples of m_V-(CH2)n-R6 include, for example, the following: 0 - 32 - 201022223, 7 N_Me A-1 N_Et A-4 N A-6 10

N

Α·16 A-18 A-19

A-20 I

A-21

N』 A-24

Α·25 N A-27 MeN~A A-29

-33 201022223 化8]

N

Α·31

A-32

Cl

N

NHMe

N

A-34

HCOHN N

A-35

N A-33 Me2Ns

N A-37 co2h

Α·38 A-36

N

A-40

A-42 NHAc

N

A-43 NH2 HN~^) A-46 A-41

CF3

A-50 nhconh2

N

A-49 OH A-52

N

MeO

A_51 N

A_54 OH A-55 A-53 MeN a N person A-56

N

A-57 -34 201022223

A-58 so3h

OMe

N

Α·61 N v ▽ 'OEt Α·59 〇CF3

MeA-60

N

COCH3 A-62 NHCOOEt OMe

N v ▽ 'OMe A-63 N^J0 A-65 HN^ 0,

N Ν A-66 A-67

N A-70

A-68 N

O A-71

Me ❹ A-69

A-72

A-74 A-73

A-75

N

Me

N

A-77 OMe CO Me NHCOPh Br

A-76 OH

A-78

A-80 A-79 -35 201022223

N

A-81

A-84

A-8S

A-90 A·91

A-93 A·94

More preferably, the specific example of N-(CH2)m-V-(CH2)n-R6 is, for example, the following. [1 1]

Preferred examples of the preferred types and substitution positions of R31, R32, R and R34 include, for example, substitution examples of the preferred benzopyran compounds in which R31, R32, R33 and R34 are substituted. One of the substitution patterns of the preferred benzopyran compound, such as the 7-position, is a substituent in which a nitro group 6 is bonded via a carbon atom. As a substituent for the permeation of a carbon atom, such as a C 6 .14 aryl group (the aryl group is unsubstituted, or is a nitro group, a C. 6 alkoxy group or a C 6 alkoxycarbonyl group). Substituted), Ci·6 yard base (the base of the institute is unsubstituted, or φ generation by side oxy (οχο groUp)), cyano, C, .6 alkoxycarbonyl or carboxyl. As another example of the substitution form of the preferred benzopyran compound, for example, a substituent bonded to a carbon atom at the 7-position and a substituent having a nitrogen or oxygen bond at the 6-position or a halogen atom may be mentioned. The substituent such as a cyano group, an alkyl group (the alkyl group is unsubstituted or substituted by a halogen atom), a cyano group or a trifluoromethyl group, is preferred. Further, the nitrogen- or oxygen-bonded substituent such as a nitro group, an amine group or a (^-6 alkoxy group). As another example of a substituted form of a preferred benzopyran compound, for example, a 6-position C can be mentioned. _6 alkoxy group, the halogen atom at the 7-position. -37- 201022223 Other examples of the substituted form of the preferred benzopyran compound include, for example, a 6-position halogen atom and a 7-position amine group. Other examples of the substituted form of the benzopyran compound include, for example, a 6-position amine group or a nitro group, and a 7-position hydroxyl group. Other examples of the substituted form of the preferred benzopyran compound include, for example, Examples of the substituent at the 5-position and the 8-position, such as a halogen atom, the substituent at the 8-position, such as a nitro group or a Cl-6 alkoxy group, is a substituted form of a preferred benzopyran compound. Other examples include, for example, those having a substituent at the 5-position and the 6-position. Examples of the 5-position substituent, such as a Ci-6 alkyl group (the alkyl group is unsubstituted or substituted by a halogen atom), the 6-position substitution a group such as a nitro group, an amine group or a halogen atom. As another example of a substituted form of a preferred benzopyran compound, For example, those having a substituent at the 6-position and the 8-position, such as a halogen atom, a (3,-6 alkoxy group or an alkyl group (the alkyl group is unsubstituted or substituted by a halogen atom), The 8-position substituent, such as a C1-6 alkyl group, a nitro group or a Cbe-based aryl group. 其他 As another example of a substituted form of a preferred benzopyran compound, for example, I have a nitro '8 at the 7 position. Examples of the substituted form of the preferred benzopyran compound include, for example, a 5-position, a hydrazine, and a 7-position substituent. Examples of the substituent, such as C! - a group of substituents of the 6-position substituent, such as a halogen atom, the substituent at the 7-position, such as a Ci.6 alkyl group, as a substituted form of a preferred benzo-halop compound Other examples can be cited -38- 201022223

For example, the 6-position is a halogen atom and the 7-position is a nitro group. Specific examples of preferred types and substitution positions of R31, R32, R33 and R34 include those in which R31, R32, R33, R34 and their bonded benzene rings are integrated as shown below. -39- 201022223 12

Β·74 -40- 201022223 A more specific example of R31, R32, R" and r34 and a specific example of the substitution position', such as r31, r32, r33, R34 and the benzene ring bonded to them The structure of the description. [Chem. 1 3]

Preferred embodiments of the compound usable in the present invention are exemplified below, but the present invention is not limited thereto. 1) R1 and R2 are methyl 'R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and R31, R32, R33, R34 and the structure represented by B-1 φ represented by the benzene ring bonded thereto And N-(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I), which is any one of Α-^Αίογ, or a pharmaceutically acceptable salt thereof. 2) 111 and R2 are a structure in which a methyl group 'R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and R2, R33, R34 and the benzene ring to which they are bonded are represented by B-2, N- (CH2) mV-(CH2)n-R6 is a benzopyran compound of the formula (I) in the range of α·1 to A107 or a pharmacologically acceptable 〇3) R1 and R2 are a methyl group, R3 The structure represented by Β·3 in which the hydroxy group 'H4 and R5 are a hydrogen atom, -41 - 201022223, R32, R33, R34 and their bonded benzene rings are integrated, N-(CH2)mV-( CH2)n-R6 is a benzopyran compound of the formula (I), which is any one of Α-1 to Α107, or a pharmaceutically acceptable salt thereof. 4) R1 and R2 are a methyl group, R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and R31, R32, R33, R34 and the benzene ring to which they are bonded are represented by a structure represented by Β-4, N -(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I), which is any one of Α-1 to Α107, or a pharmaceutically acceptable salt thereof. 5) R) and R2 are a methyl group, R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and R31, R32, R33, R34 and the benzene ring to which they are bonded are represented by a structure represented by B-5. N-(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I), which is any one of A-1 to A107, or a pharmaceutically acceptable salt thereof. 6) R1 and R2 are a methyl group, R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and R31, R32, R33, R34 and the benzene ring to which they are bonded are represented by B-6 Q. N-(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I), which is any one of A-1-A107, or a pharmaceutically acceptable salt thereof. 7) R1 and R2 are a methyl group, and R3 is a hydroxyl group. R4 and R5 are a hydrogen atom 'R31, R32, R33, R34 and a structure represented by B-7 in which the bonded benzene rings are integrated, N -(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I) which is any one of A-1 to A107 or a medically acceptable one thereof - 42 - 201022223 R and R 2 are a methyl group , R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, R32, Ρ33 η % δ R and the benzene ring to which they are bonded are represented by the weight of the ho, which is < 称, N-(CH2) mV-(CH2)n-R6 is a formula of (1) S to a benzopyran compound or a pharmaceutical substance thereof 9) R and 112 are methyl '3' is a hydroxyl group, a ruler 4 And 115 is a hydrogen atom, R32, R33 τ% λ, R4 and the benzene ring bonded to them are integrated into the structure represented by 'N_(CH2)m V (CH2)n R6 is Ashiai The benzopyran compound of the formula (I) of 〇7 or a pharmaceutically acceptable one thereof) R and R2 are a methyl group, and R3 is a hydroxyl group 'R4 and R5 are a hydrogen atom R, R33, R34 and the same The structure of the table π shown by the benzene ring is N'(CH2)m_v_(CH2)n_R6 is the formula (I) of A1~A1〇7 A benzopyran compound or a pharmaceutically acceptable salt thereof. 1 1 ) Rl and R2 are a structure in which the methyl group 'R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, 〇32^3 3^ - 'R, R4 and the benzene ring to which they are bonded are integrated. N_(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I) wherein A-1 to A107 are a compound or a pharmaceutically acceptable salt thereof. 12) R1 and R2 are a structure in which a methyl group 'R3 is a hydroxyl group' and R5 is a hydrogen atom, R32, R33, R34 and the benzene ring to which they are bonded are integrated, and are a-ι to A107. - a benzopyran compound of the formula (I) or a pharmaceutical substance thereof, R31 B-8, R31 B-9, R31 B-10, R31 B- 1 1, R31 B-12, -43- 201022223 13) R1 and R2 are methyl, R3 is hydroxyl 'H4 and R5 are hydrogen atoms, R32, R33, R34 and their linkages a benzopyrene compound of the formula (I) wherein the structure represented by the benzene ring is represented by the formula "N-(CH2)mV-(CH2)n-R6 is a-ι to A107, or a pharmaceutical thereof Contained salt. 14) R1 and R2 are a structure in which a methyl group 'R3 is a hydroxyl group', R4 and R5 are a hydrogen atom, R32, R33, and R34 are bonded to each other, and the structure is a-ι to A107. a benzopyran compound of the formula (I) or a pharmaceutically acceptable salt thereof. 1 5) R1 and R2 are a structure in which a methyl group 'R3 is a hydroxyl group', R4 and R5 are a hydrogen atom, R32, R33, R34, and a benzene ring to which they are bonded are integrated, N- (CH2) mV-(CH2)n-R6 is a benzopyran compound of the formula (I) of A-1 to A107, or a pharmaceutically acceptable salt thereof. 16) R1 and R2 are a structure in which methyl 'R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, R32, R33, R34 and the benzene ring to which they are bonded are integrated, N-(CH2)mV -(CH2)n-R6 is a benzopyran compound of the formula (I) of A-1 to A107, or a pharmaceutically acceptable salt thereof. 17) R1 and R2 are a structure in which a methyl group 'R3 is a hydroxyl group', R4 and R5 are a hydrogen atom, and R32, R33, and R34 are bonded to each other, and N-(CH2)mV is represented by one. -(CH2)n-R6 is A-1-A107, R31 B-1 3 is allowed, R31 B-14 is allowed, R31 B-1 5 is allowed, R31 B-1 6 is allowed The benzopyran compound of the formula (I) or the pharmaceutically acceptable oxime thereof in the formula (I) of R22 B-1 7 is the highest in the formula (I). R1 and R2 are methyl 'R3 is a hydroxyl group' and R4 and R5 are hydrogen atoms. The structure represented by R32, R33, R34 and the benzene ring bonded thereto is a benzopyran compound of the formula (I) of A-1 to A107, or a pharmaceutical content thereof. salt. Φ 19) 111 and R 2 are a structure represented by a methyl group 'R3 is a hydroxyl group 'R4 and R5 are a hydrogen atom, R32, R33, R34 and the benzene ring to which they are bonded are integrated, N_(CH2)mV -(CH2)n-R6 is a benzopyran compound of the formula (I) wherein Al is a sulfonyl group or a pharmaceutically acceptable salt thereof. 20) R1 and R2 are a structure in which a methyl group 'R3 is a hydroxyl group', R4 and R5 are a hydrogen atom, and R32, R33, and R34 are bonded to each other, and N-(CH2)mV is represented by one. -(CH2)n-R6 is a benzopyran compound of the formula (I) of A-1 to A107 φ, or a pharmaceutically acceptable salt thereof; 21) R1 and R2 are methyl 'R3 is a hydroxyl group' R4 and R5 is a structure represented by a hydrogen atom, R32, R33, R34 and a benzene ring to which they are bonded, and N-(CH2)mV-(CH2)n-R6 is A-ι to A107. A benzopyran compound of the formula (I) or a pharmaceutically acceptable salt thereof. 22) W and R2 are methyl 'r3 is a hydroxyl group' R4 and R5 are hydrogen atoms, R32, R33, R34 and their bonded benzene rings are integrated, and R31 B-1 8 is allowed Any of the R31 B-1 9, R31 B-20, R31 B-21, R31 B-22 -45- 201022223, N-(CH2)mV -(CH2)n-R6 is a benzopyran compound of the formula (I), which is any one of Al to A107, or a pharmaceutically acceptable salt thereof. 23) R1 and R2 are methyl 'R3 is hydroxy'... and r5 is a hydrogen atom, and R31, R32, R33, R34 and their bonded benzene rings are integrated into the structure of B_23. (CH2) mV-(CH2)n-R6 is a benzoxanthene compound of the formula (I), which is any one of A-1 to A107, or a pharmaceutically acceptable salt thereof. 24) Ri and W are methyl groups, R3 is a hydroxyl group, r4 and r5 are hydrogen atoms, and R31, R32, R33, R34 and their bonded benzene rings are integrated into a structure represented by B_24 'N-( CH2) mV-(CH2)n-R6 is a benzopyran compound of the formula (I), which is any one of A_1 to A107, or a pharmaceutically acceptable salt thereof. 25) R1 and R2 are methyl groups, R3 is a hydroxyl group, feet 4 and r5 are nitrogen atoms, and R31, R32, R33, R34 and their bonded benzene rings are integrated into a structure represented by B_25, N -(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I) of any one of a_i~A107 or a pharmaceutically acceptable salt thereof. 26) R1 and R2 are a methyl group, R3 is a hydroxyl group, R4 and r5 are a hydrogen atom, and r3i, a size of 32, 1133, a ruler 34, and a benzene ring to which they are bonded are represented by a structure represented by 3_26, N -(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I) in the form of a-1 to A107, or a pharmaceutically acceptable salt thereof. 27) R1 and R2 are a methyl group, R3 is a hydroxyl group, and R4 and r5 are a structure represented by a hydrogen atom 'r31 _ 46 · 201022223 , R32, R33, R34 and the benzene ring to which they are bonded, N-(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I) wherein N·1 to A107 is a pharmaceutically acceptable salt thereof. 28) 11] and R2 is a methyl group, R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, R32, R33, R34 and the benzene ring to which they are bonded are represented by a structure represented by 'N_(CH2)m_V -(CH2)n-R6 is a benzoquinone compound of the formula (I) wherein Α-1~Α107 Φ — or a pharmaceutically acceptable salt thereof. 29) r and R2 are methyl 'r3 is a hydroxyl group' R4 and R5 are a hydrogen atom, and R32, R33, R34 and the benzene ring to which they are bonded are represented by a structure, N-(CH2) mV-(CH2)n-R6 is a formula of A·1 to A107 (the benzoxan compound described in 〇 or its pharmaceutically acceptable salt. 3〇) r1 and R2 are methyl 'R3 is a trans-base 'R4 And R5 is a structure represented by hydrogen atoms φ, R32, R33, R34 and their bonded benzene rings. 'N-(CH2)m-V_(CH2)n-R6 is A-1~ a benzofuran compound of the formula A1 or a pharmaceutically acceptable salt thereof. 31) R1 and R2 are a methyl group, r3 is a hydroxyl group, R4 and R5 are a hydrogen atom, R32, R33, R34 and the like a benzoxan compound of the formula (I) wherein N-(CH2)m-V_(CH2)n-R6 is A·1 to A107, or a structure represented by a bonded benzene ring Salt on medicine. Permitted by B-27, R31 B-28, R31 B-29, R31 B-30, R31 B-3 1 -47- 201022223 32) R1 and R2 are a structure in which methyl 'r3 is a hydroxyl group, and r4 and R5 are a hydrogen atom 'R3i, R32, R33, R34 and the benzene ring bonded to them, represented by B·32, N- (CH2) mV-(CH2)n-R6 is a benzopyran compound of the formula (I), which is any one of A-1 to A107, or a pharmaceutically acceptable salt thereof. 33) R1 and R2 are methyl 'R3 is a hydroxyl group' R4 and R5 are a hydrogen atom 'R31, R32, R33, R34 and the structure represented by the B-33-bonded by the bonded benzene ring' N_(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I) which is a substituent of A-1 to A107, or a pharmaceutically acceptable salt thereof. 34) R1 and R2 are methyl 'R3 is a hydroxyl group' R4 and R5 are a hydrogen atom 'R31, R32, r33, R34 and their bonded benzene ring are shown in a structure represented by B-34' -(CH2)mV-(CH2)n-R6 is a formula (I) of any one of A-1-A107, and a D-pyryl compound or a pharmaceutically acceptable salt thereof. 35) Ri and R2 are a methyl group, R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and R31 ❹, 1132, 1133, 1134, and the structures represented by 8-35 of the benzene ring bonded thereto are bonded. 'N-(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I) which is any one of A-1 to A107, or a pharmaceutically acceptable salt thereof. 36) R1 and R2 are a methyl group, R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and R31, R32, R33, r34 and the benzene ring to which they are bonded are represented by a structure represented by B-36. '(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I) which is any one of A-1 to A107 or a medically acceptable one thereof - 48 - 201022223 37) R1 and R2 are The structure 'N-(CH2)m-V_(CH2)n represented by the methyl 'r3 is a hydroxyl group, R4 and R5 are a hydrogen atom, R32, R33, R34 and their bonded benzene rings are integrated. -R6 is A-1-A107, a benzopyran compound of the formula (I) or a pharmaceutically acceptable oxime thereof 38) R1 and R2 are a methyl group 'R3 is a hydroxyl group' R4 and R5 are a hydrogen atom Φ, R32 And R33, R34 and the structure represented by the benzene ring bonded thereto are integrated, and N-(CH2)mV-(CH2)n-R6 is a formula (I) of A-1-A107. A benzopyran compound or a pharmaceutically acceptable salt thereof. 39) R1 and R2 are methyl 'R3 is a hydroxyl group' R4 and R5 are a hydrogen atom, R32, R33, R34 and the benzene ring to which they are bonded are represented by the structure 'N-(CH2)mV -(CH2)n-R6 is a benzopyran compound of the formula (I) of A-1 to A107, or a pharmaceutically acceptable salt thereof. 40) R1 and R2 are a methyl group, and R3 is a hydroxyl group 'H4 and R5 are The structure in which the hydrogen atom, R32, R33, R34 and the benzene ring to which they are bonded are represented by the structure 'N-(CH2)mV-(CH2)n-R6 is A-1-A107- I) A benzopyran compound or a pharmaceutically acceptable salt thereof. 41) R1 and R2 are a methyl group, and R3 is a hydroxy group. R4 and R5 are a hydrogen atom, and R32, R33, and R34 are bonded to each other and the benzene ring bonded thereto is represented by a structure of 'N-(CH2)mV. -(CH2)n-R6 is A-1~A107, R31 B-3 7 is allowed, R31 B-38 is allowed, R31 B-39 is allowed, R31 B-40 is allowed , R31 B-4 1 -49-201022223 A benzopyridinium compound of the formula (I) or a pharmaceutically acceptable salt thereof. 42) R1 and R2 are methyl 'R3 is a hydroxyl group' R4 and r5 are a hydrogen atom, and r31, R", R33, R34 and the benzene ring to which they are bonded are represented by a structure represented by B-42. N-(CH2)m_V-(CH2)n-R6 is a benzopyran compound of the formula (I), which is any one of A-1 to A107, or a pharmaceutically acceptable salt thereof.

43) R1 and R2 are a structure in which a methyl group 'R3 is a hydroxyl group' and R4 is a hydrogen atom 'R31, 1132, 1133, a ruler 34, and 8-43 of the benzene ring to which the bond is bonded, N_(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I), which is any one of A-1 to A107, or a pharmaceutically acceptable salt thereof. 44) R1 and R2 are methyl 'R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and R31, R32, R33, R34 and the benzene ring to which they are bonded are represented by a structure represented by B_44 'N-( CH2)mV-(CH2)n-R6 is the responsibility of A-1~A107

a benzopyran compound of the formula (I) or a pharmaceutically acceptable salt thereof. 45) R1 and R2 are a methyl group, R3 is a hydroxyl group, R4 and r5 are a hydrogen atom, and R31, R32, R33, R34 and the benzene ring to which they are bonded are represented by a structure represented by B_45, N-( CH2) mV-(CH2)n-R6 is a benzopyran compound of the formula (I), which is any one of A-1 to A107, or a pharmaceutically acceptable salt thereof. 46) R1 and R2 are a structure in which methyl 'R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and r31, R32, r33, r34 and the benzene ring to which they are bonded are integrated as shown in b_46-50-201022223 'N-(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I) which is any one of A_i~ai〇7, or a pharmaceutically acceptable salt thereof. 47) R1 and R2 are a methyl group, and R3 is a hydroxyl group. R4 and R5 are a hydrogen atom, and R31, R32, R33, and R34 are bonded to the benzene ring to which they are bonded, and the structure represented by B-47 is shown. -(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I) of any one of A-1 to A107 or a pharmaceutically acceptable salt thereof. 48) R1 and R2 are methyl 'R3 is a hydroxyl group' R4 and R5 are a hydrogen atom, and R31, R32, R33, R34 and their bonded benzene rings are integrated into a structure represented by B-48. -(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I) which is any one of A-1 to A107, or a pharmaceutically acceptable salt thereof. 49) R1 and R2 are a structure in which a methyl group 'R3 is a hydroxyl group', R4 and R5 are a hydrogen atom, and R31, R32', R33, and R34 are bonded to the benzene ring to which they are bonded, and B-49 φ is integrated. N-(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I), which is any one of a-1 to A107, or a pharmaceutically acceptable salt thereof. 50) R1 and R2 are a methyl group, and R3 is a structure in which a hydroxyl group 'R4 and R5 are a hydrogen atom, and R31, R32, R33, and R34 are bonded to the benzene ring to which they are bonded, as shown by B-5 0 . N-(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I), which is any one of a- to A107, or a pharmaceutically acceptable salt thereof. 51) R1 and R2 are methyl, R3 is hydroxy' R4 and R5 are hydrogen atoms, R31-51 - 201022223, R32, R33' R34 and their bonded benzene rings are shown as B-5 1 In the structure shown, N^CHOmUCHO^R6 is a benzopyran compound of the formula (I) of any one of A-1 to A107 or a pharmaceutically acceptable salt thereof. 52) R1 and R2 are a methyl group, R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and R31, R32, R33, R34 and the benzene ring to which they are bonded are represented by a structure represented by B-52. -(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I) which is any one of A-1 to A107, or a pharmaceutically acceptable salt thereof. 53) R1 and R2 are a methyl group, R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and R31, R32, R33, R34 and the benzene ring to which they are bonded are represented by a structure represented by B-53. -(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I) which is any one of A-1 to A107, or a pharmaceutically acceptable salt thereof. 54) R1 and R2 are a methyl group, R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and R31, R32, R33, R34 and the benzene ring to which they are bonded are represented by a structure represented by B-54 Q. N-(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I), which is any one of A-1 to A107, or a pharmaceutically acceptable salt thereof. 55) R1 and R2 are a methyl group, R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and R31, R32, R33, R34 and the benzene ring to which they are bonded are represented by a structure represented by B-5 5 ' N-(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I), which is any one of A-1 to A107, or a medically acceptable one thereof - 52 - 201022223 56) R1 and R2 The structure 'N_(CH2)mV-(CH2)n- represented by the methyl 'R3 is a hydroxyl group' and R5 is a hydrogen atom, R32, R33, R34 and the benzene ring to which they are bonded are integrated. R_6 is a benzopyran compound of the formula (I) of A-1 to A107, or a pharmaceutically acceptable oxime thereof 57) R1 and R2 are a methyl group, R3 is a hydroxyl group, and R4 and R5 are a hydrogen atom, R32, R33 R, R34 and the benzene ring bonded to them are shown in ❹. The structure represented by the formula 'N-(CH2)mV-(CH2)n-R6 is a-1~A107. And smear the compound or its salt on the medicine. 58) R1 and R2 are a methyl group, and R3 is a structure represented by a hydroxyl group, wherein R4 and R5 are a hydrogen atom, and R32, R33, and R34 are bonded to each other, and N-(CH2)mV -(CH2)n-R6 is a benzopyran compound of the formula (I) wherein a (a) to a 〇 〇 — 。 。 。 。 。 。 。. -ΠΤΙ Φ 59) R1 and R2 are methyl 'R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and R32' R33, R3 and the benzene ring to which they are bonded are represented by a structure 'N-( CH2) mV-(CH2)n-R6 is a benzopyran compound of the formula (I) of A-1 to A107, or a pharmaceutically acceptable salt thereof. 60) R1 and R·2 are structures represented by methyl 'R3 is a hydroxyl group' R/ and R5 is a hydrogen atom, R32, R33, R34 and the benzene ring to which they are bonded are integrated, N-( CH2) mV-(CH2)n-R6 is a benzopyran compound of the formula (I) or a pharmaceutical substance thereof, R31 B-56 is allowed, R31 B-57 is allowed, R31 Any of the promises of B-58, R31 B-59, R31 B-60-53-201022223 61) R1 and R2 are methyl 'R3 is a hydroxyl group, R4 and R5 are hydrogen atoms, r31 , R32, R33, R34 and the structure represented by B-61 shown by their bonded benzene ring, 1^-((^2)111-乂-((^2)11-1^ a benzopyran compound of the formula (I), or a pharmaceutically acceptable salt thereof, of any one of VIII to 875. 62) R] and R2 are a methyl group 'R3 is a hydroxyl group' R4 and R5 are a hydrogen atom , R31, R32, R33' R34 and the structure represented by B-62 _ shown by their bonded benzene rings, N-(CH2)mV-(CH2)n-R6 is A-1~A107 Any of the benzoxanthracene compounds of the formula (I) or a pharmaceutically acceptable salt thereof. 63) R1 and R2 are methyl 'R3 is a hydroxyl group' R4 and R5 are a hydrogen atom R31, R32, R33' R34 and the structure represented by B-63 in which the bonded benzene rings are integrated, and NdCHJm-VqCHJn-R6 is a formula (I) of any of A-1 to A107. A benzopyrene compound or a salt thereof as permitted by the drug. 〇64) R1 and R2 are a methyl group, R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and R31, 1132, 1133, 1^34, and the benzene ring to which they are bonded are represented by a structure represented by ^64. 'N-(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I) which is any one of A-1 to A107, or a pharmaceutically acceptable salt thereof. 65) R1 and R2 are a structure in which a methyl group 'r3 is a hydroxyl group', r4 and r5 are a hydrogen atom, and r31, R32, r33, and R34 are bonded to each other, and the benzene ring to which they are bonded is represented by B·65. -(CH2)mV-(CH2)n_R is a benzopyran compound of the formula (I) or a pharmaceutically acceptable salt thereof, in the range of -54 to 201022223. 66) R1 and R2 are methyl 'R3 is a hydroxyl group, R4 and r5 are a hydrogen atom, and R32, R33, R34 and the benzene ring to which they are bonded are represented by a structure represented by 'N-(CH2)mV -(CH2)n-R6 is a benzopyran compound of the formula (I) of A-1 to A107, or a pharmaceutically acceptable salt thereof. ❹ 67) R1 and R2 are structures in which the methyl group 'R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, R32, R33, R34 and the benzene ring to which they are bonded are integrated, N-(CH2) The benzopyran compound of the formula (I) wherein mV-(CH2)n-R6 is A-1 to A107, or a pharmaceutically acceptable salt thereof. 68) R1 and R2 are a methyl group, R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and R32, R33, R34 and the benzene ring to which they are bonded are represented by a structure, N-(CH2)mV -(CH2)n-R6 is a benzopyran compound of the formula (I) wherein A-1 to A107 are Ο- or a pharmaceutically acceptable salt thereof. • 69) R1 and R2 are methyl, R3 is a hydroxyl group, R4 and R5 are hydrogen atoms, and R32, R33, R34 and the benzene ring to which they are bonded are represented by a structure, N-(CH2) The benzopyran compound of the formula (I) wherein mV-(CH2)n-R6 is A-1 to A107, or a pharmaceutically acceptable salt thereof. 7〇) R1 and R2 are methyl groups, R3 is a hydroxyl group, R4 and R5 are hydrogen atoms, R32, R33, R34 and their bonded benzene rings are integrated, and R31 B-66 is allowed. Any of the R31 B-67's, R31 B-68, R31 B-69, R31 B-70-55-201022223, the structure 'N-(CH2)mV-( CH2)n-R6 is a benzopyran compound of the formula (I) which is any one of A-丨~A107 or a medically acceptable one. 71) R1 and R2 are a methyl group, and R3 is a hydroxy group. R4 and R5 are a hydrogen atom, and R31, 1132, 1133, 1^4, and the benzene ring to which they are bonded are represented by 8-71. 'N_(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I) of any one of A-ι to A107, or a pharmaceutically acceptable salt thereof. 10 72 ) R1 and R2 are methyl 'R3 is a hydroxyl group' R4 and R5 are a hydrogen atom, and R31, R32, R33, R34 and the benzene ring to which they are bonded are represented by a structure represented by B-72. N_(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I), which is any one of A-1 to A107, or a pharmaceutically acceptable salt thereof. 73) R1 and R2 are methyl 'R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and R31 is a structure represented by 8-73 which is represented by a benzene ring bonded to them, and the benzene ring bonded thereto. N-(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I) of any one of A-1 to A107, or a pharmaceutically acceptable salt thereof. 74) R1 and R2 are methyl 'R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and R31, R32, R33, R34 and the benzene ring to which they are bonded are represented by a structure represented by B-74. -(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I) of any one of A-1 to A107, or a pharmaceutically acceptable salt thereof. 75) R1 and R2 are a methyl group, and R3 is a structure in which a hydroxyl group 'R4 and R5 are a hydrogen atom, and R31-56-201022223, R32, R33, R34 and the benzene ring to which they are bonded are represented by B_75. 'A benzopyrene compound of the formula (1) which is any one of A-1 to A107 or a pharmaceutically acceptable salt thereof. 76) R1 and R2 are a structure in which a methyl group 'R3 is a hydroxyl group', R4 and R5 are a hydrogen atom, and R31, r32, R33, and R34 are bonded to the benzene ring to which they are bonded, as shown by B-76. -(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I) wherein φ is any one of A-1 to A107, or a pharmaceutically acceptable salt thereof. 77) R1 and R2 are a methyl group, R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and R31, R32, R33, R34 and the benzene ring to which they are bonded are represented by a structure represented by B-77. -(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I) which is any one of A-1 to A107, or a pharmaceutically acceptable salt thereof. 78) R1 and R2 are a methyl group, R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and R3i, R32, R33, R34 and the benzene ring to which they are bonded are shown as B_78. The structure represented by 'N -(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (1), or a pharmaceutically acceptable salt thereof, in the range of A-1 to A1. JS3. 79) R1 and R2 are methyl groups, R3 is a hydroxyl group, R4 and R5 are hydrogen atoms, and R3!, R32, R33, R34 and their bonded benzene rings are integrated to form a structure represented by B_79' KCHOfV-iCHOn-R6 is a benzopyran compound of the formula (I), which is any one of A-1 to A107, or a pharmaceutically acceptable salt thereof. -57- 201022223 80) R1 and R2 are methyl groups, R3 is a hydroxyl group, R4 and R5 are hydrogen atoms, and R3, R32, R33, R34 and their bonded benzene rings are integrated into B-8 0 In the structure shown, N-(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I), which is any one of A-1 to A107, or a pharmaceutically acceptable salt thereof. 81) R1 and R2 are a methyl group, and R3 is a hydroxyl group. R4 and R5 are a hydrogen atom, and R31, r32, R33, and R34 are bonded to the benzene ring to which they are bonded, and the structure represented by B-81 is 'N. -(CH2)mV-(CH2)n-R6 is a benzopyran compound of the formula (I) in which A-1-A107 is _ or a pharmacologically acceptable 82) R1 is a hydroxymethyl group 1) ～82) The benzopyran compound described or a pharmaceutically acceptable salt thereof. 83) R1 and R2 are a benzopyran compound described in 1) to 82), or a pharmaceutically acceptable salt thereof. 84) A benzopyran compound described in (a) to 82) of the carbon atom bonded to R1 and R2, or a pharmaceutically acceptable salt thereof. 85) together with the carbon atom bonded to R1 and R2, is a benzopyran compound of the formula -58-201022223, or a pharmacologically acceptable 〇86) and a carbon atom bonded to R1 and R2 Together, for [1 6]

The benzopyran compound described in 1) to 82) or a pharmaceutically acceptable salt thereof. 87) together with the carbon atoms bonded to R1 and R2,

[化1 7]

^NMe 1) to 82) the benzopyran compound or its pharmaceutically acceptable 〇88) together with the carbon atom bonded to R1 and R2 is =0 of 1) to 82) benzopyran a compound or a pharmaceutically acceptable salt thereof. 89) R3 and R4 are bonded to the benzopyran compound described in 1) to 89), or a pharmaceutically acceptable salt thereof. 90) R5 is a benzopyran compound described in 1) to 90) of a methyl group or a salt thereof as permitted in the stomach. 91) A benzopyran compound according to any one of 1) to 90), or a pharmaceutically acceptable salt thereof, as an active ingredient. 92. The benzopyran compound according to any one of 1) to 90, or a pharmaceutically acceptable salt thereof, as an active ingredient, is a special arrhythmia therapeutic agent. ❹ The compound of the present invention has an asymmetric carbon at the 3 and 4 positions, and an optical isomer exists due to the asymmetric carbon, but an optically active substance similar to the racemic mixture can also be used for the purpose of the present invention. Further, since the stereo configuration of the 3 and 4 positions also includes a cis or trans isomer, it is preferably a trans isomer. Further, in the case of a compound which can form a salt, a pharmaceutically acceptable salt can also be used as an active ingredient. Pharmaceutically acceptable salts, such as hydrochloride, hydrogen bromide, sulfate,

Methanesulfonate 'acetate, benzoate, tartrate, phosphate, G lactate, maleate, fumarate, malate, gluconate and salicylate. Preferred are the hydrochloride, methanesulfonate and maleate salts. Next, the preparation of the compound of the present invention will be explained. In the compound represented by the formula (I), R4 is a hydrogen atom, and R3 is a hydroxyl group. The compound represented by (Ia) is represented by the following reaction formula, and the compound represented by the general formula (2) can be used in an inert solvent. Obtained in the reaction. -60- 201022223 【化1 8】 R31 R34 (1) 'Ν' R2 R1 (2)__ Acid catalyst -R6 r34 (I*a)

The solvent used for the reaction of the compound (1) with the compound (2). For example, an anthraquinone solvent represented by dimethyl sulfoxide, an amide solvent represented by dimethyl or dimethyl acetamide, an ethyl ether, an ethyl ethane or a tetrahydrofuran, and an ether represented by dioxane a solvent, a halogen solvent represented by chloroform or dichloroethane, a acetonitrile solvent, a nitrile solvent of propylene, an aromatic hydrocarbon solvent represented by benzene and toluene, a hydrocarbon solvent represented by heptane, and a solvent of acetic acid The ester represented by the ester is methanol, ethanol, 1-propanol, 2-propanol, alcohol represented by ethylene glycol, and water. Further, the reaction can also be carried out without a solvent. Preferred are solvents, nitrile solvents, and alcohol solvents. The reaction temperature is usually from -80 °C to the usable reaction solvent temperature, preferably -lot to 100 °C. The molar ratio of the reaction raw material is the compound (2) / compound (the range of 0.5 to 4.0, preferably 1.0 to 2.0. The acid catalyst can also be used in the reaction. The acid catalyst used is represented by hydrochloric acid, sulfuric acid) The mineral acid aluminum, titanium tetrachloride, boron trifluoride diethyl ether complex, lithium perchlorate, lithium bromide, trifluoromethanesulfonic acid mirror represented by Lewis acid, the following metformin dimethoxy The chloromethane nitrile, the hexane solvent, and the solvent are acid reflux 1), chlorination, perchloric acid, and the like. -61 - 201022223 It is preferably lithium bromide or lithium perchlorate. In the compound represented by the general formula (I), the synthesis of the optically active substance can be carried out by a method of optically dividing the racemic mixture (Japanese Patent Laid-Open No. Hei 3-141286, No. 509703 No. 7 and European Patent No. 409 1 65). Achieved. Further, the synthesis of the compound represented by the general formula (1) can be achieved by the following synthesis method. The general synthesis of indolopyran ring can be carried out according to conventional methods (JM Evans et al, J. Med. Chem. 1 984, 27, 1127, J. Med. Chem. 1 986, 29, 2194, JT North et al. Org. Chem. 1 995, 60, 3397, or Babu, KS, etc. Heterocyclic Communications, 2003, 9(5), 5 1 9 or

Ashwood VA et al., J. Med. Chem., 1 990, 3 3 (9), 2667, or JP-A-56-57785, JP-A-56-57786, JP-A-58-188880, Japanese Patent Publication No. Hei 2-141, No. Hei 10-87650, Japanese Patent Publication No. Hei. No. 209366, Japanese Patent Laid-Open No. Hei No. 2005-80368, No. 2005-90357, and International Publication No. 2005-0903 No. 57 The synthesis is carried out by the method described in the publication No. 2005-080368. The general synthesis of the coumarin ring can be carried out according to conventional methods (M. Narayana et al, J. Org. Chem., 1 962, 27, 4704, R. G Harvey et al. 'J. Org. Chem., 1 988, 201022223 53,3 93 6. R_ s· Mali et al., Synthesis, 1 977, 464, F. Effenberger et al., Chem. Ber., 1 987, 1 20, 3 73, and J. Sakakibara et al., Chem. Pharm. Bull. , 1 987, 3 5, 1 796, Synthesis, 1986, 1026, etc.). The compound represented by the general formula (1) can be subjected to a conventional method (j. M. Evans et al., J. Med. Chem. 1 984, 27, 1127, J. Med. Chem. 1 986, 29, 2194, JT North). J. Org. Chem. 1 995, 60, φ 3397, or JP-A-56-57785, JP-A-56-57786, JP-A-58-8 - 8 8 8 8 0 The method described in the general formula (2) is produced by the method described in the general formula (2), and the method described in JP-A No. Hei. 【化19

In the compound represented by the formula (I), the compound represented by the formula (Ib) wherein R31 or R32 is a phenyl group (the phenyl group may be optionally substituted by q of R16 (R16 and q are the same as the above)) is as defined in the following reaction formula. In general, it can be produced by reacting a compound represented by the general formula (Ic) with a boron oxy compound represented by the compound (3) under a metal catalyst. Similarly, in the compound represented by the general formula (I), R31 or R32 is a compound represented by (Id) of the cyano group, and the compound represented by the general formula (ΙΟ can be represented by a metal catalyst and a general formula). (4) Represented as -63- 201022223 The cyanating agent is produced by reaction.

Metal catalyst

R (c

(wherein R1, R2, R5, R6, m, η, V, R31, R33 and R34 are the same as defined above, and X1 is a chlorine atom, a bromine atom, a methanesulfonyloxy group, a fluorene-toluenesulfonyloxy group. The leaving group of the trifluoromethanesulfonyloxy group or the like. The solvent used for the reaction of the compound represented by the general formula (I-c) with the compound (3) or the compound (4) may, for example, be as follows. For example, the hydrazine solvent represented by dimethyl sulfoxide, the guanamine solvent represented by dimethylformamide or dimethyl acetamide, ethyl ether, dimethoxyethane or tetrahydrofuran, An ether solvent represented by cyclopentyl methyl ether, a dentate solvent represented by dichloromethane, chloroform or dichloroethane, a nitrile solvent represented by acetonitrile or propionitrile, acetone, methyl ethyl ketone, A ketone solvent represented by methyl isobutyl ketone, an aromatic hydrocarbon solvent represented by benzene or toluene, a hydrocarbon solvent represented by hexanyl or heptane, and an ester solvent represented by ethyl acetate. Further, the reaction can also be carried out in the absence of a solvent. A hydrocarbon solvent, a flavonoid solvent or a guanamine solvent is preferred. The reaction temperature is usually -80 °C to the reflux temperature using a reaction solvent, preferably 50 ° C to 150 ° C. The molar ratio of the reaction raw material, the compound (3) or the compound (4) / the compound (Ic) is in the range of 〇 5 to 20.0, preferably 1. 〇 〇 〇 〇 〇 , ,, such as, a trialkylamine represented by a base amine or ethyl diisopropylamine, pyridine, 2,6-lutidine, 2,6-di-t-butylpyridine, 2,6-di-t- Butyl-4 -methyl oxime ratio steep, proton sponge represented by the amine, potassium _t-butoxide, sodium-t-butoxide, sodium ethoxide, potassium ethoxide, alkanol metal, hydrogen An inorganic base represented by sodium oxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogencarbonate or sodium hydrogencarbonate is preferably an alkoxide metal or an inorganic test. A metal catalyst can also be added to the reaction. As a metal catalyst, such as copper hydride represented by copper iodide, copper chloride or copper oxide, palladium chloride, palladium bromide, palladium iodide, dichlorobis(acetonitrile)palladium, dichlorobis(benzonitrile) Palladium, dichloro φ bis(triphenylphosphine)palladium, dichlorobis(diphenyl-o-ethane)palladium, dichlorobis(diphenylphosphinopropane)palladium, dichlorobis(diphenylphosphine) Palladium catalysts such as palladium, palladium acetate, tetrakistriphenylphosphine palladium, palladium dibenzylideneacetone, etc., and a ligand may be added when a metal catalyst is used. The ligand may, for example, be a phosphine-based ligand represented by triphenylphosphine 'tributylphosphine, diphenylphosphinoethane, diphenylphosphinopropane or diphenylphosphinobutane. In the compound represented by the formula (I), the compound of the formula (Ie) wherein R31 or 1132 is a Cm alkylcarbonylamino group or a C6_14 arylcarbonylamino group is represented by the following reaction formula, wherein the compound represented by the formula (Ie) is -65-201022223, It can be produced by reacting a compound represented by the general formula (I-Ο in the presence of a base with a compound represented by the compound (5) or the compound (6).

Ζ H R34 (I-e) 3 3

(wherein R1, R2, R3, R4, R5, R6, m, n, v, R31, R and R34 are the same as defined above, X is a leaving group such as a chlorine atom or a bromine atom, and Z is a Cu alkyl group or C6_14 aryl) However, when R5 is a hydrogen atom, a compound represented by the formula (If) is introduced with a protecting group such as a t-butoxycarbonyl group at a position of R5 before reacting with the compound (5) or the compound (6). Further, (Ie) can be produced by introducing an alkylcarbonylamino group or a C6-14 arylcarbonylamino group and then performing deprotection. Introduction and deprotection of a protecting group such as t-butoxycarbonyl group can be carried out by a known method (for example, Protecting Groups in Organic Synthesis, second editi ο η, T · W · Gre en e and P. GM W uts, John Wiley & Sons, Inc., published in the publication of the method, etc.). The solvent used for the reaction of the compound represented by the formula (I-f) with the compound (5) or the compound (6) may, for example, be as follows. For example, the hydrazine solvent represented by dimethyl hydrazine, the guanamine solvent represented by dimethylformamide or dimethyl acetamide, ethyl ether, and dimethoxy-66- 201022223 ethane Or an ether solvent represented by tetrahydrofuran or cyclopentyl methyl ether, a halogen solvent represented by dichloromethane, chloroform or dichloroethane, a nitrile solvent represented by acetonitrile or propionitrile, acetone, methyl ethyl A ketone solvent represented by a ketone or methyl isobutyl ketone, an aromatic hydrocarbon solvent represented by benzene or toluene, a hydrocarbon solvent represented by hexane or heptane, and an ester solvent represented by ethyl acetate. Further, the reaction can also be carried out without a solvent. It is preferably a halogen solvent, an ether solvent or no solvent. The reaction temperature of φ is usually -80 ° C to the reflux temperature using a reaction solvent, preferably -10 ° C to 80 ° C. The molar ratio of the reaction starting material, the compound (5) or the compound (6)/compound (1-〇 in the range of 5.5~2 0.0, preferably in the range of 1.0~10_0, such as triethylamine, B a trialkylamine represented by a diisopropylamine, pyridine, 2,6-lutidine, 2,6-di-t-butylpyridine, 2,6-di-t-butyl-4 Methylate, proton sponge represents an inorganic base represented by a steep amine, hydroquinone sodium oxide, potassium hydroxide or potassium carbonate, preferably triethylamine, ethyldiisopropylamine, pyridine Further, the compound represented by the general formula (Ι-f) can be subjected to a known deamination reaction (for example, Protecting Groups in Organic Synthesis, by subjecting the compound represented by the general formula (Ie) in the presence of an acid or a base. Manufactured by second edition, TW Greene and PGM Wuts, published by John Wiley & Sons, Inc., etc. -67- 201022223

In the compound represented by the formula (I), the compound represented by the general formula (Ig) wherein R3! or R3 2 is a hydroxyl group can be produced by reacting a compound represented by the general formula (U) under an acid catalyst. . 【化23】

η ν

R3 R2 __

Rl acid catalyst

(wherein R_1, R2, R3, R4, R5, R6, m, n, v and r31 are the same as defined above, and R21 is a c丨_6 alkyl group or the like). Synthesis of a compound represented by the formula (1-g) The solvent used is as follows. For example, an sulfonium solvent represented by dimethyl hydrazine, a guanamine solvent represented by dimethylformamide or dimethylacetamide, ethyl ether, dimethoxyethane or tetrahydrofuran, An ether solvent represented by oxalic acid or diethylene glycol dimethyl ether, a halogen solvent represented by dichloromethane, chloroform or dichloroethane, a nitrile solvent represented by acetonitrile or propionitrile, benzene, toluene芳的芳-68 - 201022223 Aromatic hydrocarbon solvent, hydrocarbon solvent represented by hexane and heptane, ester solvent represented by ethyl acetate, methanol, ethanol, propanol, 2-propanol, ethylene An alcohol solvent represented by an alcohol, an organic acid solvent represented by acetic acid or trifluoroacetic acid, and water. Further, the reaction can also be carried out without a solvent. A halogen solvent or an aromatic hydrocarbon solvent is preferred. The acid catalyst to be used may, for example, be an inorganic acid represented by hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid, methanesulfonic acid, organic sulfonic acid H represented by p-toluenesulfonic acid, aluminum chloride, titanium tetrachloride, and trifluoride. Boron diethyl ether complex, perchloric acid, zinc chloride, zinc bromide, zinc iodide, iron (III) chloride, iron (II) chloride, copper (I) chloride, copper chloride ( II) The Lewis acid represented. It is preferably a Lewis acid such as boron trifluoride diethyl ether complex. The reaction temperature used in the reaction is usually -80 ° C to the reflux temperature of the reaction solvent, preferably -78 ° C to room temperature. The molar ratio of the reaction raw material, the acid catalyst/compound (I-h) is in the range of 0.5 to 2 0.0, preferably 1 to 5. Further, the compound represented by the general formula (Ig) can be a known method (for example, JJ Plattners J. Am. Chem. Soc., 1972, 94, 8613, etc.) such that the compound represented by the general formula (Ii) is acid or It is produced by deamination in the presence of a base. -69- 201022223 【化24】

RJ R2 R' acid or base

N3i N

R3 R2 Ri (wherein R1, R2, R3, R4, R5, R6, m, η, V, R31, R33 and R34 are the same as defined above, and R22 is an alkylcarbonyl group, a C6.14 arylcarbonyl group, etc.) Among the compounds represented by the formula (I), the synthesis of the optically active substance can be achieved by a method of optically dividing the racemic mixture (Japanese Patent Laid-Open No. Hei 3-141286, No. 5,097,037, and European Patent No. 409,165). Further, the synthesis of the optically active substance of the compound represented by the general formula (2) can be carried out by a method of asymmetric synthesis (Japanese Patent Publication No. Hei 5-507645, Japanese Patent Application Laid-Open No. Hei No. Hei No. Hei. As disclosed above, the inventors have found that the compound represented by the general formula (I) has a strong non-reactive period extension as in the above, as in the above-mentioned publication, No. 5, 533, effect. The effect of prolonged non-response period as an effective mechanism of anti-arrhythmia is an important indicator of the effectiveness of clinical arrhythmia. A known anti-arrhythmia drug with a non-reactive phase prolongation as the main mechanism (eg, Da Sotalol, etc. of Vaughan Williams' anti-arrhythmia classification group) is based on prolonging the ventricular myoelectric activity potential associated with prolongation of non-response period The sudden induction of torsades de pointes and other sudden deaths of 201022223 is a major issue, and the treatment of atrial fibrillation as the main arrhythmia (ventricular tachycardia, atrial flutter, atrial fibrillation, etc.) becomes a problem. . In order to solve this problem, the inventors of the present invention conducted a study on a compound which is non-anterior to the ventricular muscle and which has a selective non-reactive period of atrial muscle, and found that the compound represented by the general formula (I) does not react to the ventricular muscle. The period and the activity potential have an effect, and the selective non-reaction period of the atrial muscle is prolonged by 0. The findings of the present inventors differ from the prior art in that the compound population can be given a prolonged period of selective amenity to the atrial muscle, which also has an effect on the duration of the activity potential of the extracted ventricular muscle, and The electrocardiogram QT of anesthetized animals has an effect and is revealed. From the above, the present compound does not have an arrhythmia-inducing effect on the ventricular muscle, and can be safely used in arrhythmia in which the atrial muscle is the main body compared with the existing technique. This technique is related to atrial arrhythmia and is used, for example, as an episode, chronic, preoperative, intraoperative or postoperative anti-atrial fibrillation agent, anti-atrial flutter, anti-atrial atrial pulse therapy or prevention. Use to prevent embolism caused by atrial arrhythmia, prevent ventricular arrhythmia or frequency caused by atrial arrhythmia or frequent pulse, prevent atrial arrhythmia or frequency based on prevention of ventricular arrhythmia or frequency The pulse prevents the prognosis from getting worse. The present invention provides an effective amount of a pharmaceutical composition or a veterinary drug composition comprising a compound represented by the general formula (I). As the administration form of the compound of the present invention, for example, an injection (subcutaneous, intravenous, intramuscular, intraperitoneal injection), an ointment, a sitting agent, an atomizer or the like, a parenteral administration or a tablet, a capsule, or a granule Agent, nine doses, syrup-71 - 201022223 Agents, liquids, emulsions, suspensions, etc. are administered orally. The composition of the above-mentioned medicinal or veterinary drug containing the compound of the present invention contains about 0.01 to 99.5 %, preferably about 0.1 to 30%, based on the total weight of the total composition. The compound of the present invention or a composition containing the same may contain other pharmaceutically or veterinary drug-active compounds. Further, such compositions may contain a plurality of compounds of the invention. Although the clinical administration amount of the compound of the present invention varies depending on the age, the body weight, the sensitivity of the patient φ, the degree of the symptoms, and the like, the dosage is generally effective, and the adult is 0.003 to 1.5 g, preferably 0.01 to 0.6 g. . However, it is also possible to use amounts outside the above range as needed. The compounds of the present invention are administered by pharmaceutical preparations. That is, tablets, capsules, granules, and nine doses for oral administration may be used as excipients such as white sugar, lactose, glucose, starch, mannitol; binders such as hydroxypropylcellulose, syrup , gum arabic, gelatin, sorbitol, tragacanth, methyl cellulose, polyvinyl pyrrolidone; disintegrating agent, such as starch, carboxymethyl cellulose or its calcium salt, microcrystalline cellulose, polyethylene glycol; Lubricants, such as talc, magnesium or calcium stearate, cerium oxide; lubricants such as sodium lauryl, glycerol, and the like, are prepared. For injections, solutions, emulsions, suspensions, syrups and nebulizers, solvents of the active ingredients such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butanediol, polyethylene glycol can be used. Alcohol; surfactants, such as sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene ethers of hydrogenated castor oil, lecithin; suspensions, -72- 201022223 For example, carboxymethyl cellulose sodium salt, cellulose derivative such as methyl cellulose, natural rubber such as scutellaria gum, gum arabic; preservatives such as ester of hydroxybenzoic acid, chlorination Ammonium benzoate, sorbate, etc. are prepared. As the ointment of the percutaneous absorption type preparation, for example, white petrolatum, flowing paraffin, higher alcohol, polyethylene glycol ointment, hydrophilic ointment, aqueous gum base or the like can be used. The sitting agent can be prepared using, for example, cocoa butter, polyethylene glycol, lanolin, fatty acid triglyceride, coconut oil, polysorbate or the like. [Embodiment] [Examples] Hereinafter, the present invention will be described in detail by way of examples, but the invention is not limited to the examples. [Synthesis example] Further, Ph, PhSalen Manganese complex (XX), Cyc,

The PhSalen Manganese complex (XY) is an optically active compound which is not represented by the following structural formula, and is synthesized by the method described in JP-A-7-28 5 98 3 . -73- 201022223 【化2 5】

Further, in the description of the compound name in the present embodiment, the symbol * added to R or S is the estimated absolute arrangement. Synthesis Example 1 1-{3-Hydroxy-2,2-dimethyl-7-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-chromene- 6-yl}propan-2-one [Chemical 2 6]

< 1 -1 > Synthesis of 1-(2,2-methyl-nitro-7-nitro-2H-chromo-6-yl)propylamine-2-oxime -74- 201022223 [Chem. 27]

Sodium nitrite (1.04 g, 15.0 mmol), copper (II) chloride (2.00 g, 15_0 mmol), vinyl acetate (7.50 mL, 68.0 mmol)

a water-acetone mixed solution, at a temperature of 〇 ° C, 6-amino-7-nitro-2,2-dimethyl-2H-chromene (3.00 g, 13.6 mmol) and concentrated hydrochloric acid (3.00 mL, After 2 8.6 mmol) of the acetone solution, the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into dilute hydrochloric acid and extracted with ether. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4:1) to give the object (yield: 42%). Shape: red solids ^-NMRCCDCh) δ ; 1.46 (s, 6H), 2.30 (s, 3H), 3.98 (s, 2H), 5.82 (d, J = 9.9 Hz, 1H), 6.32 (d, J = 9.9 Hz, 1H), Φ 6.82 (s, 1H), 7.55 (s, 1H). MS(EI) m/z; 261 [M] + < 1 -2 > 1_ (3-bromo-4-hydroxyl) Synthesis of -2,2-dimethyl-7-nitro-3,4-dihydro-2H-chromene-6-yl)propan-2-one-75- 201022223

QH

a mixed solution of dimethyl sulfoxide-water in 1 · ( 2,2-dimethyl-7-nitro-2H-chromen-6-yl)propan-2-one (1.00 g ' 3.83 mmol) 33.0 mL), N-bromosuccinimide (2.00 g, 11.5 mmol) was added at 〇 ° C, and stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture, and the organic phase was washed with saturated aqueous ammonium chloride and brine, and dried over anhydrous magnesium sulfate. The residue was recrystallized from hexane-ethyl acetate to give the object (yield: 80%). Shape: light yellow crystal melting point: 1 9 5 °C (decomposition) ^-NMRiCDCh) δ ; 1 . 2 6 (s, 3 Η), 1 _ 4 3 (s, 3 Η), 2.3 1 (s, 3 Η ), 2.80 (br s, 1H), 3.96 (d, J = 17.6Hz, 1H), 4.11 (d, J =1.7 Hz, 1H), 4.15 (d, J = 17.6 Hz, 1H), 4.91 (d, J = 9.5 Hz, 1H), 7.4 (s, 1H), 7.58 (s, 1H). MS(EI)m/z; 3 5 7 [M] + < 1 -3 > 1- (2,2 -Synthesis of dimethyl-5-nitro-la,7b-dihydro-2H-Oxireno[c]chroman-6-yl)propan-2-one-76- 201022223

1-(3-Bromo-4-hydroxy-2,2-dimethyl-7-nitro-3,4-dihydro-chromen-6-yl)propan-2-one (900 mg, 2.51 mmol) In a 1,4-dioxane-water mixed solution (1 l.OmL), sodium hydroxide (120 mg, 3.01 mmol) was added at 0 ° C, and stirred at room temperature for 5 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with saturated aqueous ammonium chloride and brine, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane·ethyl acetate = 1 : 1) to give the object (yield: 6 7%). Shape: pale orange solid IH-NMR (CDC13) (5 ; 1.23 (s, 3H), 1.53 (s, 3H), 2.24 (s,

3H), 3.48 (d, J = 4.4Hz, 1H), 3.82 (d, J = 17.4 Hz, 1H), 3.85 (d, J = 4.4Hz, 1H), 4.09 (d, J - 17.4 Hz, 1H) , 7.16 (s, 1H), 7.49 (s, 1H). MS (EI) m/z; 277 [M] + < 1-4 > l-{3-hydroxy-2,2-dimethyl- Synthesis of 7-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-211-chromen-6-yl}propan-2-one-77-201022223 0]

1-(2,2-methyl-5-nitro-la,7b-->chloro-211-0 x ireno [c] dilute, 6-yl) propylidene-2-indole (200 mg, 0.721 mmol), a desertification clock (250 mg, 2.8 8 mmol), 2-phenylethylamine (349 mg, 2.8 8 mmol) in acetonitrile (2.0 mL) was stirred at 65 °C for 2 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with saturated aqueous sodium hydrogen sulfate and brine and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1 : 1) to afford (yield: 82%). Shape: pale brown solid 'H-NMRiCDCb) δ ; 1.18 (s, 3H), 1.49 (s, 3H), 2.30 (s, 3H), 2.75-3.0 (m, 4H), 3.55 (d, J = 10.2Hz , 1H), 3.66 (d, J = 10.2Hz, 1H), 3.83 (d, J = 17.6 Ηζ, ΙΗ), 3.89 (d, J = 17.6 Hz, 1H), 6.74 (s, 1H), 7.2-7.35 (m, 5H), 7.53 (s, 1 H). MS (FAB) m/z; 399 [M + H] + hereinafter, a ring was synthesized from a 2H-chromene compound via a 3-bromo-4-hydroxy compound. The method of converting the oxygen compound to the amino alcohol compound is Meth〇d A. Synthesis Example 2 -78- 201022223 1-(3-Hydroxy-2,2-dimethyl-7-nitro-4-{[2-(4-chlorophenyl)ethyl]amino} -3,4 -dihydro-2H-chromen-6-yl)propan-2-one [Chemical 3 1]

1-( 2,2-Dimethyl-7-nitro-la, 7b-dihydro-2H-Oxireno [c] color-6-yl) propyl 2-ketone (150 mg, 0-541 mmol) and 2 -(4-Chlorophenyl)ethylamine (303 μί, 2.16 mmol) was synthesized in the same manner as in Synthesis Example 1. (Yield 7 9 %) Shape: pale brown amorphous MS (FAB) m/z; 43 3 [M + H] + ❿ Synthesis Example 3 2,2-dimethyl-6-nitro- 4-[ (2-phenylethyl)amino]-3,4-dihydro-2H-chromene-3,7-diol [Chemical 3 2]

7-Methoxymethoxy-2,2-dimethyl-6-nitro-4-[(2-phenylethyl-79-201022223)amino]-3,4-dihydro-2H 4M chlorinated solution (400 // L) was added to the ethanol solution (3.00 mL) of chromen-3-ol maleate 0.15 5 mmol, synthesized in International Publication No. 2005090357), and was carried out at 90 ° C. Stir for hours. The organic layer was washed with saturated aqueous sodium hydrogen sulfate aqueous solution and dried over anhydrous magnesium sulfate. Purification by column chromatography (chloroform) gave the title compound (yield: shape: yellow liquid 'H-NMRCCDCb) ά; 1.19 (s, 3H), 1.50 (s, 3H), 4H), 3.47 (d, J = 10.2 Hz, 1H), 3.60 (d, J = H 6.44 (s, 1H), 7.15-7.30 (m, 5H), 7.91 (s, 1H). MS(ESI + ) m/z; 3 59[ M+1] + MS(ESr) m/z; 3 57 [M-1] + Synthesis Example 4 6-Amino-2,2-dimethyl-4-[(2-phenylethyl)amine ]-3,4-ene·3,7-diol [Chemical 3 3] (94.0 mg, a hydrogenated dioxane-soluble reaction solution containing a saturated salt slag, 9 4%). 3.0 (m, ).2 Hz, 1H), dihydro-2H-color

6-Amino-7-methoxymethoxy-2,2-dimethyl-ethyl)amino]-3,4-dihydro-2Η-chromen-3-ol maleic acid-80 - 4-[(2-phenyl salt (94.0 mg 201022223, 0.155 mmol, synthesized by the method described in International Publication No. 2005090357), which was synthesized in the same manner as in Synthesis Example 3. Yield: 8 4 % Shape: light yellow Liquid MS (ESr) m/z; 327 [M-1] + Synthesis Example 5 φ 2,2-dimethyl-7-nitro-4-[(2-phenylethyl)amino]-3, 4-Dihydro-21^-chromene-3,6-diol hydrobromide 34]

6-Methoxy-7-nitro-2,2-dimethyl-6-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-211-color In a solution of methylene chloride (1.1 mL) of ene-3-ol (11〇1^, 0.3〇111111〇1, synthesized by the method disclosed in International Publication No. 2005 0 803 6 8) at 0 ° C A 1 M hydrogen bromide-dichloromethane solution (〇.89 mL) was added and stirred for 1 hour. Water was added, and after quenching, methanol was further added, and the solid matter was filtered off, so that the solution was distilled off under reduced pressure. After the solid residue was washed and filtered, the solid was dried under reduced pressure at 50 ° C to give the title compound (yield: 68%). Shape: yellow solid -81 - 201022223 ^-NMRCDMSO-de) <5 ; 1.09 (s, 3H), l·41 3H)> 2-89- 3.40 (m, 4H), 3.93-4.02 (m, 1H), 4.43 -4.52 (m, 1H), 6.28 (d, J = 5.7 Hz, 1H), 7.22-7.42 (m, 6H), 9.09 (brs, 1H), 9.51 (brs, 1H) MS(EI) m/z; 3 5 8 [M]+ * Synthesis Example 6 7-bromo-6-methoxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3, 4-dihydrohydrogen-2Η-chromen-3-ol [Chemical 3 5]

7-Amino-6-methoxy-2,2-dimethyl-6-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-2Η-color Acet-3-ol (〇.75§' 2.2mmo1, synthesized by the method described in International Publication No. 2005080368), acetic acid (4.5mL), aqueous hydrogen bromide solution (4.5mL) in a mixed solution ' at -2 0 An aqueous solution of sodium nitrite (167 mg, 2.4 mmol) was added at ° C, and stirred at -5 °C for 5 minutes (solution A). On the other hand, an aqueous solution of bromide (4.5 mL) (solution B) of copper (I) bromide (I) (316 mg, 2.2 mmol) was additionally prepared. After the solution B was added at -5 °C, the solution B was stirred for 20 minutes. After adding ethyl acetate and water, the mixture was stirred at room temperature for 1 hour -82-201022223, and then added with ammonia water for extraction. The organic phase was dried, and the solvent was evaporated, and then purified to silica gel column chromatography (hexane: ethyl acetate = 2:1) to give a pale yellow crystal. The obtained crude product was washed with a mixture of diisopropyl ether and hexane, and the crystals were collected by filtration to give the object (yield: 43%). 〇 shape: colorless crystals, H-NMR CCD Ch. 5; 1.13 (s, 3H), 1.45 (s, 3H), 2.75-2.97 ❻ (m, 4H), 3.55-3.63 (m, 2H), 3.69 (s, 3H), 6.55 (s, 1H), 7.00 (s, 1H), 7.20-7.36 (m, 5H) MS (ESI+) m/z; 406 [M+]], 408 [M + 3] + Synthesis Example 7 3-hydroxy-6-methoxy- 2,2- Methyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-chromene-7-carbonitrile φ [Chem. 36]

7-Bromo-6-methoxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-chromen-3-ol ( L〇〇mg, 0.25mmol), zinc cyanide (29mg, 0.25mmol) and tetrakis(diphenylscale) ruthenium (9mg) in dimethylformamide (1mL) solution in microwave (140W) Next, -83-201022223 200 ° C for l〇 minutes reaction. Ethyl acetate and water were added to the reaction mixture for extraction, and the organic phase was washed with a saturated aqueous solution of sodium carbonate and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2 : 1) to afford the desired product (yield: 3%). Shape: pale yellow solids 'H-NMR CCD Ch) 5 ; 1.13 (s, 3H), 1.45 (s, 3H), 2.70-2.97 (m, 4H), 3.58 (d, J = 9.9 Hz, 1H), 3.66 ( d, J = 9·9 Hz, 〇1H), 3.71 (s, 3H), 6.66 (s, 1H), 6.96 (s, lH), 7.20-7.36 (m, 5H) MS(ESI + )m/z 122(bp), 3 5 3 [M+1] + Synthesis Example 8 3-Hydroxy-2,2-dimethyl-6-nitro-4-[(2-phenylethyl)amino]_3 , 4_ dihydro-2H-chromene-7-carbonitrile ❹ [Chemical 3 7]

< 8-1 > 2,2-Dimethyl-6-nitro-2H-chromene-7-ol -84- 201022223 [Chem. 3 8]

4M hydrogen chloride of 7-methoxymethoxy-2,2-dimethyl-6-nitro-2H-chromene ( 4.66 g, 17.6 mmol, synthesized by the method disclosed in International Publication No. 2005090357) A solution of 1,4-dioxane (44 mL) was stirred at 100 ° C for 2 hours. After allowing the reaction solution to cool, the solvent was distilled off. After the ethyl acetate and water were added to the residue, the mixture was extracted. The organic phase was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated to give a crude material. < 8-2 > Synthesis of 2,2-dimethyl-6-nitro-2H-chromen-7-yltrifluoromethanesulfonate [Chem. 3 9]

A solution of 2,2-dimethyl-6-nitro-2H-chromen-7-ol (3.88 g, 17-5 mmol) in toluene (19 niL) was added triethylamine (3'67 mL ' 26.3 Mm〇l) and anhydrous trifluoromethanesulfonic acid (4.43 mL, 26.3 mmol) were stirred overnight. After the addition of toluene and water, the organic phase was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 14:1) to afford the desired material (yield: 2 3 %). Shape: pale yellow solid 'H-NMR (CDC13) δ ; 1.5 1 (s, 6 Η), 5 · 8 2 (d, J = 1 0 · 2 Η ζ, 1Η), 6.35 (d, J = 10.2 Hz, 1H), 6.74 (s, 1H), 7.87 (s, 1H) < 8-3 >

Synthesis of 2,2-dimethyl-6-nitro-2H-chromene-7-carbonitrile

(4.61g - 13.1mmol), diphenylphosphinoferrocene (5 7 9 mg, 1.04mmol), tris(dibenzylideneacetone)dipalladium (4 7 8 mg, 0.5 2 mm ο 1 ) A solution of powder (205 mg, 3-13 mmol) and zinc cyanide (919 mg, 8.83 mmol) in dimethylacetamide (4 6 ml) was stirred at 130 ° C for 1 hour. After the reaction solution was allowed to cool, ethyl acetate and a saturated aqueous solution of sodium chloride were added, and the solid was filtered over celite, and the filtrate was separated, and the organic phase was washed with saturated aqueous sodium carbonate and saturated aqueous After the magnesium was dried, the solvent was distilled off. The residue was purified by a silica gel column chromatography (ethyl acetate = 9:1), and the obtained crude product was washed with a mixture of ethyl acetate and heptane (9:1) to give the object (yield: twenty four%). Shape: yellow-red solids-86- 201022223 1H-NMR(CDC13) 5 ; 1.51 (s, 6H), 5.90 (d, J = 9.9 Hz, 1H), 6.38 (d, J = 9.9 Hz, 1H), 7.15 (s, 1H), 7.96 (s, 1H) MS (EI) m/z; 169 (bp), 23 0 [M] + < 8-4 > 2,2-monomethyl-6-nitro - la, 7b -mononitro-2H-Oxireno[c]

[化4 1] o2n

Add m-chloroperbenzoic acid (904 mg - 5.24 mmol) to a solution of 2,2-dimethyl-6-nitro-2H-chromene-7-carbonitrile (603 mg, 2.62 mmol) in chloroform (24 mL) Stir at room temperature overnight. After the reaction mixture was added to a saturated aqueous solution of sodium carbonate, the mixture was extracted twice, and then the organic phase was dried over anhydrous magnesium sulfate to remove solvent. The residue was purified by silica gel column chromatography (hexanes ethyl acetate: chloroform = 4 : 1 : 1) to afford the object (yield: 4 5%).

'H-NMR^CDCIM; 1.36 (s,3H),1.65 (s,3H), 3_62 (d, J =4.5 Hz, 1H), 4.01 (d, J = 4.5 Hz, 1H), 7.25 (s, 1H) ), 8.40 (s, 1H) MS (ESI + ) m/z; 247 [M + l] + -87- 201022223 < 8-5 > 3-hydroxy-2,2-dimethyl-6-nitrate Synthesis of benzyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-chromene-7·carbonitrile in 2,2-dimethyl-6-nitro-1&amp ;,71>-Dihydro-211-0\4£11〇[£:]chromene-5, carbonitrile (290mg, 1.18mmol) in 1,4-dioxane (0.58mL) Lithium chlorate (125 mg ' 1.18 mmol) and 2-phenylethylamine (0.18 mL, 1.4 1 mmol) were stirred at 85 ° C for 1 hour and half. After the reaction mixture was allowed to cool, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate:=3:1) to give the desired compound (yield: 7 2%). : Red amorphous material 'H-NMRCCDCb) <5; 1.21 (s, 3H), 1.53 (s, 3H), 2.74-3.01 (m, 4H), 3.54 (d, J = 10.2 Hz, 1H), 3.72 (d, J = 10.2 Hz, 1H), 7.20-7.3 8 (m, 6H), 8.16 (s, 1H) MS(ESI + )m/z; 368 [M+l] + below, from 2H-color The olefin compound, which is synthesized using m-perbenzoic acid, is converted to an amino alcohol compound by Method B. Synthesis Example 9 6-Amino-3-hydroxy-2,2·dimethyl-4-[(2-phenylethyl)amino]_3,4-dihydro-2H-chromene-7-carbonitrile (Compound A·) -88- 201022223 【化42】

6-Amino-3-hydroxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-chromene-7-carboxamide ( Compound A") 【化43】

3-Hydroxy-2,2-dimethyl-6-nitro- 4-[(2-phenylethyl)amino]-3,4-hydrogen-2H-colorcan-7-carbazide 6 〇 mg, 〇 _i6 mmol) in methanol (1.8 mL) in a solution of 'force [] into 5% p-carbon (6 mg), and stirred overnight under nitrogen atmosphere at room temperature. After removing the solid matter by filtration through diatomaceous earth, the solvent was distilled off. The residue was purified by silica gel column chromatography (only hexane·ethyl acetate: 1:1 to ethyl acetate) to give the title compound A' (yield: 43%) and compound A &quot ; (yield: 3 5 %). (Compound A') • H-NMR CCDCh) δ ; 1.21 (s, 3H), 1.43 (s, 3H), 2.69-2.99 (m, 4H), 3.50-3.60 (m, 2H), 3.87 (brs, 2H) , 6.13 (s, 1H), -89- 201022223 6.79 (s, 1H), 7.20-7.3 8 (m, 6H), 8.16 MS(EI)m/z; 3 3 7 [M] + (Compound A " • H-NMR CCD Ch) δ ; 1.13 (s, 3H), 1-45 (s, 3H), 1.84 (brs, 2H), 2.74-3.00 (m, 4H), 3.5 0-3.59 (m, 2H), 5.10 (brs, 1H), 5.71 (brs, 2H), 6.11 (s, 1H), 6.80 (s, 1H), 7.20-7.28 (m, 5H) φ MS(EI)m/z; 3 5 5 [M ] + Synthesis Example 1 311(311*,43*)-6-bromo-2,2-dimethyl-7-nitro-4-[(2-phenylethyl)amino]-3,4- Dihydro-2H-chromen-3-ol [44]

(311*,48*)-6-Amino-2,2-dimethyl-7-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-2H - chromen-3-ol (5. 〇g' 14, 0mmo1 'International Publication No. 2005 0903 5 synthesized by the method described in the literature 7) in acetic acid - hydrogen bromide (1: 1, 60mL) solution - An aqueous solution of sodium nitrite (965 mg, 14.0 mmol / water 7 mL) was added dropwise at 45 ° C for 45 minutes to stir at this temperature for 5 minutes. Adding a reaction solution to a solution of copper (I) bromide (-90-201022223 3.01 g, 21.0 mmol) cooled to -20 ° C in hydrogen bromide (30 mL) was stirred at this temperature for 2 hours and then raised to Stir at room temperature until foaming is not visible. The reaction mixture was diluted with ethyl acetate and washed with water, aqueous ammonia and brine, and then evaporated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3:1) to give the object (yield: 85%). MS (EI + ) m / z; 421 [M+l ] + 〇 Synthesis Example 1 1 (3R*, 4S*)-6-chloro-2,2-dimethyl-7-nitro-4-[ ( 2. Phenylethyl)amino]-3,4-dihydro-2H-chromen-3-ol [Chem. 45]

(3R*,4S*)-6-Amino-2,2-dimethyl-7-nitro.4_[(2-phenylethyl)amino]-3,4-dihydro-2Η-color The enol-3-ol was used as a raw material, and instead of copper (I) bromide, instead of copper chloride and hydrogen bromide, hydrochloric acid was used, and a target product was obtained based on Synthesis Example J (yield: 17%). Shape: peach crystal MS (EI + ) m / z; 3 77 [M+l] + Synthesis Example 12 -91 - 201022223 (311*,45*)-7-Amino-6-bromo-2,2-di Methyl-4-[(2-phenylethyl)aminodi 3,4-hydrogen-2H-chromo-3-ol [Chem. 46]

(311*,48*)-6-Chloro-2,2-dimethyl-7-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-2H- To a solution of chromene-3_ol (2.46 g, 5 - 84 mmol) in ethanol (25 mL), water (5 mL) and iron powder (1.08 g, 19~3 mmol) were added, and concentrated hydrochloric acid (246 // L) was added at room temperature. After stirring at 70 ° C for 3 hours, let cool to room temperature. The reaction mixture was diluted with ethyl acetate and washed with EtOAc EtOAc EtOAc (EtOAc) The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5 : 1 - 4 : 1 ) to give the desired compound (yield 65%). Shape: liquid MS (ΕΓ) m / z; 391 [M+l ] + Synthesis Example 13 (3 Han*, 48*)-7-amino-6-chloro-2,2-dimethyl-4-[ (2-phenylethyl)amino]-3,4-dihydro-2H-chromen-3-ol 201022223 [Chem. 4 7]

(311*,43*)-6-chloro-2,2-dimethyl-7-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-2H- The chromene-3-ol was used as a raw material, and the object compound was obtained based on Synthesis Example 12 (yield: 52%). Shape = liquid MS (ΕΓ) m / z; 3 47 [M+l] + Synthesis Example 14 3- {3-Hydroxy-2,2-dimethyl-7-nitro-4-[(2-phenyl) Ethyl)amino]-3,4-dihydro-211-chromen-6-yl}benzoate ethyl ester 〇Η匕48]

6-Bromo-2,2-dimethyl-7-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-211-chroman-3-ol (42.111 ^, 0.1111111〇1) in a solution of 1,4-di-1! oxane, adding 3-ethoxycarbonylphenylboronic acid (38.8 mg, 0.2 mmol) and triphenylene (10.5 mg, 0.04) under nitrogen atmosphere Methyl), palladium(II) acetate (2.2 mg, 0.01 mmol), and 2M sodium bicarbonate water-93-201022223 solution (75 μL) were stirred under reflux for 1 hour. The reaction solution was allowed to cool to room temperature, diluted with ethyl acetate, and the organic layer was washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3:1 - 2:1) to obtain the desired product. Yield). Shape: Liquid 'H-NMR CCDCh) (5; 1.25 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H), 1.53 (s, 3H), 2.73 -3.00 (m, 4H), 3.61 (d, J = 9.9 Hz, 1H), 3.73 (d, J = 9.9 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 7.01 (d, J = 0.6 Hz, 1H), 7.05-7.20 (m, 5H), 7.30-7.42 (m, 2H), 7.50 (t, J = 7.6 Hz, 1H), 7.93 (s, 1H), 8.05-8.14 (m, 1H). In the following, Synthesis Example 15-17 is synthesized. On the basis of Example 14, the title compound was synthesized as 1 2 2,2-dimethyl-7-nitro-6-phenyl-4-[(2-phenylethyl)amino]-3,4-di Hydrogen-2H-chromen-3-ol [49]

94-201022223 Shape: Liquid ^-NMRiCDCh) <5 ; 1.21 (s, 3H), 1.51 (s, 3H), 2.70-3.00 (m, 4H), 3.58 (d, J = 9.9 Hz, 1H), 3.69 (d, J = 9.9 Hz, 1H), 6.90-7.50 (m, 12H) Synthesis Example 1 6

6-(4-Methoxyphenyl)-2,2-dimethyl-7-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-color En-3-ol [Chemical 5 0]

φ shape: liquid MS (EI + ) m / z; 449 [M + l] Synthesis Example 1 7 2,2-Dimethyl-7-nitro-6-(3-nitrophenyl)-4-[ (2-Phenylethyl)amino]-3,4-dihydro-2H-chromen-3-ol-95- 201022223 [Chemical 5 1]

Shape: liquid

MS (EI + ) m / z; 464 [M+l] MS (EI + ) m / z; 462 [Ml] Synthesis Example 1 8 3-hydroxy-2,2-dimethyl-7-nitro-4 -[(2-phenylethyl)amino]-3,4-dihydro-2H-chromene-6-carbonitrile [Chemical 5 2]

❹6-Bromo-2,2-dimethyl-7-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-211-chromen-3-ol ( 18,2.37111111〇1) of dimethylformamide (15 ml) was added with copper cyanide (224 mg, 2.61 mmol), and stirred at 1 ° C for 6 hours. The reaction solution was allowed to cool to room temperature, diluted with water and extracted with chloroform. The combined organic layers were washed with aqueous ammonia and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography (hexane: ethyl acetate = 4:1 - 2:1) to obtain the desired product. Rate: 8%). Shape · 'Brown oil MS (EI + ) m / z; 3 68 [M+l] + MS (EI + ) m / z; 3 66 [Ml] + Synthesis Example 1 9 φ 3-hydroxy-2, 2-Dimethyl-7-nitro-4-[(2-phenylethyl)amino]-3,4·dihydro-2H-chromene-6-carboxylic acid methyl ester [Chemical 5 3]

< 1 9-1 > Synthesis of 2,2-dimethyl-7-nitro-2H-chromene-6-carboxylic acid methyl ester

MeOOC 02N is 6-bromo-7-nitro-2,2-dimethyl-2H-chromene (1.04 g, 3.6 6 mm ο 1, Ash woo d Valerie A. et al., J. Med. Chem. , -97-201022223 1990,33 (9) '2667-72 is based on the synthesis of dimethyl hydrazine (5ml), and methanol (5ml) in a mixed solution, under nitrogen, add palladium acetate at room temperature ( II) (82.2 mg > 0.336 mmol), diphenylphosphinobutane (156.1 mg, 0.3661 mmol). Triethylamine (2.04 ml, 14.64 mmol) was added at this temperature, and the internal environment was replaced with carbon monoxide, and the mixture was stirred at room temperature to 80 °C for 2 days (in the middle, triethylamine was added). The reaction solution was cooled to room temperature, and the reaction mixture was diluted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8:1) to give the desired product (yield: 1 4) %).

1H-NMR (CDC13) (5; 1.48 (s, 6H), 3.87 (s, 3H), 5.81 (d, J = 9.9 Hz, 1H), 6.34 (d, J = 9.9 Hz, 1H), 7.16 (s , 1H), 7.40 (s, 1H). The synthesis was carried out by Method B. <19-2 > 2,2-Methyl-5-nitro-18,71)-dihydro-211-0 \1^11〇[(:]Color-burning-6-residual acid methyl ester [5 5]

-98- 201022223 3Η), 3.57 (d, J 1 Hz, 1 Η), 7.16 •H-NMRCCDCh) <5 ; 1.32 (s, 3H), 1.61 (s, =4.4 Hz, 1H), 3.89 (s , 3H), 3.96 (d, J = 4 (s, 1H), 7.87 (s, 1H). < 19-3 > yl)amino]-3,4- 3 -transyl-2,2- —Methyl-7-nitro- 4-[(2-phenylethylenedihydro-2H-chromene-6-carboxylic acid methyl ester

Shape: pale yellow powder crystal MS (EI + ) m / z; 401 [M+l] MS (ΕΓ) m / z; 3 99 [Ml] Synthesis Example 20 Base) Amino]-3,4- 3 - Base-2,2-methyl-7-nitro-4-[(2-phenylethylenedihydro-2H-chromene-6-carboxylic acid

【化5 6】

Methyl 3-hydroxy-2,2-dimethyl-7-nitro-4-[(2-]-3,4-dihydro-2H-chromene-6-carboxylate (104 mg methanol (4 m 1) A solution of 1 86 sodium hydroxide ethyl)amine (0.26 mmol) (1.86 ml -99-201022223) was added to the solution, and the mixture was stirred at 7 (TC for 15 minutes). The reaction solution was allowed to cool to room temperature. It was neutralized with 1 Torr of hydrochloric acid, and crystallized by filtration, and washed with water to give the object (yield: 62%). Shape: colorless powder crystal MS (EI + ) m / z; 3 87 [M+l] + MS ( EI + ) m / z; 3 85 [Ml] + Synthesis Example 2 1 〇(311*,48*)-7-amino-3-3-hydroxy-2,2-dimethyl-4-[(2-benzene Ethylethyl)amino]-3,4-dihydro-2H-chromene-6-carboxylic acid methyl ester [5 7]

< 21 -1 > [(3R*,4S* )-6-bromo-3-hydroxy-2,2-dimethyl-7-nitro-3,4 2H-chromen-4-yl]( Synthesis of 2-phenylethyl)carbamic acid esters [Chemical 5 8]

OH

-100- 201022223(3R* , 4S* )-6-Bromo-2,2-dimethyl-7-nitro-yl)amino]-3,4-dihydro-2H-chromene-3- After adding potassium carbonate (2.) and chloroformic acid vinegar (0.87 ml, 5.1 mmol) to a solution of alcohol (2.74 g, tetrahydrofuran (15 ml), water was added to the reaction solution, and ethyl acetate was introduced into the layer. Washing with water and saturated brine. The organic layer was dried and concentrated under reduced pressure, and the residue was purified by EtOAc EtOAc: EtOAc: EtOAc: / z; 5 5 5 [M+l] + MS (EI + ) m / z; 5 5 3 [Ml] + < 21 -2 > (3R*, 4S*)-4-[{(benzyloxy) Synthesis of (carbonyl)}(2-phenyl)-3-hydroxy-2,2-dimethyl-7-nitro-3,4-dihydro-2H-hair vinegar [Chemical 5 9] 4-[ ( 2-phenylethyl 5 .1 mm ο 1 ) 1 g, 1 5.3 mmo 1 . Dilute the reaction line to confirm the reaction with anhydrous magnesium sulfate (hexane (yield: 78 ° /. Amine-based dilute-6·decanoate

[(3R*,4S*)-6-bromo-3-hydroxy-2,2-dimethyl-hydro-2H-chromen-4-yl](2-phenylethyl)carbamic acid 7-nitro -3,4-Dibenzyl ester (588 mg - 101 - 201022223, 1.06 mmol) in a mixed solution of dimethyl argon (3 ml) and methanol (3 ml), and added triphenylphosphine at room temperature under nitrogen atmosphere ( 1 1 1 mg, 0.424 mmol), acetic acid IE (11) (8 2 · 2 mg, 0.3 3 6 mm ο 1 ). Triethylamine (0.591 ml, 4.24 mmol) was added at this temperature, and the internal environment was replaced with carbon monoxide, followed by stirring at room temperature to 70 ° C for 4 days. The reaction solution was cooled to room temperature, and the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate=3:1) ). < 21-3 > (3R' 4S# )-7-Amino-4-{[(benzyloxy)carbonyl](2-phenylethyl)amino} -3 -hydroxy-2,2- Synthesis of Methyl dimethyl-3,4-dihydro-2H-chromene-6-carboxylate [Chem. 60]

(3R' 4S*)-4-{[(Benzyloxy)carbonyl](2-phenylethyl)amino}-3-hydroxy-2,2-dimethyl-7-nitro-3, 4-Dihydro-211-chromene-6-carboxylic acid methyl ester (146.6 mg, 0.274 mmol) in ethanol (2 ml), -102-201022223 Add palladium-carbon (20 mg) at room temperature under hydrogen Stir for 15 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4:1) to give the desired product (yield: 72%). < 21-4 > (3R*, 4S*)-7-amino-3-hydroxy-2,2-dimethyl-4-[(2-phenylethyl) φamino]-3, Synthesis of methyl 4-dihydro-2H-chromene-6-carboxylate to (3R*,4S*)-7-aminobenzyloxy)carbonyl](2-phenylethyl)amino} -3 Palladium-carbon (20 mg) in a solution of methyl 2-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromene-6-carboxylate (100.2 mg, 0.1986 mmol) in methanol (2 mL) In a hydrogen atmosphere, stirring is carried out at room temperature. After confirming the completion of the reaction, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethanol) to give the object (yield: 85 %). φ shape: yellow liquid 1H-NMR (CDC13) 5 ; 1.16 (s, 3H), 1.45 (s, 3H), 2.70-3.00 (m, 4H), 3.45 (d, J = 9.9 Hz, 1H), 3.55 ( d, J = 9.9 Hz, 1H), 3.84 (s, 3H), 5.63 (br, 2H), 6.03 (s, 1H), 7.13-7.38 (m, 5H), 7.64 (s, 1H). Example 22 and Synthesis Example 23 were synthesized by the method described in the literature (Babu, K. Suresh et al. Heterocyclic Communications (2003), 9(5), 5 1 9-526.) by 3-methyl-phenol. A mixture of 2,2,5-trimethyl-211-chromene and 2,2,7-trimethyl-211-chromene-103-201022223 was synthesized using Method A. Synthesis Example 22 6-Bromo-2,2,5-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-211-chromen-3-ol [Chemical 6 1】

<22-1> 3,6-Dibromo-2,2,5-trimethyl-3,4-hydro-2H-chromen-4-ol [Chem. 6 2]

Yield: 2 5 % Shape: pale yellow solid 1H-NMR (CDC13) <5; 1.42 (s, 3H), 1 · 5 7 (s, 3 Η), 2 · 4 6 (s, 3 Η), 2.60 (d, J = 5.4 Hz, 1H), 4.23 (d, J = 6.2 Hz, 1H), 5.06 (t, J = 6.2, 5.4 Hz, 1H), 6.59 (d, J = 8.7 Hz, 1H), 7.39 -104- 201022223 (d, J = 8.7 Hz, 1H). < 22-2 > 6-bromo-2,2,7-trimethyl-la, 7b-dihydro-2H-Oxireno[c]焴【化63】

B shape: pale yellow amorphous 1H-NMR (CDC13) δ ; 1.25 (s, 3H), 1.56 (s, 3H), 2.53 (s, 3H), 3.47 (d, J - 4.6 Hz, 1H), 4.16 (d, J = 4.6 Hz, 1H), 6.56 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H). < 22-3 > ® 6-bromo-2,2 ,5-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-211-chromen-3-ol Yield: 36% (2 step yield). Light brown amorphous material ^-NMRCCDCb) 5 ; 1.24 (s, 3H), 1.38 (s, 3H), 2.10 (s, 3H), 2.29 (br, 1H), 2.73-2.85 (m, 5H), 3.67 ( ABq, J = 5.8Hz, 2H), 6.56 (d, J = 8.8Hz, 1H), 7.16-7.33 (m, 6H). MS(FAB)m/z; 390, 392 [M + H] + -105 - 201022223 Synthesis Example 23 6-Bromo-2,2,7-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2^1-chromene-3- Alcohol

< 23-1 > 3,6-Dibromo-2,2,7-trimethyl-3,4-dihydro-2H-chromen-4-ol [Chem. 65]

OH

Br 〆 yield: 1 7 % Shape: light yellow solid 1 H-NMR (CDC13) δ ; 1.37 (s, 3H), 1.58 (s, 3H), 2.31 (s, 3H), 2.7 1 (d, J = 3,3Hz, 1 H), 4.06 (d, J = 9.3 Hz, 1H), 4.84 (d, J = 9.3Hz, 1H), 6.69 (s, 1H), 7.60 (s, 1H). < 23- 2 > -106- 201022223 6-Bromo-2,2,5-trimethyl-la,7b-dihydro-2H-Oxireno[c]chromene [6 6]

Shape: pale brown amorphous form] H-NMR (CDC13) (5; 1.24 (s, 3H), 1.56 (s, 3H), 2.32 (s, ❹ 3H), 3.46 (d, J = 4.2Hz, 1H ), 3.83 (d, J = 4.2 Hz, 1H), 6.71 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H). < 23-3 > 6-bromo-2 , 2,7-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-211-chromen-3-ol yield: 69% (2 step yield) φ shape: pale yellow amorphous] H-NMR (CDC13) (5; 1.14 (s, 3H), 1.45 (s, 3H), 2.29 (s, 3H), 2.78-2.98 (m, 5H), 3.47 ( d, J = 10.2Hz, 1H), 3.59 (d, J = 10.2Hz, 1H), 6.67 (s, 1H), 7.14 (s, 1H), 7.22-7.27 (m, 3H), 7.35 (t, J = 7.2 Hz, 2H). MS(FAB)m/z; 390, 392 [M + H] + Hereinafter, Synthesis Example 24 is based on the method described in the literature (Babu, K.

Suresh et al. Heterocyclic Communications (203), 9 (5), 519-526.), N-(2) synthesized by N-(2-hydroxy-6-nitrophenyl)acetamide ,2-Dimethyl-7-nitro-2H-chromen-8-yl)acetamidine-107-201022223 Amine, synthesized using Method B. Synthesis Example 2 4 N- {3-Hydroxy-2,2-dimethyl-7-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-211-chromene -8-yl}acetamide [6 7]

<24-1> N-(2,2-Dimethyl-5-nitro-la, 7b-dihydro-2H-Oxireno[c]chromen-4-yl)acetamide [Chem. 6 8]

Yield: 68% Shape: pale yellow solid 'H-NMR (CDC13) δ; 1.3 1 (s, 3H), 1.63 (s, 3H), 2.18 (s, 3H), 3.57 (d, J = 4.5 Hz, 1H), 3.96 (d, J - 4.5Hz, 1H), -108- 201022223 7.32 (d, J = 8.4Hz, 1H), 7.50 (d, J = 8.4Hz, 1H), 7.5 (br, 1H). &lt; 24-2 &gt; N- { 3-hydroxy-2,2-dimethyl-7-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-2H -chromen-8-yl}acetamide yield: 6 2 % φ shape: pale yellow amorphous <H-NMR (CDCl3) &lt;5; 1.20 (s, 3H), 1.52 (s, 3H), 2.18 (s, 3H), 2.71-2.93 (m, 5H), 3.53 (d, J = 10.0Hz, 1H), 3.69 (d, J = 10.0Hz, 1H), 6.89 (dd, J = 8.6, 1.1Hz , 1H), 7.19-7.39 (m, 6H), 7.5 1 (br, 1H). MS(FAB)m/z; 400 [M + H] + Hereinafter, Synthesis Example 25 is based on the method described in the literature (Babu, K. Suresh et al. Heterocyclic Communications (203), 9 Φ (5) '5 1 9-526.), synthesized by 4-nitro-3-(trifluoromethyl)phenol 2, 2-Dimethyl-6-nitro-7-(trifluoromethyl)-2H-chromene was synthesized using Method B. Synthesis Example 2 5 2,2-Dimethyl-6-nitro_4_[(2-phenylethyl)amino]-7-(trifluoromethyl)-3,4-dihydro-2H-chromene- 3-ol-109- 201022223 【化6 9】

&lt; 25-1 &gt; 2,2-dimethyl-6-nitro-5-(trifluoromethyl)-la, 7b-dihydro-2H-Oxireno [c] color suspicion

Yield: 8 9 % Shape: pale brown amorphous 1 H-NMR (CDC13) δ ; 1.35 (s, 3H), 1.63 (s, 3H), 3.60 (d, J = 4.2 Hz, 1H), 3.98 ( d, J = 4.2 Hz, 1H), 7.22 (s, 1H), 8.10 (s, 1H). &lt; 25-2 &gt; 2,2-dimethyl-6-nitro-4-[(2- Phenylethyl)amino]-7-(trifluoromethyl)-3,4 - one gas - 2H - color 酉-3-酉 yield: 6 9 % Shape: pale yellow amorphous] H-NMR (CDC13) 5 ; 1.21 (s, 3H), 1.52 (s, 3H), 1.67 (br, 201022223 1H), 2.76-2.97 (m, 5H), 3.54 (d, J = 10.1Hz, 1H), 3.70 ( d, J = 10.1 Hz, 1H), 7.18 (s, 1H), 7.21-7.37 (m, 5H), 7.77 (s, 1 H). MS(FAB)m/z; 4 1 1 [M + H] + Hereinafter, Synthesis Example 26 is based on the method described in the literature (Babu, K. Suresh et al. Heterocyclic Communications (2 0 0 3 ) &gt; 9 (5), 519-526.), 4-nitro-3- The 2,2-dimethyl-6-nitro-5-(trifluoromethyl)-2H-chromene of φ synthesized by (trifluoromethyl)phenol was synthesized using Method B. Synthesis Example 26 2,2-Dimethyl-6-nitro-4-[(2-phenylethyl)amino]-5-(trifluoromethyl)-3,4-dihydro-2H-color En-3-ol

&lt;26-1&gt;2,2-Dimethyl-6-nitro-7-(trifluoromethyl)-1&amp;,71)-dihydro-21·!-Oxireno[c]色嫌-111 - 201022223 【化72】

▽ Ο Yield: 80% Shape: light yellow solid 1H-NMR (CDC13) (5; 1.35 (s, 3 Η), 1.61 (s, 3 Η), 3.55 (d, J = 4.5 Hz, 1H), 4.28 ( m, 1H), 7.05 (d, J = 8.7 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H). &lt; 26-2 &gt; 2,2-dimethyl-6-nitro-4 Synthesis of -[(2-phenylethyl)amino]-5-(trifluoromethyl)-3,4-dihydro-2H-chromen-3-ol [Chem. 73]

Yield: 8 5 % Shape: pale yellow amorphous material ^-NMRiCDCh) &lt;5; 1.20 (s, 3H), 1.48 (s, 3H), 1.88 (br, 1H), 2.47-2.74 (m, 4H) , 2.80 (br, 1H), 3.55 (d, J = 8.9Hz, 1H), 4.07 (d, J = 8.9Hz, 1H), 7.02 (d, J = 9.2Hz, 1H), 7.16-7.31 (m, 5H), 7.56 (d, J = 9.2 Hz, 1H). 201022223 MS(FAB)m/z; 4 1 1 [M + H] + Synthesis Example 27 Group]-3,4- 8·Amino-2, 2-Dimethyl-7-nitro-4-[(2-phenylethyl)dihydro-2Η-chromen-3-ol [化74]

&gt; 1-{3-Pheptyl-2,2-dimethyl-7-nitro-4-[(2-anilino)-3,4-dihydro-2Η-chromene-8-yl} To a solution of acetamide (66 mg, ) in ethanol (〇.5 mL), add 6M hydrochloric acid (0.2) at 90 ° C for 3 · 5 hours of stirring. After cooling, add 丨μ KOH (mL) for neutralization. The extract was extracted with ethyl acetate, and the organic sodium hydrogen carbonate aqueous solution and saturated brine were washed with anhydrous sulfuric acid, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography ( alcohol = 20 : 1 ) to obtain the objective. Material (yield: 79%). Shape: light brown amorphous

'H-NMRiCDCb) 5 ; 1.18 (s, 3H), 1.55 (s, 3H), (m, 5H), 3.58 (ABq, J = 9.9Hz, 2H), 6.30 (d, J 1H), 6.38 (br , 2H), 7.19-7.35 (m, 5H), 7.62 (d, J 1 Η). Ethyl ethyl) 0 · 17mm o1 aL ), after drying in a sodium solution with saturated magnesium, chloroform: A».74-2.92 = 9.2 Hz, = 9.2 Hz, -113-201022223 MS(FAB) m/z; 3 5 8 [M + H] + Synthesis Example 28 6-Amino-2,2-dimethyl-4-[(2 -Phenylethyl)amino]-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-3-ol [Chem. 75]

2,2-Dimethyl-6-nitro-4-[(2-phenylethyl)amino]-7-(trifluoromethyl)-3,4-dihydro-2H-chromene- The 3-alcohol was used as a raw material, and the object compound was obtained based on Synthesis Example 12 (yield: 52%). Yield: 7 2 % Shape: pale yellow amorphous 'H-NMR CCDCh) δ ; 1.13 (s, 3H), 1.45 (s, 3H), 1.8 (br, 1H), 2.71-3.00 (m, 5H), 3.55 (ABq, J = 10.1Hz, 2H), 3.66 (br, 2H), 6.17 (s, 1H), 6.88 (s, 1H), 7.23 -7.29 (m, 3H), 7.36 (t, J = 7.2Hz) , 2H). MS (FAB) m/z; 381 [M + H] + Synthesis Example 29 6-Amino-2,2-dimethyl-4-[(2-phenylethyl)amino]- 5-(trifluoromethyl-114- 201022223)-3,4-dihydro-2H-chromen-3-ol [Chem. 76]

2,2-Dimethyl-6-nitro-4-[(2-phenylethyl)amino]-5-(trifluoromethyl)-3,4-dihydro-2H-chromene- 3-ol was used as a raw material, and based on Synthesis Example 12, the objective compound was obtained (yield: 52%). Yield: 5 5 % Shape: pale yellow amorphous material • H-NMR CCD Ch) 5 ; 1.15 (s, 3H), 1.42 (s, 3H), 1.79 (br, 1H), 2.52-2.76 (m, 5H), 3.56 (d, J = 8.0Hz, 1H), 3.95 (br, 2H), 3.96 (d, J = 8.0Hz, 1H), 6.57 (d, J = 8.7Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H), 7.13-7.29 (m, 5H). MS(FAB)m/z; 381 [M + H] + Hereinafter, Synthesis Examples 30 to 31 are described in International Publication No. 20〇5〇90357. The method is synthesized. Synthesis Example 3 0 (3R\ 4S*)-6-methoxy-2,2-dimethyl-7-nitro-4-[(2-phenylethyl)amino]-3,4 -di Hydrogen-2H-chromene-3-ol-115- 201022223 【化77】

^-NMR (CDC13) (5: 1.15 (s, 3H), 1.47 (s, 3H), 2.73-2.95 (m, 4H), 3.60 (d, J = 10.0 Hz, 1H), 3.68 (d, J = 10.0 Hz, 1H), 3.73 (s, 3H), 6.78 (s, 1H), 7.21-7.35 (m, 6H) MS (El): 3 72 [M + ] Synthesis Example 3 1 (3R*, 4S>2 ,2,8-trimethyl-7-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-21^chromen-3-ol [Chem. 7 8]

• H-NMR (CDC13) 5: 1.16 (s, 3H), 1.52 (s, 3H), 2.31 (s, 3H), 2.72-2.91 (m, 4H), 3.54 (d, J = 10.0 Hz, 1H) , 3.67 (d, J = 10.0 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 7.19 (m, 6H) MS (El): 3 56 [M + ] -116 201022223 Hereinafter, Synthesis Example 32 And 33 series according to the method described in the literature (Babu, K. Suresh et al. Heterocyclic Communications (2003), 9(5) '5 1 9-526.), synthesized by 2-methylphenol 2, 2 , 8 -Trimethyl 2 oxime chromene, and 2-methoxy-2,2-dimethyl- 2 fluorene-chromene synthesized by 2-methoxyphenol, synthesized using Method Α. Synthesis Example 3 2〇6_Bromo-2,2,8-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-chromen-3-ol [ 7 9]

&lt;32-1&gt; 3,6-Dibromo-2,2,8-trimethyl-3,4-hydro-211-chromen-4-ol (obtained with 3-bromo-2,2,8- a mixture of trimethyl-3,4-hydro-2H-chromen-4-ol) [Chemical 8 0]

-117- 201022223 Shape: pale brown amorphous 'H-NMRCCDCh) δ ; 1.36 (s, 3H), 1.60 (s, 3H), 2.13 (s, 3H), 2.67 (d, J = 4.6Hz, 1H) , 4.06 (d, J = 9.6Hz, 1H), 4.84 (dd, J = 9.6, 4.6Hz, 1H), 7.17-7.20 (m, 1H), 7.42-7.44 (m, 1H). &lt; 32-2 &gt;

6-Bromo-2,2,4-trimethyl-13,715-dihydro-211-0\丨"11〇[&lt;:] chromene (obtained with 2,2,4-trimethyl-la, 7b - Dihydro-2H-Oxiren〇 [c] mixture of chromenes [Chemical 8 1]

H-NMR (CDC13) &lt;5; 1.21 (s,3 Η),1 · 5 9 (s, 3 Η), 2.1 2 (s, 3H), 3.47 (d, J = 4.1 Hz, 1H), 3.82 (d, J = 4.1 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H), 7.29 (d, J = 2.1 Hz, 1H). &lt; 32-3 &gt; 6-bromo-2,2 , 8-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-214-chromen-3-ol yield: 6% (3 step yield) -118 - 201022223 Shape: pale brown amorphous 'H-NMR (CDC13) δ ; 1.13 (s, 3H), 1.47 (s, 3H), 2.11 (s, 3H), 2.75-2.96 (m, 5H), 3.48 ( d, J - 10.0Hz, 1H), 3.59 (d, J = 10.0Hz, 1H), 6.96 (d, J = 2.1Hz, 1H), 7.10 (d, J = 2.1Hz, 1H), 7.20-7.29 ( m, 3H), 7.32-7.3 7 (m, 2H). MS (FAB) m/z; 390, 392 [M + H] + φ Synthesis Example 3 3 5-bromo-8-methoxy-2,2 -Dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-chromen-3-olification 82]

&lt; 33 -1 &gt; 3,5-dibromo-8-methoxy-2,2-dimethyl-3,4-hydro-2H-chromen-4-ol (obtained with 3-bromo-8 a mixture of -methoxy-2,2-dimethyl-3,4-hydro-2H-chromen-4-ol) -119- 201022223 [Chem. 8 3]

Shape: light yellow solid • H-NMRCCDCla) &lt;5; 1.57 (s, 3H), 1.62 (s, 3H), 3.36 (d, J = 4.1 Hz, 1H), 3.83 (s, 3H), 4.31 (d , J = 4.4Hz, 1H), 5.12 (t, J = 4.4, 4.1Hz, 1H), 6.72 (d, J = 8.7Hz, 1H), 7.12 (d, J = 8.7Hz, 1H). &lt; 33 -2 &gt;7_Bromo-4_methoxy-2,2-dimethyl-1&amp;,71)-dihydro-21^0\4611〇[(:]chromene (obtained with 4-methoxyl) a mixture of benzyl-2,2-dimethyl-la,7b-dihydro-2H-Oxireno[c]

Shape: pale yellow amorphous 'H-NMRCCDCls) 5 ; 1.28 (s, 3H), 1.64 (s, 3H), 3.46 (d, J = 8.7 Hz, 1H), 3.57 (d, J = 8.7 Hz, 1H ), 3.68 (s, 3H), 6.73 (d, J = 7.5Hz, 1H), 7.08 (d, J = 7.5Hz, 1H). -120- 201022223 &lt; 33-3 &gt; 5-bromo-8- Yield of methoxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-chromen-3-ol: 1 7 % (3 Step yield) Shape: pale brown amorphous, H-NMR (CDC13) &lt;5; 1.24 (s, 3H), 1.52 (s, 3H), 2.58-2.79 (m, 5H), 3.68 (ABq, J = 7.4 Hz, 2H), 3.81 (s, 3H), 6.63 (d, ❻ J = 8.7 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 7.15-7.21 (m, 3H), 7.24- 7.29 (m, 2H). MS (FAB) m/z; 406, 408 [M + H] + hereinafter, Synthesis Example 3 4 to Synthesis Example 3 7 is based on the method described in the literature (Babu, K. Suresh et al. Heterocyclic Communications (2003), 9(5), 519-526.), 2,2-dimethyl-8-nitro-6 synthesized by 2-nitro-4-(trifluoromethyl)phenol 6-methoxy-2,2-dimethyl-8.nitro-Q 2H-color synthesized by -(trifluoromethyl)-2H-chromene and 4-methoxy-2-nitrophenol 5-Fluoro-2,2-dimethyl-8- synthesized from ene ' 5-fluoro-2-nitrophenol The synthesized -2H- chromene-yl and 4-bromo-3,5-dimethyl phenol 6-bromo -2,2,5,7-tetramethyl -2 Η- chromene, was synthesized using Method Β. Synthesis Example 3 4 2,2-Dimethyl-8-nitro-4-[(2-phenylethyl)amino]-6-(trifluoromethyl)-3,4-dihydro-2H- Chromen-3-ol-121 - 201022223 [Chem. 8 5]

&lt; 34-1 &gt; 2,2-dimethyl-4-nitro-6-(trifluoromethyl)-la, 7b-dihydro-2H-Oxireno [c] color suspicion [Chem. 8 6]

N〇2

F3C Yield: 40% Shape: Yellow oil 1H-NMR (CDC13) (5; 1.39 (s, 3H), 1.68 (s, 3H), 3.62 (d, J = 4.4 Hz, 1H), 4.03 (d , J = 4.4 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 8.09 (m, 1H). &lt; 34-2 &gt; 2,2-dimethyl-8-nitro- 4- [(2-Phenylethyl)amino]-6-(trifluoromethyl)-3,4-dihydro-2H-chromen-3-ol Yield: 6 5 % 122- 201022223 Shape: Light brown Amorphous material ^-NMRCCDCls) δ ; 1.24 (s, 3H), 1.56 (s, 3H), 2.72-2.98 (m, 5H), 3.64 (d, J = 10.1 Hz, 1H), 3.78 (d, J = 10.1 Hz, 1H), 7.20-7.3 7 (m, 5H), 7.57 (br, 1H), 7.94 (m, 1H). MS (FAB) m/z; 411 [M + H] + Synthesis Example 3 5 6 -Methoxy-2,2-methyl-8-nitro-4-[(2-phenylethyl)amino]_3,4-dihydro-211-chromen-3-ol 8 7]

&lt; 35-1 &gt; 6-Methoxy-2,2-dimethyl-4-nitro-la,7b-dihydro-2H-Oxireno[c] chromene [Chem. 8 8]

123 201022223 Yield: 74% Shape: Yellow amorphous 1H-NMR (CDC13) 5; 1.30 (s, 3H), 1.63 (s, 3H), 3.53 (d, J = 4.5 Hz, 1H), 3.82 (s , 3H), 3.92 (d, J = 4.5Hz, 1H), 7.17 (d, J = 3.1Hz, 1H), 7.33 (d, J = 3.1Hz, 1H). &lt; 35-2 &gt; 6 - A Oxy-2,2-dimethyl-8-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-211-chromen-3-ol Yield: 7 7 % Shape: brown amorphous 1H-NMR (CDC13) 5; 1.18 (s, 3H), 1.51 (s, 3H), 2.73-2.93 (m, 5H), 3.64 (ABq, J = 10.1Hz, 2H) , 3.74 (s, 3H), 6.90 (dd, J = 3.0, 0.9Hz, 1H), 7.20-7.24 (m, 4H), 7.3 0-7.3 6 (m, 2H). MS(FAB)m/z; 3 73 [M + H] + Synthesis Example 36 5-Fluoro-2,2-dimethyl-8-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro- 2H-chromen-3-ol-124- 201022223 【化89】

N〇2 &lt; 3 6-1 &gt;

7-fluoro-2,2-dimethyl-4-nitro-1&amp;,713-dihydro-2}1-0&gt;^1^11〇[(^色烯 [化9 0]

N〇2 yield: 8 7 %

Shape: yellow oil ^-NMRCCDCh) 5; 1.38 (s, 3H), 1.66 (s, 3H), 3.58 (d, J = 4.4 Hz, 1H), 4.30 (d, J = 4.4 Hz, 1H), 6.76 (dd, J = 9.2, 8.1Hz, 1H), 7.88 (dd, J = 9.2, 5.9Hz, 1H). &lt; 36-2 &gt; 5-Fluoro-2,2-dimethyl-8-nitrate 4- 4-((2-phenylethyl)amino]-3,4-dihydro-2H-chromen-3-ol yield: 7 7 % Shape: yellow brown amorphous-125- 201022223 ' H-NMR (CDC13) (5; 1.22 (s, 3H), 1.55 (s, 3H), 2.60-2.87 (m, 4H), 3.2 (br, 1H), 3.66 (d, J = 9.0 Hz, 1H) , 3.91 (d, J = 9.0 Hz, 1H), 6.66 (t, J = 9.3, 9.3 Hz, 1H), 7.16-7.33 (m, 5H), 7.80 (dd, J = 9.3, 6.0 Hz, 1H). MS (FAB) m/z; 361 [M + H] + Synthesis Example 3 7 6-bromo-2,2,5,7-tetramethyl-4-[(2-phenylethyl)amino]- 3,4-Dihydro-2H-chromen-3-ol [Chemical 9 1]

Yield: 8 4 % Shape: pale orange solid [Formulation Example] Formulation Example 1 Tablets The compound of the present invention l〇g Lactose 2 60 g Microcrystalline cellulose 600 g 3 50 g Corn starch-126- 201022223 Hydroxypropyl cellulose L〇〇g CMC-Ca 150 g Magnesium stearate 30 g Total amount l, 500 g After mixing the above components in a usual manner, a sugar-coated tablet containing 1 mg of the active ingredient in one tablet was prepared, and the ingot was ingot. Further, CMC_Ca is carboxymethylcellulose calcium. Formulation Example 2 Capsules Compound of the present invention l〇g Lactose 4 40 g Microcrystalline cellulose l, 〇〇〇g Magnesium stearate 50 g Full amount l, 500 g After mixing the above ingredients in a usual manner, they are filled in gelatin capsules. A capsule of 10,000 capsules containing 1 mg of the active ingredient in 1 capsule was prepared. Formulation Example 3 Soft capsules Compounds of the invention l〇g PEG400 479g -127- 201022223 Saturated fatty acid triglyceride 1,500g Peppermint oil 1 g Polysorbate 80 l〇g Total amount 2,000g After mixing the above ingredients It is filled with soft gelatin capsule No. 3 in the usual method, and is made into a soft capsule containing 1 mg of active ingredient in 1 capsule. 10,000 gel preparation Example 4 Ointment Compound of the present invention l.〇g mobile paraffin ίο.〇g setanol 20.0g White Vaseline 68.4 g Ethyl benzoate 〇. lg 1-menthol 〇. 5 g Total amount 1 OO. Og The above ingredients were mixed in a usual manner as a 1% ointment. Formulation Example 5 Sitting Agent Compound of the present invention 1 g -128- 201022223 Wei Tai Pu H15氺478g Wei Tai Pu W35* 520g Polysorbate 80 1 g Full amount l, 〇〇〇g * triglyceride The brand name of the compound is Weitaipu = Witepsol" φ The above ingredients are frequently melted and mixed, injected into a container and cooled and solidified to make 1,000 lg sitting agents containing 1 mg of the active ingredient. Formulation Example 6 Injection

Lmg 5 mL When the compound of the present invention is used for the injection of distilled water, after dissolution, the [pharmacological test example] is used to influence the effective non-reaction period. The test method is to anesthetize the Migru sodium with pentobarbital, and perform the middle chest opening under artificial respiration management. And cut the happy film to make the heart exposed. The electrocardiogram measurement was performed by placing a bipolar electrode on the surface of the right atrial free wall, the right atrial appendage, and the right ventricular free wall. The vagus nerve stimulation is performed using an electrical stimulation device that penetrates the indwelling nickel-chromium wire in the vagus nerve on both sides of the neck. Conditions for vagal nerve electrical stimulation -129- 201022223 for the ECG R R interval is about 1 〇 m s e c prolonged before the start of stimulation. The atrial and ventricular effective non-response periods were measured under the vagus nerve stimulation on both sides and the basic stimulation cycle of 300 msec, using a programmed electrical stimulation device, using the S 1-S2 external stimulation method. For the electrical stimulation of the heart palpitations, a current of 2 times the threshold is used, and after 1 〇 continuous S 1 stimulation is given in the basic stimulation cycle, the extra-stimulus S2 is added. In order to determine the effective non-reaction period, the S 1-S2 interval was shortened by 2 msec each time, and the point at which the reaction of the extra-stimulus S2 disappeared was an effective non-reaction period. The evaluation is performed on the atrial and ventricular effective non-response period before the drug is administered, and then each compound is administered intravenously at a dose of mg3 mg/kg or 0.6 mg/kg, and after 5 minutes, the atrial and ventricle are not effective. Determination of the reaction period. As a result, the prolongation time of the atrial and ventricular effective non-response period (Δ msec ) = [effective non-reaction period after drug administration] - [effective non-reaction period before drug administration] is expressed as an average 値 of 2 to 3 cases. Further, the compound to be administered is a free form, or a maleate or a hydrochloride is used depending on the case. General procedure for maleate formation In a solution of the compound (1 equivalent) in ethanol, maleic acid (1 equivalent) was added under reflux and stirred. After cooling, hexane was added, and the crystals were obtained by filtration, and dried under reduced pressure to give the desired product. -130-201022223 General method of hydrochloride formation In a solution of the compound (1 equivalent) in ethanol, a 10% hydrogen chloride-methanol solution (5 volume times) was added at room temperature, followed by stirring. Ether was added and stirred at 0 °C. The crystals obtained by filtration were crystallized and dried under reduced pressure to give the title compound. Results φ As shown in Table 1, the compound of the present invention showed an effect of prolonging atrial selective and non-reactive period.

Synthesis example number administration amount (mg/kg) Stereoscopic configuration atrial non-reaction period prolongation effect (Δmsec) 3 0.6 Racemic maleate 16.0 5 0.3 (3R* , 4S*) Free body 20.7 6 0.3 (3R *,4S" free body 18.0 7 0.3 (3R*,4S*) free body 16.0 9-A' 0.6 racemate maleate 18.0 9-A&quot; 0.6 racemate free body 16.0 10 0.3 (3R*, 4S *) Maleate 16.0 11 0.3 (3R*, 4S*) Maleate 27.3 13 0.6 (3R*, 4S" Free body 15.0 23 0.6 Race free body 30.7 30 0.3 (3R*, 4S*) Horse Acidate 18.7 [Industrial Applicability] The compound of the present invention has an effect of prolonging the effective non-reactive period of atrial selectivity, which can be used as an anti-atrial fibrillation drug and an upper ventricular rhythm remediation-131 - 201022223 therapeutic, available As a pharmaceutical product, the compound of the present invention contributes to the safety treatment of the above-mentioned arrhythmia disease because of its small influence on the ventricle.

Claims (1)

201022223 VII. Patent application scope: h A benzopyran compound or a pharmaceutically acceptable salt thereof, which is characterized by the formula (I) [Chemical 1] &quot;(CH2)n-R6 R and R are each independently 'a hydrogen atom, C!·6 alkyl group (the alkyl group may be halogen atom, C1·6 methoxy group (the alkoxy group may be optionally substituted by a halogen atom) Or optionally substituted by a group) or a C6_M aryl group (the aryl group may be via a halogen pronator, a hydroxyl group, a nitro group, a cyano group, a Cm alkyl group (the alkyl group may be via a halogen atom, a Cl_0 alkoxy group) The alkoxy group may be optionally substituted by a halogen atom) or a hydroxy group may be optionally substituted) or the ci. 6 alkoxy group (which may be optionally substituted by a halogen atom) may be optionally substituted, or R1 &amp; R2 together represent 〇 '= s , τλ 7 ( 7 is a hydrogen atom, C ^ 6 yards (the base can be halogen atom ' via a base or C1 · 6 alkoxy (the alkoxy can be optionally substituted by a halogen atom) Substituted), hydroxy, C1_6 alkoxy (the alkoxy group may be optionally substituted by a halogen atom), c^4 aryl, C2-9 heteroaryl (the aryl and heteroaryl groups may be substituted (R) Is a halogen atom, a hydroxyl group, a c, a -6 alkyl group (the pendant group can be abbreviated, an atom, a hydroxyl group or a Cl alkoxy group (the alkoxy group can be optionally taken by a halogen-133- 201022223 atom) ) Optionally substituted) , Cbe alkoxy (the alkoxy group, cyano group, formamyl group, formamidine group, orthoamine group, indeed, Base, C丨-6 alkylaminocarbonyl, di-, di-C 1 -6, C1 -6 alkylsulfonylamino, amine-carboxamidine, 6-alkylaminocarbonyl, -6-alkylcarbonyl , C, · 6 alkoxycarbonyl, sulfonylamino, alkyl sulfonyl, carboxyl or C6, 4 aryl carbonyl) optionally substituted, 〇 is an integer of ^3, when 〇 is 2 or 3 'R1G can For the same or different)), or together with the carbon atoms of the bond, (wherein 'j is an integer from 0 to 7, k is an integer from 0 to 7, and G is a single bond, CR8R9 (R8 and R9 are each independently a hydrogen atom, a C1-6 alkyl group (the alkyl group may be a halogen atom) , a hydroxyl group, a Ci.6 alkoxy group (the alkoxy group may be optionally substituted by a halogen atom), a C6-14 aryl group, a C2.9 heteroaryl group (the aryl group and the heteroaryl group may each be R1 ( (R1G and hydrazine are in the same meaning as defined above) and optionally substituted) 6 alkylcarbonyloxy, nitro, cyano, methionyl, carbylamino, amino, q-6 alkylamino, di C! .6 alkylamino group, s. 6 alkylcarbonylamino group, C 6 alkylsulfonylamino group, amine carbenyl group, G. 6 alkylaminocarbonyl group, di C!. 6 alkylamino group Carbonyl, C^6 alkylcarbonyl, C..6 alkoxycarbonyl, sulfonylamino, (^-6 alkylsulfonyl, carboxy or sulfonyl optionally substituted) -134- 201022223, C6·!4 a square group, a C2·9 heteroaryl group (the aryl group and the heteroaryl group may be optionally substituted by R10 (R1Q and hydrazine in the same meaning as described above)), a thiol group, and a Ci_6 oxy group (the hospital oxygen) The base may be optionally substituted by a dentate atom), a nitro group, a chloro group, a mercapto group, a formamidine group, a sulfonylamino group, a sulfonate group. Base, amine group, fee-based fee base, a Ci·6-based base-based 'Cl—homo-based sulfhydryl group, Cm-based sulfonylamino group, amine-mercapto-based group, c^6 alkylaminocarbonyl group , Ci 2 hexylaminocarbonyl, C!·6 alkylcarbonyl, Cl_e alkoxycarbonyl, sulfonylamino Q, Cl·6 alkylsulfonyl, carboxyl, C6. “arylcarbonyl or c2. a 9heteroaryl fluorenyl group (the arylcarbonyl group and the heteroaryl group may be optionally substituted by R1(R1〇 and 〇 in the same meaning as defined above)), or R8 and R9 may become 〇 or =s) 'nr^cr11 may be a hydrogen atom, c!-6 alkyl group (the alkyl group may be halogen atom, Ci-alkoxy group (the alkoxy group may be optionally substituted by a halogen atom), a hydroxyl group, a C6_M aryl group , c2_9 heteroaryl (the aryl and heteroaryl groups may be optionally substituted by 0 RlQ (Rl〇 and 〇 have the same meaning as defined above)) C1-6 alkylaminocarbonyl, di-C16 alkyl® Aminocarbonyl, Cl.6 alkylcarbonyl, C3-8 cycloalkylcarbonyl, c,-6 alkoxycarbonyl, Cm alkylsulfonyl, carboxyl, C(j M arylcarbonyl or C2.9 heteroaryl Any substitution of a carbonyl group), a C1_6 alkylaminocarbonyl group, a di-c16 alkylaminocarbonyl group C,·6 alkylcarbonyl, C3·8 cycloalkylcarbonyl, Ci 6 alkoxycarbonyl, Cu alkylsulfonyl, C6_M arylsulfonyl, or c2-9 heteroarylsulfonyl (the aromatic) Both the sulfonyl group and the heteroarylsulfonyl group may be optionally substituted by the above-mentioned r1〇 (R10 and hydrazine in the same meaning as defined above), a carboxyl group, a 〇-14-arylcarbonyl group or a C2.9 heteroarylcarbonyl group ( The arylcarbonyl group and the heteroarylcarbonyl group may be optionally substituted by one RQ (riq and hydrazine in the same meaning as described above) -135- 201022223), ο, s, SO or S〇2), and R3 is a transbasic group. Or Ci6 ethoxylated or bonded to R4, R4 is a hydrogen atom or bonded to R3, m is an integer of 0~4, η is an integer of 0~4, V is a single bond, CR12R13 (Ru has the same meaning as r8, r13 has the same meaning as r9), NR14 (R14 has the same meaning as Rh), 〇, 8, 8〇 or S〇2 - R5 is a hydrogen atom or C!_6 alkyl group (the alkyl group can be It is a halogen atom, a Ci 6 alkoxy group (the alkoxy group may be optionally substituted by a halogen atom) or an arbitrary substitution group via a radical, and R is a hydrogen atom, a thiol group (the hospital group may be a halogen atom, a oxy group) Alkoxy can be halogen Any optionally substituted), an amine group, a fluorenyl group or a hydroxy group optionally substituted), a C3.8 cycloalkyl group, a C3-8 cycloalkenyl group (the cycloalkyl group and the cycloalkenyl group may be a halogen atom, a C1-6 alkyl group (the alkyl group) It may be optionally substituted by a halogen atom, (^_6 alkoxy (the alkoxy group may be optionally substituted by a halogen atom), an amine group, a carboxyl group or a hydroxyl group), c]-6 alkoxy group (the alkoxy group may be a halogen atom) Any substitution), an amine group, a carboxyl group or a hydroxyl group optionally substituted), an amine group, a C, .6-based amine group, a di-Ci-6 alkylamino group, a C6"4 arylamino group '^2-9 heteroaryl group Amino groups (the arylamine group and the heteroarylamine group are all p's of Rl 5 (R15 and R1). The same meaning 'p and 〇 have the same meaning) arbitrarily substituted), C6-M aryl, C2_9 heteroaryl (the aryl and heteroaryl groups can be p by R18 (rH and Rl. same meaning, p is the same as 〇 Meaning) optionally substituted) ' or C2_9 heterocyclic group (the heterocyclic group may be a halogen atom, Ci 6 alkyl-136. 201022223 group may be a halogen atom, c].6 alkoxy (the alkoxy group may be toothed Any substitution of a pertinar atom), an amine group, an alkyl group or a hydrazine group, a CI2 alkoxy group (the oxy group may be optionally substituted by a halogen atom), a C614 aryl group, a c29 heteroaryl group (the square group and the hetero group) The bases can be optionally substituted by P's rM (r15 has the same meaning as r1G, P has the same meaning as 0). 'Through, nitro, aryl, formate, amide, amine, (16) Amine group, diCl 6-based amine group, C, -6 alkylcarbonylamino group, Cl 6 alkylsulfonylamino group, amine carbaryl hydrazine, Cl. 6 alkylaminocarbonyl, diCl·6 Alkenylaminocarbonyl, C,.6 alkylcarbonyl, Cu alkoxycarbonyl, sulfonylamino, Ci.6 alkylsulfonyl, carboxy or arylcarbonyl optionally substituted), R31 and R32 are each independently C16 alkyl, € 16 alkoxy, c! phenylcarbonylamino, (^-6 alkylaminocarbonyl, bis(alkylamino), C, .6 carbonyl, Ch alkoxycarbonyl, Cl-6 alkyl Sulfosyl (the alkoxy group, alkoxy group, alkylcarbonylamino group, C1_6 alkylaminocarbonyl group, bis--6-alkylaminocarbonyl group, alkylcarbonyl group, alkoxycarbonyl group and alkylsulfonyl group) It may be halogen atom, hydroxyl group, c! -6 alkoxy group (the alkoxy group may be optionally substituted by a halogen atom or a Ci-6 alkoxy group), C6.M aryl group, C2-9 heteroaryl group (the aryl group) And heteroaryl groups can be optionally substituted by q R16 (R16 and R1G have the same meaning, q has the same meaning as 〇), C!-6 alkylcarbonyloxy, nitro, cyano, formamyl, formazan Amino, amine, Ci. 6 alkylamino, di C -6 alkyl amine, 0!. 6 alkyl carbonyl amine, C -6 alkyl sulfonylamino, amine methyl fluorenyl , Ch 6 alkylaminocarbonyl, di Q -6 alkylaminocarbonyl, (6-6 carbonyl, Cm alkoxy fluorenyl, sulfonylamino, C 6 alkylsulfonyl, carboxyl or sulfonate Any substitution), C6-m aryl, C2_9 heteroaryl, -137- 201022223 arylcarbonyl, C2-9 heteroaryl carbonyl (the aryl , a heteroaryl group, an arylcarbonyl group and a heteroarylcarbonyl group may be optionally substituted by q ( Ri6 and q have the same meanings as defined above), a halogen atom, a hydroxyl group, a nitro group, a cyano group, a decyl group, a formamide. a sulfonylamino group, a sulfo group, an amine group, an amine carbaryl group, a sulfonylamino group or a carboxyl group, and R33 and R34 are each independently a hydrogen atom, a C.6 alkyl group, a d_6 alkoxy group, C! 6 alkylcarbonylamino, Cb6 alkylaminocarbonyl, diCl-6 alkylaminocarbonyl, Cu alkylcarbonyl, C丨-6 alkoxycarbonyl, alkylsulfonyl (the alkyl, alkoxy, The alkylcarbonylamino group, the d.6 alkylaminocarbonyl group, the dialkylaminocarbonyl group, the alkylcarbonyl group, the alkoxycarbonyl group and the alkylsulfonyl group may be a halogen atom, a hydroxyl group or a Cl-6 alkoxy group (the alkane) The oxy group may be optionally substituted by a halogen atom or a Ci.6-group oxy group, a c6.14 aryl group, or a C2-9 heteroaryl group (the aryl group and the heteroaryl group may be substituted by q of r16 (r16 has the same meaning as r1q) 'q and 〇 are the same meaning) and optionally substituted), (: 1-6 alkylcarbonyloxy, nitro, cyano, carbaryl, formamidine, amine, Cl-6 alkylamine, two C! .6 alkylamino, C^6 alkyl Amino group, Cl.6 alkylsulfonylamino group, amine carbenyl group, Ci.6 alkylaminocarbonyl group, diCl 6 alkylaminocarbonyl group, Ci.6 alkylcarbonyl group, Cm alkoxycarbonyl group , sulfonylamino, Cl_6 alkylsulfonyl, carboxy or sulfo optionally substituted), C6_14 aryl, C2-9 heteroaryl, C6_M arylcarbonyl, c2.9 heteroarylcarbonyl (the aryl, heteroaryl) And an arylcarbonyl group and a heteroarylcarbonyl group may be optionally substituted by q of R16 (R16 and q have the same meanings as defined above), a halogen atom, a hydroxyl group, a nitro group, a cyano group, a decyl group, a formamidine group, a sulfonate group. It is represented by a mercaptoamine group, a sulfo group, an amine group, an aminecarbamyl group, a sulfonylamino group or a carboxyl group. -138- 201022223 2 · A benzopyran compound as described in ηβ, or a pharmaceutically acceptable salt thereof, wherein 'RI and R2 are methyl groups, R3 is a hydroxyl group, R4 and R5 are a gas atom, and V is a single m is 2 or 3 and η is 〇. 3. A benzopyran compound according to item 1, wherein R and R are a methyl group, R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and v is a cr12r&quot; (r12^). Ci6 alkyl, Ci6 alkoxy (the alkyl and alkoxy group may be substituted by a halogen atom) or a hydroxyl group, R13 is a hydrogen atom), m is 1 or 2, and η is hydrazine. 4. The benzopyran compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are a methyl group, R3 is a hydroxyl group, R4 and R5 are a hydrogen atom, and V is \1114 (1114 is Ci_6). The alkyl group, the Cu alkoxy group (the alkyl group and the alkoxy group may be substituted by a halogen atom) or the gas atom) 'm is 1 or 2' η is 〇. 5. A benzopyran compound as claimed in claim 2, 3 or 4, or a salt permissible as said pharmaceutically acceptable drug, wherein R6 is a Ci-6 alkyl group. 6. A benzopyran compound as claimed in claim 2, 3 or 4 or a pharmaceutically acceptable salt thereof, wherein 'R6' is a C3·8 ring hospital base. 7. A benzopyran compound as claimed in claim 2, 3 or 4 or a pharmaceutically acceptable salt thereof, wherein R6 is a C6-m aryl group. 8. A benzoxanthene compound or a pharmaceutically acceptable salt thereof as claimed in claims 5, 6 and 7 wherein '-139- 201022223 contains a benzene ring of R31, R32, R33 and R34 according to formula (II) &gt;33 [wherein R31 and R32 are each independently, and are a Cu alkyl group, a Cu alkoxy Cu alkylcarbonylamino group, a Cu6 alkylaminocarbonyl group, a di Cu alkylaminocarbonyl group, a (^.6 alkyl group). Carbonyl group, (:, .6 alkoxycarbonyl group, Ci-6 alkylsulfonyl group (the alkyl group, alkoxy group, alkylcarbonylamino group, C, -6 alkylaminocarbonyl group, dialkylamino group) The carbonyl group, the alkylcarbonyl group, the alkoxycarbonyl group and the alkylsulfonyl group may be optionally substituted by a halogen atom, a hydroxyl group or a (1-6 alkoxy group (the alkoxy group may be optionally substituted by a halogen atom or a Cm alkoxy group), (: 6_14 aryl, C2j heteroaryl (the aryl and heteroaryl groups may be optionally substituted by q R16 (R16 and Rio have the same meaning 'q and 〇 have the same meaning), Cl-6 alkylcarbonyloxy, Nitro, cyano, methionyl, carbylamino, amine, Cl 6 alkylamino, di C!-6 decylamine, Cl-6 alkylcarbonylamino, Ci 6 alkylsulfonylamine Base, amine methyl, C!-6 alkylaminocarbonyl, diCl 6 alkylaminocarbonyl, C -6 -6 fluorenyl, Cl 6 alkoxycarbonyl, sulfonylamino, Cl. 6 alkane Any sulfonyl, sulfhydryl or sulfo group substituted, C614 aryl, c2_9 heteroaryl, C6- An arylcarbonyl group, a C 2 9 heteroarylcarbonyl group (the aryl group, heteroaryl group, aryl fluorenyl group and heteroaryl carbonyl group may be optionally substituted by q r16 (r16 and q are the same as defined above)), halogen Atom, hydroxy, nitro, cyano, formamidine-140- 201022223 base, formamidine, sulfonylamino, sulfo, amine, amine carbaryl, sulfonylamino or carboxy, R and R Each of them is a chlorine atom, a Ci_6 yard, a Ci.6 alkoxy group, a c1-6 alkylcarbonylamino group, a Cu alkylaminocarbonyl group, a diCl-6 alkylamino group, and a C丨·6. Affinity carbonyl, C -6 -6 oxycarbonyl, Ci-6 yard based expansion (the hospital base, the hospital oxy group, the hospital carbonyl amine group 'the hospital amine base group, the di C! -6 alkyl group The aminocarbonyl group, the alkylcarbonyl group, the alkoxycarbonyl group and the alkylsulfonyl group can be optionally substituted by a halogen atom, a hydroxyl group, a CU6 alkoxy group (the alkoxy group can be optionally substituted by a halogen atom or a Cm alkoxy group), c6_14 a group, a c29 heteroaryl group (the aryl group and the heteroaryl group may be optionally substituted by q of R16 (r16 and Rio have the same meaning 'q and 〇 have the same meaning), Ο:, -alkylcarbonyloxy, nitro , cyano, carbaryl, formazan Base, amine group, Cl 6 alkylamino group, dialkylamino group, c, -6 alkylcarbonylamino group, Cl 6 alkylsulfonylamino group, amine methyl group, C!. 6 alkylamine Carbocarbonyl, di-Ci6 alkylaminocarbonyl 'Cm-based group, c!_6-yard oxycarbonyl, expanded amine, Ci 6-based sulfonyl, carboxy or sulfo optionally substituted), c6.14 An aryl group, a c2.9 heteroaryl group, a Ce-i4 arylcarbonyl group, a C2-9 heteroarylcarbonyl group (the aryl group, the heteroaryl group, the arylcarbonyl group and the heteroarylcarbonyl group may be n16 by r16 (r16) And q have the same meaning as defined above), halogen atom, hydroxyl group, nitro group, cyano group, formic acid group, formamidine group, sulfonylamino group, sulfo group, amine group, amine methyl group, sulfonamide Expressed by base or carboxyl group]. 9. The benzopyran compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R31 is an alkyl group (the alkyl group may be a halogen atom, a hydroxyl group or a -141 - 201022223 alkoxy group (the alkoxy group) Any optionally substituted by a halogen atom or a Ci—alkoxy group), a halogen atom, a hydroxyl group, a C.6 alkoxy group (which may be optionally substituted by a halogen atom) or a nitro group, and R32 is a Cm alkyl group ( The alkyl group may be optionally substituted by a halogen atom, a hydroxyl group or an alkoxy group (which may be optionally substituted by a halogen atom or a C4 alkoxy group), a halogen atom, a hydroxyl group, a Ci. 6 alkoxy group (the alkoxy group) It may be optionally substituted by a halogen atom, a nitro group or an amine group, and R33 and R34 are a hydrogen atom. 10. A benzopyran compound as claimed in claim 5, 6 and 7, or a pharmaceutically acceptable salt thereof, wherein the benzene ring containing R31, R32, R33 and R34 is of the formula (m). R34 R3 R3 (Μ) [wherein R31 and R32 are each independently, and are Cl_6 alkyl, Cl_6 alkoxy, Ci-6 alkylcarbonylamino, hydrazine:, -6 alkylaminocarbonyl, di c!_6 Alkylaminocarbonyl, C^6 alkylcarbonyl, 匕.6 alkoxycarbonyl, Cl.6 alkylsulfonyl (the alkyl, alkoxy, alkylcarbonylamino, d4 alkylaminocarbonyl)匕6 alkylaminocarbonyl, alkylcarbonyl, alkoxycarbonyl and alkylsulfonyl can be halogen atom, hydroxyl group, (^.6 alkoxy group (the alkoxy group can be halogen atom or alkane) Oxygen optionally substituted), C6.14 aryl, C2.9 heteroaryl-142 - 201022223 (The aryl and heteroaryl groups can be optionally substituted by q of r16 (R16 and R10, q and 〇 have the same meaning) ), (: u6 alkyl carbonyl oxide, cyano group, methionyl group, formamidine group, amine group, C^-6-based group Cl. 6-alkylamino group, C丨-6 alkylcarbonylamino group, c丨·6 alkyl extension, amine carbaryl, q. 6 alkylaminocarbonyl, diCl 6 alkylamine Cl·6 fluorenyl, C -6 alkoxycarbonyl, sulfonylamino, C] Any substitution of fluorenyl, carboxy or sulfo), c6-14 aryl, c2.9 ❹ C^4 arylcarbonyl, C2j heteroarylcarbonyl ( The aryl, heteroarylcarbyl and heteroaryl groups can be optionally substituted by q r16 (r16 and q and meaning), halogen atom, hydroxyl group, nitro group, cyano group, formamidine group, sulfonyl group Amino group, sulfo group, amine group, amine formamidine group or carboxyl group, R33 and R34 are each independently, and are a hydrogen atom, a Cl.6 alkyl group, a group, a C?6 alkylcarbonylamino group, a Ct.6 alkyl group. Aminocarbonyl, diaminocarbonyl, C -6 alkylcarbonyl, C 丨 6 alkoxycarbonyl, C 丨 φ fluorenyl (the alkyl group, alkoxy group, alkylcarbonylamino group, q -6 alkane) The base, the di-Cbe alkylaminocarbonyl group, the alkylcarbonyl group, the alkoxycarbonylsulfonyl group may be optionally substituted by a halogen atom, a hydroxyl group, (^.6 alkoxy group (the alkane halogen atom or (^-6 alkoxy group) , C6-14 aryl aryl (the aryl and heteroaryl groups can be optionally substituted by q R16 (R16 and meaning, q and 〇 have the same meaning)), C|-6 alkyl nitro, cyano , mercapto, megluminyl, amine, Ci-6, s. 6, alkylamino, Cu6 alkylcarbonylaminoalkyl, amine carbaryl 'Ci-6 alkyl amine Carbonyl group, diCl_6 alkyl group, nitroamino group, dinonylamino group Carbonyl, .6 alkylsulfonylaryl, aryl, aryl, the same group, formazan, sulfonyl C 1 -6, oxy, C 1 -6, hexafluoro sulfonylcarbonyl, and oxyl The base can be, C2_9 hetero R1() is the same carbonyloxy group, arylamino group, sulfonylaminocarbonylcarbonyl-143-201022223, Cu alkylcarbonyl, C!-6 alkoxycarbonyl 'sulfonylamino group, Cl 6 The sulfonyl group, the carboxyl group or the sulfo group is optionally substituted) 'c: 6-, 4 aryl, c29 hetero group, C6. fluorenyl carbonyl, C 2.9 heteroaryl carbonyl (the aryl group, heteroaryl group) , an arylcarbonyl group and a heteroarylcarbonyl group may be optionally substituted by q of pg _ q and the same meaning), a halogen atom, a hydroxyl group, a nitro group, an aryl group, a mercapto group, a formamidine group, It is represented by a sulfonylamino group, a sulfo group, an amine 'amine alkanoyl group, a sulfonylamino group or a carboxyl group. 11. The benzopyran compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein 1131 is C!·6 alkyl (the alkyl group may be a halogen atom, a transalkyloxy group (the alkane) The oxy group may be optionally substituted by a halogen atom or an alkoxy group) or the G.6 alkylcarbonyl group may be optionally substituted with a 'C6^4 aryl group (the aryl group may be optionally substituted by q R16 (R16 and q have the same meanings as defined above) Substituted), dentate atom, hydroxyl group, C^6 alkoxy group (the alkoxy group may be optionally substituted by a halogen atom), nitro group, an aryl group, an amine group, a Ci.6-yard parent group, a Ci_6 alkoxy group a group, a carboxyl group, a 尺 32 is a Ci. 6 alkyl group (the alkyl group may be optionally substituted by a halogen atom, a hydroxyl group or a Ci 6 alkoxy group (the alkoxy group may be optionally substituted by a halogen atom or a C!·6 alkoxy group) Any substitution) a halogen atom, a hydroxyl group, a C1-6 alkoxy group (the alkoxy group may be optionally substituted by a pixel atom or a Cl. 6-group oxy group), a nitro group, a cyano group, an amine group, a &lt;^•6 alkyl group A carbonylamino group or an amine carbenyl group, R33 and R34 are a hydrogen atom, and when R32 is a nitro group, R31 is not an amine group. 12. The benzoxanthate compound as claimed in claims 5, 6 and 7 or the salt permitted by the drug of 144-201022223, wherein the benzene ring containing R31, R, R 3 and R34 is of the formula (〗 V ) (IV) [wherein R31 and R32 are each independently' are c]-6 alkyl, d-6 alkoxy, α-6 alkylcarbonylamino, alkylaminocarbonyl, diCi 6 alkylamino Carbonyl group, Cu alkylcarbonyl group, C!-6 alkoxycarbonyl group, Ci 6 alkylsulfonyl group (the alkyl group, alkoxy group, alkylcarbonylamino group, Ci-6 alkylaminocarbonyl group, one Cl·) 6 垸-based fe: base carbon-based, yard-based ore-based, alkoxy group and the base group can be halogen atom, hydroxyl group, (^.6 alkoxy group (the alkoxy group can be halogen atom or C]·6 alkoxy optionally substituted), (6-14 aryl, C2.9 heteroaryl (the aryl and heteroaryl groups can be q of r]6 (r16 has the same meaning as r1g' q In the same sense as hydrazine) optionally substituted), Cl_6 alkylcarbonyloxy, nitro, cyano, formyl, carbenamine, amine, Cl-6 alkylamine, di-Cualkylamine, Cu alkyl Carbonylamino, Cl.6 alkylsulfonylamino, aminemethanyl, C, alkylaminocarbonyl, bis(alkylaminocarbonyl, C)-6 carbonyl, Cu alkoxy Carbonyl, sulfonylamino, Cl_6 alkylsulfonyl, carboxy or sulfo optionally substituted), C6-14 aryl, C2-9 heteroaryl C6-M aryl fluorenyl, (: 2-9 heteroaryl carbonyl (the aryl, heteroaryl, aryl-145-201022223 decyl and heteroaryl carbonyl groups can be q by r16 (ri6 and q with the aforementioned In the same sense) optionally substituted), halogen atom, hydroxy group, nitro group, cyano group, methionyl group, amylamino 'sulfonylamino group, sulfo group, amine group, amine carbaryl group, sulfonylamino group or carboxyl group , R33 and R34 are each independently, and are a hydrogen atom, a Ci6 alkyl group, a Ci6 alkoxy group, a Cm-based carbonylamino group, a Ci6 alkylaminocarbonyl group, a di-Ci6 alkylamino group, a c,6 alkylcarbonyl group. , Cl 6 alkoxycarbonyl, Ci 6 alkylsulfonic acid (the aristoloyl, alkoxy, alkylcarbonylamino, Ci6 alkylaminocarbonyl, di-C,6-hexylaminocarbonyl, alkyl The carbonyl group, the alkoxycarbonyl group and the alkyl acid extension group may be optionally substituted by a halogen atom, a hydroxyl group or a C6 alkoxy group (the alkoxy group may be optionally substituted by a halogen atom or a Cm alkoxy group), a fluorene 6-14 aryl group, or a C2_9 group. Heteroaryl (the aryl and heteroaryl groups can be optionally substituted by q r16 (r16 and r1〇 have the same meaning 'q and 〇 have the same meaning), (:^6 alkylcarbonyloxy, nitro, cyanide Base, formazan, Amidino, amine, Ci 6 alkylamino, -C!-6 alkylamino, c!-6 alkylcarbonylamino, Cl 6 alkylsulfonylamino, amine methyl sulfhydryl, C! .6 alkylaminocarbonyl, diCl 6 alkylaminocarbonyl, C. 6 carbonyl, Cl 6 alkoxycarbonyl, sulfonylamino, Ci 6 alkylsulfonyl, carboxy or sulfo optionally substituted a c6-14 aryl group, a c2-9 heteroaryl group, a aryl group, a C2.9 heteroarylcarbonyl group (the aryl group, the heteroaryl group, the arylcarbonyl group, and the heteroarylcarbonyl group may all be q) R]6 (Ri6 and q have the same meanings as defined above), halogen atom, hydroxyl group, nitro group, cyano group, formamyl group, formamidine group, sulfonylamino group, sulfo group, amine group, amine group A Represented by a brewing group, a sulfonylamino group or a residue. 13. The benzopyran compound of claim 12 or a salt thereof, wherein R31 is a nitro group or an amine group, and R32 is a Cl-hospital group. An atom, a boundary group or a decyloxy group (the alkoxy group may be optionally substituted by a halogen atom) may be an amine group or an amine group or a group of R6 and R34 which are a hydrogen atom. A benzopyran compound or a pharmaceutically acceptable salt thereof, the lanthanide: 1, 1-{ 3-hydroxy-2,2-dimethyl-7-nitro-4-[(2-phenylethyl) Amino]-3,4-dihydro-2H-chromen-6-yl}propan-2-one, 丨_ (3_趣基·2 2_ dimethyl-7.nitro_4_ { [2_ (4_Chlorophenyl)ethyl]amino} _3,4-dihydro-2Η-chromen-6-yl)propan-2-one, 2,2-dimethyl-6·nitro_4· [(2-phenylethyl)amino]-3,4-dihydro-211-chromene-3,7-diol, 6-amino-2,2-methyl-4-[(2- Benzoethyl)amino]-3,4-dihydro-211-color dilute-3,7-diol, 2,2-dimethyl-7-nitro-4-[(2-phenylethyl) Amino group]· © 3,4-dihydro-2Η-chromene-3,6-diol, 7-bromo-6-methoxy-2,2-dimethyl-4_ [(2-benzene) Ethylethyl)amino]-3 ,4-dihydro-2Η-chroman-3-ol, 3-hydroxy-6-methoxy-2,2-dimethyl-4-[(2-phenylethyl)amino]_3,4 _Dihydro_211_chromene-7-carbonitrile, 3-hydroxy-2,2-dimethyl-7-nitro_4_[(2-phenylethyl)amino]-3,4-dihydrogen - 2Η -chromene-7-carbonitrile, 6-amino-3-hydroxy-2,2-dimethyl-4-[(2-phenylethyl)amino]_3,4-dihydro-2Η -chromene-7-carbonitrile, 6-amino-3-hydroxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2? Trohen-7-carboxyguanamine, 3-{ 3 -hydroxy-2,2·dimethyl-7-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro _2H-chromene-6-yl}benzoin-147- 201022223 acid ethyl, 2,2-dimethyl-7-nitro-6-phenyl-4-[(2-phenylethyl)amine ]-3,4-dihydro-2H-chromen-3-ol, 6-(4-methoxyphenyl)-2,2-dimethyl-7-nitro-4-[(2-benzene) Ethylethyl)amino]-3,4-dihydro-2H-chromene-3-ol, 2,2-dimethyl-7-nitro-6-(3-nitrophenyl)-4- [(2-Phenylethyl)amino]-3,4-dihydro-2H-chromen-3-ol, 3-hydroxy-2,2-dimethyl-7-nitro-4-[( 2-phenylethyl)amino]-3,4-dihydro-2H-chromene-6-carbonitrile, 3-carbyl-2,2- _• -7-Nitro-4-[(2-propenylethyl)amino]_ 3,4-dihydro-211-chromene-6-carboxylic acid methyl ester, 3-hydroxy-2,2-dimethyl 5--7-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-chromene-6-carboxylic acid, 7-amino-3-hydroxy-2, Methyl 2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-211-chromene-6-carboxylate, 6-bromo-2,2,5- Trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-chromen-3-ol, N-{3-hydroxy-2,2-dimethyl- 7-Nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-chromene-8-yl}acetamide, 2,2-dimethyl-6- Nitro-4-[(2-phenylethyl)amino]-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-3-ol, 2,2-dimethyl -6-nitro-4-[(2-phenylethyl)amino]-5-(trifluoromethyl)-3,4-dihydro-2H-chromen-3-ol, 8-amino group -2,2-dimethyl-7-nitro-4-[(2-phenylethyl)amino]_3,4_-gas-211-chromic-3-ol, 6-amino-2, 2-monomethyl-4-[(2-phenylethyl)amino]-7-(trifluoromethyl)-3,4-dihydro-2H-chroman-3-ol, 6-amino group -2,2-Methyl-4-[(2-phenylethyl)amino]-5-(trifluoromethyl)-3,4-dihydro-2H-chromen-3-ol, 2 ,2-dimethyl-8-nitrate 4-[(2-Phenylethyl)amino]-6-(trifluoromethyl)-3,4-dihydro-2H-chromen-3-ol, 5-fluoro-2,2-di Methyl-8-nitro-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-chromen-3-ol, 6-methoxy-2,2-di Methyl-8-nitro-148- 201022223 -4-[(2-phenylethyl)amino]-3,4-dihydro-2H-chromen-3-ol, 6-bromo-2,2 , 8-trimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-chromen-3-ol, 5-bromo-8-methoxy-4- [(2-Phenylethyl)amino]-3,4·dihydro-21^-chromen-3-ol or 6-bromo-2,2,5,7-tetramethyl-4-[( 2-Phenylethyl)amino]-3,4-dihydro-2H-chromen-3-ol. A medicinal composition comprising the benzopyran compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient 〇16. A cardiac arrhythmia therapeutic agent, characterized in that The benzopyran compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, is contained as an active ingredient. -149- 201022223 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 -3- 201022223 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: [Chemical 1] r3^V^^^r3 , R2 R5, XCH2)m-V-(CH2)n-R6 R31 R4 -4-