TW200948817A - Aminocyclohexane derivatives - Google Patents

Abstract

It is eager in the development of a medicament showing broad extent and strongly antibacterial activity to Gram-positive bacteria, Gram-negative bacteria, and the antibiotics-resistant bacteria thereof, and having high safety. In this circumstance, the inventors keep up an uninterrupted study and have found that the compound represented by the following formula (I) or the salt thereof showing broad extent and strongly antibacterial activity to Gram-positive and Gram-negative bacteria, and meanwhile, having high safety, which can be used to be as antibacterial medicaments and prophylactic and therapeutic medicaments to infections, consequently, the present invention is achieved. Namely, the present invention provides a compound represented by the Following formula (I), the salts, or hydrates thereof. Namely, the present invention is: (1) a compound represented by the following formula (I), the pharmacologically acceptable salts, or hydrates thereof.

Description

200948817 VI. Description of the Invention: The present invention relates to a novel compound having a superior antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, or a salt thereof, and an antibacterial agent containing the same. [Prior Art] At the medical site, various antibiotics or synthetic antibacterial agents have been used for the treatment of infectious diseases. However, in recent years, drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococcus (VRE), and penicillin-resistant pneumococcal (PRSP) have emerged. The treatment of patients infected with these drug-resistant bacteria has become an important issue. In addition, a number of drug-resistant bacteria that have acquired resistance to multiple drugs have emerged, and infectious diseases from multiple drug-resistant bacteria have become refractory diseases and become worldwide. Big problem. An antibiotic or an antibacterial agent which is effective against such a drug-resistant bacterium is strongly expected. For example, Patent Document 1 discloses a quinolinone-based compound which exhibits an effect against a drug-resistant Gram-positive bacterium. Further, as a compound having an action mechanism different from the existing drug, the compounds described in Patent Documents 2 to 6 and the like are known. PRIOR ART DOCUMENT PATENT DOCUMENT Patent Document 1 International Publication No. 2002/40478 Booklet Patent Document 2 International Publication No. 2006/1 34378 Booklet Document 3 International Publication No. 200 6/137485 Booklet Patent Document 4 International Publication No. 200 Booklet No. 7/16610 Patent Document 5 International Publication No. 2007/71936 Booklet Patent Document 6 International Publication No. 2007/8 1 597 Booklet 200948817 Summary of the Invention The subject to be solved by the invention is Gram-positive The development of pharmaceuticals, Gram-negative bacteria, and these resistant bacteria exhibiting a wide range of strong antibacterial activity and high safety is eagerly desired. In view of the above, the present inventors have continuously conducted a review and found that the compound represented by the formula (I) or a salt thereof exhibits a wide range and strongness against Gram-positive bacteria and Gram-negative bacteria. The present invention has been completed as a preventive/therapeutic agent for antibacterial agents and infectious diseases which has high antibacterial activity and high safety. That is, the present invention provides a compound represented by the following formula (I), a salt thereof, or a hydrate of the above. That is, the present invention provides: (1) a compound represented by the formula (I) or a pharmacologically acceptable thereof

In the formula, X1 and X2 each independently represent a nitrogen atom or a carbon atom bonded to one hydrogen atom; X3 represents a nitrogen atom or a general formula CRla (wherein the substituent Ru represents a halogen atom, a cyano group, and may be substituted a lower alkyl fluorenyl group or a group selected from the substituent group α): X4 represents a nitrogen atom or a general formula CRlb (wherein the substituent R1 represents a halogen atom, a cyano group, a lower alkyl alkane group which may be substituted or selected from A group of the substituent group α 200948817; A1 represents a general formula CR2 (wherein the substituent R2 represents: a bond with an atom on an adjacent L1, or a bond with an adjacent A2 to form a double bond a bond, a halogen atom, a cyano group, or a group selected from the substituent group α, or a nitrogen atom; Α2 represents a general formula CR3R4 (wherein the substituents R3 and R4 are each independently: when A1 is a general formula CR2, a bond to A1, or a bond to form a double bond, a halogen atom, a cyano group, or a group selected from the substituent group α, or a bond to A3 (A3 itself is a bond) R3, R4 are integrated to form a side oxy group or form a Substituted hydroxyimino), NR5 (wherein, the substituent R5 is: when Α1 is a general formula CR2, the bond with Α1 is integrated, or the bond with Α3 (Α3 itself is a bond of Α4) a bond which forms a double bond, or a group selected from the substituent group α, an oxygen atom, or an oxidizable sulfur atom; Α3 is a general formula CR6R7 (wherein the substituents R6 and R7 are each independently: 200948817 The bond to the adjacent A2 or A4 is bonded to form a double bond, a halogen atom, a -cyano group, or a group selected from the substituent group α, or R6 and R7 are integrated to form a pendant oxy group, or form a hydroxyimine group which may be substituted, NR8 (wherein, the substituent R8 represents: a bond of 〇 with an adjacent Α2, or a bond with Α4 to form a double bond, or a substituent group α a base, an oxygen atom, an oxidizable sulfur atom, or a bond; Α4 represents the general formula CR9R1() (wherein the substituents R9 and R1() are each independently:

a bonding bond which forms a double bond with a bonding bond of adjacent A3 (A3 itself is a bonding bond, A2) to form a double bond, a halogen atom, a cyano group, or a group in which a hydroxyl group which may be substituted is selected from the substituent group α Or a combination of R9 and R1() to form a pendant oxy group, an imido group), NR11 (wherein the substituent R11 represents: A2) and an adjacent A3 (A3 itself is a binding bond field #200948817 a bond that forms a double bond, or a group selected from the substituent group α, an oxygen atom, or an oxidizable sulfur atom; L1 represents a bond with Α1 and can be substituted with a group selected from the substituent group β Carbon atom: Q1 is a structure between L1 and L2 represented by the following formula (II) (* each represents a bond)

Ζ1 and Ζ4 each independently represent the general formula CR2e (wherein the substituent R20 represents a halogen atom, a cyano group, or a group selected from the substituent group α), or a nitrogen atom; Ζ2, Ζ3, Ζ5, and Ζ6 each independently represent: General formula CR21R22 (wherein the substituents R21 and R22 each independently represent: a halogen atom, a cyano group, or

It is selected from a substituent group (the group of X, or R21, R22 are integrated to form a pendant oxy group, or a substituted hydroxyimino group); Z7 represents a nitrogen atom which may be substituted with a group selected from the substituent group γ , an oxygen atom, an oxidizable sulfur atom, or a bond, L2 represents a general formula: Υ3-Υ4-Υ5 - (Υ3 represents an atom which can be bonded to Ζ7 on Q1, a pendant oxy group, and a substituent group selected from a gamma-substituted carbon atom, or an oxidizable sulfur atom; Υ4 represents a bond, 200948817, a gastric substitution of a group from the substituent δ of the stomach and which can form a multiple bond with an adjacent carbon atom; Υ5 represents a bond, a carbon atom substituted by a group selected from the substituent group δ and capable of forming a multiple bond with an adjacent carbon atom, a nitrogen atom which may be substituted with a group selected from the substituent group γ, an oxygen atom, or an oxidizable sulfur Atom); Ο Q2 is a heterocyclic structure of a fused bicyclic "6-membered ring/6-membered ring_" or "6-membered ring/membered ring" represented by the following formula (III), or a single atomic number of 5 to 7 Ring structure (* indicates the bond with L2),

(ΙΠ)

〇Z8, Z9, Z1Q, Ζ15, Ζ16, and Ζ17 are each independently represented: a carbon atom or a nitrogen atom which may be substituted with a group selected from the substituent group ε and a lower alkoxy group which may be substituted; Ζ11, Ζ14, Ζ18, and Ζ2<) each independently represent: a nitrogen atom, an oxygen atom, or an oxidizable sulfur atom which may be substituted with a group selected from the group of substituents, 200948817 Further, these may be adjacent to z12, Z13, Or Z19 forms a double bond; Z12, Z13, and Z19 each independently represent: a carbon atom which may be substituted with a group selected from the substituent group ε, and a pendant oxy group, and a nitrogen atom which may be substituted with a group selected from the substituent group ζ , an oxygen atom, or an oxidizable sulfur atom; further, these may form a double bond with an adjacent atom, Ζ21, Ζ22, Ζ23, Ζ24, Ζ25, Ζ26, Ζ27, Ζ28, Ζ29, Ζ30, Ζ31, Ζ32, Ζ33, Ζ34, Ζ35, Ζ36, Ζ37, and Ζ38 each independently represent a carbon atom which may be substituted with a group selected from the substituent group η, a nitrogen atom which may be substituted with a group selected from the substituent group 、, an oxygen atom, or Oxidized sulfur atom, and further, such The attached atoms form a double bond.

[Substituent group α]: a hydrogen atom, a lower alkyl group which may be substituted, a lower alkenyl group which may be substituted, a monocyclic hydrocarbon ring group or a heterocyclic group which may be substituted, a hydroxyl group which may be protected or substituted, Substituted lower alkoxy, protected or substituted amine group, azide group, substituted methylidene group, protected carboxyl group, substituted amino group carbonyl group, substituted lower alkyl group A sulfonyl group, a lower alkyl sulfinyl group which may be substituted, and an amine sulfonyl group which may be substituted. [Substituent group Ρ]: a hydrogen atom, a halogen atom, a cyano group, a protected or substituted hydroxyl group, a protected or substituted amino group, a protected carboxyl group, a substituted aminocarbonyl group, or a substituted group The lower alkylsulfonyl group, the substituted aminosulfonyl group, the pendant oxy group, and the hydroxyimino group which may be substituted. -10-200948817 [Substituent group γ]: a hydrogen atom, a lower alkyl group which may be substituted, a lower alkyl alkane group which may be substituted, a protected carboxyl group, a substituted aminocarbonyl group, a substitutable lower stage An alkylsulfonyl group, and a substituted aminosulfonyl group. [Substituent group δ]: a hydrogen atom, a halogen atom, a hydroxy group which may be protected or substituted, a lower alkoxy group which may be substituted, a pendant oxy group, and a hydroxyimino group which may be substituted. [Substituent group ε] · A hydrogen atom, a halogen atom, and a lower-grade hospital group which can be substituted. Ο [Substituent group ζ]: a hydrogen atom, a lower alkyl group which may be substituted, a hydroxyl group which may be protected or substituted, and a lower alkoxy group which may be substituted. [Substituent group η]: a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted, a lower alkenyl group which may be substituted, a hydroxyl group which may be protected or substituted, a lower alkoxy group which may be substituted, a cyano group, Protected pendant oxy group, substituted hydroxyimino group, protected carboxyl group, substituted aminocarbonyl group, and amine group which may be protected or substituted. [Substituent group Θ]: a hydrogen atom, a lower alkyl group which may be substituted, a hydroxyl group which may be protected or substituted, a lower alkyl alkane group which may be substituted, a lower alkoxycarbonyl group which may be substituted, may be substituted The aminocarbonyl group, the substituted aminosulfonyl group, and the lower alkylsulfonyl group which may be substituted; (2) The compound of the above (1) or a pharmacologically acceptable salt thereof, wherein X1 (3) The compound of the above (1) or a pharmacologically acceptable salt thereof, wherein X4 is CH; (4) The compound according to any one of the above (1) to (3) or a pharmacological agent thereof And a pharmacologically acceptable salt thereof, wherein A4 is an oxygen atom, and a pharmacologically acceptable salt thereof, wherein A1 is an oxygen atom; (6) The compound of any one of the above (1) to (3), wherein A1 is a nitrogen atom and A4 is an oxygen atom; (7) the above (1)~( 6) The compound according to any one of the compounds of the formula (I) or a pharmacologically shared salt thereof, wherein the compound of the general formula (I) is a tricyclic structure represented by the general formula (la) Indicates the bond with L1; X2, Rla,

Rlb, R5, R8, and R11 are as defined for the substituent of the general formula (I):

The compound described in any one of the above (A) or a pharmacologically acceptable salt thereof, wherein L1 is -CH2· or -C(=〇) (9) The compound according to any one of (8), wherein Q1 is a structure between L1 and L2 represented by the following formula (IV), wherein R23 and R24 are each independently Hydrogen atom, hydroxymethyl, (2-amino-1,2-di-oxyethyl)aminomethyl, (aminosulfonyl)aminomethyl, 1,2,3-triazole- 1-yl, hydroxy, aminocarbonyloxy, amine, ethylamino, methylamino, dimethylamino, azide, carboxyl, aminocarbonylcarbonyl, pendant oxy, or oxime -methylhydroxyimino group; * each represents a binding bond)

(10) The compound of any one of the above (1) to (9), wherein L2 is -CH2- or -CH2-CH2-; (11) (1) to (1) Or a pharmacologically acceptable salt thereof, wherein Q2 is 2,3-dihydro[1,4]dioxino[2,3-b]pyridine -7·yl, 2,3-dihydro[1,4]dioxin[2,3-c] pyridine-7-yl, 2,3-dihydrobenzo[1,4]dioxin -6-yl, 8-methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]indole-6-yl, 8-methyl-3-oxooxy -3,4-dihydro-2Η-benzo[1,4]indole-6-yl, 5-methyl-3-oxooxy-3,4-dihydro-2H-benzo[1,4噚-6-yl, 7-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]indole-6-yl, 2-methyl-3. Oxy-3,4-dihydro-2H-benzo[1,4]indole-6-yl, 2-fluoro-3-indolyl-3,4-dihydro-2H-benzo[1, 4] 哔-6-yl, 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-yl, 3-sided oxy -3,4-dihydro-2H-benzo[1,4]sain-6-yl, 3-sidedoxy-13- 200948817 -3,4-dihydro-2H-pyrido[3,2- b][l,4] timol-6·yl or cyclohexyl; (12) a medicine The compound according to any one of the above items (1) to (11) or a pharmacologically acceptable salt thereof; (13) a use of the above (1) to (11) (1) An antibacterial agent characterized by containing the compound according to any one of the above (1) to (u) or a pharmacologically acceptable thereof, or a pharmacologically acceptable salt thereof; And a pharmacologically acceptable salt thereof. The compound according to any one of the above (1) to (11) or a pharmacologically acceptable salt thereof.效果 Effect of the invention The compound of the formula (I) or a salt thereof has strong antibacterial activity and is useful as an antibacterial agent. Further, the compound of the general formula (I) or a salt thereof has a strong antibacterial effect against a drug-resistant fungus such as MRSA, and is excellent in tissue migration property, and is useful as an antibacterial agent. [Embodiment] Mode for carrying out the invention Hereinafter, the compound of the present invention will be described in detail. As used herein, unless otherwise specified, "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; "lower courtyard" means methyl, ethyl, η-propyl, η-butyl. , a linear or branched alkyl group having a carbon number of 1 to 6 such as η-pentyl, isopropyl, isobutyl, first butyl or second butyl, and "lower suspicion" A linear or branched alkenyl group having 1 to 6 carbon atoms such as methylidene, ethyl bromide, 1-propenyl or 2-propenyl. "Lower alkoxy" means methoxy, ethoxy, η-propoxy, n-butyl-14 - 200948817 oxy, η-pentyloxy, isopropoxy, isobutoxy, third a linear or branched alkoxy group having a carbon number of 1 to 6 such as a butoxy group, etc. "lower alkyl fluorenyl group" means an ethyl fluorenyl group, an η-propyl fluorenyl group, an η-butyl fluorenyl group, an isobutyl fluorenyl group, and a trimethyl group. A linear or branched thiol group having a carbon number of 1 to 6 such as a thiol group. The "lower alkylsulfinyl" group means a methyl sulfinyl group, an ethylsulfinyl group, an η-propylsulfinyl group, an isopropylsulfinyl group or the like having a carbon number of 1 to 6 A chain or branched alkyl sulfinylene group. 〇 "Lower alkylsulfonyl" means a linear or branched carbon number of 1 to 6 such as methylsulfonyl, ethylsulfonyl, η-propylsulfonyl, or isopropylsulfonyl. Dendritic alkylsulfonyl. The "lower alkoxycarbonyl group" means a linear chain having a carbon number of 2 to 7 such as a methoxycarbonyl group, an ethoxycarbonyl group, a η-propoxycarbonyl group, an isopropoxycarbonyl group, a third butoxycarbonyl group or the like. Branched alkoxycarbonyl. The "lower alkyl group which may be substituted" includes an unsubstituted lower alkyl group, for example, a lower alkyl group substituted with a hydroxyl group, an alkoxy group, an amine group, a carboxyl group, an amine mercapto group, a halogen atom or the like, and examples thereof Hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl, aminomethyl, carboxymethyl, aminemethylmethylmethyl, 2- Fluoroethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, and the like. The "lower alkenyl group which may be substituted" includes an unsubstituted lower alkenyl group such as a lower alkenyl group substituted by a hydroxyl group, an alkoxy group, an amine group, a carboxyl group, an amine mercapto group, a halogen atom or the like, and examples thereof may be mentioned. A group, a difluoromethylene group, a vinyl group, a 1-fluorovinyl group, a 2-carboxyvinyl group, a 3-hydroxy-1-propenyl group, a 3-amino-1-propenyl group or the like. -15- 200948817 "Substitutable lower-grade alkoxy group" includes an unsubstituted lower-grade alkoxy group, for example, a lower alkoxy group substituted by a hydroxyl group, an alkoxy group, a halogen atom or the like, and may be exemplified as 2-hydroxy group B. Alkoxy, 2-methoxyethyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethyloxy, 丨-fluoroethyloxy, 1,1 - Difluoroethyloxy, 2,2,2-trifluoroethyloxy, and the like. The "lower alkyl alkane group which may be substituted" includes an unsubstituted lower alkyl fluorenyl group, for example, a lower alkyl fluorenyl group substituted with a hydroxyl group, an alkoxy group, a halogen atom or the like, and examples thereof include a hydroxyethyl group and a methoxy group. Ethylene, trifluoroethenyl, 2-fluoro-2-methylpropanyl and the like. The "lower alkylsulfinyl group which may be substituted" includes an unsubstituted lower alkylsulfinyl group, for example, a lower alkylsulfinyl group substituted by a hydroxyl group, an alkoxy group, a halogen atom or the like. Examples thereof include 2-hydroxyethylsulfinyl group, 2-methoxyethylsulfinyl group, fluoromethylsulfinyl group, difluoromethylsulfinyl group, trifluoromethylsulfinyl group, 2-fluoroethylsulfinyl, 1,1, difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, and the like. The "lower alkylsulfonyl group which may be substituted" includes an unsubstituted lower alkylsulfonyl group, for example, a lower U-alkylsulfonyl group substituted by a hydroxyl group, an alkoxy group, a halogen atom or the like, and examples thereof 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonate Base, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl and the like. "Substitutable aminocarbonyl" includes unsubstituted aminocarbonyl ', for example, substituted by methyl, 2, hydroxyethyl, 2-methoxyethyl, 2-fluoroethyl, ethyl fluorenyl, etc. The aminocarbonyl group may, for example, be N-methylaminocarbonyl, hydrazine, fluorenyl-dimethylaminocarbonyl, fluorenyl-(2-hydroxyethyl)aminocarbonyl or hydrazine-(2-methoxy-16- 200948817 Ethyl)aminocarbonyl, N-(2.fluoroethyl)aminocarbonyl, N-(ethinyl)aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, and the like. "Substitutable aminosulfonyl" includes unsubstituted aminosulfonyl, for example, methyl, 2-hydroxyethyl, 2-methoxyethyl, 2-fluoroethyl, ethyl Examples of the amino group sulfonyl group substituted by a mercapto group include N-methylaminosulfonyl group, N,N-dimethylaminosulfonyl group, and N-(2-hydroxyethyl)aminosulfonyl group. , N-(2-methoxyethyl)aminosulfonyl, N-(2-fluoroethyl)aminosulfonyl, N-(ethinyl)aminosulfonyl, etc. The protected hydroxy group includes, in addition to the unprotected hydroxy group, a hydroxy group which may be substituted with all of the groups which may be used as a usual hydroxy protecting group. For example, Greene, Wuts et al., Protective Groups in Organic Synthesis, 4th edition, pp. 1 6-366, 2006, John Wiley & Sons, Inc. Specific examples thereof include a methyl group, an ethenyl group, a trimethylethenyl group, a tert-butyl group, a benzyl group, a methoxymethyl group, a benzyloxymethyl group, a methanesulfonyl group, and a P group. -Toluenesulfonyl group, trimethyldecylalkyl group, tert-butyldimethylmethylalkyl group or the like is used as a protective group. The "hydroxy group which may be substituted" means, in addition to the unsubstituted hydroxyl group, for example, a hydroxyl group substituted with a phenyl group, a pyridyl group, an aminocarbonyl group, an aminosulfonyl group or the like. The "protectable amine group" includes, in addition to the unprotected amine group, all the groups which can be generally used as the amine group protecting group, and examples thereof include, for example, Greene, Wuts et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 696-926, 2006, John Wiley & Sons, Inc. Examples. Specific examples thereof include a mercapto group, an ethyl fluorenyl group, a trifluoroethyl fluorenyl group, a trichloroethylene group, a trimethyl ethane group, a benzhydryl group, a fluorenyl group, and a -17-200948817 trityl group. Allyl, benzyl, P-methoxybenzyl, methoxycarbonyl, benzyloxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyloxycarbonyl, methanesulfonyl, P a toluenesulfonyl group, a benzylidene group, a diphenylmethylene group, a diphenylphosphonium group, a tert-butylsulfinyl group, a trimethyldecyl group, a tert-butyldimethylalkyl group, or the like. The "substituted amino group" means, in addition to the unsubstituted amino group, for example, methyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 2-fluoroethyl a substituted amino group such as a phenyl group, a pyridyl group, an aminocarbonyl group or an aminosulfonyl group. Ο "Protectable carboxyl group" includes all of the groups which can be used as a usual carboxyl group in addition to the unprotected carboxyl group, and examples thereof include Greene 'Wuts et al., Protective Groups in Organic Synthesis, No. 4 Edition, pp. 53 3 - 646, 2006, John Wiley &

An example of the records of Sons, Inc. Specific examples thereof include a methyl group, an ethyl group, a third butyl group, a (9-fusyl)methyl group, an allyl group, a benzyl group, a diphenylmethyl group, a trityl group, and a trimethyl decane. Base, tert-butyldimethylmethylalkyl and the like. The "substituted hydroxyimino group" means, in addition to the unsubstituted hydroxyimino group, for example, a methyl group, a difluoromethyl group, a 2-diabase group, a 2-methoxy group, and the like. Hydroxyimine substituted with an oxygen atom such as ethyl, 2-fluoroethyl, (hydroxycarbonyl)methyl, difluoro(hydroxycarbonyl)methyl, benzyl, decyl, aminocarbonyl, aminosulfonyl, and the like Base. The "protectable side oxy group" includes, in addition to the unprotected pendant oxy group, all the groups which can be used as a usual carbonyl protecting group, and for example, Greene, Wuts, etc., Protective Groups in Organic

Synthesis, 4th edition, pp. 43 5-527, 2006, j〇hn Wiley & -18- 200948817

An example of the records of Sons, Inc. Specific examples thereof include a dimethyl ketal group, a 1,3-dioxanyl group, and a 1,3-dioxolyl group. The "lower alkoxycarbonyl group which may be substituted" means, in addition to the unsubstituted lower alkoxycarbonyl group, for example, a lower alkoxy group substituted with a halogen atom, a hydroxyl group, an alkoxy group, a substituted amino group or the like. Examples of the carbonyl group include a 2-hydroxyethyloxycarbonyl group, a 2-methoxyethyloxycarbonyl group, a fluoromethoxycarbonyl group, a difluoromethoxycarbonyl group, a trifluoromethoxycarbonyl group and the like. The "mercaptomethyl group which may be substituted" means, in addition to the unsubstituted formazan group, for example, amidoxime, anthracene-methylammonium group and the like. The "monocyclic hydrocarbon ring group or heterocyclic group which may be substituted" means a ring which may contain a carbon, nitrogen, oxygen or sulfur atom in the ring constituent atom and which constitutes a saturated or unsaturated cyclic substitution of 3 to 7. Base, for example, except phenyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thiophenyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrahydrofuranyl Examples of the unsubstituted monocyclic substituent such as a oxazolidinyl group, a pyrrolidinyl group or a phenolyl group include a monocyclic substituent substituted with a pendant oxy group, a carboxyl group, an amine formazan group or the like. Wait. ❹ "Oxidizable sulfur atom" may, for example, be -S ( 〇 2 ) -, -S ( 0 ) -, and -S-. Hereinafter, specific examples and preferred examples of the present compound will be exemplified. X1 and X2 each independently represent a nitrogen atom or a carbon atom bonded to one hydrogen atom. Preferably, X1 is a nitrogen atom, X2 is a carbon atom or a nitrogen atom bonded to one hydrogen atom, and particularly preferably, X1 is a nitrogen atom. X2 is a carbon atom bonded to one hydrogen atom. X3 represents a nitrogen atom, or a general formula CRla (wherein Ria means a halogen atom, a cyano group, a lower alkyl alkane group which may be substituted, or a group selected from the substituent group α), -19-200948817 The general formula CRla is Preferably, the substituent Rla is a halogen atom, a cyano group, a lower alkoxy group which may be substituted, a lower alkyl group which may be substituted, a monocyclic hydrocarbon ring group which may be substituted or a heterocyclic group, may be protected or substituted a hydroxy group, a lower alkoxy group which may be substituted, an amine group which may be protected or substituted, an azide group, a substituted methylide group, a protected carboxyl group, a substituted amino group carbonyl group, may be substituted The lower alkylsulfonyl group, the lower alkyl sulfinyl group which may be substituted, and the aminosulfonyl group which may be substituted. Specific examples of Rla include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, an ethyl sulfonyl group, an η-propyl fluorenyl group, an η-butyl fluorenyl group, an isobutyl fluorenyl group, a trimethyl acetyl group, and a hydroxy group B. Sulfhydryl, methoxyethyl, aminoethyl, methylaminoethyl, dimethylaminoethyl, fluoroacetamido, difluoroacetamido, trifluoroethenyl, 2-fluoro-2-methylpropanyl, 2,2-difluoropropenyl, methyl, ethyl, η-propyl, η-butyl, η-pentyl, isopropyl, isobutyl , second butyl, tert-butyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, methoxyethyl, amine Methyl, methylaminomethyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl Base, 1-fluoroethyl, 2,2,2-decyltrifluoroethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl, amidino-2-hydroxyethyl, 2- Amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1.hydroxyl Ethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-1,2-di-oxyethyl, 1-amino-1-carboxyl Methyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, vinyl, 1-fluorovinyl, 2-fluoroethylene Base, 2,2-difluorovinyl, 1-propenyl, 2-propenyl, 2-carboxyvinyl, 2-carboxy-1-fluorovinyl, 2-carboxy-2-fluorovinyl, 2-carboxyl -20- 200948817 -1,2-Difluorovinyl, 2-carboxy-1-hydroxyvinyl, 2·carboxy-2·hydroxyvinyl, 3-hydroxy-1-propenyl, 3-amino-1- Propylene, phenyl, 3-carboxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-carboxy-2-pyridyl, 5-carboxy-2.pyridyl, 5-carboxy-3 -pyridyl, 6-carboxy-3-pyridyl, thiophenyl, 4-carboxythiophenyl, 5-carboxythiophenyl, 2-thiazolyl, 4-carboxy-2-thiazolyl, 5-carboxy-2 -thiazolyl, 4-thiazolyl, 2-carboxy-4-thiazolyl, 5-thiazolyl, 2-carboxy-5-thiazolyl, 1-pyrrolyl, 3-carboxy-1-pyrrolyl, 2-pyrrolyl , 4·carboxy-2-pyrrolyl, 5-carboxy-2-pyrrolyl, 3-pyrrolyl 5-〇carboxy-3-pyrrolyl, 1-pyrazolyl, 3-carboxy-1-pyrazolyl, 4-carboxy-1-pyrazolyl, 3-pyrazolyl, 5-carboxy-3-pyrazole , 4-pyrazolyl, 4-pyrazolyl, 1-imidazolyl, 4-carboxy-1-imidazolyl, 2-imidazolyl, 4-carboxy-2-imidazolyl, 4-imidazolyl, 2-carboxyl 4-imidazolyl, 1,2,3-triazol-1-yl, 4-carboxy-1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1 ,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 5-carboxy-1,3,4-triazol-2-yl, 2-tetrahydrofuranyl, 4-carboxyl -2-tetrahydrofuranyl, 5-carboxy-2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 5-carboxy-3-tetrahydrofuranyl, 2-oxooxazolidin-3-yl, 5-carboxy-2-oxo Keazolidine-3-yl, 2-oxooxazolidin-4-yl, 2-oxooxazolidin-5-yl, 4-morpholino, 2-carboxy-4-? Florinyl, hydroxy, methoxymethyloxy, benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecyloxy, triethyldecyloxy, third Dimethyl decyloxy, tert-butyldiphenyl decyloxy, ethoxycarbonyl, trifluoroethaneoxy, trichloroethylene , trimethylacetoxy, benzyloxy, fluorenyl-methoxybenzyloxy, ρ·nitrobenzyloxy, benzhydryloxy, trityloxy, amine Carbonyloxy, methoxy, ethoxy, η-propoxy, η-butoxy, η-pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethyl Alkoxy, 2-methoxy-21 - 200948817 ethoxyethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2·fluoroethyloxy, 1-fluoroethyloxy 1,1-Difluoroethyloxy, 2,2,2-trifluoroethyloxy, carboxymethyloxy, 2-aminoethyloxy, amine, formazanyl, B Mercaptoamine, trifluoroacetamidoamine, trichloroacetamidoamine, trimethylethenylamine, benzhydrylamine, mercaptoamine, tritylamino, alkene Propylamino, benzylamino, fluorenyl-methoxybenzylamino, methoxycarbonylamino, benzyloxycarbonylamino, (9-fusyl)methoxycarbonylamino, allyl Alkoxycarbonylamino group, methanesulfonylamino group, anthracene-toluenesulfonylamino group, benzylideneamino group, diphenylmethyleneamino group, two Phenylphosphonium amino group, tert-butylsulfinylamino group, trimethylsulfonylamino group, tert-butyldimethylsilylalkylamine group, methylamino group, dimethylamino group, Ethylamino, isopropylamino, 2-hydroxyethylamino, 2-methoxyethylamino, 2-fluoroethylamino, phenylamino, pyridylamino, aminocarbonyl Amine, aminosulfonylamino, azide, methionyl, aminoguanidino, oxime-methylaminomethyl, fluorenyl-ethenylamino, carboxy, methoxycarbonyl, ethoxy Carbonyl, tert-butoxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, diphenylmethyloxycarbonyl, trityloxycarbonyl, Trimethyldecyloxycarbonyl, tert-butyldimethylsilyloxycarbonyl, (methoxycarbonyloxy)methyloxycarbonyl, 1-(methoxycarbonyloxy)ethyloxy Carbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, 1-(t-butoxycarbonyloxy)ethyloxycarbonyl '(cyclohexyloxycarbonyloxy)methyloxycarbonyl 1-(cyclohexyloxycarbonyloxy Ethyloxycarbonyl, aminocarbonyl, fluorene-methylaminocarbonyl, hydrazine, hydrazine-dimethylaminocarbonyl, fluorenyl-(2-hydroxyethyl)aminocarbonyl, hydrazine-(2-methoxy Ethyl)aminocarbonyl, fluorenyl-(2-fluoroethyl)aminocarbonyl, fluorenyl-(ethionyl)aminocarbonyl, hydrazine (methanesulfonyl)aminocarbonyl, methylsulfonyl-22-200948817 Sulfhydryl, ethylsulfonyl, η-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl , difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1, difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl , aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, η-propylsulfin Sulfhydryl, isopropylsulfinyl, 2-hydroxyethylsulfinyl, 2-methoxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, Trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, amineMethylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, fluorene-methylaminosulfonyl, anthracene, fluorenyl-dimethylaminosulfonyl, fluorene- ( 2 -hydroxyethyl)aminosulfonyl, Ν-(2-methoxyethyl)aminosulfonyl, fluorenyl-(2-fluoroethyl)aminosulfonyl, and Ν-(acetyl Aminosulfonyl and the like. Preferable examples of Rla include a fluorine atom, a chlorine atom, a bromine atom, a cyano group, an ethyl fluorenyl group, an η-propyl fluorenyl group, an η-butyl fluorenyl group, an isobutyl fluorenyl group, a trimethyl acetyl group, a hydroxyethyl fluorenyl group, and the like. Methoxyethyl, trifluoroethenyl, 2-fluoro-2-methylpropenyl, methyl, ethyl, η-propyl, η-butyl, η-pentyl, isopropyl , isobutyl, t-butyl, tert-butyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl, 2-fluoro Ethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, methoxy, ethoxy, η-propoxy, η-butoxy, η - pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethyloxy, 2-methoxyethyloxy, fluoromethoxy, difluoromethoxy, Trifluoromethoxy, 2-fluoroethyloxy, 1-fluoroethyloxy, 1,1-difluoroethyloxy, 2,2,2-trifluoroethyloxy, aminocarbonyl, Ν-Methylaminocarbonyl, hydrazine, hydrazine-dimethylaminocarbonyl, N-(2-hydroxyethyl)amino-23- 200948817 carbonyl, N-(2-methoxyethyl)amine Carbonyl, N- (2- Ethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, η-propylsulfonyl, Isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2_fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, methylsulfinyl, ethylsulfinyl, η -propylsulfinyl, isopropylsulfinyl, 2-hydroxyethylsulfinyl, 2-methoxyethylsulfinyl, fluoromethylsulfinate, difluoromethyl Sulfosyl, trifluoromethylsulfinyl '2-fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfin Sulfhydryl, aminosulfonyl, fluorenyl-methylaminosulfonyl, anthracene, fluorenyl-dimethylaminosulfonyl, fluorenyl-(2-hydroxyethyl)aminosulfonyl'Ν- ( 2. A methoxyethyl)aminosulfonyl group, an anthracene-(2-fluoroethyl)aminosulfonyl group, and an anthracene-(ethionyl)aminosulfonyl group. More preferred examples of Rla include a fluorine atom, a chlorine atom, a bromine atom, a cyano group, an ethyl fluorenyl group, an η-propyl fluorenyl group, a trifluoroethane group, a methyl group, an ethyl group, an isopropyl group, and a hydroxymethyl group. , 1-hydroxyethyl, octafluoroethyl, 1-fluoroethyl, 2,22-fluorene trifluoroethyl, 1,1-difluoroethyl, methoxy, ethoxy, fluoromethoxy, Difluoromethoxy, trifluoromethoxy, aminocarbonyl, hydrazine-methylaminocarbonyl, ν, Ν-dimethylaminocarbonyl, methylsulfonyl, fluoromethylsulfonyl, difluoromethyl Sulfosyl, trifluoromethylsulfonyl, methylsulfinyl, fluoromethylsulfinyl, monofluoromethylsulfanyl, trifluoromethylsulfinyl, amine sulfonate A group, a methylaminosulfonyl group, and an anthracene, a fluorenyl-dimethylaminosulfonyl group, and the like.

A particularly preferred example of Rla is methoxy and cyano. X4 represents a nitrogen atom, or a general formula CRlb (wherein Rlb means a halogen original-24-200948817, a cyano group, a lower alkyl alkane group which may be substituted, or a group selected from the substituent group α), CRlb is preferred, wherein the substituent 1111> is a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group which may be substituted, a lower alkenyl group which may be substituted, a monocyclic hydrocarbon ring group which may be substituted or a heterocyclic ring a hydroxy group which may be protected or substituted, a lower alkoxy group which may be substituted, an amine group which may be protected or substituted, an azide group, a substituted methoxy group, a protected carboxyl group, may be substituted An aminocarbonyl group, a lower alkylsulfonyl group which may be substituted, a lower alkylsulfinyl group which may be substituted, and an aminosulfonyl group which may be substituted. In the above, specific examples of 1111) include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, an ethyl fluorenyl group, a fluorenyl-propyl fluorenyl group, an n-butyl group, an isobutyl group, a trimethyl acetyl group, and Hydroxyethylene, methoxyethyl, aminoethyl, methylaminoethyl, dimethylaminoethyl, fluoroacetamido, difluoroacetinyl, trifluoroacetamidine , 2-fluoro-2-methylpropanyl, 2,2-difluoropropenyl, methyl, ethyl, η-propyl, η-butyl, η-pentyl, isopropyl, iso Butyl, second butyl, tert-butyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl , aminomethyl, dimethylaminomethyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl , 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2·carboxyethyl, 2-carboxy-1 -hydroxyl Ethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-1,2-di-oxyethyl, 1-amino-bu-carboxy , 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, vinyl, 1-fluorovinyl, 2-fluorovinyl , 2,2-difluorovinyl, 1-propenyl, 2-propenyl, 2-carboxy-25- 200948817

Vinyl, 2-carboxy-1-fluorovinyl, 2-carboxy-2-fluorovinyl, 2-carboxy-1,2-difluorovinyl, 2-carboxy-1-hydroxyvinyl, 2-carboxy- 2-hydroxyvinyl, 3-hydroxy-1-propenyl, 3-amino-1-propenyl, phenyl, 3-carboxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4 -carboxy-2-pyridyl, 5-carboxy-2-pyridyl, 5-carboxy-3-pyridyl, 6-carboxy-3-pyridyl, thiophenyl, 4-carboxythiophenyl, 5-carboxysulfur Phenyl, 2-thiazolyl, 4-carboxy-2-thiazolyl, 5-carboxy-2-thiazolyl, 4-thiazolyl, 2-carboxy-4-thiazolyl, 5-thiazolyl, 2-carboxy-5 -thiazolyl, 1-pyrrolyl, 3-carboxy-1-pyrrolyl, 2-pyrrolyl, 4-carboxy-2-pyrrolyl, 5-carboxy-2-pyrrolyl, 3-pyrrolyl, 5-carboxy- 3-pyrrolyl, 1-pyrazolyl, 3-carboxy-1-pyrazolyl, 4-carboxy-1-pyrazolyl, 3-pyrazolyl, 5-carboxy-3-pyrazolyl, 4-pyridyl Azyl, 4-pyrazolyl, 1-imidazolyl, 4-carboxy-1-imidazolyl, 2-imidazolyl, 4-carboxy-2-imidazolyl, 4-imidazolyl, 2·carboxy-4-imidazolyl 1,2,3-triazol-1-yl, 4-carboxy-1,2,3-triazol-1-yl, 1,2,3-triazole-4- 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 5-carboxy-1,3,4-triazol-2yl, 2-tetrahydrofuranyl, 4 -carboxy-2-tetrahydrofuranyl, 5-carboxy-2.tetrahydrofuranyl, 3-tetrahydrofuranyl, 5-carboxy-3-tetrahydrofuranyl, 2-oxooxazolidin-3-yl, 5-carboxy-2- Oxyl oxazolidin-3-yl, 2-oxooxazolidin-4-yl, 2-oxooxazolidin-5-yl, 4-morpholino, 2-carboxy-4- Morformolyl, hydroxy, methoxymethyloxy, benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecyloxy, triethyldecyloxy, third Butyl dimethyl fluorenyloxy, tert-butyldiphenyl fluorenyloxy, ethoxycarbonyl, trifluoroacetoxy, trichloroacetoxy, trimethyl ethyloxy, Benzyloxy, P-methoxybenzyloxy, P-nitrobenzyloxy, benzhydryloxy, trityloxy, aminocarbonyloxy, methoxy, ethoxy Base, η-propoxy, η-butoxy, η·pentyloxy, iso-26- 200948817 propoxy, isobutoxy, tert-butoxy, 2-hydroxyethyloxy, 2- Methoxyethyloxy, fluorine Oxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethyloxy, 1-fluoroethyloxy, 1,1-difluoroethyloxy, 2,2,2-trifluoro Ethyloxy, carboxymethyloxy, 2-aminoethyloxy, amine, decylamino, ethionylamino, trifluoroethenylamino, trichloroethenylamino , trimethyl ethinylamino 'benzylidene amino group, mercaptoamine group, tritylamino group, allylamino group, benzylamino group, P-methoxybenzylamino group, Methoxycarbonylamino, benzyloxycarbonylamino, (9-fusyl)methoxycarbonylamino, allyloxycarbonylcarbonylamino, methanesulfonylamino, P-toluenesulfonate Amino group, benzylidene amine group, diphenylmethyleneamino group, diphenylphosphonium amino group, tert-butylsulfinylamino group, trimethyldecylamino group, third Dimethyl decylamino group, methylamino group, dimethylamino group, ethylamino group, isopropylamino group, 2-hydroxyethylamino group, 2-methoxyethylamino group, 2 -fluoroethylamino group, phenylamino group, thiamidinoamine group, aminocarbonylamino group, aminosulfonylamino group, azide group, Sulfhydryl, amidoxime, hydrazine-methylammonium, fluorenyl-acetamidohydrazino, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, (9-fluorenyl) Oxidylcarbonyl, allyloxycarbonyl, benzyloxycarbonyl, diphenylmethyloxycarbonyl, trityloxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethyl Alkyloxycarbonyl, (methoxycarbonyloxy)methyloxycarbonyl, 1-(methoxycarbonyloxy)ethyloxycarbonyl, (t-butoxycarbonyloxy)methyloxy Carbocarbonyl, bis(t-butoxycarbonyloxy)ethyloxycarbonyl, (cyclohexyloxycarbonyloxy)methyloxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethyloxy Carbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)amine Carbocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N--27- 200948817 (ethyl)aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, B Sulfosyl group, η-propyl sulfonyl group, different Sulfosyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2- Fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl , dimethylaminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, η-propylsulfinyl, isopropylsulfinyl, 2-hydroxyethylsulfin Indenyl, 2-methoxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl 1,1-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, aminomethylsulfinyl, dimethylaminosulfinyl, amine Sulfonyl, fluorene-methylaminosulfonyl, anthracene, fluorenyl-dimethylaminosulfonyl, fluorenyl-(2-hydroxyethyl)aminosulfonyl, fluorene-(2-methoxy Ethyl)aminosulfonyl, fluorenyl-(2-fluoroethyl)aminosulfonyl, and fluorenyl-(ethionyl)aminosulfonyl. Preferable examples of R1 b include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, an ethyl group, an η-propyl group, an η-butyl group, an η-pentyl group, an isopropyl group, and a different form. Butyl, t-butyl, tert-butyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl , aminomethyl, 1-aminoethyl, 2-aminoethyl, 2-fluoroethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, 1,1-difluoro 1,1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1 -carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2- Amino-1,2-dioxyethyl, 1-amino-1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxyl -1-sided oxyethyl, vinyl, 1-propene-28- 200948817, 2-propenyl, 1-fluorovinyl, 2-fluorovinyl, 2,2-difluorovinyl, 2-carboxyl Vinyl, 2-carboxy-1-fluorovinyl, 2-carboxy-2-fluorovinyl 2-carboxy-1,2-difluorovinyl, 2-carboxy-1-hydroxyvinyl, 2-carboxy-2-hydroxyvinyl, 3-hydroxy-1-propenyl, 3-amino-1-propene Base, phenyl, 3-carboxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-carboxy-2-pyridyl, 5-carboxy-2-pyridyl, 5-carboxy-3- Pyridyl, 6-carboxy-3-pyridyl, thiophenyl, 4-carboxythiophenyl, 5-carboxythiophenyl, 2-thiazolyl, 4-carboxy-2-thiazolyl, 5-carboxy-2- Thiazolyl, 4-thiazolyl, 2-carboxy-4-thiazolyl, 〇5-thiazolyl, 2-carboxy-5-thiazolyl, 1-pyrrolyl, 3-carboxy-1-pyrrolyl, 2-pyrrolyl , 4-carboxy-2-pyrrolyl, 5-carboxy-2-pyrrolyl, 3-pyrrolyl, 5-carboxy-3-pyrrolyl, 1-pyrazolyl, 3-carboxy-1-pyrazolyl, 4 -carboxy-1-pyrazolyl, 3-pyrazolyl, 5-carboxy-3-pyrazolyl, 4-pyrazolyl, 4-pyrazolyl, 1-imidazolyl, 4-carboxy-1-imidazolyl , 2-imidazolyl, 4-carboxy-2-imidazolyl, 4-imidazolyl, 2-carboxy-4-imidazolyl, 1,2,3-triazol-1-yl, 4-carboxy-1,2, 3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 5- Carboxylate -1,3,4-triazol-2-yl, 2-tetrahydrofuranyl, 4-carboxy-2-indoletetrahydrofuranyl, 5-carboxy-2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 5-carboxy-3-tetrahydrofuran , 2-sided oxyoxazolidin-3-yl, 5-carboxy-2-oxooxazolidin-3-yl, 2-oxooxazolidin-4-yl, 2-sided oxy Oxazolidine-5-yl, 4-morpholino, 2-carboxy-4-morpholine, hydroxy, aminocarbonyloxy, methoxy, ethoxy, η-propoxy, η- Butoxy, η-pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethyloxy, 2-methoxyethyloxy, fluoromethoxy, di Fluoromethoxy, trifluoromethoxy, 2-fluoroethyloxy, 1-fluoroethyloxy, 1,1-difluoroethyloxy, 2,2,2-trifluoroethyloxy , residue methyloxy, 2-aminoethyloxy, amine, carbenylamino, ethenyl-29- 200948817

Amino, trifluoroacetamidoamine, trichloroacetamidoamine, trimethylethenylamine, benzhydrylamine, mercaptoamine, tritylamino, allyl Amino, benzylamino, P-methoxybenzylamino, methoxycarbonylamino, benzyloxy 'carbonylamino, (9-fluorenyl)methoxycarbonylamino, allyl Oxycarbonylamino group, methanesulfonylamino group, P-toluenesulfonylamino group, benzylidene amine group, diphenylmethyleneamino group, diphenylphosphonium amino group, tert-butyl group Sulfosylamino, trimethyldecylamino, tert-butyldimethylalkylamino, methylamino, dimethylamino, ethylamino, isopropylamino, 2 -hydroxyethylamino, 2-methoxyethylamino, 2-fluoroethylamino, phenylamino, pyridylamino, aminocarbonylamino, aminosulfonylamino, A Sulfhydryl, aminoguanidino, 〇-methylaminomethyl, 〇-acetamidohydrazino, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N- ( 2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)amine Carbonyl, N-(ethionyl)aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, η-propylsulfonyl, isopropylsulfonate , 2, hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethyl Sulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, methylsulfinyl, ethylsulfinyl, η-propylsulfin Sulfhydryl, isopropylsulfinyl, 2-hydroxyethylsulfinyl, 2-methoxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, Trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, aminesulfonate Mercapto, fluorenyl-methylaminosulfonyl, anthracene, fluorenyl-dimethylaminosulfonyl, fluorenyl-(2-hydroxyethyl)aminosulfonyl, fluorene-(2-methoxyB An aminosulfonyl group, an anthracene-(2-fluoroethyl)aminosulfonyl group, and an anthracene-(ethionyl)aminosulfonyl group. -30- 200948817 More preferred examples of Rlb include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, an ethyl group, a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, and an amine. Methyl, 1-aminoethyl, 2-aminoethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1 ,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1.hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxy-2-hydroxyethyl , 2-carboxy-1,2-dihydroxyethyl, 2-amino-1,2-dioxyethyl, 1-amino-1-carboxymethyl, 1-amino-2-carboxyl , 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, ethylenyl, 2-propenyl, 1-fluorovinyl, 2-fluorovinyl, 2,2 -difluorovinyl, 2-carboxyvinyl, 2-carboxy-1-hydroxyvinyl, 2-carboxy-2-hydroxyvinyl, 3-hydroxy-1-propenyl, 3-amino-1-propenyl , 3-carboxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-carboxy-2-pyridyl, 5-carboxy-2-pyridyl, 5-carboxy-3-pyridyl, 6 -carboxy-3-pyridyl, thiophenyl, 4-carboxysulfur , 5-carboxythiophenyl, 2-thiazolyl, 4-carboxy-2-thiazolyl, 5-carboxy-2-thiazolyl, 4-thiazolyl, 2-carboxy-4-thiazolyl, 5-thiazolyl , 2-carboxy-5-thiazolyl, 1-pyrrolyl, 3-carboxy-1-pyrrolyl, 2·pyrrolyl, fluorenyl 4-carboxy-2-pyrrolyl, 5-carboxy-2-pyrrolyl, 3- Pyrrolyl, 5-carboxy-3-pyrrolyl, 1-pyrazolyl, 3-carboxy-1-pyrazolyl, 4·carboxy·1-pyrazolyl, 3-pyrazolyl, 5-carboxy-3- Pyrazolyl, 4-pyrazolyl 4-pyrazolyl, 1-imidazolyl, 4-carboxy-1-imidazolyl, 2-imidazolyl, 4-carboxy-2-imidazolyl, 4-imidazolyl, 2 -carboxy-4-imidazolyl, 1,2,3-triazol-1-yl, 4-carboxy-1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 5-carboxy-1,3,4-triazol-2-yl, 2-tetrahydrofuranyl, 4 -carboxy-2-tetrahydrofuranyl, 5-carboxy-2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 5-carboxy-3-tetrahydrofuranyl, 2-oxooxazolidin-3-yl, 5-carboxy-2- Oxyl oxazolidin-3-yl, -31- 200948817 2-oxooxazolidin-4-yl, 2-oxooxazolidin-5-yl' 4-morpholine, 2- Carboxy-4- Florinyl, hydroxy, aminocarbonyloxy, methoxy, 2-mercaptoethyloxy, fluoromethoxy, difluoromethoxy, carboxymethyloxy, 2-aminoethyloxy , Amino, Ethylamino, methoxycarbonylamino, methanesulfonylamino, methylamino, dimethylamino, ethylamino, isopropylamino, 2-hydroxy Amino group, 2-methoxyethylamino group, 2-fluoroethylamino group, pyridylamino group, aminocarbonylamino group, aminosulfonylamino group, formazan group, aminoguanidino group, hydrazine -methylaminomethyl, fluorenyl-acetamidoguanidino, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, methylsulfonyl, methylsulfinium Alkyl, amidinosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, and N-(ethinyl)aminosulfonyl. Particularly preferred examples of R1 are a hydrogen atom, a cyano group, a methyl group, a 2-carboxy-1,2-dihydroxyethyl group, a 2-carboxyvinyl group, a 5-carboxythiophenyl group, a decyl group, an amino group, an anthracene group. - methylaminomethyl, and 0-ethylguanidinium. Α1 represents a general formula CR2 [wherein R2 means a bond (either integral with an atomic bond adjacent to L1 or integrated with a bond of an adjacent Α2 to form a double bond), a halogen atom, a cyano group, or The group selected from the substituent group α, a hydrazine or a nitrogen atom is preferably a nitrogen atom, but is also preferably a general formula CR2. In this case, the substituent R2 is selected from a bond (with an atom on the adjacent L1). The bonding bond becomes a body, or a bond with an adjacent Α2 is integrated to form a double bond), a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group which may be substituted, a lower alkyl sulfonyl group which may be substituted, Substituted monocyclic hydrocarbon ring or heterocyclic group, protected or substituted hydroxy group, substituted lower alkoxy group, protected or substituted amine group, azide group, substituted methyl group , a protected carboxyl group, a substituted aminocarbonyl group, a substituted lower alkylsulfonyl group, a substituted lower -32-200948817 alkyl sulfinyl group, and a substituted amine group Sulfonyl. Here, specific examples of R2 include a bond (either a bond to an atom on an adjacent L1 or a bond to an adjacent bond of A2 to form a double bond), a hydrogen atom, a fluorine atom, or a chlorine. Atom, bromine atom, cyano group, methyl group, ethyl group, η-propyl group, η-butyl group, η-pentyl group, isopropyl group, isobutyl group, second butyl group, tert-butyl group, hydroxymethyl group 'Methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl, aminomethyl, methylaminomethyl, dimethyl Aminomethyl, 1-aminoethyl, 2-aminopurinylethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2,2, 2-Trifluoroethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2 Diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2 -carboxyl 1,2-dihydroxyethyl, 2-amino-1,2-dioxyethyl, 1-amino-1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amine -2-carboxyethyl, 2-carboxy-1-oxoethyl, vinyl, fluorovinyl, 2-fluorovinyl, 2,2-difluorovinyl, 1-propenyl, 2- Propylene, hydrazine 2-carboxyvinyl, 2-carboxy-1-fluorovinyl, 2-carboxy-2-fluorovinyl, 2-carboxy-1,2-difluorovinyl, 2-carboxy-1-hydroxyl Vinyl, 2-carboxy-2-hydroxyvinyl, 3-hydroxy-1-propenyl, 3-amino-1-propenyl, phenyl, 3-carboxyphenyl, 2-pyridyl, 3-pyridyl , 4-pyridyl, 4-carboxy-2-pyridyl, 5-carboxy-2-pyridyl, 5-carboxy-3-pyridyl, 6-carboxy-3-pyridyl, thiophenyl, 4-carboxysulfur Phenyl, 5-carboxythiophenyl, 2-thiazolyl, 4-carboxy-2-thiazolyl, 5-carboxy-2-thiazolyl, 4-thiazolyl, 2-carboxy-4-thiazolyl, 5-thiazole , 2-carboxy-5-thiazolyl, 1-pyrrolyl, 3-carboxy-1-pyrrolyl, 2-pyrrolyl, 4-carboxy-2-pyrrolyl, 5-carboxy-2-pyrrolyl, 3 -pyrrolyl, -33- 200948817 5-carboxy-3-pyrrolyl, 1-pyrazolyl, 3-carboxy-1-pyrazolyl, 4-carboxy-1-pyrazolyl, 3-pyrazolyl, 5 -carboxy-3-pyrazolyl, 4-pyrazolyl, 4-pyrazolyl, 1-imidazole 4-carboxy-1-imidazolyl, 2-imidazolyl, 4-carboxy-2-imidazolyl, 4-imilinyl, 2-carboxy-4-imidazolyl, 1,2,3-triazole-1- Base, 4·carboxyl 1,2,3·triazol-1-yl, 1,2,3-triazol-4-yl, 1,3,4-triazol-1-yl, 1,3,4 -triazol-2yl, 5-carboxy-1,3,4-triazol-2-yl, 2·tetrahydrofuranyl, 4-carboxy-2-tetrahydrofuranyl, 5-carboxy-2-tetrahydrofuranyl, 3- Tetrahydrofuranyl, 5-carboxy-3-tetrahydrofuranyl, 2-oxooxazolidin-3-yl, 5-carboxy-2-oxooxazolidin-3-yl, 2-oxooxazole - cardinyl, 2-oxooxazolidin-5-yl, 〇4_morpholino, 2-carboxy-4-morpholine, hydroxy, methoxymethyloxy, benzyloxy Methyloxy, tetrahydropyranyloxy, trimethyldecyloxy, triethyldecyloxy, tert-butyldimethylsilyloxy, tert-butyldiphenyldecyl Oxyl, ethoxylated, trifluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, fluorenyl-methoxybenzyloxy, hydrazine-nitro Benzyloxy, benzhydryloxy, trityloxy, aminocarbonyloxy , methoxy, ethoxy, η-propoxy, η-butoxy, η-pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethyloxy , 2-methoxyindenyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethyloxy, 1-fluoroethyloxy, 1,1_2 Fluoryloxy, 2,2,2-trifluoroethyloxy, carboxymethyloxy, 2-aminoethyloxy, amine, formazanyl, ethylamino, three Fluorinylamino, trichloroacetamidoamine, trimethylethenylamine, benzhydrylamine, mercaptoamine, tritylamino, allylamine, benzyl Amino group, fluorenyl-methoxybenzylamino group, methoxycarbonylamino group, benzyloxycarbonylamino group, (9-fluorenyl)methoxycarbonylamino group, allyloxycarbonylamino group , methanesulfonylamino, fluorene-toluenesulfonylamino, benzylidene-34-200948817 amine, diphenylmethyleneamino, diphenylphosphonium, tributyl Sulfhydrylamino group, trimethyldecylamino group, tert-butyldimethylmethylalkylamino group, methylamino group, dimethylamino group, Amino, isopropylamino, 2-hydroxyethylamino, 2-methoxyethylamino, 2-fluoroethylamino, phenylamino, pyridylamino, aminocarbonylamine Amino, sulfonylamino, azide, methionyl, aminoguanidino, oxime-methylaminomethyl, fluorenyl-ethenylamino, carboxy, methoxycarbonyl, ethoxycarbonyl , a third butoxycarbonyl group, a (9-fluorenyl)methoxycarbonyl group, an allyloxycarbonyl group, a benzyloxycarbonyl group, a diphenylmethyloxyanthracenecarbonyl group, a trityloxycarbonyl group, Trimethyldecyloxycarbonyl, tert-butyldimethylsilyloxycarbonyl, (methoxycarbonyloxy)methyloxycarbonyl, 1-(methoxycarbonyloxy)ethyloxy Carbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, 1-(t-butoxycarbonyloxy)ethyloxycarbonyl, (cyclohexyloxycarbonyloxy)methyloxycarbonyl , 1-(cyclohexyloxycarbonyloxy)ethyloxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl) Aminocarbonyl, N-(2.methoxyethyl) Alkylcarbonyl, N-(2-fluoroethyl)aminocarbonyl, NO(ethinyl)aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, Η-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, Trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2·trifluoroethylsulfonyl, aminomethylsulfonyl , methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, η-propylsulfinyl, isopropylsulfin Indenyl, 2-hydroxyethylsulfinyl, 2-methoxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl , 2-fluoroethylsulfinium-35- 200948817 base, 1,1·difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, aminomethylsulfin , dimethylaminosulfinyl, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2-hydroxyethyl) amine Sulfonyl, N-(2-methoxyethyl)aminosulfonyl, N-(2-fluoroethyl)aminosulfonyl, and N-(ethinyl)aminosulfonyl . Preferable examples of R2 include a bond (either a bond to an atom on an adjacent L1 or a bond to an adjacent bond of A2 to form a double bond), a hydrogen atom, a fluorine atom, or a cyano group. Methyl, ethyl, η-propyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyindolyl, 1-methoxyethyl, Aminomethyl, methylaminomethyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2- Fluoroethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyl Ethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-1,2-di-oxyethyl, 1-amino-1.carboxyl Methyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxyindole-1-yloxyethyl, hydroxy, aminocarbonyloxy, methoxy, Ethoxy, 2- Ethyloxy, 2-methoxyethyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethyloxy, 1-fluoroethyloxy, 1 ,1·difluoroethyloxy, 2,2,2-trifluoroethyloxy, carboxymethyloxy, 2-aminoethyloxy, amine, etidylamino, methoxy Carbonylamino, methanesulfonylamino, methylamino, dimethylamino, ethylamino, isopropylamino, 2-hydroxyethylamino, 2-methoxyethylamino , 2-fluoroethylamino, aminocarbonylamino, aminosulfonylamino, carboxy, aminocarbonyl, hydrazine-methylaminocarbonyl-36- 200948817, N,N-dimethylamine Carbocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethinyl) Aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, Fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2- Trifluoroethyl sulfonate Sulfhydryl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, aminosulfonyl, N-methylaminosulfonyl, N, N-dimethylaminodecylsulfonyl, N-(2-hydroxyethyl)aminosulfonyl, N-(2-methoxyethyl)aminosulfonyl, N-(2-fluoro Ethyl)aminosulfonyl, and N-(ethinyl)aminosulfonyl and the like. More preferably, it is a bond (either integral with a bond of an atom on an adjacent L1 or a bond with an adjacent bond of A2 to form a double bond), a hydrogen atom, a fluorine atom, a cyano group, a methyl group, or an ethyl group. , hydroxymethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, 2-fluoroethyl, 1,2 -dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-^amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-b Hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl '2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-1, 2-tertiary oxyethyl, 1-amino-1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2.carboxyethyl, 2-carboxy-1-sided oxygen Ethyl ethyl, hydroxy, aminocarbonyloxy, methoxy, ethoxy, fluoromethoxy, difluoromethoxy, 2-carboxymethyloxy, 2-aminoethyloxy, amine , Ethylamino, methoxycarbonylamino, methanesulfonylamino, methylamino, dimethylamino, 2-hydroxyethylamino, 2-fluoroethyl Aminocarbonylamino, aminosulfonylamino, carbenyl, carboxyl, -37- 200948817 aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N -(ethinyl)aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl , aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, aminosulfonyl, N-methylaminosulfonyl, N,N- Dimethylaminosulfonyl, and N-(ethinyl)aminosulfonyl and the like. A particularly preferred example of R2 is a hydrogen atom. As described above, A2 represents a general formula CR3R4, NR5, an oxygen atom, or an oxidizable sulfur atom, but is preferably a general formula CR3R4. When 〇A2 is a general formula CR3R4, R3 and R4 are each independently a bond (when A1 is a carbon atom, the bond with A1 is integrated, or the bond of A3 (A3 is a bond of A3) is Integrated to form a double bond), a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group which may be substituted, a lower alkenyl group which may be substituted, a monocyclic hydrocarbon ring group which may be substituted or a heterocyclic group, may be protected Or a substituted hydroxy group, a substituted lower alkoxy group, a protected or substituted amino group, an azide group, a substituted carbachyl group, a protected carboxyl group, a substituted amino group carbonyl group, a substituted lower alkylsulfonyl group, a lower alkylsulfinyl group which may be substituted, a substituted aminosulfonyl group, or a pendant oxy group formed by the combination of R3 and R4, or may be Substituted hydroxyimino group. Here, as specific examples of R3 and R4, each is independently a bond (when A1 is a carbon atom, the bond with A1 is integrated, or the bond of a3 (A3 itself is a bond of A4) is integrated. And forming a double bond), a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, an ethyl group, an η-propyl group, an η-butyl group, a η-pentyl group, an isopropyl group, an isobutyl group, Second butyl, tert-butyl, hydroxymethyl, methoxymethyl, hydrazine-hydroxyethyl, 2-hydroxyethyl, 2-methoxy-38- 200948817 ethyl, 1-methoxy Base, aminomethyl, methylaminomethyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl, 1-amino-2.hydroxyl Base, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1 -hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-1,2-di-oxyethyl, 1-amine -1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxyindole-1-yloxyethyl, vinyl, 1-fluorovinyl , 2-fluorovinyl, 2,2-difluorovinyl, 1-propenyl, 2-propenyl, 2-carboxyvinyl, 2-carboxy-1-fluorovinyl, 2-carboxy-2-fluoroethylene Base, 2-carboxy·1,2-difluorovinyl, 2-carboxy-1-hydroxyvinyl, 2-carboxy-2-hydroxyvinyl, 3-hydroxy-1-propenyl, 3-amino-1 -propenyl, phenyl, 3-carboxyphenyl, 2-pyridyl, 3-oxaridinyl, 4-pyridyl, 4-carboxy-2-pyridyl, 5-carboxy-2-pyridyl, 5-carboxyl 3-pyridyl, 6-carboxy-3-pyridyl, thiophenyl, 4-carboxythiophenyl, 5-carboxythiophenyl, 2 thiazolyl, 4-carboxy-2-thiazolyl, 5-carboxyl -2-thiazinyl, 4-thiazinyl, 2-mercapto-4-indenyl, 5-thiocyano, 2-indolyl-5-saltyl, 1-pyrrolyl, 3-carboxyl 1-pyrrolyl, 2-pyrrolyl, 4-carboxy-2-pyrrolyl, 5-carboxy-2-pyrrolyl, 3-pyrrolyl, 5-carboxy-3-pyrrolyl, 1-pyrazolyl, 3 -carboxy-1-pyrazolyl, 4-carboxy-1.pyrazolyl, 3-pyrazyl, 5-carboxy-3 Pyrazolyl, 4-pyrazolyl, 4-pyrazolyl, 1-imidazolyl, 4-carboxy-1-imidazolyl, 2-imidazolyl, 4-carboxy-2-imidazolyl, 4-imidazolyl, 2-carboxy-4-imidazolyl, 1,2,3-triazol-1-yl, 4-carboxy-1,2,3-triazol-1-yl, 1,2,3-triazole-4- , 1,3,4-triazole-buyl, ·1,3,4-triazol-2-yl, 5-carboxy-1,3,4-triazol-2-yl, 2-tetrahydrofuranyl, 4-carboxy-2-tetrahydrofuranyl, 5-carboxy-2-yl-39- 200948817 tetrahydrofuranyl, 3·tetrahydrofuranyl, 5-carboxy-3-tetrahydrofuranyl, 2-oxooxazolidin-3-yl, 5 Carboxy-2-oxooxyoxazolidin-3-yl, 2-oxooxazolidin-4-yl, 2-oxooxazolidin-5-yl, 4-morpholinyl, 2 -carboxy-4-morpholino, hydroxy, methoxymethyloxy, benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecyloxy, triethyldecyl Oxyl, tert-butyldimethylsilyloxy, tert-butyldiphenylphosphinoalkyloxy, ethoxylated, trifluoroacetoxy, trichloroacetoxy, trimethyl Mercaptooxy, benzyloxy, fluorenyl-methoxybenzyloxy, fluorenyl-nitrobenzyl , benzyloxy, trityloxy, aminocarbonyloxy, methoxy, ethoxy, η-propenyloxy, η-butoxy, η-pentyloxy, iso Propyloxy, isobutoxy, tert-butoxy, 2-hydroxyethyloxy, 2-methoxyethyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethyloxy, 1-fluoroethyloxy, 1,1-difluoroethyloxy, 2,2,2-trifluoroethyloxy, carboxymethyloxy*, 2-amino Ethyloxy, amino, decylamino, ethionylamino, trifluoroethenylamino, trichloroacetamidoamine, trimethylethenylamine, benzhydrylamine , mercaptoamine, tritylamino, allylamino, benzylamino, fluorenyl-methoxybenzylamino, methoxycarbonylamino, benzyloxycarbonylamino, (9- fluorenyl) methoxycarbonylamino, allyloxycarbonylamino, methanesulfonylamino, ρ-toluenesulfonylamino, benzylideneamine, diphenylmethylene Amino group, diphenylphosphonium amino group, tert-butylsulfinylamino group, trimethyldecylamino group, tert-butyl dimethyl Base alkylamino group, methylamino group, dimethylamino group, ethylamino group, isopropylamino group, 2-hydroxyethylamino group, 2-methoxyethylamino group, 2-fluoroethyl Amino group, phenylamino group, pyridylamino group, aminocarbonylamino group, aminosulfonylamino group, azide group, formyl group, amino group, 〇-methylamino group, 0- Ethyl hydrazinyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-40-200948817 oxycarbonyl, (9-fusyl)methoxycarbonyl, allyloxycarbonyl, benzyl Oxycarbonyl, diphenylmethyloxycarbonyl, trityloxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethylsilyloxycarbonyl, (methoxycarbonyloxy) Methyloxycarbonyl, 1-(methoxycarbonyloxy)ethyloxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, 1-(t-butoxycarbonyloxy) Ethyloxycarbonyl, (cyclohexyloxycarbonyloxy)methyloxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethyloxycarbonyl, aminocarbonyl, N-methylaminocarbonyl ,N,N-dimethylaminocarbonyl , N-(2-fluorenylhydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N.(2-fluoroethyl)aminocarbonyl, N-(ethinyl) Aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, η-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonate Base, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonic acid, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-di Fluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, Methylsulfinyl, ethylsulfinyl, η-propylsulfinylene, ^ isopropylsulfinylene, 2-hydroxyethylsulfinyl, 2-methoxyethyl Sulfonyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-difluoroethylsulfin Indenyl, 2,2,2-trifluoroethylsulfinyl, aminomethylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, fluorene-methylamino Sulfur-based, Ν, Ν- Methylaminosulfonyl, fluorenyl-(2-hydroxyethyl)aminosulfonyl, fluorenyl-(2-methoxyethyl)aminosulfonyl, fluorenyl-(2-fluoroethyl)amine Sulfosyl, and fluorenyl-(ethenyl)aminosulfonyl, pendant oxy, hydroxyimino, 0-methylhydroxyimino, 0-(fluoromethyl)hydroxyimino, 0 -(Difluoromethyl)hydroxyimino, 〇-(trifluoromethyl)-41- 200948817 hydroxyimino, ο-(carboxymethyl)hydroxyimino, 〇·(difluorocarboxymethyl) A hydroxyimino group, a 0-(2-carboxyisopropyl)hydroxyimino group, or the like. Preferred examples of R3 and R4 include a bond which is independently a bond (when Α1 is a carbon atom and a bond of Α1, or a bond of Α3 (Α3 itself is a bond of Α4)) And forming a double bond), hydrogen

Atom, fluorine atom, cyano group, methyl group, ethyl group, η-propyl group, hydroxymethyl group, methoxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 1 -methoxyethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, Trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl, 1-amino 2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-1,2-di- oxyethyl, 1 -Amino-1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2,carboxyethyl, 2-carboxy-1-oxoethyl, hydroxy, aminocarbonyloxy Base, methoxy, ethoxy, η-propoxy, η-butoxy, η-pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethyloxy Base, 2-methoxyethyloxy, fluoromethoxy, difluoromethoxy, three Methoxy, 2-fluoroethyloxy, fluoroethyloxy, 1,1-difluoroethyloxy, 2,2,2-trifluoroethyloxy, carboxymethyloxy, 2 - aminoethyloxy, amine, formylamino, etidylamino, methoxycarbonylamino, methanesulfonylamino, methylamino, dimethylamino, ethyl Amino, isopropylamino, 2-hydroxyethylamino, 2-methoxyethylamino, 2·fluoroethylamino, phenylamino, pyridylamino, aminocarbonylamino Aminosulfonylamino, carboxy, aminocarbonyl, fluorene-methylaminocarbonyl, hydrazine, hydrazine-dimethylaminocarbonyl '-42- 200948817 N-(2-hydroxyethyl)aminocarbonyl , N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethinyl)aminocarbonyl, N-(methanesulfonyl)amine Carbonyl, methylsulfonyl, ethylsulfonyl, η-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluorine Methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2 2,2-Trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methylsulfinyl, ethyl Sulfosyl, η-propylsulfinyl, oxapropylsulfinyl, 2-hydroxyethylsulfinyl, 2-methoxyethylsulfinyl, fluoromethylsulfin Mercapto, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2,2,2- Trifluoroethylsulfinyl, aminomethylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, fluorene-methylaminosulfonyl, anthracene, fluorene-dimethyl Aminosulfonyl, fluorenyl-(2-hydroxyethyl)aminosulfonyl, fluorenyl-(2-methoxyethyl)aminosulfonyl, fluorenyl-(2-fluoroethyl)amine Sulfonyl, fluorenyl-(ethenyl)aminosulfonyl, pendant oxy, hydroxyimino, 0-methylhydroxyimino, 0·(fluoromethyl) 〇w hydroxyimino, hydrazine -(Difluoromethyl)hydroxyimino, fluorenyl-(trifluoromethyl)hydroxyimino, 0-(carboxymethyl)hydroxyimino, fluorene-(difluorocarboxymethyl)hydroxyimino , 0-(2-carboxyisopropyl) Imino and so on. More preferably, R3 and R4 are each a bond (when A1 is a carbon atom, a bond with Αι is integrated, or a bond of A3 (A3 itself is a bond) is A4) One to form a double bond), a hydrogen atom, a methyl group, a hydroxymethyl group, a methoxymethyl group, a 1-hydroxyethyl group, a 2-ethylidene group, an aminomethyl group, a methylaminomethyl group, a dimethyl group Aminomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,2-dihydroxyethyl, 1-amino-2-43-200948817 hydroxyethyl, 2-amino-1 -hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxyl 2-hydroxyethyl, 2-carboxy-12-dihydroxyethyl, 2-amino-1,2-dioxyethyl, 1-amino-1-carboxymethyl, 1-amino- 2-carboxyethyl, 2·amino-2-carboxyethyl, 2-carboxy-oxime-side oxyethyl, aminocarbonyloxy, amine, formazanylamine, ethenylamine, Methoxycarbonylamino, methanesulfonylamino, methylamino, dimethylamino, aminocarbonylamino, aminosulfonyl Base, carboxyl group, aminocarbonyl group, N-methylaminocarbonyl group, N,N-dimethylaminodecyl 'N-(ethinyl)aminocarbonyl, N-(methanesulfonyl)amino group G Carbonyl, methylsulfonic acid, 2-hydroxyethylsulfonyl, fluoromethylsulfonyl, difluoromethyl fluorenyl, trifluoromethylsulfonyl, aminomethylsulfonyl, methyl Aminomethylmethyl thiol, dimethylaminomethylsulfonyl, methylsulfinyl, 2-hydroxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfin , trifluoromethylsulfinyl, aminomethylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, N-methylaminosulfonyl, N, N- Dimethylaminosulfonyl, N-(2-ylethyl)aminosulfonyl, N-(ethinyl)aminosulfonyl, pendant oxy, hydroxyimino, anthracene A hydroxyimino group, a fluorenyl-(fluoromethyl) hydroxyindenylene group, a fluorenyl (carboxymethyl) hydroxyimino group, or the like. Particularly preferred is a bond (when A1 is a carbon atom, the bond with Αι is integrated, or the bond of A3 (A3 itself is a bond of a bond) is integrated to form a double bond), a hydrogen atom, a methyl group. And side oxy. When A2 is NR5, the substituent R5 is a bond (when Α is a carbon atom, the bond with A1 is integrated, or the bond of A3 (A4 is a bond of A3) is integrated to form a double bond) a hydrogen atom, a lower alkyl group which may be substituted, a lower alkyl alkane group which may be substituted, a monocyclic hydrocarbon ring which may be substituted - 44 - 200948817 or a heterocyclic group, a hydroxyl group which may be protected or substituted, may be used Substituted lower alkoxy, protected or substituted amine group, azide group, substituted carbachyl group, protected carboxyl group, substituted amino group carbonyl group, substituted lower alkyl sulfonate A mercapto group, a lower alkyl sulfinyl group which may be substituted, and an amine sulfonyl group which may be substituted. Here, as a specific example of R5, a bonding bond (when A1 is a carbon atom, a bond with A1 is integrated, or a bond of A3 (A3 itself is a bond of A4)) is integrated to form a double bond. ), hydrogen atom, methyl group, oxime ethyl group, η-propyl group, η-butyl group, η-pentyl group, isopropyl group, isobutyl group, second butyl group, tert-butyl group, hydroxymethyl group, A Oxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl, aminomethyl, methylaminomethyl, dimethylamino Methyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2,2,2-tri Fluoroethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2.diamine Ethylethyl, 1-carboxymethyl, carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxyindole-2-hydroxyethyl, 2-carboxy- 1,2-dihydroxyethyl, 2-amino-1,2-dioxyethyl, 1-amino-1-carboxymethyl, 1-amino-2.carboxyethyl, 2-amine Carboxy-2-carboxyethyl 2-carboxy-1-oneoxyethyl, 2-hydroxy_1_sideoxyethyl, 2-amino-1-one-oxyethyl, 2-(methylamino)-1-side oxygen Ethyl ethyl, 2-(dimethylamino)-1-oxoethyl, 2,3-di-propylpropyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxy Propyl, 2,3-diaminopropyl, ethyl, 1-fluorovinyl, 2-fluorovinyl, 2,2-difluorovinyl, 1-propenyl, 2-propanol 2-mercaptoethyl, 2-resin-1-cross-ethyl, 2-mercapto-2-fluorovinyl, 2-carboxy-1,2-difluorovinyl, 2-carboxy-1- Hydroxyvinyl, 2-45-200948817 carboxy-2-hydroxyvinyl, 3-hydroxy-1-propenyl, 3-amino-1-propenyl, phenyl, 3-carboxyphenyl, 2-pyridyl , 3-pyridyl, 4·pyridyl, 4-carboxy-2-pyridyl, 5-carboxy-2·pyridyl, 5-carboxy-3-pyridyl, 6-carboxy-3-pyridyl, thiophenyl , 4-carboxythiophenyl, 5-carboxythiophenyl, 2-thiazolyl, 4-carboxy-2-thiazolyl, 5-carboxy-2-thiazolyl, 4-thiazolyl, 2-carboxy-4-thiazole , 5-thiazolyl, 2-carboxy-5-salthazolyl, 1-pyrrolyl, 3-carboxy-1-pyrrolyl, 2-pyridyl Group, 4-carboxy-2-pyrrolyl, 5-carboxy-2-pyrrolyl, 3-pyrrolyl, 5-carboxy-3-pyrrolyl, 1-pyrazolyl, 3-carboxy-1-pyrazolyl,

4-carboxy-1-pyrazolyl, 3-pyrazolyl, 5-carboxy-3-pyrazolyl, 4-pyrazolyl, 4-pyrazolyl, 1-imidazolyl, 4-carboxy-1-imidazole , 2-imidazolyl, 4·carboxy-2-imidazolyl, 4-imidazolyl, 2-carboxy-4-imidazolyl, 1, 2,3-triazol-1-yl, 4-carboxy-1,2, 3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 5- Carboxy-1,3,4•triazol-2-yl, 2-tetrahydrofuranyl, 4-carboxy-2-tetrahydrofuranyl, 5-carboxy-2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 5-carboxy-3-tetrahydrofuran , 2-sidedoxy-Ofoxazin-3-yl, 5-carboxy-2-oxooxazolidin-3-yl, 2-oxooxazolidin-4-yl, 2-sided oxy Oxazolidine-5-yl, 4·morpholinyl, 2-carboxy-4-morpholine, hydroxy, methoxymethyloxy, benzyloxymethyloxy, tetrahydropyranyl Oxy, trimethyl decyloxy, triethyl decyloxy, tert-butyl dimethyl decyloxy, tert-butyl diphenyl decyloxy, ethoxylated, trifluoro Ethyloxy, trichloroacetoxy, trimethylethenyloxy, benzyloxy, P-methoxybenzyl Oxyl, P-nitrobenzyloxy, benzhydryloxy, trityloxy, aminodecyloxy, methoxy, ethoxy, n-propoxy, n-butyl Oxyl, n-pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethyloxy, 2-methoxyethyloxy, fluoromethoxy, difluoro Methoxy, trifluoromethoxy, -46- 200948817 2- gas ethyloxy, 1-vapor ethyloxy, 1,1-diethyleneethyloxy, 2,2,2-trifluoroethyl Alkoxy group, carboxymethyloxy group, 2-aminoethyloxy group, amine group, formylamino group, etidylamino group, trifluoroethylamino group, trichloroacetamido group, Trimethyl ethinylamino, benzhydrylamino, decylamino, tritylamino, allylamino, benzylamino, P. methoxybenzylamino, A Oxycarbonylamino group, benzyloxycarbonylamino group, (9-fusyl)methoxycarbonylamino group, allyloxycarbonylamino group, methanesulfonylamino group, p-toluenesulfonylamine Base, benzylideneamine, diphenylmethyleneamino, diphenylphosphoniumamino, hydrazine tert-butylsulfinylamino, trimethylhydrazine Alkylamino group, tert-butyldimethylmethylalkylamino group, methylamino group, dimethylamino group, ethylamino group, isopropylamino group, 2-hydroxyethylamino group, 2-methyl group Oxyethylamino group, 2-fluoroethylamino group, phenylamino group, pyridylamino group, aminocarbonylamino group, aminosulfonylamino group, azide group, formamyl group, aminoguanidinyl group , 〇-methylaminomethyl, 〇-acetamidamino, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyl Alkoxycarbonyl, benzyloxycarbonyl, diphenylmethyloxycarbonyl, trityloxycarbonyl, trimethyldecyloxycarbonylcarbonyl, tert-butyldimethylsilyloxy Carbonyl, (methoxycarbonyloxy)methyloxycarbonyl, 1-(methoxycarbonyloxy)ethyloxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, 1- (tert-butoxycarbonyloxy)ethyloxycarbonyl, (cyclohexyloxycarbonyloxy)methyloxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethyloxycarbonyl, amine Carbonyl, N-methylaminocarbonyl, N N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethenyl)aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, η-propylsulfonyl, isopropylsulfonyl, -47- 200948817

2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonate 1,1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylamine Methylsulfonyl, methylsulfinyl, ethylsulfinyl, η-propylsulfinylene, isopropylsulfinyl, 2-hydroxyethylsulfinyl, 2- Methoxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1- Difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, aminomethylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, anthracene -Methylaminosulfonyl, hydrazine, fluorenyl-dimethylaminosulfonyl, fluorenyl-(2-hydroxyethyl)aminosulfonyl, fluorenyl-(2-methoxyethyl)amine A sulfonyl group, a fluorenyl-(2-fluoroethyl)aminosulfonyl group, and an anthracene-(ethionyl)aminosulfonyl group. When Α2 is an oxidizable sulfur atom, for example, _S(〇2)-, -S(Ο)-, and -s- may be exemplified.

A3 represents a general formula CR6R7, a general formula NR8, an oxygen atom, an oxidizable sulfur atom, or a bond, as described above, but is preferably a general formula CR6R7, a general formula NR8, an oxygen atom, and a bond. When A3 is a general formula CR6R7, the substituents R6 and R7 are each independently a bond (a bond is formed integrally with the adjacent bond of A2 or A4), a hydrogen atom, a halogen atom, a cyano group, and may be substituted. Lower alkyl, substitutable lower alkyl fluorenyl, substituted monocyclic hydrocarbon ring or heterocyclic group, protected or substituted hydroxy group, substituted lower alkoxy group, protected or substituted Amino group, azido group, substituted meyl group, protected carboxyl group, substituted aminocarbonyl group, substituted lower alkylsulfonyl group, substituted lower alkyl sulfinic acid A mercapto group, a substituted aminosulfonyl group, or a pendant oxy group or a substituted hydroxyimino group formed by the combination of -48-200948817 R6 and R7. Here, as specific examples of R6 and R7 It can be exemplified that each is independently a bond (a bond is formed integrally with the adjacent bond of A2 or A4), a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, an ethyl group, an n- Propyl, η-butyl, η-pentyl, isopropyl, isobutyl, second butyl, third butyl , hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl, aminomethyl, methylaminomethyl , dimethylaminomethyl, 1·aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1·fluoroethyl, 2,2,2-Trifluoroethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl 1,2-Diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxy-2-hydroxyl Ethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-1,2. di-oxyethyl, 1-amino-1-carboxymethyl, 1-amino-2- Carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, vinyl, 1-fluorovinyl, 2-fluorovinyl, 2,2-difluorovinyl , 1-propenyl, 2-propenyl, 2-carboxyvinyl, fluorene 2-carboxy-1-fluorovinyl, 2-carboxy-2-fluorovinyl, 2-carboxy-1,2-difluorovinyl , 2-carboxy-1-hydroxyvinyl, 2-carboxy-2-hydroxyvinyl, 3-hydroxy-1-propene , 3-amino-1-propenyl, phenyl, 3-carboxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-carboxy-2-pyridyl, 5-carboxy-2 -pyridyl, 5-carboxy-3-pyridyl, 6-carboxy-3.pyridyl, thiophenyl, 4-carboxythiophenyl, 5-carboxythiophenyl, 2-thiazolyl, 4-carboxy-2 -salrazolyl, 5-carboxy-2-thiazolyl, 4-thiazolyl, 2-carboxy-4-thiazino, 5-thiazolyl, 2-carboxy-5-thiazolyl, 1-pyrrolyl, 3- Carboxy-1-pyrrolyl, 2-pyrrolyl, 4-carboxy-2-pyrrolyl, 5-carboxy-2-pyrrolyl, 3-pyrrolyl, 5-carboxy-3--49- 200948817 pyrrolyl, 1 -pyrazolyl, 3-carboxy-1-pyrazolyl, 4-carboxy-1-pyrazolyl, 3-pyrazolyl, 5-carboxy-3-pyrazolyl, 4-pyrazolyl, 4-pyridyl Azyl, 1-imidazolyl, 4-carboxy-1-imidazolyl, 2-imidazolyl, 4-carboxy-2-imidazolyl, 4-imidazolyl, 2-carboxy-4-imidazolyl 1, 2,3 - triazol-1-yl, 4-carboxy-1,2,3.triazol-1-yl, 1,2,3-triazol-4-yl, 1,3,4-triazol-1-yl , 1,3,4-triazol-2-yl, 5-carboxy-1,3,4-triazol-2-yl, 2-tetrahydropyranyl, 4-carboxy-2-tetrahydrofuranyl, 5- Carboxy-2-tetrahydrogen Cyclol, 3-tetrahydrofuranyl, 5-carboxy-3-tetrahydrofuranyl, 2-oxooxazolidin-3-yl, 5-carboxy-2-oxooxazolidin-3-yl, 2-sided Oxyoxazolidine-4-yl, 2-oxooxazolidin-5-yl, 4-morpholinyl, indole-2-carboxy-4-morpholine, hydroxy, methoxymethyloxy Base, benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecyloxy, triethyldecyloxy, tert-butyldimethylalkyloxy, third Diphenylphosphinoalkyloxy, ethoxylated, trifluoroacetoxy, trichloroacetoxy, trimethylethenyloxy, benzyloxy, fluorenyl-methoxybenzyloxy , Ρ-nitrobenzyloxy, benzhydryloxy, trityloxy, aminocarbonyloxy, methoxy, ethoxy, η·propoxy, η-butoxy , η-pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethyloxy, 2-methoxyethyloxy, fluoroantimonyloxy, difluoromethyl Oxy, trifluoromethoxy, 2-fluoroethyloxy, 1-fluoroethyloxy, 1,1-difluoroethyloxy, 2,2,2-trifluoroethyloxy, carboxyl Methyl Base, 2-aminoethyloxy, amine, carbenylamino, etidylamino, trifluoroethylamino, trichloroacetamido, trimethylethenylamine , benzhydrylamino group, mercaptoamine group, tritylamino group, allylamino group, benzylamino group, fluorenyl-methoxybenzylamino group, methoxycarbonylamino group, benzyl group Oxycarbonylamino group, (9-fluorenyl)methoxycarbonylamino group, allyloxycarbonylamino group, methanesulfonylamino group, fluorene-toluenesulfonic acid amine group, benzylidene amine group, Diphenyl-50- 200948817 methyleneamino, diphenylphosphoniumamino 't-butylsulfinylamino, trimethyldecylamino, tert-butyldimethylalkyl Amino, methylamino, dimethylamino, ethylamino, isopropylamino, 2-hydroxyethylamino, 2-methoxyethylamino, 2-fluoroethylamino , phenylamino, pyridylamino, aminocarbonylamino, aminosulfonylamino, azide, formyl, amidino, oxime methylamino, oxime Aminoguanidine, carboxyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, diphenylmethyloxycarbonyl, tritylmethyloxycarbonyl, trimethyldecyloxycarbonyl , tert-butyldimethylsilyloxycarbonyl, (methoxycarbonyloxy)methyloxycarbonyl, 1-(methoxycarbonyloxy)ethyloxycarbonyl, (t-butoxy) Carbonyloxy)methyloxycarbonyl, 1-(t-butoxycarbonyloxy)ethyloxycarbonyl, (cyclohexyloxycarbonyloxy)methyloxycarbonyl, 1-(cyclohexyloxy) Carbonyloxy)ethyloxycarbonyl, aminocarbonyl, N.methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2 -Methoxyethyl)aminocarbonyl, Ν(2-fluoroethyl)aminocarbonyl, N.(ethinyl)aminocarbonyl, hydrazine-(methanesulfonyl)aminocarbonyl, A Sulfosyl, ethylsulfonyl, η-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonate Sulfhydryl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethyl Sulfonyl, 1,1, difluoroethylsulfonyl, 2,2,2·trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethyl Aminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, η-propylsulfinyl, isopropylsulfinyl, 2-hydroxyethylsulfinyl, 2-methoxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1, 1-difluoroethylsulfinium-51 - 200948817 base, 2,2,2-trifluoroethylsulfinyl, aminomethylsulfinyl, dimethylaminomethylsulfinyl , Aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2-hydroxyethyl)aminosulfonyl, N-(2- Methoxyethyl)aminosulfonyl, N-(2-fluoroethyl)aminosulfonyl, and N-(ethinyl)aminosulfonyl, pendant oxy, hydroxyimino, 0-methylhydroxyimino, fluorenyl-(fluoromethyl)hydroxyimino, fluorenyl-(difluoromethyl)hydroxyimino, fluorenyl-(trifluoromethyl)hydroxyimino, 〇-( Carboxymethyl)hydroxyimino, 〇-(two Carboxymethyl) hydroxyimino, 〇_ (2-carboxy-propyl) hydroxyimino like. Preferable examples of R6 and R7 include a bond (an integral bond with an adjacent bond of A2 or A4 to form a double bond), a hydrogen atom, a fluorine atom, a cyano group, a methyl group, and an ethyl group. Η-propyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl, aminomethyl, methyl Aminomethyl, dimethylaminomethyl, hydrazine-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-gas Ethyl, 2,2,2-dioxaethyl, 1,1-fluoroethyl, 1,2-monoethyl, 1-amino-2-hydroxyethyl, 2-amino-1-hydroxy Ethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1·carboxy-1-hydroxymethyl, 2·carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxy-2 -hydroxyethyl, 2·carboxy-1,2-dihydroxyethyl, 2-amino-1,2-dioxyethyl, 1-amino-1-carboxymethyl, amino-2- Residual ethyl, 2-amino-2-carboxyethyl, 2-carboxy-ethyloxyethyl, hydroxy, aminocarbonyloxy, methoxy, ethoxy, η·propoxy, n _butoxy, n_ Oxyl, isopropoxy, isobutoxy, tert-butoxy, 2-mercaptoethyloxy, 2-methoxyethyloxy, fluoromethoxy, difluoromethoxy, tri Methoxy, 2-oxoethyloxy, 1-fluoroethyloxy, hydrazine, 1-difluoroethyloxy, 2,2,2- 200948817 trifluoroethyloxy, carboxymethyloxy Base, 2-aminoethyloxy, amine, formazanylamine, etidylamino, methoxycarbonylamino, methanesulfonylamino, methylamino, dimethylamino , ethylamino, isopropylamino, 2-hydroxyethylamino, 2-methoxyethylamino, 2-fluoroethylamino, phenylamino, pyridylamino, amine Carbonylamino, aminosulfonylamino, carboxyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-( 2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethinyl)amine fluorenylcarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, η-propylsulfonyl, isopropylsulfonyl, 2-hydroxy Ethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1 ,1·difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethyl Sulfonyl, methylsulfinyl, ethylsulfinyl, η-propylsulfinyl, isopropylsulfinyl, 2-hydroxyethylsulfinyl, 2-methoxy Isosulfonyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-difluoro Isosulfonyl, 2,2,2-trifluoroethylsulfinyl, aminomethylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, fluorene-methyl Aminosulfonyl, anthracene, fluorenyl-dimethylaminosulfonyl, fluorenyl-(2-hydroxyethyl)aminosulfonyl, fluorenyl-(2-methoxyethyl)aminosulfonyl , Ν-(2-fluoroethyl)aminosulfonyl, fluorenyl-(ethylidene)aminosulfonyl, pendant oxy, hydroxyimino, 0-methylhydroxyimino, 〇·( Fluoromethyl)hydroxyimino, 〇-( Fluoromethyl)hydroxyimino, 〇-(iso-[0-yl, aminimimine] hydroxy) propylisomethyl-Μ 竣2 ( ( _ -ο ο ', ylamine amine Hydroxyl xly Nly-based methylfluorotricarboxylate (0-53-200948817 as a more preferred example of R6 and R7) may be exemplified by a bond which is independent of each other (when A1 is a carbon atom, the bond with A1 becomes a body' Or a bond with A3 (A3 itself is a bond in the case of A4) to form a double bond), a hydrogen atom, a methyl group, a hydroxymethyl group, a methoxymethyl group, a 1-hydroxyethyl group, a 2-hydroxy group Ethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,2-dihydroxyethyl, 1-amino 2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-1,2-di-ethoxyethyl, 1-amino-1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1. Alkyl, aminocarbonyloxy, amino, decylamino, ethylamino, methoxycarbonylamino, methanesulfonylamino, methylamino, dimethylamino, amine Carbonylamino, aminosulfonylamino, carboxyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-( Ethyl carbonyl), N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, 2-hydroxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, Trifluoromethylsulfonyl, aminomethyl U sulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methylsulfinyl, 2-hydroxyethyl Sulfosyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, aminomethylsulfinyl, dimethylaminosulfinyl, Aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2-hydroxyethyl)aminosulfonyl, N-(acetic acid) Aminosulfonyl, pendant oxy, hydroxyimino, 〇-methylhydroxyimino, 〇-(fluoromethyl) hydroxy Amine group, 〇-(carboxymethyl)hydroxyimino group, etc. Particularly preferred as a bonding bond, a hydrogen atom, a methyl group, a hydroxyl group, a carboxyl group, a methoxycarbonyl-54-200948817 group, an ethoxycarbonyl group, and a side oxygen base. When A3 is NR8, the substituent R* is a bond (a double bond is formed integrally with the adjacent a2 or a bond with A4), a hydrogen atom, a lower alkyl group which may be substituted, a lower alkyl which may be substituted Mercapto, substituted monocyclic hydrocarbon ring or heterocyclic group, protected or substituted hydroxy group, substituted lower alkoxy group, protected or substituted amine group, azide group, Substituted mercapto group, protected carboxyl group, substituted aminocarbonyl group, substituted lower alkylsulfonyl group, substituted lower alkyl sulfinyl group, or substituted amine hydrazine Sulfosyl group. Here, specific examples of R8 include a bond (a double bond is formed integrally with an adjacent A2 or a bond with A4), a hydrogen atom, a methyl group, an ethyl group, an η-propyl group, and a η-butyl group. Base, η-pentyl, isopropyl, isobutyl, second butyl, tert-butyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methyl Oxyethyl, 1-methoxyethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl , difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2,2,2-trifluoroethenyl, 1,1-difluoroethyl, 1,2-dihydroxy Ethyl, 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2-hydroxy-1,2-dihydroxyethyl, 2-amino-1,2_2 Side oxyethyl, 1-amino-1-carboxymethyl, 1-amino-2 carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl 2, hydroxy-1-epoxyethyl, 2-amine -1-sided oxyethyl, 2-(methylamino)-1-oxoethyl, 2-(dimethylamino)-1-oxoethyl, 2,3-dihydroxy Propyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2,3-diaminopropyl, vinyl, 1-fluoro-55- 200948817 vinyl, 2- Fluorovinyl, 2,2-difluorovinyl, 1-propenyl, 2-propenyl, 2-carboxyvinyl, 2-carboxy-1-fluorovinyl, 2-carboxy-2-fluorovinyl, 2 - Carboxy-1,2-difluorovinyl, 2-carboxy-1-hydroxyvinyl, 2-carboxy-2-hydroxyvinyl, 3-hydroxy-1-propenyl, 3-amino-1-propenyl , phenyl, 3-carboxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-carboxy-2-pyridinyl, 5-carboxy-2-pyridyl, 5-carboxy-3- Pyridyl, 6-carboxy-3-pyridyl, thiophenyl, 4-carboxythiophenyl, 5-carboxythiophenyl, 2-thiazolyl, 4-carboxy-2-thiazolyl, 5-carboxy-2- Thiazolyl, 4-salthazolyl, 2-carboxy-4-thiazolyl, 5-thiazolyl, 2-carboxy-5-thiazolyl, 1-pyrrolyl, 3-carboxy-1-pyridyl, 2·pyrrole Base, 4·carboxy-2-pyrrolyl, 5-carboxy-2-pyrrolyl, 3-pyrrolyl, 5-carboxy-3-pyrrolyl, 1-pyrazolyl, 3-carboxy-1-pyrazolyl, 4-carboxy-1-pyrazolyl, 3-pyrazolyl, 5-carboxy-3-pyrazolyl , 4-pyrazolyl, 4-pyrazolyl, 1-imidazolyl, 4-carboxy-1-imidazolyl, 2-imidazolyl, 4-carboxy-2-imidazolyl, 4-imidazolyl, 2-carboxyl- 4-imidazolyl, 1,2,3-triazol-1-yl, 4-carboxy-1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1, 3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 5-carboxy-1,3,4-triazol-2-yl, 2-tetrahydrofuranyl, 4-carboxy- 2-tetrahydrofuranyl, 5-carboxy-2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 5-carboxy-3-tetrahydrofuranyl, 2-oxooxazolidin-3-yl, 5-carboxy-2-oxo噚 oxazolidin-3-yl, 2· oxaoxazolidin-4-yl, 2-oxooxazolidinyl-5-yl, 4-morpholino, 2-carboxy-4-? Polinyl, hydroxy, methoxymethyloxy, benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecyloxy, triethylsulfanyloxy, tert-butyl Dimethyl decyloxy, tert-butyldiphenyl decyloxy, ethoxycarbonyl, trifluoroacetoxy, trichloroacetoxy, Methyl ethinyloxy, benzyloxy, fluorenyl-methoxybenzyloxy, fluorenyl-nitrobenzyloxy, benzhydryloxy, trityloxy, amine-56- 200948817 carbonyloxy, methoxy, ethoxy, η-propoxy, η-butoxy, η-pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2- Hydroxyethyloxy, 2-methoxyethyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethyloxy, 1-fluoroethyloxy, 1 ,1-difluoroethyloxy, 2,2,2-trifluoroethyloxy, carboxymethyloxy, 2-aminoethyloxy, amine, formazanyl, ethyl Amino, trifluoroethenylamino, trichloroacetamidoamine, trimethylethenylamine, benzhydrylamine, mercaptoamine, tritylamino, allyl Amino, benzylamino, fluorenyl-methoxybenzylamino, methoxycarbonylhydrazino, benzyloxycarbonylamino, (9-phenanthryl)methoxycarbonylamino, allylic Alkoxycarbonylamino, methanesulfonylamino, fluorene-toluenesulfonylamino, benzylideneamine, diphenylmethyleneamino, diphenyl Phosphonylamino group, tert-butylsulfinylamino group, trimethyldecylamino group, tert-butyldimethylmethylalkylamino group, methylamino group, dimethylamino group, ethyl group Amino, isopropylamino, 2-hydroxyethylamino, 2-methoxyethylamino, 2-fluoroethylamino, phenylamino, pyridylamino, aminocarbonylamino , Aminosulfonylamino, azide, methionyl, aminoguanidino, oxime-methylammonium, oxime-acetamidohydrazino, fluorenylcarboxy, methoxycarbonyl, ethoxycarbonyl , tert-butoxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, diphenylmethyloxycarbonyl, trityloxycarbonyl, three Methyl decyloxycarbonyl, tert-butyldimethyl decyloxycarbonyl, (methoxycarbonyloxy)methyloxycarbonyl, 1-(methoxycarbonyloxy)ethyloxycarbonyl (tert-butoxycarbonyloxy)methyloxycarbonyl, 1-(t-butoxycarbonyloxy)ethyloxycarbonyl, (cyclohexyloxycarbonyloxy)methyloxycarbonyl, 1-(cyclohexyloxycarbonyloxyl) Ethyloxycarbonyl, aminocarbonyl, hydrazine-methylaminocarbonyl, hydrazine, hydrazine-dimethylaminocarbonyl, hydrazine (2-hydroxyethyl)amino-57- 200948817 carbonyl, N- (2 -Methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethinyl)aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methyl Sulfonyl, ethylsulfonyl, η-propylsulfonyl, isopropyl fluorenyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethyl acid , difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, anthracene, 1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonate Stuffed base, aminomethylsulfonyl 'methylaminomethylsulfonyl, dimethylaminomethyl extended, methyl sulfenyl, ethylsulfinyl, η-propyl Sulfosyl, iso-diyl sulfhydryl, 2-hydroxyethylsulfinyl, 2,methoxyethylsulfinyl, fluoromethyl sulfhydryl, difluoromethylsulfin , trifluoromethylsulfinyl, 2-fluoroethylindenylene, 1,1-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, amineMethylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, fluorene-methylaminosulfonyl, anthracene, fluorenyl-dimethylaminosulfonyl, Ν_(2· Alkylsulfonyl, anthracene-(2-methoxyethyl)amine-based fluorenyl, Ν-(2-fluoroethyl)aminosulfonyl, and Ν-(ethinyl) Aminosulfonyl and the like. Preferable examples of R8 include a bond (a double bond is formed integrally with an adjacent Α2' or a bond with Α4), a hydrogen atom, a methyl group, an ethyl group, an η-propyl group, and a hydroxyl group. Ethyl, 2-methoxyethyl, 2-aminoethyl, 2·fluoroethyl, 2,2,2-trifluoroethyl, 1-carboxymethyl, 2-carboxyethyl, 2-carboxyl 2-hydroxyethyl, 2-amino-1,2-dioxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, 2-hydroxy- 1-sided oxyethyl, 2-amino-1-oneoxyethyl, 2-(methylamino)-1-sided oxyethyl, 2·(dimethylamino)-1- Side oxyethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2,3-diaminopropyl, hydroxy, A Oxy, ethoxy, 2-hydroxyethyloxy, carboxymethyloxy, 2-aminoethyloxy, methyl-58-200948817 oxycarbonyl, ethoxycarbonyl, aminocarbonyl, N- Methylaminocarbonyl, N,N-dimethylaminocarbonyl, Ν(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, Ν-(2- Fluoroethyl)aminocarbonyl, fluorene-(ethenyl) Aminocarbonyl, hydrazine-(methanesulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluorine Methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2-tri Fluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, indolylsulfinyl, ethylsulfinyl , η-propylsulfinyl, isopropylsulfinyl, 2-hydroxyethylsulfinyl, 2-methoxyethylsulfinyl, fluoromethylsulfinyl, difluoro Methylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2,2,2-trifluoroethyl Sulfonyl, aminomethylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, fluorenyl-methylaminosulfonyl, anthracene, fluorenyl-dimethylaminosulfonyl , Ν-(2-hydroxyethyl)aminosulfonyl, fluorenyl-(2-methoxyethyl)aminosulfonyl, fluorenyl-(2-fluoroethyl)aminosulfonyl, and Ν-(acetyl group) Sulfo acyl group and the like. Further, as a more preferable specific example of R8, a bond (a double bond is formed integrally with the adjacent bond of Α2 or Α4), a hydrogen atom, a methyl group, a carboxymethyl group, a 2-carboxyethyl group, 2-carboxy-2-hydroxyethyl, 2-amino-1,2-dioxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, 2 -hydroxy-1-oxoethyl, 2-amino-1-oneoxyethyl, 2-(methylamino)-1-yloxyethyl, 2-(dimethylamino) - 丨-side oxyethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2,3-diaminopropyl' Hydroxy, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, n,N-dimethylaminocarbonyl, N-(2-59 - 200948817 hydroxyethyl)aminocarbonyl, N-(2.methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethinyl)aminocarbonyl, N -(methanesulfonyl)aminocarbonyl, methylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methylsulfin醯基, Methylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, and N- (Ethylene) Aminosulfonyl and the like. Particularly preferred examples of R8 are a bond, a hydrogen atom, and a hydroxyl group. When A3 is an oxidizable sulfur atom, for example, _s(〇2) -' -S ( Ο )-, and -S- may be mentioned. A4 represents a general formula CR9R1G, a general formula NR11, an oxygen atom, or an oxidizable sulfur atom, as described above, but is preferably a general formula CR9R1(), a general formula NR11, and an oxygen atom. When A4 is a general formula CR9R1D, R9 and R1G are each independently a bond (a bond is formed integrally with a bond of adjacent A3 (A3 itself is a bond of A3)), a hydrogen atom, a halogen atom, and a cyanogen. a lower alkyl group which may be substituted, a lower alkyl alkane group which may be substituted, a monocyclic anthracene ring group or a heterocyclic group which may be substituted, a protected or substituted hydroxyl group, a lower alkoxy group which may be substituted Amino, a protected or substituted amine group, an azide group, a substituted carbachyl group, a protected carboxyl group, a substituted aminocarbonyl group, a substituted lower alkyl sulfonyl group, Substituted lower alkylsulfinylene, substituted aminosulfonyl, and R9, R1G are pendant oxy groups formed or integrated, or substituted hydroxyimido groups. Here, as specific examples of R9 and R1(), each of them may be a bond alone (in combination with A3 (A3 itself is a bond of A3) - 60-200948817 bond is integrated to form a double bond) , hydrogen atom, fluorine atom, chlorine atom, bromine atom, cyano group, methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, isopropyl group, isobutyl group, second butyl group, Tributyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl, aminomethyl, methylamine Methyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoro Base, 2,2,2-trisylethyl, 1,1_monoethyl, 1,2·-yl-ethyl, 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl 1,1,2-aminoethyl, carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-ylethyl, 2-carboxy-2- Hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-1,2-dioxyethyl, 1-amino-1-carboxymethyl, amidino-2- Carboxylate Ethylethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, vinyl '1-fluorovinyl, 2-fluorovinyl, 2,2·difluorovinyl , 1-propenyl, 2-propenyl, 2-carboxyvinyl, 2-carboxy-1-fluorovinyl, 2-carboxy-2-vinylvinyl, 2-carboxy-1,2-difluorovinyl, 2-carboxy-1-hydroxyvinyl, 2-carboxy-2-hydroxyvinyl, 3-hydroxy-1-propenyl, 3-amino-1-propenyl, fluorenylphenyl, 3-carboxyphenyl, 2 Pyridyl, 3-pyridyl, 4-pyridyl, 4-carboxy-2-pyridyl, 5-carboxy-2-pyridyl, 5-carboxy-3-pyridyl, 6-carboxy-3-pyridyl, Thiophenyl, 4-carboxythiophenyl, 5-carboxythiophenyl, 2-salbenyl, 4-carboxy-2-thiazolyl, 5-carboxy-2-thiazolyl, 4-salzolyl, 2- Carboxy-4-thiazolyl, 5-thiazolyl, 2-carboxy-5-thiazolyl, 1-pyrrolyl, 3-carboxy-1-pyrrolyl, 2-pyrrolyl, 4-carboxy-2-pyrrolyl, 5 -carboxy-2-pyrrolyl, 3-pyrrolyl, 5-carboxy-3-pyrrolyl, 1-pyrazolyl, 3-carboxy-1-pyrazolyl, 4-carboxy-1-pyridinyl, 3- Pyrazolyl, 5-carboxy-3-pyrazolyl, 4-pyrazolyl, 4-pyrazolyl, 1-mi Azyl, 4-carboxy-1-imidazolyl, 2-imidazolyl, 4-carboxy-61- 200948817-2-imidazolyl, 4-imidazolyl, 2-carboxy-4-imidazolyl, 1,2,3- Triazol-1-yl, 4-carboxy-1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 5-carboxy-1,3,4-triazol-2-yl, 2-tetrahydrofuranyl, 4-carboxy-2-tetrahydrofuranyl, 5-carboxy-2- Tetrahydrofuranyl, 3-tetrahydrofuranyl, 5-carboxy-3-tetrahydrofuranyl, 2-oxooxazolidin-3-yl, 5-carboxy-2-oxooxazolidin-3-yl, 2-side Oxyoxazolidin-4-yl, 2-oxooxazolidin-5-yl, 4-morpholino, 2-carboxy-4-morpholine, hydroxy, methoxymethyloxy , benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecyloxy, triethyldecyloxy, tert-butyldimethylalkyloxy, hydrazine Diphenylphosphinoalkyloxy, ethoxylated, trifluoroethyloxy, trichloroethoxycarbonyl, trimethylethenyloxy, benzyloxy, P-methoxybenzyloxy Base, P-nitrobenzyloxy, benzhydryloxy, trityloxy, amine Carbocarbonyloxy, methoxy, ethoxy, η-propoxy, η-butoxy, n-pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxy Ethyloxy, 2-methoxyethyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethyloxy, fluoroethyloxy, 1,1 -difluoroethyloxy, 2,2,2-trifluoroethyloxy, carboxymethyloxy, 2-aminoethyloxy, amine, formazanylamine, acetylamine , trifluoroacetamidoamine, trichloroacetamidoamine, trimethylethenylamine, benzhydrylamine, mercaptoamine, tritylamino, allylamine Base, benzylamino, P-methoxybenzylamino, methoxycarbonylamino, benzyloxycarbonylamino, (9-fluorenyl)methoxycarbonylamino, allyloxy Carbonylamino, methanesulfonylamino, P-toluenesulfonylamino, benzylideneamine, diphenylmethyleneamino, diphenylphosphoniumamino, tert-butylsulfin Mercaptoamine, trimethyldecylamino, tert-butyldimethylalkylamino, methylamino, dimethylamino, B Amino group, isopropyl-62-200948817 amine group, 2-hydroxyethylamino group, 2-methoxyethylamino group, 2-fluoroethylamino group, phenylamino group, pyridylamino group, Aminocarbonylamino group, aminosulfonylamino group, azide group, formamyl group, aminoguanidino group, oxime-methylaminomethyl group, 0-acetamidamino group, carboxyl group, methoxycarbonyl group, Ethoxycarbonyl, tert-butoxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, diphenylmethyloxycarbonyl, trityloxy Carbocarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethylmethyloxycarbonyl, (methoxycarbonyloxy)methyloxycarbonyl, 1-(methoxycarbonyloxy)B Alkoxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, i-(t-butoxycarbonyloxy)ethyloxycarbonyl, (cyclohexyloxycarbonyloxy) A Alkoxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethyloxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2- Hydroxyethyl)aminocarbonyl, N-(2-methoxy Ethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, (ethylidene)aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonate Sulfhydryl, η-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, fluorene difluoromethyl Sulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, amine Sulfosyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, η-propylsulfinyl, iso Propylsulfinyl, 2-hydroxyethylsulfinyl, 2-methoxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethyl Sulfosyl, 2-fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, aminomethylsulfin , dimethylaminomethylsulfinyl, aminosulfonyl, fluorenyl-methylaminosulfonyl, anthracene, fluorenyl-dimethylaminosulfonyl, fluorene-(2-hydroxyethyl) -63- 2009 48817-amino)sulfonyl, Ν(2-methoxyethyl)aminosulfonyl, N-(2-fluoroethyl)aminosulfonyl, N-(ethinyl)amine Sulfonyl, pendant oxy, hydroxyimino, fluorene-methylhydroxyimino, 0-(fluoromethyl)hydroxyimino, 0-(difluoromethyl)hydroxyimino, 〇-( Trifluoromethyl)hydroxyimino, 0-(carboxymethyl)hydroxyimino, fluorenyl-(difluorocarboxymethyl)hydroxyimino, 0-(2-carboxyisopropyl)hydroxyimino Wait.

Preferable examples of R9 and R1() include a bond (integrally bonded to an adjacent A3 (A3 itself is a bond in the case of a bond) to form a double bond), a hydrogen atom, and a fluorine. Atom, cyano, methyl, ethyl, η-propyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxy Ethyl ethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl Base, 2-fluoroethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl' 1,1-difluoroethyl, 1,2-dihydroxyethyl, 1-amino-2- Hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxyl 1-hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2·amino-1,2-di-oxyethyl, 1-amino -1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, hydroxy, aminocarbonyloxy, A Oxyl, ethoxy, 2·hydroxy Ethyloxy, 2-methoxyethyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethyloxy, 1-fluoroethyloxy, 1, 1-difluoroethyloxy, 2,2,2-trifluoroethyloxy, carboxymethyloxy, 2-aminoethyloxy, amine, formazanylamine, acetylamine , methoxycarbonylamino, methanesulfonylamino, methylamino, dimethylamino, ethylamino, isopropylamino, 2-hydroxyethylamino, 2-methoxy Ethylethylamine, -64- 200948817 2-fluoroethylamino, phenylamino, pyridylamino, aminocarbonylamino, aminosulfonylamino, carboxyl, N-methylamine Carbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl) Aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, 2-hydroxyethylsulfonyl, 2- Methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1·difluoro Sulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, 0 methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methyl Sulfosyl, ethylsulfinyl, 2-hydroxyethylsulfinyl, 2-methoxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl , trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, amine Methylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, N-methylaminosulfonyl, anthracene, dimethylaminosulfonyl, fluorene- ( 2 -hydroxyethyl)aminosulfonic acid 'Ν-(2.methoxyethyl)aminosulfonyl, fluorenyl-(2-fluoroethyl)aminosulfonyl, fluorene-(ethenyl) Amino sulfonyl sulfonyl group, pendant oxy group, hydroxyimino group, fluorenyl-methylhydroxyimino group, 0-(fluoromethyl)hydroxyimino group, fluorenyl-(difluoromethyl)hydroxyimino group, 0-(Trifluoromethyl)hydroxyimino, 〇-(carboxymethyl)hydroxyimino, 0-(difluorocarboxymethyl)hydroxyimino, 0-(2-carboxyisopropyl)hydroxy Imino group and the like. More preferably, R9 and R1() are each a bond (integrally bonded to abutting A3 (A3 itself is a bond in the case of a bond) to form a double bond), a hydrogen atom, and a fluorine. Atom, cyano, methyl, ethyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, methylaminomethyl, dimethylamino Methyl, hydrazine-aminoethyl, 2_-65- 200948817 Aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, ι,ι-difluoroethyl, 1,2-dihydroxy , 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-1,2-di-side Oxyethyl, 1-amino-1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-yloxyethyl, Hydroxy, aminocarbonyloxy, methoxy, 2-hydroxyethyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, carboxymethyloxy, 2-amine Ethyloxy, amino, decylamino, ethyl hydrazino, methoxycarbonyl Q amine, methanesulfonylamino, methylamino, dimethylamino, ethylamine , 2-hydroxyethylamino, 2-fluoroethylamino, aminocarbonylamino, aminosulfonylamino, carboxyl, N-methylaminocarbonyl, N,N-dimethylamine Carbocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethinyl) Aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, 2-hydroxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethyl Sulfosyl, 2-fluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylamine mercaptomethylsulfonyl, methylsulfinyl , 2-hydroxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, amine Isosulfonyl, dimethylaminosulfinyl, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylamino Sulfhydryl, N-(ethinyl)aminosulfonyl, pendant oxy, hydroxyimino, fluorene-methylhydroxyimino, fluorenyl-(fluoromethyl)hydroxyimino, 0-(carboxyl Methyl) hydroxyimino group and the like. Particularly preferred are a hydrogen atom, a hydroxyl group, a pendant oxy group, a bonding bond, a hydroxyimino group, and a fluorenyl-methylhydroxyimino group. -66- 200948817 When A4 is a general formula NR11, the substituent R11 in the formula is a bond (a bond is bonded to the adjacent A3 (A3 itself is a bond of A3), and a double bond is formed), and a hydrogen atom , a lower alkyl group which may be substituted, a lower alkyl alkane group which may be taken, a monocyclic hydrocarbon ring group or a heterocyclic group which may be substituted, a hydroxyl group which may be protected or substituted, a lower alkoxy group which may be substituted A group, an amine group which may be protected or taken, an azide group, a substituted meyl group, a protected carboxyl group, a substituted aminocarbonyl group, a substituted lower alkyl sulfonyl group, The lower alkylsulfinyl group of the & or the aminosulfonyl group which may be substituted. Here, as a specific example of R11, a bonding bond (a bonding bond is formed integrally with an adjacent Α3 (Α3 itself is a bonding bond in the case of a bonding bond) to form a double bond), a hydrogen atom, a methyl group, and an ethyl group. , η-propyl, η-butyl, η-pentyl, isopropyl, isobutyl, t-butyl, tert-butyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 1-aminoethyl, 2 -Aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl 1,1,2-dihydroxyethyl, oxime 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2·carboxy-1-hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2 -amino-1,2-dioxyethyl, 1-amino-1.carboxymethyl, 1-amino-2.carboxyethyl, 2-amino-2-carboxyethyl, 2- Carboxy-1-oxoethyl, 2-hydroxyl - pendant oxyethyl, 2-amino-1-oneoxyethyl, 2-(methylamino)-1-oxoethyl, 2-(dimethylamino)-1- Side oxyethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2,3-diaminopropyl, vinyl, 1-fluorovinyl, 2-fluorovinyl, 2,2-difluorovinyl, -67- 200948817 1-propenyl, 2-propenyl, 2-carboxyvinyl, 2-carboxy-1-fluorovinyl , 2-carboxy-2-fluorovinyl, 2-carboxy-1,2-difluorovinyl, 2-carboxy-1-hydroxyvinyl, 2-carboxy-2-hydroxyvinyl, 3-hydroxy-1- Propenyl, 3-amino-1-propenyl, phenyl, 3-carboxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-carboxy-2-pyridyl, 5-carboxy- 2-pyridyl, 5-carboxy-3-pyridyl, 6-carboxy-3-pyridyl, thiophenyl, 4·carboxythiophenyl, 5-carboxythiophenyl, 2-thiazolyl, 4-carboxy- 2-thiazolyl, 5-carboxy-2-thiazolyl, 4-thiazolyl, 2-carboxy-4-thiazolyl, 5-thiazolyl, 2-carboxy-5-thiazolyl, 1-pyrrole

, 3-carboxy-1-pyrrolyl, 2-pyrrolyl, 4-carboxy-2-pyrrolyl, 5-carboxy Q-2-pyrrolyl, 3-pyrrolyl, 5-carboxy-3-pyrrolyl, 1 -pyrazolyl, 3-carboxy-1-pyrazolyl, 4-carboxy-1-pyrazolyl, 3-pyrazolyl, 5-carboxy-3-pyrazolyl, 4-pyrazolyl, 4-pyridyl Azyl, 1-imidazolyl, 4-carboxy-1-imidazolyl, 2-imidazolyl, 4-carboxy-2.imidazolyl, 4.imidazolyl, 2-carboxy-4-imidazolyl, 1,2,3 - triazol-1-yl, 4-carboxy-1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,3,4-triazol-1-yl 1,3,4-triazol-2-yl, 5-carboxy-1,3,4-triazol-2-yl, 2-tetrahydrofuranyl, 4-carboxy-2-tetrahydrofuranyl, 5-carboxy-2 -tetrahydrofuranyl, 3-tetrahydrofuranyl, 5-carboxy-3-tetrahydrofuranyl, 2-oxooxazolidin-3-yl, 5-carboxy-2-oxooxazolidin-3-yl, 2 - oxooxazolidin-4-yl, 2-oxooxazolidin-5-yl, 4-morpholinyl, 2-carboxy-4-morpholine, hydroxy, methoxymethyl Oxyl, benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecyloxy, triethyldecyloxy, tert-butyldimethylalkyloxy , tert-butyldiphenylphosphonyloxy, ethoxycarbonyl, trifluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, P-methyl Oxybenzyloxy, P-nitrobenzyloxy, benzhydryloxy, trityloxy, aminocarbonyloxy, methoxy, ethoxy, n-propoxy, η·丁-68- 200948817 oxy, η-pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethyloxy, 2-methoxyethyloxy, Fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethyloxy, 1-fluoroethyloxy, 1,1-difluoroethyloxy, 2,2,2· Trifluoroethyloxy, carboxymethyloxy, 2-aminoethyloxy, amine, formazanylamine, ethionylamino, trifluoroethenylamine, trichloroethylidene Amino, trimethylacetamidoamine, benzhydrylamine, mercaptoamine, tritylamino, allylamine, benzylamine, ρ-methoxybenzylamine a methoxycarbonylamino group, a benzyloxycarbonylamino group, a (9-fusyl)methyl methoxycarbonylamino group, an allyloxycarbonylamino group, Methanesulfonylamino, fluorene-toluenesulfonylamino, benzylideneamine, diphenylmethyleneamino, diphenylphosphoniumamino, tert-butylsulfinylamino , trimethyldecylamino group, tert-butyldimethylmethylalkylamino, methylamino, dimethylamino, ethylamino, isopropylamino, 2-hydroxyethylamino , 2-methoxyethylamino, 2-fluoroethylamino, phenylamino, pyridylamino, aminocarbonylamino, aminosulfonylamino, azido, formazan , Aminoguanidine, 〇-methylaminomethyl, 0-ethionylamino, carboxyl, methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, (9-fluorenyl) methoxy Carbocarbonyl, allyloxycarbonyl, benzyloxycarbonyl, diphenylmethyloxycarbonyl, trityloxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethyloxane Alkoxycarbonyl, (methoxycarbonyloxy)methyloxycarbonyl, 1-(methoxycarbonyloxy)ethyloxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl , 1-(Tertidinoxycarbonyloxy)B Oxycarbonyl, (cyclohexyloxycarbonyloxy)methyloxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethyloxycarbonyl, aminocarbonyl, hydrazine-methylaminocarbonyl, hydrazine, Ν-Dimethylaminocarbonyl, Ν-(2-hydroxyethyl)aminocarbonyl, Ν-(2-methoxyethyl)aminocarbonyl, Ν--69- 200948817 (2-fluoroethyl) Aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, η-propylsulfonyl, isopropyl Sulfosyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoro Ethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, Dimethylaminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, η-propylsulfinylene, isopropylsulfinylene, 2-hydroxyethylsulfinium , 2-methoxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2 -fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, aminomethylsulfinyl, dimethylamine A sulfinyl group, an aminosulfonyl group, a fluorenyl-methylaminosulfonyl group, an anthracene, a fluorenyl-dimethylaminosulfonyl group, a fluorenyl-(2-hydroxyethyl)aminosulfonyl group, Ν-(2-methoxyethyl)aminosulfonyl, fluorenyl-(2-fluoroethyl)aminosulfonyl, and fluorenyl-(ethionyl)aminosulfonyl.

Preferred examples of R11 include a hydrogen atom, a methyl group, an ethyl group, an η-propyl group, a 2-hydroxyethyl group, a 2-methoxyethyl group, a 2-aminoethyl group, and a 2-fluoroethyl group. , 2,2,2-trifluoroethyl, 1-carboxymethyl, 2-carboxyethyl, 2-carboxy-2-hydroxyethyl, 2-amino-1,2-di- oxyethyl, 1-amino-1-carboxymethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, 2-hydroxy-1-oxoethyl, 2-amino -1-sided oxyethyl, 2-(methylamino)-1-oxoethyl, 2-(dimethylamino)-1-oxoethyl, 2,3-dihydroxy Propyl, 2-amino-3-hydroxypropyl, methoxy, 2-hydroxyethyloxy, 2-methoxyethyloxy, 2-aminoethyloxy, amine, methanesulfonate Merylamino, methylamino, dimethylamino, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, Ν--70-200948817 methylaminocarbonyl, N,N-dimethylamine Carbocarbonyl, N_(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2·fluoroethyl)aminocarbonyl, N-(ethinyl) Aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonate Ethyl, ethylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl , 2-fluoroethylsulfonyl, 1, difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonate Mercapto, dimethylaminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, 2-hydroxyindoleethylsulfinyl, 2-methoxyethylsulfinyl , fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, aminomethylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, N-methylaminosulfonyl, N,N-Dimethylaminosulfonyl, N-(2-hydroxyethyl)aminosulfonyl, N-(2-methoxyethyl)aminosulfonyl, N-(2- Fluoroethyl)aminosulfonyl, and N-(ethinyl)aminosulfonyl. Further preferred examples of R11 include a hydrogen atom, a methyl group, an ethyl group, a hydrazine 2-hydroxyethyl group, a 2-aminoethyl group, a 2-fluoroethyl group, a 1-carboxymethyl group, and a 2-carboxyethyl group. , 2-carboxy-2-hydroxyethyl, 2-amino-1,2-di-oxyethyl, ^-amino-1-carboxymethyl, 2-amino-2-carboxyethyl, 2- Carboxy-1-oxoethyl, 2-hydroxy-1-oxoethyl, 2-amino-1-oneoxyethyl, 2-(methylamino)-1-sided oxyethyl , 2-(dimethylamino)-1-oxoethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, methoxy, amine, methoxy Carbonyl, ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(ethinyl) Aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, 2-hydroxy-71-200948817-ethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonate , trifluoromethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methylsulfinyl, 2-hydroxy Thiosulfonyl, fluoromethyl Sulfonyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, aminomethylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, N- Aminosulfonyl group, N,N-dimethylaminosulfonyl group, anthracene-(2.hydroxyethyl)aminosulfonyl group, and anthracene-(ethionyl)aminosulfonyl group. Particularly preferred is a hydrogen atom. When Α4 is an oxidizable sulfur atom, examples thereof include -S ( 02 ) f) -, -S(O)-, and _ S. Here, in the following formula (la)' which is a part of the general formula (I), the substituent in the ring is not specified, and the part which is a constituent element of the ring is centered on χ1 to X4 and A1 to A4. Specific examples of the three-ring structure (* indicates the bond with L1. X2, Rla, Rlb, r5, R8, and R" and the formula (1)

-72- 200948817

-73- 200948817

-74- 200948817

Further, as a more preferable example of the general formula (la), the following structures (* represents a bond with L1. Definitions of substituents of X2, Rla, Rlb, R5, R8, and R11 and formula (I) the same). -75- .0 200948817

L1 is a lower-grade which can be substituted by a hydroxyl group selected from a hydrogen atom, a halogen atom, a cyano group, a protected or substituted hydroxyl group, a protected or substituted amine group, a protected carboxyl group, and a substituted amino group carbonyl group. a carbon atom substituted with a sulfonyl group, a substituted amine sulfonyl sulfonyl group, a pendant oxy group, and a hydroxyimino group which may be substituted. Here, 'specific examples of the group substituted in L1 include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a hydroxyl group, an aminocarbonyloxy group, a methoxymethyloxy group, and a benzyloxy group. Methyloxy, tetrahydropyranyloxy, trimethylsilyloxy, triethyldecyloxy, tert-butyldimethylsilyloxy, tert-butyldiphenylnonane Alkoxy, ethoxylated, trifluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, ρ·methoxybenzyloxy 'P-nitrate Base benzyloxy, benzhydryloxy, trityloxy, amine, decylamino, ethionylamino, trifluoroethenylamino, trichloroacetamido , trimethyl ethinylamino, benzhydrylamino, decylamino, tritylamino, allylamino, benzylamino, p-methoxybenzylamino, Methoxycarbonylamino, benzyloxycarbonylamino, (9-fluorenyl)methoxycarbylamino, allyloxycarbonylamino, methanesulfonylamino, p-toluenesulfonate Amino group, benzylidene group, diphenylmethyleneamino group Diphenyl-76- 200948817 phosphonium amino group, tert-butylsulfinylamino group, trimethyldecylamino group, tert-butyldimethylammonium alkyl group, methylamino group, two Methylamino, ethylamino, isopropylamino, 2-hydroxyethylamino, 2-methoxyethylamino, 2-fluoroethylamino, phenylamino, pyridylamine Base, aminocarbonylamino group, aminosulfonylamino group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group, (9-fluorenyl)methoxycarbonyl group, allyloxy group Carbocarbonyl, benzyloxycarbonyl, diphenylmethyloxycarbonyl, trityloxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethylsilyloxycarbonyl, (A) Oxidylcarbonyloxy)methyloxycarbonyl, 1-(methoxycarbonyloxy)ethyloxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, 1-(third Butoxycarbonyloxy)ethyloxycarbonyl, (cyclohexyloxycarbonyloxy)methyloxycarbonyl, 1·(cyclohexyloxycarbonyloxy)ethyloxycarbonyl, Aminocarbonyl, N -methylaminocarbonyl , N,N-Dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)amine Alkylcarbonyl, N-(ethionyl)aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, η-propylsulfonyl V, isopropyl Sulfonyl, 2-hydroxyethylsulfonyl, 2,methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoro Ethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, Dimethylaminomethylsulfonyl, aminosulfonyl, fluorenyl-methylaminosulfonyl, anthracene, fluorenyl-dimethylaminosulfonyl, fluorenyl-(2-hydroxyethyl)amine Sulfosyl, fluorenyl-(2-methoxyethyl)aminosulfonyl, fluorenyl-(2-fluoroethyl)aminosulfonyl, fluorenyl-(ethenyl)aminosulfonyl, Sideoxy, hydroxyimino, 〇-methylhydroxyimino, 0-(fluoromethyl)hydroxyimino, 〇-(difluoromethyl)hydroxyimino, 0-(trifluoromethyl ) -77- 200948817 hydroxyimino, ο-(carboxyl Methyl)hydroxyimino, ο-(difluorocarboxymethyl)hydroxyimino, 0-(2-carboxyisopropyl)hydroxyimino, and the like.

Preferable examples of the group substituted in L1 include a hydrogen atom, a cyano group, a hydroxyl group, an aminocarbonyloxy group, an amine group, a decylamino group, an ethenylamino group, a methoxycarbonylamino group, and methane. Sulfhydrylamino, methylamino, dimethylamino, 2-hydroxyethylamino, 2-fluoroethylamino, aminocarbonylamino, aminosulfonylamino, carboxyl, amine Carbocarbonyl, fluorene-methylaminocarbonyl, hydrazine, fluorenyl-dimethylaminocarbonyl, fluorenyl-(2-hydroxyethyl)aminocarbonyl, fluorenyl-(ethylidene)aminocarbonyl, hydrazine-(methane Sulfhydryl)aminocarbonyl, methylsulfonyl, 2-hydroxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, aminomethyl Sulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, aminosulfonyl, fluorene-methylaminosulfonyl, anthracene, fluorenyl-dimethylamino Sulfonyl, fluorenyl-(2-hydroxyethyl)aminosulfonyl, fluorenyl-(ethenyl)aminosulfonyl, pendant oxy, hydroxyimino, 0-methylhydroxyimino, 0-(fluoromethyl)hydroxyimino, 〇-(difluoromethyl)hydroxyimino, 0-(trifluoromethyl)hydroxy Group, 〇- (carboxymethyl) hydroxyimino, O- (carboxymethyl difluoromethyl) hydroxyimino, 〇- (2-carboxy-propyl) hydroxyimino like. More specific examples of the group substituted with L1 include a hydrogen atom, a cyano group, a hydroxyl group, an aminocarbonyloxy group, an amine group, a methoxycarbonylamino group, a methanesulfonylamino group, a methylamino group, and a second group. Methylamino, aminocarbonylamino, aminosulfonylamino, carboxy, aminocarbonyl, fluorene-methylaminocarbonyl, hydrazine, fluorenyl-dimethylaminocarbonyl, fluorene-(ethenyl) Aminocarbonyl, hydrazine-(methanesulfonyl)aminocarbonyl, methylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl Base, aminosulfonyl, fluorenyl-methylaminosulfonyl, anthracene, fluorenyl-dimethylaminosulfonyl, fluorenyl-(2-hydroxyethyl)aminosulfonyl, fluorene-(B -78- 200948817 fluorenyl)aminosulfonyl, pendant oxy, hydroxyimino, 0-methylhydroxyimino, fluorenyl-(fluoromethyl)hydroxyimino, fluorene-(carboxymethyl) Hydroxyimine group and the like. A particularly preferred specific example of L1 is a carbon atom substituted by a hydrogen atom or a pendant oxy group. Q1, as described above, represents a certain 6 between L1 and L2 represented by the following formula (II)

a member ring and a structure extending one atomic portion from the direction of L2,

Formula CR2() is preferred,

When Z1 and Z4 are a general formula CR2(), the substituent R2G is a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group which may be substituted, a lower alkyl alkane group which may be substituted, a monocyclic hydrocarbon which may be substituted Cyclo or heterocyclic, protected or substituted hydroxy, substituted lower alkoxy, protected or substituted amine, azide, substituted methyl group, protected carboxyl group And a substituted aminocarbonyl group, a lower alkylsulfonyl group which may be substituted, a lower alkylsulfonyl group which may be substituted, and an aminesulfonyl group which may be substituted. Here, specific examples of R2() include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, an ethyl group, an η-propyl group, an η-butyl group, an η-pentyl group, and an isopropyl group. Base, isobutyl, t-butyl, tert-butyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxy Ethyl ethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl Base, 2-fluoroethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl, 1-amino-2- Hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-79-200948817 diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl , 2-carboxy-1-hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-1,2-di- oxyethyl, 1-amino-bucarboxymethyl, 1·amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, vinyl, 1-fluoro Vinyl, 2-fluorovinyl, 2,2-difluorovinyl, 1-propenyl, 2-propenyl, 2-carboxyvinyl, 2-carboxy-1-fluorovinyl,

2-carboxy-2-fluorovinyl, 2-carboxy-1,2-difluorovinyl, 2-carboxy-1-hydroxyvinyl, 2-carboxy-2-hydroxyvinyl, 3-hydroxy-1-propene , 3-amino-1-propenyl, phenyl, 3-carboxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-carboxy-2-pyridyl, 5-carboxy-2 -pyridyl, 5-carboxy-3.pyridyl, 6-carboxy-3-pyridyl, thiophenyl, 4-carboxythiophenyl, 5-carboxythiophenyl, 2-thiazolyl, 4-carboxy-2 -thiazolyl, 5-carboxy-2-thiazolyl, 4-thiazolyl, 2-carboxy-4-thiazolyl, 5-thiazolyl, 2-carboxy-5-thiazolyl, 1-pyrrolyl, 3-carboxy- Buzzranyl, 2-pyrrolyl, 4-carboxy-2-pyrrolyl, 5-carboxy-2-pyrrolyl, 3-pyrrolyl, 5-carboxy-3-pyrrolyl, 1-pyrazolyl, 3- Carboxy-1-pyrazolyl, 4-carboxy-1-pyrazolyl, 3-pyrazolyl, 5-carboxy-3-pyrazolyl '4-pyrazolyl, 4-pyrazolyl, 1-imidazolyl 4-carboxy-1-imidazolyl, 2-imidazolyl, 4-carboxy-2-imidazolyl, 4-imidazolyl, 2-carboxy-4-imidazolyl, 1,2,3-triazol-1-yl , 4-carboxy-1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,3,4-triazol-1-yl, 1,3, 4-triazol-2-yl, 5-carboxy-1,3,4-triazol-2-yl, 2-tetrahydrofuranyl, 4-carboxy-2-tetrahydrofuranyl, 5-carboxy-2-tetrahydrofuranyl, 3 -tetrahydrofuranyl, 5-carboxy-3-tetrahydrofuranyl, 2-oxooxazolidin-3-yl, 5-carboxy-2-oxooxazolidin-3-yl, 2-oxooxycarbazole Pyridin-4-yl, 2-oxooxazolidin-5-yl, 4-morpholino, 2-carboxy-4-homofolinyl, hydroxy, aminocarbonyloxy, methoxymethyl Oxyl, benzyloxymethyloxy, -80- 200948817 tetrahydropyranyloxy, trimethyldecyloxy, triethyldecyloxy, tert-butyldimethylalkyloxy , tert-butyldiphenylphosphinoalkyloxy, ethoxylated, trifluoroethyloxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, P- Oxybenzyloxy, P-nitrobenzyloxy, benzhydryloxy, trityloxy, methoxy, ethoxy, η-propoxy, n-butoxy, Η-pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethyloxy, 2-methoxyethyloxy, fluoromethoxy, difluoromethoxy , trifluoro Methoxy, 2-fluoroethyloxy, 1-fluoroethyloxy, 1,1-difluoroethyloxy, 2,2,2-trifluoroethyloxy, carboxymethyloxy , 2-aminoethyloxy, amine, carbenylamino, etidylamino, trifluoroethenylamino, trichloroacetamidoamine, trimethylethenylamine, Benzylamino, mercaptoamine, tritylamino, allylamino, benzylamino, fluorenyl-methoxybenzylamino, methoxycarbonylamino, benzyloxy Alkylcarbonylamino, (9-fluorenyl)methoxycarbonylamino, allyloxycarbonylamino, methanesulfonylamino, fluorene-toluenesulfonylamino, benzylideneamine, Phenylmethyleneamino, diphenylphosphoniumamino, tert-butylsulfinylamino, trimethyldecylamino, hydrazine tert-butyldimethylalkylamino, A Amino group, dimethylamino group, ethylamino group, isopropylamino group, 2-hydroxyethylamino group, 2-methoxyethylamino group, 2-fluoroethylamino group, phenylamine Base, pyridylamino group, aminocarbonylamino group, aminosulfonylamino group, azide group, formamyl group, amino group, hydrazine- Aminoguanidino, 〇-acetamidoguanidinyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyloxycarbonyl , benzyloxycarbonyl, diphenylmethyloxycarbonyl, trityloxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethylalkyloxycarbonyl, (methoxy) Carbonyloxy)methyloxycarbonyl, 1-(methoxycarbonyloxy)ethyl-81 - 200948817 oxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, ι-( Tributoxycarbonyloxy)ethyloxycarbonyl, (cyclohexyloxycarbonyloxy)methyloxycarbonyl, i-(cyclohexyloxycarbonyloxy)ethyloxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-( 2-fluoroethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, η-propylsulfonate Sulfhydryl, isopropylsulfonyl, 2-hydroxyethyl Sulfhydryl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1- Difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl , Aminosulfonyl, dimethylaminosulfonyl, methylsulfinyl, ethylsulfinyl, η-propylsulfinylene, isopropylsulfinyl, 2-hydroxy Ethylsulfinyl, 2-methoxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethyl Sulfosyl, 1,1-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, aminomethylsulfinyl, dimethylaminosulfin Base, aminosulfonyl, fluorenyl-methylaminosulfonyl, anthracene, fluorenyl-dimethylaminosulfonyl, fluorenyl-(2-hydroxyethyl)aminosulfonyl, fluorene-(2 -Methoxyethyl)aminosulfonyl, fluorenyl-(2-fluoroethyl)aminosulfonyl, and fluorenyl-(ethionyl)aminosulfonyl. Preferable specific examples of R2() include a hydrogen atom, a fluorine atom, a cyano group, a methyl group, an ethyl group, an η-propyl group, a hydroxymethyl group, a methoxymethyl group, a 1-hydroxyethyl group, and a 2-hydroxy group. Hydroxyethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl Base, 2-fluoroethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1,2-82-200948817 dihydroxyethyl, 1-amine 2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, carboxy-l-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-1,2-di- oxyethyl, 1 -amino-1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, hydroxy, aminocarbonyloxy Base, methoxy, ethoxy, 2-hydroxyethyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, carboxymethyloxy, amine, ethenylamine, Methanesulfonylamino group, methylamine , dimethylaminoindenyl, ethylamino, 2-hydroxyethylamino, 2-fluoroethylamino, aminocarbonylamino, aminosulfonylamino, carboxyl, aminocarbonyl, N _Methylaminocarbonyl, hydrazine, hydrazine dimethylaminocarbonyl, N. (2-hydroxyethyl)aminocarbonyl, N-(ethinyl)aminocarbonyl, hydrazine-(methanesulfonyl) Aminocarbonyl, methylsulfonyl, ethylsulfonyl, 2-hydroxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl 'amine Methylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, 2-hydroxyethylsulfinyl , fluoromethylsulfinyl, difluoromethylsulfonyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, aminomethylsulfinyl, dimethyl Aminosulfinyl, aminosulfonyl, anthracene methylaminosulfonyl, anthracene, fluorenyl-dimethylaminosulfonyl, fluorenyl-(2.hydroxyethyl)aminosulfonyl And Ν-(ethinyl)aminosulfonyl group and the like. More preferable examples of R2() include a hydrogen atom, a cyano group, a methyl group, a hydroxymethyl group, an aminomethyl group, a methylaminomethyl group, a dimethylaminomethyl group, a fluoromethyl group, and a second group. Fluoromethyl, trifluoromethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 1-amino-1-carboxymethyl, hydroxy, aminocarbonyl-83- 200948817 oxy, methoxy, fluoromethoxy, difluoro Methoxy, trifluoromethoxy, carboxymethyloxy, amine, etidylamino, methanesulfonylamino, methylamino, dimethylamino, 2-hydroxyethylamino , Aminocarbonylamino, Aminosulfonylamino, Carboxyl, Aminocarbonyl, N-Methylaminocarbonyl, N,N-Dimethylaminocarbonyl, Methylsulfonyl, Methylsulfin A mercapto group, an aminosulfonyl group, an N-methylaminosulfonyl group, and an N,N-dimethylaminosulfonyl group are particularly preferably a hydrogen atom.

Z2, Z3, Z5 and Z6, as described above, each independently represent the general formula CR21R22, and the substituents R21 and R22 each independently mean a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group which may be substituted, and a lower alkyl alkane which may be substituted. a monocyclic hydrocarbon ring or heterocyclic group which may be substituted, a protected or substituted hydroxy group, a lower alkoxy group which may be substituted, an amine group which may be protected or substituted, an azide group, may be substituted A thiol group, a protected carboxyl group, a substituted aminocarbonyl group, a substituted lower alkyl sulfonyl group, a substituted lower alkyl sulfinyl group, and a substituted amine sulfonate The fluorenyl group, or R21 or R22, is a pendant oxy group formed integrally or a hydroxyimino group which may be substituted. Here, specific examples of R21 and R22 include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, an ethyl group, a η-propyl group, a η·butyl group, and a 〇η-pentyl group. Isopropyl, isobutyl, t-butyl, tert-butyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1- Methoxyethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, three Fluoromethyl, 2-fluoroethyl, 1-acetoethyl, 2,2,2-difluoroethyl, 1,1-fluoroethyl, 1,2-dihydroxyethyl, 1-amino- 2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2 -carboxy-1-hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxy-84 - 200948817 ethyl, 2-amino-1,2-dioxy Ethyl, 1-amino-1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-yloxyethyl, (2 -amino-1,2-di-oxyethyl)aminomethyl, Aminosulfonyl)aminomethyl, vinyl, 1-fluorovinyl, 2-fluorovinyl, 2,2-difluorovinyl, 1-propenyl, 2-propenyl, 2-carboxyvinyl , 2-carboxy-1·fluorovinyl, 2-carboxy-2-fluorovinyl, 2-carboxy-1,2-difluorovinyl, 2-carboxy-1-hydroxyvinyl, 2-carboxy-2- Transylvinyl, 3-hydroxy-1-propenyl, 3-amino-1-propenyl, phenyl, 3-carboxyphenyl, 2-pyridyl, 3-pyridyl, 0 4-pyridyl, 4 -carboxy-2-pyridyl, 5-carboxy-2-pyridyl, 5-carboxy-3-pyridyl, 6-carboxy-3-pyridyl, thiophenyl, 4-carboxythiophenyl, 5-carboxysulfur Phenyl, 2-thiazolyl, 4-carboxy-2-thiazolyl, 5-carboxy-2.thiazolyl, 4-thiazolyl, 2-carboxy-4-thiazolyl, 5-thiazolyl, 2-carboxy-5 -thiazolyl, 1-pyrrolyl, 3-carboxy-1-pyrrolyl, 2-pyrrolyl, 4-carboxy-2-pyrrolyl, 5-carboxy-2-pyrrolyl, 3-pyrrolyl, 5-carboxy- 3-pyrrolyl, 1-pyridyl, 3-carboxy-1-pyrazolyl, 4-carboxy-1-pyrazolyl, 3-pyrazolyl, 5-carboxy-3-pyranyl, 4-pyridyl Azyl, 4-pyrazolyl, 1-imidazolyl, 4-carboxy-1-imidazolyl, anthracene 2-imidazolyl, 4-carboxy-2.imidazolyl, 4-imidazolyl, 2-carboxy-4-imidazolyl, 1,2,3-triazol-1-yl, 4-carboxy-1,2,3 - triazol-1-yl, 1,2,3-triazol-4-yl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 5-carboxyl -1,3,4-triazol-2-yl, 2-tetrahydrofuranyl, 4-carboxy-2-tetrahydrofuranyl, 5-carboxy-2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 5-carboxy-3-tetrahydrofuranyl , 2-sided oxyoxazolidin-3-yl, 5-carboxy-2-oxooxyoxazolidin-3-yl, 2-oxooxyoxazolidin-4-yl' 2-sided oxime Azolidin-5-yl, 4-morpholino, 2-carboxy-4-morpholine, hydroxy, aminocarbonyloxy, methoxymethyloxy, benzyloxymethyloxy, Tetrahydropyranyloxy, trimethyldecyloxy, triethylsulfanyloxy, -85- 200948817 tert-butyldimethylsilyloxy, tert-butyldiphenyldecyloxy Base, ethoxylated, trifluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, P-methoxybenzyloxy, P-nitrobenzyl Alkoxy, benzhydryloxy, trityloxy, methoxy, ethoxy Η-propoxy, n-butoxy, η-pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethyloxy, 2-methoxyethyloxy , fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethyloxy, 1-fluoroethyloxy, 1,1-difluoroethyloxy, 2,2, 2-Trifluoroethyloxy, carboxymethyloxy, 2-aminoethyloxy, amine, formazanylamine, ethionylamino, trifluoroethenylamine, trichloroethane Mercaptoamine, trimethylacetamidoamine, benzhydrylamine, mercaptoamine, tritylamino, allylamine, benzylamine, ρ-methoxybenzyl Amino group, methoxycarbonylamino group, benzyloxycarbonylamino group, (9-fluorenyl)methoxycarbonylamino group, allyloxycarbonylamino group, methanesulfonylamino group, hydrazine- Tosylsulfonylamino, benzylideneamine, diphenylmethyleneamino, diphenylphosphoniumamino, tert-butylsulfinylamino, trimethyldecylamino, Third butyl dimethyl fluorenylalkylamine, methylamino, dimethylamino, ethylamino, isopropylamino, 2-hydroxyethyl Amino, 2-methoxyethylamino, 2-fluoroethylamino, phenylamino, pyridylamino, aminocarbonylamino, aminosulfonylamino, azide, A Sulfhydryl, aminoguanidino, 〇-methylaminomethyl, 0-ethionylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, (9-fluorenyl) Oxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, diphenylmethyloxycarbonyl, trityloxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethyl矽alkyloxycarbonyl, (methoxycarbonyloxy)methyloxycarbonyl, 1-(methoxycarbonyloxy)ethyloxycarbonyl, (t-butoxycarbonyloxy)methyloxy Carbonyl, 1-(-86-200948817 tributoxycarbonyloxy)ethyloxycarbonyl, (cyclohexyloxycarbonyloxy)methyloxycarbonyl, i-(cyclohexyloxycarbonyloxy) Ethyloxycarbonyl, aminocarbonyl, N-methylaminocarbonyl 'N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methoxy Ethyl)aminocarbonyl, N-(2-fluoroethyl)amine , N-(ethinyl)aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, η-propylsulfonyl, isopropylsulfonyl Base, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-0 fluoride Sulfosyl, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, two Methylaminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, η-propylsulfinylene, isopropylsulfinylene, 2-hydroxyethylsulfinyl , 2-methoxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2·fluoroethylsulfinyl, 1 ,1-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, aminomethylsulfinyl, dimethylaminosulfinyl, aminesulfonyl , Ν-methylaminosulfonyl, anthracene, fluorenyl-dimethylaminosulfonyl, fluorenyl-(2-hydroxyethyl)aminosulfonyl, fluorene-(2-methoxyB Aminosulfonyl , Ν-(2-fluoroethyl)amine 'sulfonyl, fluorenyl-(ethenyl)aminosulfonyl, pendant oxy, hydroxyimino, hydrazine-methylhydroxyimino, hydrazine- (fluoromethyl) hydroxyimino, 〇-(difluoromethyl)hydroxyimino, 〇-(trifluoromethyl)hydroxyimino, fluorenyl-(carboxymethyl)hydroxyimino, hydrazine- (Difluorocarboxymethyl)hydroxyimino group, and 0-(2-carboxyisopropyl)hydroxyimino group. Preferred examples of R21 and R22 include a hydrogen atom, a fluorine atom, a cyano group, a methyl group, an ethyl group, an η-propyl group, a hydroxymethyl group, a methoxymethyl group, a 1-hydroxyethyl group, and a 2- Hydroxyethyl, aminomethyl, methylaminomethyl, dimethylamine-87- 200948817 methyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl , trifluoromethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, carboxymethyl Base, 1-carboxy-1.hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxy-2.hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl , 2-amino-1,2-dioxyethyl, 1-amino-1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, (2-amino-1,2-di-oxyethyl)aminomethyl, (aminosulfonyl)aminomethyl, 2-thiazolyl , 4-carboxy-2-thiazolyl, 5-carboxy-2-thiazolyl, 4-thiazolyl, 2-carboxy-4-thiazolyl, 5-thiazolyl, 2-0-carboxy-5-salthyl, 1 -pyrrolyl, 3-carboxy-1-pyrrolyl, 2·pyrrolyl, 4- Benzyl-2-pyrrolyl, 5-carboxy-2-pyrrolyl, 3-pyrrolyl, 5-carboxy-3-pyrrolyl, 1-pyrazolyl, 3-carboxy-1-pyrazolyl, 4-carboxy- 1-pyrazolyl, 3-pyrazolyl, 5-carboxy-3-pyrazolyl, 4-pyrazolyl, 4·pyrazolyl, 1-imidazolyl, 4-carboxy-1-imidazolyl, 2- Imidazolyl, 4-carboxy-2-imidazolyl, 4-imidazolyl, 2-carboxy-4-imidazolyl, 1,2,3-triazol-1-yl, 4-carboxy-1,2,3-tri Zin-1-yl, 1,2,3-triazol-4-yl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 5-carboxy-1 , 3,4-triazol-2-yl, 2-tetrahydrofuranyl, 4-carboxy-2-tetrahydrofuranyl, 5-carboxy-2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 5-carboxy-3-tetrahydrofuranyl, 2-sided oxyoxazolidin-3-yl, 5-carboxy-2-oxooxazolidin-3-yl, 2-oxooxazolidin-4-yl, 2-oxooxycarbazole Pyridin-5-yl, 4-morpholinyl, 2-carboxy-4-homofolinyl, hydroxy, aminocarbonyloxy, methoxy, ethoxy, 2-hydroxyethyloxy, fluoromethyl Oxyl, difluoromethoxy, trifluoromethoxy, carboxymethyloxy, 2-aminoethyloxy, amine, ethenylamino, methoxycarbonyl Amine, methanesulfonylamino, methylamino, dimethylamino, 2-hydroxyethylamino, 2-methoxyethylamino, aminocarbonylamino, aminosulfonyl- 88 - 200948817 Amino, azide, formyl, carboxyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)amine Carbocarbonyl, N-(ethionyl)aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, 2-hydroxyethylsulfonyl, fluoromethylsulfonyl, difluoro Methylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonate Methylsulfinyl, 2-hydroxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethyl Sulfosyl, aminomethylsulfinyl Q decyl, dimethylaminosulfinyl, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylamino Sulfonyl, N-(2-hydroxyethyl)aminosulfonyl N-(ethionyl)aminosulfonyl, pendant oxy, hydroxyimino, 0- Methylhydroxyimino, 0-(fluoromethyl)hydroxyimino, 〇-(difluoromethyl)hydroxyimino, 〇-(trifluoromethyl)hydroxyimino, 0-(carboxyl A hydroxyimino group, a fluorenyl-(difluorocarboxymethyl)hydroxyimino group, and a 0-(2-carboxyisopropyl)hydroxyimino group. Further examples of R21 and R22 include a hydrogen atom, a fluorine atom, a cyanonyl group, a methyl group, a hydroxymethyl group, an aminomethyl group, a methylaminomethyl group, a dimethylaminomethyl group, and a fluoromethyl group. , difluoromethyl, trifluoromethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-diamino Ethyl, ^carboxymethyl, 1-carboxy-1-hydroxymethyl, 1-amino-1-carboxymethyl, 2-carboxy-1-oxoethyl, (2-amino-1,2 -di- oxyethyl)aminomethyl, (aminosulfonyl)aminomethyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl '1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1,2,3-triazol-1-yl 1,2,3-triazol-4-yl, ^, eletriazole-1-yl, 1,3,4-triazol-2-yl, 2-tetra-89-200948817 hydrofuranyl, 3- Tetrahydrofuranyl, 2-oxooxazolidin-3-yl, 2-oxooxazolidin-4-yl, 2-oxooxazolidin-5-yl, 4-morpholinyl, hydroxy , aminocarbonyloxy, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy Base, carboxymethyloxy, 2-aminoethyloxy, amine, etidylamino, methoxycarbonylamino, methanesulfonylamino, methylamino, dimethylamino Aminocarbonylamino, aminosulfonylamino, azide, carboxyl, aminocarbonyl, N-methylaminocarbonyl, anthracene, fluorenyl-dimethylaminocarbonyl, N-(ethinyl) Aminocarbonyl, hydrazine-(methanesulfonyl)aminocarbonyl, methylsulfonyl, methylsulfinyl, aminosulfonyl, fluorenyl-methylaminosulfonyl, hydrazine, hydrazine Dimethylaminosulfonyl, fluorenyl-(ethionyl)aminosulfonyl, pendant oxy, hydroxyimino, fluorene-methylhydroxyimino, fluorenyl (fluoromethyl) hydroxyimine Base, and hydrazine (carboxymethyl) hydroxyimino group and the like. Particularly preferred examples of R21 and R22 are a hydrogen atom, a hydroxymethyl group, a (2-amino-1,2-di-oxyethyl)aminomethyl group, or an (aminosulfonyl)aminomethyl group. 1,2,3-triazol-1-yl, hydroxy, aminocarbonyloxy, amine, ethyl hydrazino, methylamino, dimethylamino, azide, carboxyl, amine A carbonyl group, a pendant oxy group, and a fluorenyl-methylhydroxyimino group. © Ζ7, as defined above, represents a nitrogen atom which may be substituted, an oxygen atom, a sulfur atom which may be oxidized, or a bond, preferably a nitrogen atom which may be substituted. When Ζ7 is a nitrogen atom, the substituted group on the nitrogen atom is a hydrogen atom, a lower alkyl group which may be substituted, a lower alkyl sulfonyl group which may be substituted, a protected carboxyl group, a substituted aminocarbonyl group, A lower alkylsulfonyl group which may be substituted, and a substituted aminosulfonyl group. Here, specific examples of the substituent on the nitrogen atom include a hydrogen atom, a methyl group, an ethyl group, an η-propyl group, an η-butyl group, an η-pentyl group, an isopropyl group, and an iso-90- group. 200948817 Butyl, t-butyl, tert-butyl, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2,3-dihydroxypropyl, 2-amino-3 -hydroxypropyl, 3-amino-2.hydroxypropyl, 2,3-diaminopropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1-carboxymethyl, 2 -carboxyethyl, 2-carboxy-2-hydroxyethyl, 2-amino-1,2-dioxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxo Ethyl ethyl, ethyl fluorenyl, η-propyl fluorenyl, η-butyl fluorenyl, isobutyl decyl, trimethyl ethenyl, hydroxyethyl methoxy, methoxy ethoxy, amino ethane, methyl amine Ethyl benzyl, dimethylaminoethyl fluorenyl, fluoroethyl fluorenyl, difluoroacetinyl, trifluoroethenyl, 0 2-fluoro-2-methylpropanyl, 2,2-difluoropropane Mercapto, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, diphenylmethyloxy Base carbonyl , trityloxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethylsilyloxycarbonyl, (methoxycarbonyloxy)methyloxycarbonyl, 1-(A Oxycarbonyloxy)ethyloxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, hydrazine-(t-butoxycarbonyloxy)ethyloxycarbonyl, (cyclohexyloxy) Carbocarbonyloxy)methyloxycarbonyl, 1-(cyclohexyloxycarbonyloxy)decyloxycarbonyl, aminocarbonyl, fluorene-methylaminocarbonyl, hydrazine, hydrazine-dimethylamino Carbonyl, fluorenyl-(2-hydroxyethyl)aminocarbonyl, fluorenyl-(2-methoxyethyl)aminocarbonyl, fluorenyl-(2-fluoroethyl)aminocarbonyl, fluorene-(ethenyl) Aminocarbonyl, Ν-(methanesulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, η-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonate Base, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-di Fluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, Methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, aminosulfonyl, fluorene-methylaminosulfonyl, ν, Ν- -91 - 200948817 dimethylamino Sulfonyl, N-(2-hydroxyethyl)aminosulfonyl, N-(2-methoxyethyl)aminosulfonyl, N-(2-fluoroethyl)aminosulfonyl And N-(ethinyl)aminosulfonyl and the like. Preferred examples thereof include a hydrogen atom, an ethyl hydrazide group, a hydroxyethane group, a methoxyethenyl group, an aminoethyl fluorenyl group, a methylaminoethyl fluorenyl group, and a dimethylaminoethyl fluorenyl group. Methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, 3-amine 2-hydroxypropyl, 2,3-diaminopropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1-carboxymethyl, 2·carboxyethyl, 2-carboxyl -2-hydroxyethyl, 2-amino-1,2-dioxaoxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, methoxy Carbonyl, ethoxycarbonyl, aminocarbonyl, hydrazine-methylaminocarbonyl, hydrazine, hydrazine-dimethylaminocarbonyl, hydrazine-(ethyl hydrazino)aminocarbonyl, hydrazine (methanesulfonyl) amine Carbocarbonyl, methylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, 2-fluoroethylsulfonyl, aminomethylsulfonate Mercapto, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, aminosulfonyl, fluorene-methylaminosulfonyl, anthracene, fluorenyl-dimethylaminosulfonate醯基,和Ν- (Ethyl)aminosulfonyl and the like. As a more preferable example, a hydrogen atom, an ethyl fluorenyl group, a hydroxyethyl hydrazyl group, an amino ethane group, a methyl amino ethane group, a dimethyl amino acetyl group, a methyl group, and a 2-hydroxy group are mentioned. Ethyl, 2-aminoethyl, 2,3-dihydroxypropyl, 2·amino-3-hydroxypropyl, 3·amino-2-hydroxypropyl, 2,3-diaminopropyl , 2-fluoroethyl, 1-carboxymethyl, 2-carboxyethyl, 2-carboxy-2-hydroxyethyl, 2-amino-1,2-di- oxyethyl, 2-amino- 2-carboxyethyl, 2-carboxy-1-oxoethyl, methoxycarbonyl, aminocarbonyl, hydrazine-methylaminocarbonyl, hydrazine, hydrazine-dimethylaminocarbonyl, hydrazine-(B Mercapto)carbonylcarbonyl, fluorene-(methanesulfonyl)aminocarbonyl, -92- 200948817 methylsulfonyl, aminosulfonyl, N-methylaminosulfonyl, N,N-di A methylaminosulfonyl group and an N-(ethinyl)aminosulfonyl group are particularly preferably a hydrogen atom. A preferred example of Q1 is a structure between L1 and L2 shown by the following formula. formula:

-93- 200948817

L2 is a general formula - Υ3-Υ4-Υ5- as described above, and Υ3 of this constituent element represents a carbon atom which may be substituted and an oxidizable sulfur atom, preferably a carbon atom which may be substituted. Substituents are a hydrogen atom, a pendant oxy group, a lower alkyl group which may be substituted, a lower alkyl alkane group which may be substituted, a protected carboxyl group, a substituted aminocarbonyl group, a lower alkyl group which may be substituted A sulfonyl group, and a substituted aminosulfonyl group. Here, specific examples of the substitutable group on the carbon atom include a hydrogen atom, a pendant oxy group, a methyl group, an ethyl group, an η-propyl group, an η-butyl group, an η-pentyl group, and an isopropyl group. Isobutyl, second butyl, tert-butyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxy ^, aminomethyl, methylaminomethyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl , 2-fluoroethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyl Ethyl, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy- 1-hydroxyethyl, 2-carboxy-2.hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl '2-amino-1,2-di-oxyethyl, 1-amino- 1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, acetamidine-94-200948817, η- Propyl fluorenyl, η-butenyl, isobutyl decyl, trimethyl ethane , hydroxyethyl fluorenyl, methoxyethyl fluorenyl, amino ethane fluorenyl, methyl amino ethane hydrazino, dimethyl amino ethane fluorenyl, fluoroethyl fluorenyl, difluoro acetyl, trifluoro Ethyl, 2-fluoro-2-methylpropenyl, 2,2-f-fluoropropenyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, (9-Ferki) Methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, diphenylmethyloxycarbonyl, trityloxycarbonyl, trimethyldecyloxycarbonyl, tert-butyl Methyl decyloxycarbonyl, (methoxycarbonyloxy)methyloxycarbonyl, 1-(methoxycarbonyloxy)ethyloxycarbonyl, (t-butoxycarbonyloxy)-methyl Alkoxycarbonyl, 1-(t-butoxycarbonyloxy)ethyloxycarbonyl, (cyclohexyloxycarbonyloxy)methyloxycarbonyl, 1-(cyclohexyloxycarbonyloxy)B Alkoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, hydrazine, hydrazine dimethylaminocarbonyl, fluorenyl-(2-hydroxyethyl)aminocarbonyl, fluorene-(2-methoxyB Aminocarbonyl, fluorenyl-(2-fluoroethyl)aminocarbonyl, Ν-(ethinyl)aminocarbonyl, anthracene-(methanesulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, η-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, fluorene 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonate Mercapto, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethyl Aminomethylsulfonyl, aminosulfonyl, fluorene-methylaminosulfonyl, anthracene, fluorenyl-dimethylaminosulfonyl, fluorenyl-(2-hydroxyethyl)aminosulfonyl A fluorenyl group, a fluorenyl-(2-methoxyethyl)aminosulfonyl group, an anthracene-(2-fluoroethyl)aminosulfonyl group, and an anthracene-(ethionyl)aminosulfonyl group. Preferable examples of the substitutable group on the carbon atom include a hydrogen atom, an ethyl fluorenyl group, an η-propyl fluorenyl group, a hydroxyethyl fluorenyl group, a methoxyethyl fluorenyl group, and an amino acetonitrile-95-200948817 group. , methylaminoethenyl, dimethylaminoethyl fluorenyl, fluoroethane, 2,fluoro-2-methylpropanyl, 2,2-difluoropropenyl, methyl, ethyl , η-propyl, hydroxymethyl, methoxymethyl, 2-hydroxyethyl, 2-methoxyethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 2_Aminoethyl, fluoromethyl, di-gas methyl, di-gas methyl, 2-gas ethyl, 2,2,2-diethylene ethyl, 1,1- _ethyl ethyl, 1,2 Dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1- Hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-1, 2-tertiary oxyethyl, 1-amino-1-0-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1- side Oxyethyl, carboxyl, methoxycarbonyl, ethoxy Base, aminocarbonyl, hydrazine-methylaminocarbonyl, hydrazine, hydrazine-dimethylaminocarbonyl, fluorenyl-(2-hydroxyethyl)aminocarbonyl, fluorenyl-(ethylidene)aminocarbonyl, hydrazine -(methanesulfonyl)aminocarbonyl, methylsulfonyl, 2-hydroxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, amine Methylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, aminosulfonyl, fluorene-methylaminosulfonyl, anthracene, fluorene-dimethyl An aminoaminosulfonyl group, a fluorenyl-(2-hydroxyethyl)Q-aminosulfonyl group, an anthracene-(ethenyl)aminosulfonyl group, a pendant oxy group, and the like. More preferable examples of the substitutable group on the carbon atom include a hydrogen atom, an ethyl hydrazino group, a hydroxyethyl fluorenyl group, an aminoethyl fluorenyl group, a methylaminoethyl fluorenyl group, and a dimethylaminoethyl fluorenyl group. Fluorinyl, methyl, hydroxymethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, fluoromethyl, 1,2-dihydroxyethyl, 1-amino- 2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2·diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2 -carboxy-1-hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-96- 200948817 -1,2-dioxy 2 , 1-amino-bucarboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, carboxyl, amine Carbonyl group, N-methylaminocarbonyl group, N,N-dimethylaminocarbonyl group, N-(ethionyl)aminocarbonyl group, N-(methanesulfonyl)aminocarbonyl group, methylsulfonyl group, Aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, aminosulfonyl, N-methylaminosulfonic acid, N, N-di methyl The aminosulfonyl group, the N-(ethinyl)aminosulfonyl group, and the pendant oxy group are particularly preferably a hydrogen atom or a pendant oxy group.

0 Y3 is an oxidizable sulfur atom, and specific examples thereof include -S(〇2)-, -S(Ο)-, and -S-. Y4 which is a constituent element of L2, as described above, means a bonding bond (a multiple bond with a carbon atom adjacent to Y5), or a carbon atom which may be substituted, preferably a bond. When Y4 is a carbon atom, the group substituted on the carbon atom is a hydrogen atom, a halogen atom, a protected or substituted hydroxyl group, a substituted lower alkoxy group, a pendant oxy group, or a substituted hydroxyimine base. Here, specific examples of the group substituted on the carbon atom include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an aminocarbonyloxy group, a methoxymethyloxy group, and a benzyloxy group. Methyloxy, tetrahydropyranyloxy, trimethyldecyloxy, triethylsulfanyloxy, tert-butyldimethylsilyloxy, second butyl-phenyl sand Alkoxy, ethoxylated, trifluoroethyleneoxy, trichloroethoxycarbonyl, trimethylethenyloxy, benzyloxy, ρ·methoxybenzyloxy, P-nitrate Benzyloxy, benzhydryloxy, trityloxy, methoxy, ethoxy, η-propoxy, η-butoxy, η-pentyloxy, isopropoxy , isobutoxy, tert-butoxy, 2-hydroxyethyloxy, 2-methoxyethyl-97- 200948817 oxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy , 2-fluoroethyloxy, 1-fluoroethyloxy, 1,1-difluoroethyloxy, 2,2,2-trifluoroethyloxy, carboxymethyloxy, 2-amine Ethyloxy, pendant oxy, hydroxyimino, 〇-methylhydroxyimino, 〇-(fluoromethyl) hydroxy Amino, 0-(difluoromethyl)hydroxyimino, 〇·(trifluoromethyl)hydroxyimino, 0-(carboxymethyl)hydroxyimino, 〇-(difluorocarboxymethyl) A hydroxyimino group, a 0-(2-carboxyisopropyl)hydroxyimino group, or the like. Preferred examples of the group substituted on the carbon atom are a hydrogen atom, a fluorine atom, a hydroxyl group, an aminocarbonyloxy group, a methoxy group, an ethoxy group, a 2-hydroxyethyloxy group, and a 2-methoxyethyl group. Oxyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethyloxy, 1,1-difluoroethyloxy, 2,2,2-trifluoroethyloxy Base, carboxymethyloxy, 2-aminoethyloxy, pendant oxy, hydroxyimino, 〇-methylhydroxyimino, 〇-(fluoromethyl)hydroxyimino, 〇-( Difluoromethyl)hydroxyimino, 〇-(trifluoromethyl)hydroxyimino, fluorenyl-(carboxymethyl)hydroxyimino, 0-(difluorocarboxymethyl)hydroxyimino, 0 -(2-carboxyisopropyl)hydroxyimino group and the like. More preferred examples of the group substituted on the carbon atom are a hydrogen atom, a fluorine atom, a hydroxydecyl group, an aminocarbonyloxy group, a methoxy group, a carboxymethyloxy group, a 2-aminoethyloxy group, a pendant oxy group. Further, a hydroxyimino group, a fluorenyl-methylhydroxyimino group, a fluorenyl-(fluoromethyl)hydroxyimino group, and a 0-(carboxymethyl)hydroxyimino group are particularly preferably a hydrogen atom. Y5 which is a constituent element of L2, as described above, represents a bond (forms a multiple bond with a carbon atom adjacent to Y4), a carbon atom which may be substituted, a nitrogen atom which may be substituted, an oxygen atom, or an oxidizable sulfur atom It is preferably a bond or a carbon atom which may be substituted. Here, the substitutable group on the carbon atom may, for example, be a hydrogen atom, a fluorine atom, a -98-200948817 chlorine atom, a bromine atom, a hydroxyl group, an aminocarbonyloxy group, a methoxymethyloxy group, or a benzyloxy group. Alkoxy, tetrahydropyranyloxy, trimethyldecyloxy, triethylsulfanyloxy, tert-butyldimethylsilyloxy, tert-butyldiphenyldecyloxy , ethoxylated, trifluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, P-methoxybenzyloxy, P-nitrobenzyl Alkoxy, benzhydryloxy, trityloxy, methoxy, ethoxy, η-propoxy, η-butoxy, η·pentyloxy, isopropoxy, iso Butoxy, tert-butoxy, 2-hydroxyethyloxy, 2-methyloxyethyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoro Ethyloxy, 1-fluoroethyloxy, 1,1-difluoroethyloxy, 2,2,2-trifluoroethyloxy, carboxymethyloxy, 2-aminoethyloxy Base, pendant oxy, hydroxyimino, 〇-methylhydroxyimino, 〇-(fluoromethyl)hydroxyimino, 〇-( Fluoromethyl)hydroxyimino, 0-(trifluoromethyl)hydroxyimino, fluorenyl-(carboxymethyl)hydroxyimino, 0-(difluorocarboxymethyl)hydroxyimino, and 0 -(2-carboxyisopropyl)hydroxyimino group and the like. Preferred examples of the substitutable group on the carbon atom are a bond (a bond with a carbon atom of the adjacent ruthenium 5), a hydrogen atom, a fluorine atom, a hydroxyl group, an aminocarbonylcarbonyl group, a methoxy group, an ethoxy group. , 2-hydroxyethyloxy, 2-methoxyethyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethyloxy, 1,1-difluoro Ethyloxy, 2,2,2-trifluoroethyloxy, carboxymethyloxy, 2-aminoethyloxy, pendant oxy, hydroxyimino, 0-methylhydroxyimino , 0-(fluoromethyl)hydroxyimino, fluorenyl-(difluoromethyl)hydroxyimino, 0-(trifluoromethyl)hydroxyimino, fluorenyl-(carboxymethyl)hydroxyimino And 0·(difluorocarboxymethyl)hydroxyimino group, 〇·(2-carboxyisopropyl)hydroxyimino group, and the like. More preferred examples of the substitutable group on the carbon atom are a bond (a multiple bond with a carbon atom of the adjacent ruthenium 5), a hydrogen atom, a fluorine atom, a hydroxyl group, an aminocarbonyl group -99-200948817 oxy group, a methoxy group, Carboxymethyloxy, 2-aminoethyloxy, pendant oxy, hydroxyimino, 〇-methylhydroxyimino, 〇-(fluoromethyl)hydroxyimino, 〇-(carboxyl A hydroxyimino group or the like is particularly preferably a hydrogen atom.

Here, specific examples of the substitutable group on the nitrogen atom include a hydrogen atom, an ethenyl group, an η-propenyl group, an η-butyl group, an isobutyl group, a trimethylethyl group, and a hydroxyethyl group. Oxidyl, aminoethyl, methylaminoethyl, dimethylaminoethyl, fluoroacetamido, difluoroacetinyl, trifluoroethenyl, 2-fluoro- 2-methylpropenyl, 2,2-difluoropropenyl, methyl, ethyl, η-propyl, η-butyl, η-pentyl, isopropyl, isobutyl, second Base, tert-butyl, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, 3- Amino-2.hydroxypropyl, 2,3-diaminopropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1·carboxymethyl, 2-carboxyethyl, 2- Carboxy-2-hydroxyethyl, 2-amino-1,2-dioxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-ethyloxyethyl, methoxycarbonyl , ethoxycarbonyl, tert-butoxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, diphenylmethyloxycarbonyl, triphenyl Oxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethylsilyloxycarbonyl, (methoxycarbonyloxy)methyloxycarbonyl, 1-(methoxycarbonyloxy) Ethyloxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, 1-(t-butoxycarbonyloxy)ethyloxycarbonyl, (cyclohexyloxycarbonyloxy)-methyl Alkoxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethyloxycarbonyl, aminocarbonyl, anthracene-methylaminocarbonyl, anthracene, fluorenyl-dimethylaminocarbonyl, anthracene-(2- Hydroxyethyl)aminocarbonyl, fluorenyl-(2-methoxyethyl)aminocarbonyl, fluorenyl-(2-fluoroethyl)aminocarbonyl, fluorenyl-(ethylidene)aminocarbonyl, hydrazine-( Methanesulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, η-propylsulfonyl-100- 200948817 mercapto, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2 -methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethyl Sulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methylamine Methylsulfonyl, dimethylaminomethylsulfonyl, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2 -hydroxyethyl)aminosulfonyl, N-(2-methoxyethyl)aminosulfonyl, N-(2-fluoroethyl)aminosulfonyl, and N-(ethinyl) Aminosulfonyl and the like.较佳 Preferred examples of the substitutable group on the nitrogen atom include a hydrogen atom 'ethyl hydrazide group, a hydroxyethane group, a methoxyethyl group, an aminoethyl group, a methylaminoethyl group, Dimethylaminoethenyl, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2,3-dihydroxypropyl, 2-amino- 3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2,3-diaminopropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1-carboxymethyl, 2-carboxyethyl, 2-carboxy-2-hydroxyethyl, 2-amino-1,2-dioxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1- side Oxyethyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, 〇N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(ethinyl)aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, 2,hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, 2-fluoroethyl Sulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, aminosulfonyl, N-methylaminosulfonyl, N , N-dimethyl Sulfo acyl group, and N- (acetyl) amino Sulfonic group. More preferable examples of the substitutable group on the nitrogen atom include a hydrogen atom, an ethyl fluorenyl group, a hydroxyethyl fluorenyl group, an aminoethyl fluorenyl group, a methylaminoethyl fluorenyl group, and a dimethylaminoethyl fluorenyl group. ,methyl, 2-hydroxyethyl, 2-aminoethyl, 2,3-dihydroxy-101- 200948817 propyl, 2-amino-3-hydroxypropyl ' 3-amino-2-hydroxyl Propyl, 2,3·diaminopropyl, 2-fluoroethyl, 1-carboxymethyl, 2·carboxyethyl, 2-carboxy-2-hydroxyethyl, 2-amino-1,2- Bilateral oxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, methoxycarbonyl, aminocarbonyl, hydrazine-methylaminocarbonyl, hydrazine, hydrazine - dimethylaminocarbonyl, fluorenyl-(ethionyl)aminocarbonyl, hydrazine-(methanesulfonyl)aminocarbonyl, methylsulfonyl, aminosulfonyl, hydrazine-methylaminosulfonate A mercapto group, an anthracene group, an anthracene-dimethylaminosulfonyl group, and an anthracene-(ethenyl)aminosulfonyl group are particularly preferably a hydrogen atom. Here, as a preferable example of L2, _Ch2_ and _Ch2-CH2_ and the like can be cited. Q2, as described above, represents a heterocyclic structure of a fused 2-ring "6-membered ring/6-membered ring" or a "6-membered ring/membered ring" represented by the following formula (III), or a single-ring structure having an atomic number of 5-7. Preferably, it is a heterocyclic structure of a fused 2-ring "6-membered ring/6-membered ring" or a "6-membered ring/membered ring".

A sub or a carbon atom that can be substituted. (III) Each of them is a gas atom. The substituent which may be substituted on the carbon atom is a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted, and a lower alkoxy group which may be substituted. Specific examples thereof include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, an n-propyl group, a η-butyl group, an η-pentyl group, an isopropyl group, an isobutyl group, and a second butyl group. Base, tert-butyl, hydroxymethyl, methoxymethyl, 1 hydroxyethyl, 2-hydroxyethyl, 2-methylolethyl, 1-methoxyethyl, aminomethyl, Methylaminomethyl, dimethyl-102- 200948817 aminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro Ethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2 -amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl Base, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-1,2-dioxyethyl, 1-amino-1-carboxyl , 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-yloxyethyl, methoxy, ethoxy, n-propoxy, N_butoxy, n_ 0 pentyloxy, isopropoxy, isobutoxy , a third butoxy group, a 2-hydroxyethyloxy group, a 2-methoxyethyloxy group, a fluoromethoxy group, a dimethoxymethoxy group, a trifluoromethoxy group, a 2-fluoroethyloxy group, 1-fluoroethyloxy, 1,1-difluoroethyloxy, 2,2,2-trifluoroethyloxy, carboxymethyloxy, and 2-aminoethyloxy. Preferred examples are a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a hydroxymethyl group, a methoxymethyl group, a 2-hydroxyethyl group, an aminomethyl group, a methylaminomethyl group, and a dimethylamino group. Base, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl , 2-aminoindol-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1.hydroxymethyl, 2-carboxyethyl, 2-carboxy- 1-hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-1,2-di-oxyethyl, 1-amino- 1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, methoxy, 2-hydroxyethyloxy A group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a carboxymethyloxy group, and a 2-aminoethyloxy group. More preferred are hydrogen atom, fluorine atom, chlorine atom, methyl group, aminomethyl group, methylaminomethyl group, dimethylaminomethyl group, fluoromethyl group, difluoromethyl group, trifluoro-103- 200948817 Methyl, 1,2,dihydroxyethyl, 1-amino-2-hydroxyethyl, 2·amino. 丨-ylethyl, 1,2-diaminoethyl, 2-amino -1,2-di-oxyethyl, 2-carboxy-1-oneoxyethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2-amino Particularly preferred are an ethyloxy group and the like, and a hydrogen atom, a methyl group, and a methoxy group are particularly preferred.

Zll, Z14, Z18, and Z20, as described above, each independently represent a nitrogen atom, an oxygen atom, or an oxidizable sulfur atom, and form a double bond with the adjacent Zl2, Z13, or Z19, preferably z11 and z18. As an oxygen atom or a sulfur atom, Z14 and Z2° are nitrogen atoms or oxygen atoms which may be substituted. The substitutable group on the nitrogen atom is a hydrogen atom, a lower alkyl group which may be substituted, a hydroxyl group which can be protected, and a lower alkoxy group which may be substituted.

Specific examples thereof include a hydrogen atom, a methyl group, an ethyl group, an η-propyl group, an η-butyl group, a pentyl group, an isopropyl group, an isobutyl group, a second butyl group, a third butyl group, and a hydroxymethyl group. Methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl, aminomethyl, methylaminomethyl, dimethylamine Methyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2,2,2- Trifluoroethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-di Aminoethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2,3-diaminopropyl, 1-carboxyl , 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl , 2-amino-1,2-dioxyethyl, 1-amino-1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-yloxyethyl, hydroxy, aminocarbonyloxy, methoxymethyloxy , benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecane-104- 200948817 oxy, triethyl decyloxy, tert-butyldimethyl decyloxy, Tert-butyldiphenylphosphonyloxy, ethoxycarbonyl, trifluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, P-methoxy Benzyloxy, P-nitrobenzyloxy, benzhydryloxy, trityloxy, methoxy, ethoxy, η-propoxy, η-butoxy, η- Pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethyloxy, 2-methoxyethyloxy, fluoromethoxy, difluoromethoxy, tri Fluoromethoxy, 2-fluoroethyloxy, 1-fluoroethyloxy, 1,1-difluoroethyloxy, 2,2,2-trifluoroethyloxy, carboxymethylmethyl An oxy group, a 2-aminoethyloxy group or the like; preferably a hydrogen atom, a methyl group, an ethyl group, a 2-hydroxyethyl group, a 2-aminoethyl group, a 2-fluoroethyl group, a 2,2,2 group -trifluoroethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2,3-diaminopropyl, 1-carboxyl Methyl, 2- Ethyl ethyl, 2-carboxy-2-hydroxyethyl, 2-amino-1,2-dioxyethyl, 2-amino-2.carboxyethyl, 2·carboxy-1-yloxy Ethyl, hydroxy, methoxymethyloxy, methoxy, 2-hydroxyethyloxy, 2-methoxyethyloxy, carboxymethyloxy, and 2-aminoethyloxy Wait. Further, a hydrogen atom, a methyl group, a 2-hydroxyethyl group, a 2-aminoethyl group, a 2-fluoroethyl group, a 1-carboxymethyl group, a 2-carboxyethyl group, a 2-amino group-1, 2 may be mentioned. - two-sided oxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, hydroxy, methoxy, 2-hydroxyethyloxy, carboxymethyloxy And 2-aminoethyloxy group, etc., particularly preferably a hydrogen atom. When Ζ11, Ζ14, Ζ18, and Ζ2() are oxidizable sulfur atoms, specifically, -S-, -S(O)-, -s(02)-, and the like can be exemplified. Z12, Z13 and Z19, as described above, each independently represent a carbon atom which may be substituted, a nitrogen atom which may be substituted, an oxygen atom, or an oxidizable sulfur atom, and may form a double bond with an adjacent atom from -105 to 200948817, but Preferred are carbon atoms which may be substituted. The substitutable group on the carbon atom is a hydrogen atom, a halogen atom, a pendant oxy group, and a lower alkyl group which may be substituted. Specific examples thereof include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a η-propyl group, an n-butyl group, an η-pentyl group, an isopropyl group, an isobutyl group, and a second group. Base, tert-butyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl, aminomethyl, Methylaminomethyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1 -fluoroethyl, 2,2,2- 0 trifluoroethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino 1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2 -carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-1,2-dioxyethyl, 1-amino-1-carboxymethyl, 1 -Amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, and pendant oxy. Preferred examples are a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a hydroxymethyl group, a methoxymethyl group, a 2-hydroxyethyl group, a 2-methoxyethyl group, an aminomethyl group, a methyl C3 amine group. Methyl, dimethylaminomethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2·trifluoroethyl, hydrazine , ΐ-difluoroethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2·diaminoethyl, 1 a carboxymethyl group, a 2-amino-1,2-di- oxyethyl group, a 2-carboxyl-l-oxyethyl group, a pendant oxy group, and the like. More preferred are hydrogen atom, fluorine atom, methyl group, hydroxymethyl group, aminomethyl group, methylaminomethyl group, dimethylaminomethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl '2-amino-1-hydroxy-106- 200948817 ethyl, 1,2-diaminoethyl, 2-amino Further, a 1,2-di-oxyethyl group, a 2-carboxy-1-oxoethyl group, and a pendant oxy group are particularly preferably a hydrogen atom, a pendant oxy group, a fluorine atom, and a methyl group. The substitutable group on the nitrogen atom is a hydrogen atom, a lower alkyl group which may be substituted, a hydroxyl group which can be protected, and a lower alkoxy group which may be substituted. Specific examples thereof include a hydrogen atom, a methyl group, an ethyl group, an η-propyl group, an η-butyl group, an η-pentyl group, an isopropyl group, an isobutyl group, a second butyl group, a third butyl group, and a hydroxy group. , methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethenyl, 1-methoxyethyl, aminomethyl, methylaminomethyl' Methylaminomethyl, 1-aminoethyl, 2-aminoethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropane Base, 2,3-diaminopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, 1 ,1-difluoroethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl' 1,2-diaminoethyl, 1 -carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxy-2-mercaptoethyl, 2-indolyl-1,2 -dihydroxyethyl, 2-amino-1,2-dioxyacetamido, 1-amino-1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino- 2-carboxyethyl, 2-carboxy-1-oxoethyl, hydroxy, aminocarbonyloxy, methoxy Methyloxy, pre-oxymethyloxy, tetrahydropyranyloxy, trimethyl-indenyloxy, triethyl sand-based oxy, tert-butyl dimethyl sand Alkoxy, tert-butyldiphenylphosphonyloxy, ethoxycarbonyl, trifluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, hydrazine -methoxybenzyloxy, fluorenyl-nitrobenzyloxy, benzhydryloxy, trityloxy, methoxy, ethoxy, η-propoxy, η-butoxy Base, η_pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethyloxy, 2-methoxyethyl-107- 200948817 oxy, fluoromethoxy , difluoromethoxy, trifluoromethoxy, 2-fluoroethyloxy, 1·fluoroethyloxy, 1,1-difluoroethyloxy, 2,2,2-trifluoroethyl An oxy group, a carboxymethyloxy group, a 2-aminoethyloxy group or the like. Preferred examples thereof include a hydrogen atom, a methyl group, an ethyl group, a 2-hydroxyethyl group, a 2-methoxyethyl group, a 2-aminoethyl group, a 2,3-dihydroxypropyl group, and a 2-amino group-3. -hydroxypropyl, 3-amino-2-hydroxypropyl, 2,3-diaminopropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1-carboxymethyl, 2 -carboxyethyl, 2-carboxy-2-hydroxyethyl, 2-amino-1,2. di-oxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxo Ethyl ethyl, hydroxy, methoxy, ethoxy, 2-hydroxyethyloxy, 2-indolylmethoxyethyloxy, carboxymethyloxy, 2-aminoethyloxy and the like. More preferable examples thereof include a hydrogen atom, a methyl group, a 2-hydroxyethyl group, a 2-aminoethyl group, a 2.3-dihydroxypropyl group, a 2-amino-3-hydroxypropyl group, and a 3-amino-2-hydroxy group. Propyl, 2.3-diaminopropyl, 2-fluoroethyl, 2-amino-1,2-dioxyethyl, 2-carboxy-1-oxoethyl, hydroxy, methoxy , 2-hydroxyethyloxy, 2-aminoethyloxy, and the like.

When Ζ12, Ζ13 and Ζ19 are oxidizable sulfur atoms, specifically, -S-, -S(O)-, -S(02)- and the like can be exemplified. Z21, Z22, Z23, Z24, Z25, Z26, Z27, Z28, Z29, Z30, z31, Z32, Z33, Z34, Z35, Z36, Z37, and Z38, as described above, each independently represents a carbon atom which may be substituted, a substituted nitrogen atom, an oxygen atom, or an oxidizable sulfur atom may form a double bond with an adjacent atom, but the substitutable group on the carbon atom is a hydrogen atom, a halogen atom, a cyano group, and a lower substitutable group An alkyl group, a lower alkyl alkane group which may be substituted, a protected hydroxyl group, a lower alkoxy group which may be substituted, an amine group which may be protected or substituted, a protected carboxyl group, a substituted aminocarbonyl group, A protected pendant oxy group, and a hydroxyimino group which may be substituted by -108-200948817. Here, specific examples of the substitutable group on the carbon atom include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, an ethyl group, an η-propyl group, an η-butyl group, and a η group. -pentyl, isopropyl, isobutyl, t-butyl, tert-butyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxy , 1-methoxyethyl, aminomethyl 'methylaminomethyl' dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoro Methyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, 1,1_0 difluoroethyl, 1,2-dihydroxyethyl, 1 -Amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyl Ethyl, 2-carboxy-1-hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-1,2-dioxy 2 , 1-amino-1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-ethyloxyethyl, methylene, Fluoromethylene, difluoromethylene, vinyl , 1-fluorovinyl, 2-fluorovinyl, 2,2-difluorovinyl, 1-propenyl, 2-propenyl, 2-carboxyvinyl, 2-carboxy-1-fluorovinyl, 2- Carboxylicium-2-fluorovinyl, 2-carboxy-1,2-difluorovinyl, 2-mercapto-1-hydroxyethyl, 2-carboxy-2-hydroxyvinyl, 3-hydroxy-1- Propenyl, 3-amino-1-propenyl, hydroxy, methoxymethyloxy, benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecyloxy, three Ethyl decyloxy, tert-butyldimethyl decyloxy, tert-butyldiphenyl decyloxy, ethoxycarbonyl, trifluoroacetoxy, trichloroacetoxy, Trimethylacetoxy, benzyloxy, fluorenyl-methoxybenzyloxy, fluorenyl-nitrobenzyloxy, benzhydryloxy, triphenylphosphonyloxy, aminocarbonyl Oxy, methoxy, ethoxy, η-propoxy, η-butoxy, η-pentyloxy, isopropoxy, isobutoxy, tert-109- 200948817 oxy, 2 -hydroxyethyloxy, 2-methoxyethyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethyloxy, 1-fluoro Ethyloxy, 1,1-difluoroethyloxy, 2,2,2-trifluoroethyloxy, carboxymethyloxy, 2-aminoethyloxy, amine, formazan Amino, ethinylamino, trifluoroacetamidoamine, trichloroacetamidoamine, trimethylethenylamine, benzhydrylamine, mercaptoamine, trityl Amino, allylamino, benzylamino, P-methoxybenzylamino, methoxycarbonylamino, benzyloxycarbonylamino, (9-fusyl)methoxycarbonylamine , allyloxycarbonylamino, methanesulfonylamino, P-toluenesulfonylamino, benzylideneamine, diphenylmethyleneamino, © diphenylphosphoniumamine Base, tert-butylsulfinylamino group, trimethylsulfonylamino group, tert-butyldimethylsilylamino group, methylamino group, dimethylamino group, ethylamino group, different Propylamino, 2-hydroxyethylamino, 2-methoxyethylamino, 2-fluoroethylamino, phenylamino, pyridylamino, aminocarbonylamino, aminosulfonate Mercaptoamine, carboxyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, (9-fluorenyl) Methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, diphenylmethyloxycarbonyl, trityloxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethyl Alkyloxycarbonyl, (formyloxycarbonyloxy)methyloxycarbonyl, 1-(methoxycarbonyloxy)ethyloxycarbonyl, (t-butoxycarbonyloxy)methyl Oxycarbonyl, 1-(t-butoxycarbonyloxy)ethyloxycarbonyl, (cyclohexyloxycarbonyloxy)methyloxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethyl Oxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, hydrazine, hydrazine dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl Aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, pendant oxy, 1,3-di Oxol-2-yl, 1,3-110-200948817 dioxan-2-yl, 1,1-dimethoxy, 1,1-diethoxy, 1,3-disulfide Heterocyclic pentan-2-yl, 1,3-dithiacyclo-2-yl, 1,1-dimethylthio, 1,1-diethylthio 1,3-oxathiolan-2-yl, 1,3-oxathiacyclo-2-yl, hydroxyimino, fluorene-methylhydroxyimino, 0-(fluoromethyl Hydroxyimino, 〇·(difluoromethyl)hydroxyimino, 0-(trifluoromethyl)hydroxyimino, 0-(carboxymethyl)hydroxyimino, 〇-(difluorocarboxyl Methyl)hydroxyimino group, 0-(2-carboxyisopropyl)hydroxyimino group, and the like. Preferable examples of the substitutable group on the carbon atom include a hydrogen atom, a fluoroproton, a cyano group, a methyl group, an ethyl group, a hydroxymethyl group, a methoxymethyl group, a 2-hydroxyethyl group, and a 2- Methoxyethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro Ethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino-1- Hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxy- 2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-1,2-dioxyethyl, 1-amino-1-carboxymethyl, 1-amino -2-carboxyethyl fluorenyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, methylene, fluoromethylene, difluoromethylene, vinyl, 1 -fluorovinyl, 2-fluorovinyl, 2,2-difluorovinyl, propylene, 2-propenyl, 2-carboxyvinyl, 2-carboxy-1-fluorovinyl, 2-carboxy-2 -fluorovinyl, 2-carboxy-1,2-difluorovinyl 2-carboxy-1-hydroxyvinyl, 2-carboxy-2-hydroxyvinyl, 3-hydroxy-1-propenyl, 3-amino-1-propenyl, hydroxy, aminocarbonyloxy, methoxy , ethoxy, 2-hydroxyethyloxy, 2-methoxyethyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethyloxy, 1, 1-Difluoroethyloxy, 2,2,2-trifluoroethyloxy, carboxymethyloxy, 2-aminoethyl-111- 200948817 oxy, amine, formazanyl, Ethyl mercaptoamine, methoxycarbonylamino, methanesulfonylamino, methylamino, dimethylamino, ethylamino, isopropylamino, 2-hydroxyethylamino, 2-methoxyethylamino, 2-fluoroethylamino, aminocarbonylamino, aminosulfonylamino, carboxyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, N- Methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2- Fluoroethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, pendant oxy, 1,3-dioxolane -2-yl, 1,3, dioxan-2-yl, 1,1-dimethoxy, hydroxyimino, 0-methylhydroxyimino, fluorenyl-(fluoromethyl)hydroxyimine Base, 〇-(difluoromethyl)hydroxyimino, 〇-(trifluoromethyl)hydroxyimino, 〇-(carboxymethyl)hydroxyimino, 〇-(difluorocarboxymethyl) hydroxy Imino group, fluorene-(2-carboxyisopropyl)hydroxyimino group, and the like. More preferable examples of the substitutable group on the carbon atom include a hydrogen atom, a fluorine atom, a cyano group, a methyl group, a hydroxymethyl group, a 2-hydroxyethyl group, an aminomethyl group, a methylaminomethyl group, and a second group. Methylaminomethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-dihydroxyethyl, 1-amino-2- Hydroxyethyl '2-amino-1-hydroxyethyl' 1,2-diaminoethyl, 2-amino-1,2-di-oxyethyl, 2-carboxy-1-yloxy Ethyl, methylene, fluoromethylene, difluoromethylene, hydroxy, aminocarbonyloxy, methoxy, 2, hydroxyethyloxy, fluoromethoxy, difluoromethoxy, tri Fluoromethoxy, 2-aminoethyloxy, amine, carbenylamino, ethionylamino, methoxycarbonylamino, methanesulfonylamino, methylamino, dimethyl Amino group, 2-hydroxyethylamino group, 2-methoxyethylamino group, aminocarbonylamino group, aminosulfonylamino group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, amine group Carbonyl, N-methylaminocarbonyl, N,N--112- 200948817 dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl , N_(ethenyl)aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, pendant oxy, U3_dioxol-2-yl, 1,3-dioxan-2- a hydroxyimino group, a hydrazine-methylhydroxyimino group, a fluorenyl-(fluoromethyl)hydroxyimino group, a fluorenyl-(carboxymethyl)hydroxyimino group, etc., particularly preferred examples thereof include a hydrogen atom and fluorine. Atom, cyano, methylene, hydroxy, methoxy, methanesulfonylamino, pendant oxy, 1,3-dioxol-2-yl, hydroxyimino, hydrazine-methyl Hydroxyimine group and the like. The substitutable group on the nitrogen atom is a hydrogen atom, a lower alkyl alkane group which may be substituted, a lower alkyl group which may be substituted, a protected hydroxyl group, a lower alkoxycarbonyl group which may be substituted, a substituted amine a carbonyl group, a lower alkylsulfonyl group which may be substituted, and an amine sulfonyl group which may be substituted. Here, specific examples of the substitutable group on the nitrogen atom include a hydrogen atom, an ethenyl group, an η-propenyl group, an η-butyl group, an isobutyl group, a trimethylethyl group, a hydroxyethyl group, and Methoxyethyl, aminoethyl, methylaminoethyl, dimethylaminoethyl, fluoroacetamido, difluoroacetinyl, trifluoroethenyl, 2-fluoro -2-methylpropanyl, 2,2-difluoropropanyl 'methyl, ethyl, η η-propyl, η-butyl, η-pentyl, isopropyl, isobutyl, Dibutyl, tert-butyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl, amine Base, methylaminomethyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl , 1-fluoroethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amine 1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1.hydroxyethyl, 2-carboxy-2 -hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-1,2-dioxyethyl, -113- 200948817 1-amino-1-carboxymethyl, 1 -Amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxy Propyl, 3-amino-2-hydroxypropyl, 2,3-diaminopropyl, hydroxy, methoxymethyloxy, benzyloxymethyloxy, tetrahydropyranyloxy , trimethyl decyloxy, triethyl decyloxy, tert-butyldimethyl decyloxy, tert-butyldiphenyl decyloxy, ethoxycarbonyl, trifluoroacetate Oxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, p-methoxybenzyloxy, P-nitrobenzyloxy, benzhydryloxy, Trityloxy, aminocarbonyloxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylamine Carbonyl group, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethinyl) )amine Carbonyl group, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, η-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl , 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoro Ethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, amine Sulfosyl, hydrazine-methylaminosulfonyl, hydrazine, hydrazine dimethylaminosulfonyl, fluorenyl-(2-hydroxyethyl)aminosulfonyl, fluorene-(2-methoxy Alkylethyl)aminosulfonyl, fluorenyl (2-fluoroethyl)aminosulfonyl, and fluorenyl-(ethionyl)aminosulfonyl. Preferred examples of the substitutable group on the nitrogen atom include a hydrogen atom, an ethyl hydrazide group, a hydroxyethyl fluorenyl group, a methoxyethyl fluorenyl group, an aminoethyl fluorenyl group, a methylaminoethyl fluorenyl group, and a dimethyl group. Aminoethyl fluorenyl, fluoroacetamido, methyl, ethyl, η-propyl, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-fluoroethyl, 2,2,2- -114- 200948817 Trifluoroethyl, 1-carboxymethyl, 2-carboxy-2-hydroxyethyl, 2-amino-1,2-di- oxyethyl, 2-amine 2-carboxyethyl, 2-carboxy-1-oxoethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl , 2,3-Diaminopropyl, hydroxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylamine Carbocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methanesulfonyl)aminocarbonyl, methylsulfonyl, 2-hydroxyethyl Sulfonyl, fluoromethylsulfonyl, 2-fluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl Aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2-hydroxyethyl)aminosulfonyl, and N-(ethylidene) Aminosulfonyl and the like. More preferable examples of the substitutable group on the nitrogen atom include a hydrogen atom, an ethyl fluorenyl group, a hydroxyethyl fluorenyl group, an aminoethyl fluorenyl group, a methylaminoethyl fluorenyl group, and a dimethylaminoethyl fluorenyl group. Fluorinyl, methyl, ethyl, 2-hydroxyethyl, 2-aminoethyl, 2-fluoroethyl, 2-amino-1,2-di- oxyethyl, 2,3- Dihydroxyindole V-propyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2,3-diaminopropyl, methoxycarbonyl, ethoxycarbonyl, Aminocarbonyl, hydrazine-methylaminocarbonyl, hydrazine, hydrazine-dimethylaminocarbonyl, fluorenyl-(2-hydroxyethyl)aminocarbonyl, methylsulfonyl, 2-hydroxyethylsulfonyl , fluoromethylsulfonyl, 2-fluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, aminesulfonyl A group, a fluorenyl-methylaminosulfonyl group, an anthracene, a fluorenyl-dimethylaminosulfonyl group, and the like. Ζ21,Ζ22,Ζ23,Ζ24,Ζ25,Ζ26,Ζ27,Ζ28,Ζ29,Ζ30, -115- 200948817 z31, Z32, Z33, Z34, Z35, Z36, Z37, and z38 are oxidizable sulfur atoms, Specifically, -S-, -s(0)-, -s(o2)-, and the like can be exemplified. Specific examples of Q2 include π, 2, 3]thiadiazolo[5,4-b]pyridin-6-yl, 1Η-indolebi[2,3-b]disc-2-yl , 2,3-dihydro[1,4]dioxin[2,3-b]pyridin-6-yl, 2,3-dihydro[1,4]dioxin[2,3-b Pyridine-7-yl, 2,3-dihydro[1,4]dioxin[2,3-c]pyridin-7-yl, 2,3-dihydrobenzo[1,4] diindole English-6-yl, 2-sided oxy-2,3-dihydro-1H-pyrido[2,3-b][l,4]indole-7-yl, 2-sided oxy-2, 3-Dihydro-1H-pyrido[2,3-b][l,4]thin-7-yl, 3,4-dihydro-2H-benzo[1,4]fluorene-6-yl , 3-methyl-2-oxo-2,3-dihydrobenzoxazol-6-yl, 3-sided oxy-3,4-dihydro-2H-benzo[1,4]indole Well-6-yl, 8-methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]indole-6-yl, 8-methyl-3-sided oxygen 3-,4-dihydro-2H-benzo[1,4]non-6-yl, 5-methyl-3-oxooxy-3,4-dihydro-2H-benzo[1, 4] 噚耕-6-yl, 7-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]indole-6-yl, 2-methyl-3- Sideoxy-3,4-dihydro-2H-benzo[1,4]indole-6-yl, 2-fluoro-3-oxooxy-3,4-dihydro-2H-benzo[1] , 4] 噚耕-6-yl, 3-sided oxy-3,4-dihydro-2H -pyrido[3,2-b][l,4]indole-6-yl, 8-methoxy-3-oxirane-3,4-dihydro-2H-pyrido[3,2- b][l,4]噚-6-yl, 7-methyl-3-oxo- 3,4-dihydro-2H-pyrido[3,2-1)][1,4]噚Trap-6-yl, 7-chloro-3-yloxy-3,4-dihydro-211-pyrido[3,2-b][l,4]Df-t--6-yl, 7-fluoro 3-oxooxy-3,4-dihydro-2H-pyrido[3,2-1?][1,4]indole-6-yl, 2-methyl-3-oxooxy-3 ,4-dihydro-211-pyrido-116- 200948817 [3,2-b][l,4]噚-6-yl, 2-fluoro-3-oxo-3,4-dihydro- 2H-pyrido[3,2-b][l,4]indole-6-yl, 3-sidedoxy-3,4-dihydro-2H-benzo[1,4]thiazolidine-6- ,8-methoxy-3-indolyl-3,4-dihydro-2H-benzo[1,4]thienyl-6-yl, 7-methyl-3-oxooxy-3, 4-Dihydro-2H-benzo[1,4]thia trap-6-yl, 2·methyl-3-oxooxy-3,4-dihydro-2H-benzo[1,4]thin -6-yl, 2-fluoro-3-oxo- 3,4-dihydro-2H-benzo[1,4]thienyl-6-yl, 4-sided oxy-4H-pyrido[1 , 2-a]pyrimidin-2-yl, 6·nitro-benzo[1,3]dioxol-5-yl, 7-fluoro-3-oxooxy-3,4-dihydro -2H·benzo[1,4]non-6-yl, 8-hydroxy-1-o-oxy-1,2-amino- Isoindolin-3-yl, 8-cyanoin-2-yl, Benzo[1,2,3]thiadiazole-5-yl, 1,3-benzothiazol-5-yl,[1 , 3] thiazolo[5,4-b]pyridine-6·yl, 2-sided oxy-2,3·dihydro-1H-pyrido[3,4-b][l,4]噚哄- 7-yl, 2-oxooxy-2,3-dihydro-1H-pyrido[3,4-b][l,4]thiat-7-yl, 3-sidedoxy-3,4· Dihydro-2H-pyrido[3,2-b][l,4]thienyl-6-yl, 7-chloro-3-yloxy-3,4-dihydro-2H-pyrido[3, 2-b][l,4]thiat-6-yl, 7-fluoro-3-o-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]thio Plough-6-yl, 8-methoxy-3-oxooxy-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiat-6-yl, 7- Methyl-3-fluorene sideoxy-3,4-dihydro-2H-pyrido[3,2_b][l,4]salt-6-yl, 2-methyl-3-oxooxy-3 , 4-dihydro-2H-pyrido[3,2-b][l,4]thiat-6-yl, 2-fluoro-3-o-oxo-3,4-dihydro-2H-pyridine [3,2-b][l,4]thia trap-6-yl, 6-sided oxy-6,7-dihydro-5H-indole and [3,4-bHl,4]噚耕-3 -yl,6-sideoxy•6,7·dihydro-5H-indole and [3,4_bni,4]thin-3-yl, 7-sided oxy 5,6,7,8-tetrahydro -1,8-naphthyridin-2-yl, 7-chloro-3-yloxy-3,4-dihydro-2H-pyridine And [3,2-b][l,4]曙耕-6-yl, (3S)-2,3-dihydro-[1,4]dioxin and [2,3-b]pyrene 3-yl, [1,3]oxathiolane[5,4-c]pyridine-6-yl, 3,4-dihydro-2H-piperacino[2,3-c]pyridine ·6·yl, 2,3-dihydro[L4]oxathia-117- 200948817 cyclohexadieno[2,3-c]pyridine-7-yl, 5-fluoro-2,3-dihydro- 1,4-benzodioxin-7-yl, 2,3-dihydro-i-benzofuran-5-yl, 2,3-dihydro[1,4]oxythiazepine [2,3-b]pyridine-7-yl, 6,7-dihydro[14]oxathialidene[3,2-c]indole-3-yl, 6,7·dihydrogen [14] Oxathiacyclohexadien[2,3-c]indole-3-yl, 6,7-dihydro[ι,4]dioxin[2,3-c] 3-yl, 2,3-dihydrofuro[2,3-c]pyridine-5-yl, 5-sideoxy-12,3,5-tetrahydroindol-7-yl, 6,7 --Chloro-5H-indolo[2,3-c]pyridin-3-yl, 7-carbylmethyl-6,7-dihydro[1,4]dioxin[2,3_c]嗒--3-yl, 5,6-dihydrofuro[2,3-c] 嗒-3-yl, cycloheptyl, 2-nitrocarbazide, 2-nitrozinyl, 3-oxo Sulfhydryl, 2-thioindolyl, 3-thioindolyl, cyclohexyl, 1-hydroxycyclohexyl, 1-methylcyclohexyl, 1-methylsulfonylamine Cyclohexyl,: 1_ cyano cyclohexyl group, a 2-oxo-cyclohexyl, 4-dioxaspiro [4. 5] indole-6-yl, 2-hydroxyiminocyclohexyl, 2-methoxyiminocyclohexyl, 3-oxocyclohexyl, 1,4-dioxaspiro[4·5]fluorene -7-yl, 3-hydroxyiminocyclohexyl, 3-methoxyiminocyclohexyl, 2,2-difluorocyclohexyl, 3,3·difluorocyclohexyl, 4,4-difluorocyclo Hexyl, trans-2-fluorocyclohexyl, cis-2-fluorocyclohexyl, trans-3-fluorocyclohexyl, cis-3-fluorocyclohexyl, trans-4-fluorocyclohexyl, cis- 4-fluorocyclohexyl, 2-fluoro-1-cyclohexenyl, 2-methylenecyclohexyl, 2-methyl-indole-cyclohexenyl, trans-2-methylcyclohexyl, cis- 2_methyl hexyl, trans-3-methylcyclohexyl, cis-3-methylcyclohexyl, trans 4-methylcyclohexyl, cis-4-methylcyclohexyl, trans- 2-hydroxycyclohexyl, _form-2-hydroxycyclohexyl, trans-3-hydroxycyclohexyl, cis-3-ylcyclohexyl, trans-4-hydroxycyclohexyl, cis-4-hydroxyl Hexyl, trans-2-methoxycyclohexyl, cis-2-methoxycyclohexyl, trans-3-methoxycyclohexyl, 1-spray-3-methoxycyclohexyl, 2-tetrahydro Piperidyl, 3-tetrahydropyranyl, diterpene, 2_sideoxy-丨·piperidinyl, 2-piperidinyl, Ν-methyl_2--118- 200948817 piperidinyl, 3 · oxo-2-piperidinyl, N-methyl·3-sideoxy 2-piperidinyl, 2-oxo-3-indolyl, N-methyl-2-oxo-3-pipedyl, 2-norbulinyl, 3-norbulinyl, 4 -hofolinyl, cyclopentyl, 1-hydroxycyclopentyl, methylcyclopentyl, methanesulfonylaminocyclopentyl, cyanocyclopentyl, oxocyclopentyl, 1,4-di Oxyspiro[4·4]壬_6·yl, 2-hydroxyiminocyclopentyl, 2-methoxyiminocyclopentyl, 3-oxocyclopentyl, 1,4 -1 Oxygen snail [4. 4] 壬-7-yl, 3-hydroxyiminocyclopentyl, 3-methoxyiminocyclopentyl, 2,2-difluorocyclopentyl, 3,3-difluorocyclopentyl, Trans-2-fluorocyclopentyl, cis-cis-2-fluorocyclopentyl, trans-3-fluorocyclopentyl, cis-3-fluorocyclopentyl, 2-fluoro-1-cyclopentene , 2-methylenecyclopentyl, 2-methyl-1-cyclopentenyl, trans-2-methylcyclopentyl, cis-2-methylcyclopentyl, trans-3- Methylcyclopentyl, cis-3-methylcyclopentyl, trans-2-hydroxycyclopentyl, cis-2-hydroxycyclopentyl, trans-3-hydroxycyclopentyl, cis- 3-hydroxycyclopentyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 1-pyrrolidinyl, 2-oxo-l-pyrrolidinyl, 2-pyrrolidinyl, N-methyl-2-pyrrolidine 3-, 3-oxo-2-pyrrolidinyl, N-methyl-3-oxo-2-indenyl, tert-styl, 2-oxo-3-glagastyl, N-methylhydrazine W-yl-2-oxo-3-pyrrolidinyl, 2-thienyl, 3-fluoro-2-indolyl, 4-fluoro-2-thiophenyl, 5-fluoro-2-thienyl, 3, 4-difluoro-2·thienyl, 3,5-difluoro-2-thienyl, 4,5·difluoro-2-thienyl, 3-chloro-2-thienyl, 4-chloro-2-thiophene 5-chloro-2-thiophene , 3,4-dichloro-2-thienyl, 3,5-dichloro-2-thienyl, 4. 5-Dichloro-2-thienyl, 3-chloro-4-fluoro-2-thienyl, 3-chloro-5-fluoro-2-thienyl, 4-chloro-3-fluoro-2-thienyl, 4 -chloro-5-fluoro-2-thienyl, 5-chloro-3-fluoro-2-thienyl, 5-chloro-4-fluoro-2-thienyl, 3-thienyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2. 6-Difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorobenzene-119- 200948817, 2,3,5-trifluorophenyl , 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 3,4,5-trifluorophenyl, 2-chlorophenyl , 3-chlorophenyl, 4-chlorophenyl, 2. 3-Dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3. 4-Dichlorophenyl, 3,5-dichlorophenyl, 2·chloro-3-fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro- 6-fluorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chloro-6-fluorophenyl, 4-chloro- 2-fluorophenyl, and 4-chloro-3-fluorophenyl. As a preferred example, 2,3-dihydro[1,4]dioxin[2,3-b]pyridin-7-yl, 2,3-dihydro[1,4]dioxin is exemplified. [2,3-c]pyridin-7-yl, 2,3-dihydrophenylindolo[1,4]dioxin-6-yl, 3-oxooxy-3,4-dihydro-2H- Benzo[1,4]fluorenyl-6-yl, 8-methoxy-3-oxooxy-3,4-dihydro-2H-benzo[1,4]indole-6-yl, 5 -Methyl-3-oxooxy-3,4-dihydro-2Η-benzo[1,4]indole-6-yl, 7-methyl-3-oxooxy-3,4-dihydro - 2Η -Benzo[1,4]噚-6-yl, 2-methyl-3-oxo-3,4-dihydro-2Η-benzo[1,4]fluorene-6-yl 2-fluoro-3-oxooxy-3,4-dihydro-2-indole-benzo[1,4]indole-6-yl, 3-oxo-3,4-dihydro-2?-pyridine And [3,2-b][l,4]噚耕-6-yl, 8-methoxy-3-. oxo- 3,4-dihydro-2Η-pyrido[3,2-b] [l,4]噚耕-6-yl, 8-methyl-3-oxo- 3,4-dihydro-2H-benzopyrene [1,4]噚-6-yl, 7-A 3-O-oxy-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-yl, 7-chloro-3-o-oxy-3, 4-Dihydro-2H-pyrido[3,2-b][l,4]non-6-yl, 7-fluoro-3-o-oxo-3,4-dihydro-2H-discidine [3,2-1>][1,4]噚耕-6-based, 2-methyl-3-oxooxy-3,4-dihydro-21^pyrido[3,2-15][1,4]fluorene-6-yl, 2-fluoro-3-oxooxy -3,4-dihydro-211-pyrido[3,2-1)][1,4]indole-6-yl, 3-o-oxo-3,4-dihydro-211-benzo[ 1,4]thiazol-6-yl, 8-methoxy-3-indolyl-3,4-dihydro-2H-benzo[1,4]thias-6-yl, 7-methyl 3-oxooxy-3,4-dihydro-2H-benzo[1,4]thiados-6-yl, 2-120-200948817 methyl-3-oxooxy-3,4-di Hydrogen-2H-benzo[1,4]thia trap-6-yl, 2-fluoro-3-oxooxy-3,4-dihydro-2H-benzo[1,4]thinyl-6-yl , 7-fluoro-3-oxooxy-3,4-dihydro-2H-benzo[1,4]indole-6-yl, 2-sided oxy-2,3-dihydro-1H-pyridine And [3,4-1>][1,4]曙哄-7-yl, 2-sided oxy-2,3-dihydro-111-pyrido[3,4-13][1,4] Titrate-7-yl, 3-sidedoxy-3,4-dihydro-211-pyrido[3,2-b][l,4]thinyl-6-yl, 7-chloro-3- side Oxy-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiat-6-yl, 7-fluoro-3-indolyl-3,4-dihydro- 2H-pyrido[3,2-1)][1,4]thiazol-6-yl, 8-methoxy-3-oxo-3,4-dihydro-211-pyridinium[ 3,2-b][l,4]thiat-6-yl, 7-methyl-3-oxirane-3,4- Hydrogen-2H-pyrido[3,2-b][l,4]thienyl-6-yl, 2-methyl-3-oxooxy-3,4-dihydro-211-pyridyl[3, 2-1)][1,4]thia trap-6-yl, 2-fluoro-3-sidedoxy-3,4-dihydro-2H-pyrido[3,2-b][l,4] Thiol-6-yl, 6-sided oxy-6,7-dihydro-5H-indeno[3,4-b][l,4]Df -3-yl, 6-sided oxy- 6,7-Dihydro-5H-indole and [3,4-b][l,4]thiat-3-yl, 6,7-dihydro[1,4]dioxin[2,3 -c]嗒-3-yl, cyclohexyl, 1-methylcyclohexyl, 1-methylsulfonylaminocyclohexyl, fluorenyl-cyanocyclohexyl, 2-oxocyclohexyl, 1,4- Dioxaspiro[4. 5] 癸-6-yl, 2-O methoxyiminocyclohexyl, 1,4-dioxaspiro[4. 5] 癸-7-yl, 2,2-difluorocyclohexyl, 2-fluoro-1-cyclohexenyl, 2-methylenecyclohexyl, 2-methyl-1-cyclohexenyl, trans -2-methylcyclohexyl, cis-2-methylcyclohexyl, trans-2-hydroxycyclohexyl, cis-2-hydroxycyclohexyl, trans-2-methoxycyclohexyl, cis- 2-methoxycyclohexyl, 2-tetrahydropyranyl, 2-oxooxyl 1-piperidinyl, cyclopentyl, 2-thienyl, and 2,4-difluorophenyl. As a more preferable example, 2,3-dihydro[1,4]dioxin[2,3-b]pyridin-7-yl, 2,3-dihydro[1,4]dioxin is exemplified. [2,3-c]pyridin-7-yl, 2,3-dihydrobenzo[1,4]dioxin-6-yl, 3-sidedoxy-3,4-dihydro-2H-benzene And [1,4] 哔耕-6--121- 200948817 base, 8-methoxy-3-sideoxy-3,4-dihydro-2H-benzo[1,4]曙-6- , 8-methyl-3-oxooxy-3,4-dihydro-2H-benzo[1,4]indole-6-yl, 5-methyl-3-oxooxy-3,4 -dihydro-2H-benzo[1,4]indole-6-yl, 7-methyl-3-oxooxy-3,4-dihydro-2H-benzo[1,4]噚- 6·yl, 2-methyl-3-oxooxy-3,4-dihydro-2H-benzo[1,4]indole-6-yl, 2-fluoro-3-indolyl-3 4-Dihydro-2H-benzo[1,4]indole-6-yl, 3-sidedoxy-3,4-dihydro-2H-pyrido[3,2-b][l,4] Hf 哄-6-yl, 3-sided oxy-3,4-dihydro-2H-benzo[1,4]thia trap-6-yl, 2-sided oxy-2,3-dihydro-1H · Pyrido[3,4-b][l,4]噚耕-7·yl, 2-sided oxy-2,3-dihydro-1H-pyrido[3,4-b][l,4 Thiazide-7-yl, 3-sided oxy-3,4-dihydro-2^1-pyrido[3,2-15][1,4]thinyl-6-yl, 6-side oxygen Base-6,7-dihydro-5H-indole and [3,4-1>][1, 4] Indole-3-yl '6-sideoxy-6,7-dihydro-5H-indole and [3,4-b][l,4]thiat-3-yl, 6,7- Dihydro[1,4]dioxin[2,3-c]indole-3-yl, cyclohexyl, 2-oxocyclohexyl, 2,2-difluorocyclohexyl, 2-fluoro-1 - cyclohexenyl, 2-thienyl, and 2,5. difluorophenyl. As a particularly preferred example, 2,3-dihydro[1,4]dioxin[2,3-b]pyridin-7-yl, 2,3-dihydro[1,4]dioxin is exemplified. [2,3-c]pyridin-7-yl, 2,3-dihydrobenzo[1,4]dioxin-6-yl, 8-methoxy-3-oxirane-3,4- Dihydro-2H-benzo[1,4]indole-6-yl, 8-methyl-3-oxooxy-3,4-dihydro-2H-benzo[1,4]indole-6 -yl, 5-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]indole-6-yl, 7-methyl-3-oxo-3, 4-Dihydro-2H-benzo[1,4]indole-6-yl, 2-methyl-3-oxooxy-3,4-dihydro-2H-benzo[1,4] -6-yl, 2-fluoro-3. oxo-3,4-dihydro-2H-benzo[1,4]indole-6-yl, 3-sided oxy-3,4-dihydro -2H-pyrido[3,2-1>][1,4]噚-6-yl, 3-oxo-3,4-dihydro-211-benzo[1,4]thirsty- Hexyl, 3-tertiaryoxy-3,4-dihydro-2H-pyrido[3,2-b][l,4]thia trap-6--122-200948817 base, cyclohexyl group and the like. Here, as a preferred example of the compound represented by the general formula (I), 6-[({trans-4-[(9-methoxy-3,4-dihydrobenzo[11][1]) ,6]naphthyridine-1(21〇-yl)methyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l,4]噚哄-3 (4H)- Ketone, 6-[({trans-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl) )methyl]cyclohexyl}amino)methyl]-2H·pyrido[3,2_b][l,4]indole-3(4H)-one, 6-[({trans-4-[ ( 9-Methoxy-3-methyl-2,3-dihydro_1H-[1,4]indole[2,3-c]quinolin-1-yl)methyl]cyclohexyl} Amino)methyl]-2H-pyrido[3,2-b][l,4]indole-3(4H)-one, 6-[({trans-4-[(9-methoxy) -2-methyl-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]- 2H-pyrido[3,2-b][l,4]indole-3(4H)-one, trans-N-(2-cyclohexylethyl)-4-[(9-methoxy- 2,3-Dihydro·1Η-[1,4]噚 and [2,3-c]quinolin-1-yl)methyl]cyclohexaneamine, 6-[({trans- 4-[ (9-Methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl)methyl]cyclohexyl}amino)methyl] ·2Η-1,4 -benzothiazepine-3 (4Η)-ketone, trans-Ν·(2,3-dihydro-1,4-benzodioxin-6-yl-av-methyl)-4-[(9- Methoxy-2,3-dihydro·1Η-[1,4]indole[2,3-c]quinolin-1-yl)methyl]cyclohexylamine, 6-[({trans -4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinolin-1yl)methyl]cyclohexylguanidinyl )methyl]-2-methyl-2H-1,4-benzoindole-3(4H)-one, 6-[({trans-4-[(9-methoxy-2,3-) Dihydro-1H-[1,4]indolo[2,3-c]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]-8-methyl-2H-1,4 -benzoindole-3(4H)-ketone, oxime-[({trans-4-[(9-methoxy-2,3-dihydro-1H-[1,4] 噚耕和[2 ,3-c]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]_7_methylbenzoindole-3(4H)-one, 1- ({ l-[2- ( 2,3-Dihydro-1,4-benzodioxin_6_-123- 200948817 yl)ethyl]piperidin-4-yl}methyl)-9-methoxy-2,3-dihydro -1H-[1,4] 噚耕和[2,3-(;] sputum, :^(2-cyclohexylethyl)-{1-[(2-methoxy-7,8,9, 10-tetrahydrophenidin-10-yl)methyl]piperidin-4-yl}amine, 6-[({ 1-[(2-methoxy-7,8,9,10-tetrahydrophenanthridine) -10-yl)methyl]piperidin-4- Amino)methyl]-2H-1,4-benzophenone-3(4H)-one, 6-[({trans-4-[(9-methoxy-2,3-) Hydrogen-1H-[1,4]indole[2,3-c]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-b] [l,4] Tiod-3 (4H)-ketone, trans-N-( 2,3-dihydro[1,4]dioxin[2,3-c]pyridin-7-ylmethyl )-4-[(9-Methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinolin-1-yl)methyl]cyclohexaneamine , trans-N-( 2,3-Dihydro[1,4]dioxines [2,3-b]pyridin-6-ylmethyl)-4·[(9-methoxy-2, 3-Dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl)methyl]cyclohexaneamine, (2E)-3-{9-methoxy- 1-[(trans-4-{[(3-olyloxy-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-yl)methyl) Amino}cyclohexyl)methyl]-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-7-yl}acrylic acid, (2E)-3- {9-methoxy-1-[(trans-4-{[(3-)oxy-3,4-dihydro-211-pyrido[3,2-1^[1,4]thia trap -6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinolin-7-yl} acrylic acid , (2E ) -3-[l - ({ l-[2- ( 2,3-dihydro-1,4-benzene) And dioxin-6-yl)ethyl]piperidin-4-yl}methyl)-9-methoxy-2,3-dihydro-1H-[1,4] 噚耕[2,3 -c]quinoline-7-yl]acrylic acid, 9-methoxy-1-[(trans-4-{[(3-o-oxy-3,4-dihydro-211-pyrido[3, 2-1>][1,4]噚耕-6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro-1H-[1,4]噚 and [2, 3-c]quinoline-7-carbonitrile, 9-methoxy-1-[(trans-4.{[(3-a)- 3,4-dihydro-2H-pyrido[3,2 -b][l,4]噚耕-6-yl)methyl]amino}cyclohexyl)methyl]·2,3-dihydro-1Η-[1,4]噚耕和[2,3- c] quinoline-7-carbamimidoxime, 9-methoxy-1-[(trans-124-200948817 formula-4-{[(3-o-oxy-3,4-dihydro-2H-pyridine) And [3,2-b][l,4]噚耕-6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro-1H-[1,4]噚[2,3-c] sialolin-7-carbamimidoxime-acetamidopurine, 9-methoxy-l-[(trans-4-{[(3- oxo-3,4-) Dihydro-211-pyrido[3,2-1>][1,4]11§哄-6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro-1H- [1,4] 噚耕和[2,3-c]quinoline·7·carbamidine, 5-{ 9-methoxy-1-[(trans-4-{ [( 3-sided oxy-) 3,4-dihydro-2Η-pyrido[3,2-b] [l,4]噚耕-6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro-1H-[1,4]噚[[,3,3-c] Porphyrin-7-yl}thiophene-2-carboxylic acid, 〇6-[({(1811,2811,481〇-2-hydroxy-4-[(9-methoxy-2,3-dihydro-1H-) [1,4] 噚耕和[2,3-c]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l,4噚 -3-3 ( 4H)-ketone, 6-[ ({( 1SR, 2SR, 4SR) -2-hydroxy-4-[( 9-methoxy-2,3 · dihydro-1 Η-[1, 4] 噚 and [2,3-c] sialolin-1-yl)methyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l,4]thia trap -3(4H)-one, 6-[({(1311,2118,481〇-2-hydroxy-4-[(9-methoxy-2,3-dihydro-1H-[1,4]噚)阱[2,3-c]quinolin-1-yl)methyl]cyclohexyl}amino)carbamyl]-2H-pyrido[3,2-b][l,4]曙耕-3 (4H) · Ketone, 6-[({(1811,2118,4811)-2-hydroxy-4-[(9-methoxy-2,3-dihydro-1H-[1,4]噚) [2,3-c]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l,4]t-tung-3(4H) -ketone, 6-[({(18 ft, 2811,481 〇-2-azido-4-[(9-methoxy-2,3-dihydro-1H-[1,4] 曙[2,3-c]quinoline-bu)methyl]cyclohexane Amino)methyl]-2H-pyrido[3,2-b][l,4]indole-3(4H)-one, 6-[({(18 feet, 2118,481〇-2) -azido-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl)methyl] ring Hexyl}amino)methyl-125- 200948817 yl]-2H-pyrido[3,2-b][l,4]indole-3(4H)-one, 6-[({( 1SR,2SR,4SR) -2-(Dimethylamino)-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline-1 -yl)methyl]cyclohexylguanidino)methyl]-2H-pyrido[3,2-b][l,4]Bf cultivable-3(4H)-one, 6-[({( 1SR, 2SR,4SR) -4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl)methyl]- 2-([1,2,3]triazol-1-yl)cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l,4]噚耕-3 (4H) -ketone, 6-[({( 1SR, 2RS, 4SR) -4-[(9-methoxy-2,3-dihydro-1H-[1,4]噚 and [2,3-'c Quinoline-1-yl)methyl]-2-([1,2,3]triazol-buyl)cyclohexyl}guanidino)methyl]-2H-pyrido[3,2-b] [l,4]噚耕-3 (4H)-ketone, 6-[ ({( 1SR,4SR) ·4-[ ( 9-methoxy- 2,3-dihydro- lH,[l,4] Df trap and [2,3-(:]quinolin-1-yl)methyl]-2-( (£)-methoxyimino)cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l,4]indole-3(4H)-one, 6-[ ({( 1SR, 2SR, 4SR) · 4-[(9·methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinolin-1-yl) )methyl]-2-(methylamino)cyclohexyl}amino)

Methyl]-2H-pyrido[3,2-b][l,4]indole-3^4H)-one, 1-[(trans-4-{[(3-o-oxy-3) 4-Dihydro-2Η·pyrido[3,2-b][l,4]indole-6-yl)methyl]amino}cyclohexyl)methyl]·2,3-dihydro-1H- [1,4] 曙耕和[2,3-c]quinoline-9-carbonitrile, and 6-[({( 1RS,2SR,4RS) -2-(hydroxymethyl)-4-[( 9- Methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c] sialolin-1-yl)methyl]cyclohexyl}amino)methyl]-2H - Pyrido[3,2-b][l,4]indole-3(4H)-one and the like. As a more preferable example of the compound of the general formula (I), 6-[({trans--4·[(9-methoxy-2,3-dihydro-1H-[1,4]噚哄) is exemplified. And [2,3-c]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l,4]Df cultivum-3 ( 4H ) -126- 200948817 -ketone, 6-[({trans-4-[(9-methoxy-2,3-dihydro-1H-[1,4]曙[[,3,3-c]] Quinoline-1-yl)methyl]cyclohexyl}amino)methyl]-2H-1,4-benzothiazepine-3 (4H)-one, trans-N-(2,3-dihydro-1 , 4-benzodioxin-6-ylmethyl)-4-[(9-methoxy- 2,3·monohydro(-1H-[1,4]曙哄[2,3-c ]Salina-1-yl)methyl]cyclohexaneamine, 6-[({trans-4-[(9-methoxy-2,3-dihydro-1H-[1,4]噚) And [2,3-c]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]-211-pyrido[3,2-15][1,4]thia trap-3 (41 〇-ketone, trans-;^-(2,3-dihydro[1,4]dioxin[2,3-c]pyridin-7-ylmethyl)-4-[ (9-methoxy Base-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinolin-1-yl)methyl]cyclohexaneamine, trans-N-(2, 3-Dihydro[1,4]dioxines[2,3-b]pyridin-6-ylmethyl)-4-[(9-methoxy-2,3-dihydro-1H-[1 , 4] 噚耕和[2,3- c]quinolin-1-yl)methyl]cyclohexaneamine, 9-methoxy-1-[(trans-4-{[(3-o-oxy-3,4-dihydro-2H-) Pyrido[3,2-b][l,4]non-6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro-1H-[1,4]噚And [2,3-c]quinoline-7-carbonitrile, 6-[({(13 ft, 2311,4 81 〇-2-hydroxy-4-[(9-methoxy-2,3-dihydro) -1H-[1,4]噚[[,2,3-c] porphyrin-1-yl)methyl]cyclohexyl}amino)methyl hydrazino]-2H-pyrido[3,2-b] [l,4]噚耕-3 ( 4H )-ketone, 6-[({(1811,2811,4811)-2-hydroxy-4-[(9-methoxy-2,3-dihydro-1H) -[1,4] 噚耕和[2,3-c]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l, 4] Thiacin-3 ( 4H)-keto, 6-[({(1811,2]18,4811)-2-hydroxy-4-[(9-methoxy-2,3-dihydro-1H- [1,4]噚 and [2,3-c]quinolin-1-yl)methyl]cyclohexylguanidino)methyl]-2H-pyrido[3,2-b][l,4 ]曙耕-3 ( 4H)-ketone, 6-[({(1811,2118,481〇-2-hydroxy-4-[(9-methoxy-2,3-dihydro-1H-[1, 4] 噚耕和[2,3-c]quinolin-1-yl)methyl]cyclohexyl}amino)methyl-127- 200948817 yl]-2H-pyrido[3,2-b][l, 4] Respiratory-3 ( 4H )-ketone, 6-[({(1) 311,2811,481〇-2-azido-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline- 1-yl)methyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l,4]indole-3(4H)-one, 6-[({(1811) , 2 -8,481 〇-2-azido-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline-1 ·Methyl]cyclohexyl}amino)methyl]-211-pyrido[3,2-1)][1,4]indole-3 (41〇-ketone, 6-[({( 1SR) , 2SR, 4SR) -4-[(9-methoxy-2,3-dihydro-111-[1,4]indole[2,3-c]quinolin-1-yl)methyl] -2-([1,2,3]triazol-1-yl)cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l,4]噚哄-3 ( 4H )-ketone, 6-[ ({( 1SR,4SR) -4-[( 9-methoxy-2,3-dihydro- lH-[l,4]Df 哄[2,3-<: Quinoline-1-yl)methyl]-2-((£)-methoxyimino)cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l, 4] 噚-3,4(4H)-one, and 1-[(trans-4-([3- 3-oxy-3,4-dihydro-2H-pyrido[3,2-b][ 1,4]Df-well-6-yl)methyl]amino}cyclohexyl)methyl]-2,3·dihydro-1H-[1,4]indole[2,3-c]quinoline -9-nitrile, etc. Next, the production method of the compound of the present invention will be explained. The compound of the present invention represented by the general formula (I) can be produced by various methods. For example, the compound (I) of the present invention can be produced by the following method. For example, in the case of 'Α^Ν, the compound (I) can be produced from the compound of the general formula (2) according to the scheme 1.

V total 0 6b

Illustrative 1-128-200948817 Here, LG1 in the general formula (3a) is a substituted cleavage group on a reactive atom in the L1 structure which is then bonded to A1, and may remain in the compound of the general formula (4) after the reaction. In it, it may not remain. Further, when the reactivity of the reactive atom is sufficiently high, LG1 may not be present. Examples of LG1 include chlorine, bromine, iodine atom, methanesulfonyloxy group, P-toluenesulfonyloxy group, and trifluoromethanesulfonyloxy group. - PG1 in the general formulae (3a), (3b), (4), which is a substituted protecting group on a reactive atom in the Q1 structure which is then bonded to L2, although in the manufacture of a compound of the general formula (4) It has the reactivity affecting the reactive atom, but it may not be present. The L" in the general formula (3b) is a short structure of only one part of the methylene chain in the L1 structure. The general formula (3b) may be not only the aldehyde shown, but also a carbonyl compound (3c) such as a ketone.

LG2 in the general formula (6a) is a leaving group substituted with a reactive atom in the L2 structure which is bonded to Q1, and may remain in the compound of the general formula (I) after the reaction, or may not remain. Further, when the reactivity of the reactive atom is sufficiently high, LG2 may not be present. Examples of LG2 include chlorine, bromine, an iodine atom, a methanesulfonyloxy group, a P-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. The general formula (6b) may be not only the aldehyde shown, but also a carbonylation of a ketone or the like - 129-200948817 (6c). L21 in the general formula (6b) is a short structure of only one portion of the methylene chain in the L2 structure.

When the compound of the general formula (4) is produced, for example, it can be produced by reacting an amine derivative of the general formula (2) with a compound of the general formula (3a) in the presence of a base and an optional iodide. This reaction can be carried out according to the method described in Advanced Organic Chemistry, 5th Edition (by Michael B. Smith and Jerry March), pages 499 to 500, pages 513 to 515, 2001, published by John Wiley & Sons, Inc. The method is carried out.

The solvent to be used in the reaction may be any one which does not adversely affect the reaction, and examples thereof include alcohols such as methanol, ethanol, 2-propanol, η-butanol, and 2-methyl-2-propanol. , halogen hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone, 2-butanone and third butyl methyl ketone , diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, anisole, diphenyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and Ethers such as ethylene glycol monomethyl ether, sub-millings such as dimethyl argon, esters such as ethyl acetate and t-butyl acetate, hydrazine, hydrazine-dimethylformamide, hydrazine , such as guanamine, dimethylamine or 1-methyl-2-pyrrolidone, such as guanamine or water, may be used in combination. The base to be used in the reaction may, for example, be triethylamine, diisopropylethylamine, imidazole, pyridine, dimethylaminopyridine, hexamethylguanidine or 1,5-diazabicyclo[ 4·3·0]壬-5-ene, 1,8-diazabicyclo[5,4,〇]unda-7-ene, 1,3,4,6,7,8-hexahydro-211- Pyrimido[1,2-&]pyrimidine, 2-telebutyl--130- 200948817 Amino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2 -diazophospholine, lithium diisopropylamide, n-butyllithium, lithium hexamethyldialkyldisil azide, hexamethyldidecyl azide Inorganic alkali such as sodium, hexamethyldioxanyl potassium azide or the like, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, carbonic acid, potassium phosphate, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride Alkali, etc. Further, examples of the iodide to be used include potassium telluride, sodium iodide, and lithium iodide. Further, it may coexist with the relevant mobile catalyst as necessary. Examples of the related mobile catalyst include tetra-n-butylammonium chloride, triethylbenzylammonium chloride, and 18-crown-6. With respect to the general formula (2), the amount of rhodium used in this reaction is preferably from 1 to 10 mol, and the iodide is preferably 0.01 to 10 mol. The relevant mobile catalyst is 0.01 to 10 times Mo. The reaction temperature is -100 to 250 ° C, preferably -80 to 150 ° C, and the reaction time is preferably 10 minutes to 24 hours.

Other examples, for example, when the general formula (3a) is an epoxide, the amine derivative of the general formula (2) and the compound of the general formula (3a) are reacted in the presence of a base or a Lewis acid as desired. A northern compound of the general formula (4) can be produced. This reaction can be carried out according to the method described in Advanced Organic Chemistry, 5th Edition (by Michael B. Smith and Jerry March), page 504, 2001, published by John Wiley & Sons, Inc., or the like. Others, for example, where the general formula (3a) is a Michael acceptor, the amine derivative of the general formula (2) and the compound of the general formula (3a) are optionally used as a base, or a Lewis The reaction of the acid can be carried out in the presence of an acid -131 - 200948817 to produce a compound of the general formula (4). This reaction can be described in Advanced Organic C hemistry, 5th edition (Michae 1 B. S mith and Jerry M arch), 1022-1024, 2001, published by John Wiley & Sons, Inc. According to its method. In the case where the general formula (3a) is an acid halide or a mixed acid anhydride, for example, the amine derivative of the general formula (2) and the compound of the general formula (3) are used in the presence of a base. The compound of the general formula (4) can be produced by the reaction. When the general formula (3) is a carboxylic acid or the like, the amine derivative of the general formula (2) and the compound of the general formula (3a) are used in the condensing agent and the amide. A compound of the general formula (4) can be produced by reacting in the presence of a base. This reaction can be Advanced Organic Chemistry, 5th edition (by Michael B. Smith and Jerry March), pp. 516-512, 2001, John Wiley The method described in the publication of Sons, Inc., etc.; the basis and experiment of the synthesis of the victory, (Spring House), pages 89 to 142, 1985, the method described in Jiushan Publishing, etc. The solvent to be used is preferably one which does not adversely affect the reaction, and examples thereof include alcohols such as methanol, ethanol, 2-propanol, η-butanol, and 2-methyl-2-propanol, and dichloride. Halogen hydrocarbons such as methane, chloroform and 1,2·dichloroethane, benzene, and And aromatic hydrocarbons such as xylene, ketones such as acetone, 2-butanone, and third butyl methyl ketone, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, Ethers such as anisole, diphenyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and ethylene glycol monomethyl ether, sub-millings such as dimethyl sub-milling, acetic acid Esters such as ethyl ester, tert-butyl acetate, etc., N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone The solvent may be used in combination with water, etc. -132-200948817 Examples of the acid halide, the mixed acid anhydride, and the like include, for example, acid halides such as acid chlorides, acid bromides, and acid fluorides. a mixed acid anhydride obtained by a reaction of a carboxylic acid with ethyl chlorocarbonate, isobutyl chlorocarbonate or trimethylethenyl chloride in the presence of a base, P-nitrophenyl ester of a carboxylic acid, N- Hydroxyammonium imidate, N-hydroxy saponin, pentafluorophenyl ester, 1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole, 3,4·dihydrogen -3-hydroxy-4-side oxygen -1,2,3-benzotrimyl ester, active esters such as 1-hydroxy-7-azabenzotriazole ester, etc. Such acid halides, mixed acid anhydrides, etc. may be precursors The carboxylic acid or the like is synthesized and used without isolation. Examples of the base used in the reaction include triethylamine, diisopropylethylamine, imidazole, pyridine, dimethylaminopyridine, and hexamethyl. Base, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a Pyrimidine, 2-tert-butylimido-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazophosphine, lithium diisopropylamide , an organic base such as η-butyllithium, hexamethyldioxanyl azide, sodium hexamethyldidecyl azide, and hexamethyldidecyl azide, sodium hydrogencarbonate, carbonic acid An inorganic base such as sodium, potassium carbonate, 0 carbonic acid planing, potassium phosphate, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride. As the condensing agent used in the reaction, for example, hydrazine, fluorene-dicyclohexylcarbodiimide, hydrazine-ethyl-hydrazide-(3-dimethylamino)carbodiimide, diisopropyl a carbodiimide such as a carbodiimide, a carbonyl group such as carbonyldiimidazole, an acid azide such as a diphenylphosphonium azide group, or an acid cyanide such as diethylphosphonium cyanide. Compounds, 1-[bis(dimethylamino)methylene]-1Η-benzotrixenyl hexafluorophosphate 3-oxide, 1-[bis(dimethylamino)methylene] -1Η-benzotriazole gun tetrafluoroborate 3-oxide, 1-[bis(di-133- 200948817 methylamino)methylene]-5-chloro-1 Η-benzotriazole gun six Fluoride phosphate 3-oxide, 1-[bis(dimethylamino)methylene]-5-chloro-1Η-benzotriazole gun, tetrafluoroborate 3-oxide, etc. 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate, bromo(pyrrolidinium)scale hexafluorophosphate, benzotriene Zin-1-yloxy ginseng (pyrrolidine) iron hexafluorophosphate, 2-chloro-1,3-dimethyl-2-imidazole gun hexafluorophosphate, hydrazine, hydrazine-bis (2-sided oxygen) Alkyl-3-oxazolidinylphosphinyl chloride or the like. The base and the condensing agent used in the reaction are used in an amount of from 0.01 to 50 moles, preferably from 1 to 5 moles, per mole of the general formula (2). The reaction temperature is -80 to 150 ° C, preferably -2 0 to 120 ° C, and the reaction time is preferably from 1 minute to 48 hours. The compound of the formula (4) can be produced by reacting an amine derivative of the general formula (2) with a carbonyl compound of the general formula (3b) in the presence of a reducing agent. This reaction can be disclosed in WO2007/081597, WO2007/071936, or Advanced Organic Chemistry, fifth edition (by Michael B. Smith and Jerry M arch), pages 1187 to 1189, 2001, John Wiley & Sons, The methods described in the publication of Inc. or the methods thereof are carried out. The solvent to be used in the reaction may be any one which does not adversely affect the reaction, and examples thereof include alcohols such as methanol, ethanol, 2-propanol, butanol, and 2-methyl-2-propanol, and Halogen hydrocarbons such as methyl chloride, chloroform and 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; diethyl ether, diisopropyl ether, tert-butyl methyl ether, and Ether, dimethyl ether, tetrahydrofuran, anisole, diphenyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and ethylene glycol monomethyl-134-200948817 ether Anthraquinones such as arsenic, ethyl acetate, tert-butyl acetate, etc., N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl- These solvents may be used in combination with guanamines such as 2-pyrrolidone and water. The reducing agent to be used in the reaction may, for example, be a hydrogenated dysfunction compound such as lithium aluminum hydride, sodium borohydride, sodium triethoxy borohydride or sodium cyanoborohydride, borane, sodium or sodium amalgam ( Amalgam) and so on. Further, contact reduction using Raney nickel, platinum oxide or palladium black, and reduction using lanthanum zinc and an acid may be used. In this reaction, the reducing agent is used in an amount of from 1 to 20 moles, preferably from 1 to 5 moles, per mole of the compound of the formula (2). The reaction temperature is -50 to 200 ° C, preferably -10 to 100 ° C, and the reaction time is preferably 10 minutes to 72 hours. For the production of the compound of the general formula (5), for example, when the reactive atom on Q1 of the compound of the general formula (4) is a nitrogen atom and PG1 is a nitrogen protecting group, depending on the kind of the protecting group, for example, Greene, Wuts et al., Protective Group s in Organic Synthesis, 4th edition, pp. 696-926, 2006, by John Wiley & Sons, Inc., or according to methods thereof. When the compound of the general formula (I) is produced, for example, when the reactive atom on Q1 of the compound of the general formula (5) is a nitrogen atom, the compound of the general formula (2) is the same as the general formula (3a). The method of obtaining a compound of the general formula (4) by reacting a compound can be produced by reacting a compound of the general formula (5) with a compound of the general formula (6a). Further, by reacting a compound of the general formula (2) with a compound of the general formula (3b) to obtain a compound of the general formula -135-200948817 (4), a compound of the formula (5) can be The compound of the formula (6b) is produced by reacting. In the above production method, any of the compounds, the substituents and functional groups of the compounds may be suitably protected by a protecting group, and may be deprotected at an appropriate stage. Further, the compound of the general formula (I) can be produced from the compound of the general formula (2) according to the scheme 2.

Illustratively, a method of obtaining a compound of the general formula (2) by reacting a compound of the general formula (2) with a compound of the general formula (3a) or (3b), via a compound of the general formula (2) It can be produced by reacting with a compound of the general formula (7a) or (7b). In this case, the general formula (7b) may be not only the aldehyde shown, but also a carbonyl compound (7c) such as a ketone.

The compound of the general formula (2) can be produced by the scheme 3, for example, -136- 200948817

2

Scheme 3 Here, the LG group in the general formulas (8), (10), and (11), LG4 may remain in the general formula (10) or < after the reaction, or may not remain. Further, LG3 and LG4 may be converted to an appropriate precursor functional group in the following stages, and when LG3 and LG4 are sufficiently high, LG4 may not exist. As an example, chlorine, bromine, an iodine atom, a methanesulfonyloxyoxy group, a trifluoromethanesulfonyloxy group, etc. are mentioned. When PG2, PG3 or hydrogen in the general formula (9), (10), (1 1 ) is an amine-based protecting group, for example, Protective Groups in Organic Synthesis 696-92 can be cited. 0 0 6 years, John Wiley & Sons, Son. The compound of the formula (2) of PG2'PG3 can be produced by a compound of the formula (10) of the general formula (8) as long as it does not interfere with the reaction. 5, LG4 is detached: 2) the compound manufacturing method is appropriate, the anti-LG3, LG4, p-toluene sulfonate of A2 atom is the amine-protecting group Greene, Wuts, 4th edition, the first nc. It can be hydrogen. The compound is obtained by the general method of -137-200948817, that is, the same method as the compound of the general formula (2) and the compound of the general formula (3a), for the preparation of the compound of the general formula (4), The compound of the formula (9) is reacted to produce a compound of the general formula (1). In this case, the compound of the general formula (9) can be replaced with a metal azide. In this case, after the reaction, the azide group is reduced to an amine (in the compound of the general formula (10), both PG2 and PG3 are hydrogen). Used in the subsequent reaction. The nuclear substitution reaction of the azide ion used in this case is carried out in the presence of a desired compound, and can be carried out in Advanced Organic Chemistry, 5th edition (Michael B. Smith and Jerry March), pp. 515-516. In 2001, the method described by John Wiley & Sons, Inc., or the like, was carried out according to the method thereof. The solvent to be used in the azide reaction may have no adverse effect on the reaction, and examples thereof include methanol, ethanol, 2-propanol, η-butanol, and 2-methyl-2-propanol. Halogen hydrocarbons such as alcohols, dichloromethane, chloroform and 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; acetone, 2-butanone, and tert-butyl methyl ketone Ketones, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, anisole, diphenyl ether, B

Esters such as flavonoids such as dimethyl sulfite, ethyl acetate, and tert-butyl acetate; hydrazine, hydrazine-dimethylformamide, hydrazine, hydrazine-dimethylacetamide and These solvents may be used in combination with guanamines such as 1-methyl-2-pyrrolidone and water. Examples of the iodide to be used include potassium iodide and sodium iodide. Examples of the azide ion to be used include sodium azide, a trimethylsulfonium alkyl azide group and the like. -138 200948817 Relative to the general formula (8), the iodide used in this reaction is preferably used in an amount of oi 〜1〇 imo, and the azide ion is preferably 1 to 10 times the compound of the general formula (8). ear. The reaction temperature is 〇200 ° C, preferably 20 to 120 ° C, and the reaction time is 5 minutes to 4 8 hours. The reduction of the formed azide compound may be exemplified by contact hydrogen addition via a palladium carbon catalyst, hydrogenated reduction catalyst such as lithium aluminum hydride or sodium borohydride, thiol, triphenylphosphine, or the like. Hydroxyphenyl decane, polymethylhydroquinone oxane and a catalytic amount of hexabutyltin hexane. The solvent to be used in the reduction reaction may have no adverse effect on the reaction, and examples thereof include alcohols such as methanol, ethanol, 2-propanol, η-butanol, and 2-methyl-2-propanol. a halogen hydrocarbon such as dichloromethane, chloroform or 1,2-dichloroethane; an aromatic hydrocarbon such as benzene, toluene or xylene; a ketone such as acetone, 2-butanone or a third butyl methyl ketone; Diethyl ether, diisopropyl ether, third butyrate methyl ether, dioxane, tetrahydrofuran, anisole, diphenyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether And an ether such as ethylene glycol monomethyl ether, an anthracene such as dimethyl dimethyl hydrazine, an ester such as ethyl acetate or a third butyl acetate; hydrazine, hydrazine-dimethylformamide And hydrazine, hydrazine, dimethylamine and 1-methyl-2-pyrrolidone, such as guanamine and water, may be used in combination. The reducing agent is preferably used in an amount of from 1 to 10 moles per mole of the azide-based compound. The reaction temperature is 〇200 ° C, preferably 0 to 120 ° C, and the reaction time is preferably 5 minutes to 4 8 hours. Secondly, in the case where the compound of the general formula (1〇), PG2, and PG3 are not hydrogen, the one or both sides are deprotected, or the PG2, PG3-139-200948817 is unilateral or both. In the case of hydrogen, the protective group is deprotected as it is, and the cyclization reaction is carried out in the presence of a base, an iodide or a catalyst, and then either PG2 or PG3 is not hydrogen. The compound of general formula (2) can be produced by deprotecting the amine protecting group. This reaction can be published by Advanced Organic Chemistry, 5th edition (by Michael B. Smith and Jerry March), pages 513 to 515, pages 8 64 to 8 66, 2001, published by John Wiley & S ons, Inc. Or Metal-Catalyzed Cross-Coupling Reactions, Volume 2, Second Edition (Armin de meijere et al., pp. 699-760, 2004, 〇WILEY-VCH Verlag GmbH & Co. KGaA Publishing, etc. or According to its method. The solvent to be used in the reaction may be any adverse effect on the reaction, for example, alcohols such as methanol, ethanol, 2-propanol, η-butanol, and 2-methyl-2-propanol, and dichloride. Halogen hydrocarbons such as methane, chloroform and 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone, 2-butanone and t-butyl methyl ketone, and diethyl ketone Ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, anisole, diphenyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and ethylene An ether such as an alcohol monomethyl ether, a flavonoid such as dimethyl hydrazine, an ester such as ethyl acetate or a third butyl acetate; hydrazine, hydrazine, dimethylformamide, hydrazine, hydrazine; - Hydrazines such as dimethylacetamide and 1-methyl-2-pyrrolidone, water, etc., may be used in combination. The base to be used in the reaction may, for example, be triethylamine, diisopropylethylamine, imidazole, pyridine, dimethylaminopyridine, hexamethylguanidine or 1,5-diazabicyclo[ 4.3.0] indole-5-ene, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,3,4,6,7,8-hexahydro-2indole-pyrimidine And [l,2-a]pyrimidine, 2-t-butyl y-140- 200948817 Amino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-heavy Nitrophosphine, lithium diisopropylamide, η-butyllithium, lithium hexamethyldidecyl azide, sodium hexamethyldidecyl azide, and hexamethyldidecyl azide An organic base such as an organic base such as potassium, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, carbonic acid planer, potassium phosphate, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, potassium t-butoxide, sodium methoxide, A metal alkoxide such as sodium ethoxide or the like. Further, examples of the iodide to be used include potassium iodide, sodium iodide, and lithium iodide. 〇 as a catalyst to be used, for example, palladium acetate (II), a palladium carbon catalyst, bis(dibenzylideneacetone)palladium (0), ginseng (dibenzylideneacetone) dipalladium (ruthenium), Dichlorobis(acetonitrile)palladium(II) and the like and Metal-Catalyzed Cross-Coupling Reactions, Volume 2, Second Edition (Armin de meij ere et al., ed., 705, 2004, WILEY-VCH Verlag GmbH & Co.KGaA publishes a catalyst prepared in advance such as a ligand described in a ligand, or a catalyst generated in such a reaction system, or Metal-Catalyzed Cross-Coupling Reactions, Volume 2, Second Edition (Armin demeijere, etc.) (edited by man), Ο 70th, 7th, 2004, WILLEY-VCH Verlag GmbH & Co.KGaA published catalysts. Further, it may coexist with the relevant mobile catalyst as necessary. Examples of the related mobile catalyst include tetra-n-butylammonium chloride, triethylbenzylammonium chloride, and 18-crown-6. The base of the reaction is preferably used in an amount of from 1 to 10 moles per mole of the compound of the formula (10), and the iodide is preferably 〇.〇1 to 1 oxime. The catalyst is preferably used in an amount of from 0.05 to 10 times by mole relative to the compound of the general formula (10). The relevant mobile catalyst should be 0.01 to 10 times Mo. The reaction temperature is -100 to 250 ° C, preferably 20 to 150 ° C, and the reaction time is preferably 1 minute to 72 hours. Further, the compound of the general formula (2) can also be produced from the compound of the general formula (8) via the compound of the general formula (11). That is, the same method as the production of the compound of the general formula (2) from the compound of the general formula (10) can be applied to an intermolecular reaction, and a general compound (2) can be produced by reacting a compound of the general formula (2) with a compound of the general formula (9). a compound of formula (11). Further, in this case, the compound of the general formula (9) may be substituted with a metal azide. In this case, after the reaction, the azide group is reduced to an amine (the compound of the general formula (11) Q, and both of PG2 and PG3 are Hydrogen) can be used to continue the reaction. Next, when the compound of the general formula (11), PG2, or PG3 has no hydrogen, the one or both of the compounds of the formula (11) are deprotected, or the PG2, PG3 is either hydrogen or PG3 as it is, or After deprotection of the protecting group, the compound of the general formula (2) can be guided by the same method as the compound of the general formula (2) and the compound of the general formula (3a) to produce the compound of the general formula (4). Further, when PG3 is hydrogen, the compound of the general formula (2) can also be produced directly from the compound of the general formula (8) and the compound of the general formula (9). That is, the compound of the general formula (8) can be directly guided to the general formula (2) by the same method as the preparation of the compound of the general formula (11) from the compound of the general formula (8) and the compound of the general formula (9). Compound. The compound of the general formula (4) can also be produced from the compound of the general formula (8) according to Scheme 4. In other words, when PG2 is not hydrogen, the compound of the general formula (8) is reacted with the same method as the compound of the general formula (9) and the compound of the general formula (9). The compound of the general formula (12) is synthesized as a compound of the general formula (12), and then the compound of the general formula (13) is synthesized, and then PG2 is deprotected by the same method as the compound of the general formula (2). A compound of the general formula (4) can be produced. Or, by synthesizing a compound of the general formula (8) with a compound of the general formula (12) via a phase-like method of producing a compound of the general formula (11) from a compound of the general formula (8) and a compound of the general formula (9) The compound of the formula (14), after deprotecting PG2, can be used to produce the compound of the general formula (4) in the same manner as the compound of the general formula (11).

In the case where PG2 is hydrogen, the compound of the general formula (8) can be obtained by the same method as the direct production of the compound of the general formula (2) from the compound of the general formula (8) and the compound of the general formula (9). Compound of formula (12), anti-143- 200948817, should be prepared as a compound of general formula (4). Further, the compound of the general formula (4) can also be produced from a compound of the general formula (8) via a compound of the general formula (10) or the general formula (11). That is, when the compound of the general formula (10) is not hydrogen in the case where both of PG2 and PG3 are not hydrogen, or when one or both of PG2 and PG3 are hydrogen, or After the protective group is deprotected, it can be guided to the general formula (13) by the same method as the compound of the general formula (2) and the compound of the general formula (3a) or (3b) to produce the compound of the general formula (4). Compound. Next, PG2 is deprotected, and a compound of the general formula (4) can be produced by the same method as the production of the compound of the general formula (2) from a general formula (1). Further, in the case where the compound of the general formula (11) is deprotected unilaterally or in two cases when both of PG2 and PG3 are free of hydrogen, or when either or both of PG2 and PG3 are hydrogen, the same or After the protection group is deprotected, the compound of the general formula (14) can be oriented by the same method as the compound of the general formula (2) and the compound of the general formula (3a) or (3b). . Next, the compound of the general formula (4) can be produced by the same method as the method of producing the compound of the general formula (2) from the compound of the general formula (11). A more specific example of the above manufacturing method is shown in Scheme 5. -144- 200948817

Scheme 5 Automated pi (15) and compound (16), by the method described in Journal of medicinal chemistry, Vol. 33, pp. 527-533, 1990, etc., Q to produce compound (8a) 'Next, via Compound (8a) and ammonia gas (9 〇 saturated suitable solvent is heated in a sealed tube to produce compound (2a). Further, compound (8 a) and 2,4-dimethoxyanisidine (9b) can be used. Compound (17) is produced by heating in the presence of a palladium catalyst and a base, followed by deprotection of 2,4-dimethoxybenzyl to produce a compound (2. Further, compound (8a) and potassium ruthenium After the compound (10a) is produced by the action of quinone imine (9c), the thiol protecting group is deprotected to the compound (10b), and the compound (2a) can be produced by heating in the presence of a base. L〇b) can also be produced by reacting the compound (8a) with sodium azide to synthesize the compound (l〇c), followed by reduction of the azide group with triphenylphosphine/-145-200948817 water. 2a), according to Scheme 6, for example, in the presence of a base, reacting with iodide 3aa to direct compound (4a), After the Boc group is deprotected to the compound (5a), for example, the target compound (I)-a can be produced by amination reaction with the aldehyde 6ba.

TFA/DCM then aq. NaHCO^

Scheme 6 Further, as shown in Scheme 7, it can be produced by reacting compound (8a), for example, in the presence of a base with compound (1 2a ), or by reacting compound (1 Ob ), for example, in the presence of a base with 3ab. Compound (13a) can be produced by heating in the presence of a base or heating in the presence of a palladium catalyst and a base. Further, the compound (4b) can be directly produced by heating the compound (8a) and the compound (12a) in the presence of a base or heating in the presence of a palladium catalyst and a base. The compound (4b) can be guided to the compound of the general formula (I) via the methods and the like described so far. -146- 200948817

Another specific example is given.

c$2c (V toluene heat diagram 8 will be Chemical pharmaceutical Britain, Vol. 55, No. 82 1 -824 Ο

The compound (18), which is described by the compound (18) described in 1971 and the like, is reacted with phosphorus oxychloride to synthesize the compound (19), and then reacted with 2-aminoethanol to produce the compound (20). The obtained compound (20) is allowed to react with bromine in acetic acid to produce a compound (2 1 ) which is selectively introduced into a bromine atom. Compound (2b) can be produced by heating it in the presence of a base or by heating in the presence of a copper catalyst and a base. As shown in the scheme 8, from the compound (2b), the compound of the general formula (I) can be produced by the same method as described above. In the compound of the formula (I), A4 is a nitrogen atom, an oxygen atom or the like -147-200948817 The compound can also be produced according to the scheme 9. Here, LG5 is a leaving group, and may remain in the compound of the general formula (8) or the general formula (13) after the reaction, or may not remain. When the reactivity of the A3 atom is sufficiently high, the LG5 may not exist. Examples of LG5 include chlorine, bromine, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like. The general formula (23b) and (24b) are not only the aldehyde shown, but also a carbonyl compound such as a ketone of 3c, 6c or an α-ketoester. That is, when Α4 is a nitrogen atom which may be substituted, the compound of the general formula (22) and the compound of the general formula (23a) or (23b) are passed through the compound of the general formula (2) and the general formula (3a). Alternatively, the compound of the formula (3b) can be reacted in the same manner as the compound of the formula (4) to produce a compound of the formula (8). Thereafter, a compound of the general formula (I) can be produced via the method described above or the like.

Scheme 9 Similarly, a compound of the general formula (13) can be produced from a compound of the general formula (22) and a compound of the general formula (24a) or -148 200948817 (24b), from the compound of the general formula (13), via The compound of the general formula (I) can be produced by a method. When A4 is an oxygen atom, a compound of the general formula (22) and a compound of the general formula (23) are produced from a compound of the general formula (2) and a compound of the general formula (3a). By reacting in a similar manner, a compound of the general formula (8) can be produced. For example, Advanced Organic Chemistry, 5th edition (by Michael B. Smith and Jerry March), pages 477 to 488, 2001, John Wiley & Sons, The method described in the publication of Inc., or the method according to the method, can be carried out, and then the compound of the general formula (I) can be produced by the method described above, etc. Similarly, the compound of the general formula (22) and the general formula (2) can be produced. The compound of the formula (13) is produced from the compound of the formula (13), and the compound of the general formula (I) can be produced from the compound of the general formula (13) via the above-mentioned method. More specific examples of the above production method are shown in the scheme 10.

Scheme 10-149-200948817 That is, the compound (25) described in Journal of medicinal chemistry >, Vol. 36, No. 1669-1673, B93, etc., is hydrolyzed, and the obtained carboxylic acid compound (26) and the third butyl alcohol are obtained. Compound (27) can be produced by heating together with diphenylphosphoric acid azide. After the Boc protecting group of the compound (27) is deprotected to the compound (28), the compound (8b) can be produced by reacting with a chloroacetic acid chloride. Then, the compound (13b) is obtained by heating with a base (8b) together with the compound (12b), and the compound (13b) can be produced by further heating. The compound (4c) can be guided to the general formula via the methods described so far ( A compound of the formula (I). In the structure of the compound of the formula (I), when A1 is a carbon atom which may be substituted, for example, it can be produced by the following production method. Here, RA11 is Li-Q^LlQ2 itself, or after A substituent of lLqLlIq2 or a substituent which can be converted into lLqLlLq2, which is a substituted group of carbon A1, or a functional group which can be converted into a substituent, can be introduced. Further, either RAU or RA12, or Since the two are a substituent of an electron-attracting property, the methylene group between RA11 and RA12 of the compound (22) is deprotonated in the presence of ruthenium. Examples of the electron-attracting substituent include a ketone group. , ester group, nitrile group, nitro group, carboxyl group, hydrazine, hydrazine, sulfonate, and the like.

(I)

Scheme 11 That is, a compound of the general formula (8) can be produced by first reacting a compound of the general formula (8) with a compound of the general formula (29) -150-200948817, for example, in the presence of a base. This reaction can be carried out, for example, by the method described in Advanced Organic Chemistry, 5th edition (by Michael B. Smith and Jerry March), pages 548 to 556, 2001, published by John Wiley & Sons, Inc., or the like. Next, the compound of the general formula (31) can be reacted in the presence of a base or a catalyst as desired to produce a compound of the general formula (31). This reaction can be, for example, Advanced Organic Chemistry, 5th edition (by Michael B. Smith and Jerry March), pages 8 69 to 8 70, 2001, John Wiley & Sons, Inc., or Chemical Reviews, The method described in 106, pp. 26 51-2, 710, 006, etc., or according to its method. The solvent to be used in the reaction may be any one which has no adverse effect on the reaction, and examples thereof include alcohols such as methanol, ethanol, 2-propanol, η-butanol, and 2-methyl-2-propanol, and a halogen hydrocarbon such as methyl chloride, chloroform or 1,2-dichloroethane; an aromatic hydrocarbon such as benzene, toluene or xylene; a ketone such as acetone, 2-butanone or t-butyl methyl ketone; Ethyl ether, diisopropyl ether, tert-butyl fluorenyl methyl ether, dioxane, tetrahydrofuran, anisole, diphenyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether And ethers such as ethylene glycol monomethyl ether, hydrazines such as dimethyl hydrazine, esters such as ethyl acetate and t-butyl acetate; hydrazine, hydrazine-dimethylformamide, A solvent such as hydrazine, hydrazine-dimethylammoniumamine or 1-methyl-2-pyrrolidone, or the like may be used in combination. As the hydrazine used in the reaction, for example, triethylamine, diisopropylethylamine, imidazole, pyridine, dimethylaminopyridine, hexamethylguanidine, 1,5-diazabicyclo[ 4.3.0] indole-5-ene, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,3,4,6,7,8-hexahydro-2indole-pyrimidine And [l,2-a]pyrimidine, 2-t-butyl y-151 - 200948817 Amino-2·diethylamino-1,3-dimethyl-perhydro-1,3,2· Nitrophosphine, lithium diisopropylamide, η-butyllithium, lithium hexamethyldidecyl azide, sodium hexamethyldidecyl azide, and hexamethyldidecyl azide An inorganic base such as an organic base such as potassium, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, carbonic acid planer, potassium phosphate, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride. Examples of the catalyst used in the reaction include palladium acetate (ruthenium), palladium carbon catalyst, bis(dibenzylideneacetone)palladium (ruthenium), and bis(dibenzylideneacetone)dipalladium (0). , dichlorobis(acetonitrile)palladium (II), etc., and a catalyst prepared in advance from a ligand described in BINAP, Tol-BINAP et al., Chemical Reviews, Vol. 106, pp. 2658-2659, 2006, etc. Or catalysts derived from such reaction systems, or Metal-Catalyzed Cross-Coupling Reactions, Volume 2, Second Edition (Armindemeijere et al., ed., 707, 2004, WILEY-VCHVerlagGmbH& Co.KGaA Publication of the recorded catalysts, etc. With respect to the compound of the general formula (30), the amount of the ruthenium used is preferably from 1 to 10 times by mole, and the catalyst is preferably from 0.001 to 10 times by mole. The reaction temperature is 0 to 200 ° C, preferably 0 to 120 ° C, and the reaction time is 5 〇 minutes to 7.2 hours. When the compound of the general formula (31) is also a compound of the general formula (I), the compound of the general formula (I) can be produced by chemically converting any of RA11 and RA 12 or both. When RA12 of the compound of the general formula (31) is an ester group or a carboxyl group, the compound of the general formula (32) can be produced by deesterification by an appropriate method or by decarbonation. When the compound of the formula (32) is also a compound of the general formula (1) itself, the compound of the general formula -152-200948817 (I) can be produced by chemically converting Ra η as appropriate. More specifically, as shown in the scheme 12, for example, the compound of the general formula (29) is a general formula of the following formula (for example, the malonate of 29a, via the method described, via the compound of the general formula (8) A compound of the general formula (30a) can be used to produce a compound of the general formula (31a).

❹

After the illustration 12, for example, a compound of the general formula (33a) can be produced by selectively hydrolyzing only a single ester group of the compound of the general formula (3 1a) using a base and water. This reaction can be, for example, a method described in Advanced Organic Chemistry, 5th edition (by Michael B. Smith and Jerry March), pages 469 to 474, 2001, J〇hnWiley & Sons, Inc., etc. The method is carried out. Next, a compound of the general formula (32a) can be produced by heating a compound of the general formula (33a) in the presence of an acid, a base or a salt as desired. This reaction, for example, can be Advanced Organic Chemistry, 5th edition (by Michael B. Smith and Jerry March), pp. 808-813, 2001.

The method described by John Wiley & Sons, Inc., et al., or the method according thereto. Further, a compound of the general formula (32a)-153-200948817 can also be directly produced from the compound of the general formula (31a). For example, a compound of the general formula (31a) can be present in an aqueous aprotic polar solvent, and a base is present. Under heating, a heated Krapcho deactivating oxygenation reaction can be used. This reaction can be described in Strategic Applications of Name Reactions in Organic Synthesis (Laszlo Kurti et al.), pp. 252-25, page 3, 2005, published by Elsevier Inc., or Synthesis, pp. 805-8 22, 1982, etc. The method is carried out according to the method thereof. The compound of the formula (33a), which is reduced by a reducing agent or converted to an acid halide or an acid anhydride, can be converted to a compound of the general formula (34a) by reduction. This reaction can be carried out, for example, by the method described in Comprehensive Organic Transformations, 2nd Edition (Richard C. Larock), 1114-1116, 112 1 page, 1999, published by John Wiley & Sons, Inc. . The reducing agent to be used in the reaction may, for example, be a decane/tetrahydrofuran conjugate, a borane/dimethyl sulfide complex or a sodium borohydride. Further, the compound of the general formula (34a) can also be produced by treating a compound of the formula (31) with a suitable reducing agent. This reaction can be carried out by Advanced Organic Chemistry, 5th edition (by Michael B. Smith and Jerry March). Page 533, 2001, published by John Wiley & Sons, Inc., etc., or according to the method thereof. As the reducing agent used in the reaction, for example, lithium aluminum hydride or diisobutyl aluminum hydride can be cited. And sodium aluminum hydride, sodium (2-methoxyethoxy)aluminum, etc. Next, for example, a compound of the general formula (34a) can be oxidized to produce a compound of the formula (35a). Can be used in Comprehensive Organic Transformations, 2nd Edition (Richard C. Larock), -154- 200948817, 1st page 234-1249, 1999, John Wiley & Sons, Inc. The oxidizing agent used in the reaction is, for example, an activated dimethyl argon, a Dess-Martin high-valent iodine compound, a chromium trioxide, a dichromic acid via sulfur trioxide pyridine, chlorinated sulfhydryl or the like. , dichromate, azopyridine gun chlorochromate, pyridinium dichromate, tetra-η-propyl ammonium perrhenate, etc. In addition, the amount of catalyst can be more than the theoretical amount of oxidant and chemical amount The co-oxidant is used in combination. Further, the compound of the general formula (35a) can also be produced by treating the compound of the general formula (31a) with a suitable reducing agent. This reaction can be advanced organic Chemistry' 5th edition (Michael B. Smith and Jerry March), p. 533, 2001, published by John Wiley & Sons, Inc., etc., or according to the method thereof. As the reducing agent used in the reaction, for example, lithium aluminum hydride, two Isobutyl aluminum hydride, sodium aluminum hydride, sodium (2-methoxyethoxy)aluminum, etc. Next, the compound of the general formula (35〇 and the compound of the general formula (36), and the general formula (2) The compound of the formula (3b) is the same as the compound of the formula (4). The compound of the formula (37a) can be produced by reacting the compound of the formula (37a). Orientation of general formula (I) Further, as shown in Figure 13, the compound of the general formula (32a) is directed to a compound of the general formula (31a) via a compound of the general formula (33a), (34a), (35a), (37a). The same procedure as for the compound of formula (I) can be carried out via a compound of formula (38a) '(39a) '(40a)' (41a) to a compound of formula (I). 155- 200948817

Illustration 13 〇 Give a specific example. As shown in Figure 14, for example, a compound (30b) can be produced by heating a mixture of the compound (8a) and diethyl malonate in the presence of potassium carbonate, and the obtained 30b can be produced by heating in the presence of a palladium catalyst and a base. Compound (31b). The compound (31b) can be produced by heating the aqueous N,N-dimethylformamide in the presence of lithium chloride to produce the deesterified compound (32b), followed by reduction by Red-A1 to produce the aldehyde compound (40b). Compound (41b) can be produced by reacting a mixture of compound (40b) and amine compound (36a) with sodium triethylphosphonium hydride, and 41b can be obtained from the compound of formula (I) by the method described so far. .

Scheme 14 - 156 - 200948817 Further, the compound of the general formula (I) can also be produced according to the scheme 15.

In the above, Y1 is hydrogen or an electron-attracting substituent which facilitates the aromatic substitution reaction, and examples thereof include a carboxyl group, an ester group, a cyano group, a nitro group and the like. Y2 can be converted from Y1, and can be converted to a substituent having a cyclic structure of -Α^Α'ΑΐΑ4- together with Y3 or the like. Similarly, hydrazine 3 is a substituent which is substituted on the main atom in Α1 and can be converted into a cyclic structure containing -A^A^AlA4- together with Y2 or the like. Y4 and Y5 may be hydrogen, and may be converted to a substituent of RA11 and RA12. EWG1 is an adjacent methylene group or deprotonation of a methine group easily, and between the compound of the general formula (42) and the compound of the general formula (48), an aromatic core-nuclear substitution reaction or cross-linking is easily generated. The electron attracting substituent of the coupling reaction. That is, first, a compound of the general formula (42) and a compound of the general formula (9) are reacted in the same manner as in the production of the compound of the general formula (2) from the compound of the general formula (10), whereby a general formula can be produced. Compound of (43). Next, for the compound of the general formula (43), Y1 is converted to Y2, and a compound of the general formula (44) can be produced by appropriately performing an operation of deprotecting the protective group PG2 and introducing it into Y3. Thereafter, a compound of the general formula (44) can be subjected to a suitable cyclization reaction to produce a compound of the general formula (45), -157-200948817. The compound of the general formula (45) is via the general formula (2) by the same method as described so far. a compound which can be directed to a compound of general formula (I). As a suitable cyclization reaction for directing the compound of the general formula (44) to the compound of the general formula (45), for example, an etherification reaction, an esterification reaction, a guanidation reaction, a urethanization reaction, a urea reaction reaction may be mentioned. , Amination reaction, reduced amination reaction, methanoling reaction, Mannich reaction, Knoevenagel reaction, Dieckmann cyclization reaction, other carbon-carbon binding reaction, Fittig reaction, Horner-Emmons reaction, Peterson reaction, Grignard reaction Other Barbier type reactions, Reformatsky reactions, Baylis-Hillman reactions, cross-linking coupling reactions, metathesis reactions, etc., each of which reacts with etherification: Advanced Organic Chemistry '5th edition (Michael B. Smith and Jerry March), 477~482, 996~997, 1180~1183, 2001, John Wiley & Sons, Inc. Publishing; Esterification: Ibid., pp. 482-490, 997~998 ; amidation reaction: ibid, pp. 506~514, 1001~1002; carbamate reaction: ibid., 482~493, 1182~1183 page: urealation reaction: ibid., 1191; amination reaction: ibid., pp. 499~5 05; reduction of amination reaction: ibid., pp. 1187~1189; aldol reaction: ibid., pp. 1218~1224; Mannich reaction: ibid., 1189 ~ 1191; Dieckmann cyclization: ibid., pp. 569-571; Knoevenagel reaction: ibid., pp. 1225~1228; other carbon-carbon binding reactions: ibid., pp. 536-573; Michael addition reaction : ibid., 996~1002, 1 022 ～1 030 pages; Baylis-Hillman reaction: ibid., p. 1212; Fittig reaction, Horner- Emmons reaction: ibid., pp. 1231~1237; Peterson reaction: ibid., 1228~ 1229 pages; Grignard anti-158- 200948817 should, other Barbier type reactions: ibid., pp. 1 20 5~1211; Reformatsky reaction: ibid., p. 1212; cross-linking coupling reaction: Metal-Catalyzed Cross-Coupling Reactions, Volume 1, Volume 2, Second Edition (Armin de meijere et al., 2004, WILEY-VCH VerlagGmbH &Co.KGaA; Translocation Reaction: Angewante Chemie International Edition of English, Vol. 44, No. 4490-4527, 200 5 years, etc., or according to its method. Further, in the same manner as in the production of the compound of the general formula (43) from the compound of the general formula (42) and the chemical compound of the general formula (9), the compound of the general formula (42) and the general formula (12) can be used. A compound of the general formula (46), which is obtained from a compound of the formula (43), a compound of the general formula (44), a compound of the general formula (45), a compound of the general formula (2), In the same manner as the compound of the general formula (I), a compound of the general formula (I) can be produced from a compound of the general formula (46) via a compound of the general formula (47) or a compound of the general formula (4). Further, when A1 is a carbon atom which may be substituted, the compound of the general formula (30) is the same as the compound of the general formula (31), and the compound of the general formula (42) and the general formula are The compound of the formula (48) is produced from the compound of the general formula (49), and the compound of the general formula (43), the compound of the general formula (44), the compound of the general formula (45), the compound of the general formula (2), The general formula (I) can be produced by the same method as the compound of the general formula (I), from the compound of the formula (49), via the compound of the general formula (50), or the compound of the formula (31). Compound. When the compound of the general formula (I) of the present invention has a basic group such as an amine group, when it reacts with an acid or has an acidic group such as a carboxyl group, -159-200948817 can be reacted by reacting with a base. salt. Examples of the salt of the basic group include a mineral acid such as a hydrochloride, a hydrogen bromide or an iodide gas salt such as a hydrogen halide, a nitrate, a perchlorate, a sulfate or a phosphate. a salt; a lower alkane sulfonate such as a methanesulfonate, a trifluoromethanesulfonate or an ethanesulfonate, an arylsulfonate such as a besylate or a p-toluenesulfonate, an acetate, or an apple Acid salt, fumarate, succinate,

An organic acid salt of citrate, ascorbate, tartrate, oxalate, maleate, or the like; or glycinate, a persalt, arginine, alanate, glutamic acid Amino acid salts such as salts and aspartame. Further, the acid group-based salt may, for example, be an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt; a metal salt such as a bauxite metal salt such as a calcium salt or a magnesium salt; an aluminum salt or an iron salt; Inorganic salt of ammonium salt or the like, t-octylamine salt, dibenzylamine salt, morpholin salt, glucosamine salt, alkyl phenylglycine salt, ethylenediamine salt, N-methyl glucose Amine salt, sulfonium salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-diethylenediamine salt, chloroprocaine salt, proca An amine sulfonium salt such as an organic salt such as a salt, a diethanolamine salt, an N-benzylphenethylamine salt, a piperidine salt, a tetramethylammonium salt or a hydroxymethylaminomethane salt; or a glycine Amino acid salts of acid salts, ammonium sebacates, arginine salts, alanine salts, glutamine salts, aspartates, and the like. When the compound of the general formula (I) of the present invention or a salt thereof has an asymmetric carbon atom in the molecule, there are stereoisomers which are R-coordinated and S-coordinated, and each of them, or any ratio thereof Any of the compounds are included in the present invention. These stereoisomers can be optically divided, for example, by synthesizing the compound (I) using an optically divided starting compound or by subjecting the synthesized compound (I) to a desired optical division or separation method as desired. -160- 200948817 Any of the compounds of the general formula (I) of the present invention or a salt thereof, which are optically foreign, each of the optical isomers and a mixture of such optical isomers are included in the present invention. The compound of the general formula (I) of the present invention or a salt thereof, which is placed in the atmosphere or recrystallized, absorbs water, has sorbed water, or becomes a hydrate, and such aqueous compounds and salts are also It is included in the present invention. The compound (I) of the present invention can be used as a medicine for humans, animals, fish, etc., or as a preservative for pesticides and foods because of its strong antibacterial activity and high safety. When the compound (I) of the present invention is used as a medicine, the administration amount varies depending on the age, sex, symptoms, and the like of the patient, and it is more preferable that the adult is from 5 Omg to lg '100 mg to 80 mg per day. In addition, the dosage for use as an animal varies depending on the purpose and purpose, the size of the animal to be treated, the type of pathogen to be infected, and the degree of the day. Generally, it is 1 mg to 200 mg, 5 mg to 100 mg per lkg of animal body weight. For better. The amount of this day is once a day, or divided into 2 to 4 times. Also, the amount of one day may exceed the above amount as necessary. The pharmaceutical of the present invention contains the compound (I), a salt thereof or the like of the present invention as an active ingredient, and the administration form thereof is not particularly limited and may be appropriately selected, and for example, it may be a tablet, a powder, a granule or a capsule. Oral solids for liquid preparations, solutions, syrups, elixirs, oily or aqueous suspensions, liquid preparations, non-oral preparations for injections, suppositories, etc.; fine granulated powders, liquid aerosols, etc. Inhalation agent: any of an external preparation, an eye drop, a patch, and the like. These administration forms can be formulated in accordance with a pharmaceutically acceptable carrier, in a modulation method of various preparations which are usually used. The solid preparation may contain the compound (I) and a pharmaceutically acceptable carrier as the carrier, and examples thereof include a sputum-containing agent, a bulking agent-161-200948817, a binding agent, and a crinkling agent. , solution accelerators, wetting agents, lubricants, and the like. Examples of the liquid preparation include a solution, a suspension, an emulsion, and the like, and a suspension agent, an emulsifier, or the like may be contained as an additive. As an injection, a stabilizer, a preservative, a solution adjuvant, or the like may be used in the preparation, and a solution containing a solution containing such an adjuvant may be stored in a container and then freeze-dried or the like as a solid preparation, and may be used as a preparation prepared at the time of use. . Further, a single dose can be stored in the container, and the multiple dose can be stored in the same container. Examples of the external preparation include a solution, a suspension, an emulsion, an ointment, a gel, a cream, a lotion, a spray, and the like. The pharmaceutical composition of the present invention may contain, in addition to the compound (I) of the present invention, an antibacterial agent selected from other clinically useful antibacterial agents (for example, a macrocyclic ring, a quinolinone system, a β-endoyamine, or an amine group). A known drug of one or more of a sugar system), and/or other anti-infective drug substance (for example, an antifungal triazole or an amphotericin), or may be administered together with such a drug. As above

The known drug can be a carbapenem which is widely used for therapeutic purposes, and for example, meropenem or imipenem can be mentioned. Further, in order to improve the activity against Gram-negative bacteria and the bacterial resistance to an antibacterial agent, the compound of the present invention may contain a bactericidal transdermal protein (BPI) product or a discharge pump inhibitor, or may be administered together with such a drug. versus. The present invention will be described in further detail below with reference to the examples and examples, but the invention is not limited thereto. EXAMPLES [Reference Example 1] 3-(hydroxymethylene)tetrahydropyran-2-one sodium salt -162- 200948817

Sodium hydride (oily, containing 60%, 14.48g, under nitrogen atmosphere)

0.3 6 mol) was washed with η-hexane, suspended in dehydrated ether (360 mL), and ice-cooled. δ-valerolactone (24.96 g, 0-25 mol) and ethyl formate (27.75 g, 0.37) were added dropwise over 2 hours and 45 minutes. A mixture of mol) was added thereto, followed by stirring at room temperature. One hour and 30 minutes after the start of stirring at room temperature, the reaction solution was solidified by precipitation of crystals, and dehydrated ether (360 mL) was added thereto, followed by stirring for 40 minutes. Then, after stirring overnight at 4 ° C, the volatiles were evaporated under reduced pressure to give a crude compound (29. 1H-NMR (3 00MHz, CD3OD) 5: 1.73-1.79 (2Hm), 2.32 (2H, t, J = 6.4 Hz), 4.12 (2H, t, J = 5.1 Hz), 8.91 (lH, s).

[Reference Example 2] 3 - {[(4-Methoxyphenyl)amino]methylene}tetrahydropyran-2-one

A suspension of crude 3-(hydroxymethylene)tetrahydropyran-2-one sodium salt (28.7 g) obtained in Reference Example 1 in ethanol (880 mL) was added with p-anisamine hydrochloride (36.0) g, 〇. 22 mol), stirred at 70 ° C for 2 hours. After the reaction was stopped, it was directly filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride (yield, washed with 1N hydrochloric acid and brine, and dried over anhydrous magnesium sulfate). The resulting solid was added to the obtained crude product to give a solid, y-hexanes - 163 - 200948817, to afford 25.18 g (44%) of the compound as a brown solid. 1H-NMR (300MHz, CDCl3) 8: 1.94-2.02 (2H, m), 2.4 1 (2H, td, J = 6.6, 1.7 Hz), 3.79 (3H, s), 4.28 (2H, t, J = 5.2 Hz), 6.26 (lH, d, J = 13 • 9 Hz), 6.82-6.98 (4H, m), 8.07 (lH, dt, J = 13.9, 1.7 Hz), MS (FAB) m/z: 234 (M + H) + .

[Reference Example 3] 4-chloro-3-(3-chloropropyl)-6-methoxyquinoline

To the 3-{[(4-methoxyphenyl)amino]methylene}tetrahydropyran-2-one (5.00 g, 21 mmol) obtained in Reference Example 2, was added hydrazine chloride (21 mL). , reflux for 2 hours. The ice-cold reaction solution was poured into ice and heated to boiling. The resulting black insoluble matter was filtered and the filtrate was cooled to 〇 ° C. The precipitated solid was filtered, and recrystallized from ether and water to give the title compound as a brown solid. 3.93 g ( 68% ) 〇

1H-NMR (300MHz, CDCl3) 6: 2.14 - 2.23 (2H, m), 3.11 Q (2H, t, J = 7.5 Hz), 3.60 (2H, t, J = 6.4 Hz), 3.98 (3H, s) , 7.3 6 (lH, dd, J = 9.1, 2.7 Hz), 7.45 (lH, d, J = 2_7 Hz), 7.98 (lH, d, J = 9.1 Hz), 8.61 (l H, s). MS (FAB m/z: 270, 27 1,272 (M + H) + .

[Reference Example 4] (trans-4-{[3-(4-chloro-6-methoxyquinolin-3-yl)propylamino]methyl}cyclohexyl)carbamic acid benzyl ester-164 - 200948817

4-Chloro-3-(3-chloropropyl)-6-methoxyquinoline (200 mg, 〇.74 mmol) obtained in Reference Example 3 [trans-4-(aminomethyl) ring] Hexyl] carboxylic acid benzyl ester (described in J〇urnal 〇f medicinal chemistry, 1997, 40 volumes, 11 '1565-1569 pages, 194 mg, 0.74 mmol), potassium carbonate (225 mg, 1.63 mmol), potassium iodide (123 mg) , 0.74 mmol) of a solution of 0 N,N-dimethylformamide (4 mL) was warmed at 40 ° C. N,N-dimethylformamide was evaporated under reduced pressure, and the residue was evaporated to ethyl acetate. The obtained residue was purified by EtOAcjjjjjjjjjjj lH-NMR (400MHz, CDC13) 5: 0.96-1.17 (4H, m), 1.40 (1 H, brs), 1.8 1-1.93 (4H, m), 2.04 (2H, d, J = 10.7 Hz), 2.46 (2H,d,J = 6.6Hz), 2.69(2H,t,J = 7.1Hz), 2.98(2H,t,J = 7.7Hz), 3.46(lH,brs) 〇,3_98(3H,s), 4.5 9 (lH, brs), 5.08 (2H, s), 7.28-7.36 (6H, m), 7.46 (1 H, d, J = 2.7 Hz), 7.97 (1 H, d, J = 9.0 Hz), 8.59 ( lH, s). MS (ESI) m/z: 495 (M + H) + .

[Reference Example 5] {trans- 4-[(9-methoxy-3,4-dihydro-2H-benzo[h][l,6]naphthyridin-1-yl)methyl]cyclohexyl }Benzyl carbamic acid ester 200948817 The (trans-4-{[3-(4-chloro-6-methoxyquinolin-3-yl)propylamino]methyl} ring obtained in Reference Example 4 A solution of benzyl benzyl carbamate (113 mg '0.23 mmol) in N,N-dimethylacetamide (5 mL) was stirred at 140 ° C overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous sodium sulfate and brine. The obtained residue was purified by silica gel column chromatography (chloroform:methanol = 50:1 - 10:1) to afford the title compound (5 mg) as a pale brown solid. 1H-NMR (400MHz, CDC13) 6: 1.12-1.29 (4H, m), 1.77-1.95 (3H, m), 2.00-2.09 (2H, m), 2.08-2.18 (2H, m), 2.86 (2H , t, J = 6.5 Hz), 3.07 (2H, d, J = 7.3 Hz), 3.25-3.27 (2H, m), 3.50 (lH, brs), 3.91 (3H, s), 4.55-4.67 (lH, m), 5.10 (2H, s), 7.22-7.39 (7H, m), 7.8 9 (lH, d, J = 9.0 Hz), 8.34 (lH, s). MS (ESI) m/z: 460 (M + H)+.

[Example l] 6-[({trans-4-[(9-methoxy-3,4-dihydrobenzo[h][l,6]naphthyridin-1 (2H)-yl)) Cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l,4]indole-3( 4H )-one

{trans-4-[(9-methoxy-3,4-dihydro-2H-benzo[h][l,6]naphthyridin-1-yl)methyl] obtained in Reference Example 5] Cyclohexyl}benzyl carbamate (128 mg, 0.279 mmol) was dissolved in methanol (5 mL) and 1N hydrochloric acid (0.56 mL), and 10% palladium carbon catalyst (M, containing about 50% water, 60 mg) was added here. Catalytic hydrogenation was carried out for 1 hour at room temperature. After filtering the catalyst, decompression -166- 200948817 concentrated the filtrate. The obtained residue was dissolved in dichloromethane (2.5 mL), and then 3-tris-oxy-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-formaldehyde was added. (described in International Publication No. 2006/032466, etc., 50 mg, 0.28 mmol), triethylamine (77 pL, 0.56 mmol), sodium cyanoborohydride (_20.2 mg, 0.31 mmol), and acetic acid (16 μί '0.28 mmol) Stir overnight at room temperature. A 10% aqueous sodium carbonate solution was added to the reaction mixture, and the organic layer was extracted with chloroform, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography (chlorobenzene): methanol = 10:1 - chloroform:methanol: triethylamine = 10: 1: 0.1) to give the title compound 77 mg ( 68 % ) . 1H-NMR (400MHz, CDC13) 6: 1.04-1.3 1 (4H, m), 1.84-1.97 (3 H, m), 1.97-2. ll (4H, m), 2.36 (1 H, s), 2.44 -2.54 (1 H, m), 2.86 (2H, t, J = 6.5 Hz), 3.08 (2H, d, J = 7.3 Hz), 3.27-3.29 (2H, m), 3.83 (2H, s), 3.90 (3H, s), 4.64 (2H, s), 6.92 (lH, d, J = 8.1 Hz), 7.16-7.27 (2H, m), 7_32 (1H, d, J = 2.7 Hz), 7.89 (lH, d, J = 9_3 Hz), 8.34 (1H, s). MS (ESI) m/z: 48 8 (M + H) + . 0 [Reference Example 6] 2-[(6-methoxyquinoline- 4-yl)amino]ethanol

CI 4_Chloro-6-methoxyquinoline (described in Bioorganic & Medicinal Chemistry Letters * 2006, 16 volumes '20' 5 3 84-5 3 8 8 pages, 20'0g, 0.103 mol) The mixture was stirred with heating at 120 ° C for 17 hours in 2-aminoethanol (100 mL). The solvent was distilled off under reduced pressure. The residue was dissolved in chloroform: -167 - 200948817 Methanol: Water = 20: 3 : 1 The solvent of the lower layer was washed with water. After drying over anhydrous sodium sulfate, the solvent was evaporated. 1H-NMR (400MHz, CDC13) 6: 3.52 (2H, q, J = 5.3 Hz), 3.94 (3H, s), 4.03 (2H, t, J = 5.3 Hz), 5.16 (lH, brs), 6.45 ( lH,d,J = 5.4 Hz), 6.99 (lH,d,J = 2.7 Hz), 7.3 1 (lH, dd, J = 9.2, 2.8 Hz), 7.92 (lH, d, J = 9.3 Hz), 8.46 (lH,d,J = 5.1 Hz). MS (ESI) m/z: 2 19 (M + H) + .

[Reference Example 7] 2-[(3-Bromo-6-methoxyquinolin-4-yl)amino]ethanol

2-[(6-Methoxyquinolin-4-yl)amino]ethanol (18.94 g, 86.8 mmol) obtained in Reference Example 6 was dissolved in acetic acid (190 mL), and bromine (4.45 mL, 8 6.9 mmol) was stirred for 8 hours. The solvent was distilled off under reduced pressure, and water was added, and then a 5N aqueous sodium hydroxide solution was added to make the mixture. The extract was extracted with a solvent of chloroform:methanol:water = 7:3:1 and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, it was suspended in ethyl acetate-hexane and stirred at 40 ° C. After standing at room temperature, the solid was filtered to give the title compound 23.29g (90%) " 1H-NMR (400 MHz, CDCl3) 5: 3.73 - 3.67 (2H, m), 3.86 (2H, t, J = 5.0 Hz), 3.93 (3H, s), 4.89 (lH, s), 7.32 (lH, dd, J = 9.3, 2.4 Hz), 7.38 (lH, d, J = 2.9 Hz), 7.9 2 (lH , d, J = 9.0 Hz), 8.61 (lH, s). MS (ESI) m/z: 297, 299 (M + H) + . -168 - 200948817 [Reference Example 8] 9-methoxy-2,3 -dihydro-1H-[1,4]indole and [2,3-c]quinoline

2-[(3-Bromomethoxysin-4-yl)amino]ethanol (22.30 g, 75.1 mmol) obtained in Reference Example 7 was dissolved in N,N-dimethylformamide (250 mL) A third-stage potassium butoxide (12.63 g, 112.6 mmol) was added under ice cooling, and stirred at 160 ° C for 13 hours. The solvent was evaporated under reduced pressure. After drying over anhydrous sodium sulfate, the solvent was evaporated, evaporated, mjjjjjjj 1H-NMR (400MHz, CDCl3) 6: 3.66-3.70 (2H, m), 3.92 (3H, s), 4.3 3 (2H, t, J = 4.4 Hz), 4.5 9 (lH5brs), 6.83 (lH, d , J = 2.7 Hz), 7.19 (l H, dd, J = 9.3, 2.7 Hz), 7.87 (lH, d, J = 9.0 Hz), 8.3 1 (lH, s). MS (ESI) m/z: 2 1 7(M + H)+.

[Reference Example 9] {trans-4-[(9-methoxy-2,3-dihydro-1H·[1,4]噚耕〇[2,3-c]quinolin-1-yl )methyl]cyclohexyl}aminecarboxylic acid tert-butyl ester

The -methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]saline (200 mg, 0.925 mmol) obtained in Reference Example 8 were dissolved in N,N- Dimethylformamide (10 mL) was added with sodium hydride (oily, containing 55%, 80.7 mg, 1.85 mmol) under ice-cooling, and stirred at room temperature for 25 min. Add [trans-4-(iodomethyl)-169-200948817 cyclohexyl]aminecarboxylic acid tert-butyl ester (described in International Publication No. 2008/078305, etc., 377 mg, l.llmmol), and warm to room Stir for 24 hours while warming. Ethyl acetate was added, and the mixture was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and purified mjjjjjjjjjjjjj NMR (400MHz, CDC13) 6: 1.03- 1.33 (6H, m), 1.46 (9H, s), 2.09-2.18 (4H, m), 2.98 (2H, d, J = 7.3 Hz), 3.27 (2H, t , J = 4.4 Hz), 3.9 1 (3H, s), 4.22 (2H, t, J = 4.4 Hz), 4.43 (lH, brs), 7.16 (lH, dd, J = 9. 2, 2.8 Hz), 7.25-7.27(lH,m), 7.89 (lH,d,J = 9.3 Hz), 8.37 (lH, s). MS (ESI) m/z: 428 (M + H) + .

[Reference Example 10] trans-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl) A Cyclohexylamine

{trans-4-[(9-methoxy-2,3-dihydro-1Η·[1,4]indolo[2,3-c]quinolin-1-) obtained in Reference Example 9. The third methyl butyl ester of methyl]cyclohexyl}aminecarboxylate (145.6 mg, 0.341 mmol) was dissolved in dichloromethane (5 mL), and the mixture was stirred for 2 hr. After distilling off the solvent under reduced pressure, a saturated aqueous solution of sodium hydrogencarbon It was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give EtOAc (EtOAc: EtOAc: 1H-NMR (400MHz, CDC13) 5: 1.16-1.29 (4H, m), 1.39-1.65 (2 -170- 200948817 Η, m), 1.78-1.89 (1H, m), 1.95-2.02 (2H, m) , 2.08-2.15(2H,m), 2.6 7-2.76(1 H,m), 2.9 8 (2H,d,J = 7.3Hz), 3.2 8 (2H,t,J = 4.4Hz), 3.92 ( 3H , s), 4.22 (2H, t > J = 4.4 Hz), 7.16 (lH, dd, J = 9.0, 2.7 Hz), 7.29 (lH, d, J = 2.7 Hz), 7.89 (lH, d, J = 9.0 Hz), 8.38 (lH, s).

[Example 2] 6-[({trans-4-[(9.methoxy-2,3-dihydro-1H-[1,4]indolo[2,3-c]quinoline- 1-yl)methyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l,4]indole-3(4H) ketone

The trans-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl group obtained in Reference Example 10 was obtained. )methyl]cyclohexaneamine (46.8 mg, 0.143 〇11!1〇1), 3-sided oxy-3,4-dihydro-211-pyrido[3,2-15][1,4]噚.-6-formaldehyde (described in International Publication No. 2006/032466, etc., 28.0 mg, 0.15 7 mmol) was suspended in methanol: dichloromethane = 1: 1 mixed solvent (2 mL), and acetic acid (〇.〇12 mL) was added under ice cooling. , 0.215 mmol), sodium cyanoborohydride (10.4 mg, 0.157 mmol), and stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and then dissolved in chloroform:methanol: water = 7 : 3 : 1 solvent, and washed with water. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (chloroform: methanol: water = 20:3:1). The obtained crude was triturated with dichloromethane (hexane). 1H-NMR (400MHz, CDC13) 6: 1.13-1.40 (4H, m), 1.89 (lH, m), 2.13 (4H, m), 2.59 (lH, m), 2.98 (2H, d, J = 7.1 Hz ), 3.28 (2H, t, J = 4. -171 - 200948817 2Hz), 3.8 8(2H, s), 3.9 1(3H, s), 4.22 (2H, t, J = 4.3Hz), 4.6 5( 2H, s), 6.95 (lH, d, J = 8.1 Hz), 7.16 (lH, dd, J = 9.0, 2.7 Hz), 7.22 (lH, d, J = 8 • lHz), 7_28 (lH, d, J = 2.7 Hz), 7.89 (lH, d, J = 9.3 Hz), 8.38 (lH, s). MS (ESI) m/z: 490 (M + H) + .

[Reference Example 11] 1-[(6-Methoxyquinolin-4-yl)amino]propan-2-ol

4-Chloro-6-methoxy porphyrin (described in Bioorganic & Medicinal Chemistry Letters, 2006, Vol. 16, No. 20, 5 3 84-53 88 pages > UOg, 5.16 mmol) was suspended in (± 1-Amino-2-propanol (2 mL) was stirred at 120 ° C for 3 days. After distilling off the solvent under reduced pressure, the solvent was dissolved in chloroform:methanol: water = 20:3:1, and washed with water. After drying over anhydrous sodium sulfate, the solvent was evaporated. !H-NMR (400 MHz > CDC13) 6: 1.38 (3Η»d> J = 6.4 Hz) > 3^4-3.22 (1H, m), 3.37-3.45 (1H, m), 3.84-3.87 (3H, m), 4.19-4.28 ( 1H, m), 5.30 ( 1H, brs), 6.32 - 6.36 ( 1H, m), 6.91-6.93 ( 1H, m), 7.23 - 7.27 ( 1H, m), 7.85 - 7.90 ( 1H, m ) ' 8.3 5-8.39 ( 1 H,m ).

[Reference Example 12] 1-[(3-Bromo-6-methoxyquinolyl)amino]propan-2-ol

-172- 200948817 1-[(6-Methoxyquinolin-4-yl)amino]propan-2-ol (1.25 g, 5.16 mmol) obtained in Reference Example 11 was dissolved in acetic acid (lOrnL), ice cold Bromine (〇.276 mL, 5.38 mmol) was added and stirred for 18 hours. Further, bromine (0.276 mL, 5.38 mmol) was added and stirred for 24 hours, and bromine (0.552 mL, 10·76 ηηηη1) was added and stirred for 6 hours, and then the solvent was evaporated under reduced pressure. The residue was suspended in water. After adding 5 NaOH aqueous solution to make a solution under ice cooling, the mixture was extracted with a solvent of chloroform:methanol:water = 20:3:1. After drying over anhydrous sodium sulfate, the solvent was evaporated to dryness crystalljjjjjjjjjjjjjj 1H-NMR (40 〇MHz, CDC13) 6: 1.28 (3H, dd, J = 6.4, l · 5 Ηζ), 2.12 (lHsbrs), 3.3 8-3.46 (lH, m), 3.57-3.65 (lH, m ), 3.93-3.94 (3Η, m), 4.0 1- 4.1 〇(ιη,m), 4.89-4.96(1 Η,m) , 7.30-7.35 (lH,m),7.37-7.40(lH,m), 7.9 0-7.94 (lH, m), 8.61 - 8.62 (1H, m). MS (ESI) m/z: 3 11 (M + H) + .

[Reference Example 13] 9·methoxy-3_methyl-23_dihydroindole cultivating [2,3.c] quinoline

1-[(3-Bromo-6-methoxyquinolin-4-yl)amino]propan-2-ol (728 mg, 2.34 mmol) obtained in Reference Example 12 was dissolved in hydrazine, hydrazine-dimethyl Methionamine (1 〇 mL) was added to a third-stage potassium butoxide (394 mg, 3.5 1 mmol) under ice cooling. The mixture was stirred at 23 ° for 23 hours. After distilling off the solvent under reduced pressure, hydrazine was dissolved in anhydrous residue. The chloromethane was washed with a saturated aqueous solution of sodium hydrogencarbonate - 173 - 200948817. After drying over sodium sulfate, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (chloroform, methanol) to afford the title compound 268.3 50%) 1H-NMR (400 MHz, CDCl3) 8: 1.46 (3H, d, J = 6.3 Hz), 3.28-3.3 5 (lH, m), 3.61-3.67 (lH, m), 3.92 (3H, s), 4.22-4.30 (1 H, m), 4.59 (lH, brs), 6.83 (lH, d, J = 2.7 Hz), 7.19 (lH, dd, J = 9.3, 2.7 Hz), 7 • 87 ( lH,d,J = 9.3 Hz), 8.31 (lH, s). MS (ESI) m/z: 23 1 (M + H)+.

[Reference Example 14] {trans-4-[(9.methoxy-3-methyl-2,3-dihydro-1H-[1,4] indole [2,3-c]quinoline -1-yl)methyl]cyclohexyl}aminecarboxylic acid tert-butyl ester

9-Methoxy-3-methyl-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinoline (268 mg, 1.17 mmol) obtained in Reference Example 13 It was dissolved in N,N-dimethylformamide (3 mL), and sodium hydride (oily, containing 55%, 102 mg, 2.34 mmol) was added under ice cooling for 1 hour. Addition of [trans-4-(iodomethyl)cyclohexyl]aminecarboxylic acid tert-butyl ester (described in International Publication No. 2008/078305, etc., 476 mg, 1.40 mmol) of N,N-dimethylformamidine The amine (3 mL) solution was stirred for 16 hours while warming to room temperature. Add chloroform:methanol:water = 20:3: 1 underlayer solvent, wash with water. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (chloroform, methanol) to afford 54.4 mg (11%) as a thin orange foam. 1H-NMR (400 MHz, CDC13) 5: 1.19 (3H, m), 1.42-1.49 (1 3H, m -174 - 200948817 ), 1.76-1.87 (2H, m), 2.08-2.23 (2H, m) , 2.39-2.47 (lH, m), 2.71-2.79 (2H, m), 3.21-3.29 (lH, m), 3.30-3.36 (lH, m), 3.48 (lH, brs), 3.91 (3H, s) , 4.11-4.20 (lH, m), 4.41-4.48 (lH, m), 7.16 (lH5dd, J = 9.052.7 Hz), 7.24 (lH, d, J = 2.7 Hz), 7.88 (lH, d, J = 9 .OHz), 8.38 (lH, s). MS (ESI) m/z: 44 2 (M + H)+.

[Reference Example 15] trans- 4- [(9-methoxy-3-methyl-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline- 1-yl)methyl]cyclohexaneamine

The {trans-4-[(9.methoxy-3-methyl-2,3-dihydro-1H-[1,4]噚[[,3,3-c]] obtained in Reference Example 14 The quinolin-1-yl)methyl]cyclohexyl}aminecarboxylic acid tert-butyl ester (54.4 mg, 0.123 mmol) was dissolved in dichloromethane (3 mL), and then trifluoroacetic acid (5. ·5 hours. After distilling off the solvent under reduced pressure, a saturated aqueous solution of sodium hydrogencarbonate was added under ice cooling to give basicity. The mixture was extracted with a solvent of chloroform:methanol:water = 20:3:1 and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 44.9 mg (yield) of the title compound as an orange oil. *H-NM R (400MHz, CDC13) 6: 1.03-1.38 (5H, m), 1.45 (3H, d, J = 6.3Hz), 1.77-1.88 (2H, m), l .92-2.05 (2H, m), 2.31-2.41 (lH, m), 2.65-2.81 (4H, m), 3.24 (lH, m), 3.34 (lH, m), 3.91 (3H, s), 4.10-4.20 (1H, m) , 7.15 (1H, dd, J = 9.0, 2.7 Hz), 7.26-7.29 (lH, m), 7.88 (lH, d, J = 9.3 Hz), 8.38 (lH, s). -175- 200948817 [Examples 3]6-[({trans-4-[(9-methoxy-3-methyl- 2,3-dihydro-1H-[1,4] Pf哄[2,3-c] quin啉-1-yl)methyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-15][1,4]indole-3(41〇-ketone

The trans-4-[(9-methoxy-3-methyl-2,3·dihydro-1H-[1,4]indole[2,3-c]quina obtained in Reference Example 15 will be obtained. Polin-1-yl)methyl]cyclohexaneamine (4 4.9 mg, 0.13 1 mmol), 3-sided oxy-3,4-dihydro-2-indole-indolepyridin[3,2-b][l 4) 噚耕-6-formaldehyde (described in International Publication No. 2006/032466, etc., 25.8 mg, 0.145 mmol) suspended in methanol: dichlorocarbazine = 1: 1 mixed solvent (4 mL), and acetic acid was added under ice cooling ( O. OllmL, 0.197 mmol), sodium cyanoborohydride (9.6 mg, 0.145 mmol). After distilling off the solvent under reduced pressure, the solvent was dissolved in chloroform:methanol:water = 20:3:1 and washed with saturated aqueous sodium hydrogen carbonate. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (chloroform:methanol:water=20:3:1). The resulting crude was triturated with ether-hexanes to give a white solid. <RTI ID=0.0>>>>> ,d,J = 6.1Hz), 1.79-2.1 9(6H,m),2.3 8(lH,m),2.5 5(lH,m),2.7 l-2.80(2H,m),3.21-3.27(lH , m), 3.34 (lH, m), 3.86 (2H, s), 3.91 (3H, s), 4.14 (lH, m), 4.65 (2H, s), 6.94 (lH, d, J = 8.3 Hz) , 7.16 (lH, dd, J = 9.2, 2.8 Hz) > 7.22 (lH, d, J = 7.8 Hz), 7.28-7.26 (lH, m) #7.89 (1 H, d, J = 9.3 Hz), 8.3 8 (lH, d, J = 3.4 Hz) · -176- 200948817 MS (ESI) m/z: 504 (M + H) + .

[Reference Example 16] 2-[(6-Methoxyquinolin-4-yl)amino]propan-1-ol

4- 4-Chloro-6-methoxyquinoline (described in Bioorganic & Medicinal Chemistry Letters, 2006, Vol. 16, No. 20, 53 84-53 88 pages > l.OOg, 5.16 mmol) was suspended in ( DL)-2-Amino-1-propanol (2 mL) was stirred at 120 ° C for 24 hours and at 160 ° C for 4 hours. After distilling off the solvent under reduced pressure, the solvent was dissolved in chloroform:methanol:water=7:3:1, and washed with water. After drying over anhydrous sodium sulfate, the solvent was evaporated. 1H-NMR (400MHz, CDCl3) 6: 1.37 (3H, d, J = 6.4Hz), 3.74-3.9 4(7H,m), 4_8 6-4.9 l(lH,m),6.43-6.47( lH, Brm), 6.94 (1 H, s), 7.27-7.32 (1 H, m), 7.90 (1 H, d, J = 9.0 Hz), 8.40-8.44 (1 H, m). MS (ESI) m/ z: 233 (M + H) + .

[Reference Example 17] 2-[(3-Bromo-6-methoxyquinolin-4-yl)amino]propan-1-ol

2-[(6-Methoxyquinolin-4-yl)amino]propan-1-ol (1.142 g ' 4.92 mmol) obtained in Reference Example 16 was dissolved in acetic acid (10 mL), and br. 〇.265 mL, 5.17 mmol) was stirred for 18 hours. Further, bromine (〇.265 mL, 5.17 mmol) was added and stirred for 6 hours, and then the solvent was evaporated under reduced pressure. -177- 200948817 Suspension in water, adding 5N aqueous sodium hydroxide solution to make it alkaline under ice cooling, and extracting with a solvent of chloroform:methanol:water = 7:3:1. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (chloroform:methanol = 1 :1) to afford 1.25 4 g (82%) as a tan solid. 1H-NMR (40 〇 MHz, CDCl3) 5: 1.24 (3H, d, J = 6.4 Hz), 2.33 (lH, brs), 3.65 (lH, dd, J = 11.2, 7.1 Hz) 53.78 (lH, dd, J = 11.2, 4.2 Hz), 3.93 (3H, s), 4.02-4.12 (lH, m), 4.34 (lH, d, J = 10.7 Hz), 7.3 2 (lH, dd, J = 9.2, 2.3 Hz) ), 7.48 (lH, d, J = 2.7 Hz), 7.92 (lH, d, J = 9.0 Hz), 8.64 (lH, s). MS (ESI) m/z: 3 11 (M + H) + .

[Reference Example 18] 9-methoxy-2-methyl-2,3-dihydro-1H-[1,4]indole[2,3-c]

2-[(3-Bromo-6-methoxyquinolin-4-yl)amino]propan-1-ol (887.1 mg, 2.85 mmol) obtained in Reference Example 17 under a nitrogen atmosphere, (dibenzylideneacetone) dipalladium (79 mg, 0.086 mmol), 2-di-tertiary butyl squam-2'-(1^,;^-dimethylamino)biphenyl (34.111^, 0.100111111〇1), carbonic acid planer (1.39 g, 4.28 mmol) was suspended in toluene (50 mL), warmed at 100 ° C and stirred for 7 days. The solvent was distilled off under reduced pressure, and then dissolved in dichloromethane and washed with water. After drying over anhydrous sodium sulfate, the solvent was evaporated, evaporated, mjjjjjjj 1H-NMR (400MHz, CDCl3) 6: 1.37 (3H, d, J = 6.1 Hz), 3.74-3.8 6 (2H, m), 3.94 (3H, s), 4.29-4.34 (lH, m), 4.57 ( lH, br s), 6.86 - 178- 200948817 (lH, d, J = 2.7 Hz), 7.19 (lH, dd, J = 9.3, 2.7 Hz), 7.87 (lH, d, J = 9.3 Hz), 8.30 ( 1 H, s). MS (ESI) m/z: 23 1 (M + H) + .

[Reference Example 19] {trans-4-[(9-methoxy-2-methyl-2,3-dihydro-1H-[1,4] indole [2,3-c] porphyrin] -1-yl)methyl]cyclohexyl}aminecarboxylic acid tert-butyl ester

9-Methoxy-2-methyl-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinoline (162.8 mg, 0.707 mmol) obtained in Reference Example 18. It was dissolved in N,N-dimethylformamide (3 mL), and sodium hydride (oily, 55%, 62 mg, 1.414 mmol) was added under ice cooling for 1 hour. Addition of [trans-4-(iodomethyl)cyclohexyl]aminecarboxylic acid tert-butyl ester (described in International Publication No. 2008/078305, etc., 288 mg, 0.848 mmol) of N,N-dimethylformamidine The amine (2 mL) solution was stirred for 22 hours while warming to room temperature. Add chloroform:methanol:water = 20:3: 1 underlayer solvent, wash with water. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (chloroform-methanol) to afford 78.2 mg (25%) 1H-NMR (400MHz, CDCl3) 6: 1.10-1.26 (6H, m), 1.40-1.49 (1 lH5m), 1.75-1.89 (2H, m), 2.07-2.23 (2H, m), 2.39-2.48 (lH , m), 2.61 (lH, dd, J = 14.2, 5.1 Hz), 3.29 (lH, m), 3.39 (lH, m), 3.43 - 3.52 (l H, m), 3.91 (3H, s) , 4.43 (lH, brs), 4.64 (lH, s), 7.16 (lH, dd, J = 9.0, 2.7 Hz), 7.26 (lH, s), 7.89 (lH, d, J = 9.0 Hz), 8.37 ( lH, s). MS (ESI) m/z: 442 (M + H) + . -179 - 200948817 [Reference Example 20] trans- 4-[(9-methoxy-2-methyl- 2, 3-dihydro-1H-[1,4]indolo[2,3-c]porphyrin-yl)methyl]cyclohexaneamine

The {trans-4-[(9-methoxy-2-methyl-2,3-dihydro-1Η·[1,4]噚[[3,3-c]] obtained in Reference Example 19 was obtained. The third butyl ester of quinoline-1-yl)methyl]cyclohexyl}aminecarboxylate (78.2 mg, 0.177 mmol) was dissolved in dichloromethane (3 mL). <3> hour. After distilling off the solvent under reduced pressure, a saturated aqueous solution of sodium hydrogencarbon The mixture was extracted with a solvent of chloroform:methanol:water = 20:3:1 and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 65.9mg (yield) of the compound as an orange oil. 1H-NMR (400MHz, CDC13) 5: 1.03 - 1.27 (8H, m), 1.30-1.41 (1H, m), 1.76-1.9 1 (2H, m), 1.93-2.07 (2H, m), 2.3 5-2.43(lH,m), 2.6 l(lH,m), 2.68-2.77(lH,m), 3.28(lH,m), 3.36-3.43(lH,m),3.92( 3H,s), 4.03-4.11(2H,m), 7.16(lH,dd,J = 9.2,2.8Hz), 7.29 (lH,d,J = 2.7Hz), 7.89(lH,d,J = 9.3Hz),8.3 8( lHss).

[Example 4] 6-[({trans-4-[(9-methoxy-2-methyl-2,3-dihydro-1H-[1,4] 噚 并[2,3- c]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-1)][1,4]噚耕-3(41〇-ketone

-180- 200948817

The trans-4-[(9-methoxy-2-methyl-2,3-dihydro-1Η-[1,4]噚[[,3-c] obtained in Reference Example 20 was obtained. Quinolin-1-yl)methyl]cyclohexaneamine (65.9 mg, 0.193 mmol), 3· sideoxy-3,4-dihydro-2H-pyrido[3,2-b][l,4 ] 曙 -6 -6 aldehyde (described in International Publication No. 2006/032466, etc., 37.8 mg, 0.212 mmol) was suspended in methanol: dichloromethane = 1: 1 mixed solvent (4 mL), and acetic acid (0.017 mL) was added under ice cooling. 0.290 mmol), sodium cyanoborohydride (14.0 mg, 0.212 mmol) was stirred at room temperature for 15 h. After distilling off the solvent under reduced pressure, the solvent was dissolved in chloroform:methanol:water = 20:3:1 and washed with water. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (chloroform:methanol: water = 20:3:1). The obtained crude was triturated with methylene chloride-ether, and the solid was filtered to afford 32.0 mg (31%) as a white solid. 1H-NMR (400MHz, CDC13) 6: 1.01-1.16 (4H, m), 1.20-2.25 (6H, m), 2.36-2.46 (lH, m), 2.55-2.67 (2H, m), 3.22- 3.33 (1H, m), 3.35-3.44 (1H, m), 3.80-3.83 (lH, m), 3.88-3.95 (5H, m), 4.01- 4.14 (2H, m), 4.62-4.69 (3H, m ), 6.96 ( lH, d, J = 8.1H z) , 7.11-7.30 (3H, m), 7.90 (l H, d, J = 9.0 Hz), 8.38 (1 H, s) · MS (ESI) m /z:504(M + H) + .

[Reference Example 21] 2-Chloro-N-(4-chloro-6-methoxyquinolin-3-yl)acetamide

4-Chloro-6-methoxyquinolin-3-ylamine (described in International Publication No. 2004/058 144, 300 mg, 1.44 mmol) in dichloromethane (22 mL) -181 - 200948817 solution was cooled in an ice water bath Aqueous potassium carbonate solution (5 3 7 mg, 3-89 mmol / 15 mL) and chloroethyl sulphate chloride (. Further, an aqueous potassium carbonate solution (26 8 mg, 0.97 mmol / 2 mL) and chloroethyl hydrazino chloride (yield: 77 mL, 0.927 mmol) were stirred at the same temperature for 30 minutes. After separating the aqueous layer, the organic layer was dried over magnesium sulfate. The residue was purified with EtOAc EtOAc EtOAc (EtOAc) 1H-NMR (400MHz, CDC13) 6: 3.99 (3H, s), 4.3 2 (2H, s), 7.33-7.40 (2H, m), 8.0 1 (lH, d, J = 8.3 Hz), 8.93 (lH) , brs), 9.62 (lH, s). MS (ESI) m/z: 285 (M + H) + .

[Reference Example 22] [trans-4-({[(4-chloro-6-methoxysalthon-3-yl)methylamino)methyl]amino}methyl)cyclohexyl]aminecarboxylic acid Tert-butyl ester

2-Chloro-N-(4-chloro-6-methoxysalthrin-3-yl)acetamide (447 mg, 1.57 mmol) obtained in Reference Example 21 was dissolved in N,N-dimethylformamide. Amine (9 mL), sequentially added potassium carbonate (237 mg, 1.73 mmol) and [4-(aminomethyl)cyclohexyl]aminecarboxylic acid tert-butyl ester (483 mg, 2.12 mmol) of N, N A solution of dimethylformamide (9 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. EtOAc was washed with saturated brine, 10% aqueous sodium carbonate and brine, and dried over magnesium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 1H-NMR (400 MHz, CDC13) 6: 1.08 - 1.20 (4H, m), 1.46 (9H, s), 1.76 (lH, brs), 1.90- 1.97 (2H, m), 2.04-2.12 (2H, m), 2.63 (2H, d, J = 6.4 Hz), 3.42 (lH, brs), 3.52 (2H, s), 4.00 (3H, s), 4.41 (lH, brs), 7.3 1-7.37 (2H, m), 8.01 (lH, d, J = 9.2 Hz), 9.82 (1H, s), 10.14 (1H, s). MS (ESI) m/z: 47 7 (M + H) + .

[Reference Example 23] 1-(trans-4-aminocyclohexyl)methyl-9-methoxy-1,4-dioxin Hydrogen-2H-pyrido[2,3-c]quinoline- 3-ketone

[trans-4-({[(4-chloro-6-methoxy-quinolin-3-ylaminecarbhydryl)methyl]amino}methyl)cyclohexyl] obtained in Reference Example 22] The third butyl carbamate (366 mg (0.767 mmol) of N,N-dimethylacetamide (14 mL) Q solution was heated at 100 ° C for 3 hours. After cooling, diluted with ethyl acetate and 10% After washing with a sodium carbonate aqueous solution and a saturated aqueous sodium chloride solution, the residue was evaporated to drynesshhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh One part of the cyclized product (100 mg, 0.23 mmol) was dissolved in dichloromethane (4.55 mL), and trifluoroacetic acid (0.45 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was chloroform··methanol = 5:1 The solution was diluted and added with a 10% aqueous solution of sodium carbonate. The organic layer was separated, dried over magnesium sulfate, and then purified by fractional layer chromatography (chrome, chloroform:methanol:water=8:3:0.5) to obtain colorless-183. 200948817 Solid labelled compound 53.2 mg (52%). 1H-NMR (400 MHz, DMSO-d6) 6: 1.00 (2H, q, J = l 1.8 Hz), 1.27 (2H, dd, J = 22.7, 12.2 Hz) 51.6 1-1.74 (lH, m), 1.78- 1.94 (4H, m), 2. 84-2.9 4(1 H,m), 2.97 (2H,d,J = 6.9Hz), 3.75(2H,s),3.8 8 (3H,s), 7.20-7.27 (2H,m), 7.67(2H,brs) , 7.82 (lH, d, J = 9.2 Hz), 8.33 (lH, s), 10.79 (1H, brs). MS (ESI) m/z: 341 (M + H) + .

[Example 5] 9-methoxy-1-[(trans-4-{[(3-olyl-3,4-dihydro-211-pyrido[3,2-13][1, 4]噚耕-6-yl)methyl]amino}cyclohexyl)methyl]-1,4-dihydro-2H-pyrido[2,3-c]quinolin-3-one

1-(trans-4-aminocyclohexyl)methyl-9-methoxy-1,4-dihydro-2H-pyrido[2,3-c]quinoline obtained in Reference Example 23 3-ketone (7 4 mg, 0.218111111〇1), 3-sided oxy-3,4-dihydro-211-pyrido[3,2-1)][1,4]indole-6-formaldehyde ( It is described in International Publication No. 2006/032466, etc., and 50.5 mg, 0.283 mmol) was dissolved in chloroform (3.75 mL), methanol (1.50 mL), and acetic acid (37.4 μl, 0.654 mmol) was added and stirred at room temperature for 1 hour. Sodium hydrogen triethoxyborohydride (50.8 mg, 0.240 mmol) was added and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with aq. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc -184- 200948817 1H-NMR (400MHz, DMSO-d6) 5: 0.85-0.98 (2H, m), 1.00-1.1 5 (2H, m), 1.61-1.73 (2H, m), 1.79 (2H, d, J = l 1.9 Hz), 1.87- 1.96 (2 H, m), 2.98 (2Hsd, J = 6.9 Hz), 3.74 (4H, m), 3.86 (3H, s), 4.59 (2H, s), 7.00 ( lH,d,J = 8.3Hz), 7.18-7.3 1(3H,m),7.8 1(lH,d,J = 9.2Hz), 8.32(lH,s),10.77(lH,s),11.16(lH , brs). MS ESI) m/z: 503 (M + H)+.

[Example 6] trans-N-(2-cyclohexylethyl)-4-[(9-methoxy-2,3-dihydro-1H-[1,4] 噚耕和[2,3 -c]quinolin-1-yl)methyl]cyclohexaneamine

The trans-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole-[2,3-c] sialolin-1-yl group obtained in Reference Example 10 was obtained. Methyl]cyclohexaneamine (54.9 mg, 0.16 8 mmol) 'cyclohexyl ketone (27.6 mg, 0.218 mmol) was dissolved in dichloromethane (3 mL), and acetic acid (0.012 mL, 0.22 2 mmol) was added at room temperature. Sodium hydrogen hydride hydride (45.0 mg, 0.202 mmol) was stirred for 6 hours. The solvent was distilled off under reduced pressure, and the mixture was dissolved in chloroform:methanol:water = 7:3:1, and washed with water. After drying over anhydrous sodium sulfate, the solvent was evaporated to dryness crystalljjjjjlilililililililililililililili 1H-NMR (400MHz, CDC13) 5: 0.94 - 1.80 (22H, m), 2.16-2.26 (1H, m), 2.29-2.40 (2H, m), 2.89-3.03 (3H, m), 3.25-3.30 ( 2H,m), 3.92(3H,s), 4.23(2H,t,J = 4.3Hz), 7.17(lH,dd,J = 9.0,2.7Hz), 7.24( 1H,d,J = 2_7Hz) , 7.90 (1 H, d, J = 9.0 Hz), 8.38 (1 H, s). -185- 200948817 MS (ESI) m/z: 438 (M + H) +.

[Example 7] 6-[({trans-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline- 1-yl)methyl]cyclohexyl}amino)methyl]-211,4-benzosin-3 (4H)-one

Trans-4-[(9-methoxy-2,3-dihydro-111-[1,4]indole[2,3-(1]quinolin-1) obtained in Reference Example 1 -yl)methyl]cyclohexaneamine (0.05 (^, 0.15 mmol) in dichloromethane (5 mL), 3-tris-oxy-3,4-dihydro-2H-1,4-benzothiazide哄-6-甲醒 (described in Bioorganic & Medicinal Chemistry Letters, 2007, Vol. 17, No. 10, 2723-2727, etc., 0.03 5 g, 0.18 mmol) and sodium triethoxy borohydride (O. 〇65g, 0.3 1 mmol), and stirred at room temperature for 3 hours. Aq. (Dichloromethane:methanol = 1 〇: 1) was purified to give the title compound as a pale yellow foamy material 〇. 〇 53 g (68%). 1H-NMR (400 MHz, CDC13) 6: 1.1 3-1.40 (3H, m), 1.50-1.96 (3 H, m), 2.1 0-2.19 (4H, m), 2.57-2.68 ( 1 H, m), 2.98 (2H, d, J = 7.3 Hz), 3.28 (2H, t , J = 4.4 Hz), 3.37 (2H, s), 3.83 (2H, s), 3.92 (3H, s), 4.23 (2H, t, J = 4.4 Hz), 6.96-7.0 1 (2H, m), 7.16 (lH, dd, J = 9.0, 2.4 Hz), 7.27-7.29 (2H, m), 7.89 (lH, d, J = 9.0 Hz) , 8.38 (lH, s). MS (ESI) m/z: 5 05 (M + H) + [Example 8] trans-N- (2,3-dihydro-1,4-benzodi曙英-6-ylmethyl) -186- 200948817 -4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c] porphyrin .1-yl)methyl]cyclohexaneamine

❸

The trans-4-[(9-methoxy-2,3-dihydro-lH-[l,4]Df[[,3-c]quinolin-1-yl group obtained in Reference Example 10] a solution of methyl]cyclohexaneamine (〇〇5〇g, 0.15mmol) in dichloromethane (5mL), adding 2,3-dihydro-1,4-this and a _____ (. Recorded in Bi〇organic & Medicinal

Chemistry Letters '2007, Volume 17, No. 10, 2723-272, 7 pages, etc., 0.030g, 0_18mmol) and hydrogenated sodium triethoxyborohydride (〇.〇65g, 0.3 1 mmol), stirred at room temperature for 3 hours . A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was applied to dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj !HN MR(400MHz, CDC13)6:1.1 1-1.38(3 H,m), 1.49-1.94 (4 H,m),2.08-2.17(4H,m),2.5 3-2.63(lH,m), 2.97 (2H,d,J = 7.3Hz), 3.27(2H,t,J = 4.3Hz), 3.77(2H5s)53.91(3H,s), 4.20-4.24(2H,m), 4.25(2H,s) , 6.82-6.85 (2H, m), 6.88 (lH, s), 7.16 (lH, dd, J = 9.2, 2.8 Hz), 7.27-7.29 (lH, m), 7.89 (lH, d, J = 9.3 Hz) , 8.38 (lH, s). MS (ESI) m/z: 476 (M + H) + [Example 9] 6·[ U trans-4-[(9-methoxy-2,3- Dihydro-1H-[1,4]indole and [2,3-c]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]-2-methyl-187- 200948817 -2H -1,4-benzopyrene-3 (4H)-ketone

Trans-4·[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl obtained in Reference Example 10 Add methyl 2-methyl-3-oxooxy-3,4-dihydro-2H-1,4-benzene to methylene]cyclohexaneamine (0.050 g, 0.15 mmol) in dichloromethane (5 mL)噚耕-6-formaldehyde (described in International Publication No. 2001 1/08 1 324, etc., 0.040 g, 0.18 mmol) and sodium triethoxy borohydride (0.065 g, 0.3 1 mmol), stirred at room temperature 4.5 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and dichloromethane was evaporated. After drying over anhydrous magnesium sulfate, the solvent was evaporated, evaporated, mjjjjjjj 1H-NMR (400MHz, CDCl3) 6: 1.14-1.35 (4H, m) J1.56 (3H, d, J = 6.8 Hz), 1.5 8-1.94 (2H, m), 2.09-2.18 (4H, m) , 2.53-2.63 (lH, m), 2.99 (2H, d, J = 7.3 Hz), 3.28 (2H, t, J = 4.4 Hz), 3.79 (2H, s), 3.92 (3H, s), 4.23 ( 2H, t5J = 4.4 Hz), 4. 60 (lH, q, J = 6.8 Hz), 6.85-6.87 (lH, m), 6.92 (2H, s), 7.16 (lH, dd, J = 9.2, 2.8 Hz) ), 7.28-7.30 (lH, m), 7.89 (lH, d, J = 9.3 Hz) 5 8.38 (1H, s). MS (ESI) m/z: 5 03 (M + H) + [Reference Example 24 2-fluoro-2-(4-methylindolyl-2-nitrophenoxy)acetate-188- 200948817

°-<4_Hydroxy-3-nitrobenzaldehyde (836 mg, 5.00 mmol), bromofluoroacetic acid ethyl acetate (1.203 g, 6.50 mmol), cesium carbonate (760 mg, 5.50 mmol), and N,N-dimethyl A mixture of carbamide (5 mL) was heated and stirred for 9 hours on an oil bath of 70 °C. 1N Hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product of the labeled compound was obtained as a red-orange solid 〇 ^ 1.610 g (quantitative). 1H-NMR (400MHz, CDCl3) 6: 1.37 (3H, t, J = 7.1 Hz), 4.36-4.4 2 (2H, m), 6.10 (lH, d, J = 57.3 Hz), 7.54 (lH, d, J = 8.7 Hz) s 8.15 (lH, dd, J = 6.9, 1.8 Hz), 8.41 (lH, d, J = 1.8 Hz), 10.02 (lH, s). MS (ESI) m/z: 326 ( M + MeOH + Na) + .

[Reference Example 25] 2-fluoro-3-oxooxy-3,4-dihydro-21 1,4-benzopyrene -6-carbaldehyde oxime

The crude 2-fluoro-2-(4-carbenyl-2-nitrophenoxy)acetate obtained in Reference Example 24 (1.61 g, about 5.00 mmol) was dissolved in acetic acid (50 mL). Iron powder (2_79 g, 50.0 mmol) was added, and the mixture was heated and stirred on an oil bath of 60 ° C for 2.5 hours. After distilling off the solvent under reduced pressure, 2N hydrochloric acid was added to the residue to dissolve iron powder, which was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous solution of sodium hydrogencarbonate, water, and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was evaporated to diethyl ether. 144 mg (15%) ° 1H-NMR (400 MHz, CDC13) 5: 6.12 (lH, d, J = 5 0.9 Hz), 7.3 4 (lH, d, J = 8.3 Hz), 7.56 (lH, s), 7.66 (lH, d, J = 8.3 Hz), 9.23 (lH, brs), 9.96 (lH, s). MS (ESI) m/z: 196 (M + H) + .

[Example l] 2-fluoro-6-[({trans-4-[(9-methoxy-2,3-dihydro-1H-[1,4] 噚耕和[2,3- c]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]-2H-1,4-benzoindole-3(4H)-one

The trans-4·[(9-methoxy-2,3-dihydro-111-[1,4]曙[[,3-(:]quinolin-1-) obtained in Reference Example 10 To a solution of methyl]cyclohexaneamine (0.05〇8, 0.15mmol) in dichloromethane (5mL), 2-fluoro-3-oxooxy 3,4-dihydro-2H-1,4 -Benzene hydrazine-6-formaldehyde (〇.〇36g, 0.18mmol) and hydrogenated sodium triethoxyborohydride (0.065g, 0.31mmol), stirred at room temperature for 18 hours. Saturated sodium bicarbonate was added to the reaction mixture. The aqueous solution was extracted with methylene chloride. After dried over anhydrous magnesium sulfate, the solvent was evaporated evaporated evaporated. 0.048g ( 62% ). 1H-NMR (400MHz, CDC13) 5: 1.1 3-1.36(5H,m), 1.47-2.09(4 H,m), 2.10-2.19(4H,m),2.56-2.66( lH,m), 2.99 (2H,d,J = 7.3Hz), 3.28 (2H,t,J = 4.4Hz), 3.82-3.87(lH,m)' 3.9 1(3H,s), 4.22(2H, t, J = 4.4 Hz), 7.01-7.08 (2H, m), 7.0 8-7.19 -190- 200948817 (2H, m), 7.28 (lH, d, J = 2.8 Hz), 7.89 (lH, d, J = 9.2 Hz), 8.38 (lH, s). MS (ESI) m/z: 507 (M + H) + [Example ll] 6-[ ({trans -4-[ (9-A) -2,3-dihydro-1H-[1,4]indolo[2,3-c]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]_8-methyl- 211-1,4-benzoindole-3(411)-ketone

Trans-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl obtained in Reference Example 10 a solution of methyl]cyclohexaneamine (0.050 g, 0.15 mmol) in dichloromethane (5 mL), s. Benzopyrene-6-formaldehyde (described in International Publication No. 2004/052373, 0.03 5g, 0.18 mmol) and sodium triethoxysulfonium hydride (0.065 g, 0.31 mmol) were stirred at room temperature for 18 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was applied to dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was evaporated to dryness crystals crystals crystals crystals . *H-NMR (40 0MHz, CDC13) 8:1 .15-1.28 (2H,m),l .32- 1.46(1 H,m), 1.48-2.11(4H,m),2.12-2.2 1(2H , m), 2.23 (3H, s), 2.61-2.7 l (lH, m), 2.98 (2H, d, J = 7.3 Hz), 3.28 (2H, t, J = 4.4 Hz), 3.75-3.78 (2H , m), 3.92 (3H, s), 4.23 (2H, t, J = 4.6 Hz), 4.52 (2H, s), 6.78-6.84 (2H, m), 7.17 (lH, dd, J = 9.2, 2.8 Hz), 7.2 8 (2H, d, J = 2.8 Hz), 7.89 (lH, d, J = 9.2 Hz), 8.38 (lH, s). • 191- 200948817 MS (ESI) m/z: 503 (M + H) + [Example 12] 8-methoxy-6-[({trans-4-[(9-methoxy-2,3-dihydro-1H-[1,4]) [2,3-c]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]-2H-1,4-benzopyrene-trap-3(4H)-one

Trans-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl obtained in Reference Example 10 'Methyl]cyclohexaneamine (〇.〇50g, 0.15mmol) in dichloromethane (5mL) and methanol (2mL) in a solution of '8-methoxy-3-oxirane-3,4-di Hydrogen-2H-1,4-benzoxanthene-6-formaldehyde (described in International Publication No. 2007/1 1 1 21 2, etc., 0_032g, 0.15 mmol), and hydrogenated sodium triethoxyborohydride (〇. 〇65g, 0.31mmol), stirred at room temperature for 22 hours. Next, sodium triethoxyborohydride (0.06 5 g, 0.3 1 mmol) was additionally added, and the mixture was stirred at room temperature for 4 hours. After adding acetic acid (0.008 mL, 0.15 mmol), and further stirring at room temperature for 4 hours, hydrogenated sodium triethoxyborohydride (〇. 〇 65 g, O.31 mmol) was added and stirred at room temperature for 20 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and ethyl acetate was evaporated. After drying over anhydrous magnesium sulfate, the solvent was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1H-NMR (40 0MHz, CDC13) 5: 1. 1 6-1.35 (4H, m), 1.67-1.97 (3 H, m), 2.10-2.19 (3H, m), 2.5 5-2.65 (lH, m ), 2.99 (2H, d,

J = 7.3 Hz), 3.28 (2H, t, J = 4.3 Hz), 3.79 (2H, s), 3.91 (3H, s), 3.92 (3H - 192 - 200948817, s), 4.23 (2H, t, J = 4.3 Hz), 4.62 (2H, s), 6.52 (lH, s), 6.64 (lH, s), 7. 17 (lH, dd, J = 9.2, 2.8 Hz), 7.28 (lH, d, J = 2.9 Hz), 7.90 (lH, d, J = 9.0 Hz), 8.38 (1H, s). MS (ESI) m/z: 5 1 9 (M + H) + [Reference Example 26] 4- ( 2- Ethoxy-2-oxoethoxyethoxy)-2-methyl-5-nitrobenzoic acid 2-ethoxy-2-oxoethyl ester

4-N-N-2-methyl-5-nitrobenzoic acid (described in Helvetica Chimica Acta > 1951, 34, pp. 149-1 54, 1. 3 70 g, 6.95 mmol) of N, N-II Add methyl carbonate (20 mL) solution to potassium carbonate (2.88 g, 20.8 mmol), ethyl bromoacetate (3 · 8 5 mL, 3 4 · 7 mmo 1 ), and heat and stir on an oil bath at 60 ° C. 3 hours. The reaction solution was poured into 1 N hydrochloric acid and extracted with ethyl acetate. The obtained extract was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc: 1H-NMR (400 MHz, CDCl3) 6: 1.28 - 1.33 (6H, m), 2.68 (3H, s), 4.26 - 4.30 (4H, m), 4.826 (2H, s), 4.8 3 2 (2 Η, s ), 6.8 0 (1 Η, s), 8 · 6 5 (lH, s). MS (ESI) m/z: 370 (M + H) + , 392 (M + Na) + .

[Reference Example 27] 7-Methyl-3-oxooxy-3,4-dihydro-2H-1,4-benzoindole- 6-carboxylic acid 2-ethoxy-2-oxoethoxy B Base ester-193- 200948817

2-(2-ethoxy-2-oxoethoxyethoxy)-2-methyl-5-nitrobenzoic acid 2-ethoxy-2-oxoethyl group obtained in Reference Example 26. A solution of the ester (610 mg ' 1.65 2 mmol) in methanol (35 mL) was added to a 10% palladium carbon catalyst (Μ, containing about 50% water, 305 mg) and stirred at room temperature for 15 hours under a hydrogen atmosphere under normal pressure. After filtering the catalyst, the solvent was distilled off under reduced pressure, and the residue was purified by Biotage Co., Ltd. (Certrifugal Precolumn 25M; Eluent, Hexane: Ethyl acetate = 9 : 丨 -4 : 1-2 : 1 -1 : 1) Purification to obtain 244 mg (50%) of the title compound as a white solid. 1H-NMR (400MHz, CDCl3) 5: 1.3 1 (3H, t, J = 7.1 Hz), 2.56 (3H, s), 4.27 (2H, q, J = 7.2 Hz), 4.67 (2H, s), 4 · 8 1 (2H, s), 6.8 5 (1 Η, s), 7.54 (lH, s), 8.33 (lH, brs). MS (ESI) m/z: 29 4 (M + H) + .

[Reference Example 28] 6-Hydroxymethyl-7-methyl-3-oxooxy-3,4-dihydro-2H-1,4-

7-Methyl-3-oxo-3,4·dihydro-2H-1,4-benzoxamic-6-carboxylic acid 2-ethoxy-obtained in Reference Example 27 A solution of 2-oxoethylethyl ester (241 mg, 822. 822 mmol) in dichloromethane (4 mL), EtOAc (EtOAc: EtOAc, EtOAc Stir at the same temperature for 1.5 hours. Methanol (1 mL) was added to the reaction mixture to terminate the reaction, and the mixture was allowed to stand at room temperature, and a 0.5 N aqueous sodium potassium tartrate solution was added thereto and stirred overnight. Distillation under reduced pressure -194- 200948817 After the organic solvent, the insoluble material was filtered and washed with water. The title compound 108 mg (68%) was obtained as a yellow solid. 1H-NMR (400MHz, DMSO-d6) 8: 2.13 (3H, s), 4.37 (2H'd, J = 5.0 Hz), 4.49 (2H, s), 5.06 (lH, t, J = 5.3 Hz), 6.73 (lH, s), 6.92 (lH, s), 10.60 (lH, brs) _ MS (ESI) m/z: 1 94 (M + H) + .

[Reference Example 29] 7-Methyl-3-oxooxy-3,4-dihydro-2H-1,4-benzoindole-6-formaldehyde

6-Hydroxymethyl-7-methyl-3-oxo-3,4-dihydro-2H-1,4-benzopyrene trap (106 mg, 0.549 mmol) obtained in Reference Example 28 A methane (6 mL) suspension was added to a Dess-Martin high-valent iodine compound (312 mg, 〇. 714 mmol) and stirred at room temperature for 2.5 hours. After adding a 5% aqueous solution of sodium thiosulfate to the reaction mixture, it was extracted with a mixed solvent of chloroform:methanol = 9:1. The organic layer was combined, washed with EtOAc EtOAc. The residue was suspended in diethyl ether:ethyl acetate = 1 : 1 mixed solvent, and the insoluble material was filtered. The label compound 51 mg (49%) was obtained as a thin yellow powder. 1H-NMR (400MHz, CDC13) 6: 2.61 (3H, s), 4.70 (2H, s), 6.85 (1H, s), 7.29 (1H, s), 7.99 (0.8H, brs), 10.18 (lH, s). MS (ESI) m/z: 1 92 (M + H) + .

[Example 13] 6-[({trans-4-[(9-methoxy-2,3-dihydro-lH-[l,4]Df-trap[2,3-c]quinoline- 1-yl)methyl]cyclohexyl}amino)methyl]-7-methyl-195- 200948817 -2H-1,4-benzoxanthene-3( 4H )-one

Trans-4·[(9-methoxy-2,3-dihydro-111-[1,4]噚[[,3-(:] sialolin-1-) obtained in Reference Example 10 a solution of methyl]cyclohexaneamine (0.04 (^, 0-12 mmol) in dichloromethane (5 mL), and added to the 7-methyl-3-oxooxy-3,4-dihydro- 2H-1,4-benzoxanthene-6-formaldehyde (0.028 g, 0.18 mmol) and hydrogenated sodium triethoxyborohydride (〇_〇52 g, 〇.25 mmol) were stirred at room temperature for 68 hours. The solution was added to aq. EtOAc. EtOAc (EtOAc m. Labeling compound of yellow foamy substance 〇.〇33g (54%). 1 H-NMR (400 MHz, CD Cl3) δ : 1.17-1.33 (3H, m), 1.34-1.48 (2 H, m), 1.84- 2.12(3H,m), 2.13-2.25(2H,m), 2.28(3H,s), 2.65-2.7 6(lH,m), 3.00 (2H,d,J = 7.3Hz), 3.29(2H,t , J = 4.3 Hz), 3.79 (2H, s), 3.93 (3H, s), 4.23 (2H, t, J = 4.4 Hz), 4.46 (2H, s), 6.75-6.78 (lH, m), 6.94 -6.98 (lH, m), 7.17 (lH, dd, J = 9.2, 2.8 Hz), 7.28-7.30 (lH , m), 7.90 (lH, d, J = 9.3 Hz), 8.39 (lH, s). MS (ESI) m/z: 5 03 (M + H) + [Reference Example 30] 4-bromo-3- Methyl-2-nitrophenol

-196- 200948817 A solution of 3-methyl-2-nitrophenol (3.063 g '20.0 mmol) in acetic acid (50 mL), EtOAc (EtOAc (EtOAc) The reaction solution was poured into ice water and extracted with diethyl ether. The extract was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated. The crude product of the labeled compound was obtained as a yellow solid, 4.88 g (quant.). 1H-NMR (400 MHz, CDCl3) 5: 2.62 (3H, s), 6.92 (lH, d, J = 8.3 Hz), 7.6 6 (1 Η, d, J = 8.7 Hz), 9.3 0 ( 1 H , brs).

MS (ESI) m/z: 23 2 (M-H).

[Reference Example 31] (4-Bromo-3-methyl-2-nitrophenoxy)ethyl acetate

The crude product of 4-bromo-3-methyl-2-nitrophenol obtained in Reference Example 30 (4 · 8 7 g, 2 0. Ommo 1 ), potassium carbonate (3.3 2 g, 2 4 · 0 mmo) 1) A mixture of ethyl bromoacetate (2.89 mL, 26.0 mmol) and N,N-dimethylformamide (40 mL Q) was stirred and stirred at 60 ° C for 3 hours. The reaction solution was ice-cooled and poured into 1% hydrochloric acid and extracted with ethyl acetate. The obtained extract was washed with water and a saturated aqueous solution of sodium sulfate and dried over anhydrous sodium sulfate. The crude product of the labeled compound was obtained as an orange solid, 6.85 g (quant.). 1H-NMR (400MHz, CDCl3) 6: 1.28 (3H, t, J = 7.1 Hz), 2.34 (3H, s), 4.25 (2H, q, J = 7.0 Hz), 4.68 (2H, s), 6 · 7 Ο ( 1 Η, d, J = 9 · 2 Hz), 7·56 (1H, d, J = 8.7 Hz). MS (ESI) m/z: 320 (M + H) + .

[Reference Example 32] 6-bromo-5-methyl-2H-1,4-benzopyrene-trap-3 ( 4H)-one -197- 200948817

The crude product of (4-bromo-3-methyl-2-nitrophenoxy)ethyl acetate obtained in Reference Example 31 (2.59 g ' 7.56 mmol), iron powder (4.22 g '75.6 mmol), and acetic acid The mixture (40 mL) was stirred with heating at 60 ° C for 30 minutes. The reaction solution was diluted with a mixed solvent of chloroform:methanol = 9:1, and Celite was filtered to remove insolubles. After the mother liquid was concentrated under reduced pressure, the residue was partitioned between chloroform:methanol = 5:1 mixture solvent and saturated aqueous hydrogen carbonate. After separating the organic layer, the aqueous layer was further extracted with a mixed solvent of chloroform:methanol = 5:1, and the organic layer was combined and dried over anhydrous sodium sulfate. The column was filtered through a short gelatin, and the mother liquor was concentrated under reduced pressure. To the residue was added hexane:ethyl acetate = 4:1, and the solvent was crystallized and filtered to give the title compound 1.95 g (93%) as a white solid. 〇1H-NMR (400 MHz, CDC13:CD3〇D = 1 :1) 6: 2.35 (3H, s), 4.53 (2H, s), 6.75 (lH, d, J = 8.7 Hz), 7.18 (lH, d, J = 8.7 Hz). MS (ESI) m/z :242(M + H) + .

[Reference Example 33] 5-methyl-6-[(E)-2-phenylvinyl]-2H-1,4-benzopyrene Ο • 3 ( 4H) · ketone

6-Bromo-5-methyl-3-oxooxy-3,4-dihydro-2-indole-1,4-benzoxanthene (242 mg, 1.000 mmol) obtained in Reference Example 32, (E) -2-phenylethenylboronic acid (222 mg, 1.50 mmol), ginseng (dibenzylacetone) dipalladium (27 mg > 〇.03 mmol) 'dicyclohexyl-(2',6'-dimethoxyl linkage Phenyl-2-yl-198- 200948817 ) a mixture of o- (25 mg, 0.06 mmol), potassium dibasic (6 3 7 mg, 3.0 0 mmo 1 ), and dioxane (6 mL), 110 ° under nitrogen. The oil bath of C was heated and stirred for 6 hours. The reaction solution was diluted with a mixed solvent of chloroform:methanol = 5:1. The insoluble material was removed by Celite filtration. After the mother liquid was concentrated under reduced pressure, the residue was dissolved in a mixture solvent of chloroform·methanol = 9:1, and filtered through a short gelatinous column. The residue was crystallized from hexanes: ethyl acetate = 2:1, and EtOAc (EtOAc) O 1H-NMR (400 MHz, CDC13) 5: 2.29 (3H, s), 4.6 0 (2H, s), 6.87- 6.91 (2H, m), 7.24-7.29 (3H, m), 7.37 (2H, t , J = 7.6 Hz), 7.50 (2H, d, J = 7.8 Hz), 7.89 (lH, brs). MS (ESI) m/z: 266 (M + H) + .

[Reference Example 34] 5-methyl-3-oxooxy-3,4-dihydro-2H-l,4-benzopyrene-6-formaldehyde

5-Methyl-6-[(E)-2-phenylvinyl]-2H-1,4-benzoindole-3(4H)-one obtained in Reference Example 33 (0.23 g, 0.87 mmol) A solution of methanol (70 mL) and dichloromethane (20 mL) was stored at -78 ° C, and ozone gas was poured therein. The injection was continued for 15 minutes as it was, and it was confirmed that the reaction liquid turned blue to stop the injection of ozone gas. After replacing with nitrogen, dimethyl sulfide (〇.64 mL, 8.7 mmol) was added and stirred at room temperature for 22 hours. After distilling off the solvent, it was purified by silica gel chromatography (1, methylene chloride:methanol = 1 : 1 : 2nd, hexane: ethyl acetate = 1:1) to give pale yellow crystals -199 - 200948817 Marker compound 0.1 06g ( 64% ). 1H-NMR (400 MHz, CDCl3) a: 2.5 9 (3H, s), 4.6 8 (2H, s), 7. 〇l (lH, d, J = 8.3 Hz), 7.49 (lH, d, J = 8.3 Hz), 7.90-7.97 (lH, m), 10.10 (lH, s).

[Example 14] 6-[({trans-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c] porphyrin- 1·yl)methyl]cyclohexyl}amino)methyl]methyl-2H-1,4-benzoxan-3 ( 4H )-one

Trans-4-[(9-methoxy-2,3-dihydro-lH-[l,4]Df[2,3-c]quinolin-1-yl obtained in Reference Example 10 a solution of methyl]cyclohexaneamine (〇.040g, 0.12mmol) in dichloromethane (5mL), which was added to 5-methyl-3-oxooxy-3,4-dihydro- 2H-1,4-Benzene hydrazine-6·formaldehyde (0.029 g » 0.1 5 mmol) and sodium triethoxy borohydride (0·0 5 4 g, 0.25 mmol) were stirred at room temperature for 17 hours. Next, methanol (1 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. Further, sodium hydrogen triacetate borohydride (0.054 g, 0.25 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After drying over anhydrous magnesium sulfate, the solvent was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal 1H-NMR (400MHz, CDC13) 6: 1.17-1.36 (4H, m), 1.54-1.71 (2H, m), 2.09-2.19 (4H, m), 2.26 (3H, s), 2.5 5-2.66 - 200- 200948817 (lH,m), 2.99 (2H,d,J = 7.3Hz), 3.28 (2H,t,J = 4.4Hz),3.8 1(2H,s),3 • 93(3H,s), 4.21-4.27 (2H, m), 4.54-4.58 (2H, m), 6.8 1-6.87 (lH, m), 6.94-7.02 (lH, m), 7· 15-7.19 (lH, m), 7.27- 7.33 (lH, m), 7.87-7. 95 (1H, m), 8.38 (1H, s). MS (ESI) m/z: 503 (M + H) + [Ref. 35] methoxy-1 ,2,3,4-tetrahydrobenzo[h][l,6]naphthyridine

4-Chloro-3-(3-chloropropyl)-6-methoxyquinine (3_00g, 111.5 mmol) and benzoquinone (6.00 g) obtained in Reference Example 3 were placed in BombRoll at 45 °C. In the form of a solution, ammonia gas was blown in, and after tight plugging, the mixture was stirred at 160 ° C for 2 hours. The reaction solution was cooled, added with a 1N aqueous solution of sodium hydroxide, and extracted with dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate (MgSO4). 1H-NMR (300MHz, CDC13) 5: 2.02 (2H, quint, J = 6.0 Hz) 52.85 (2H, t5J = 6.0 Hz), 3.57 (2H, m) 53.90 (3H, s), 5.69 (lH, brs) , 7. 〇 3 (lH, d, J = 2.7 Hz), 7.22 (lH, dd, J = 9.2, 2.7 Hz), 7-85 (lH, d, J = 9.2 Hz), 8.16 (lH, s) MS (FAB) m/z: 21 5 (M + H) + .

[Reference Example 36] 4-[(9-Methoxy-3,4-dihydrobenzo[11][1,6]naphthyridin-1(21〇-yl)methyl]piperidine-1-carboxylate Acid tertiary butyl ester-201 - 200948817

Potassium iodide (557 mg, 3.35 mmol) was dissolved in N,N-dimethylformamide (10.5 mL), and 4-(bromomethyl)piperidine-1-carboxylic acid tert-butyl ester was added under a nitrogen atmosphere. (93 2 mg, 3.3 5 mmol), stirred at 50 ° C for 50 minutes (solution A). On the other hand, 9-methoxy-1,2,3,4-tetra-argon-benzo[h][l,6]naphthalene (3,59 mg, 1.68 mmol) obtained in Reference Example 35 was dissolved in N. N-dimethylformamide (17.5 mL) was added with a solution of sodium hydride (yield: 60%, 134 mg, 3.35 mmol). After 20 minutes, the solution A was added, and the mixture was stirred at room temperature for 1 hour, and then stirred at 5 (TC for 1 hour) at 60 ° C overnight. An aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with acetic acid Z* ester to sat. The extract was washed with water, dried over anhydrous magnesium sulfate (MgSO4). 13%)°

1H-NMR (300MHz, CDCl3) 5: l.ll-1.3 1 (2H, m), 1.46 (9H, s), 1.89-2.10 (5H, m), 2.72 (2H, m), 2.87 (2H, t , J = 6.5Hz), Q 3.11(2H,d,J = 2.9Hz), 3.29(2H,m),3.91(3H,s),4.16(2H,brs),7.2 2- 7.28(2H,m) , 7.89 (lH, d, J = 9.0 Hz), 8.34 (lH, s). MS (FAB) m/z: 412 (M + H) + .

[Example 15] 1-{ [1-(2-cyclohexylethyl)piperidin-4-yl]methyl}-9-methoxy-1,2,3,4-tetrahydrobenzo[11 ][1,6]naphthyridine

-202- 200948817 4-[(9-Methoxy-3,4-dihydrobenzo[h;][l,6]naphthalene-stham-1(2H)-yl)methyl group obtained in Reference Example 36 The piperidine-dicarboxylic acid third-stage butyl vinegar (8 4 mg, 0.20 mmol) was dissolved in dichloromethane (1. 6 mL), trifluoroacetic acid (0.8 mL) was added and stirred at room temperature for 50 min. After concentrating the reaction mixture under reduced pressure, the obtained residue was dissolved in methylene chloride (1.6 mL), under nitrogen atmosphere and ice-cooling, and cyclohexyl acetaldehyde (38 mg, 0.30 mmol) and hydrogenated sodium triethoxy hydride (66 rng, 0-30 mmol), stirred at room temperature for 2 h 30 min. Further, under ice cooling, cyclohexylacetaldehyde oxime (25 mg, 0.20 mmol), hydrogenated sodium triethoxy borohydride (44 mg, 0.20 mmol), dichloromethane (0.8 mL), and stirred at room temperature for 2 hours and 20 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was applied to dichloromethane and washed with brine. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, the obtained residue was purified by EtOAc EtOAc (EtOAc:EtOAc . This was dissolved in chloroform, and a 4N hydrochloric acid / dioxane solution (2 mL) was added thereto, and the mixture was stirred for 5 minutes, and then concentrated under reduced pressure. Diethyl ether was added thereto, the solid was filtered, and dried to give 51 mg (yield: 89%) of the title compound as a pale yellow solid. 1H-NMR (300MHz, CD3OD) 5: 0.82-1.64 (1 5H, m), 1.79 (2H, d, J = 13.9 Hz), 2.0 1 (2H, m), 2.23 (lH, m), 2.78-2.85 (4H, m), 2.97 (2 H, m), 3.43 (2H, d, J = 12.3 Hz), 3.63 (2H, t, J = 5.6 Hz), 3.87 (3H, s), 3. 92 (2H , d, J = 7.3 Hz), 7.34 (lH, d, J = 2.5 Hz), 7.46 (lH, dd, J = 9.2, 2.5 Hz), 7.7 1 (lH, d, J = 9.2 Hz), 8.10 ( lH, s). MS (FAB) m / z: 422 (M + H) + .

[Reference Example 37] 4-[(9-Methoxy-3,4-dihydrobenzo[h][l,6]naphthyridin-1(2H)-yl)carbonyl]piperidine-1-carboxylic acid Third-grade butyl ester-203- 200948817

N-N-dimethyl group of 9-methoxy-1,2,3,4-tetrahydro-benzo[h][l,6]naphthyridine (915 mg, 4.27 mmol) obtained in Reference Example 35 A solution of meglumine (40 mL) was added to sodium hydride (oily, containing 60%, 205 mg, 5.12 mmol), and stirred at room temperature for 20 min, then piperidine-1,4-dicarboxylic acid 1- A solution of 4-(4-nitrophenyl)ester (1.79 g, 5.12 mmol) in N,N-dimethylformamide (23 mL) was stirred. After that, sodium hydride (oily, containing 60%, 200 mg, 5.00 mm 〇l) was added, and after stirring at room temperature for 20 minutes, piperidine-1,4-dicarboxylic acid 1-tertiary butyl ester 4- was added. A solution of 4-nitrophenyl) ester (895 mg, 2.5 5 mmol) in N,N-dimethylformamide (9 mL) was applied to a so-called room-temperature stirring operation, and then was applied twice at about 2 hours, and then stirred overnight. Implemented once. An aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and the mixture was evaporated. The residue was purified by EtOAc (MeOH: EtOAc: EtOAc: EtOAc: EtOAc: (26%). 1H-NMR (300MHz > CDCl3) 6: 1.2 1 (lH, m), 1.40 (9H, s), 1.69-2.44 (8H, m), 2.75-2.98 (3H, m), 3.88 (3H, s), 4.11 (2H, m), 4.85 (lH, m), 6.9 7 (lH, s), 7.35 (lH, d, J = 8.4 Hz), 8.03 (lH, d, J = 8.4 Hz), 8.63 (lH, s)· MS(FAB)m/z: 426(M + H)+.

[Example 16] [1-(2-Cyclohexylethyl)piperidin-4-yl](9-methoxy-3,4-dihydrobenzo[h][l,6]naphthyridine-1 (2H)-yl)methanone-204- 200948817

4-[(9-Methoxy-3,4-dihydrobenzo[h][l,6]naphthyridin-1 (2H)-yl)carbonyl]piperidine-1- obtained in Reference Example 37 A solution of the carboxylic acid tert-butyl ester (300 mg, 0.71 mmol) in dichloromethane (3 mL) was evaporated.

After concentrating the reaction mixture under reduced pressure, m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ), stirred at room temperature for 1 hour and 20 minutes. Further, under ice cooling, cyclohexylacetaldehyde (67 mg > 0.53 mmol) and hydrogenated sodium triethoxyborohydride (116 mg, 〇·5 3 mmol) were added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was applied to dichloromethane and washed with brine. After drying over anhydrous MgSO.sub.4, EtOAc (EtOAc:EtOAc) This was added to diethyl ether and η-hexane to solidify, and the mixture was filtered to give the title compound (yield: 8 mg). 1H-NMR (300MHz, CDCl3) 5: 0.83 (2H, m), 1.1 5-2.26 (22H, m), 2.65-2.97 (5H, m), 3.87 (3H, s), 4.87 (lH, m), 6.98(lH,s), 7.34(lH,d,J = 8.9Hz), 8.01(lH,d,J = 8.9Hz), 8.61(lH,s). MS(FAB)m/z:43 6(M + H)+.

[Reference Example 38] 4-[(9-Methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl)methyl]piperidin Third butyl pyridine carboxylic acid -205- 200948817

9-Methoxy-2,3-dihydro·1Η-[1,4]indole and [2,3-c]quinoline (1.51 g, 6.98 mmol) obtained in Reference Example 8 were dissolved in dimethyl The hydrazide (35 mL) was added with sodium hydride (oily, containing 55%, 365 mg ' 8.3 7 mmol) under ice cooling, and stirred at the same temperature for 1 hour. 4-(.methyl)piperidine-1-carboxylic acid tert-butyl ester (2.36 g, 8.37 mm) was added, and the mixture was stirred while stirring to room temperature for 24 hours. Ethyl acetate was added, and the mixture was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated, evaporated, mjjjjjjjjjj 〇1H-NMR (400MHz, CDCl3) 5: 1.24-1.42 (2H, m), 1.48 (9H, s), 1.94-2.09 (3H, m) s2.84-2.68 (2H, m), 3.02 (2H, d, J = 7.1 Hz), 3.29 (2H, t, J = 4.4 Hz), 3.92 (3H, s), 4.24 (4H, m), 7.17 (lH, dd, J = 9.0, 2.7 Hz), 7.25 ( lH,d,J = 2.7 Hz), 7.90 (lH, d, J = 9.0 Hz), 8_38 (lH, s). [Reference 39] 9-methoxy-1-[(piperidin-4-yl) )methyl]-2,3-dihydro-1H-[1,4]Df cultivating [2,3-c]quinoline

4-[(9-Methoxy-2,3-dihydro-1H-[1,4]indolo[2,3-c]quinolin-1-yl)methyl group obtained in Reference Example 38 The piperidine carboxylic acid tert-butyl ester (633 mg, 1.53 mmol) was dissolved in dichloromethane (10 mL), and then trifluoroacetic acid (2 mL·) was stirred under ice cooling for 5 hours. The solvent was distilled off under reduced pressure, and ice--------. After extracting with chloroform and drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give 485 mg (yield) of the title compound as a brown oil. 1H-NMR (400MHz, CDC13) 5: 1.3 l-1.44 (2H, m), 1.92-2.07 (3 H, m), 2.65-2.75 (2H, m), 3.0 1 (2H, d, J = 6.8 Hz ), 3.24 - 3.17 (2H, m), 3.29 (2H, t, J = 4.4 Hz), 3.94 (3H, s), 4.23 (2H, t, J = 4.4 Hz), 7_17 (lH, dd, J = 9.0, 2.9 Hz), 7_30 (lH, d, J = 2.7 Hz), 7.89 (lH, d, J = 9.3 Hz), 8.3 8 (lH, s). 0 [Example 17] 1- ({ l- [2-(2,3-Dihydro-1,4-benzodioxin-6-yl)ethyl]piperidin-4-yl}methyl)-9-methoxy-2,3-di Hydrogen-1H-[1,4]噚 and [2,3-c]quinoline

9-Methoxy-1·[(piperidin-4-yl)methyl]-2,3-dihydro-1Η-[1,4]噚[2,3- obtained in Reference Example 39 c] porphyrin (169 mg, 〇0.540 mmol), (2,3·dihydro-1,4-benzodioxin-6-yl)acetaldehyde (125 mg, 0.7 02 mmol) dissolved in methanol: dichloromethane = 1: 1 mixed solvent (10 mL), acetic acid (〇. 〇 46 ml, 0.810 mmol) and sodium cyanoborohydride (39.3 mg, 〇. 5 94 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 13 hours. After distilling off the solvent under reduced pressure, the residue was dissolved in chloroform to sat. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (chloroform-methanol). After adding 4N hydrochloric acid/dioxane solution (0.316 ml) 'ultrasonic treatment> to diethyl ether-ethanol and ultrasonic treatment, the solid was filtered to obtain a labeled compound 183 mg (58-207-200948817 1H) as a thin yellow solid. -NMR (400 MHz, CDCl3) 6: 1.46-1.65 (2H, m), 1.88 (lH, brs), 1.98-2.11 (4H, m), 2.55-2.64 (2H, m), 2.69-2.78 (2H , m), 3.〇3(2H,d,J = 7.3Hz), 3.07-3_16(2H,m), 3.29 (2H,t,J = 4.4Hz), 3.94(3H,s),4.2 1- 4.27 (6H, m), 6.68 (lH, dd, J = 8. 2, 2.1 Hz), 6.73 (lH, d, J = 2.0 Hz), 6.79 (lH, d, J = 8.1 Hz), 7.17 (lH) , dd, J = 9_0, 2.7 Hz), 7.29 (lH, d, J = 2.7 Hz), 7.89 (lH, d, J = 9.0 Hz), 8.3 8 (lH, s). MS (ESI) m/z :476(M + H) + .

[Reference Example 40] 2-[3-(4-Chloro-6-methoxyquinolin-3-yl)propyl]malonic acid diethyl ester

a solution of 4-chloro-3-(3·chloropropyl)-6-methoxyquinoline (5.00 g, 18.5 mmol) obtained in Reference Example 3 in N,N-dimethylformamide (100 mL) Potassium carbonate (12.8 g, 92_6 mm 〇l) and diethyl malonate (ll_2 mL, 74.0 mm 〇l) were added thereto and stirred at 80 ° C for 24 hours. The reaction mixture was partitioned between EtOAc (EtOAc m. The organic layer was combined and washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated, and the residue was purified (jjjjjjjjjjjjjjj Quantitative). 1H-NMR (400MHz, CDC13) 6: 1.26 (6H, t, J = 7.1 Ηζ), 1.76 (2H, m), 2.03 (2H, m), 2.96 (2H, t, J = 7.8 Hz), 3.3 8 (lH,t, -208- 200948817 J = 7_5Hz), 3.98 (3H, s), 4_19 (4H, m), 7.35 (lH, dd, J = 2_8, 9.3 Hz), 7. 45 (lH, d, J = 2.8 Hz), 7.96 (lH, d, J = 9.3 Hz), 8.56 (lH, s). [Reference 41] 2-methoxy-8,9-dihydro-711-phenanthridine-10, 10-dicarboxylic acid diethyl ester

4-[3·(4-Chloro-6-methoxyquinolin-3-yl) propyl]malonate diethyl ester (7.20 g, 18.3 mmol) of tetrahydrofuran obtained in Reference Example 40 (100 mL) solution, sodium hydride (oily, containing 55 %, 83 8 mg, 19.2 mmol), tris(tert-butyl)phosphine (443 μί, 1 ·83ηηηο1 ) and bis(dibenzylidene) were added under argon atmosphere. Acetone) dipalladium (837 mg, 0.914 mmol) was stirred at 7 ° C for 16 hours. The reaction mixture was diluted with ethyl acetate and filtered over Celite. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=3:1 - 1 : 2) to give the title compound 5.77 g (yield: 2-[3-(6-A) Oxyquinolin-3-yl)propyl]propane

-209- 200948817 The 2-methoxy-8,9-dihydro-7H-phenanthridine-10,10-dicarboxylic acid diethyl ester (5.77§) obtained in Reference Example 41 Water (871 μ! hydrazine and lithium chloride (2.05 g, 4 8.4 mmol) was added to a solution of carbamide (80 mL), and the mixture was stirred at 140 ° C for 11 hours. The insoluble material was filtered through Celite. The residue was slurried using diisopropyl ether:hexane = 1 : 1 mixed solvent, and the solid was filtered to give the title compound 2.48 g (47%) as a pale brown solid. The title compound was obtained as a light brown solid (yield: 28 g, 5%). The total yield was 2.76 g (52%). 1H-NMR (400 MHz, CDCl3) 6:1.20 (3H, t, J = 7.1 Hz), 1.93 (lH , m), 2.01-2.12 (2H, m), 2.33 (lH, m), 2.90 (lH, dd, J = 6.3, 9.8H z), 3.0 1 (lH, m), 4.15 (2H, m), 4.26 (lH, m), 7.06 (lH, d, J = 2.7 Hz), 7.27 (lH, dd, J = 2.7, 9.3 Hz), 7.95 (lH, d, J = 9.3 Hz), 8.54 (lH, s ).

[Reference Example 43] 2-methoxy-7,8,9,10-tetrahydrophenanthridine-10-formaldehyde

a solution of 2,methoxy-7,8,9,10-tetrahydrophenanthridine-10-carboxylic acid ethyl ester (1.00 g, 3.50 mmol) in toluene (30 mL) obtained in Reference Example 42. Next, a hydrogenated bis(2-methoxyethoxy)aluminum sodium/toluene solution (65%, 3.2 mL, 10.5 mmol) was added at 〇 °C. After warming to room temperature and stirring for 4 hours, the reaction was quenched by the addition of a 10% aqueous solution of Rochelle (5 mL). The aqueous layer was made basic with a 1N aqueous sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was combined and washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated, and the obtained residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc % ) ° 1H-NMR (400MHz, CDCl3) 5: 1.81 (lH, m), 1.92-2.05 (2H, m), 2.42 (lH5m), 2.93 (2H, m), 3.87 (3H5s), 4.13 (lH, m), 6.98 (lH, d, J = 2.7 Hz), 7.29 (lH, dd, J = 2.7, 9.0 Hz), 7.97 (lH, d, J = 9.0 Hz), 8.52 (l H, s), 9.70 (l H,d,J = 2.2Hz).

[Reference Example 44] { l-[(2-Methoxy-7,8,9,10-tetrahydrophenanthrin-10-yl)methyl]piperidin-4-yl}carbamic acid tert-butyl ester

(Piperidine-4 was added to a solution of 2·methoxy-7,8,9,10-tetrahydrophenanthryl-10-carbaldehyde (200 mg, 0.829 mmol) in dichloromethane (10 mL). The base butyl carbamate butyl ester (249 mg, 1.24 mmol) was stirred with sodium hydrogen triacetate borohydride (277 mg, 1.24 mmol) for 22 hours. After adding 1 N aqueous sodium hydroxide solution, it was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate (MgSO4), filtered and evaporated. The residue was slurried with diisopropyl ether. The solid was filtered, and then applied to the title compound (yield: methylene chloride: methanol = 10:1). The filtrate was concentrated and purified by EtOAc EtOAc (EtOAc:EtOAc: Total yield 25 8 mg (73 % ) 〇1H-NMR (400MHz, CDC13) 5: 1.46 (9H, s), 1.42-1.56 (lH, m), 1.67-1.95 (5H, m), 2.02 (lH, brd, J = l 1.5Hz), 2.21 (2H, m), 2.34 (1 H, brd, J = 1 3.0 Hz), 2.47-2.59 (2H, m), 2.79-2.94 (3H, m), -211- 200948817 3.15 (lH, m), 3.48_3.55 (2H, m), 3.92 (3H, s), 4.46 (lH, brs), 7.26 (1 H, dd, J = 2.7, 9.3 Hz), 7.33 (lH, d, J = 2.7 Hz), 7.92 ( lH, d, J = 9.3 Hz), 8.45 (1H, s).

[Reference Example 45] 1-[(2-Methoxy-7,8,9,10-tetrahydrophenidin-10-yl)methyl]piperidin-4-ylamine

Reference Example 44 obtained {1-[(2-methoxy-7,8,9,10-tetrahydrophenidin-10-yl)methyl]piperidin-4-yl}carbamic acid tert-butyl A solution of the base (174 mg, 0.409 mmol) in dichloromethane (8 mL) was then evaporated. The reaction solution was concentrated under reduced pressure and the residue was dissolved in water. After adding 1 N aqueous sodium hydroxide solution to make a basicity, it was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate (MgSO4). 1H-NMR (400MHz, CDC13) 6: 1.43 (2H, m), 1.68 (1H, m), 1.79 -1.94 (6H, m), 2.1 0 (2H, m), 2.33 (lH, brd, J = 12.9 Hz), 2.4 3-2.56 (2 H, m), 2.68 (lH, m), 2.76-2.92 (3H, m), 3.13 (lH, brd, J = 1 1 .0 Hz), 3.5 0 (lH, m), 3.91 (3H, s), 7.24 (lH, dd, J = 2.7, 9.1 Hz), 7.3 5 (lH, d, J = 2.7 Hz), 7.91 (lH, d, J = 9.1 Hz), 8.42 (lH, s).

[Example 18] N-(2-cyclohexylethyl) 1-[(2-methoxy-7,8,9,l〇-tetrahydrophenanthridine-l-yl)methyl]piperidine- 4-yl}amine-212- 200948817

1-[(2-Methoxy-7,8,9,10-tetrahydrophenidin-10-yl)methyl]piperidin-4-ylamine (122 mg, 0.375 mmol) obtained in Reference Example 45 The solution of dichlorocarbyl (10 mL) was added to cyclohexylethane (61.5 mg, 0.487 mmol) and sodium triethoxyborohydride (119 mg, 0.562 mmol) and the mixture was stirred for 17 hours. A saturated aqueous solution of sodium hydrogencarbonate was added and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate (MgSO4). The residue was purified by silica gel column chromatography (chloroform:methanol: water = 20:3:1) to hexanes. The solid was filtered and dried to give the title compound (yield: 128%). 1H-NMR (400MHz, CDCl3) 6: 0.92 (2H, m), 1.12-1.3 2 (5H, m), 1.40-1.5 1 (4H, m), 1.62-1.73 (6H, m), 1.85- 1.97 (4H,m), 2.12(2H,m), 2.35(lH,brd,J=12.4Hz), 2.46-2.60(3H,m), 〇2.68(2H,t,J = 7.5Hz), 2.79- 2.95(3H,m), 3.19 (1 H,brd,J=l 1.7Hz), 3.5 4 ( 1 H, m), 3.9 3 (3 H, s), 7.26 (1 H,dd,J = 2.4, 9.3 Hz), 7.3 9 (lH, d, J = 2.4 Hz), 7.93 (lH, d, J = 9.3 Hz), 8.46 (lH, s). HRMS (ESI) m/z: 436.33217 (calculated as C28H42N30: 436.33279).

[Example 19] 6-[({1-[(2-methoxy-7,8,9,10-tetrahydrophenidin-10-yl)methyl]piperidin-4-yl}amino) Methyl]-2H-1,4-benzopyrene-3 (4H)-keto-213- 200948817

1-[(2-Methoxy-7,8,9,10-tetrahydrophenidin-10-yl)methyl]piperidin-4-ylamine (67.0 mg, 0.206 mmol) obtained in Reference Example 45 a solution of dichloromethane-tetrahydrofuran (4 mL - 2 mL), adding 3-oxooxy-3,4-dihydro-2H-1,4-benzoindole-6-carbaldehyde (37 mg, 0.206 mmol) and hydrogenation Sodium triethoxyborohydride (69 mg, 0.309 mmol) was stirred for 12 hours. A saturated aqueous solution of sodium hydrogencarbonate was added and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and then filtered and evaporated. The residue was purified by fractional layer chromatography (yield, chloroform:methanol: water = 20 : 3 : 1 solvent), and the obtained pale yellow crystals were pulverized by adding hexane: ether = 1 : 1 mixed solvent. The solid was filtered and dried to give the title compound (yield: 79%).

1H-NMR (400MHz, CDCl3) 5: 1.20 (2H, m), 1.60- 1.73 (3H, m), 1.85 (lH, m), 1.97-2.13 (4H, m), 2.34 (lH, brd, J = 13.4 Hz), 2.47 (1H, dd, J = 9.9, 12.8 Hz), 2.56 (lH, dd, J = 2.8, 12.8 Ηζ), 2.67 (1 H, m), 2.78-2-9 5 (4H, m), 3.20 (lH, m), 3.52 (lH, m), 3.83 (2H, brs), 3.92 (3H, s), 4.50 (2H, s), 6.87 (lH, d, J = 8.1 Hz), 6.92 (lH, dd, J = 1.5, 8.1 Hz), 7.23 - 7.29 (2H, m), 7.35 (lH, d, J = 2.7 Hz), 7.92 (lH, d, J = 9 • OHz), 8.45 ( lH, s). HRMS (ESI) m / z: 487.27037 (calculated as C29H35N403: 487.27091).

[Example 20] 6-[({trans-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline- 1-yl)methyl]cyclohexyl}amino)methyl]-2H-pyridine-214- 200948817

The trans-4-[(9-methoxy-2,3-dihydro-1^1-[1,4]indole[2,3-(:]quinoline-) obtained in Reference Example 10 was obtained. 1-yl)methyl]cyclohexaneamine (65.511^, 0.200111111〇1), 3-sided oxy-3,4-dihydro-211-pyrido[3,2-13][1,4]thiophene Plough-6-formaldehyde (described in International Publication No. 2006/032466, etc., 42.7tng, 0.220 mm 〇1) was suspended in methanol: dichloromethane = 1: 1 mixed solvent (2 mL), and acetic acid (0.017 mL) was added under ice cooling. 0.300 mmol), sodium cyanoborohydride (14.6 mg, 0.22 mmol), stirred at room temperature for 13 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in chloroform:methanol:water = 7:3:1 The extract was washed with aq. EtOAc EtOAc (EtOAc m. C. The solid was filtered to give 60.0 mg (yield: EtOAc) m), 2.52-2.57 (lH, m), 2.98 (2H, d, J = 7.3 Hz), 3.28 (2H, t, J = 4.1 Hz), 3.48 (2H, s), 3.88 (2H) , s), 3.9 1 (3H, s), 4.22 (2H, t, J = 4.4 Hz), 6.98 (lH, d, J = 8.0 Hz), 7.16 (lH, m), 7.27 (2H, m), 7.59 (lH, d, J = 7.8 Ηζ), 7.89 (1 H, d, J = 9.0 Hz), 8.02 (lH, brs), 8.3 8 (1 H, s). MS (ESI) m/z: 506 (M + H) + .

[Example 21] trans-N-(2,3-dihydro[1,4]dioxines[2,3-c]pyridine-7-ylmethyl)_4-[(9-methoxy) - 2,3-Dihydro·1Η-[1,4]indole[2,3-c]quino-215- 200948817

The trans-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]porphyrin-bu) obtained in Reference Example 10 was used. Methyl]cyclohexaneamine (57.1 mg ' 0.174 mmol), 2,3-diamino {1,4]dioxin and [2,3-c]disc-7-methyl (31.6 mg, 0.191 mmol) The mixture was suspended in methanol (dichloromethane = 1 : 1) (2 mL), anhydrous sodium sulfate (198 mg) was added and stirred at room temperature overnight. Thereafter, hydrogenated sodium triethoxyborohydride (48.6 mg '0.218 mm 〇l) was added, and the mixture was stirred at room temperature for 19 hours. After distilling off the solvent under reduced pressure,

The residue was dissolved in chloroform:methanol:water = 7:3:1, and the solvent was washed with saturated aqueous sodium hydrogen carbonate. After drying over anhydrous sodium sulfate, the mixture was filtered and evaporated. The residue obtained was purified by column chromatography (chloroform-methanol). The obtained crude was triturated with methylene chloride-hexane, and the solid was filtered to afford 25.0 mg (30%) 1H-NMR (400MHz, CDCl3) 6: 1.15 - 1.34 (4H, m) 51.88 (2HJbrs), 2.12 (4H, d, J = 11.2 Hz), 2.56 (lH, t, J = 10.5 Hz), 2.97 (2H ,d,J = 7_3Hz), 3.28(2H,t,J = 4.2Hz), 3.85(2H,s),3,9 1(3H,s),4 • 22(2H,t,J = 4.2Hz) , 4.28-4.34 (4H, m), 6.82 (lH, s), 7.16 (lH, m), 7 _29 (lH, s), 7.88 (lH, d, J = 9.0 Hz), 8.12 (1 H, s ), 8.3 8 (lH, s). MS (ESI) m / z: 47 7 (M + H) +.

[Example 22] trans-N-(2,3-Dihydro[1,4]dioxines[2,3-b]pyridin-6-ylmethyl)-4-[ (9-methoxy) Base-2,3-dihydro-1Η-[1,4]Π§ till and [2,3-c]quino-216- 200948817

The trans-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indolo[2,3-c]quinolin-1-yl group obtained in Reference Example 10 was obtained. )methyl]cyclohexaneamine (88.6 mg, 0.271 mmol), 2,3-dihydro[1,4]dioxin[2,3-b]pyridine-6-carbaldehyde (described in International Publication No. 2006) /032466, etc., 49.2 mg, 0.298 mmol) 0. Methanol (methylene chloride) = 1:1 mixed solvent (3 mL), anhydrous sodium sulfate (308 mg). After that, hydrogenated sodium triethoxyborohydride (75.6 mg, 0.339 mmol) was added, and the mixture was stirred at room temperature for 19 hr. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform:methanol:water=7:3:1, and the solvent was washed with saturated aqueous sodium hydrogen carbonate. After drying over anhydrous sodium sulfate, the mixture was filtered and evaporated. The residue was purified by column chromatography (chloroform-methanol). Omg (22%). The title compound was obtained as a white solid. 〇*HN MR(400MHz, CDC13)5: 1.14-1.3 l(5H,m),l.88(1 H,m), 2.11(4H,d,J=11.5Hz),2.54(lH,t,J = 10.3 Hz), 2.97 (2H, d, J = 7.3H z), 3.28 (2H, t, J = 4.3 Hz), 3.8 1 (2H, s), 3.9 1 (3H, s), 4.24 (4H, m) 54. 44-4.46(2H,m), 6.86(1 H,d,J = 7.8Hz), 7.16(2H,m), 7.29( lH,d,J = 2·7Ηζ), 7.88( lH, d, J = 9.3 Hz), 8.3 8 (1 H, s) _ MS (ESI) m/z: 477 (M + H) + .

[Reference Example 46] {[(2-Bromo-4-methoxyphenyl)amino]methylene}malonic acid-ethyl ester -217- 200948817

2-Bromo-4-methoxyaniline (described in The Journal of Organic Chemistry, 2005, Vol. 70, No. 7, No. 2870-2873 > 13.89 g, 68.75 mmol) > Ethoxy Diethyl methylenemalonate (16.67 ml, 82.5 0 mmol) was dissolved in toluene (1 50 mL) and heated to reflux over 1 hour. After allowing to cool, the solid obtained by distilling off the solvent under reduced pressure was added hexane: ethyl acetate = 3:1 mixed solvent, and the mixture was stirred at 40 ° C for 30 minutes to dissolve. The resulting solution was subjected to ultrasonic treatment to form crystals, which were allowed to stand at room temperature for 1 hour. The crystals thus obtained were filtered, washed with hexane: ethyl acetate = 3:1 to give the title compound 14.63 g (yield: 57%). Further, after concentrating the filtrate, hexane was added thereto, and ultrasonic treatment was carried out to obtain a solid, thereby obtaining a labeled compound 7_62 g (30%) as a brown solid. 1H-NMR (400MHz, CDCl3) S: 1.33 (3H, t, J = 7.1 Hz), 1.38 (3H, t, J = 7.2 Hz), 3.8 1 (3H, s), 4.25 (2H, q, J = 7.2 Hz), 4.34 (2H, q, J = 7-2 Hz), 6.92 (lH, dd, J = 2.8, 8.9 Hz), 7.15 (lH, d, J = 7.2 Hz), 7_21 (l H > d, J = 8.8 Hz), 8.41 (lH, d, J = 13.7 Hz), 11.18 (lH, d, J = 15.1 Hz). [Reference Example 47] 8-bromo-4-hydroxy-6-methoxyquinoline 3-carboxylic acid ethyl ester

The {[(2-bromo-4-methoxyphenyl)amino]-218- 200948817 methylene}malonate diethyl ester (7.62 g, 2 0.47 mmol) obtained in Reference Example 46 was suspended in The EATONE reagent (30 mL) was stirred at 90 t for 24 hours. The reaction mixture was ice-cooled, and then slowly added to an aqueous solution of sodium carbonate (23.9 g, 225.17 mmol / 200 mL) while maintaining an internal temperature of 1 〇 ° C or less. The solid was filtered and washed with water. The obtained solid was dissolved in a chloroform-methanol mixed solvent and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and hexane-ether was added to the residue for honing. The solid was filtered, washed with hexane, and dried at 50° C to afforded 4.85 g (73%) 〇1H-NMR (400MHz, CDCl3) 5: 1.46 (3H, t, J = 7.1 Hz), 3.95 (3H, s), 4.49-4.5 l (2H, m), 7.61 (lH, brs), 7.77 (lH) , brs), 9.09 (lH, brs).

[Reference Example 48] 8-Bromo-4-chloro-6-methoxyquinoline-3-carboxylic acid ethyl ester

The 8-bromo-4-hydroxy-6-methoxyquinoline-3-carboxylic acid ethyl ester (4.0 g, 12.26 mmol) obtained in Reference Example 47 was added to phosphorus oxychloride (20 mL) at 5 °. C was stirred for 2 hours. After ice-cooling, the mixture was stirred under ice-cooling, and then added with 28% aqueous ammonia. The filtered solid was precipitated, washed with water, dissolved in chloroform and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated. mjjjjjjjjjjjjjjj 1H-NMR (400MHz, CDCl3) 5: 1.46 (3H, t, J- 7.2 Hz), 4. 〇〇 (3H, s) 94.50 (2H, q, J = 7.2 Hz), 7.63 (lH, dsJ = 2.7) Hz), 7.86 - 219- 200948817 (lH, d, J = 2.7 Hz), 9.15 (lH, s).

[Reference Example 49] 8-bromo-4-[({trans-4-[(3rd-butoxycarbonyl)amino]cyclohexyl}methyl)amino]-6-methoxyquinoline- 3-carboxylic acid ethyl ester

The 8-bromo-4-chloro-6-methoxyquinoline-3-carboxylic acid ethyl ester (1.77 g, 5.14 mmol) obtained in Reference Example 48, [trans-4-(aminomethyl)] Cyclohexyl] carboxylic acid grade 3 butyl ester (1.41 g, 6.17 mmol) was dissolved in dimethyl hydrazine (25 mL), triethylamine (1.07 ml, 7.71 mmol) was added and stirred at 80 ° C for 11 hr. After cooling, ether was added, and the mixture was washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal 1H-NMR (400MHz, CDCl3) 6: 1.12-1.17 (4H, m), 1.4 1 (3H5t, J = 7.1Hz), 1.44 (9H, s), 1.62 (lH, brs), 1.91-1.94 (2H, m), 2.O5-2.08 (2H, m), 3.41 (lH, brs), 3.61 (2H, t, J = 5.6 Hz), 3.90 (3H, s), 4.39 (2H, q, J = 7.1 Hz) ), 7.49 (lH, d, J = 2.7 Hz), 7.73 (lH, d, J = 2.7 Hz), 9.04 (lH, m), 9.12 (lH, s).

[Reference Example 50] [trans-4-({8-bromo-3-(hydroxymethyl)-6-methoxyquinolin-4-yl]amino}methyl)cyclohexyl]aminecarboxylic acid Grade 3 butyl ester

-220- 200948817 Lithium aluminum hydride (138 mg, 3.62 mmol) was suspended in tetrahydrofuran (15 mL) under a nitrogen atmosphere at -60 ° C. 8-bromo-4-[({trans-4) -[(3rd-order butoxycarbonyl)amino]cyclohexyl}methyl)amino]-6-methoxyquinoline-3-residic acid ethyl ester (1.62g, 3.02mmol) in tetrahydrofuran ( 15 mL) was dropped. Suddenly, the mixture was stirred for 24 hours while warming to room temperature. Under ice cooling, water (〇.15 mL), 5N aqueous sodium hydroxide solution (0.15 mL), and water (0.45 mL) were sequentially added and stirred overnight. The solvent was distilled off under reduced pressure, and the obtained residue was suspended in chloroform, and the insoluble material was filtered with Celite. The filtrate was concentrated under reduced pressure and the residue was purified mjjjjlililililililili 1H-NMR (400MHz, CDCl3) 6: 1.10-1.18 (4H, m) 51.42 (9H, s), 1.53 (5H, brs), 1.92- 1.95 (2H, m), 2.06-2.08 (2H, m), 3.38 (lH, brs), 3.59 (2H, t, J = 5.9 Hz), 3.8 8 (3 H, s), 7.47 (1 H, d, J = 2.7 Hz), 7.71 (lH, d, J = 2.7) Hz), 9.02 (lH, m), 9.10 (lH, s).

[Reference Example 51] (trans-4-{[(8-bromo-3·methyl)-6-methoxyquinolin-4-yl)amino]methyl}cyclohexyl)carbamic acid grade 3 Butyl ester

[trans-4-({[8-bromo-3-(hydroxymethyl)-6-methoxyquinolin-4-yl]amino}methyl)cyclohexyl]amine obtained in Reference Example 50 The butyl carboxylic acid grade 3 butyl ester (6.98 g, 14.12 mmol) was dissolved in dichloromethane (1 mL), and then added with EtOAc (14.86 g, 170.9. After the Celite filtration, the filtrate was concentrated under reduced pressure. EtOAcjjjjjjj 1H-NMR (400MHz, CDCl3) 6: 1.16 (4H, m), 1.43 (9H, s), 1.68 (lH, brs), 1.95-2.08 (4H, m), 3.41 (lH, brs), 3.72 (2H ,t,J = 6.0Hz), 3.89(3H,s), 4.37(lH,m), 7.60(lH,d,J = 2.7Hz), 7.76(lH,d,J = 2.7Hz),8.58(lH , s), 9.8S (lH, s), 10.19 (lH, m).

[Reference Example 52] (trans-4· {[(8-bromo-3-hydroxy-6-methoxyindol-4-yl)amino]methyl}cyclohexyl)carbamic acid, butyl butyl ester

Add m-chloroperbenzoic acid (2.10 g, 12.2 mmol) and potassium carbonate (1.69 g, 12.2 mmol) with methanol:dichloromethane = 1 : 1 mixed solvent (60 mL) at -15 ° C. Then, the compound obtained in Reference Example 51 (trans-4-([(8-)-3-methyl-3-ylidene-6-methoxysalin-4-yl)amino]methyl}cyclohexyl)amine was added dropwise. Methyl formate grade 3 butyl ester (2.0 g, 4.06 mmol) in methanol: dichloromethane = 1 : 1 (20 mL). After stirring for 2 hours, a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was stirred for 4 hours under ice-cooling, and extracted with a solvent of chloroform:methanol·water = 7:3:1, and the extract was combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure.mjjjjjjjjjjjjjjjjjjjjj , CDC13)6: 1.06 -1.1 7(4H,m), 1.43 (9H,s), -222- 200948817 1.5 1 (lH,brs),1.86- 1.89(4H,m),3.30-3.38(3H,m ), 3.89 (3H, s), 4.4 1 (lH, m), 7.16 (lH, m), 7.52 (lH, m), 8.35 (lH, s). [Reference Example 53] {trans- 4-[ (7-Bromo-9-methoxy-2,3-dihydro-1H-[1,4] indole[2,3-c]quinolin-1-yl)methyl]cyclohexyl}aminecarboxylic acid Grade 3 butyl ester

Reference Example 52 obtained (trans-4-{[(8-bromo-3-hydroxy-6-methoxyindol-4-yl)amino]methyl}cyclohexyl)aminecarboxylic acid grade 3 Butyl ester (1.55 g, 3.2 4 mmol) was dissolved in N,N-dimethylacetamide (15 mL), and potassium carbonate (2.69 g, 19.44 mmol) and 1,2-dibromoethane (0.84) were added at room temperature. mL, 9.72 mmol), stirred at 80 ° C for 11 hours. After cooling, diethyl ether was added, and the mixture was washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to dryness crystals crystals crystals crystals crystals 1H-NMR (400MHz, CDCl3) 5: l.ll-1.28 (4H, m), 1.44 (9H, s), 1.78 (lH, brs), 2.06-2.14 (4H, m), 2.92-2.93 (2H, m), 3.24 (2H, t, J = 4.4 Hz), 3.45 (lH, brs), 3.88 (3H, s), 4.21 (2H, t, J = 4.4 Hz), 4.40 (lH, brs), 7.25 ( 1 H,m), 7.53 (1 H, d, J = 2.7 Hz), 8.47 ( lH, s).

[Reference Example 54] (2E) -3-[l - ({trans-4-[(3rd-butoxycarbonyl)amino]cyclohexyl}methyl)-9-methoxy-2,3 -dihydro-1H-[1,4]indole and [2,3-c]quinolin-7-yl]ethyl acrylate-223- 200948817

The {trans-4-[(7-bromo-9-methoxy-2,3-dihydro-1H-[1,4]噚[[3,3-c] quinine] obtained in Reference Example 53 Phenyl-1-yl)methyl]cyclohexyl}aminecarboxylic acid, tert-butyl ester (200 mg, 0.395 mmol), potassium carbonate (109 mg, 0.790 mmol), tetrabutylammonium bromide (2 5 7 mg, 0.7 90 mmo 1 Dissolved in N,N-dimethylacetamide (4 mL), and added ethyl acrylate (0.106 mL, 0.988 mmol) and dichlorobis(triphenylphosphine)palladium (11) (29 mg, under a nitrogen atmosphere). 0.04 0mmol). The nitrogen substitution operation was carried out three times, and the mixture was stirred for 12 hours at 12 (TC). After cooling, water was added to extract with chloroform. The extract was dried over anhydrous sodium sulfate, filtered, and then evaporated under reduced pressure. The title compound (116.1 mg (0.221 mmol * 56%)) was obtained as a yellow oil (1H-NMR (400 MHz, CDC13) 6: 1.12-1.26 (4H, m), l .34(3H,t,J = 7.2Hz), 1.44(9 H ,8),1.7 8( lH,brs), 2.1 2 (4H,m),2.9 3 (2H,d,J = 7.3Hz), 3.25-3.26(2H,m), 3.44(lH,brs),3.90(3H,s), 4. 20-4.22(2H,m),4.2 7(2 H,q,J = 7.2Hz),4.4 0 (1 H, brs), 6.66 (lH, d, J = 16.3 Hz), 7.33 (lH, d, J = 2.9 Hz), 7.41 (lH, d, J = 2.7 Hz), 8.41 (lH, s), 8.78 (lH, d, J = 16.3Hz).

[Reference Example 55] ( 2E) -3 - { 1·[(trans-4-aminocyclohexyl)methyl]-9-methoxy-2,3-dihydro-1Η-[1,4] Sorghum and [2,3-c]salolin-7-yl}ethyl acrylate-224- 200948817

(2E) -3-[l-({trans-4-[(3rd-butoxycarbonyl)amino]cyclohexyl}methyl)-9-methoxy·2 obtained in Reference Example 54 , 3-dihydro-11^-[1,4] hydrazine and [2,3-〇]quinolin-7-yl]ethyl acrylate (355.511^, 0.67 6mmol) dissolved in dichloromethane (7mL) Under ice cooling, trifluoroacetic acid (1 mL) was added and stirred for 4 hours. The solvent was distilled off under reduced pressure, and the mixture was sat. The extract was extracted with chloroform:methanol:water = 7:3:1, and the extract was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the title compound (29. 1H-NMR (400MHz, CDCl3) 6:1.15-1.24 (4H, m), 1.34 (3H, t, J = 7.2 Hz), 1.80 (1H, brs), 1.98 (2H, m), 2.07 (2H, m) ), 2_69 (lH, m), 2.93 (2H, d, J = 7.6 Hz), 3.26 (2H, t, J = 4.3 Hz), 3.91 (3H, s), 4. 2 1 (2H, t, J = 4.4 Hz), 4.2 7 (2H, q, J = 7.2 Hz), 6.6 6 (lH, d, J = 16.3 Hz) Q , 7.19 (lH, m), 7.36 (lH, d, J = 2-7 Hz) ), 7.40 (lH, d, J = 2.2 Hz), 8.41 (l H, s), 8.79 (lH, d, J = 16.3 Hz).

[Reference Example 56] ( 2E) -3- { 9-methoxy- l-[(trans-4-{[(3-o-oxy-3,4-dihydro-2H-pyrido[3, 2-b][l,4]腭哄-6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro-1H-[1,4]indole[2,3 -c]quinoline-7-yl}ethyl acrylate

-225- 200948817 (2E)-3-{1-[(trans-4-aminocyclohexyl)methyl]-9-methoxy-2,3-dihydro·1Η obtained in Reference Example 55 -[1,4] 噚耕和[2,3-c]Salanta-7-yl}-propyl ethanoethyl vinegar (296.7 mg '0.676 mmol), 3·sideoxy-3,4-dihydro- 2H-pyrido[3,2-b][l,4]indole-6·formaldehyde (described in International Publication No. 2006/032466, etc., 132 mg, 0.744 mmol) suspended in methanol··dichloromethane=1: 1 A mixed solvent (10 mL) was added, and acetic acid (yield: 58 mL, l.OMmmol) and cyanoborohydride (49-2 mg, 0.744 mmol) were added under ice cooling, and stirred at room temperature for 13 hours. The solvent was distilled off under reduced pressure, and the solvent was dissolved in chloroform:methanol:water = 7:3:1, and washed with saturated aqueous sodium hydrogen carbonate. After drying over anhydrous sodium sulfate, the mixture was filtered and evaporated. The residue was purified by EtOAc EtOAc (EtOAc) 1H-NMR (400MHz, CDCl3) 6: 1.12-30 (4H5m), 1.34 (3H, t, J = 7_ 1Hz), 1.85 (1H, brs), 2.08-2.ll (4H, m), 2.50-2.55 (lH,m), 2.93(2H,d,J = 7.3Hz), 3.26(2H,t,J = 4.3Hz),3_83(2H,s),3.90(3H, s),4.2 1(2H,t , J = 4.3 Hz), 4.28 (2H, q, J = 7.2 Hz), 4.63 (2H, s), 6.66 (lH, d, J = 16.1 Hz), 6.92 (lH, d, J = 8.1 Hz), 7.19 (lH, d, J = 8.1 Hz), 7.3 6 (lH, d, J = 2.7 Hz), 7.40 (lH, d, J = 2.7 Hz), 8.4 1 (lH, s), 8.79 (lH, d , J = 16.1Hz).

[Example 23] (2E) -3 -{9-methoxy-l-[(trans-4-{[(3-o-oxy-3,4-dihydro-2H-pyrido[3, 2-b][l,4]噚T-6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro-1H-[1,4]噚 and [2,3 -c]quinoline-7-yl}acrylic acid-226- 200948817

(2E)-3-{9-methoxy-1-[(trans-4-{[(3-oxo-oxy-3,4-dihydro-2H-pyridyl) obtained in Reference Example 56. 3,2-b][l,4]噚耕-6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro-1H-[1,4]哔 and [2 , 3_c] quinoline-7-yl}-propyl acrylate acid ester (383.3 mg, 0.652 mmol) was suspended in 〇90% aqueous ethanol (20 mL) under ice-cooling, and added 20% aqueous sodium hydroxide solution (0.39 mL, 3.26 mmol) The mixture was stirred at 50 ° C for 3 hours. After cooling, the solvent was evaporated under reduced pressure, and the residue was dissolved in water. The solvent was extracted with chloroform:methanol:water = 7:3:1, and the extract was concentrated under reduced pressure. The residue was dissolved in a methanol-dichloromethane mixed solvent, and the plug was filtered to remove insolubles. The filtrate was concentrated under reduced pressure, and ethyl acetate was added and the mixture was stirred at 40 ° C for 30 min. After cooling, a solid was obtained by filtration to afford 193 mg (53%).

1H-NMR (400MHz, DMSO-d6) 5: 1.10-1.17 (5H, m), 1.82-2.0 7 (6H, m), 2.89-2.96 (2H, m), 3.22-3.27 (2H, m) , 3.74 (2H, s), 3.91 (3H, s), 4.20-4.25 (2H, m), 4.61 (2H, s), 6.76 (1 H, d, J = 16.3 Hz), 7. 〇 4 (lH , d, J = 8.0 Hz), 7.3 1 (lH, d, J = 8.0 Hz), 7.37 (lH, d, J = 2.7 Hz), 7.66 (lH, d, J = 2.7 Hz), 8.3 9 (lH , s), 8.72 (lH, d, MS (ESI) m/z: 5 60 (M + H) + .

[Reference Example 57] (2E) -3-{9-methoxy-l-[(trans-_4-{[(3-sideoxy-227- 200948817-yl-3,4-dihydro-2H-pyridine) And [3,2-b][l,4]thinyl-6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro-1H-[1,4] [2,3-c]quinoline-7-yl}ethyl acrylate

(2E) -3·{1-[(trans-4-aminocyclohexyl)methyl]-9-methoxy-2,3-dihydro-1Η-[1, obtained in Reference Example 55. 4] 噚耕和[2,3-c]quinoline-7-yl}ethyl acrylate (51.8 mg, 0.122 mmol), 3-sided oxy-3,4-dihydro-211-pyridine[3 , 2-1^[1,4]thiazol-6-carbaldehyde (described in International Publication No. 2006/032466, etc., 26.1 mg, 0.134 mmol) suspended in methanol: dichloromethane = 1: 1 mixed solvent (2 mL) Acetic acid (0.0 mL, 0.183 mmol) and sodium cyanoborohydride (8.9 mg, 0.13 4 mm) were added at room temperature and stirred at room temperature for 16 hours. After distilling off the solvent under reduced pressure, the residue was dissolved in chloroform:methanol: water = 20:3:1, and the solvent was washed with saturated aqueous sodium hydrogen carbonate. After drying over anhydrous sodium sulfate, it was filtered, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), and then purified by chromatography (yield, chloroform:methanol = 25:1). %). 1H-NMR (400 MHz, CDC13) 5: 1.17-1.29 (4H, m), 1.36 (3H, t, J = 7.2 Hz), 1.87 (lH, brs), 2.08-2.16 (4H, m), 2.5 1- 2.59(lH,m), 2.96(2H,d,J = 7.1Hz), 3.28(2H,t,J=4.3Hz), 3.48(2H,s),3.87 (2H,s),3.92(3H , s), 4.23 (2H, t, J = 4.3 Hz) 94.30 (2H, q, 7.0 Hz), 6.6 8 (lH, d5J = 16.1 Hz), 6.98 (lH, d, J = 7.8 Hz) 57.3 8 ( lH,d,J = 2.7 Hz), 7.42 (lH,d,J = 2.4 Hz), 7.58 (lH,d,J = 7.6 Hz), 8.43 (lHis), 8.8 1 (lH, -228 - 200948817) d, J = 16.1Hz).

[Example 24] (2E) -3 - { 9 -methoxy·ι_[(trans _4_ { [(3_ oxaoxy-3,4-dihydro-2H-pyrido[3,2- b][l,4]thiazol-6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro- lH-[l,4]Df till [2,3-c Quinoline-7-yl} acrylic acid

(2E ) -3- { 9-methoxy-1-[(trans-4-{ [( 3-sided oxy-3,4-dihydro-2H-pyridyl) obtained in Reference Example 57. 3,2-b][l,4]thorbic-6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro-lH-[l,4]Pf till [2 , 3-c] quinoline-7-yl}-propyl ethanoethyl vinegar (55.0 mg, 0.091 mmol) suspended in 90% aqueous ethanol (3 mL) under ice cooling, 20% aqueous sodium hydroxide (0.077 mL, 0.638) Methyl), stirred at 50 ° C for 4 hours. After allowing to cool, the solvent was distilled off under reduced pressure, and the residue was dissolved in water, and then neutralized with 1N hydrochloric acid under ice cooling. The solvent was distilled off under reduced pressure, and the residue was suspended in methanol-dimethylamine, and filtered, and filtered to remove insolubles. The filtrate was concentrated under reduced pressure, and the obtained residue was purified using reverse phase liquid chromatography (Develosil, 2 cm <|) x 10 cm, acetonitrile-water mixed solvent containing 0.1% formic acid. Omg (48%). The title compound was obtained as a pale yellow solid. MS (ESI) m/z: 5 76 (M + H) + .

[Reference Example 58] 8-Bromo-4-({[(3-butoxycarbonyl)piperidin-4-yl]methyl}amino)-6-methoxyquinoline-3-carboxylate Acid ethyl ester-229- 200948817

The 8-bromo-4-chloro-6-methoxyquinoline-3-carboxylic acid ethyl ester (3.00 g, 8.71 mmol) obtained in Reference Example 48, 1-(3rd-butoxycarbonyl)- 4-(Aminomethyl)piperidine (2.28 mL, 10.45 mmol) was dissolved in dimethyl argon (45 mL), triethylamine (1.82 mL, 13.07 mmol), and stirred at 80 ° C. hour. After cooling, ether was added, and the mixture was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified, mjjjjjjjj 1H-NMR (400MHz, CDCl3) 6: 1.22-1.25 (2H, m), 1.41 (3H, t, J = 7.1 Hz), 1.45 (9H, s), l-B0-1.83 (3H, m), 2.73 (2H, brs), 3.65 (2H5brs), 3.90 (3H, s), 4.15 (2H, brs), 4.39 (2H, q, J = 7.2 Hz), 7.48 (lH, d, J = 2.7 Hz), 7.74 (lH,d,J = 2.7Hz), 9.0 2-9.08(lH,m), 9.13(lH,s).

[Reference Example 59] 4-({[8-Bromo-3-(hydroxymethyl)-6-methoxyquinolin-4-yl]amino}methyl)piperidine-1-carboxylic acid, level 3 Butyl ester

Lithium aluminum hydride (403 mg, 10.63 mmol) was suspended in tetrahydrofuran (4 〇 mL), and 8_ bromo-4-({1-() obtained in Reference Example 58 was added dropwise at 〇 °C under nitrogen atmosphere. Grade 3 butoxycarbonyl)piperidin-4-yl]methylindolyl) -230- 200948817 -6-methoxysuccinyl-3-carboxylic acid ethyl ester (4.63 g, 8.86 mmol) of tetrahydrofuran ( 3 〇 mL) solution. The mixture was stirred for 7 hours while warming to room temperature. Under ice cooling, lithium aluminum hydride (90 mg, 2.37 mmol) was added and stirred for 1 hour. Under ice cooling, water (0.5 OmL), 20% aqueous sodium hydroxide solution (〇.50 mL) and water (1.50 mL) were sequentially added and stirred overnight. After drying with anhydrous sodium sulfate, the Celite was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was suspended in chloroform, and the insoluble material was filtered through Celite, and then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to afford 3.15g (74%). 1H-NMR (400MHz JCDCl3) 6: 1.18-1.3 1 (2H, m), 1.46 (9HJs) J 1.70- 1.86 (3H, m), 2.01 (lH, brs), 2.64-2.79 (2H, m), 3.43 ( 2H,t,J = 6.2Hz), 3.9 1(3H,s), 4.17(2H,brs),4.83(2H,s), 5.19-5.24(lH,m), 7.30(lH,d,J = 2.4 Hz), 7.71 (lH, d, J = 2.7 Hz), 8.46 (lH, m).

[Reference Example 60] 4-{[(8-bromo-3-carbamimido-6-methoxyquinolin-4-yl)amino]methyl}piperidine-1-carboxylic acid 3rd-stage butyl ester

4·(丨[8-bromo-3-(hydroxymethyl)-6-methoxyquinolin-4-yl]amino}methyl)piperidine-1-carboxylic acid obtained in Reference Example 59 A 3-stage butyl ester (3-15 g, 6.56 mmol) was dissolved in dichloromethane (30 mL). After the Celite was filtered, the filtrate was evaporated, evaporated, mjjjjjjjj 1H-NMR (400MHz, CDCl3) 6: 1.20- 1.32 (2H5m), 1.46 (9H, s), -231- 200948817 1.83-1.97 (3H, m), 2.69-2.82 (2H, m), 3.76-3.82 ( 2H,m),3.91(3H, s), 4.1 8 (2H,br s),7.6 l (lH,d,J = 2.7Hz), 7.79 ( lH,d,J = 2.7Hz), 8.62(lH, s), 9.91 (lH, s), 10.21-10.23 (lH, m).

[Reference Example 61] 4-{[(8-bromo-3-hydroxy-6-methoxyquinolin-4-yl)amino]methyl}piperidine-1-carboxylic acid grade 3 butyl ester

4-{[(8-Bromo-3-carbamimido-6-methoxyquinolin-4-yl)amino]methyl}piperidine-1-carboxylic acid obtained in Reference Example 60, Level 3 Butyl ester (2.90 g, 6.06 mmol) was dissolved in methanol: dichloromethane = 1:1 mixed solvent (60 mL), and added to potassium carbonate (2.51 g, 18.2 mmol), m-chlorobenzene at -15 ° C while stirring. Perbenzoic acid (3.14 g, 18.2 mmol) was stirred at 0 °C for 2 hours. Saturated aqueous sodium hydrogencarbonate solution was added under ice-cooling and stirred for 2 hr. It was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure.mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj *H-NMR (400MHz, CDC13)5:1.1 8-1.30(3H,m), 1.45 (9H,s), l_66-1.8 1(3H,m), 2.60-2.74(3H,m),3.44(2H , d, J = 5.6 Hz), 3.91 (3H, s), 4.03-4.19 (2H, m), 7.19 (lH, d, J = 2.7 Hz), 7.52 (lH, d, J = 2. 4 Hz), 8.28 (lH, s).

[Reference Example 62] 4-[(7-Bromo-9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl) Methyl] piperidine-1-carboxylic acid grade 3 butyl ester-232- 200948817

4-{[(8-bromo-3-hydroxy-6.methoxyquinolin-4-yl)amino]methyl}piperidine-1-carboxylic acid grade 3 butyl group obtained in Reference Example 61 The ester (1,00 g, 2.14 mm 〇l) was dissolved in N,N-dimethylacetamide (10 mL), and potassium carbonate (1.78 g, 12.87 mmol) and 1,2-dibromoethane were added at room temperature. (0.55 mL, 6.43 mmol), stirred at 80 ° C for 3 h. After cooling, diethyl ether was added, and the mixture was washed with water and saturated brine and dried over anhydrous sodium sulfate. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (chloroform-methanol) to afford white crystals. 1H-NMR (400MHz, CDC13) 6: 1.25- 1.42 (3H, m), 1.48 (9H, s), 1.93-2.05 (3H9m), 2.70-2.81 (2H, m), 2.96-3.01 (2H, m) , 3.28 (2H, t, J = 4.3Hz), 3.91 (3H, s), 4.18-4.28 (3H, m), 7.26 (lH, s), 7.56 (lH, d, J = 2.7 Hz), 8.50 ( lH, s). Q [Reference Example 63] 4-({ 7-[ ( IE) -3-ethoxy-3-oxopropen-1-yl]_9-methoxy-2,3-di Hydrogen·1Η-[1,4]indolo[2,3-c]quinoline-1-yl}methyl) piperidine-1-carboxylic acid grade 3 butyl ester

The 4-[(7-bromo-9-methoxy-2,3-dihydro-^-[1,4]indole-[2,3-c]quinoline·1· obtained in Reference Example 62. Base) methyl] piperidine carboxylic acid grade 3 butyl ester (654 mg, 1.33 mmol), potassium carbonate (368ing, 2.66 mmol), -233 200948817 tetrabutyl bromide (866 mg, 2.66 mmol) dissolved in N,N-dimethylacetamide (7 mL) was added with ethyl acrylate (〇·3 6 1 mL » 3.33 mmol), dichlorobis(triphenylphosphine)palladium(II) (95 mg, under nitrogen atmosphere). 0.133 mmol). The nitrogen substitution operation was carried out 3 times, and stirred at 1 20 ° C for 13 hours. After cooling, 'add water and extract with chloroform. The extract was dried over anhydrous sodium sulfate. EtOAc was evaporated. Ment, 48%) 〇1H-NMR (400MHz, CDC13) 6: 1.23- 1 , 3 3 (4H, m), l .3 6 (3H, t, J = 7.2 Hz), 1.48 (9H, s), l .93-2.06(3 H,m), 2.7 0-2· 8 2(2H,m), 3.00(2H,d,J = 7.1Hz), 3.2 9(2H,t,J = 4.3Hz), 3.9 3(3H, s), 4.2 5(2H, t, J = 4.4Hz), 4.3 0(2H,q,J = 7.2Hz), 6.68(1 H,d,J= 16.1Hz) ,7.33(1 H, d, J = 2.7 Hz), 7.43 (lH, d, J = 2.4 Hz), 8.44 (lH, s), 8.81 (lH, d, J = l 6 · 6 Hz) · [Reference Example 64] (2E -3-[9-methoxy-1-(piperidin-4-ylmethyl)_2,3_dihydro-1H-[1,4]indolo[2,3-c]quinoline-7 -based]ethyl acrylate

-3-Ethoxy-3_side oxygen 4-({ 7-[ ( 1E)ylpropen-1-yl]-9-methoxy-2,3_dihydro-1H obtained in Reference Example 63 -[1,4] ketone and [2 3_c]quinoline-l-yl}methyl)piperidine-1-carboxylic acid grade 3 butyl ester (327 2 , 〇.64〇mm〇l) was dissolved in Dichloromethane (5 mL) was added with tri-acetic acid (1 mL) under ice cooling for 23 hr. The solvent was distilled off under reduced pressure, and then, under ice-cooled, toluene-234-2009488. The extract was extracted with chloroform:methanol:water = 20:3:1, and the extract was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to yield 272.4mg (yield) of the title compound as a brown powder. *H-NM R (400MHz, CDC13) 5:1.20- 1.42(6H,m), 1.93-2.04

(3H, m), 2.65-2.74 (2H, m), 2.99 (2H, d, J = 6.8 Hz), 3.16-3.24 (2H, m), 3.29 (2H, t, J = 4.4 Hz), 3.95 ( 3H, s), 4.25 (2H, t, J = 4.3 Hz), 4.31 (2H, q, J = 7.2 Hz), 6.68 (lH, d, J = 16.1 Hz), 7.3 8-7.45 (2H, m) , 8 • 44 (1H, s), 8.81 (lH, d, J = 16.1Hz).

[Reference Example 65] (2E) -3-[l-({ l-[2-(2,3-dihydro-1,4-benzodioxin•6-yl)ethyl]piperidine-4 -yl}methyl)-9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]pipelin-7-yl]ethyl acrylate

Q (2E)-3-[9-methoxy-1-(piperidin-4-ylmethyl)-2,3-dihydro-1Η·[1,4]噚哄 obtained in Reference Example 64 And [2,3-c]quinolin-7-yl]ethyl acrylate (198 mg, 0.481 mmol), 2,3-dihydro-1,4-benzodioxin-6-yl acetaldehyde (102.9 Mg, 〇.5 77 mmol) suspended in methanol: dichloromethane = 1 : 1 mixed solvent (10 mL), acetic acid (〇. 〇 41 mL, 〇-722 mmol), sodium cyanoborohydride (3 5 mg, 0.529 mmol) ), stirred at room temperature for 29 hours. 2,3_Dihydro-indole, 4_benzodioxin-6-yl acetic acid (20 mg, 1.122 mmol) in methanol, methylene chloride = 1:1 (4 mL) solution, acetic acid (under ice) 0.04 lmL, 0.722 mmol), sodium cyanoborohydride (38 mg, -235-200948817 0.5 29 mmol), and stirred at room temperature for 13 hours. After the solvent was evaporated under reduced pressure, the residue was purified mjjjjlilililililili 1H-NMR (400MHz, CDCl3) 8: 1.36 (3H, t, J = 7.2 Hz), 1.53-1.6 1 (2H5m), 1.89-2.20 (3H, m), 2.73-3.13 (5H, m), 3.24- 3.32(3H,m), 3.96(4H,d,J=19.3Hz),4.2 1- 4.33(llH,m),6.64-6.86(4H,m),7.2 2-7.37(lH,m),7.41- 7.47 (lH, m), 8.43 (lH, s), 8.81 (lH, d, J = 16.3

Hz).

[Example 25] (2E) -3-[l -({ l-[2-( 2,3-dihydro-1,4-benzodioxin-6-yl)ethyl]piperidine- 4-yl}methyl)-9-methoxy-2,3·dihydro-1H-[1,4] indole [2,3-c]quinolin-7-yl]acrylic acid

(2E) -3-[1-({ 1-[2·(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl]piperidine obtained in Reference Example 65 -4-yl}methyl)-9-methoxy-2,3-dihydro-111-[1,4]indole and [2,3-(:]quinolin-7-yl]acrylic acid ethyl The ester (23 3.9 mg. 0.40 8 mmol) was suspended in a 90% aqueous solution of ethanol (1 〇mL), and then, under ice-cooling, a 20% aqueous sodium hydroxide solution (0.343 mL, 2.856 mmol) was added and stirred at 50 ° C for 4 hours. After that, the solvent was evaporated under reduced pressure, and the residue was dissolved in water <"&&&&&&&&&&&&&&&&&&&&&&&& Then, the solvent was evaporated under reduced pressure, and the obtained solid was suspended in methanol-dichloromethane, and then subjected to ultrasonic treatment, and was subjected to ultrasonication to give a solid to give 236 mg (64%) of -236-200948817 as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6) 5: 1.63 (lH, brs), 2.1 6 (2H, brs), 2.8 1-3.07 (5H, m), 3.22-3.33 (8H, m), 3.64 ( lH, brs), 3.96 (3H, s), 4.16-4.30 (7H, m), 6.69-6.86 (4H, m), 7.3 1 (lH, brs), 7.68 (lH, brs), 8.42 (lH, s ), 8.73 (lH, d, J = 16.3 Hz). MS (ESI) m / z: 546 (M + H) + .

[Reference Example 66] {trans-4-[(7-Cyano-9-methoxy-2,3-dihydro-1H-[1,4] indole [2,3-c]quinoline -1-yl)methyl]cyclohexyl}aminecarboxylic acid grade 3 butyl decyl ester

The {trans-4-[(7-bromo-9-methoxy-2,3-dihydro-1H-[1,4]腭[[,3,3-c]) saliva obtained in Reference Example 53 Phenyl-1-yl)methyl]cyclohexyl}aminecarboxylic acid, tert-butyl ester (474 mg, 0-93 5 mmol), zinc cyanide (224 mg, 1.871 mmol), ginsyl (dibenzylideneacetone) dipalladium (0) (86.1 mg, G 0.094 mmol), l,l'-bis(diphenylphosphino)ferrocene (53.7 mg, 0.094 mmol) suspended in N,N-dimethylformamide (20 mL) for 3 times Nitrogen substitution, stirring at 1 ° C for 18 hours. After allowing to cool, chloroform was added to the reaction mixture, washed with water and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated.jjjjjjjjjjj 1H-.NMR (400MHz, CDC13) 6: 1.11-1.31 (4H, m), 1.44 (9H, s), 1.78 (lH, brs), 2.07-2.16 (4H, m), 2.93 (2H, d, J = 7.3 Hz), 3.25 (2H, t, J = 4.5 Hz), 3.45 (lH, brs), 3.91 (3H, s), 4.22 (2H, t, -237- 200948817 J = 4.4 Hz), 4.41 (lH, brs), 7.48 (lH, d, J = 2.7 Hz), 7.54 (lH, d, J = 2.9

Hz), 8.5 l (lH, s).

[Reference Example 67] 1-[(trans-4-aminocyclohexyl)methyl]-9-methoxy-2,3-dihydro-1H-[1,4] 噚耕和[2,3 -c]quinoline-7-nitrile

The {trans-4-[(7-cyano-9-methoxy-2,3_dihydro-1H-[1,4]indole[2,3-c]quina) obtained in Reference Example 66 Phenyl-1-yl)methyl]cyclohexyl}carbamic acid butyl ester (288 mg, 0.63 6 mmol) was dissolved in dichloromethane (10 mL), and then trifluoroacetic acid (1 mL) was added and stirred for 4 hr. After distilling off the solvent under reduced pressure, the residue was dissolved in chloroform:methanol:water = 7:3:1, and the solvent was adjusted to basic. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated. The labeled compound 3 3 4 mg (quantitative) was obtained as a brown solid. 1H-NMR (400MHz, CDC13) 8: 1.18 (4H, t, J = 9.4 Hz), 1.75-1.8 6 (lH, m), 1.94-2.00 (2H, m), 2.04-2.10 (2H, m), 2.34 (lH, s), 2.69 (lH, brs), 2.93 (2H, d, J = 7.3 Hz), 3.26 (2H, t, J = 4.4 Hz), 3.91 (3 H, s), 4.22 (2H, t, J = 4.4 Hz), 7.12-7.24 (lH, m), 7.5 0-7.5 5 (2H, m), 8.51 (1 H, s).

[Example 26] 9-methoxy-l-[(trans-4-{[(3·-oxy-3,4-dihydro-2H-pyrido[3,2-b][l, 4]曙耕-6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro-1H-[1,4]indolo[2,3-c]quinoline-7 -nitrile 200948817

1-[(trans-4-aminocyclohexyl)methyl]-9·methoxy- 2,3-dihydro-1Η-[1,4] obtained from Reference Example 67 was cultivated and [2 ,3-c]quinoline-7-carbonitrile (224 mg, 〇.636 mmol), 3-sided oxy-3,4-dihydro-2H-pyrido[3,2-b][l,4] -6-formaldehyde (described in International Publication No. 2006/032466, etc., 125 mg, ^ 〇〇.7〇〇mmol) was suspended in methanol: dichloromethane = 1: 1 mixed solvent (10 mL), and acetic acid was added under ice cooling (〇. 〇55 mL, 954.954 mmol), hydrogenated sodium borohydride (46 mg, 0.700 mmol). The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform:methanol:water=7:3:1, and the solvent was washed with saturated aqueous sodium hydrogen carbonate. After drying over anhydrous sodium sulfate, the mixture was filtered, and then evaporated. The residue was purified by EtOAc EtOAc (EtOAc) elute 1H-NMR (400MHz, DMSO-d6) 8: 1.07-1, 19 (4H, m), 1.88 Q (lH, brs), 1.94-2.04 (4H, m), 2.41 (2H, brs), 2.95 (2H) ,d,J = 7.1Hz), 3.24-3.29(2H,m), 3.72(2H,s),3.93(3H,s),4.22-4.26(2H,m), 4-6l(2H,s), 7.03 (lH, d, J = 8.1 Hz), 7.30 (lH, d, J = 8.1 Hz), 7.54 (lH, d, J = 2.7 Hz), 7.85 (lH, d, J = 2.7 Hz), 8.47 ( lH, s), 11.15 (lH, brs). MS (ESI) m/z: 5 1 5 (M + H) + .

[Reference Example 68] {trans-4-[(7-cyano-9-methoxy-2,3-dihydro-1H-[1,4] indole [2,3-c]quinoline -1-yl)methyl]cyclohexyl} [(3-Sideoxy-3,4-dihydro-21{-pyrido[3,2-1^[1,4]曙耕-6-yl) Methyl]carbamic acid grade 3 butyl ester-239- 200948817

9-Methoxy-l-[(trans-4-{ [( 3-sidedoxy-3,4-dihydro-2Η-pyrido[3,2-b]]) obtained in Example 26. 1,4]噚哄-6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline -7-wax (126.7 mg, 0.246 mmol) was dissolved in dichloromethane (2 mL), and under ice cooling, triethylamine (〇.〇 69 mL, 0.492 mmol), and di(tri-tert-butyl)dicarbonate were added. The ester (80.5 mg, 0.369 mmol) was stirred for 27 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, which was extracted with dichloromethane and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to dryness crystals crystals crystals crystals crystals 1H-NMR (400 MHz, CDCl3) 6: 1.16-1.30 (2H, m) > 1.32-1.55 (llH, m), 1.66-1.92 (3H, m), 2.05-2.14 (2H, m), 2.91 (2H) , d, J = 7.3 Hz), 3.19-3.25 (2H, m), 3.91 (3H, s), 4.18-4.24 (2H, m), 4.34 〇 (2H, brs), 4.64 (2H, s), 5.27 -5.29 (lH, m), 6.85-6.95 (lH, m), 7.18-7.23 (lH, m), 7.47 (lH, s), 7.52-7.56 (lH, m), 8.l2-8.21 (lH, m), 8.50 (lH, s).

[Reference Example 69] [trans-4-({7-[(Z)-Amino (hydroxyimino)methyl]-9-methoxy-2,3-dihydro-1H-[1, 4] 噚耕和[2,3-c]quinoline-l-yl}methyl)cyclohexyl][(3-sideoxy·3,4·dihydro-2H-pyrido[3,2-b ][l,4]曙耕- 6-yl)methyl]aminecarboxylic acid grade 3 butyl ester-240- 200948817

Ο

The {trans-4-[(7-cyano-9-methoxy-2,3-dihydro-1Η-[1,4]indole[2,3-c] obtained in Reference Example 68. Quinoline-1-yl)methyl]cyclohexyl} [(3-Sideoxy-3,4-dihydro-211-pyrido[3,2-1)][1,4]噚-6-6- The dimethyl ester of methyl]aminoformic acid (183_9 mg, 0.29 9 mmol) was dissolved in ethanol (4 mL), and hydroxylamine hydrochloride (214 mg, 2.99 mmol), sodium carbonate (317 mg, 2.99 mmol), water ( lmL), heated to reflux for 7 hours. After cooling, the solvent was evaporated to dryness crystals crystals crystals crystals crystals 1H-NMR (400MHz, CDCl3) 6: 1.15-1.98 (2 1H, m), 2.03-2.12 (2H, m), 2.88-2.94 (2H, m), 3.20-3.25 (2H, m), 3.89 (3H) , s), 4.16-4 .2 1 (2H, m) > 4.34 (lH, brs), 4.64 (2H, s), 6.65 (lH, brs), 7.20 (lH, d, J = 7.8 Hz), 7.3 1- 7.34(lH,m), 7.73 -7.77(lH,m), 8.30(lH,s).

[Example 27] 9-methoxy-l-[(trans-4-{[(3-o-oxy-3,4-dihydro-2H-pyrido[3,2-b][l, 4]噚-6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro-1Η·[1,4]曙[[,3,3-c]quinoline-7 -carbamidine

-241 - 200948817 [Trans- 4·({7-[(ζ)-Amino (sinoimido)methyl]-9-methoxy-2,3-dihydrogen] obtained in Reference Example 69 -1Η-[1,4] 曙耕和[2,3-c]quinoline·l-yl}methyl)cyclohexyl][(3-trioxy-3,4-dihydro-2H-shacilidine And [3,2-b][l,4]decane-6-yl)methyl]aminecarboxylic acid grade 3 butyl ester (60.0nig, 0.093mmol) was dissolved in dichloromethane (2mL), ice cold, Trifluoroacetic acid (0.5 mL) was added and stirred for 4 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform:methanol:water=7:3:1. The mixture was adjusted to be basic with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with a solvent of chloroform:methanol:water=7:3:1, and the extract was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, dichloromethane-hexane was added to the residue, and the mixture was subjected to ultrasonic treatment, and the mixture was stirred at 40 ° C for 30 minutes. After allowing to cool, the solid was filtered to give the title compound 35 mg (69%) as white solid. 1H-NMR (400 MHz, DMSO-d6) 6: 1.07-1.27 (2H, tn), 1.80-2.0 6 (5H, m) 52.3 1-2.48 (2H, m), 2.92 (2H, d, J = 7.6 Hz), 3-24-3.28(2H,m), 3.29(2H,s),3.71(2H,brs),3.88(3H,s)5 4.2l-4.25(2H,m),4.60-4.62(2H , m), 6.51 (2H, brs), 7.03 (lH, d, J = I8.0Hz), 7.3 0 (lH, d, J = 8.0Hz), 7.33 (lH, d, J = 2.9Hz), 7.50 (lH,di J = 2.7 Hz), 8.34 (lH, s), 9.68 (lH, s), 11.15 (lH, brs). MS ( ESI ) m/z : 548 ( M + H ) + .

[Reference Example 70] ( 2E) -3- { l-[(trans-4-{(3rd-order butoxycarbonyl) [(3-o-oxy-3,4-dihydro-2H-pyridyl) [3,2-b][l,4]噚耕-6-yl)methyl]amino}cyclohexyl)methyl]-9-methoxy-2,3-dihydro-1H-[1, 4] 噚耕和[2,3-c]quinolin-7-yl}ethyl acrylate-242- 200948817

The (2Ε)·3_{9_methoxy·〗 _[(trans-4-{ [( 3-sided oxy-3,4-dihydro 2 Η-pyridyl][3] obtained in Reference Example 56 was dissolved. ,2-b][l,4]Df 耕- 6-yl)methyl]amino}cyclohexyl)methyl b 2,3 -dihydro-1H-[1,4]噚 and ^ [2, 3_c] quinoline-7-yl}ethyl acrylate (242.7 mg, 0.41 3 mmol) in dichloromethane (4 mL), triethylamine (〇.115 mL, 0.8 2 6 mmol), and Butyl butyl) dicarbonate (i36ing, 0.020 mmol) 'Stirring for 17 hours. Chloroform was added and washed with a saturated aqueous solution of sodium hydrogencarbonate and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal 1H-NMR (400MHz, CDC13) 6: 1.26- 1.5 3 (5H, m), 1.34 (3H, t, J ❹ = 7.2 Hz), 1.55 (9H, s), 1.72 (lH, brs) 91.82 (2H, Brs), 2.02 (lH, s), 2.06-2.13 (2H, m), 2.92 (2H, d, J = 7.3 Hz), 3.19-3.24 (2H5m), 3.90 (3H, s), 4.17-4.2 1 ( 2H,m), 4.27(2H,q,J = 7.2Hz), 4.34(1 H,brs),4.64(2H, s),6.66(1 H,d,J = l 6.3Hz) ,6.89 (1 H , brs), 7.1 8-7.22 (1H, m), 7.30-7.33 (lH, m), 7.39-7.41 (lH, m), 8.01-8.12 (lH, m), 8.40 (lH, s), 8.78 ( lH,d,J=16.1 Hz). [Reference Example 71] 3- { l-[(trans-4-{(3rd-order butoxycarbonyl)[(3-sideoxy-3,4-di) Hydrogen-2H-pyrido[3,2-bnU4]indole-6-yl)methyl]amino}cyclohexyl)methyl]-9-methoxy-2,3·dihydro-1H-[1 , 4] 噚耕和[2,3-c] -243 - 200948817 唾琳-7-yl} -2,3-dihydroxypropionate ethyl ester

(2E) -3 - { 1-[(trans-4-{(3rd-butoxycarbonyl)[(3-o-oxy-3,4-dihydro-2H-) obtained in Reference Example 70 Pyrido[3,2-b][l,4] indole-6-yl)methyl]amino}cyclohexyl)methyl]-9-methoxy-2,3-dihydro-111-[ 1,4] 曙耕和[2,3-(:]quinoline-7-yl oxime ethyl acrylate (207_511^, 〇.3 02mmol) dissolved in tetrahydrofuran: water: acetone = 2: 1: 2 mixed solvent (5mL), under ice cooling, add N-methylmorpholine-N-oxide (81.6mg, 〇-604mm〇l), oxidize (catalytic amount), stir for 29 hours. Add chloroform to saturated hydrogencarbonate The aqueous solution was washed with sodium sulfate and dried over anhydrous sodium sulfate. After filtered, the solvent was evaporated. ).

1H-NMR (400MHz, CDCl3) 8: 1.27 (3H, t, J = 7.2 Hz), 1.33-1.4 1 (6H, m), 1.54 (9H, s), 1.83 (4H, brs), 2.06-2.10 ( 2H,m)s2.93 (2H,d,J=7.3Ηζ),3·2 l-3.23(2H,m),3.8 8(3H,s),4.1 7-4.20 UH,m),4.22-4.25 (2H,m), 4.33(2H,brs) ,4.5 1(1 H,d,J = 3.2Hz),4 •64(2H,s),5.43(lH,d,J = 3.2Hz), 6.89( lH, s), 7.10 (lH, brs), 7.17-7.1 9 (1 H, m), 7.94-7.97 (1 H, m), 8.23 (1 H, s).

[Reference Example 72] 2,3-Dihydroxy-3-{ 9-methoxy-l-[(trans-4-{ [(3-o-oxy-3,4-dihydro-2H-pyridine) [3,2-b][l,4]哔-6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro-1H-[1,4] 2,3-c]quinoline-7--244- 200948817 base}ethyl propionate

〇

3-{ W (trans-4-{(3rd-butoxycarbonyl)) [3-3-oxo- 3,4-dihydro-2Η-pyrido[3,2] obtained in Reference Example 71 -bni,4]?哄-6-yl)methyl]amino}cyclohexyl)methyl b-9-methoxy-2,3_dihydro_1H_[14] 噚耕和[2,3-&lt ;:]Quinoline-7-yl}-2,3-dihydroxypropionic acid ethyl ester (190.2 mg, 0.264 mmol) was dissolved in dichloromethane (5 mL), ice-cooled, trifluoroacetic acid (1 mL) hour. The solvent was evaporated under reduced pressure, and the residue was evaporated to ethylamine. The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure.mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 6:1.10-1.24(4H,m), 1.27(3H,t,J=7.1Hz),1.80-1.9 1(4H,m),2.05-2.12(4H,m),2.47-2.56(lH,m) , 2.95 (2H, d, J = 7.1 Hz), 3.2 6 (2 H, t, J = 4.4 Hz), 3.82 (2H, s), 3.8 8 (3 Η, s), 4· 1 8-4.23 ( 3Η,m),4.23-4.26(lH,m),4.5 l-4.53(lH,m),4.63( 2H,s),5.43(lH,d,J = 2.9Hz),6.91(lH,d,J = 8.3 Hz), 7_ 1 0 (lH, d, J = 2.7 Hz), 7_ 1 9 (lH, d, J = 8.0 Hz), 7.22 (lH, d, J = 2, 7 Hz), 8.24 (lH, s).

[Example 28] 2,3-dihydroxy-3-{9-methoxy-l-[(trans-4-{[(3-245-200948817)-oxyl-3,4-dihydro- 2H-pyrido[3,2-b][l,4]indole-6-yl)methyl]amino}cyclohexyl)methyl b 2,3-dihydro-1H-[1,4]曙Plough [2,3-c]quinolin-7-yl}propionic acid

2,3-Dihydroxy-3-{ 9-methoxy-1-[(trans-4-([3- 3-oxy]3,4-dihydro-2H-) obtained in Reference Example 72. Pyrido[3,2-b][l,4]indole-6-(yl)methyl]aminoindolecyclohexyl)methyl]-2,3-dihydro 4]indole and [2,3 -c] quinoline-7-yl}propionic acid ethyl vinegar (134.2 mg, 0.216 mmol) was suspended in 90% aqueous ethanol (10 mL), and then, with ice-cooled, 20% aqueous sodium hydroxide (0.216 mL, USOmmol) 'Stirring at 50 ° C for 2 hours. After allowing to cool, the solvent was evaporated under reduced pressure, and the residue was dissolved in water, and the mixture was neutralized by adding 1N hydrochloric acid under ice cooling. The solvent was distilled off under reduced pressure, and methanol was added to the residue for ultrasonic treatment, and the mixture was stirred at 40 ° C for 30 minutes. After the insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and diethyl ether was added to the residue and subjected to ultrasonic treatment. The solid was filtered, and purified by ion-exchanged resin (HP20, water-methanol) to give the title compound 8 mg ( 6% ) as a brown solid. !H-NMR (400MHz, DMSQ-d6) 5: 1.07 - 1.24 (4H, m), 1.82-2.0 9 (5H, m), 2.40-2.49 (1 H, m), 2.84-2.98 (2H, m), 3.15-3.33 (2H, m), 3.72 (lH, s), 3.85 (3H, s), 3.91 (lH, d, J = 2.4 Hz), 4.12 (lH, s), 4.15 · 4.25 (2H , m), 4.6 1 (2H, s), 5.73-5.78 (lH, m), 5.96 (lH, d, J = 2.4 Hz), 6.47 (lH, m), 6.8 1 (lH, m), 7.04 ( lH,d,J = 8.0Hz), 7.13(lH,d,J = 2.9 H z) , 7.27-7.3 2(2H,m) , 8.28(1 H,s) ,8.48(1 H,s) ,11.1 7(1 H, brs). • 246- 200948817 MS (ESI) m/z: 594 (M + H) + .

[Reference Example 73] [trans- 4-({ 7-[(Z)-(ethoxy)imido)(amino)methyl]-9-methoxy-2,3-dihydro- 1H-[1,4]indolo[2,3_c]quinoline-buyl}methyl)cyclohexyl][(3-trioxy-3,4-dihydro-2H-pyrido[3,2 -b][l,4] 噚-6-yl)methyl]aminecarboxylic acid grade 3 butyl ester

[ [trans-4-({7-[(Z)-Amino (hydroxyimino)methyl]-9-methoxy-2,3-dihydro-1H-) obtained in Reference Example 69 [1,4]indolo[2,3-c]quinoline-l-yl}methyl)cyclohexyl][(3-trioxy-3,4-dihydro-2H-pyrido[3, 2-b][l,4]噚耕-6-yl)methyl]aminecarboxylic acid grade 3 butyl ester (40.9mg, 0.063mmol) was dissolved in tetrahydrofuran (1mL), added to the third stage butoxy Potassium (7.1 mg, 0_063 mmol), chloroacetamidine (〇.〇i 4 mL, 0.18 9 mmol) was stirred for 13 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with brine. After drying over anhydrous sodium sulfate, the mixture was filtered, and then evaporated. The residue was purified by EtOAc EtOAc (EtOAc) elute !HN MR (400MHz, CDC13) 6: 1.1 3-1.55 (1 5H, m), 1.78-1.88 (3H, m), 2.0 3-2.12 (2H, m), 2.2 5 (3H, s), 2.92 ( 2H,d,J = 7.3Hz), 3.2 0-3.26 (2H,m), 3.90(3 H,s),4.16-4.23 (2H,m), 4.29 ·4.45 (2H,m), 4.64(2H, s), 6.85-6.96 (lH, m), 7.18-7.23 (lH, m), 7_35-7.39 (lH, m), 7.92-7.94 (1 H, m), 8.24 (1 H, brs), 8.29 ( 1 H, s).

[Example 29] 9-methoxy-1-[(trans-4-{[(3-olyloxy-3,4-dihydro-211--247- 200948817 pyrido[3,2-b] ][l,4]噚耕-6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro-1H-[1,4]indole[2,3-c] Quinoline·7·carbamamine 0-acetamido

[trans-4-({ 7-[ ( Z)-(ethyl methoxyimino)(amino)methyl]-9-methoxy-2,3-di obtained in Reference Example 73 Hydrogen-1H-[1,4]indolo[2,3-c]quinoline-l-yl}methyl)cyclohexyl][(3-trioxy-3,4-dihydro-2H-pyridine And [3,2_b][l,4]曙哄-6-yl)methyl]aminecarboxylic acid grade 3 butyl ester (47.7mg, 0.069mmol) was dissolved in a chloroform (4mL), added three under ice cooling Fluoroacetic acid (〇. 5 mL) was stirred for 5 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in chloroform:methanol:water=7:3:1. The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. EtOAc m. ). MS (ESI) m / z: 5 90 (M + H) + .

[Reference Example 74] [trans-4-({7-[Amino(imino)methyl]-9-methoxy-2,3-dihydro-111-[1,4]曙 and [ 2,3-(:]Salanta-1-yl}methyl)cyclohexyl][(3_ oxo-3,4-dihydro-211-pyrido[3,2-1)][1,4 ]噚耕-6-yl)methyl]aminecarboxylic acid grade 3 butyl ester-248- 200948817

[Trans-4-({ 7-[(Z)-Amino (hydroxyimino)methyl]-9-methoxy-2,3-dihydro-1H-[] obtained in Reference Example 69. 1,4]indolo[2,3-c]quinoline-l-yl}methyl)cyclohexyl][indole-sideoxy-3,4-dihydro-2H-pyrido[3,2- b] [l,4]噚-6-yl)methyl]aminecarboxylic acid, a third butyl ester (57.6 mg, 0.08 9 mmol) was dissolved in methanol (1 mL), and 10% palladium carbon catalyst was added (Μ, It contains about 50% water, 25 mg), anhydrous acetic acid (0.1 mL), and stirred under a hydrogen atmosphere for 19 hours. After the catalyst was filtered with Celite, the solvent was evaporated under reduced pressure to give 44.5 mg (yield: 79%) as a red oil. MS (ESI) m/z: 632 (M + H) + .

[Example 30] 9-methoxy-l-[(trans-4-{[(3_sideoxy-3,4-dihydro-2H-pyrido[3,2-b][l, 4]曙哄-6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline-7 -甲脒

[Trans-4-({7-[Amino(imino)methyl]-9-methoxy-2,3-amino-1H-[1,4]) obtained in Reference Example 74哄[2,3-c]Salina- l-yl}methyl)cyclohexyl][(3-sideoxy-3,4-dihydro-2H-indole ratio steep [3,2-b] [l,4]曙-249- 200948817 哄-6-yl)methyl]aminecarboxylic acid butyl ester (445 mg, 〇.070 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid was added under ice cooling ( 〇.5rnL), carry 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in chloroform:methanol: water = 7:3:1. The organic layer was separated and dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was added to methylene chloride-hexane to tribr. and filtered to afford solid </ RTI> 6.3 mg (17%). MS (ESI) m / z: 532 (M + H) + .

[Reference Example 75] [trans-4-(丨7-[(Z)-amino(methoxyimino)methyl]:9-methoxy- 2,3-dihydro-1H-[ 1,4]噚[幷,[2,3-c]quinoline-l-yl}methyl)cyclohexyl][(3-o-oxy-3,4-dihydro-2H-pyrido[3,2 -b][l,4]噚-6-yl)methyl]aminecarboxylic acid grade 3 butyl ester

[Trans-4-({7-[(Z)-Amino (hydroxyimino)methyl]-9-methoxy-2,3-dihydro-1H-[] obtained in Reference Example 69. 1,4]噚 and [2,3-c]quinoline-l-yl}methyl)cyclohexyl][(3-trioxy-3,4-dihydro-2H-pyrido[3,2 -1)][1,4]噚耕-6-yl)methyl]aminecarboxylic acid grade 3 butyl ester (58.611^' 0.09 0mmol) dissolved in tetrahydrofuran (2mL), added to the third stage butoxy Potassium (10.2 mg, 0.090 mmol), iodine (17 mL, 0.270 mmol) was stirred for 18 hours. Under ice cooling, a third-stage potassium butoxide (10.2 mg, 〇. 〇 90 mmol) was then added to iodomethane (0.017 mL, 〇.270 mmol) and stirred for 3 hours. The reaction solution was diluted with chloroform, washed with water and dried over anhydrous sodium sulfate-250-2009488. After filtration, the solvent was evaporated under reduced pressure. EtOAc (EtOAc) MS (ESI) m/z: 662 (M + H) + .

[Example 31] 9-methoxy-l-[(trans-indole [(3-o-oxy-3,4-dihydro-2H-pyrido[3,2-b][l,4]噚耕-6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-7- Amidoxime-methyloxime

[ [trans-4-({7-[(Z)-amino(methoxyimino)methyl]-9-methoxy-2,3-dihydro-) obtained in Reference Example 75 1H-[1,4]噚[[2,3-c]quinoline-l-yl}methyl)cyclohexyl][(3-trioxy-3,4-dihydro-2H-pyridin[ 3,2-b][l,4]噚-6-yl)methyl]aminecarboxylic acid, butyl ester (30 mg, 0.045 mmol) was dissolved in dichloromethane (3 mL). (0.4mL), mixing for 3 hours. Further, under ice cooling, trifluoroacetic acid (1 mL) was added and stirred for 2 hours, and then the solvent was evaporated under reduced pressure. The residue was dissolved in chloroform:methanol:water = 7:3:1. The solvent of the lower layer was adjusted to basic with saturated aqueous sodium hydrogen carbonate. The organic layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. ethyl acetate-hexane (EtOAc) MS (ESI) m/z: 562 (M + H) + .

[Reference Example 76] 5-[l - ({trans-4-[(3rd-butoxycarbonyl)amino]cyclohexyl}methyl)-9-methoxy-2,3-dihydro- 1H-[1,4]噚 and [2,3-c]quino-251- 200948817 phenyl-7-yl]thiophene-2-carboxylic acid

The {trans-4-[(7-bromo-9-methoxy-2,3-dihydro-1Η-[1,4]噚耕[2,3-c] saliva obtained in Reference Example 53) Phenyl-1-yl)methyl]cyclohexyl}carbamic acid grade 3 butyl ester (100 mg, 0.197 mmol), dichlorobis(triphenylphosphine) palladium (II) (7.2 mg, O.OOmmol), 5 -(Dihydroxyboroboryl)-2-thiophene decanoic acid (53.6nig, 0.296mmol), sodium carbonate (31.4mg, 0.296mmol) suspended in water: 1,2-dimethoxyethane:ethanol=1: A mixed solvent of 5:3 (9 mL) was stirred at 80 ° C for 11 hours. The solvent was evaporated under reduced pressure. The extract was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 1H-NMR (400MHz, CDC13) 6: 1.09-1.3 l (6H, m), 1.44 (9H, s), 2.07-2.16 (4 H, m), 2.90-2.97 (2 H, m), 3.22-3.28 (2 H, m), 3.46 (lH, brs), 3.92 (3H5s), 4.18-4.24 (2H, m), 4.40-4.46 (lH, m), 7-25-7.3 1 (1 H, m), 7.54-7.58 (lH, m), 7.62-7.67 (lH, m), 7.82-7.8 6U H, m), 8.43-8.46 (lH, m).

[Reference Example 77] 5-[l - ({trans-4-[(3rd-butoxycarbonyl)amino]cyclohexyl}methyl)-9-methoxy-2,3-dihydro- 1H-[1,4]indolo[2,3-c]quinolin-7-yl]thiophene-2-carboxylic acid methyl ester-252- 200948817

5-[1-({trans-4-((3)-butoxycarbonyl)amino]cyclohexyl}methyl)-9-methoxy-2,3-di obtained in Reference Example 76 Hydrogen-1H-[1,4]indole and [2,3-c]quinolin-7-yl]thiophene-2-carboxylic acid (67.1 mg, 0.121 mm 〇l) dissolved in N,N-dimethyl Methionamine (2 mL) was added with sodium carbonate (15.4 mg, 0.145 mmol), iodomethane (0.076 mL, 0.121 mmol) and stirred for 19 hours. 0 Water was added, and the solvent was extracted with chloroform:methanol:water = 7:3:1, and the extract was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated. mjjjjjjjjjjjj 1H-NMR (400 MHz, CDC13) 6: 1.16-1.26 (5H, m), 1.44 (9H, s), 2.1 3 (4H, s), 2.9 6 (2H, d, J = 7. lHz), 3.26 (2H, t, J = 4.5 Hz), 3.46 (lH, s), 3.89 (3H, s), 3.92 (3H, s), 4.23 (2H, t, J = 4.3 Hz), 4.37-4.46 (lH, m), 7.27-7.29 (lH, m), 7.56 (lH, m), 7.63 (lH, d, J = 4.1 Hz), 7.79 (1 〇H, d, J = 3.9 Hz), 8.46 (lH, s ).

[Reference Example 78] 5-{ l-[(trans-4-aminocyclohexyl)methyl]-9-methoxy-2,3-dihydro-1H-[1,4] 2,3-c]quinoline-7-yl}thiophene-2-carboxylic acid methyl ester

5-[1-({trans-4-[(3rd-butoxycarbonyl)amino]cyclohexyl}methyl)-9-methoxy-2,3-di which was obtained in Reference Example 77 Hydrogen-1H-[1,4] indole and [2,3-c]salolin-7-yl]thiophene-2-carboxylic acid methyl ester (50.4mg, -253 - 200948817 〇.〇89mmol) dissolved in Dichloromethane (5 mL) was added with trifluoroacetic acid (1 mL) under ice cold and stirred for 2 hr. After distilling off the solvent under reduced pressure, the residue was dissolved in chloroform:methanol:water=7:3:1, and the solvent was adjusted to basic. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated. The title compound was obtained as a yellow solid (33.4 mg (80%). [Reference Example 79] 5-{9-methoxy-1-[(trans-4-([3- 3-oxo-3,4-dihydro-2H-pyrido[3,2-b]] [l,4]噚耕-6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro-1H-[1,4]噚[[,3,3-c]quina Phenyl-7-yl}thiophene-2-carboxylic acid methyl ester

5-{1-[(trans-4-aminocyclohexyl)methyl]-9-methoxy-2,3-dihydro·1Η-[1,4]噚 well obtained in Reference Example 78 And [2,3-c]quinolin-7-yl}thiophene-2-carboxylic acid methyl ester (33_4 mg, 0.071 mmol), 3-sided oxy-3,4-dihydro-211-pyridine[3 , 2-1)][1,4] 噚耕-6-formaldehyde (described in International Publication No. 2006/032466, etc., 14.Omg, 0.079 mmol) suspended in methanol: dichloromethane = 1: 1 mixed solvent ( 2 mL), acetic acid (0.006 ml, 0.107 mmol) and sodium cyanoborohydride (5.2 mg, 0.079 mmol) were added under ice cooling, and stirred at room temperature for 13 hr. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform:methanol:water=7:3:1, and the solvent was washed with saturated aqueous sodium hydrogen carbonate. After drying over anhydrous sodium sulfate, it was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 1H-NMR (400MHz, CDC13) 6: 1.13-1.31 (5H, m), 1.81-1.91 (lH, m), 2.06-2.14 (4H, m), 2.48-2.57 (lH, m)s 2.95 (2H ,d,J = 7.3H z), 3.28(2H,t,J = 4.4Hz),3.83(2H,s),3.89(3H,s),3.93 (3H,s),4.23 (2H,t,J = 4.3 Hz), 4.63 (2H, s), 6.92 (1 H, d, J = 8.3 Hz), 7 • 19 (lH, d, J = 8.3 Hz), 7.3 1 (lH, d, J = 2.7 Hz) ), 7.56 (lH, d, J = 2.7 Hz), 7.64 (lH, d, J = 3.9 Hz), 7.7 9 (lH, d, J = 4.1 Hz), 8.46 (lH, S) · [Example 32 ] 5-{ 9-methoxy-l-[(trans-4-{ [( 3-sidedoxy-3,4-indenylhydro-2H-pyrido[3,2-b][l, 4]噚耕-6-yl)methyl]amino}cyclohexyl)methyl]-2,3 -hydro-1H-[1,4]indolo[2,3-c]quinoline-7 -yl}thiophene-2-carboxylic acid

5·{9-methoxy-1-[(trans-4-{[(3-)oxy-3,4-dihydro-2Η-pyrido[3,2-] obtained in Reference Example 79 b;|[l,4]噚耕-6-yl)methyl]amine sulfhydryl}cyclohexyl)methyl]_2,3_dihydro-1H-[1,4] 噚耕和[2,3- c] quinoline-7-yl}thiophene-2-carboxylic acid methyl ester (53.9 mg, 〇. 〇 71 mmol) was suspended in 90% aqueous ethanol (5 mL), and added to a 20% aqueous sodium hydroxide solution (0.071) under ice cooling. mL, 0.355 mmol)' was stirred at 60 ° C for 16 hours. After allowing to cool, the solvent was evaporated under reduced pressure, and the residue was dissolved in water, and then neutralized with 1 N hydrochloric acid under ice cooling. The precipitated solid was filtered. The extract was suspended in methanol-dichloroform. An insoluble filtered solid was obtained to obtain a labeled compound 23 mg ( 53% ) as a thin yellow solid. 1H-NMR (400 MHz, DMS 〇-d6) 6: 1.10-1.27 (4H, m), 1.84-1.9 -255- 200948817 5 (lH,m),1.98-2.10(4H,m), 2.95 (2H,d,J = 7.3Hz), 3.19-3.43 (3H,m),3.8 1(2H,brs),3.8 1(2H , brs), 3.93 (3H, s), 4.2l-4.26 (2H, m), 4.63 (2H, s), 7.06 (lH, d, J = 8.3 Hz), 7.3 0 (lH, d, J = 2.4 Hz), 7.33 (lH, d, J = 8.1 Hz), 7.60 (lH, d, J = 3.9 Hz), 7.74 (lH, d5J = 2.4 Hz), 7.86 (lH, d, J = 4.2 Hz), 8.44 (lH, s), 11.22 (1H, brs). MS (ESI) m/z: 616 (M + H) + .

[Reference Example 80] (1SR, 3SR, 4SR) -4-[(Tertiary butoxycarbonyl)amino]-3-(methoxymethoxy)cyclohexanecarboxylic acid methyl ester

(Chloromethyl)methyl ether (306 pL, 4.02 mmol) was added dropwise at room temperature (1SR, 3SR, 4SR) -4-[(tertiary butoxycarbonyl)amino]-3 - Diameter-based ring hexanoic acid methyl vinegar (described in Tetrahedron Asymmetry, 2001, Vol. 12, No. 3, 455-462, l.OOg, 3.66 mmol) and N,N-diisopropylethylamine (956 pL, 5.49 mmol) in dichloromethane (30 mL). After 30 minutes from the end of the dropwise addition, (chloromethyl)methyl ether (306 pL, 4.02 mmol) and N,N-diisopropylethylamine (956 pL, 5.49 mmol) were added, and after 2 hours and 5 hours, respectively. Additional (chloromethyl) methyl ether (918 μί, 12.1 mmol) and N,N-diisopropylamine (2.87 mL, 16.5 mmol). After 42 hours from the last addition of the reagent, the reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc: EtOAc: 1H-NMR (400MHz, CDCl3) 6: 1.2 1 (lHim), 1.43 (9H5s), 1.46-1.57 (2H, m), 1.94 (lH, m), 2.23 - 2.37 (3H, m), 3.27 (lH, Dt, J = 4.1, 10.5 Hz), 3.36 (lH, m), 3.39 (3H, s), 3.67 (3H, s), 3.67 (lH, d, J = 7. lHz), 4.70 (lH, br) , 4.71 (lH, d, J = 7.1Hz).

[Reference Example 81] [(1SR, 2SR, 4SR) -4-hydroxymethyl-2-(methoxymethoxy)cyclohexyl]aminecarboxylic acid tert-butyl ester

o (1SR, 3SR, 4SR) -4-[(third-order butoxycarbonyl)amino]-3-(methoxymethoxy)cyclohexanecarboxylic acid methyl ester obtained in Reference Example 80 A solution of (1.04 g, 3.28 mmol) in THF (30 mL) was evaporated. After stirring at room temperature for 3 hours, it was heated to 40 ° C and stirred for another 20 hours. The reaction solution was cooled to 〇 ° C, and methanol (5 mL) was added, and a little 1N hydrochloric acid (5 mL) was added each time while the foaming was observed. The foamed reaction solution was poured into saturated sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc: , CDC13) 5: 1.02-1.21 (3H, m), 1.44 (9H, s), l_56 (lH, m), 1.74 (lH, m), 2.14 (lH, m), 2.22 (lH, m), 3.26 -257- 200948817 (lH,dt,J = 4.4,9.4 Hz), 3.36 (lH,m), 3.40 (3H,s), 3.47 (lH,dd,J = 6. 3,10.5 Hz), 3.5 1 ( 1H, J = 6 · 3,10·5Ηζ), 4.60 ( lH,d,J = 7.1Hz), 4.7 2( lH,br), 4.72 (lH,d,J = 7.1Hz).

[Reference Example 82] [(1SR, 2SR, 4SR) -4-(iodomethyl)-2-(methoxymethoxy)cyclohexyl]aminecarboxylic acid tert-butyl ester

[(1SR, 2SR, 4SR)-4-hydroxymethyl-2-(methoxymethoxy)cyclohexyl]aminecarboxylic acid tert-butyl ester (90 0 mg, 3.11 mmol) obtained in Reference Example 81 , pyridine (233 mg, 3.42 mmol) and triphenylphosphine (897 mg, 3.42 mmol) in tetrahydrofuran (10 mL), iodine (868 mg, 3.42 mmol of tetrahydrofuran (5 mL) at 0 ° C under nitrogen atmosphere. After stirring at 〇 ° C for 1.5 hours, the reaction solution was poured into a 10% aqueous sodium thiosulfate solution, and extracted with ethyl acetate. The organic layer was combined and washed with saturated brine. The desiccant was dehydrated, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography (hexane: ethyl acetate = 4:1 - 3:1 - 2:1) to give 78%) 1H-NMR (400MHz, CDC13) 6:1.07- 1.2 8(3H,m), 1.44(9H,s), 1.53(lH,m),1.88(lH,m),2.18-2.24 (2H, m), 3.08-3.13 (2H, m), 3.30 (lH, dt, J = 4.2, 10.5 Hz), 3.34 (lH, m), 3.40 (3H, s), 4.60 (lH, d, J = 7.1 Hz), 4.71 (lH, br), 4.7 2 (lH, d, J = 7.1 Hz). [Reference Example 83] {(1811,2811,481〇-4_[(9-methoxy-2, 3-dihydro-1H-[1,4] 噚耕和[ 2,3-c]quinolin-1-yl)methyl]-2-(methoxymethoxy)-258- 200948817 Cyclohexyl}carbamic acid tert-butyl ester

N under the nitrogen atmosphere, N. methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinoline (204 mg, 0.944 mmol) obtained in Reference Example 8 In a solution of N-dimethylacetamide (5 mL), sodium hydride (oily, &lt;RTI ID=0.0&gt;&gt; After stirring at the same temperature for 2 hours, the mixture was cooled to 〇 ° C, and [(1SR, 2SR, 4SR) -4-(iodomethyl)-2-(methoxymethoxy) obtained in Reference Example 82 was added dropwise thereto for 10 minutes. A solution of a butyl hexyl carbamic acid terephthalate (490 mg, 1.23 mmol) in N,N-dimethylacetamide (5 mL). After stirring at the same temperature for 1 hour, a saturated aqueous solution of ammonium sulfate (2 mL) was added. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate, and then filtered and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 1H-NMR (400MHz, CDCl3) 5: 1.22 - 1.36 (3HJm), 1.46 (9H, s), 1.93 (lH, m), 2.06 (lH, m), 2.31 (lH, m), 2_42 (lH, m ), 2.98 (lH, dd, J = 7_3, 13.7 Hz), 3.03 (lH, dd, J = 7.3, 13.7 Hz), 3.25 (2H, dd, J = 4.2, 4.7 Hz), 3.35 (lH, dt, J = 4.4, 10.8 Hz), 3.41 (3H, s), 3.43 (lH, m), 3.90 (3H, s), 4.21 (2H, dd, = 4.2, 4.4 Hz), 4.63 (lH, d, J = 7.0Hz), 4.76(lH,d,J=7.0Hz),4.8 5(lH,br),7.16(lH,dd,J=2.9,9.1Hz), 7. 22( lH,d,J = 2.9Hz 7.88 (1 H, d, J = 9.1 Hz), 8.37 (1 H, s). -259- 200948817 MS (ESI) m/z: 488 (M + H) + .

[Reference Example 84] (1311, 2811, 581〇-2-amino-5-[(9-methoxy-2,3-dihydro-1Η·[1,4]噚 and [2,3- c] quinoline-1·yl)methyl]cyclohexanol

{( lSR, 2SR, 4SR)-4-[(9-methoxy-2,3-dihydro-1Η-[1,4]曙[[,3-c] quinine obtained in Reference Example 83 Tert-butyl ketone-1-yl)methyl]-2-(methoxymethoxy)cyclohexyl}aminecarboxylate (41 mg, 0.0841 mmol) was dissolved in 10% hydrogen chloride / methanol solution at room temperature. After stirring at the same temperature for 24 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in a saturated aqueous solution of sodium hydrogencarbonate and extracted with a mixture solvent of dichloromethane:methanol. The organic layer was combined and dried over anhydrous sodium sulfate (MgSO4). This compound was used in the subsequent reaction without further purification. 1H-NMR (400MHz, CDCl3) 6: 1.19-1.29 (3HJm), 1.98-2.04 (3H, m), 2.33-2.35 (4H, brm), 2.53 (lH, m), 2.96 (lH, dd, J = 7.3, 13.9 Hz), 2.99 (lH, dd, J = 7.3, 13_9 Hz), 3.23 (2H, dd, J = 4.2, 4.4 Hz), 3.30 (lH, m), 3.89 (3H, s), 4.18 (2H) , dd, J = 4.2, 4.6 Hz), 7.14 (lH, dd, J = 2.7, 9.0 Hz), 7.23 (lH, d, J = 2.7 Hz), 7.87 (lH, d, J = 9_0 Hz), 8.35 ( 1 H, s). MS (ESI) m/z: 344 (M + H) + .

[Example 33] 6-[({( lSR, 2SR, 4SR)-2-hydroxy-4-[( 9-methoxy-2,3- -260- 200948817 dihydro-1 Η·[1,4] Sorghum and [2,3-c] sialolin-1-yl)methyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-bni,4]噚哄-3 (4H) -ketone

(1SR, 2SR, 5SR)-2-amino-5-[(9-methoxy-2,3-dihydro-1H-[1,4]噚 well obtained in Reference Example 84 under argon atmosphere And [2,3-c]quinolin-1-yl)methyl]cyclohexanol (30.5 mg, 〇.〇 841 mmol) and 3-oxooxy-3,4-dihydro-2-indole-pyridine[3 ,2-b][l,4]噚哄-6-formaldehyde (described in International Publication No. 2006/032466, etc., 16.5 mg, 0.0925 mmol) of methanol (3 mL) -N,N-dimethylformamide (3mL)-acetic acid (0.3mL) solution was added to the molecule.. * sieve 4A (300mg), heated and stirred at 80 ° C. After stirring at the same temperature for 1.5 hours, the reaction solution was cooled to room temperature, and hydrogenated triethyl hydrazine was added. Sodium borohydride (75.0 mg, 0.336 mmol). After stirring at the same temperature for 63 hours, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was combined and dried over anhydrous sulfuric acid, and then filtered and evaporated. The residue was purified by fractional layer chromatography (cluent, methylene chloride &lt;&quot;&gt;&gt; methanol = 10:1) to give a pale yellow amorphous form of 23.4 mg (55%). 1H-NMR (40 0MHz, CDC13) 6: 1.14-1.3 5(3H,m), 1.99(lH,m). 2.06(1 H,m),2.20(1 Η,m), 2.34(1 Η , m), 2.50 (1 H, m), 2.9 1-3.02 (2H, m), 3.22 (2H, dd, J = 3.9, 4.4 Hz), 3.60 (lH, m), 3.83 (lH, d, J =14 • 2 Hz), 3.87 (3H, s), 4.08 (lH, d, J = 14.2 Hz), 4.17 (2H, t, J = 4.4 Hz), 4 • 5 5 (2H, s), 6.85 (l H, d, J = 8.1 Hz), 7.12 (lH, dd, J = 2.7, 9.0 Hz), 7.1 5 (1 H, d, J = 8.1 Ηζ), 7·21 (lH, d, J = 2.7 Hz) ), 7.8 7 (lH, d, J = 9.0 Hz), 8.3 - 261 - 200948817 MS (ESI) m/z: 506 (M + H) + .

[Example 34] 6-[({(lSR, 2SR, 4SR)-2-hydroxy-4-[(9-methoxy-2,3·dihydro-1H-[1,4] 曙[[ 2,3-c] sialolin-1-yl)methyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l,4]thiazin-3 ( 4H) ketone

(1SR, 2SR, 5SR)-2-amino-5-[(9-methoxy-2,3-dihydro-1H-[1,4]噚 well obtained under the nitrogen atmosphere under the nitrogen atmosphere [2,3-c] porphyrin-1-yl)methyl]cyclohexanol (62.8 mg, 0,180 mmol) with 3-sided oxy-3,4-dihydro-2H-acridine [3,2 -bni,4]thiazol-6-formaldehyde (described in International Publication No. 200 6/0 32466, etc., 38.4 g, 0.19 8 mmol) of methanol (5 mL) -N,N-dimethylformamide (5 mL) Molecular sieve 4A (1. g) was added to a solution of acetic acid (〇. 5 mL) and heated to 80 °C. After stirring at the same temperature for 2 hours, the reaction mixture was cooled to room temperature, and sodium hydrogen triacetoxyborate (160 mg, 0.719 mmol) was added. After stirring at the same temperature for 17 hours, the reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate. The residue was purified by fractional layer chromatography (EtOAc, methylene chloride:methanol = 10:1) to afford pale-yellow crystals: 22.8mg (24%) 〇1H-NMR (400MHz, CDC13) 8:1.13-1.37 (3H , m), 2.01 (lH, m), 2.08 (lH, m), 2.20 (lH, m), 2.39 (lH, m), 2.5 1 (lH, m), 2.96 (lH, dd, J = 7.1, 13.6 Hz), 3.02 (lH, dd, J = 7.3, l 3.6 Hz), 3.24 (2H, dd, J = 4.2, 4 -262- 200948817 • 4 Hz), 3.41 (2H, s), 3.58 (lH, m) ), 3.84 (lH, d, J = 14.4 Hz), 3.89 (3H, s), 4.08 (lH, d, J = 14.4 Hz), 4.19 (2H, dd, J = 4.2, 4.4 Hz), 6.92 (lH) , d, J = 7.8 Hz), 7.14 (lH, dd, J = 2.7, 9.0 Hz), 7.23 (lH, d, J = 2.7 Hz), 7.5 5 (lH, d, J = 7.8 Hz), 7.87 ( lH,d,J = 9.0 Hz), 8.35 (lH, s). MS (ESI) m/z: 522 (M + H) + .

[Reference Example 85] 4-Nitrobenzoic acid (1RS, 2SR, 5SR) -2-[(Tertiary butoxycarbonyl)amino]-5-(methoxycarbonyl)cyclohexyl ester

(1SR, 3SR, 4SR) -4-[(Tertiary butoxycarbonyl)amino]-3-hydroxycyclohexanecarboxylic acid methyl ester under nitrogen atmosphere (described in Tetrahedron Asymmetry, 2001, 12 volumes) , No. 3, pages 455-462, 6.00 g, 22.0 mmol) with 4-nitrobenzoic acid (4.04 g, 24.1 mmol), and triphenylphosphine (6.33 g, 24.1 mmol) in tetrahydrofuran (250 mL) -N, To a solution of N-dimethylformamide (25 mL), a solution of diazodicarboxylate/toluene (1.9 M, 12.7 mL, 24.1 mmol) was added at room temperature over 1 min. After stirring at the same temperature for 18 hours, the reaction mixture was concentrated under reduced pressure. The obtained white individual was added with methanol as a syrup, and the solid was filtered to give 7.5 g of the title compound as a white solid. The filtrate was concentrated under reduced pressure. EtOAc m. The total output was 7.59g (82%). 1H-NMR (400MHz, CDCl3) 6: 1.42 (9H, s), 1.60-1.77 (2H, m), 1.86 (1H, ddd, J = 2.2, 12.4, 12.7 Hz), 2.00 (lH, m), 2.14 (lH,m),2.3 -263 - 200948817 9(lH,m), 2.62(lH,m),3.67(3H,s),3.83(lH,br),4.59(lH,brd,J = 6.8Hz) , 5.5 1 (lH, m), 8.20 (2H, d, J = 8.8 Hz), 8.32 (2H, d, J = 8.8 Hz). MS (ESI) m/z: 423 (M + H) + .

[Reference Example 86] (1SR, 3RS, 4SR) -4-[(third-order butoxycarbonyl)amino]-3-hydroxycyclohexanecarboxylic acid methyl ester

4-Nitrobenzoic acid (1, RS, 2SR, 5SR) -2-[(Tertiary butoxycarbonyl)amino]-5-(methoxycarbonyl)cyclohexyl ester obtained in Reference Example 85 ( A suspension of 7.37 g, 17.5 mmol) in methanol (90 mL) was added MeOH MeOH / MeOH (1········ After stirring at the same temperature for 18 hours, it was neutralized by adding a 1N hydrogen chloride / ethanol solution (〇.857 mL). After the insoluble material was filtered off, the filtrate was concentrated to dryness crystals, and the solid was filtered to afford 4.49 g (yield of methyl 4-nitrobenzoate) as a white solid. Further, the filtrate was concentrated under reduced pressure. EtOAcjjjjjjjj The total output is 5.53g. 1H-NMR (400MHz, CDCl3) 5: 1.44 (9H, s), 1.48- 1.77 (5H, m), 2.00 (lH, m), 2.10 (1 H, m), 2.70 (1 H, tt, J = 3.7, 12.2 Hz), 3.52 (lH, br), 3.67 (3H, s), 4.11 (lH, brs), 4.84 (lH, br) · [Reference Example 87] (1SR, 3RS, 4SR) -4-[ (third-stage butoxycarbonyl)amino]-3-(methoxymethoxy)cyclohexanecarboxylic acid methyl ester-264- 200948817

(1811,3118,48 ft)-4-[(tri-tert-butoxycarbonyl)amino]-3-hydroxycyclohexanecarboxylic acid methyl ester (4.98 g, obtained in Reference Example 86) under nitrogen atmosphere.

(17.5 mmol) and a solution of N,N-diisopropylethylamine (9.12 mL, 52.4 mmol) in dichloromethane (40 mL). Mm). After stirring at the same temperature for 4.5 hours, additional (chloromethyl)methyl ether (6.0 mL, 87.3 mmol) and N,N-diisopropylethylamine (15.2 mL, 8 7.3 mmol) were stirred for additional 67 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) This compound was used in the subsequent reaction without further purification. 1H-NMR (400MHz, CDCl3) 6: 1.44 (9H, s), 1.45-1.59 (3H, m), 1.79 (1H, m), 2.00 (1H, m), 2.22 (1H, ddt, J = 2.7, 11.5, 5.7 Hz), 2.62 ( lH, tt, J = 3.5, 12.5 Hz), 3.40 (3H, s), 3.53 (lH, br), 3.67 (3H, s), 3.89 (lH, brs), 4.64 ( lH, d, J = 6.6 Hz), 4.71 (lH, d, J = 6.6 Hz), 4.98 (lH, b rd, J = 8.8 Hz).

[Reference Example 88] [(1SR, 2RS, 4SR) -4-(hydroxymethyl)-2-(methoxymethoxy)cyclohexyl]aminecarboxylic acid tert-butyl ester -265- 200948817

(1SR, 3RS, 4SR) -4-[(third-order butoxycarbonyl)amino]-3-(methoxymethoxy)cyclohexanecarboxylic acid methyl ester obtained in Reference Example 87 (5.63 A solution of g, 17.5 mmol) in tetrahydrofuran (80 mL) was added with lithium borohydride (422 mg, 17.5 mmol) at room temperature under nitrogen atmosphere. After stirring at room temperature for 1 minute, it was heated at 40 ° C for 12 hours, and heated at 60 ° C for another 2.5 hours. The reaction solution was cooled to 〇 ° C, and methanol (1 〇 mL) was added, and 1 N hydrochloric acid (50 mL) was added little a little while being foamed. The foaming reaction solution was poured into saturated sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then filtered and evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc

1H-NMR (300MHz, CDC13) 5: 1.04-1.17 (2H, m), 1.44 (9H, s), 1.46-1.59 (2H, m), 1.75-1.82 (3H, m), 2.05 (lH, m) , 3.40 (3 H, s), 3.45-3.60 (3H, m), 3·87 (1 H, brm), 3.70 (1 H, d, J = 6.5 Hz), 47l (lH, d, J = 6.5 Hz), 5.01 (lH, brd, J = 8.1 Hz).

[Reference Example 89] [(1SR, 2RS, 4SR) -4-(iodomethyl)-2-(methoxymethylcyclohexyl)aminecarboxylic acid tert-butyl ester -266- 200948817

[(1SR, 2RS, 4SR)-4-(hydroxymethyl)-2-(methoxymethoxy)cyclohexyl]aminecarboxylic acid tert-butyl ester obtained in Reference Example 88 under nitrogen atmosphere (4.54 g, 15.7 mmol) and imidazole (1.17 g, 17.3 mmol), and triphenylphosphine (4.53 g, 17.3 mmol) in tetrahydrofuran (80 mL), iodine (4.38 mg, 17.3) A solution of mmol in tetrahydrofuran (20 mL). After stirring at 0 ° C for 1 hour, the mixture was warmed to room temperature and stirred for additional 1 hour. The reaction solution was poured into a 10% aqueous sodium thiosulfate solution, and extracted with ethyl acetate, and then the organic layer was combined and washed with brine. After drying over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The obtained white individual was suspended in a mixed solvent of hexane:ethyl acetate = 10:1, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. EtOAc EtOAcjjjjjjjj . 1H-NMR (400MHz, CDCl3) 6: 1.04-1.18 (2H, m), 1.44 (9H &gt;s) 5 1.57 (1 H, m), 1 _72· 1.77 (2H, m), 1.88 (1 H, m ), 2.18 (lH, m), 3.04-3. 13 (2H, m), 3.40 (3H, s), 3.50 (lH, m), 3.84 (lH, m), 4.64 (lH, d, J = 6_) 8 Hz), 4.70 (lH, d, J = 6.8 Hz), 4.97 (lH, brd, J = 8.8 Hz). [Reference Example 90] {(1811, 2118, 481〇-4-[(9-methoxy) -2,3-Dihydro-111-[1,4]噚[[,3-&lt;:] sialolin-1-yl)methyl]-2-(methoxymethoxy)cyclohexyl }Aminobutyl methacrylate-267- 200948817

9-methoxy-2,3·dihydro-1Η-[1,4]indole and [2,3-c]quinoline (833 mg ' 3.85 mmol) obtained in Reference Example 8 under a nitrogen atmosphere. Sodium hydride (oily '55%, 252 mg, 5.78 mmol) was added to a solution of hydrazine-dimethylacetamide (10 mL) at room temperature. After stirring at the same temperature for 2.5 hours, it was cooled to 〇 ° C, and [(1SR, 2RS, 4SR) -4-(iodomethyl)-2-(methoxymethoxy) obtained in Reference Example 89 was added dropwise over 1 hour. A solution of cyclohexyl]diamine terephthalate (2.00 g, 5.0 1 mmol) in hydrazine dimethyl dimethyl acetamide (10 mL). After stirring at the same temperature for 3.5 hours, a saturated aqueous solution of ammonium chloride (3 mL) was added. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate, and then filtered and evaporated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4:1 - 2:1 -1 : 2) to afford the title compound 1.68 g (yield: 89%). 1H-NMR (400MHz, CDCl3) 6: 1.24-1.33 (2H, m), 1.46 (9H, s), 1.61 (1H, dt, J = 3.7, 12.9 Hz), 1.87 (lH, m), 2.07 (lH) , m), 2.24 - 2.3 1 (2H, m), 3.0 8 (2H, brd, J = 6.8 Hz), 3.3 4 (2H, dd, J = 4. l, 4.4 Hz), 3.42 (3H, s) , 3.5 9 (lH, m), 3.91 (3H, s) 53.94 (lH, brs), 4.24 (2H, t, J = 4.4 Hz), 4.67 (lH, d, J = 6.6 Hz), 4.74 (lH, d,:T = 6.6 Hz), 5.09 (lH, brd, J = 9.2 Hz), 7.2 1 (lH, dd, J = 2.7, 9.1 Hz), 7.25 (lH, d, J = 2.7 Hz), 8.03 ( l H, brd, J = 9.1 Hz), 8.35 (lH, s).

[Reference Example 91] (1311, 2113, 581〇-2-amino-5-[(9-methoxy-2,3-di-268- 200948817)

{ ( 1SR, 2RS, 4SR) -4-[( 9-methoxy-2,3-dihydro-1H-[1,4]噚[[,3,3] obtained in Reference Example 90 at room temperature -c]Sialolin-1-yl)methyl]-2-(methoxymethoxy)cyclohexyl}carbamic acid tert-butyl ester (1.5 7 g,

3.22mmol) dissolved in 10% hydrogen chloride / methanol solution (30mL), heated to 4 (TC. After stirring at the same temperature for 60 hours, the reaction liquid was concentrated under reduced pressure, the residue was dissolved in saturated aqueous sodium hydrogen carbonate, dichloro Methane:methanol = 10:1 mixed solvent extraction. The organic layer was combined and dried over anhydrous sodium sulfate. After filtered and evaporated to dryness, the filtrate was concentrated under reduced pressure to give a pale yellow amorphous labeled compound. The compound was used in the next reaction without further purification. 1H-NMR (400 MHz, CD3 〇D) 5: 1.23 (1H, dt, J = 3.9, 12.5 Hz), 1. 38 (lH'dt, J = 2.2, 13.2 Hz), 1.61 (1 H, dt, J = 3.7, 12·2 Ηζ), 1.70 (lH, m), 2.07 (lH, m), 2-15 (lH, m), 2.37 (lH) , m), 2.64 (lH, ddd, J = 2.7, 4.4, 11.7 Hz), 2.96 (lH, dd, J = 6.6, 13.6 Hz), 3.00 (lH, dd, J = 6.0, 13.6 Hz), 3, 30 (2H, m), 3.91 (3H, s), 3.92 (lH, m), 4.22 (2H, dd, J = 4.1, 4.6 Hz), 7.1 6 (1 H, dd, J = 2.6, 9.3 Hz) , 7.3 1 (1 H, d, J = 2.6 Hz), 7 • 75 (lH, d, J = 9.3 Hz), 8, 20 (lH, s). MS (ESI) m/z: 344 (M + H) + .

[Example 35] 6-[( { ( 1SR, 2RS, 4SR ) -2-hydroxy-4-[( 9-methoxy-2,3-dihydro-1H-[1,4] 噚 并 [ [ 2,3-c] sialolin-1-yl)methyl]cyclohexyl}amino) 269 200948817

(1811,2118,581〇-2-amino-5-[(9-methoxy-2,3-dihydro-1H-[1] obtained in Reference Example 9 under nitrogen atmosphere at room temperature , 4] deutero[2,3-c]quinolin-1-yl)methyl]cyclohexanol (200 mg, 0.582 mmol) and 3-sided oxy-3,4-dihydro-2H-pyridine [3,2-bHl,4]曙耕-6-formaldehyde (described in International Publication No. 2006/032466, etc., 124 mg, 0.699 mmol) in dichloromethane (6 mL) -N,N-dimethylformamide (1.2 mL)-acetic acid (0.4 mL) was added to a solution of sodium triethyloxyborohydride (234 mg, 1.05 mmol). After stirring for 16 hours at the same temperature, the reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate. After filtered and evaporated, the filtrate was evaporated. The residue was purified by methylene chloride column chromatography (dichloromethane:methanol = 7:1 - 5:1) White amorphous 268mg (91%). -NMR (400MHz, CDC13) 5:1. 17-1.27(2H,m),1-70-1.75 (2H,m), 2.15-2.25(2H,m), 2.37 (lH,m), 2.67 (lH,ddd,J = 2.455.4, 11.0 Hz), 2.92 (1H, dd, J = 6.6, 13.7 Hz), 2.98 (lH, d, J = 6.0, 13.7 Hz), 3.23 (lH, dt, J = 14.4, 4.7 Hz), 3.31 (lH , dt, J = 14.4, 3.9 Hz), 3.90 (3H, s), 3.92 (2H, s), 4.12 (lH, brs), 4.17 (2H, dd, J = 4.1, 4.4 Hz), 4.60 (2 H) , s), 6.88 (lH, d, J = 8.0 Hz), 7.14 (lH, dd, J = 2.7, 9.3 Hz), 7.19 (lH, d, J = 8.0 Hz), 7.26 ( lH, d, J = 2.7 Hz), 7.90 (lH, J = 9.3 Hz), 8.37 ( lH, s -270 - 200948817 MS (ESI) m/z: 506 (M + H) + .

[Example 36] 6-[({(1311, 2 尺 8, 4811)-2-hydroxy-4-[(9-methoxy-2,3-dihydro-1 Η·[1,4] 噚 well And [2,3-c]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-bHl,4]thiat-3(4H)-one

〇

(1SR, 2RS, 5SR)-2-amino-5-[(9.methoxy-2,3-dihydro-1H-[1,4]indole obtained in Reference Example 91 under a nitrogen atmosphere [2,3-c]quinolin-1-yl)methyl]cyclohexanol (10 mg, 0.291 mmol) and 3-sided oxy-3,4-dihydro-211-pyridine[3, 2-1)][1,4] timol-6-formaldehyde (described in International Publication No. 2006/032466, etc., 73.5 mg, 0.379 mmol) of dichloromethane (3 mL) - hydrazine, hydrazine-dimethyl ketone To a solution of guanamine (1 mL)-acetic acid (0.2 mL), sodium triethyl succinate (130 mg, 0.582 mmol). After stirring at the same temperature for 13 hours, the reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate, and then filtered and evaporated. The residue was purified by silica gel column chromatography (dichlorobenzene:methanol = 19:1 - 9:1) to afford pale yellow amorphous 130 mg (86%). 1H-NMR (400MHz, CDCl3) 8: 1.17-1.26 (2H, m), 1.67-1.75 (2H, m), 2.14-2.23 (2H, m), 2.37 (lH, m), 2.66 (lH,ddd, J = 2.2, 4.9, 10.7 Hz), 2.90 (lH, J = 6.6, 13.7 Hz), 2.96 (lH, dd, J = 8.5, 13.7 Hz), 3 • 2 1 (lH, dt, J = 14.6, 4.8 Hz), 3.29 (lH, dt, J = 14.6, 4.1 Hz), 3.42 (2H, s), 3.86 (3H, s), 3.9 1 (2H, s), 4.12 (lH, brs), 4.16 (2H, Dd, J = 4.0, 4.2 Hz), 6.90 (lH, d, J = 7.8 Hz), 7.1 2 (1 H, dd, J = 2.7, 9.3 Hz), 7.25 ( lH, d -271 - 200948817 , J = 2.7 Hz), 7.54 (lH, d, J = 7.8 Hz), 7.88 (lH, d, J = 9.3 Hz), 8.35 (lH, s)· MS (ESI) m/z: 522 (M + H) + .

[Reference Example 92] { ( 1SR, 2RS, 4SR) -2-hydroxy-4-[( 9-methoxy-2,3-dihydro-1Η·[1,4]噚耕和[2,3- c] quinolin-1-yl)methyl]cyclohexyl}aminecarboxylic acid tert-butyl ester

Under the nitrogen atmosphere, (1SR, 2RS, 5SR) -2_amino-5-[(9-methoxy-2,3-dihydro-1H-[1,4]噚[ 2,3-c]Sialolin-1-yl)methyl]cyclohexanol (740 mg, 2.15 mmol) in tetrahydrofuran (20 mL), bis(tert-butyl)dicarbonate (51) 7 mg, 2.3 7 mm 〇l) in tetrahydrofuran (10 mL). After stirring at the same temperature for 17 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( methylene chloride:methanol = 9 : 1 - 6 : 1) to afford pale yellow amorphous 956mg (yield). ^-NMR (4 OOMHz, CDCl3) 6: 1.25 (lH, m), 1.39 (1H, m), 1.46 (9H, s), 1.68 (lH, m), 1.83 (lH, m), 2.12 -2.16(3H,m), 2.34(lH,br m), 3.01(2H,m), 3.30(2H,m),3.56(lH,br),3.90(3H,s), 4.17(lH,brs) , 4.21 (2H, brs), 4.89 (lH, br), 7.16 (lH, m), 7.22 (lH, d, J = 2_5 Hz), 7.94 (lH, brm), 8.34 (lH, s). MS (ESI) )m/z: 444(M + H)+.

[Reference Example 93] Aminic acid (IRS, 2SR, 5 SR) -2-[(third-order butoxycarbonyl-272- 200948817-yl)amino]-5-[(9-methoxy-2,3) -Dihydro-1H-[1,4]indole and [2,3-c]quinolin-1-yl)methyl]cyclohexyl ester

Under the nitrogen atmosphere, the {( 1SR, 2RS, 4SR) · 2-hydroxy-4-[(9-methoxy-2,3-dihydro-1H-[1,4] 噚 well obtained in Reference Example 92 [2,3-c] quinolin-1-yl)methyl]cyclohexyl}aminecarboxylic acid tert-butyl ester (50 mg, 0.113 mm 〇l) in dichloromethane (2.0 mL) at room temperature Trichloroethendyl isocyanate (20 μί, 0.16 9 mmol) was added. After stirring at the same temperature for 20 minutes, it was cooled to 〇 ° C and aqueous potassium carbonate (50 mg /lmL) and methanol (2mL). - While stirring slowly for 15 hours while warming to room temperature, the reaction solution was poured into water and extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate. This compound was used in the subsequent reaction without further purification. 1H-NMR (400 MHz, CDC13) 8: 1.26-1.46 (2H, m), 1.47 (9H, s), 1.58 (1 H, m), 1.95 (1 H, m), 2.11 - 2.21 (2H, m ), 2.37 (lH, m), 2.94 (lH, dd, J = 6.8, 13.7 Hz), 3.00 (lH, dd, J = 8.0, 13.7 Hz), 3.20-3.30 (2H, m), 3.7 l (lH) , m), 3.90 (3H, s), 4.21 (2H, dd, J = 4.1, 4.6 Hz), 4.8 3 (lH, d, J = 8.8 Hz), 4.9 3 (2H, s), 5.0 8 (lH , brs), 7.16 (lH, dd, J = 2.7, 9.0 Hz), 7.20 (lH, brd, J = 2.7 Hz), 7.90 (l H, d, J = 9.0 Hz), 8.36 (lH, s).

[Example 37] Aminic acid (1 ft, 2811, 531 〇 -5-[(9-methoxy-2,3-di-273 - 200948817 hydrogen-1H-[1,4] 噚 and [2 ,3-c]quinolin-1-yl)methyl]-2- { [(3-Sideoxy-3,4-dihydro-2H-pyrido[3,2-bni,4]噚耕- 6-yl)methyl]amino}cyclohexyl ester

Aminic acid (1RS, 2SR, 5SR) -2-[(third-order butoxycarbonyl)amino] 5-[(9-methoxy-2,3-) obtained in Reference Example 93 under a nitrogen atmosphere Dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl)methyl]cyclohexyl ester in crude (57 mg, 0.113 mmol) dichloromethane (20 mL) Trifluoroacetic acid (5 mL) was added to the solution at room temperature. After stirring at the same temperature for 2.5 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with a saturated aqueous After the organic layer was combined and dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue obtained is 3-p-oxy-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-formaldehyde (described in International Publication No. 2006/032466, etc. , 26 mg, 0.147 mmol) of dichloromethane (4 mL) -N,N-dimethylformamide (1 mL)-acetic acid (0.25 mL). , 0.203 mmol). After stirring at the same temperature for 13 hours, 3-trioxy-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-formaldehyde (3 mg '0.0168 mmol) was added. Sodium triethoxy borohydride (5 mg, 0.023 6 mm 〇l) was hydrogenated and stirred for additional 4 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate, and then filtered and evaporated. The residue was purified with EtOAc EtOAc EtOAc EtOAc (EtOAc (EtOAc) 1H-NMR (400MHz, CD3〇D) 6:1.23-1.3 6(2H,m), 1.66 (lH,m), 1.92 (lH,m), 2.13 (lH,m), 2.26-2.30 (2H , m), 2.70 (lH, m), 2.92 (lH, dd, J = 7.6, 13.9 Hz), 2.98 (lH, dd, J = 6.8, 13.9 Hz), 3.27 (2 H, brm), 3.78 (lH) , d, J = 13.9 Hz), 3.82 (lH, d, J = 13.9 Hz), 3.89 (3H, s), 4.15 - 4.22 (2H, m), 4.62 (2H, s), 5.11 (lH, brs) , 6.95 (lH, d, J = 8.1 Hz), 7.13 (lH, dd, J = 2.7, 9.3 Hz), 7.2 1 (lH, d, J = 2.7 Hz), 7.23 (lH, d ◎ , J = 8_l Hz), 7.74 (1H, d, J = 9.3 Hz), 8.1 8 (lH, s). MS (ESI) m/z: 549 (M + H) + .

[Reference Example 94] {( 1SR, 2SR, 4SR) -2-Azido-4-[(9-methoxy-2,3-dihydro-1H-[1,4] 噚耕和[2, 3-c]quinolin-1-yl)methyl]cyclohexyl}aminecarboxylic acid tert-butyl ester

Under the nitrogen atmosphere, the {(1SR, 2RS, 4SR)-2-hydroxy-4-[(9-methoxy-2,3-dihydro-1H-[1,4] 噚 well obtained in Reference Example 92 [2,3-c] porphyrin-1-yl)methyl]cyclohexyl}aminecarboxylic acid tert-butyl ester (2.00 g, 4.12 inm) and triethylamine (1.26 mL, 9.07 mmol) Methylenesulfonyl chloride (0.351 mL, 4.53 mmol) was added dropwise to a solution of dichloromethane (40 mL) at room temperature. After stirring at the same temperature for 19 hours, triethylamine (0.23 mL, 1.65 mmol) and methanesulfonyl chloride (m.p. The reaction solution was poured into an aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layer was combined with 275-200948817 and dried over anhydrous sodium sulfate. The obtained residue was dissolved in hydrazine, dimethyl dimethyl acetamide (20 mL), sodium azide (1 g, 7 g, 16.5 mm) was added and stirred at 80 °C. After stirring at the same temperature for 20 hours, the reaction solution was poured into aqueous sodium hydrogencarbonate and extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate, and then filtered and evaporated. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol: 30:1 - 19:1 - 9:1) to afford 1.86 g (97%) as pale yellow amorphous. 1H-NMR (400MHz, CDCl3) 5: 1.03-1.21 (2H, m), 1.3 1 (lH, m), 1,32 (9H, s), 1.79- 1.93 (2H, brm), 2.00 (lH) , m), 2.32 (lH, brm), 2.7 6-2.86 (2H, m), 3.06-3.15 (3H, brm), 3.33 (lH, br), 3.70 (3H, s), 4.0 4 (2H, brm ), 5.3 5 (lH, br), 6.97-7.03 (2H, m), 7.72 (lH, d, J = 9.0 Hz), 8.20 (lH, s). MS (ESI) m/z: 469 (M + H) + .

[Example 38] 6-[({(lSR, 2SR, 4SR)-2-azido- 4-[(9-methoxy-2,3-dihydro-111-[1,4] 噚And [2,3-(:]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l,4]噚耕·3 ( 4H)-ketone

{( 1SR, 2SR, 4SR) · 2-azido-4-[(9-methoxy-2,3-dihydro-1Η-[1,4]噚 obtained in Reference Example 94 under a nitrogen atmosphere Plowing a solution of [2,3-c] porphyrin-1-yl)methyl]cyclohexyl}carbamic acid tert-butyl ester (300 mg, 0.640 mmol) in Erqiyuan (8.0 mL) in room Add three gas-276- 200948817 acetic acid (2.0 mL) at a temperature. After stirring at the same temperature for 1.5 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with saturated aqueous sodium hydrogen sulfate and aqueous layer was evaporated. The organic layers were combined and dried over anhydrous sodium sulfate, and then filtered, and then filtered, and evaporated. [l,4]噚哄-6-formaldehyde (described in International Publication No. 2006/032466, etc., 143 mg, 0.800 mmol) in dichloromethane (15 mL) -N,N-dimethylformamide (2 mL) - In a solution of acetic acid (0.50 mL), hydrogenated sodium triethoxyborohydride (250 mg, 1.12 mmol) was added at room temperature. After stirring at the same temperature for 5 hours, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate, and then filtered and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc 1H-NMR (400MHz, CDC13) 6:1.14 (lH, m), 1.32-1.43 (2H, m), 2.00-2.05 (2H, m), 2.24 (lH, m), 2.46-2.55 ( 2H, m) &gt; 2.97 (lH, dd, J = O 7.1, 14.2 Hz), 3.00 (lH, dd, J = 7.3, 14.2 Hz), 3.20-3.3 1 (2H, m), 3.39 (lH, m ), 3_87 (lH, d, J = 14.0 Hz), 3.90 (3H, s), 4.0 1 (lH, d, J = 14 • 〇 Hz), 4.2 1 (2H, dd, J = 4.1, 4.6 Hz) , 5_28(2H, s), 6.95 (lH, d, J = 8.1 Hz), 7.18 (lH, dd, J = 2.7, 9.0 Hz), 7.20 (lH, d, J = 2.7 Hz), 7.21 (lH, d, J = 8.1 Hz), 7.92 (lH, d, J = 9.0 Hz), 8.39 (lH, s). MS (ESI) m/z: 53 1 (M + H) + .

[Reference Example 95] {( 1SR, 2SR, 4SR) -2-hydroxy-4·[ (9-methoxy-2,3-dihydro-1Η·[1,4]噚[[,3,3- c] quinoline-1-yl)methyl]cyclohexyl}aminecarboxylic acid tertiary butyl ester-277- 200948817

(lSR, 2SR, 5SR)-2-amino-5-[(9-methoxy-2,3-dihydro-1H-[1,4] sorghum obtained under Reference Example 84 under a nitrogen atmosphere And a solution of [2,3-c]quinolin-1-yl)methyl]cyclohexanol (43 7 mg, 1,28 mmol) in tetrahydrofuran (10 mL) at rt. A solution of carbonate (3 07 mg, 1.41 mmol) in tetrahydrofuran (10 mL). After stirring at the same temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) MS (ESI) m / z: 444 (M + H) + .

[Reference Example 96] {( 1SR, 2RS, 4SR) -2-Azido-4-[(9-methoxy-2,3-dihydro-1H-[1,4]噚[[, 3-c]quinolin-1-yl)methyl]cyclohexyl}aminecarboxylic acid tert-butyl ester

{( 1SR, 2SR, 4SR) -2-hydroxy-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole obtained in Reference Example 95 under a nitrogen atmosphere [2,3-c]quinolin-1-yl)methyl]cyclohexyl}aminecarboxylic acid tert-butyl ester (400 mg, 0.902 mm 〇l) t triethylamine (〇.302 mL, 2.16 mmol) In a solution of dioxin (25 mL), methanesulfonyl chloride (0.084 mL, 1.08 mmol) was added dropwise at room temperature. After stirring at the same temperature for 1.5 hours, triethylamine (0.151 mL, -278 - 200948817 1.08 mmol) and methanesulfonyl chloride (〇. 〇 420 mL, 0.541 mmol) were added and stirred for additional 21 hours. The reaction solution was poured into an aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. After the organic layer was combined and dried over anhydrous sodium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylacetamide (10 mL), and sodium azide (239 mg, 3.61 mmol) was added and stirred at 80 °C. After stirring at the same temperature for 15 hours, the reaction solution was poured into aqueous sodium hydrogencarbonate and extracted with dichloromethane. After the organic layer was combined and dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate=3: </ br </ br </ </ </ </ </ > </ </ RTI> </ RTI> </ RTI> 1 : 1 : 1 ) to obtain a white amorphous compound 407 mg ( 86% ) ° 1H-NMR (4 00 MHz) , CDC13) 6: 1.24 (lH, m), 1.46 (9H, s), 1.4 7-

1.62(2H,m),l.82(lH,m),2.09(lH,brm),2.21(lH,brm),2.30(lH,brm),3.1 0(2H,br),3.3 6(2H, Br), 3.67 (lH, brm), 3.9 2 (3H, s), 4.1 5 (lH, brs), 4.26 (2H, dd, J = 4.2, 4.3 Hz), 4.75 (lH, brd, J = 7.8 Hz) ), 7. 22-7.25 (2H, m), 8.06 (lH, br), 8.36 (lH, s).

MS (ESI) m / z: 469 (M + H) + .

[Example 39] 6-[ ({( 1SR, 2RS, 4SR) -2-azido- 4-[(9-methoxy-2,3-dihydro-111-[1,4] 噚And [2,3-^]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]-211-pyrido[3,2-1)][1,4]噚-3 411)-ketone

{( 1SR, 2RS, 4SR) -2- -279- 200948817 Azide-4-[(9-methoxy-2,3-dihydro-1Η·[1] obtained under Reference Example 96 under a nitrogen atmosphere , 4] Dihydrogenated [2,3-c]quinolin-1-yl)methyl]cyclohexyl}aminecarboxylic acid tert-butyl ester (120 mg, 0.256 mmol) in dichloromethane (4.0 mL) Trifluoroacetic acid (1.0 mL) was added at room temperature. After stirring at the same temperature for 1.5 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with saturated aqueous sodium hydrogen sulfate. After the organic layer was combined and dried over anhydrous sodium sulfate, the dried solvent was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue and 3-sided oxy-3,4-dihydro-2H-pyrido[3,2-b][l,4] fluorene-6-formaldehyde (described in International Publication No. 2006/032466, etc. '68mg' 〇.3 84mmol) of dichloromethane (10 mL) -N,N-dimethylformamide (2 mL)-acetic acid (0.50 mL), sodium hydrogen hydride (114 mg, 0.5 12 mmol). After stirring at the same temperature for 19 hours, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate, and then filtered and evaporated. The obtained residue was purified by silica gel chromatography (dichloromethane:methanol=19:1 - 9:1) and fractional chromatography (methylene chloride, methylene chloride:methanol = 9:1) to give the title compound as a white solid. 116mg (85%). 1H-NMR (400MHz, CDC13) 5:1.1 7(1H,m)91.40(lH,m), 1.60 (1H,m),1 ·92(1Η,m),2·1 2(1 H,m ), 2.24 (1 H, m), 2.32 (1 H, m), 2.79 (lH, m), 2.97 (2H, d, J = 8.0 Hz), 3.28 (2H, t, J = 4.4 Hz), 3.90 (3H, s), 3 • 94 (1 H, d, J = 4.4 Hz), 3.97 (lH, d, J = 14.4 Hz), 4.1 9-4.23 (3H, m), 4 • 63 (2H, s), 7.03 (lH, d, J = 8.1 Hz), 7.16 (lH, dd, J = 2.7, 9.0 Hz), 7.21 (lH, d, J = 2 • 7 Hz), 7.22 (1 H, d, J) = 8.1 Hz), 7.92 (1 H, d, J = 9.0 Hz), 8.3 8 (1 H, s). -280- 200948817 MS (ESI) m/z: 53 1 (M + H) + .

[Reference Example 97] { ( 1SR, 2RS, 4SR) -2-(ethinylamino)-4_[ (9. methoxy-2,3-dihydro-1Η-[1,4]噚 well [2,3-c]quinolin-1-yl)methyl]cyclohexyl}aminecarboxylic acid tert-butyl ester

{( 1SR, 2RS, 4SR)-2-azido-4-[(9-methoxy-2,3-dihydro-1H-[1,4]噚 obtained in Reference Example 96 under a nitrogen atmosphere A solution of [2,3-c]quinolin-1-yl)methyl]cyclohexyl}carbamic acid tert-butyl ester (150 mg, 0.320 mmol) in methanol (10 mL), 10% palladium carbon Medium (Μ, containing about 50% water, 100 mg). The reaction vessel was replaced with hydrogen, and after stirring at room temperature for 18 hours, anhydrous acetic acid (0.061 mL, 0.640 mmol) was added and the mixture was stirred for 30 minutes. After the catalyst was filtered, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (dichloromethane:methanol = 49:1 - 19:1 - 9:1) %). 1H-NMR (400MHz, CDCl3) 6: 1.28- 1.44 (2H, m), 1.45 (9H, s), 1.46- 1.58 (1H, m), 2.06 (3H, s), 2.06-2.12 (4H, m) , 2.96 (lH, dd, J = 6.1, 14.0 Hz), 3.06 (lH, dd, J = 7.6, 14.0 Hz), 3.18-3.30 (2H, m), 3.62 (lH, br), 3.90 (3H, s ), 4.17(2H,m), 4.44(lH,m), 5.31(lH,br), 6.54(lH,br),7.14-7.17(2H,m),7.90(lH,d,J=10.〇 Hz), 8.32 (lH, s). MS (ESI) m/z: 495 (M + H) + .

[Example 40 is -((1118,2311,5311)-5-[(9-methoxy-2,3-dihydro-281- 200948817 -1H-[1,4]噚 and [2,3 -c]salostyl-bromo)methyl]-2 - { (3-oxo- 3,4-dihydro-211-pyrido[3,2-13][1,4]噚-6 -yl)methyl]amino}cyclohexyl) acetamide

{( 1SR, 2RS, 4SR) -2-(ethyl decylamino)-4-[ ( 9-methoxy- 2,3-dihydro-1H-[1] obtained in Reference Example 97 under a nitrogen atmosphere , 4] a solution of tert-butyl [2,3-c]quinolin-1-yl)methyl]cyclohexyl}carbamic acid tert-butyl ester (1 10 mg, 0.22 7 mmol) in dichloromethane (15 mL) Trifluoroacetic acid (5 mL) was added at room temperature. After stirring at the same temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with a saturated aqueous sodium hydrogen carbonate solution, and then evaporated. After the organic layer was combined and dried over anhydrous sodium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was 94.8 mg of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-formaldehyde (described in International Publication No. 2006/032466). No., 48.5mg, 0.272mmol) in a solution of dichlorocarbyl (l〇mL)-N,N-dimethylformamide (2mL), hydrogenated sodium triethoxyborohydride (lOlmg) at room temperature '0.454 mmol). After stirring at the same temperature for 26 hours, the reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc:EtOAc -282- 200948817 1H-NMR (400MHz, CD3OD) 6: 1.28 (1H, m), 1.39 (1H, m), 1.54 (1H, m), 1.91 (1H, m), 2.05 (3H, s), 2.06-2.25 (3H, m), 2.72 (lH, m), 3.0 1 (2H, m), 3.3 0-3.34 (2H, m), 3.74 (lH, d, J = 13.9 Hz), 3.80 (lH, d, J = 13.9 Hz), 3.91 (3H, s), 4.24 (2H, dd, J = 4.2, 4.4 Hz), 4.50 (lH, m), 4.63 (2H, s), 6.95 (lH, d, J = 8.0 Hz), 7.18 (lH, dd, J = 2. 7, 9.3 Hz), 7.25 (lH, d, J = 8.0 Hz), 7.29 (lH, d, J = 2.7 Hz), 7.77 ( lH,d,J = 9.3 Hz), 8.22 (lH, s). MS (ESI) m/z: 547 (M + H) + . 0 [Reference Example 98] {(1811, 28 ft, 48 ft) - 2-(Ethylamino)-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl )methyl]cyclohexyl}aminecarboxylic acid tert-butyl ester

{( 1SR, 2SR, 4SR) -2- 〇 azide-4-[(9. methoxy-2,3-dihydro-1H-[1,4] obtained in Reference Example 94 under a nitrogen atmosphere. Add a 1% palladium solution to a solution of the tert-butyl [2,3-c]quinolin-1-yl)methyl]cyclohexyl}aminecarboxylic acid tert-butyl ester (15 Omg, 0-320 mmol) in methanol (10 mL) Carbon catalyst (μ, containing about 50% water, 100 mg). The reaction vessel was replaced with hydrogen. After stirring at room temperature for 19 hours, anhydrous acetic acid (0.045 mL, 0.480 mmol) was added and the mixture was stirred for 1 hour. After the catalyst was filtered, the residue was concentrated and the residue obtained was purified by silica gel column chromatography (dichloromethane:methanol = 49:1 - 19:1 - 9:1) to obtain 97.3 mg of a white amorphous compound ( 63%). H-NMR (400MHz, CDC13) 8: 1.09 (1 H, dt, J = l 2.0, 1 2.2 Hz), -283 - 200948817 1.26 (lH, m), 1.42 (lH, m), 1.45 (9H, s ), l_95(3H, s), 2.01 (lH, m), 2.13 (lH, m), 2.21 (lH, m), 2.37 (lH, m), 2.90 (lH, dd, J = 6.5, 13.7) Hz ), 2.99 (lH, dd, J = 8.1, 13.7 Hz), 3.16-3.29 (2H, m), 3.47 (lH, m), 3·7 1 (lH, m), 3.88 (3H, s), 4.14 - 4.21 (2H, m), 4.97 (lH, d, J = 8.8 Hz), 6.66 (lH, d, J = 7.6H), 7.15 (lH, dd, J = 2.7, 9.0 Hz), 7.18 (lH) , d, J = 2.7 Hz), 7.88 (lH, d, J = 9.0 Hz), 8.34 (lH, s). MS (ESI) m/z: 48 5 (M + H) +.

[Example 41] N-(( 1SR, 2SR, 5SR) -5-[ ( 9-methoxy-2,3-dihydro-1H-[1,4]噚[[,3,3-c] Quinoline-1-yl)methyl]-2-{[(3-Sideoxy-3,4-dihydro-2H-pyrido[3,2-b][l,4]噚哄-6- Methyl]amino}cyclohexyl) acetamidine

{( 1SR, 2SR, 4SR) -2-(ethyl decylamino)-4-[(9-methoxy-2,3-dihydro- lH-[l] obtained in Reference Example 98 under a nitrogen atmosphere , 4] Pf-trap and [2,3-c] sialolin-1-yl)methyl]cyclohexyl}aminecarboxylic acid tert-butyl ester (97.3 mg, 0.201 mmol) in dichloromethane (8 mL) Trifluoroacetic acid (2 mL) was added at room temperature. After stirring at the same temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with a saturated aqueous solution of sodium hydrogen carbonate, and then evaporated. After the organic layer was combined and dried over anhydrous sodium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue obtained is 3-p-oxy-3,4-dihydro-2H-pyridin-284- 200948817 [3,2-b][l,4]噚哄-6·formaldehyde (described in International Publication No. 2006). /03 2466, etc. '43 mg, 0.241 mmol) in dichloromethane (i 〇 mL) - hydrazine, hydrazine-dimethylformamide (2 mL), hydrogenated sodium triethoxy hydride 8 5 mg, 0.402 mmol). After stirring at the same temperature for 48 hours, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel chromatography (dichloromethane:methanol:methanol:methanol = 19:1 - 9:1) to afford 37.0mg (3 4%).

1H-NMR (40 0MHz, CDC13) 5: 1.19-1 .26 (2H, m), 1.46 (lH, m), 1.97 (3H, s), 2.06 (lH, m), 2.19 (lH, m) ), 2.28 (lH, m), 2.40 (lH, m), 2 • 85-3.01 (4H, m), 3.20-3.29 (2H, m), 3.89 (3H, s), 3_90 (lH, d, J = 13 • 4 Hz), 4.06 (1 H, d, J = l 3.4 Hz), 4.1 9-4.23 (2H, m), 4.59 (2H, s), 6.81 (lH, br), 6.97 (lH, d, J = 8.3 Hz), 7.14 (lH, dd, J = 2.7, 9.2 Hz), 7.2 1 (lH, d, J = 8.3 Hz), 7.22 (lH, d, J = 2.7 Hz), 7.89 (lH, d , J = 9.2 Hz), 8.38 (lH, s). MS (ESI) m/z: 547 (M + H) + . O [Reference Example 99] {( 1SR, 2SR, 4SR) -2-(dimethyl Amino group)_4_[(9-methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinolin-1-yl)methyl]cyclohexyl} Tertiary butyl carbamate

U 1SR, 2SR, 4SR) _2_ azido-4-[(9.methoxy-2-,3-dihydro·1Η-Π,4] 腭耕和[2] obtained under reference nitrogen gas atmosphere under nitrogen atmosphere , 3-c] sormine-285 - 200948817 -1-yl)methyl] cyclohexyl decylamine formate butyl ester (15 Omg, 0.3 20 mmol) in methanol (10 mL), add 10% Palladium carbon catalyst (Μ, containing about 50% water, l〇〇mg). The reaction vessel was replaced with hydrogen, and after stirring at room temperature for 17 hours, a 37% aqueous solution of formaldehyde (0.096 mL) and acetic acid (0.073 mL) were added and stirred for further 50 hours. After filtration of the catalyst, the filtrate was concentrated and purified to purified crystals eluted eluted eluted elut elut elut elut elut elut elut %). 1H-NMR (400MHz, CD3〇D) 6: l.ll-1.25 (2H, m), 1.3 5 (lHsm), 1.47 (9H, s), 1.96 ( 1 H, m) , 2.02 ( lH, m) , 2.15 (2H, m), 2.34 (6H, s), 2.57 (lH, brt, J = 10.8 Hz), 2.90-2.99 (2H, m), 3.21 - 3.2 8 (2H, m), 3.45 (lH, m), 3.89 (3H, s), 4.17 (2H, dd, J = 4.2, 4.4 Hz), 7.13 (lH, dd, J = 2.7, 9.3 Hz), 7.2 1 (lH, d, J = 2.7 Hz) , 7 • 73 (lH, d, J = 9.3 Hz), 8.18 (lH, s). MS (ESI) m/z: 47 1 (M + H) +.

[Example 42] 6-[({( 1SR, 2SR, 4SR) -2-(dimethylamino)-4-[(9-methoxy-2,3·dihydro-1H-[1, 4]indolo[2,3-c]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]-2H·pyrido[3,2-b] [l,4] -3 ( 4H)-ketone

Under a nitrogen atmosphere, [Reference Example 99] {(1SR, 2SR, 4SR) -2-(dimethylamino)-4-[(9-methoxy-2,3-dihydro-1H-[1, 4] a solution of tert-[2,3-c]quinolin-1-yl)methyl]cyclohexyl}aminecarboxylic acid tert-butyl ester (84.8 mg, 0.18 0 mmol) in di-methane (4.0 mL) Trifluoro-286-200948817 acetic acid (1.0 mL) was added at room temperature. After stirring at the same temperature for 18 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (methanol = 10:1), washed with saturated aqueous sodium hydrogen carbonate, and the aqueous layer was extracted with methylene chloride:methanol = 10:1. The organic layer was combined and dried over anhydrous sodium sulfate, and then filtered, and then filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained from &lt;RTI ID=0.0&gt; ][l,4]噚-6-6-formaldehyde (described in International Publication No. 2006/032466, etc., 40.0 mg, 0.225 mmol) of dichloromethane (10.OmL) -N,N-dimethylhydrazylformamidine A solution of the amine (2.0 mL)-acetic acid (0.05 mL) was added EtOAc (3. After stirring at the same temperature for 1 hour, the reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted. The organic layer was combined and dried over anhydrous sodium sulfate, and then filtered and evaporated. The obtained residue was purified by silica gel chromatography (dichloromethane:methanol = 19:1 - 9:1 - 4 : 1 ) to afford white crystals as a compound as a white compound 54.0 mg ( 56 % ) 〇1H-NMR (400 MHz, CDCl3) 5: 0.96-1.13 (2H, m), 1.5 1 (lH9m), O 1.97 (lH, m), 2.06 (lH, m), 2.15 (lH, m), 2.22 (6H, s), 2.27 (lH5m) , 2 • 49 (lH, dtsJ = 3.9, 10.5 Hz), 2.65 (lH, dt, J = 3.2, 10.5 Hz) s 2.97 (2H, d, J = 7.3 Hz), 3_26 (2H, t, J = 4.2 Hz), 3.84 (lH, d, J = 14.2 Hz), 3.88 (3 H, s), 4.08 (lH, d, J = 14.2 Hz), 4.2 1 (2H, dd, J = 4.2, 4.3 Hz) , 4.64 (2H, s), 6.98 (lH, d, J = 8.1 Hz), 7.15 (lH, dd, J = 2.7, 9.0 Hz), 7.22 (lH, d, J = 8.1 Hz), 7.23 (lH, d, J = 2.7 Hz), 7.92 (lH, d, J = 9.0 Hz), 8.39 (lH, s) · MS (ESI) m/z: 53 3 (M + H) + .

[Reference Example 100] {(1811, 2811, 481〇-4-[(9-methoxy-2,3-dihydro-287- 200948817 -1H-[1,4]噚 well[2,3- c] quinoline-1·yl)methyl]-2-([1,2,3]triazol-1-yl)cyclohexyl}aminecarboxylic acid tert-butyl ester

{( 1SR, 2SR, 4SR)-2-azido-4-[(9-methoxy-2,3-dihydro-1H-[1,4]噚 obtained in Reference Example 94 under a nitrogen atmosphere Indeno[2,3-c]quinolin-1-yl)methyl]cyclohexyl}carbamic acid tert-butyl ester (50.Omg,

A solution of 0.10 7 mmol) in toluene (2.0 mL) was added EtOAc EtOAc EtOAc (EtOAc) The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjj .

1H-NMR (400MHz, CDCl3) 5: 1.3 1 (9HJs), 1.43 (lH, m), 1.72 (lH, brm), 1.92 (1H, brm), 2.18-2.29 (3H, m), 2.66 (lH, m), 3.0 1-3 .12(2H,m),3 _22-3.3 2(2H,m),3.86(3H,s),3 _92(lH,brm), 4.22(2H,t,J = 4.4 Hz), 4.74 (lH, brm), 4.94 (lH, brd, J = 7.3 Hz), 7.1 5-7.18 (2H, m), 7.69-7.70 (2H, m) &gt; 7.91 (lH, d, J = 9.0 Hz), 8.36 (lH, s)· MS (ESI) m/z: 495 (M + H) + .

[Example 43] 6-[({(18 ft, 2311, 48 ft))-4-[(9-methoxy-2,3-dihydro•111-[1,4] fluoren[2, 3-(;]quinolin-1-yl)methyl]-2-([1,2,3]triazol-1-yl)cyclohexyl}amino)methyl]-2H-pyrido[3, 2-b][l,4]噚井-3 ( 4H) -ketone-288- 200948817

Under the nitrogen atmosphere, {( 1SR, 2SR, 4SR) -4-[( 9-methoxy-2,3-dihydro-1H-[1,4]噚[[,3,3] obtained in Reference Example 100 -c]quinolin-1-yl)methyl]-2-([1,2,3]triazol-1-yl)cyclohexyl}aminecarboxylic acid tert-butyl ester (43.9 mg, 0.0888 mmol) Trichloroacetic acid (1.0 mL) was added to a solution of dichloromethane (4.0 mL) at room temperature. After stirring at the same temperature for 4 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane:methanol = 10:1 mixture solvent, washed with saturated aqueous sodium hydrogen carbonate, and the aqueous layer was extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate. The residue obtained is 3-p-oxy-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-carbaldehyde (described in International Publication No. 200 6/0 3 24, 66, etc., 44.0 mg, 0.247 mmol) of dichloromethane (5.0 mL) -N,N-dimethylformamide (1.0 mL)-acetic acid (0.05 mL) Sodium ethoxide borohydride (80.0 mg, 0.377 mmol). After stirring at the same temperature for 4 hours, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate, and then filtered, and then filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was chromatographed on silica gel column (dichloromethane:methanol = 49:1 - 19:1 - 9:1) Purification afforded the title compound as a pale yellow solid (24.2 mg (50%) ° 1H-NMR (400 MHz, CDCl3) 6: 1.32 (1H, m), 1.59 (1H, m), 2.07 -2.16 (3H, m), 2.3 2(lH,m), 2.65(lH,m), 3.00-3.08(2H,m),3.16-3 -289- 200948817 • 33 (3H,m), 3.49 (lH,d,J=14.4Hz) , 3.54 (lH, d, J = 14.4 Hz), 3.83 (3H, s), 4.18-4.28 (2H, m), 4.5 8 (lH, m), 4.61 (2H, s), 6.68 (lH, d, J = 9.0 Hz), 7.12-7.15 (3H, m), 7.73 (lH, s), 7.78 (lH, s), 7.88 (lH, d, J = 9.4 Hz), 8.35 (lH, s). MS ( ESI) m/z: 557 (M + H) + .

[Reference Example 101] {(1811, 2118, 431〇-4-[(9-methoxy-2,3-dihydro-111-[1,4] 噚[[2,3-(〇quinoline) -1-yl)methyl]-2-([1,2,3]triazol-1-yl)cyclohexyl}aminecarboxylic acid tert-butyl ester

{( 1SR, 2RS, 4SR)-2-azido-4-[(9-methoxy-2,3-dihydro-1H-[1,4]噚 obtained in Reference Example 96 under a nitrogen atmosphere The solution of [2,3-c]quinolin-1-yl)methyl]cyclohexyl}aminecarboxylic acid tert-butyl ester (50.Omg, 0.107 mmol) in toluene (3_OmL) was added at room temperature. The phenyl vinyl was milled and heated to reflux for 96 hours. The reaction mixture was concentrated under reduced pressure. EtOAc m. (82%). 1H-NMR (400MHz, CDCl3) 6: 1.4 1 (lH, m), 1.42 (9H, s), 1.78-1.92 (2H, m), 2.16 (lH, m), 2.30 (lH, m), 2.48 ( lH,m)92.8 8(lH,brm ),2.97-3.06(2H,m), 3.18-3.28(2H,m),3.90(3H,s),3.99(lH,m), 4.15-4.22(2H, m), 4.59 (lH, d, J = 7.6 Hz), 5.16 (lH, brs), 7.16 (lH, dd, J = 2.7, 9. lHz), 7.21 (lH, d, J = 2.7 Hz), 7.5 6 (lH, s), 7.7 4 (lH, s), 7.9 1 (lH, d, J = 9.1 Hz), 8.34 (lH, s). -290- 200948817 MS (ESI) m/z: 495 (M + H) + .

[Example 44] 6-[({(18 ft, 2118,481 〇-4-[(9-methoxy-2,3-dihydro-111-[1,4] 噚耕和[2,3 -£5]quinolin-1-yl)methyl]_2-([1,2,3]triazol-1-yl)cyclohexyl}amino)methyl]-211-pyrido[3,2- 13][1,4]噚T-3(411)-ketone

-4-[(9-Methoxy-2,3-dihydro-lH-[l,4]Pf culti[2,3-c]quinolin-1-yl)methyl]-2-( [ 1,2,3]triazol-1-yl)cyclohexyl}aminecarboxylic acid tert-butyl ester (43.2 mg, 0.0873 mmol) in digastric (5.0 mL) solution, added trifluoroacetic acid at room temperature (0.5 mL). After stirring at the same temperature for 18 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane: methanol = 10:1. The solvent mixture was washed with saturated aqueous sodium hydrogencarbonate, and the aqueous layer was extracted with methylene chloride: methanol = 10:1. The organic layers were combined and dried over anhydrous sodium sulfate. The residue obtained was 33.9 mg of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-formaldehyde (described in International Publication No. 2006/032466). No., 38.3mg, 0.215mmol) of dichlorocarbyl (4.0mL) -N,N-dimethylformamide (1.0mL)-acetic acid (0.038mL) solution, adding triethyl hydrogenate at room temperature Sodium bisborohydride (61.3 mg, 0-289 mmol). After stirring at the same temperature for 21 hours, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure from -291 to 200948817. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: 1H-NMR (400MHz, CDC13) 6: 1.35 (lH, m), 1.74 (1H, m), 1.99 -2.02 (2H, m), 2.27 (lH, m), 2.56 (lH, m) 52.77 ( lH,m), 2.94-3.05 (2H,m), 3.10(1 H,m), 3.19-3.28(2H,m),3.88(3H,s), 3.90( lH,d,J =1 4.4Hz) , 3.94 ( lH, d, J = 14.4 Hz), 4.14 - 4.22 (2H, m), 4.63 (2H, s), 5.10 (lH, m), 6.94 (lH, d, J = 8.3 Hz), 7.15 ( lH, dd, J = 2.7, 9.1 Hz), 7.2 1 (lH, d, J = 2.7 Hz), 7.22 (lH, d, J = 8.3 Hz), 7.68 (lH, d, J = 1.0 Hz), 7.89 (l H, d, J = 1.0 Hz), 7.92 (l H, d, J = 9.1 Hz), 8.3 6 (lH, s). MS (ESI) m/z: 557 (M + H) + .

[Reference Example 102] { ( 1SR, 4SR) -4-[ ( 9-methoxy-2,3·dihydro-11€-[1,4] 曙[[,,,,,,,,,,,, -1-yl)methyl]-2-oxocyclohexyl}-tert-butyl amide

{( 1SR, 2RS, 4SR) -2-hydroxy-4-[(9-methoxy-2,3-dihydro-1H-[1,4] 噚 并 并 参考 参考 参考 参考 参考 参考[2,3-c] quinolin-1-yl)methyl]cyclohexyl}aminecarboxylic acid tert-butyl ester (424 mg, 0.95 6 mmol) in dichloromethane (40 mL) -Martin reagent (50 1 mg, 1.18 mmol). After stirring at the same temperature for 22 hours, the reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and 10% aqueous sodium thiosulfate, and extracted with methylene chloride. The organic layer was combined and dried over anhydrous sodium sulfate, and then filtered and evaporated. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol: EtOAc: EtOAc: EtOAc) 1H-NMR (400MHz, CDC13) 5: 1.34 (9H, s), l.40 (lH, m), 1.61 (1 H, m), 2.1 8-2.24 (3H, m), 2.58 (1 H, m ), 2.69 (1 H, m), 2.88 (1 H, dd, J = 5.4, 13.9 Hz), 2.97 (lH, dd, J = 6.6, 13.9 Hz), 3.10 (2H, dd, J = 4.1, 4.4) Hz), 3.77 (3H, s), 4.07 (2H, dd, J = 4.2, 4.4 Hz), 4.21 (lH, m), 5.52 (lH, d, J = 5.8 Hz), 7.03-7.05 (2H, m ), 7.77 (lH, d, J = 10.0H ❹ z), 8.23 (lH, s) · MS (ESI) m/z: 442 (M + H) + .

[Reference Example 103] { ( 1SR, 4SR) -4-[ ( 9 · methoxy-2,3-dihydro-1H-[1,4]噚[[,,,,,,,,,,,,,,, -yl)methyl]-2-((E)-methoxyimino)cyclohexyl}carbamic acid tert-butyl ester

{(lSR,4SR)-4-[(9-methoxy-2,3-dihydro-lH-[l,4]噚 well[2,3-] obtained in Reference Example 102 under a nitrogen atmosphere c] porphyrin·l-yl)methyl]-2-oxocyclohexyl}feccarboxylic acid second-stage butyl vinegar (98.4 mg, 0.223 mmol) sodium hydrazine acetate (23.0 mg '0.26 7 mmol) of ethanol (lO .OmL)-water (1.0 mL) Ο-Methylhydroxylamine hydrochloride (2 8 mg, 〇. 3 3 4 mmol) was added at room temperature and heated at 60 °C. After stirring at the same temperature for 2 hours, the reaction solution was poured into a phosphate buffer (ρΗ7.2) and extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate. &lt;RTI ID=0.0&gt;&gt;&gt;&gt;&gt; This compound was not purified to the above and used for the subsequent reaction. 1H-NMR (400MHz, CDCl3) 5: 1.30 - 1.5 1 (1 2H, m), 2.04 (l H, m ), 2.23 (lH, m), 2.62 (lH, m), 3.08 (2H, d, J = 7.3 Hz), 3.25-3.32 (2H, m), 3.63 (lH, dt, J = 13.4, 2, 7 Hz), 3.88 (3H, s), 3.90 (3H, s), 4.11 (lH, m), 4.20-4.25 (2H, m), 5.64 (lH, brd, J = 5.6 Hz), 7.17 (lH, dd, J = 2.7, 9.0 Hz), 7.20 (1 H, d, J = 2.7 Hz), 7.92 ( 1 H,d,J = 9.0 Hz), 8.36 (lH, s). MS (ESI) m/z: 47 1 (M + H) + .

[Example 45] 6-[({(1811,4 81〇-4-[(9-methoxy-2,3-dihydro-111-[1,4]噚耕[2,3-(( :]quinoline-1_yl)methyl]-2-((£)-methoxyimino)cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l , 4]曙 well-3( 4H)-ketone

{(lSR,4SR)-4-[(9-methoxy-2,3-dihydro-1H-[1,4]噚耕[2,3-c] obtained in Reference Example 103 under a nitrogen atmosphere [Quinolin-1-yl)methyl]-2-((E)-methoxyimino)cyclohexyl}carbamic acid tert-butyl ester (10 mg [0.223 mmol] in dichloromethane ( In a solution of 8.0 mL), trifluoroacetic acid (2.0 mL) was added at room temperature. After stirring at the same temperature for 18 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane··methanol = 10:1 mixture solvent. The mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate, and the aqueous layer was extracted with a mixture solvent of methylene chloride:methanol = 10:1. The organic layer was combined and dried over anhydrous sodium sulfate. 200948817

所得 Residue obtained with 3-sided oxy-3,4-dihydro-2-indole-pyrido[3,2-b][l,4]indole-6-formaldehyde (described in International Publication No. 2006/032466 Etc., 50.0 mg, 0.279 mmol) of dichloromethane (10 mL) -N,N-dimethylformamide (2.0 mL)-acetic acid (0.05 mL). Sodium borohydride (99.0 mg, 0.446 mmol). After stirring at the same temperature for 42 hours, the reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate, and then filtered and evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc 1H-NMR (400MHz5CDCl3) 6: 1.40 (lH, m), 1.56 (2H, dd, J = 12.7, 13.2 Hz), 2.12 (lH, m), 2.24 (lH, brd, J = 13.0 Hz), 2.3 8(lH,m), 3 .〇3(2H,d,J = 6.8Hz),3.23-3.3 2(3H,m),3.5 5(l H,brd,J=13.7Hz) ,3.84(3H , d, J = 1.7 Hz), 3.89 (3H, s), 3.98-4.03 (2H, m), 4.18-4.24 (2H, m), 4.63 (2H, s), 7.00 (1 H, d, J = 8.1 Hz), 7.15 ( lH, dd, J == 2.7, 9.0 Hz), 7.20 (1 H, d, J = 2.7 Hz), 7.21 (lH, d, J = 8.1 Hz), 7.91 (1H, d, J = 9.0 Hz), 8.38 (lH, s). MS (ESI) m/z: 5 3 3 (M + H) + .

[Reference Example 1〇4] {(1811, 2811, 481〇-2-azido-4-[(9-methoxy-2,3-=hydrogen·1Η-[1,4]曙 and [ 2,3-c] sialolin-1-yl)methyl]cyclohexyl} [(3-Sideoxy_3,4·Dihydro-2H-pyrido[3,2-b][l,4] Meeting well-6_yl)methyl]aminecarboxylic acid tertiary butyl ester-295- 200948817

6-[ ({ ( 1SR, 2SR, 4SR)-2-azido-4-[(9-methoxy-2,3-dihydro-111-[1] obtained in Example 38 under a nitrogen atmosphere , 4]噚 and [2,3-(:]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l,4] A solution of bis (tertiary butyl) dicarbonate (55.0 mg) in tetrahydrofuran (3.0 mL) was added to a solution of hydrazine-3 ( 4H)-one (121 mg, 0.228 mmol) in tetrahydrofuran (5.0 mL). After stirring at the same temperature for 3 hours, the mixture was stirred and heated at 50 ° C for further 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was chromatographed on silica gel column (dichloromethane:methanol = 49:1 - 19:1) - 9: 1) Purification afforded 138 mg (96%) of the title compound as white amorphous. 1H-NMR (400 MHz, CDCl3) 5:1.10 (lH, br), 1.43-1.54 (1 lH, b rm), 1.87- 1.98 (3H, brm), 2.50 (lH, brm), 3.03 (2H, br), 3.21-3.30 (2H, m), 3.48 (lH5br), 3.90 (3H, s), 4.03 (lH, br), 4.21. (2H, br), 4.48 (2H, br), 4.66 (2H, s), 6.99 (lH, d, J = 8.1 Hz), 7.17-7. 28 (3H, m), 8.00 (lH, d, J = 9.8 Hz), 8.37 (1 H, s). MS (ESI) m/z: 63 1 (M + H) + .

[Example 46] 6-[({(1811,2811,481〇-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3- c]quinolin-1-yl)methyl]-2-(methylamino)cyclohexyl}amino)methyl]-211-pyrido[3,2-1)][1,4]曙哄-3(411)-ketone, 6-[({(1311,2811,481〇-2-amino-4-[(9-methoxy-2,3-dihydro-1H-[1,4]] Indolo[2,3-c] sialolin-1-yl)methyl]cyclohexyl}amino)methyl-296- 200948817 yl]-2H-pyrido[3,2-b][l,4]噚-3 (4H)-ketone

{( 1SR, 2SR, 4SR) -2-0 azido-4-[(9-methoxy-2,3-dihydro-1H-[1,4] obtained in Reference Example 104 under a nitrogen atmosphere. Sorghum and [2,3-c]quinolin-1-yl)methyl]cyclohexyl} [(3-Sideoxy-3,4-dihydro-2H-pyrido[3,2-15][ 1,4]曙哄-6-yl)methyl]amine]carboxylic acid tert-butyl ester (13811^, 0.2 19mm〇l) in dichloromethane (4.0 mL), added trimethylphosphine at room temperature /toluene solution (1 M, 0.43 8 mL, 0.438 mmol). After stirring at the same temperature for 2 hours, polyformic acid (33.0 mg, 1.09 mmol) was added and stirred for 6 hours. The reaction solution was cooled to 〇 ° C, and methanol (4.0 mL) and sodium borohydride (45 mg, 1.09 mmol) were sequentially added, and the mixture was stirred for 1.5 hrs while gradually warming to room temperature. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane. After the organic layer was combined and dried over anhydrous potassium carbonate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (EtOAc, methylene chloride: methanol: 49:1 - 19:1 - 9:1). The obtained mixture was dissolved in dichloromethane (5.0 mL), and trifluoroacetic acid (1.0 mL) was added at room temperature, and the mixture was stirred at the same temperature for 17 hr. The obtained residue was dissolved in dichloromethane: methanol = 10:1 mixture solvent, washed with saturated aqueous sodium hydrogen carbonate, and the aqueous layer was methylene chloride: -297 - 200948817

Methanol = 10: 1 mixed solvent extraction. The organic layer was combined and dried over anhydrous sodium sulfate. The obtained residue was purified by reverse-phase high-speed liquid chromatography (Develosil, 2 ct (1) x 10 cm, acetonitrile in water containing 0.1% formic acid) to obtain a white solid. [({( lSR,2SR,4SR)-4-[(9-methoxy-2,3-dihydro-lH·[l,4]曙[[,,,,,,,,,,,,, Methyl]-2-(methylamino)cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l,4]indole-3(4H)-one, And 11.0 mg (10%) of 6-[({( lSR,2SR,4SR)-2-amino]4-[(9-methoxy-2,3-dihydro-1Η-[1,4] Deuterium and [2,3-c]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l,4]噚-3 (4H)-ketone. 6-[ ( { ( 1SR, 2SR, 4SR ) -4-[ ( 9-methoxy-2,3-dihydro-111-[1,4]噚 and [2,3-(;]] quinoline -1-yl)methyl]-2-(methylamino)cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l,4]indole-3 ( 4H) -ketone: 1H-NMR (400MHz, CD3〇D) 6:1.20-1.38 (3H,m), 2.14 (lH,m), 2.24 (1 H,m), 2.38 (lH,m), 2.45 (lH, m), 2.53(lH,m), 2.69(3H,s), 2.8 8 (1 H, dt, J = 3.9,1 1 . 7 H z),

3.09 (lH, dd, J = 6.8, 13.9 Hz), 3.15 (1 H , dd , J = 7.8, 1 3.9 Hz), 3.29-3, 3 9 (2H, m), 3. 8 4 ( 1 H, d, J = 1 4.2 H z), 3.93(3H,s), 3.99(lH,d,J=14.2Hz) 4 _ 2 6 - 4.2 7 (2 H,m),4.6 5 (2 H , s), 7.0 4 (lH, d, J = 8.1 Hz), 7.22 (lH, dd, J = 2.7, 9.3 Hz), 7.29 (1 H, d, J = 2.7 Hz), 7.30 (lH, d, J = 8.1 Hz), 7.8 0 ( 1 H, d, J = 9.3 H z), 8.25 (lH, s). MS (ESI) m/z: 5 1 9 (M + H) + . 6-[( {(1311,23 ft,4811)-2-amino-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indolo[2,3-c] quin啉-1-yl)methyl]cyclohexyl}amino)methyl-298- 200948817 yl]-2H-pyrido[3,2-bni,4]indole-3(4H)-one: 1H-NMR ( 400MHz, CD3〇D)5: 1.21-1.37 (3H, m), 2.12-2.19 (2H, m), 2.32-2.49 (3H, m), 2.96 (lH, dt, J = 3.9, 11.7 Hz), 3.11 (2H,d,J = 7.3Hz),3_3 1- 3.36(2H,m),3.82(lH,d,J=14.4Hz), 3.93(3H,s),3.99(lH,d,J=14.4Hz ), 4.27 (2H, dd, J = 4, l, 4.4 Hz), 4. 64 (2H, s), 7.04 (1 H, d, J = 8. 1 Hz), 7.22 (1 H, dd, J = 2.7, 9.3 Hz), 7.28 ( lH, d, J = 2.7 hz), 7.29 (lH, d, J = 8.1 Hz), 7.80 (lH, d, J = 9.3H) z), 8.24 (lH, s).

MS (ESI) m / z: 505 (M + H) +.

[Reference Example 105] (1RS, 2SR, 5RS) -2-({[Tertiary butyl(dimethyl)decyl]oxy}methyl)-6·oxabicyclo[3.2.1] s- 7-ketone

Will (1RS, 2RS, 4SR, 5SR) -2-({[Tertiary butyl(dimethyl)decyl)oxy}methyl)-4-iodo-6-oxabicyclo[3.2.1] Oct-7 ketone (described in Journal of the American Chemical Society &gt; 2003, Vol. 125, No. 35, page 10496-10497, 26.75g &gt; 67.5mmol), hydrogenated tri(first butyl) tin ( A mixture of 21.24 mL, 81.0 mmol), azabisisobutyronitrile (222 mg, 1.35 mmol), and toluene (670 mL) was stirred and stirred at 70 ° C for 3 hours under nitrogen atmosphere. After distilling off the solvent under reduced pressure, tetrahydrofuran (600 mL), 7jc (300 mL), and potassium fluoride (23.5 3 g &gt; 405.0 mmol) were stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and filtered with Celite to isolate organic layer. The separated organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The residue obtained was purified by EtOAc (EtOAc: EtOAc = EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: 1H-NMR (400MHz, CDC13) 5: 0.06 (3H, s), 0.07 (3H, s), 0.90 (9H, s), 12.22-1.39 (lH, m), 1.56-1.66 (lH, m), 1.73 (lH, d, J = 5.0 Hz), 1.82- 1.95 (2H, m), 2.02-2.06 (lH, m), 2.45-2.50 (lH, m), 2.74 (lH, d, J = 6.0Hz), 3.43 (lH, dd, J = 10.1, 6.0H?), 3.53 (lH, dd, J = 10.1, 8.3 Hz), 4.8 1 (lH, t, J = 5.0 Hz).

[Reference Example 106] (1RS, 2SR, 5RS) -2-({[Tertiary butyl(dimethyl)decyl]oxy}methyl)-6-oxabicyclo[3.2.1] s- 7-alcohol

(1RS, 2SR, 5RS) -2- ({[Ter-butyl(dimethyl)decyl)oxy}methyl)-6-oxabicyclo[3.2.1] obtained in Reference Example 105. A solution of the crude succinone-one (19.51 g, 67.5 mmol) in toluene (500 mL) was added dropwise to a solution of &lt;RTIgt;&lt;/RTI&gt; After stirring at the same temperature for 1 hour, acetic acid (7.71 mL, 135 mmol) was added, followed by aqueous sodium potassium tartrate (600 mL) and stirred at room temperature overnight. The resulting mixture was extracted with ethyl acetate. The extract was washed sequentially with water, saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjj The title compound is 17.44g (95%) ° 1H-NMR (400MHz, CDCl3) 6:0.05 (6H,m)i0.89(9H,m), 1.20 -1.80 (6H,m),2_23(lH, m), 2.3 6 (lH, m), 3.50 (2H, m), 4-52 (lH, m) -300- 200948817, 5.35 (lH, m).

[Reference Example 107] (1RS, 3SR, 4SR) -4- ({[Tertiary butyl(dimethyl)decyl]oxy}methyl)-3-vinylcyclohexanol

A suspension of methyl iodide triphenyl rust (90.56 g, 2 24 mmol) in tetrahydrofuran (400 mL) was added dropwise to a first-stage butyl lithium/hexane solution (2.77 M, 76.3 mL, 21 lmmol) over 20 min. . After stirring at the same temperature for 40 minutes, (1RS, 2SR, 5RS) -2-({[tri-butyl(dimethyl)decyl)oxy}methyl group obtained in Reference Example 106 at the same temperature. A solution of 6-oxabicyclo[3.2.1]oct-7-ol (17.44 g, 64.0 mmol) in tetrahydrofuran (100 mL) was added dropwise over 15 min. After stirring at room temperature for 3.5 hours, it was ice-cooled, and 1N hydrochloric acid was added. The extract was extracted with acetic acid ester, and the extract was washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate. After filtered, the filtrate was evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjj Oil labeled compound 15.81g (91%) ° 1H-NMR (400 MHz, CDC13) 6: 0.028 (3H, s), 〇.〇3 1 (3H, s), 0.8 8 (9H, s), 1.36 -1.53 (3H, m), 1.73-1.76 (lH, m), 1.80-1. 88 (2 H, m), 1.93-1.99 (1H, m), 2.38 (lH, m), 3.50-3.58 (2H,m), 3.76 (1 H,m), 4.97 (lH,dt,J = 6.9,1.6 Hz), 5.01 (lH,d,J=l ·4Ηζ), 5.91-6.00 (lH,m). MS (ESI) m/z: 27 (M + H) + .

[Reference Example 108] (1RS, 3SR, 4SR) -4-{[(Triphenylmethyl)oxy]methyl}-3-vinylcyclohexanol -301- 200948817

Ph

Ph, L Ph^^O

OH

(1RS, 3SR, 4SR) -4- ({[Ter-butyl(dimethyl)decyl)oxy}methyl)-3-vinylcyclohexanol (13.91g) obtained in Reference Example 107. A solution of 5 1.4 mmol) in tetrahydrofuran (77 mL) was added to a solution of tetrabutylammonium fluoride/tetrahydrofuran (1·?, 154 mL, 154 mmol) at room temperature and stirred at the same temperature for 14 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjj , 3SR, 4SR) -4-(hydroxymethyl)-3-vinylcyclohexanol crude product 1 0.45g 〇

1H-NMR (400MHz, CDCl3) 5: 1.40-1.49 (3H, m), 1.76 (lH, m), 1.87- 1.92 (3H, m), 2.42 (1 H, m), 3.55 (1 H, dd, J=l 1.0, 7.6 Hz), 3.69 (lH, dd, J=11.0, 5.9 Hz), 3.79 (lH, m), 5.02 (lH, m), 5.01 (lH, dt, J = 5.4, 1.6 Hz) , 6.01-6.10 (lH, m). Obtained (1RS, 3SR, 4SR) -4-(hydroxymethyl)-3-vinylcyclohexanol crude product l〇.45g, triethylamine (10.75 mL, 77.1 mmol), 4-(dimethylamino)pyridine (314 mg, 2.6 mmol) in N,N-dimethylformamide (25 mL), chlorotriphenylmethane (17.21 g) , 61.7 mmol), and mixed for 16 hours at the same temperature. After adding methanol (250 mL) to the reaction mixture, the mixture was stirred for 10 minutes, and then concentrated under reduced pressure to a volume of about 150 mL. This was partitioned between ethyl acetate and water, and the organic layer was separated. The obtained organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to -302 - 200948817, and the obtained residue was purified by chromatography on silica gel column (hexane: ethyl acetate = 9:1 - 4:1 - 2:1 - 1: 1 - chloroform:methanol = 8: 1), 13.11 g (64%) of the labeled compound was obtained as a thin yellow gum solid. 1H-NMR (400MHz, CDCl3) 5: 1.14-1.28 (2H, m), 1.40-1.50 (2H, m), 1.69- 1.78 (2H, m), 2.00-2.04 (2H, m), 2.33 (lH, m), 3.00 (lH, t, J = 9.0 Hz), 3.08 (lH, dd, J = 9.2, 5.0 Hz), 3.68 (lH, m), 4.8 3-4.88 (2H, m), 5.74 (lH, m), 7.20-7.30 (9H, m), 7.42-7.44 (6H, m)_ [Reference Example 109] [(1RS, 2RS, 4RS) -4-azido-2-vinylcyclohexyl] hydrazine methanol

(1RS, 3SR, 4SR) -4-{[(triphenylmethyl)oxy]methyl}-3-vinylcyclohexanol (13.11g, 3 3.0mmol) obtained in Reference Example 108 A solution of triethylamine (6.90 mL, 49.5 mmol) in dichloromethane (1 mL) was evaporated. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give (1,3,3,4,4,4,4,4,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,5 (1RS, 3SR, 4SR) · 4-{[(Triphenylmethyl)oxy]methyl}-3-vinylcyclohexyl methanesulfonate crude product 16.35g Ν, Ν-二A solution of methylformamide (85 mL)-water (15 mL) was added to sodium azide (6.44 g, 99.1 mmol), and the mixture was stirred and stirred at 65 ° C for 8 hours. Water was added to the reaction mixture and extracted with diethyl ether, and the combined extract was washed with water and saturated brine. The filtrate was concentrated under reduced pressure with dry--303 - 200948817 sodium sulfate. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 98: 2 - 95: 5 - 90: 10) to afford [(1RS, 2RS, 4RS)-4-azide as a colorless transparent oil. 13.09 g of a mixture of benzyl-2-vinylcyclohexyl]methyltriphenylmethylether and a liberated body. 12.63 g of the obtained [(1RS, 2RS, 4RS)-4-azido-2-vinylcyclohexyl]methyltriphenylmethyl ether and a mixture of excipients, and p-toluenesulfonic acid monohydrate A solution of (285 mg, 1.50 mmol) in methanol (150 mL)-tetrahydrofuran (30 mL) was stirred at 40 ° C for 2 hr. After adding sodium hydrogencarbonate to the reaction mixture to make a weak basic, the solvent was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and filtered through a pad of silica gel. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc 1H-NMR (400MHz, CDCl3) 5: 1.30-1.46 (2H, m), 1.59 (lH, td, 12.2, 4.6 Hz), 1.69-1.76 (2H, m), 1.96-1.99 (lH, m), 2.05 -2.08 (1 H, m), 2.74 (1 H, m), 3.44 - 3.59 (3H, m), 5.11-5.19 (2H, m), 5.91 (lH, dt, J = 17.0, 9.6 Hz).

[Reference Example 110] {(1RS, 2RS, 4RS) -4-[(third-order butoxycarbonyl) hydrazino]-2-vinylcyclohexyl}methanol

[(1RS, 2RS, 4RS )-4-Azido-2-ethylidenecyclohexyl]methanol (3-28 g, 18.1 mmol) of tetrahydrofuran (80 mL) obtained in Reference Example 109. Water (20 mL) Triphenylphosphine (7.13 g, 27.2 mmol) was added to the solution, and the mixture was stirred under heating at 50 °C for 3 hours. After concentrating the reaction solution under reduced pressure to about 20 mL, it was made acidic by adding 0.5 N -304 - 200948817 hydrochloric acid, and washed with diethyl ether. The washed aqueous layer was made alkaline with 4N aqueous sodium hydroxide solution, and 1,4-dioxane (60 mL) and di(tert-butyl) dicarbonate (9.88 g, 45_3 mm〇l) were added at room temperature. Stir for 20 hours. The reaction mixture was concentrated to dryness under reduced pressure. After filtration, the filtrate was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj .

1H-NMR (400MHz, CDCl3) 5: 1.13 (lH, qd, 12.2, 3.9 Hz), 1.26 - 1.44 (llH, m), 1.59-1.71 (2H, m), l_98 (lH, m), 2.09 (lH) , m), 2.66 (lH, m), 3.46 (2H, m), 3.70 (lH, m), 4_35 (lH, m), 5.10 (lH, dd, J = 1 • 3, 2_lHz), 5.16 ( lH, d, J = 17.0 Hz), 5.99 (lH, dt, J = 17.0, 9.6 Hz) [Reference Example 111] [(1RS, 3RS, 4RS) -4-(Aminomethyl)-3-Ethylene Tert-butyl butyl carbamate

{( 1RS, 2RS, 4RS ) -4-[(1~) obtained in Reference Example 110

---Gradoxycarbonyl)amino]-2-vinylcyclohexyl}methanol (3.66 g, 14.3 mmol under Teng Leng), quinone (3.16 g, 21.5 mmol) and triphenyl (5.64 g) A solution of 21.5 mmol) in tetrahydrofuran (70 mL) was added EtOAc (EtOAc m. The solvent was distilled off under reduced pressure and the residue was purified by chromatography (hexane: ethyl acetate = 4:1 - 2. ^1 1) to obtain a pale yellow gumy solid {(1RS, 3RS, 4RS) -4 r, l C 1 ^ •305 - 200948817 Bis-oxy-1,3-dihydro-2H-isoindol-2-yl)methyl]-3-vinylcyclohexyl}aminecarboxylic acid third stage Butyl ester crude product 7.28g» 1H-NMR (400MHz, CDC13) 5: 1.5 8 (1 H, qd, l 2.0, 4.0 Hz), 1.36 -1.53 (12H, m), 1.99-2.05 (3H, m ), 2.60 (lH, m), 3.5 3 (2H, d, J = 7.3 Hz), 3.73 (lH, m), 4.3 1 (lH, m), 5.17-5.20 (2Hsm), 6.07 (lH, m) , 7.70-7.89 (4H, m). The obtained {( 1RS, 3RS, 4RS) -4-[( 1,3-di- oxy-1,3-dihydro 2 Η-isoindole-2- ))methyl]-3-vinylcyclohexyl}aminecarboxylic acid tert-butyl ester crude product 7.28g' and hydrazine 1 hydrate (2.23mL, 7 1.7mmol) 〇 dissolved in ethanol (200mL), 1 Heat and stir on an oil bath at 10 ° C for 2 hours. After cooling to room temperature, methanol was added and the insoluble material was filtered off. After concentrating the filtrate under reduced pressure, chloroform was added, and the insoluble material was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj . 1H-NMR (400MHz, CDCl3) 8: 1.12 (lH, qd, 12.2, 3.8 Hz), 1.22 - 1.50 (12H, m), 1.61 (1H, m), 1.95-2.08 (2H, m), 2.49 (lH) , dd, J=12. 7,6·6Ηζ), 2.54 (1 H, dd, J = 12.8, 7.7 Hz), 2.62 (lH, m), 〇 3.68 (lH, m), 4.36 (lH, m) , 5.09 (lH, dd, J = 10.2, 1.7 Hz), 5.14 (lH, d, J = 17.1 Hz), 5.95 (lH, dt, J = 17.1, 9.8 Hz).

[Reference Example 112] 4-[({(1RS, 2RS, 4RS))-4-[(Tertiary Butoxycarbonyl)amino]-2-vinylcyclohexyl}methyl)amino]-6- Methoxyquinoline-3-carboxylic acid ethyl ester-306- 200948817

[(IRS, 3 RS, 4RS ) -4-(Aminomethyl)-3-vinylcyclohexyl]aminecarboxylic acid tert-butyl ester (4-13 g, 14.3 mmol), 4 obtained in Reference Example 11 a mixture of ethyl chloro-6-methoxyquinoline-3-carboxylate (3.81 g, 14.3 mmol), triethylamine (6.00 mL, 43.0 mmol) and dimethyl sulfoxide (45 mL)

The mixture was heated and stirred on an oil bath at 90 ° C for 16 hours. After cooling to room temperature, it was diluted with ethyl acetate, and then washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The marked compound of the brown blister solid was 6.46 g (93%). 1H-NMR (400MHz, CDCl3) 5: 1.19 (lH, m), 1.38-1.47 (14H, m), 1.80 (lH, m), 1.86 (lH, m), 2.01 (lH, m), 2.15 (lH) , m), 2.72 (lH, m), 3.62 (2H, t, J = 6.2 Hz), 3.72 (lH, m), 3.88 (3H, s), 4.39 (3H, m), 5.03-5.09 (2H, m), 5.95 (lH, m), 7.33 (lH, dd, J = 9.2, 2.8 Hz), 7.49 (lH, d, J = 2.8 Hz), 7.86 (1 H, d, J = 9.2 Hz), 8.99 (lH, s), 9.04 (lH, m).

[Reference Example 113] [( 1RS, 3RS, 4RS ) -4- { [(3-Methoxymethyl-6-methoxyquinolin-4-yl)amino]methyl}-3-vinylcyclohexyl Tert-butyl amide

-Boc

xBoc -307 - 200948817 4-[({(lRS, 2RS,4RS)-4-[(tri-tert-butoxycarbonyl)amino]-2-vinylcyclohexyl}methyl) obtained in Reference Example 112 a solution of amino]-6-methoxysalin-3-decanoic acid ethyl vinegar (6.46 g, 13.36 mmol) in tetrahydrofuran (140 mL), and then, with ice-cooled lithium aluminum hydride (1.521 g, 40.1 mmol), After stirring at room temperature for 30 minutes, it was stirred at room temperature for 1.5 hours. Add lithium hydride (0.761 g, 20.1 mmol) and stir for another 30 minutes, then ice-cool, carefully add water (2 · 17 mL), followed by 3N aqueous sodium hydroxide (2.17 mL), water (6.50 mL) . Thereafter, tetrahydrofuran (i5 〇 mL) was added, and the mixture was stirred at room temperature overnight. After diluting with ethyl acetate, anhydrous sodium sulfate was added and stirred for a while, then Celite was filtered. The filtrate was concentrated under reduced pressure to give [[1RS, 3RS, 4RS] -4- ({[3-(hydroxymethyl))-6-methoxyquinolin-4-yl]amino} Crude product of tert-butyl butyl 3-methylcyclohexyl]aminecarboxylic acid 5.66 g (96%). 1H-NMR (400MHz, CDCl3) 5: 1.13-1.30 (lH, m), 1.3 5-1.44 (1 lH, m), 1.67- 1. 82 (2H, m), 1.95-2 · 15 (2Η , ιη), 2·7 1 (ΐΗ, πι), 3.39 (lH, m), 3.69 (lH, m), 3.85-3.89 (4H, m), 4.37 (lH, m), 4.74 (2H, s) , 5.00-5.20(3H,m), 5.90-6.05 (1 Η,m), 7.25-7.28(2H,m), 7.84(lH,d,J = 8.8Hz), 8.12(lH,s). [(1RS, 3RS, 4RS) -4-({ [3-(hydroxymethyl)-6-methoxysin-4-yl]amino}methyl)-3-vinylcyclohexyl]amine A solution of 5.66 g (12.82 mmol) of methylene chloride (130 mL) was obtained. Further, a little oxidized (6.56 g &gt; 64.1 mmol) was added and stirred for 3 hours, and the insoluble material was filtered with Celite, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (chloroform: ethyl acetate = 9:1 - 4: -308 - 200948817 1-2: 1 - 1: 1 - 1: 2) to obtain a yellow foamy solid. Compound 2.96 g ( 53% ) 〇-NMR (400 MHz, CDC 13) 5: 1.20-1.30 (lH, m), 1.40-1.50 (llH, m), 1.75-2.14 (4H, m), 2.77 (lH, m) , 3.70-3.76 (3H, m), 3.8 8 (3H, s), 4.3 8 (lH, m), 5.08-5.14 (2H, m), 5.99 (lH, m), 7.37 (lH, d, J = 2.9 Hz), 7.40 (lH, d3J = 2.7 Hz), 7.60 (lH, d, J = 2.7 Hz), 8.4 8 (lH, s), 9.86 (lH, s), 10.19 (lH, brs). MS ( ESI) m/z: 440 (M + H) + .

[Reference Example 114] {(1113,3118,4118)-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline -1-yl)methyl]-3-vinylcyclohexyl}-tert-butyl amide

[(1RS, 3RS, 4RS ) -4- { [(3-methylQ fluorenyl-6-methoxyquinolin-4-yl)amino]methyl}-3-ethylene obtained in Reference Example 113 A solution of the butyl hexyl amide carboxylic acid tert-butyl ester (2.96 g, 6-74 mmol) in dichloromethane (35 mL)-MeOH (35 mL). Perbenzoic acid (2.91 g, 16.87 mmol) was stirred at the same temperature for 3 hours. A 5 % aqueous sodium thiosulfate solution was added to the reaction mixture, followed by the addition of 1N hydrochloric acid. Next, sodium hydrogencarbonate was slowly added to become weakly alkaline, followed by extraction with a mixed solvent of chloroform and chloroform:methanol = 9:1. The extract was combined and dried over anhydrous sodium sulfate. Obtaining a yellow bubble-like individual [(1RS, 3RS, 4RS) -4- { [(3-hydroxy-6-methoxyquinolin-4- 4-309- 200948817-yl)amino]methyl} -3- Vinylcyclohexyl]crudemic acid tertiary butyl ester crude product 3.55 g. 1H-NMR (400MHz, CDC13) 5:1. 10-1.30 (lH, m), 1.30-1.50 (1 lH, m), 1.76- 1.90 (2H, m), 1.95-2.09 (2H, m), 2.72 (lH,m), 3.48 (l H, dd, J = 12.6, 7.6 Hz), 3.57 (lH, dd, J = 12.6, 6.6 Hz), 3.71 (lH, m), 3.89 (3H, s) , 4.37 (lH, m), 5.11 (lH, d, J = 10.5 Hz), 5.19 (lH, d, J = 17.0 Hz), 6.01 (lH, m), 7.13 (lH, dd, J = 9.4, 2.5 Hz), 7.25 (lH, d, J = 2.8 Hz), 7.89 (1 H, d, J = 9.2 Hz), 8.20 (1 H, s). MS (ESI) m/z: 428 (M + H) + . [(1RS,3RS,4RS ) -4- { [(3-Hydroxy-6-methoxyquinolin-4-yl)amino]methyl}-3-vinylcyclohexyl]amine Crude product of tertiary butyl formate 3.55 g, 1,2-dibromoethane (1.162 mL, 13.5 mmol), potassium carbonate (2.79 g, 20.2 mmol) and N,N-dimethylformamide ( A mixture of 40 mL) was heated and stirred for 3.5 hours on an oil bath at 80 °C. The reaction solution was cooled to room temperature, and poured into water and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the filtrate was evaporated, evaporated, evaporated,jjjjjjjjjjjjjjjjjj The title compound 1.76 g (58%) was obtained as a tan solid. 1H-NMR (400MHz, CDC13) 6: 1.1 8-1.26 (lH, m), 1.41-1.5 1 (1 0H, m), 1.60-1.76 (lH, m), 2.00-2.10 (2H, m) &gt; 2.25 (lH, m), 2.33 (l H, m), 2.5 1 (lH, m), 2.77 (lH, m), 3.12-3.22 (2H, m), 3.38 (lH, m), 3.80 ( lH,m), 3.91 (3H, s), 4.18 (lHJm), 4.25 (lH, dt, J = 11.0, 3.0 Hz), 4.40 (lH, m), 5.04 (lH, s), 5.07 (lH, d , J = 4.6 Hz), 5.97 (lH, m), 7.14 - 7.19 (2H, m), 7_88 (lH, d, J = 9.2 Hz), 8.37 (1 H, s). MS (ESI) m/z :454(M + H) + . -310- 200948817 [Reference Example 115] (1RS, 2SR, 5SR) -5-[(3rd-order butoxycarbonyl)amino]-2-[(9-methoxy Benzyl-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1·yl)methyl]cyclohexanecarboxylic acid

{( 1RS, 3RS, 4RS ) -4-[( 9-methoxy-2,3-dihydro-1H-[1,4]噚[[,3,3-c] obtained in Reference Example 114 Hydrazin-1-yl)methyl]-3-ethene Q-cyclohexyl}amine carboxylic acid tert-butyl ester (785 mg, 1.73 1 mmol) in butyl alcohol (6 mL)-water (6 mL) N-Methyl-Walfene-N-oxide (264 mg, 2.25 mmol) was added at room temperature followed by tetraoxide (22 mg, 0.087 mmol). After mixing for 9 hours at the same temperature, a 5% aqueous solution of sodium thiosulfate was added thereto, and the mixture was extracted with a mixed solvent of chloroform:methanol = 9:1. The extract was combined and dried over anhydrous sodium sulfate. To a solution of the obtained thin brown foamy individual in tetrahydrofuran (10 mL)-water (10 mL), sodium thiosuccinate (926 mg, 4.33 mmol) To the reaction mixture, a 5% aqueous solution of sodium thiosulfate was added, and the mixture was extracted with chloroform:methanol = 9:1, and then the mixture was dried over anhydrous sodium sulfate and filtered. Add 2-methyl-2-butene (1.40 mL, 13.22 mmol) at room temperature to a solution of butyl alcohol (6 mL)-tetrahydrofuran (6 mL) in water (3 mL). Sodium dihydrogen phosphate 2 hydrate (771 mg, 4.9 4 mmol) was added followed by sodium chlorite (477 mg, 4.95 mmol) and stirred at the same temperature for 5 hours. After adding water (20 mL) and sodium thiosulfate·5 hydrate (2.50 g, 10 mmol) to the reaction mixture, the solvent was evaporated. The residue -311-200948817 was suspended in a mixed solvent of chloroform:methanol = 9:1, and the insoluble matter was removed by filtration through a short-tank column. The filtrate was concentrated under reduced pressure, and the residue was purified by EtOAc EtOAc (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: 407 mg (50%). !H-NMR (400MHz9CDC13: CD3OD = 2:1) 5: 0.89 (1 H, m), 1.1 3 -2.29 (15H, m), 2.78 (lH, m), 2.95 (lH, m), 3.19 (lH) , m), 3.46 (lH, m), 3.54-3.8 1 (2H, m), 3.97 (3H, s), 4.19 (lH, m), 4.30 (lH, m), 5.61 (1 H, m), 7.1 7 (1 H, dd, J = 9.2, 2.8 Hz), 7.3 2 (1 H, d, J = 2.8 Hz), 7.80 (1 H, d, J = 9.2 Hz), 8.26 (lH, s). MS (ESI) m / z: 472 (M + H) + .

[Example 47] (1113, 2811, 581〇-2-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline- 1-yl)methyl]-5-{[(3-Sideoxy-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-yl) A Amino}cyclohexanecarboxylic acid

(1RS, 2SR, 5SR) -5-[(3rd-order butoxycarbonyl)amino]-2-[(9-methoxy-2,3-dihydro-111-) obtained in Reference Example 115 [1,4]indolo[2,3-c]quinolin-1-yl)methyl]cyclohexanecarboxylic acid (56 mg '0.119 mmol) was dissolved in 4N hydrogen chloride / dioxane solution (2 mL·), Stir at the same temperature for 5 minutes. After concentrating the reaction solution under reduced pressure, the residue is steeped with 3_sideoxy_3,4·dihydro-2H-indole and [3,2-b][l,4]曙-6-methyl leaven ( |5, in International Publication No. -312-200948817 2006/032466, etc., 23 mg, 0.129 mmol) dissolved in dichloromethane (0.8 mL), methanol (0.2 mL), and added triethylamine (50 μί, 0.359 mmol), Sodium hydride triacetate (50 mg, 0.236 mmol) was stirred and stirred at room temperature for 27 h. After adding 10% aqueous citric acid solution to the reaction mixture, the solvent was evaporated under reduced pressure, and the residue was subjected to thin layer chromatography (yellow, chloroform:methanol: water = 7:3:1 under solvent, 1% triethylamine) Contains) purification. The obtained solid was suspended in ethanol, and the insoluble matter was filtered to obtain a labeled compound (yield: 7 mg (5%) of a brown powder). Q iH-NMRHOO MHz 'CDClrCDsODM : 1) δ: 1.78 (2H, m), 1.97 (lH, m) , 2.03 (lH, m), 2.24 (lH, m), 2.45-2.52 (2H, m), 2.89 (lH, m), 3.42 (lH, m), 3.64-3.72 (2H, m), 3.79-3.83 (lH,m), 3.96 (3H, s), 4. 19-4.3 8 (5H, m), 4.64 (2H, s), 7_04 (lH, d, J = 7.8 Hz), 7_27 (lH, d, J = 8.3 Hz), 7.33 (lH, d, J = 2.3 Hz), 7.40 (lH, dd, J = 9.4, 2.5 Hz), 8.02 (l H, d, J = 9.6 Hz), 8.34 (lH, s ) MS (ESI) m / z: 534 (M + H) + .

[Example 48] (1RS, 2SR, 5SR) -5-[(2,3-Dihydro[1,4]dioxin and O[2,3-c]pyridin-7-ylmethyl)amino group ]-2-[(9-Methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl)methyl]cyclohexanecarboxylate acid

(1RS, 2SR, 5SR) -5-[(3rd-order butoxycarbonyl)amino]-2-[(9-methoxy-2,3-dihydro-111-) obtained in Reference Example 115 [1,4] hydrazine and [2,3-c]quinolin-1-yl)methyl]cyclohexanecarboxylic acid (26 mg, 0.05 5 mmol) -313- 200948817 dissolved in 4N hydrogen chloride / dioxane solution ( 3 mL)-IN hydrochloric acid (0.2 mL) was stirred at the same temperature for 5 min. After concentrating the reaction mixture under reduced pressure, it was azeotroped with dioxane and ethanol. The residue was dissolved in 2,3-dihydro[1,4]dioxin[2,3-c]pyridine-7-carbaldehyde (described in International Publication No. 2006/032466, etc., 10 mg, 0.061 mmol). Dichloromethane (0.3 mL), methanol (0.06 mL), triethylamine (23pL, 0.165 mmol), and hydrogenated sodium triacetate (23 mg, 0.109 mmol) were stirred at room temperature for 21 hours. Water was added to the reaction mixture, and the mixture was extracted with a solvent of chloroform:methanol:water = 7:3:1, and the mixture was concentrated and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) 1H-NMR (400MHz, CDC13: CD3〇D = 2: 1) 6: 1.43 (lH, m), 1.63 (lH, m), 2_13 (lH, m), 2.24-2.3 1 (3H, m), 2.42 (lH, m), 2.78 (lH, m), 3.04 (1 H, m), 3.19 (1 H, m), 3.46 (2H, m), 3.66 (2H, m), 3.97-4.02 (5 H, m), 4.20 (lH, m), 4.3 1 (4H, s), 6.94 (lH, s), 7.15 (lH, d, J = 9.2 Hz), 7.32 (lH, s), 7.79 (lH, d, J = 9.2 Hz), 8.08 (lH, s), 8.26 (lH, s). MS (ESI) m/z: 521 (M + H) + .

[Example 49] (lRS, 2SR, 5SR)-5-[(2-cyclohexylethyl)amino]-2-[(9-methoxy-2,3-dihydro-lH-[l, 4]indolo[2,3-C]quinoline-l-yl)methyl]cyclohexanecarboxylic acid

-314- 200948817 (1RS, 2SR, 5SR) -5-[(3rd-order butoxycarbonyl)amino]_2-[(9-methoxy-2,3·dihydrogen) obtained in Reference Example 115 -1H-[1,4] hydrazine and [2,3-c]quinolin-1-yl)methyl]cyclohexanecarboxylic acid (30 mg, 0.064 mmol) dissolved in 4N hydrogen chloride / dioxane solution (3 mL -IN hydrochloric acid (0.2 mL), stirred at the same temperature for 5 minutes. After concentrating the reaction mixture under reduced pressure, it was azeotroped with dioxane and ethanol. The residue and 2-cyclohexylacetaldehyde (9 mg, 0.071 mmol) were dissolved in dichloromethane (5. 5 mL), methanol (0.lmL), triethylamine (27μί, 〇0_194mmol), triethyl hydrazide Sodium borohydride (27 mg, 0.127 mmol) was stirred at room temperature for 7 h. Water was added to the reaction mixture, and the mixture was extracted with chloroform:methanol:water =7:3:1, and the mixture was concentrated under reduced pressure. The residue was purified by fractional chromatography (EtOAc EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc 〇D = 2: l) 6: 0.94 (2H, m), 1.14 - 1.54 (8H, m), 1.69 (5H, m), 2.06 (lH, m), 2.24 (2H, m), 2.38 (2H, m) , 2.7 1 (lH, m), 2.93 (2H, m), 3.09 (lH, dd, J = 14.0, 4.5 Hz), 3.18 (lH, O m), 3.49 (lH, d, J = 14.6 Hz) ), 3.63 (2H, m), 3.97 (3H, s), 4.20 (lH, m), 4.29 (lH, m), 7.16 (lH, dd, J = 9.3, 2.7 Hz), 7.31 (lH, d, J = 2.7 Hz), 7.79 (lH, d, J = 9.0 Hz), 8.25 (lH, s). MS (ESI) m/z: 482 (M + H) + .

[Example 50] (1RS, 2SR, 5SR) -2-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline- 1-yl)methyl]-5-{[(3-o-oxy-3,4-dihydro-211-pyrido[3,2-1)][1,4]fluorene-6-yl) Methyl]amino}cyclohexanecarboxylic acid decylamine-315- 200948817

(1RS, 2SR, 5SR) -5·[(3rd-order butoxycarbonyl)amino]-2-[(9-methoxy-2,3-dihydro-111-) obtained in Reference Example 115 [1,4] 噚 并 and [2,3-c]quinoline-bu)methyl]cyclohexanecarboxylic acid (75 mg, 〇.l59 mmol) in dichloromethane (1 mL) Diimidazole (39 mg, 0 _ 24 1 mmol) was then stirred at room temperature for 5 hours. A mixture of ice-cold concentrated aqueous ammonia (2 mL) and tetrahydrofuran (1 mL) was added to the reaction mixture, followed by stirring at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with a mixed solvent of chloroform:methanol = 9:1. The extract was combined and dried over anhydrous sodium sulfate. After 4N hydrogen chloride/dioxane solution (2 mL) was added to the residue and stirred for 5 minutes, methanol (2 mL) was added to dissolve insoluble materials, and then the solvent was evaporated under reduced pressure. Azeotrope with methanol and methanol. The residue is combined with 3-sided oxy-3,4-dihydro-2H-pyrido[3,2-b][l,4] oxime-6-formaldehyde (described in International Publication No. 2006/032466, etc. , 26 mg, 0.14 6 mmol) dissolved in dichloromethane (1.5 mL), methanol (0.3 mL), triethylamine (69pL, 0.495mmol), hydrogenated sodium triacetoxyborate (52mg, 0.245mmol) Stir at room temperature for 2.5 days. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was mixed with chloroform:methanol = 9:1, and then extracted with a solvent of chloroform:methanol:water = 7:3:1. The extract was combined and dried over anhydrous sodium sulfate. The residue was purified by fractional layer chromatography (EtOAc, EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc) 35mg (48%). 1H-NMR (400MHz, CDC13: CD30D = 4:1) 6: 1.48 (1H, m) 5i75 (lH, m), 2.15-2.45 (5H, m), 2.70 (lH, m), 2.94 (lH, Dd, J=13.7, 3.9 Hz), 3.17 (lH, m), 3.40-3.47 (3H, m), 3.94-3.97 (5H, m), 4.20 (lH, t, J = 9.0 Hz), 4.30 (lH) , m), 4.66 (2H, s), 6.93 (lH, d, J = 8l Hz), 7.13 - 7.26 (3H, m), 7.81 (lH, d, J = 9.0 Hz), 8.28 (lH, s) MS (ESI) m / z: 53 3 (M + H) + . 〇 [Reference 116] 2-[(6.bromoquinolin-4-yl)amino]ethanol

A mixture of 6-bromo-4-chloroquinoline (4.75 g, 19.59 mmol) and 2-aminoethanol (20 mL) was stirred and stirred for 2 hr. After cooling to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted with chloroform:methanol = 5:1 mixture solvent. The hydrazine extract was concentrated under reduced pressure, and purified by silica gel column chromatography (chloroform:methanol = 9:1 - 5:1) to afford 5.05 g (97%) as a brown solid. 1H-NMR (400MHz, CDCl3: CD3OD = 9:1) 5: 3.43 (2H, t, J = 5.2 Hz), 3.91 (2H, t, J = 5.2 Hz), 6.43 (lH, d, J = 5.4 Hz) ), 7.68 (lH, dd#J = 9.0, 2.0 Hz), 7.75 (lH, d, J = 8.8 Hz), 8.15 (lH5d, J = 2.0 Hz), 8.40 (1 H, d, J = 5.6 Hz) .

[Reference Example 117] 2-[(3,6-Dibromoquinolin-4-yl)amino]ethanol -317- 200948817

丨

The solution of 2-[(6-bromoquinolin-4-yl)amino]ethanol (4.32 g, 16.17 mmol) in acetic acid (80 mL) obtained in Reference Example 116 was cooled in a cold water bath for 5 minutes. A solution of bromine (2.58 g, 16-17 mmol) in acetic acid (8 mL) was obtained. After stirring at room temperature for 1.5 hours, the solvent was evaporated under reduced pressure, and the residue was evaporated. The combined extract was dried over anhydrous sodium sulfate, filtered through EtOAc, and evaporated. The residue was suspended in chloroform, and the insoluble material was filtered to afford 5.01 g (yield: 90%) 1 H-NMR (4 00 MHz, C DC 13 : CD3 〇D = 9 :1 ) 6:3.8 1-3.8 4 (4H, m), 7.72 (lH, dd, J = 9.9, 2. lHz), 7.80 (lH, d, J = 9.0 Hz), 8.2 8 (lH, d, J = 2 • 0 Hz), 8.60 (lH, s). MS (ESI) m/z: 347 (M + H) + .

[Reference Example 118] 9-bromo-2,3-dihydro-1H-[1,4]indole-[2,3-c]quinoline

2-[(3,6-Dibromosin-4-yl)amino]ethanol (5.01 g, 14-47 mmol), copper iodide (2.756 g, 14.47 mmol), carbonic acid plantain (9.43) obtained in Reference Example 117. A mixture of g, 28.9 mmol), N,N'-dimethylethylenediamine (3.11 mL, 28.9 mmol) and toluene (150 mL) was stirred and stirred on a 90-degree oil bath for 5 hours. After distilling off the solvent under reduced pressure, the residue was suspended in chloroform:methanol = 9:1 mixture solvent, and the insoluble material was filtered. The residue was purified by hydrazine column chromatography (chloroform: methanol = 98: 2 - 95: 5 - 90: iO) to give the title compound and 2-[(3,6-dibromoquinolin-4- A mixture of amino)ethanol] 3.39 g. ο ο 3.15 g of the above mixture was dissolved in pyridine (40 mL), anhydrous acetic acid (1.528 mL, 16.15 mmol) was added at room temperature, and stirred at the same temperature for 2.5 hours. The solvent was evaporated under reduced pressure, and a saturated aqueous sodium hydrogen sulfate aqueous solution was added to the residue, and the mixture was extracted with chloroform:methanol = 9:1. The extract was combined and dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was suspended in methylene chloride (5 mL), and filtered to afford to afford to afford, as a light yellow powder, 1 s 073 g (30%, containing a quantity of 9-iodide). 1H-NMR (400 MHz, CDCl3) 6: 3.6 7 (2H, m), 4.3 2 (2H, m), 4.82 (1 H, brs), 7.5 7 (1 H, dd, J = 8 · 9, 2.0 Ηζ), 7.77 (1 H, d, J = 2.3 Hz), 7.82 ( lH, d, J = 8.6 Hz), 8.41 (lH, s). MS ( ESI ) m/z : 265 ( M + H ) + .

[Reference Example 1 19] {trans-4-[(9-bromo-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline-l-yl)) Tertiary butyl ester

N-N-dimethylacetamide of 9-bromo-2,3-dihydro 4]indole and [2,3-c]quinoline (585 mg, 2 21ιηιη〇1) obtained in Reference Example 118 (4 mL) In the solution, under ice cooling, sodium hydride (oily, containing 55%, n6 mg, 2_66 mmt) 1) was added and stirred at room temperature for 1.5 hours. Ice-cooled reaction solution, adding [trans-4-(iodomethyl)cyclohexyl]aminecarboxylic acid tert-butyl (uug, -319- 200948817 3.5 9 mmol) of N,N-dimethylacetamide over 20 minutes (2 mL) solution, followed by stirring at room temperature for 2.5 hours. Water was added to the reaction mixture, followed by extraction with a mixed solvent of chloroform:methanol = 9:1. The extract was combined and dried over anhydrous sodium sulfate. After filtered, the filtrate was concentrated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1 -&gt;1: 1 -^1:3 - ^ EMI1 : Methanol = -9: 1) Purification afforded the title compound as a white solid, 18 2 mg (17%). 1H-NMR (400MHz, CDCl3) 5: 1.18-1.33 (4H, m), 1.46 (9H, s), 1.80 (1H5m), 2.09 (2H, m), 2.16 (2H, m), 2.98 (2H, d , J = 7.3 Hz), 3.26 (2H, t, J = 4.4 Hz), 3.50 (lH, m), 4.21 (2H, m), 4.44 (l H, brs), 7.5 6 (l H, dd, J = 8.7, 2.3 Hz), 7.8 4 (lH, d, J = 8.7 Hz), 8.1 8 (1 H, d, J = 1. 8 Hz), 8.49 (lH, s).

[Reference Example 120] {trans-4-[(9-Cyano-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl) A Tertiary butyl ester

{trans-4-[(9-bromo-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl) obtained in Reference Example 119 Methyl]cyclohexyl}carbamic acid tert-butyl ester (99 mg, 0-208 mmol), zinc cyanide (25 mg, 〇.213 mmol), ginseng (di-mercaptoacetone) dipalladium (10 mg, O.Ollmmol), 1 , a mixture of 1'-bis(diphenylphosphino)ferrocene (121^, 0.022111111〇1), and &gt;1,:^-dimethylformamide (1 mL) at 90 ° C under nitrogen substitution The mixture was heated and stirred for 3 hours on an oil bath. The solvent was evaporated under reduced pressure, and the residue was suspended in ethyl acetate. After concentrating the filtrate under reduced pressure, the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 63%). 1H-NMR (400MHz, CDCl3) 8: 1.24 (4H, m), 1.46 (9H, s), 1.84 (1H, m), 2.07 (2H, m), 2_15 (2H, m), 3.03 (2H, d , J = 7.3 Hz), 3.3 1 (2H, t, J = 4.4 Hz), 3.46 (lH, m), 4.24 (2H, t, J = 4.4 Hz), 4_42 (lH, brs), 7. 65 ( lH, dd, J = 8.7, 1.8 Hz), 8.05 (lH, d, J = 8.7 Hz), 8.3 8 (lH, s), 8.59 (lH, s). MS (ESI) m/z: 42 3 ( M + H) + . o [Example 51] l-[(trans-4-([3- 3-oxy-3,4-dihydro-2H-pyrido[3,2-b][l , 4] 噚耕-6-yl)methyl]amino}cyclohexyl)methyl]-2,3-dihydro-111-[1,4] 噚[[,3,3-〇]quinoline- 9-nitrile

{trans-4-[(9-Cyano-2,3-dihydroindole-1H-[1,4]indole[2,3-c]quinolin-1-) obtained in Reference Example 120 To a solution of methylene]cyclohexyl}amine carboxylic acid tert-butyl ester (53 mg < 0.126 mmol) in dichloromethane (2 mL After concentrating the reaction solution under reduced pressure, azeotrope (2 times) was used. The residue is combined with 3-sided oxy-3,4-dihydro-2H-pyridyl[3,2-1&gt;][1,4]_cultivated-6-formaldehyde (described in International Publication No. 2006/032466 Et, 29mg, 〇.163mmol) dissolved in chloroform (1.2mL), methanol (〇.12mL)' Add triethylamine (35pL, 0.251mmol), vaporized sodium triethoxyborohydride (40mg, 0·1) 89 mmol) was stirred at room temperature for 7 hours. To the reaction mixture were added -321-200948817 and an aqueous solution of sodium hydrogencarbonate, and extracted with a mixed solvent of chloroform:methanol = 9:1. After the extract t was combined, it was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to thin layer chromatography (gelatin, containing the first 'chloroform:methanol:water=7:3:1 lower solvent; second time, chloroform:methanol=9:1,1% triethylamine) purification. The obtained solid was solidified in methanol to obtain a labeled compound (yield: 35 mg (yield: 57%)). ^-NMRi 400MHz, CDC13)6:1.14-1.50(4H,m), 1.87(lH,m), 2·07-2.20(4H,m), 2.68( lH,m),2.99(2H,d,J = 7.3 Hz), 3 _32 (2H, m ), 3.99 (2H, m), 4.25 (2H, m), 4.61 (2H, s), 6.95 (lH, d, J = 7.8 Hz), 7.22 (lH, d, J = 7.8 Hz), 7.60 (lH, d, J = 8.3 Hz), 8.01 (lH, d, J = 8.7 Hz), 8.36 (lH, s), 8.60 (lH, s). MS (ESI) m/z: 485 (M + H) + .

[Reference Example 121] 4-[({trans-4-[(Tertiary Butoxycarbonyl)amino]]cyclohexyl}methyl)amino]-6-methoxyquinoline-3-carboxylate Acid ethyl ester

[Trans-4-(aminomethyl)cyclohexyl]aminecarboxylic acid tert-butyl ester (684 mg, 3_00 mmol), 4-chloro-6-methoxyporphyrin_3-carboxylic acid ethyl ester ( A mixture of 797 mg, 3.00 mmol), triethylamine (i.25 mL, 8.97 mm 〇l) and dimethyl hydrazine (9 mL) was stirred and stirred under a nitrogen-subst. The reaction solution was diluted with ethyl acetate and washed with water and brine. After drying over anhydrous sodium sulfate, the mixture was filtered and evaporated. The residue was chromatographed (hexane: ethyl acetate = 2:1 -1 -1 - 1: 2) to -322 - - - - - - - - - - - - - - - - - - - - - - - - - - ). lH-NMR (400MHz, CDCl3) 5: 1.15 (4H, m), 1.41-1.44 (12H, m), 1.70 (lH, m), l_95 (2H, m), 2.07 (2H, m), 3.41 (lH) , m), 3.65 (2H, t, J = 5.7 Hz), 3.90 (3H, s), 4.39 (2H, q, J = 7.2 Hz), 7.3 5 (lH, dd, J = 9.2, 2.8 Hz), 7.5 1 (lH, d, J = 2.8 Hz), 7.88 (lH, d, J = 9.2 Hz), 9.00 (l H, s), 9.0 3 (1 H, m). MS (ESI) m/z: 45 8 (M + H) + .

[Reference Example 122 Πtrans-4-({[3-(hydroxymethyl)-6-methoxyquinolin-4-indenyl]amino}methyl)cyclohexyl]aminecarboxylic acid tert-butyl ester

4-[({trans-4-[(Tertiary Butoxycarbonyl)Amino]cyclohexylfluorenylmethyl)amino]]6-methoxyquinoline-3- obtained in Reference Example 121 A solution of carboxylic acid ethyl vinegar (7.58 g, 16.59 mmol) in tetra-furfur (160 mL) was added, and the lithium aluminum hydride (661 mg, 17.42 mmol) was added for 5 minutes under ice cooling for 40 minutes at the same temperature. Thereafter, lithium aluminum hydride (66 1 mg, 17.4 mmol) was further added at the same temperature for 5 minutes, followed by stirring at room temperature for 5 hours. The reaction solution was ice-cooled, and diluted with tetrahydrofuran (1 6 〇m L), followed by careful addition of water (1.26 mL), 3N aqueous sodium hydroxide (1.26 mL), water (3.78 mL). 4 hours. To the reaction mixture was added chloroform:methanol = 9:1 mixed solvent, and then anhydrous sodium sulfate was added and stirred for a while, and then filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( EtOAc: EtOAc: EtOAc: EtOAc: EtOAc -323- 200948817 1H-NMR (400 MHz, CDCl3) 5:1 ·15 (4 Η, ιη), 1.44 (9 Η, 8), 1.69 (lH, m), 1.95 (2H, m), 2.07 (2H, m ), 3.45 (lH, m), 3.70 (2H, m), 3.91 (3H, s), 4.3 9 (lH, m), 4.76 (2H, s), 5.5 6 (lH, m), 7.27-7.29 ( 2H,m), 7.88 (lH,d,J = 9.6Hz), 8_l 8(lH,s).

[Reference Example 123] 4-[({trans-4-[(Tertiary Butoxycarbonyl)amino]cyclohexyl}methyl)amino]]-6-methoxyquinoline-3-carbaldehyde

[Trans-4-({[3-(hydroxymethyl)-6-methoxyquinolin-4-yl]amino}methyl)cyclohexyl]aminecarboxylic acid, obtained in Reference Example 122 Manganese dioxide (85%, 5.83 g, 57.0 mmol) was added to a solution of butyl ester (4.73 g, 1 1 -40 mmol) in dichloromethane (12 mL). Then manganese dioxide (85%, 5.83 g, 5 7.0 mmol) was added and stirred overnight. After adding methanol (12 mL) to the reaction mixture, the filtrate was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 1H-NMR (400MHz, CDCl3) 5: 1.19 (4H, m), 1.45 (9H, s), 1.72 (1H, m), 2_01 (2H, m), 2.09 (2H, m), 3.43 (lH, m) ), 3.78 (2H, t, J = 6.0 Hz), 3.91 (3H, s), 4.40 (lH, m), 7.40 (lH, dd, J = 9.2, 2.8 Hz), 7.62 (l H, d, J = 2.8 Hz), 7.89 (lH, d, J = 9.2 Hz), 8.49 (lH, s), 9.86 (lH, s), 10. 21 (lH, m).

[Reference Example 124] (trans-4-{[(3.hydroxy-6-methoxysin-4-yl)amine-324- 200948817]]methyl}cyclohexyl)carbamic acid tert-butyl ester

4-[({trans-4-[(Tertiary Butoxycarbonyl)amino]cyclohexyl}methyl)amino]-6-methoxyquinolin-3- obtained in Reference Example 123 To a solution of formaldehyde (2.07 g, 5_00 mmol) in dichloromethane (25 mL)-methanol (25 mL), EtOAc (EtOAc, EtOAc, 12.50 mmol), stirred at the same temperature for 2 hours. A 5% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with chloroform and chloroform:methanol = 9:1 mixture solvent. The organic layer was dried over anhydrous sodium sulfate, and filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjjj The solid labeled compound was 1.7 8 6 g (89%). 1H-NMR (400MHz, CDCl3) 6: l.ll (4H, m), 1.45 (9H, s), 1.63 (1H, m), 1.92 (2H, m), 2.04 (2H, m), 3.41 (lH) , m), 3.66 (2H, m), 3.87 (3H, s), 4.44 (lH, m), 7.24 (lH, m), 7.34 (lH, m), 7.89 (lH, m), 8.55 (lH, m).

[Reference Example 125] ({4-[({trans-4-((tert-butoxycarbonyl)amino)cyclohexyl}methyl)amino]-6-methoxyquinoline-3- Ethyl acetate

(Trans-_4-{[(3-hydroxy-6-methoxy-325-200948817 quinolin-4-yl))amino]methyl}cyclohexyl) amide formic acid obtained in Reference Example 124 To a solution of butyl ester (120 g, 0.3 OO mmol) in hydrazine dimethyl dimethyl carbamide (1.5 mL), potassium carbonate (50 mg, 0.362 mmol) was added sequentially under ice-cooling, followed by ethyl bromoacetate (33 pL, 0.296 mmol), and slowly stirred for 17 hours while standing at room temperature. The reaction solution was poured into a 10% aqueous citric acid solution, followed by addition of a saturated aqueous sodium hydrogencarbonate solution to make a weak base. The mixture was extracted with EtOAc. EtOAc (EtOAc) — 2 : 1 — 1 ·· 1) Purification gave the title compound 99 mg (69%) as a yellow solid. 〇, H-NMR (400MHz, CDCl3) 6: 1.12 (4H, m), 1.30 (3H, t5 J = 7.1 Hz), 1.44 (9H, s), 1.56 (lH, m), 1.95 (2H, m) , 2.05 (2H, m), 3.3 9 (3H, m), 3.92 (3H, s), 4.27 (2H, q, J = 7.2 Hz), 4.37 (lH, m), 4.73 (2H, s), 7.20 -7.2 5(2H,m), 7.87 (lH,d,J = 9.2 Hz), 8.02 (lH, brs), 8.36 ( lH, s). MS (ESI) m/z: 488 (M + H) + .

[Reference Example 126] {trans-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl) Methyl]cyclohexyl} aminic acid tertiary butyl G

({4-[(·){trans-4-[(Terto-butoxycarbonyl)amino]cyclohexyl}methyl)amino]-6-methoxy porphyrin obtained in Reference Example 125 A solution of ethyl -3-yl}oxy)acetate (96 mg, 0.197 mmol) in EtOAc (5 mL) The reaction mixture was diluted with ethyl acetate - 326 - 200948817, and washed with water and brine, dried over anhydrous sodium sulfate and filtered. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 1H-NMR (400MHz, CDCl3) 6: 0.86 (4H, m), 1.39 (9H, s), 1.46-1.55 (3H, m), 1.87 (2H, m), 3.22 (lH, m), 3.93 (3H, s), 4.18 (2H5d, J = 6.9Hz), 4.22 (lH, m), 4.61 (2H, s), 7.06 (lH, d, J = 2.8 Hz), 7.3 1 (lH, dd, J = 9.2, 2.8 Hz), 8.0 1 (lH, d, J = 9.2 Hz), 8.59 (lH, s).

MS (ESI) m / z: 44 2 (M + H) +.

[Example 52] 9-methoxy-1-[(trans-4-{[(3-o-oxy-3,4-dihydro-211-pyrido[3,2-1]][1 , 4] 噚耕-6-yl)methyl]amino}cyclohexyl)methyl]-1H-[1,4] 曙[[,2,3-c]quinoline-2 (3H)-one

{trans-4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-) obtained in Reference Example 126 To a solution of the methylene]cyclohexyl}amine carboxylic acid as a third butyl (53 mg, 0. 120 mmol) in dichloromethane (2 mL). After concentrating the reaction mixture under reduced pressure, azeotrope (2 times) was used with toluene and then azeotroped with isopropyl alcohol. The residue is combined with 3-terpoxy-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-formaldehyde (described in International Publication No. 2006/03 2466) Et, 28mg, 〇.157mmol) dissolved in chloroform (1.2mL), methanol (0_12mL)' added triethylamine (331^, 〇.237mm〇i), hydrogenated triethyl borohydride sodium-327 - 200948817 ( 3 8 mg, 0 · 179 mmol) was stirred at room temperature for 16 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with a mixed solvent of chloroform:methanol = 9:1. The extract was combined and dried over anhydrous sodium sulfate. The residue was purified by fractional chromatography (EtOAc, EtOAc:MeOH: 15: The solid obtained was solidified in methanol to give a white compound (yield: 35 mg, 58%).

1H-NMR (400MHz, CDCl3) 6: 0.78 (2H, m), 0.93 (2H, m), 1.55 (3H, m), 1.83 (2H, m), 2.27 (lH, m), 3.71 (2H, s ), 3.93 (3H#s), 4.18 (2H, d, J = 6.9 Hz), 4.6 1 (2H, s), 4.62 (2H, s), 6.84 (lH, d, J = 8.0 Hz), 7. 06 (lH, d, J = 2.3 Hz), 7.15 (lH, d, J = 8.0 Hz), 7.30 (lH, dd, J = 9.5, 2.6 Hz), 8.01 (lH, d, J = 9.2 Hz), 8.59 (lH, s). MS (ESI) m/z: 504 (M + H) + .

[Reference Example 127] {trans-4-[(8-methoxy-2-oxo[1,3]oxazolo[5,4-c]quinolin-1 (2H)-yl) A Tertiary butyl group

The third butyl ester of (trans-4-{[(3-hydroxy-6-methoxyquinolin-4-yl)amino]methyl}cyclohexyl)aminecarboxylic acid obtained in Reference Example 124 ( To a solution of 120 g, 0.300 mmol of N,N-dimethylformamide (1.5 mL), carbonyldiimidazole (73 mg, 0.450 mmol) was added, and the mixture was stirred under heating at 60 ° C for 5 hours. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The title compound was obtained as a white solid 136 mg (quant.). -328- 200948817 1H-NMR (400MHz}CDCl3) 6: 1.07 (2H, m), 1.36 (2H, m), 1.43 (9H, s), 1.86 (2H, m), 1.96 (lH, m), 2.08 (2H, m), 3.44 (lH, m), 3.95 (3H, s), 4.11 (2H, d5J = 7.3 Hz), 4.36 (lH, m), 7.19 (lH, d, J = 2.8 Hz), 7 .3 8 (lH, dd, J = 9.2, 2.3 Hz), 8.08 (lH, d, J = 9.6 Hz), 8.73 (lH, s). MS (ESI) m/z: 42 8 (M + H) + .

[Example 53] 8-methoxy-l-[(trans-4-{[(3-o-oxy-3,4·dihydro-2H-pyrido[3,2-b][l, 4] 噚哄-6-yl)methyl]amino}cyclohexyl)methyl][1,3]oxazolo[5,4-c]salin-2(1H)·one

{trans-4-[(8-methoxy-2-oxo[1,3]oxazolo[5,4-c]salostyl-1 (2H)-yl) obtained in Reference Example 127 To a solution of the methylene]cyclohexyl}aminecarboxylic acid as a crude butyl hydride (134 mg, 0.296 mmol) in dichloromethane (4mL), trifluoroacetic acid (2mL) was added and stirred at room temperature for 30 min. Decompression

The residue is combined with 3-sided oxy-3,4-dihydro-2H-pyrido[3,2-b][l,4] oxime-6-formaldehyde (described in International Publication No. 2006/032466, etc. , 73 mg, 0.4 10 mmol), dissolved in chloroform (3 mL), methanol (0.3 mL), triethylamine (88 pL, 0.631 mmol), and hydrogenated sodium triacetoxyborate (100 mg, 0.472 mmol). hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was extracted with chloroform:methanol = 9:1. The extract was combined and dried over anhydrous sodium sulfate. The residue was purified by fractional chromatography (yield: chloroform:methanol=15:1 χ2) -329 - 200948817. The solid obtained was solidified in methanol to give 98 mg (yield: 64%) of the compound as a thin green powder.

1H-NMR (400MHz, CDCl3) 8: 1.12 (2H, m), 1.30 (2H, m), 1.86 (2H, m), 1.99-2.05 (3H, m), 2.5 1 (lH, m), 3.80 ( 2H, s), 3.94 (3H, s), 4.11 (2H, d, J = 6.9 Hz), 4.63 (2H9s), 6.90 (lH, d, J = 8.0 Hz), 7.18-7.20 (2H, m), 7.3 8 (lH, dd, J = 9.5, 2.6 Hz), 8.08 (lH5d, J = 9.7 Hz), 8.74 (lH, s). MS (ESI) m/z: 490 (M + H) + .

[Reference Example 128] (1RS, 2SR, 5RS) -5-[(benzyloxy)methyl]-2-[(b

Phenylethyl)amino]cyclohexanecarboxylic acid methyl ester, (lRS, 2SR, 5SR)-5-[(benzyloxy)methyl]-2-[(l-phenylethyl)amine Methyl cyclohexanecarboxylate

4-(Benzyloxy)methylcyclohexanone (described in Journal of medicinal chemistry, 1983, Vol. 36, No. 6, 654-670, 57.64 g, 264.1 mmol) in toluene (80 mL) The solution was warmed on an oil bath at 90 ° C, and sodium hydride (oily, containing 55%, 46. lg ' 1.056 mol) and dimethyl carbonate (44.5 lmL, 0.528 mol) of toluene (46 0 mL) were added dropwise over 40 minutes. )suspension. After heating and stirring at the same temperature for 2.5 hours, the reaction solution was ice-cooled, and toluene (1 L) and acetic acid (84.6 mL &lt; After careful care, add ice water and extract with toluene. The extract was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The residue obtained was a mixture of 1-phenylethylamine (40.86 mL, 0.317 mol) '-330-200948817 p-toluenesulfonic acid monohydrate (2.51 g, 13.2 mmol) and benzene (1_5 L) at 1 15 The oil bath of °C was heated to reflux for 14 hours while removing water with a Dean-Stark reflux cooler. The reaction mixture was diluted with toluene, washed with saturated aqueous sodium bicarbonate, water and brine, and dried over anhydrous sodium sulfate. To the obtained residue and a solution of acetic acid (EtOAc, EtOAc, EtOAc (EtOAc) After stirring at the same temperature for 30 minutes, it was stirred at room temperature for 18 hours.馏 After distilling off the solvent under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate aqueous solution were added to the residue, and then sodium hydrogencarbonate was added to make weakly basic. The organic layer was separated, washed with saturated aqueous sodium bicarbonate, water and brine, and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate=9:1 - 6 : 1-4 : 1-2 : 1 ), and (1RS, 2SR, 5RS) -5-[(benzyl) Methyloxy)methyl]-2-[(1-phenylethyl)amino]cyclohexanecarboxylic acid methyl ester 53.5 5g ( 53% ) with (1RS, 2SR, 5SR) -5-[(benzyl Alkyloxy)methyl]-2-[(l-phenylethyl)amino]cyclohexanecarboxylic acid hydrazine methyl ester 28.78 g (29%) of a yellow oil. (1RS, 2SR, 5RS) -5-[(Benzyloxy)methyl]-2-[(1-phenylethyl)amino]cyclohexanecarboxylic acid methyl ester: 1H-NMR (400MHz, CDC13)6: 1.17(lH,m),l.24(3H,d, J = 6.9Hz), 1.27-1.33(lH,m),l.45-1.53(2H,m),l.60 -1.70 (2H, m), 1.85 (1 H, m), 2.50 (1 H, dt, 12.8, 3.7 Hz), 3.2 9-3.3 5 (3H, m), 3.67 (1 H, q, J = 6.4 Hz), 3.72 (3H, s), 4.48 (2H, s), 4.50 (lH, d, J = 3.2 Hz), 7.1 9-7.35 (1 OH, m). (1RS, 2SR, 5SR) - 5-[(Benzyloxy)methyl]-2-[(1-phenylethyl-331-200948817-yl)amino]cyclohexanecarboxylic acid methyl ester: 1H-NMR (400MHz, CDCl3)S: 0.95 (lH, m), l.ll (lH, td, J = 13.3, 4.6 Hz), 1.27 (3H, d, J = 6.4 Hz), 1.66-1.98 (4H, m), 2.07 (lH, m) , 2.44 (lH, m), 3.05 (lH, m), 3'21 (2H, d, J = 6.0 Hz), 3.7 l (3H, s), 3.96 (lH, q, J = 6.9 Hz), 4.44 (2H, s), 4.47 (lH, m), 7.22-7.3 7 (10H, m).

[Reference Example 129] [(1118, 2811, 4118)-4-[(benzyloxy)methyl]-2-(hydroxymethyl)cyclohexyl]aminecarboxylic acid tert-butyl ester

(1RS, 2SR, 5SR) obtained in Reference Example 128 · 5-[(Benzyloxy)methyl]-2-[(1-phenylethyl)amino]cyclohexanecarboxylic acid methyl ester (27.98 g, 73.3 mmol) in tetrahydrofuran (730 mL). After stirring at the same temperature for 1.5 hours, it was stirred at room temperature for 30 minutes. After the reaction solution was ice-cooled, carefully add water (6.6 lmL), 3N aqueous sodium hydroxide solution (6.61 mL), water (19.8 2 mL), and then stir at room temperature for one night, add anhydrous sodium sulfate and stir for a while, then Celite filtered out insolubles and concentrated the decoction under reduced pressure. A 20% palladium hydroxide carbon catalyst (containing about 50% water, 12.36 g) was added to a solution of the obtained residue in methanol (7 mL). After the catalyst was filtered, the filtrate was concentrated under reduced pressure. To a solution of the obtained residue in tetrahydrofuran (3 50 mL), bis(tris-butyl)dicarbonate (22.93 g, 105.1 mmol) was added at room temperature and stirred for 16 hours at the same temperature from -332 to 200948817. The solvent was evaporated under reduced pressure, and the residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc Compound 16.07 g (65%). 1H-NMR (400MHz JCDCl3) 6: 1.32 (lH, m), 1.45 (10H, m) J1.5 〇-1.60 (3H, m), 1.74 (lH, m), 1.94 (2H, m), 3.34-3.43 (4H, m), 3.90 (lHsm), 4.50 (2H, m), 5.08 (lH, m), 7.27-7.37 (5H, m).

[Reference Example 130] {(1118,2311,4118)-4-[(benzyloxy)methyl]-2-[(methoxymethoxy)methyl]cyclohexyl}aminecarboxylic acid tert-butyl Base ester

[(1RS, 2SR, 4RS ) -4·[(benzyloxy)methyl]·2_(hydroxymethyl)cyclohexyl]aminecarboxylic acid tert-butyl ester obtained in Reference Example 129 (16.07 g, 46.0 mmol) of dichloromethane (230 mL) was added N,N-diisopropylethylamine ( 28.07 mL, 161.2 mmol) under ice cooling, followed by ◎ (chloromethyl) methyl ether (l. 49 mL, 138.1 mmol). After stirring at room temperature for 17 hours, the reaction mixture was concentrated under reduced pressure for about half portion, and then diluted with ethyl acetate. This was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc ' *H-NMR (400MHz, CDC13) 6:1. 14 (1 H, m), 1.30 (lH, m), 1.43 (10H, m), 1.73- 1.84 (4H, m), 2.27 (lH, m ), 3.25 (2H, d, J = 6.0 Hz), 3.37 (3H, s), 3.5 1 (lH, dd, J = 10.1, 5.5 Hz), 3.67 (lH, m), 3.81 (lH, t, - 333 - 200948817 J=9.4Hz), 4.47(2H, s), 4.6 1(2H, s), 5.44(lH, m), 7.27-7.3 6(5H,m )· [Reference Example 131] {(1RS, 2SR, 4RS) -4-(hydroxymethyl)·2-[(methoxymethoxy)methyl]cyclohexyl}aminecarboxylic acid tert-butyl ester

{( 1RS, 2SR, 4RS) -4-[(benzyloxy)methyl]-2-[(methoxymethoxy)methyl]cyclohexyl}aminecarboxylic acid obtained in Reference Example 130 A solution of the butyl acrylate (18.19 g, 46.0 mmol) in methanol (500 mL) was added to a palladium carbon catalyst (M, containing about 50% water, mp. After the catalyst was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified (jjjjjjjjjjjjjjjjj . 1H-NMR (400MHz, CDCl3) a: 1.14 (lH, m), 1.30 (lHJm), 1.40 -1-50 (10H, m), 1.60 (lH, m), 1.74 - 1.89 (3H, m), 2.3 1 (lH5m), 3.38 (3H, s), 3.44 (2H, t, J = 5.7 Hz), 3.52 (lH, dd, J = 9_6, 5_5 Hz), 3.69 (lH, m), 3.82 (lH, t, J = 9.2 Hz), 4.62 (2H, s), 5.43 (lH, m).

[Reference Example 13 2] { ( 1RS, 2SR, 4RS) -4-(iodomethyl)-2-[(methoxymethoxy)methyl]cyclohexyl}carbamic acid tert-butyl ester

{( 1RS, 2SR, 4RS) -4- (hydroxyl -334 - 200948817) obtained in Reference Example 131

Tertiary butyl 2-[(methoxymethoxy)methyl]cyclohexyl}carbamic acid amine (14.92 g, 46.0 mmol), triphenylphosphine (30.19 g, 115-1 mmol), imidazole (7.84) A solution of g, 115.1 mmol) in dichloromethane (400 mL) was then evaporated. After the 5% aqueous solution of sodium thiosulfate was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the mixture was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc: . 1H-NMR (400MHz, CDCl3) 6: 1.15 (lH, m), 13 1 (lH, m), 1.43 _1 .50 (1 OH, m), 1. 55-1.60 (1Η, ιη), 1.85 · 1.91 (3H, m), 2.29 (lH, m), 3.06 (2H, m), 3.39 (3H, s), 3.51 (lH, dd, J = 10.1, 5.5 Hz), 3.67 (lH, m ), 3.78 (1 H, t, J = 8.9 Hz), 4.62 (2H, s), 5.39 (lH, m) · [Reference Example 133] {(1118, 2811, 4118)-4-[(9-A Oxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl)methyl]-2-[(methoxymethoxy) A Tertiary butyl ester

N-N of 9-methoxy-2,3-dihydro-1H-[1,4]indole-[2,3-c]quinoline (8.51 g, 39.4 mmol) obtained in Reference Example 8. To a solution of dimethylacetamide (60 mL), sodium hydride (oily, containing 55%, 3-094 g, 70.9 mm) was added under ice cooling for 5 minutes, followed by stirring at room temperature for 1.5 hours. Thereafter, the reaction solution was ice-cooled to be added to Reference Example 132 for 5 minutes ({RS, 2SR, 4RS) -335 - 200948817 -4-(iodomethyl)-2-[(methoxymethoxy)methyl a solution of cyclohexyl}tert-butyl carbamic acid tert-butyl ester (16.27 g, 3 9.4 mmol) in hydrazine-dimethylacetamide (60 mL). The reaction mixture was stirred at room temperature for 8 hr and then extracted with ethyl acetate. The extract was combined and dried over anhydrous sodium sulfate. After filtered, the filtrate was evaporated, evaporated, mjjjjjjjjjjjjjj 12.16g (62%). 1H-NMR (4 00MHz, CDC13) 8: 1.30 (lH, m), 1.44 - 1.57 (1 1 H, m ), 1.90-2.05 (3H, m), 2.13 (lH, m), 2.24 (lH, m) ), 2.94 (2H, m), 3.24 (2H, t, J = 4.4 Hz), 3.41 (3H, s), 3.61 (lH, dd, J = 9.6, 5.5 Hz), 3.74 (lH, m), 3.8 9-3.94(4H,m), 4.22(2H,t,J = 4.4Hz), 4.66(2H,m),5.5 0 (lH,m),7.16(lH,dd,J = 9.2,2.8Hz), 7.24 (lH, d, J = 2.8 Hz), 7.89 (1 H, d, J = 9.2 Hz), 8.38 (lH, s).

[Example 54] 6-[({(lRS, 2SR, 4RS)-2-(hydroxymethyl)-4-[(9-methoxy-2,3·dihydro-1H-[1,4]] Deuterium and [2,3-c]quinolin-1-yl)methyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][l,4]噚耕-3 ( 4H )-ketone

{( 1RS, 2SR, 4RS ) -4-[( 9-methoxy-2,3-dihydro- lH-[l,4]Df till [2,3-c] obtained in Reference Example 133 a solution of the third butyl ester of quinolin-1-yl)methyl]-2-[(methoxymethoxy)methyl]cyclohexyl}aminecarboxylate (262 mg, 0.523 mmol) in dichloromethane (3 mL) Trifluoroacetic acid (3 niL) was added and stirred at room temperature for 3.5 hours. After concentrating the reaction solution under reduced pressure, azeotrope was used (3 - 336 - 200948817 times). The residue is combined with 3-oxo-3,4·dihydro-2H-pyrido[3,2-b][l,4]indole-6-formaldehyde (described in International Publication No. 2006/032466, etc. , 102mg, 〇.5 73mmol) dissolved in dichloromethane (5mL), methanol (1mL), added triethylamine (25 5μί, 1.830mmol), hydrogenated sodium triethoxyborohydride (222mg, 1.04 7 mmol) ) Stir at room temperature for 24 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was extracted with chloroform:methanol = 9:1. After the combined extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Of the obtained residue 3 30 mg, 212 mg was dissolved in tetrahydrofuran (4 mL), and bis(tert-butyl)dicarbonate (267 mg, 1.22 3 mmol) was added at room temperature for 6 hours. The solvent was evaporated under reduced pressure, and the residue was purified mjjjjjlilililililililililililililili The resulting product was dissolved in 7N hydrochloric acid (8 mL) at room temperature and stirred at the same temperature for one hour. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the residue, and the mixture was extracted with chloroform:methanol = 9:1. The combined extract was dried over anhydrous sodium sulfate, and after reduced, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to fractional layer chromatography (silica gel, first time, chloroform:methanol:triethylamine=450:50:1; second time, chloroform:methanol:water=7:3:1 lower solvent) purification. The compound 21 mg (12%) was obtained as a white solid. 1H-NMR (400 MHz, CDC13) 6: 1.20-1.3 6 (3H, m), 1.87-2.00 (3H, m), 2.19 (lH, m), 2.57 (lH, m), 2.91 (2H, d , J = 6.9 Hz), 3.01 (lH, m), 3.24 (2H, t, J = 4. lHz), 3.65 (lH, m), 3.8 7 (lH, d, J = 13.8 Hz), 3.92 (3H, s), 4.03 (lH, d, J = 13.3 Hz), 4.22 (2H, t, J = 4.4 Hz), 4.30 (lH, t -337 - 200948817, J = 10.8 Hz), 4.64 (2H, s), 6.90 (lH, d, J = 8.3 Hz), 7.17 (lH, dd, J = 9.2, 2.8 Hz), 7.20_7.2 3 (2H, m), 7.90 (lH, d, J = 9.2 Hz), 8.38 (lH, s). MS (ESI) m/z: 5 20 (M + H) + .

[Reference Example 134] {( 1RS, 2SR, 4RS) -2-(transmethyl)-4-[(9-methoxy- 2,3-dihydro-lH-[l,4]Bf哄[2,3-c]quinolin-1-yl)methyl]•cyclohexyl}carbamic acid tert-butyl ester

{(1RS, 2SR, 4RS) -4-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c] obtained in Reference Example 133 a solution of cisolin-1-yl)methyl]-2-[(methoxymethoxy)methyl]cyclohexyl}carbamic acid tert-butyl ester (12.16 g, 24.3 mmol) in methanol (100 mL) Concentrated hydrochloric acid (100 mL) was added under ice cooling, followed by stirring at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, a saturated aqueous solution of sodium hydroxide was slowly added to the residue under ice-cooling to make a mixture. The mixture was extracted with methylene chloride:methanol = 9:1. The extract was combined and dried over anhydrous sodium sulfate. The obtained residue was dissolved in tetrahydrofuran (120 mL). EtOAc (EtOAc, EtOAc) The solvent was evaporated under reduced pressure.yield eluted elution elution elution 1H-NMR (400MHz, CDC13) 5: 1.44-1.55 (1 1 H, m), 1.5 - 1.67 ( lH, m), 1.84 (lH, m), 1.93 (2H, m), 2.15 (2H) , m), 3.02 (2H, m), 3.26 (-338 - 200948817 2H, t, J = 4.4 Hz), 3.6 1 (lH, dd, J = 9.6, 5.5 Hz), 3.63 (lH, m), 3.75 (lH , m), 3.91 (4H, m), 4_22 (2H, t, J = 4.6 Hz), 5.3 1 (lH, m), 7.17 (lH, dd, J = 9.2, 2.8 Hz), 7.23 (lH , d, J = 2.8 Hz), 7.90 (lH, d, J = 9.2 Hz), 8.3 8 (1H, s). MS (ESI) m/z: 358 (M-Boc + H) + .

[Reference Example 135] (1RS, 2SR, 5SR) -2-[(Tertiary butoxycarbonyl)amino]-5-[(9-methoxy-2,3-dihydro-1H-[1 , 4] 噚耕和[2,3-c] sialolin-1-

{( 1RS, 2SR, 4RS ) -2-(hydroxymethyl)-4-[(9-methoxy-2,3-dihydro-1H-[1,4]噚 well obtained in Reference Example 134 And a solution of [2,3-c]quinolin-1-yl)methyl]-cyclohexyl}aminecarboxylic acid tert-butyl ester (5 6 mg, 0.1 23 mmol) in dichloromethane (1 mL), room temperature Dess-Martin high hydrazine iodine compound (78 mg, 0.184 mmol) was added and stirred at the same temperature for 1.5 hours. A 5% aqueous sodium thiosulfate solution was added to the reaction mixture, and extracted with a mixed solvent of ethyl acetate:methanol = 95:5. The extract was washed with a 5% aqueous sodium thiosulfate solution, water, and brine, and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a pale yellow gum solid (1RS, 2SR, 5SR) -2- [(third-order butoxycarbonyl)amino]-5-[(9-methoxy-2,3-dihydro-lH-[l,4]Df cultivating [2,3-indole]quinoline -1-yl)methyl]cyclohexanecarbaldehyde 4〇11^ (72%). 1H-NMR (400MHz, CDC13) 5: 1.24-1.3 3 (lH, m), 1.46-1.70 (1 2H, m), 1.94 (1 Η, m), 2.14 (lH, m), 2.60 (1 H, m), 2.96-3.04 - 339- 200948817 (2H, m), 3.09 (lH, m), 3.23 (2H, t, J = 4.4 Hz), 3.82 (lH, m), 3.9 1 (3H, s), 4.22 (2H, t, J = 4.1 Hz), 5.3 8 (lH, m), 7.16-7.18 (lH, m), 7.21 (lH, m), 7.90 (lH, d, J = 9.2 Hz), 8.38 ( lH, s), 9.82 (lH, s).

(1RS, 2SR, 5SR) -2-[(third-order butoxycarbonyl)amino]-5-[(9-methoxy-2,3-dihydro-1H-[1] obtained above , 4]噚 and [2,3-c] sialolin-1-yl)methyl]cyclohexanecarboxaldehyde (40 mg, 0.088 mmol), sodium dihydrogen phosphate (41 mg, 0.263 mmol), 2-butyl- 2-butene (74 μί, 0.699 mmol) was dissolved in tert-butyl butyl alcohol (0.5 mL)-tetrahydrofuran (〇.5 mL)-water (0.25 mL), and, under ice cooling, sodium chlorite (25 mg, 0.25 9 mmol) , stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of chloroform:methanol = 9:1. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. ^-NMR (400MHz, CDC13) 5: 1.23-1.3 l (lH, m), 1.40-1.49 (10H, m), 1.75-2.05 (4H, m), 2.54 (lH, m), 3.02 (2H, m ), 3.11(lH,m), 3.34(2H}m)s3.75(lH,m),3.88(3H,s), 4.22(2H,m),5.92 (lH,m),7.16(lH,dd , J = 8.9, 2.5 Hz), 7.19-7.22 (lH, m), 7.91 (lH, d 〇, J = 9.2 Hz), 8.35 (lH, s).

[Example 55] (1118, 2811, 581〇-5-[(9-methoxy-2,3-dihydro-1H-[1,4]indolo[2,3-c]quinoline- 1-yl)methyl]-2-{[(3-oxo-oxy-3,4-dihydro-2H-pyrido[3,2-b][l,4]Pf cultivable-6-yl) Methyl]amino}cyclohexanecarboxylic acid-340- 200948817

ο.

(1RS, 2SR, 5SR) -2-[(third-order butoxycarbonyl)amino]-5-[(9-methoxy-2,3-dihydro-1Η-) obtained in Reference Example 135. [1,4]噚[[,,,,,,,, Trifluoroacetic acid (〇. 5 mL) was added. After stirring at the same temperature for 2 hours, the reaction mixture was concentrated under reduced pressure and then azeotroped with toluene and isopropyl alcohol. The obtained residue was combined with 3-oxo-3,4-dihydro-2H-pyrido[3,2-bni,4]indole-6-formaldehyde (described in International Publication No. 2006/032466, etc., 15 mg). , 0.084 mmol) dissolved in chloroform (〇. 8 mL), methanol (0.2 mL), triethylamine (35 pL, 0.251 mmol), hydrogenated sodium triethyloxyborate (36 mg, 0.170 mmol) at room temperature Stir for 16 hours. After adding water to the reaction mixture, the mixture was extracted with chloroform:methanol = 9:1, and the mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by a thin layer chromatography (yield: EtOAc, EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: 1H-NMR (400 MHz, CDC13: CD3OD = 5: 1) δ: 1.17-1.3 5 (2H, m), 1.86 (1H, m), 2.03-2.20 (2H, m), 2.22 (lH, m) , 2.75 (lH, m), 2.91 (lH, m), 3.02 (2H, m), 3.15 (lH, m), 3.33 (2H, m), 3.92 (3H, s), 4.06 ( lH, d, J =13.9 Hz), 4.20 (lH, d, J = 14.1 Hz), 4.25 (2H, m), 4.66 (2H, s), 6.92 (1H, d, J = 8.0 Hz), 7.18 (lH, dd, J) = 9.1, 2.8 Hz), 7.25-7.28 (2H, m), 7.84 (lH, d, J = 9.3 Hz), 8.29 (lH, s) · -341- 200948817 MS (ESI) xn/z: 53 4 ( M + H) + .

[Reference Example 136] Acetic acid {( lRS, 2SR, 5SR)-2-(dibenzylamino)-5-[(9-methoxy-2,3-dihydro-1H-[1,4]fluorene [2,3-c]quinolin-1-yl)methyl]cyclohexyl}methyl ester

{( 1RS, 2SR, 4RS ) -2-(hydroxymethyl)-4-[(9-methoxy-2,3-dihydro-1H-[1,4]噚 well obtained in Reference Example 134 And a solution of [2,3-c]quinolin-1-yl)methyl]-cyclohexyl}aminecarboxylic acid tert-butyl ester (6.40 g, 14.00 mmol) in pyridine (45 mL) Acetic acid (1.72 mL, 18.2 mmol) was stirred at the same temperature for 24 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was filtered and evaporated. To a solution of the obtained residue in dichloromethane (40 mL), trifluoroacetic acid (20 mL) was stirred at room temperature for 40 min. The reaction solution was concentrated under reduced pressure and azeotroped using toluene and isopropyl alcohol. To a solution of the above-obtained residue, benzaldehyde (7.11 mL, 70.0 mmol) and triethylamine (9.76 mL, 70.0 mmol) in dichloromethane (100 mL). g, 42.0 mmol), stirred at the same temperature for 16 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was evaporated. The extract was combined and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (chlorobenzene:methanol: 98: 2 - 90: -342 - 200948817 10) to afford 8.33 g (quant. 1H-NMR (400MHzsCDCl3) 5: 1.05-1.20 (2H, m), 1.45 (lH, m), 1.93 (lH, m), 2.04-2.10 (2H, m), 2.08 (3H, s), 2.15 (lH) , m), 2.58 (lH, m), 2.81 (lH, m), 2.91 (2H, m), 3.17-3.27 (2H, m), 3.67 (2H, d, J = 14.2 Hz), 3.836 (2H, d, J = 14.7 Hz), 3_839 (3H, s), 4.19 (2H, m), 4.48 (lH, t, J = 10.5 Hz), 4.55 (lH, dd, J = 11.0, 4.6 Hz), 7.14 ( lH, dd, J = 9.2, 2.8 Hz), 7.2 1- 7.3 7 (llH, m), 7.87 (lH, d, J = 9.2 Hz), 8.34 〇 (lH, s).

[Reference Example 137] { ( 1RS, 2SR, 5SR) -2-(dibenzylamino)-5-[ (9-methoxy- 2,3-dihydro- lH-[l,4] Df-trap And [2,3-c]quinolin-1·yl)methyl]cyclohexyl}methanol

乙酸 acetic acid obtained in Reference Example 136 [(1RS, 2SR, 5SR) -5-[(9-methoxy-2,3-dihydro-1H-[1,4] 噚耕[2,3- a solution of c]quinolin-1-yl)methyl]-2-(tritylamino)cyclohexyl]methyl ester (8.33 g, 14.00 mmol) in tetrahydrofuran (63 mL)-methanol (42 mL) IN aqueous sodium hydroxide solution (42 mL, 42.0 mmol) was added and stirred at the same temperature for 1 hour. The reaction liquid was concentrated under reduced pressure to about 40 mL, and the residue was extracted with a mixed solvent of chloroform:methanol = 9:1 and a mixed solvent of chloroform:methanol:water = 20:3:1. The extract of the combined extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chlorobenzene:methanol: 98: 2 - 95: 5 - 90: - 343 - 200948817 10) to obtain 7.63 g (quant.) of the labeled compound as a thin yellow gum solid. 1H-NMR (400MHz, CDCl3) 6: 1.11 (1H, m), 1.28 (lHsm), 1.58 -1.61 (1H, m), 1.85-2.05 (3H, m), 2.16 (lH, m), 2.72 (lH,m), 2.88(2H,d,J = 7.3Hz), 2.95(lH,m),3.2 1(2H,m),3.7 1(2H,d,J=14· 2Hz),3.72(lH , m), 3.91 (3H, s), 3.95 (2H, d, J = 14.2 Hz), 4.19 (2H, m), 4.30 (lH, t, J = 10.3 Hz), 7.16 (lH, dd, J = 9.2, 2.8 Hz), 7.22 (lH, d, J = 2.8 Hz), 7.23 - 7.3 5 (1 0H, m), 7.8 8 (lH, d, J = 9.2 Hz), 8.36 (lH, s). Reference Example 138] (1RS, 2RS, 4RS) -2-(azidomethyl)-N,N-dibenzyl-4-[(9-methoxy-2,3-dihydro-1H-[ 1,4]indolo[2,3-c]quinolin-1-yl)methyl]cyclohexylamine

Amino)-5-[(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl)methyl]cyclohexyl Methanol (3.32 g, 6.09 mmol), and a solution of triethylamine (1.357 mL, 9.74 mmol) in dichloromethane (30 mL). After stirring at the same temperature for 1.5 hours, triethylamine (〇.679 mL, 4.87 mmol), methanesulfonyl chloride (〇.3 06 mL, 3.95 mmol) was added, and stirred at the same temperature for 1.5 hours. Stir at room temperature for 0.5 hours. The reaction solution was diluted with ethyl acetate and washed with water and brine. After drying over anhydrous sodium sulfate, the mixture was filtered and evaporated. -344- 200948817 A solution of N,N-dimethylformamide (20 mL) was added to EtOAc (EtOAc m. The reaction solution was diluted with ethyl acetate and washed with water and brine. After drying over anhydrous sodium sulfate, the mixture was filtered and evaporated. The residue was purified by silica gel column chromatography (EtOAc:EtOAc:EtOAc

1H-NMR (40 0MHz, CDCl3) 6: 1.15 (lH, m), 1.44 (1H, m), 1.60 -1.73 (5H, m), 2.11 (lH, m), 2.40 (lH, dd, J = 12.9, 6.8 Hz), 2.53 (lH, dd, J = 12.9, 8.5 Hz), 2.76 (lH, dd, J = 13.5, 5.5 Hz), 2.94 (lH, m), 3.0 7 (2H, m) , 3.49 (2H, d, J = 13.4 Hz), 3.62 (2H, d, J = 13.4 Hz), 3.7 9-3.8 7 (1 H, m), 3.8 3 (3H, s), 4.15-4.18 (2H , m), 7.1 5 (lH, dd, J = 9.0, 2.7 Hz), 7. 19 (lH, d, J = 2.7 Hz), 7.2 3-7.33 (1 0H, m), 7.88 (lH, d, J = 9.0Hz), 8.37(lH, s).

[Reference Example 139] (1RS, 2RS, 4RS) -2-(aminomethyl)-N,N-dibenzyl-4-[(9-methoxy- 2,3-dihydro-1 fluorene- [1,4]噚 and [2,3-c]quinolin-1-yl)methyl]cyclohexylamine

{( 1RS, 2RS, 4RS ) -2-(azidomethyl)-N,N-dibenzyl-4-[(9-methoxy-2,3-dihydro) obtained in Reference Example 138 a solution of -1H-[1,4] hydrazine and [2,3-c]salolin-1·yl)methyl]cyclohexylamine (1.33 g, 2.37 mmol) in tetrahydrofuran (20 mL)-methanol (10 mL). Nickel chloride 2-345-200948817 hydrate (1.125 g, 4.73 inm) was added under ice cooling, followed by sodium borohydride (358 mg, 9.46 mmol) over 5 minutes. After stirring at room temperature for 2 hours, a saturated aqueous solution of sodium hydrogencarbonate and a mixed solvent of chloroform:methanol = 9:1 were added, followed by Celite filtration. The organic layer was separated from the filtrate and dried over anhydrous sodium sulfate. The crude product of the labeled compound was obtained as a thin yellow gum-like solid, l-312 g (quantitative).

1H-NMR (400MHz, CDCl3) 5:1.3 5- 1.95 (8H, m), 2.34 (lH, dd, J = 12.6, 6.9 Hz), 2.49 (lH, dd, J = 12.6, 7.4 Hz), 2.83 2.88(lH,m), 3.05(lH,dd,J=13.7,8.0Hz), 3.14(2H,m), 3.49(2H,d,J=13.2Hz), 3.54(2H,d,J = 13.7Hz ), 3.85 (4H, m), 4.13 - 4.2 3 (2H, m), 7.14 (lH, dd, J = 9.2, 2.9 Hz), 7.20-7.37 (llH, m), 7.88 (lH, d, J = 9.2 Hz), 8.37 (1H, s).

[Reference Example 140] N-({( 1RS, 2RS, 5RS )-2-(dibenzylamino)·5-[(9·methoxy-2,3-dihydro-1H-[1,4] ][],[2,3-c]quinolin-1-yl)methyl]cyclohexyl}methyl)ethanediamine

(1RS, 2RS, 4RS) -2-(aminomethyl) _&gt;!, :^-dibenzyl-4-[(9-methoxy-2,3-dihydro) obtained in Reference Example 139 -111-[1,4] 噚 并 and [2,3-(1] quinoxalin-1-yl)methyl]cyclohexylamine (2 85 mg, 0.53 2 mmol) in ethanol (1.5 mL) Ethyl (ethyloxy)acetate (i87 mg, -346 - 200948817 1.59 7 mmol) was stirred and stirred on an oil bath of 80 ° C for 24 hours. The solvent was evaporated under reduced pressure. The oxime, chloroform:methanol = 97:3, 2 times) was purified to give a white powdery compound (yield: 68%, ethyl acetate, ethyl acetate).

1H-NMR (400MHz, CDCl3) 6: 1.35 - 1.79 (7H, m), 2.10 (1H, m), 2.37 (1H, dd, J = 12.8, 6.9 Hz), 2.56 (lH, dd, J = 12.8, 7.8 Hz), 2.78 (l H, dd, J = 13.8, 6.0 Hz), 2.9 9 (lH, dd, J = 13.8, 7.8 Hz), 3.10 (2H, m), 3.48 (2H, d, J) =13.8 Hz), 3.61 (2H, d, J = 13.3 Hz), 3.84 (3H, s), 4.06 (10 H, m), 4.17 (2H, m), 5.64 (lH, m), 7.15-7.3 8 (12H, m), 7.70 (lH, d, J = 7.8 Hz), 7.89 (1 H, d, J = 9.6 Hz), 8.38 (1 H, s) · MS (ESI) m/z: 608 ( M + H) + .

[Example 56] N- { [(1RS, 2RS, 5RS) · 5--[(9-Methoxy-2,3-dihydro-1^[1,4]噚[[,3,3-〇] Quinoline-1-yl)methyl]-2-{[(3-trioxy-3,4-dihydro-2H-pyrido[3,2-b][l,4]噚耕-6 -yl)methyl]amino}cyclohexyl]methyl}ethanediamine

N-({( 1RS, 2RS, 5RS) -2-(dibenzylamino)-5-[(9-methoxy-2,3-dihydro-1H-[1] obtained in Reference Example 140 , 4] 20% of a solution of [2,3-c]quinolin-1-yl)methyl]cyclohexyl}methyl)ethanedioxanamide (215 mg, 0.35 4 mmol) in methanol (10 mL) % palladium hydroxide on carbon-347-200948817 (containing about 50% water, 108 mg), stirred at room temperature for 8 hours under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. 98 mg of the obtained residue 144 mg with 3-terpoxy-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-carbaldehyde (described in International Publications) No. 2006/032466, etc., 41 mg, 0.230 mmol) was dissolved in chloroform (2 mL), methanol (0.2 mL). After a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, the mixture was extracted with chloroform:methanol = 9:1, and the mixture was dried over anhydrous sodium sulfate, filtered, and filtrated. The residue was purified by trituration (EtOAc, EtOAc: EtOAc: EtOAc: EtOAc) lH-NMR (400MHz, CDCl3: CD3OD = 9:1) 5: 1.66-2.01 (8H, m), 2.28 (lH, m), 2.68 (lH, m), 2.75 (lH, m), 3.10 (lH, m), 3.17-3.34 (3 H, m), 3.82 (2H, m), 3.90 (3H, s), 4.26 (2H, s), 4.63 (2H, s), 6.89 (lH, d, J = 8.0) Hz), 7.18-7_2 1 (2H, m), 7.25 (lH, s), 7.87 (lH, d, J = 9.2 Hz), 8.30 (lH, s). MS (ESI) m/z: 590 (M) + H) + .

[Reference Example 141] [({( 1RS, 2RS, 5RS) -2-(dibenzylamino)_5-[(9-methoxy-2,3-dihydro-1H-[1,4]曙) Plowing [2,3-c]quinoline-i-yl)methyl] ring

Benzyl}methyl)amine sulfonyl] amide benzyl-348- 200948817 {( 1RS, 2RS, 4RS) -2-(aminomethyl)-N,N-dibenzyl obtained in Reference Example 139 4-[(9-Methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinolin-1-yl)methyl]cyclohexylamine (121 mg , 0.226 mmol), a solution of triethylamine (63 μί, 0.452 mm 〇I) in dichloromethane (2 mL), and a solution of benzyl (chlorosulfonyl) carbamic acid benzyl chloride (about 0.68 M, 0.665 mL, 0.452 mmol), then stirred at room temperature for 2 hours. Dilute with chloroform and wash with saturated aqueous sodium bicarbonate. After drying over anhydrous sodium sulfate, the mixture was filtered and evaporated. The residue was purified by silica gel column chromatography (chloroform: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: The labeled compound (47%) 〇1H-NMR (400MHz, CDC13) 6: 1.3 0-1.60 (7H, m), 1.76 (lH, m), 1.98 (lH, m), 2.2 1 (lH, dd, J =12.8, 5.0 Hz), 2.56 (lH, dd, J = 12.8, 10 • lHz), 2.80 (lH, dd, J = 14.2, 6.4 Hz), 2.92 (lH, dd, J = 13.8, 7.8 Hz), 3.12(2H,m), 3.32(2H,d,J = 13.8Hz), 3.54(lH,m),3_63(2H,d,J=l 3.3Hz),3.85(3H,s), 4.17(2H, m), 5.06 (lH, d, J = 11.9 Hz), 5.12 (lH Q , d, J = 11.9 Hz), 7.10 - 7.41 (18H, m), 7.90 (lH, d, J = 10.1 Hz), 8.38 (l H, s).

[Example 57] &gt; 1-{[(1118, 2118, 5118)-5-[(9-methoxy-2,3-dihydro-1H-[1,4] 噚耕和[2,3 -c]quinolin-1-yl)methyl]_2-{ [( 3-oxo- 3,4-dihydro-2H-pyrido[3,2-b][l,4] -6-yl)methyl]amino}cyclohexyl]methyl}diamineamine-349- 200948817

[({( 1RS, 2RS, 5RS) -2-(dibenzylamino)-5-[(9-methoxy-2,3-dihydro-1H-[1] obtained in Reference Example 13 1 , 4] hydrazine and [2,3-c] porphyrin-1-yl)methyl]cyclohexyl}methyl)amine sulfonyl] benzyl carbamate (75 mg, 0.100 mmol) in methanol (5 mL) A 20% palladium hydroxide carbon catalyst (about 50% aqueous, 38 mg) was added to the solution, and the mixture was stirred at room temperature for 8 hours under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was combined with 3-oxooxy-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-formaldehyde (described in International Publication No. 2006/032466) Ethyl alcohol (3 mL) was dissolved in chloroform (2 mL), methanol (0.2 mL). After a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, the mixture was extracted with chloroform:methanol = 9:1, and the mixture was dried over anhydrous sodium sulfate. The residue was purified by EtOAc (EtOAc EtOAc:EtOAc:EtOAc:EtOAc ° 1H-NMR (400MHz, CDC13: CD3〇D = 9: 1) δ: 1.50-1.70 (2H, m), l-70-1.90 (3H, m), 1.90-2.10 (2H, m), 2.30 (lH,m), 2.85 (lH,m), 2.90 (lH,m)i3.10-3.30(4H,m)J3.89(lHJm),3.9 1(3H,s), 4.05(lH,m) , 4.26 (2H, s), 4.63 (2H, s), 6.91 (lH, d, J = 8.0 Hz), 7.17- 7.23 (3H, m), 7.86 (lH, d, J = 8.6 Hz), 8.30 ( lH, s). -350- 200948817 MS (ESI) m/z: 59 8 (M + H) + . &lt;Antibacterial Activity&gt; According to CLSI (The Clinical and Laboratory Standards Institute) guidelines: "M7-A7 Methods For Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Seventh Edition, the antibacterial activity of the compounds of the present invention was determined by a micro liquid dilution method. The strain used S. aureus FDA209P strain. The results are shown in Table 1. Example No. MIC (β g / mL) 1 0.5 5 0.5 6 0.25 〇 [Table i] _ Industrial Applicability The compound (I) of the present invention has antibacterial activity against bacteria which are causes of various infectious diseases. It can treat, prevent or alleviate diseases caused by such pathogens. Examples of the bacteria effective as the compound (I) of the present invention include Staphylococcus, Streptococcus pyogenes, Streptococcus hemolyticus, Enterococcus, Pneumococcal, Neisseria, Coliform, Citrobacter, and Shigella. , Klebsiella, Enterobacter, Serratia, Proteus, Pseudomonas, Bacillus, Acinetobacter, mycoplasma, etc. as such Diseases caused by pathogens, including edema, pustules, -351.. 200948817

Carb (carbuncle), erysipelas, honeycomb inflammation, lymphatic (section) inflammation, finger pus salt, subcutaneous abscess, sweat gland inflammation, clustered acne, infectious powder tumor, perianal abscess, mastitis, trauma, thermal injury, surgery Trauma, etc. in secondary infection, throat phlebitis, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, secondary infection of chronic respiratory diseases, pneumonia, pyelonephritis , cystitis, prostatitis, epididymal stagnation, gonococcal urethritis, non-gonococcal urethritis, cholecystitis, cholangitis, bacterial red sputum, enteritis, uterus inflammation, intrauterine infection, Barthol's Gland) inflammation, eyelid inflammation, stye, tendonitis, meibomian gland inflammation, corneal ulcer, otitis media, paranasal inflammation, periarthritis, periorbital inflammation, tendonitis, peritonitis, endocarditis, sepsis, myelitis Inflammation, skin infections, etc. [Simple description of the diagram] Μ 〇 /,,, [Description of main component symbols] iffi 〇 ο -352-

Claims (1)

200948817 VII. Patent application scope: 1. A compound represented by formula (I) or a pharmacologically acceptable compound thereof Permissible salts, (I) {wherein 'X1 and X2 each independently represent a nitrogen atom or a carbon atom of a knot; X3 represents a nitrogen atom or a general formula CRla (wherein the substituent Rla represents a halogen atom, a cyano group, a sulphur group a mercapto group or a group selected from the substituent group α); X4 represents a nitrogen atom or a general formula CRlb (wherein the substituent Rb represents a halogen atom, a cyano group, a decyl group, or a group selected from the substituent group α) Α1 represents a general formula CR2 or a nitrogen atom (wherein the substituent R2 represents: a bond which is integrated with a bond on an adjacent L1, and a bond bond which is integrated to form a double bond, a halogen atom, a bond One hydrogen atom may be substituted with a low substitution or a contiguous A2 cyano group, or a group selected from the substituent group α); Α2 represents a general formula CR3R4f, or is formed integrally with A3 (A3) In the above, the substituents R3 and R4 are each independently represented: when A1 is a general formula CR2, the bond with A1 becomes a bond of the bond itself, and the bond of A4) is a bond of the bond, -353 - 200948817 halogen atom, a cyano group, or a group selected from the group of substituents α, or R3, r4 are integrated to form a pendant oxy group or form a substituted hydroxyimine group), NR5 (wherein the substituent R5 represents: when A1 is a general formula CR2, the bond with A1 is integrated, or A3 (A3 itself is a bond in the case of A4), the bond is integrated to form a bond of a double bond, or a group selected from the group of substituents α, an oxygen atom, or an oxidizable sulfur atom; Α3 represents a general In the formula, the substituents R6 and R7 each independently represent: a bond adjacent to A2 or a bond with A4 to form a double bond, a halogen atom, a gas group, or a group selected from the substituent group α. Or R6' R7 is integrated to form a pendant oxy group, or a substituted hydroxyimino group is formed, NR8 (wherein the substituent R8 represents: a bond with an adjacent ruthenium 2 or a bond of Α4) a bond of a double bond, or a group selected from the group of substituents α), -354-200948817 an oxygen atom, an oxidizable sulfur atom, or a bond; A4 represents a general formula CR9R1() (wherein the substituent R9 and Independent representatives of Ri〇: with adjacent A3 (A3 itself In the case of a bond, the bond of a2) is integrated to form a double bond bond, a halogen atom, a 0 cyano group, or a group selected from the substituent group α, or R9 and R1 &lt; 5 are integrated to form a pendant oxy group. Or forming a hydroxyimino group which may be substituted, NR11 (wherein the substituent Rii represents a bond which forms a double bond with a bond bond of the adjacent A3 (wherein A3 itself is a bond) Or a group selected from the group of the substituent group α, an oxygen atom, or a sulfur atom which may be oxidized; L1 represents a carbon atom which is bonded to Α1 and which may be substituted with a group selected from the substituent group β; Q1 is represented by the following formula ( II) indicates a certain structure between L1 and L2 (* each represents a bond) Ζ1 and Ζ4 each independently represent the general formula cr20 (wherein the substituent R20 represents -355-200948817, a halogen atom, a cyano group, or a group selected from the substituent group α), or a nitrogen atom; Ζ2, Ζ3, Ζ5, and Ζ6 Independently representative: General formula CR21R22 (wherein the substituents R21 and R22 each independently represent: a halogen atom, a cyano group, or a group selected from the substituent group α, or R21, R22 are integrated to form a pendant oxy group, or form a hydroxyimino group which may be substituted; Ζ7 represents a nitrogen atom which may be substituted with a group selected from the substituent group γ, an oxygen atom, an oxidizable sulfur atom, or a bond; L2 represents a general formula - Y3-Y4- Y5- (Υ3 is an atom-side oxy group bonded to Ζ7 on Q1, and a carbon atom which may be substituted by a group selected from the substituent group γ, or an oxidizable sulfur atom; Υ4 represents a bond, and can be selected a radical substituted from a substituent group δ, a carbon atom capable of forming a multi-bond with an adjacent carbon atom; Υ5 represents a bond, a carbon which may be substituted with a group selected from the substituent group δ, and which may form a multiple bond with an adjacent carbon atom An atom, a nitrogen which may be substituted with a group selected from the substituent group γ a substrate, an oxygen atom, or an oxidizable sulfur atom; Q2 is a fused bicyclic "6-membered ring/6-membered ring" or a "6-membered ring/membered ring" represented by the following formula (III) Ring structure, or single-ring structure of atomic number 5~7 -356-200948817 (* indicates the bond with L2) ( melon) Z8, z9, Z10, z15, Z16, and Z17 are each independently represented a substituent group ε, and a carbon atom or a nitrogen atom which may be substituted with a group selected from a lower alkoxy group which may be substituted; ζ11, ζ14, Ζ18, and Z2G are each independently represented: may be selected from a group selected from the group of substituents a nitrogen atom, an oxygen atom, or an oxidizable sulfur atom; Further, these may form a double bond with the adjacent Ζ12, Ζ13, or Ζ19; Ζ12, Ζ13, and Ζ19 each independently represent: a carbon atom which may be substituted with a group selected from the substituent group ε and the pendant oxy group, a nitrogen atom selected from a substituent of the substituent group, an oxygen atom, or an oxidizable sulfur atom; further, these may form a double bond with an adjacent atom: Ζ21, Ζ22, z23, Ζ24, Ζ25, Ζ26, Ζ27 , Ζ28, Ζ29, Ζ30, Ζ31, Ζ32, Ζ33, Ζ34, Ζ35, Ζ36, Ζ37, and Ζ38 are each independently represented: a carbon atom which may be substituted with a group selected from the substituent group η, -357-200948817 may be selected from a nitrogen atom substituted with a substituent of the group θ, an oxygen atom, or an oxidizable sulfur atom, and these may form a double bond with an adjacent atom; [Substituent group α]: a hydrogen atom, a substitutable lower Alkyl, substituted lower alkenyl, substituted monocyclic hydrocarbon or heterocyclic, protected or substituted hydroxy, substituted lower alkoxy, protected or substituted amine Base, azide group, substituted methyl group, protected carboxyl group , a substituted aminocarbonyl group, a lower alkylsulfonyl group which may be substituted, a lower alkylsulfonyl group which may be substituted, and a substituted aminosulfonyl group; [Substituent group β]: a hydrogen atom, a halogen atom, a cyano group, a protected or substituted hydroxyl group, a protected or substituted amine group, a protected carboxyl group, a substituted aminocarbonyl group, a substituted lower alkylsulfonyl group Substitutable aminosulfonyl group, pendant oxy group, and substituted hydroxyimino group; [Substituent group γ]: hydrogen atom, lower alkyl group which may be substituted, lower alkyl alkane which may be substituted a protected carboxyl group, a substituted aminocarbonyl group, a substituted lower alkylsulfonyl group, and a substituted aminosulfonyl group; [substituted group δ]: a hydrogen atom, a halogen atom a hydroxy group which may be protected or substituted, a lower alkoxy group which may be substituted, a pendant oxy group, and a hydroxyimino group which may be substituted; [Substituent group ε]: a hydrogen atom, a halogen atom, and a substituted Lower alkyl; [substituted group ζ]: hydrogen atom, lower alkyl group which may be substituted, hydroxy group which may be protected or substituted And a lower alkoxy group which may be substituted; [Substituent group η]: a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted, -358-200948817 a lower alkenyl group which may be substituted, may be protected or substituted a hydroxy group, a lower alkoxy group which may be substituted, a cyano group, a protected pendant oxy group, a substituted hydroxyimino group, a protected carboxyl group, a substituted aminocarbonyl group, and may be protected or Substituted amine group; [Substituent group θ]: a hydrogen atom, a lower alkyl group which may be substituted, a protected or substituted hydroxyl group, a lower alkyl alkane group which may be substituted, a lower alkoxycarbonyl group which may be substituted, A substituted aminocarbonyl group, a substituted aminosulfonyl group, and a lower alkylsulfonyl group which may be substituted. 〇 2. A compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein X1 is a nitrogen atom. 3. A compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein X4 is CH. 4. A compound or a pharmacologically acceptable salt thereof, according to any one of claims 1 to 3, wherein A1 is a nitrogen atom. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein A4 is an oxygen atom. A compound or a pharmacologically acceptable salt thereof, wherein A1 is a nitrogen atom and A4 is an oxygen atom, as described in any one of claims 1 to 3. 7. The compound of any one of claims 1 to 6 or a pharmacologically shared salt thereof, wherein the tricyclic structure represented by the general formula (la) of the partial structure of the general formula (I), AV A1^2 (la) -359- XX 200948817 (* represents the bond with L1; X2, Rla, Rlb, r5, R8, and Rii are the same as the substituents of general formula (I)), and are of the following formula structure: 8. The compound of any one of claims 1 to 7 or a pharmacologically acceptable salt thereof, wherein L1 is -CH2- or -C(=0)-. 9. The compound of any one of claims 1 to 8 or a pharmacologically acceptable salt thereof, wherein Q1 is a structure between L1 and L2 represented by the following formula (IV) (wherein R23 And R24 is a substituent on a cyclohexane ring, each independently being a hydrogen atom, a hydroxymethyl group, a (2-amino-1,2-di-oxyethyl) amidinomethyl group, (aminosulfonyl) Aminomethyl, 1,2,3-triazol-1-yl, hydroxy, aminocarbonyloxy, amine, etidylamino, methylamino, dimethylamino, azide a base, a carboxyl group, an aminocarbonyl 'sideoxy' or a 0-methylhydroxyimino group; * each represents a binding bond); The compound of any one of claims 1 to 9 or a pharmacologically acceptable salt thereof, or a hydrate thereof, wherein L2 is -CH2- or ch2-ch2-- 11. A compound or a pharmacologically acceptable salt thereof, according to any one of claims 1-10, wherein Q2 is 2,3-dihydro[1,4]dioxin (dioxino) [2 ,3-b]pyridine-7-yl, 2,3-dihydro[1,4]dioxin[2,3-c]pyridin-7-yl, 2,3-dihydrobenzo[1, 4] Dioxin-6-yl, 8-methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]indole-6-yl, 8-methyl- 3-Sideoxy-3,4-dihydro-2H-benzo[1,4]indole-6-yl, 5-methyl-3-oxo-3,4-dihydro-2H-benzene And [1,4]噚-6-yl, 7-methyl-3-oxo-3,4-dihydro-211-benzo[1,4]indole-6-yl, 2-a 3-O-oxy-3,4-dihydro-2H-benzo[1,4]indole-6-yl, 2-fluoro-3-o-oxy-3,4-dihydro-2H- Benzo[1,4]indole-6-yl, 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-yl, 3-oxooxy-3,4·dihydro-2H-benzo[1,4] thioglycol-6-yl, 3-oxooxy-3,4-dihydro-2-indole-pyridyl[3,2 -b][l,4] thioglycol-6-yl or cyclohexyl. A compound of any one of claims 1 to 11 or a pharmacologically acceptable salt thereof. A use of a compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof. An antibacterial agent which is characterized by containing a compound according to any one of claims 1 to n or a pharmacologically acceptable salt thereof. A therapeutic agent for infectious diseases, which comprises a compound according to any one of claims 1 to 3 or a pharmacologically acceptable salt thereof. -361- 200948817 IV. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the component symbols of this representative figure: None. 5. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: ❹