TW200946528A - Piperidine derivatives - Google Patents

Abstract

The purpose of the present invention is the development of a medicine which exhibits broad-spectrum and strong antibacterial activity against Gram-positive bacteria, Gram-negative and those resistant bacteria and has high safety. Under the circumstances, the inventors of the invention carried out a diligent study, with a result that a compound represented by following formula (I) and its salts exhibiting broad-spectrum and strong antibacterial activity against Gram-positive and Gram-negative bacteria and having high safety as an antibacterial agent and a therapeutic or preventive agent for infectious diseases were found, and therefore the invention was completed. Namely, the present invention provides a compound represented by general formula (I), its pharmaceutically acceptable salts and their hydrates Namely, the present invention is a compound represented by formula (I): or its pharmaceutically acceptable salts.

Description

200946528 VI. Description of the Invention: [Technical Field] The present invention relates to novel compounds having excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, or a salt thereof, and an antibacterial agent containing the same Technology] In the medical field, various antibiotics or synthetic antibacterial agents are used to treat infectious diseases. However, resistance to methicillin-resistant Staphylococcus aureus (MRS A), vancomycin-resistant Enterococcus faecium (VRE), and penicillin-resistant pneumococcal (PRSP) has emerged in recent years. The treatment of patients infected with such drug-resistant bacteria has become an important issue. In addition, a plurality of drug-resistant bacteria having resistance to a plurality of drugs have appeared, and infectious diseases caused by a plurality of drug-resistant bacteria are refractory diseases and have become a major problem in the world. An antibiotic or an antibacterial agent which is effective for such a drug-resistant bacterium is strongly desired. For example, Patent Document 1 discloses a swannone-based compound exhibiting an effect against a drug-resistant Gram-positive bacterium. In addition, the compound described in Patent Documents 2 to 6 is known as a compound having a function different from that of an existing drug. Prior Art Document [Patent Document 1] International Publication No. 2002/40478 Manual [Patent Document 2] International Publication No. 200 6/134378 Manual [Patent Document 3] International Publication No. 200 6/137485 Manual [Patent Document 4] International Publication No. 2007/16610 [Patent Document 5] International Publication No. 2007/7 1 93 No. 4-1 - 200946528 [Patent Document 6] International Publication No. 2007/8 1 597 Manual [Disclosure] Invention Office The problem to be solved is to develop an agent which exhibits broad-spectrum and strong antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, and their resistant bacteria, and has high safety. Means for Solving the Problem Under the circumstances, the inventors conducted a dedicated review, and found that the compound represented by the following formula (I) or a salt thereof exhibits a broad display against Gram-positive bacteria and Gram-negative bacteria. The present invention has been completed by providing high-efficiency antibacterial activity and high safety as a preventive and therapeutic drug for antibacterial agents and infectious diseases. The present invention provides a compound represented by the formula (I), a pharmacologically acceptable salt thereof, and a pharmaceutical composition containing the prodrug thereof as an active ingredient (especially for use in the prevention or treatment of infectious diseases), for use in the manufacture A compound represented by the formula (I), a pharmacologically acceptable salt thereof and a prodrug thereof, which are used in the composition of the pharmaceutical composition (especially for the prevention or treatment of infectious diseases), the formula (I) A method of preventing or treating a disease (especially an infectious disease) by administering a compound, a pharmacologically acceptable amount of a pharmacologically acceptable salt thereof and a prodrug thereof to a warm-blooded animal (especially a human). That is, the present invention provides: (1) a compound represented by the formula (I) or a pharmacologically acceptable salt thereof,

200946528 {wherein, χ1 and χ2 each independently represent a nitrogen atom or a carbon atom to which a nitrogen atom is bonded; X3 represents a nitrogen atom or a formula CRla (wherein Rla represents a halogen atom, a cyano group, and a substituted group) a lower alkyl fluorenyl group or a group selected from the substituent group α), X4 represents a nitrogen atom or a formula CRlb (wherein 'Rlb represents a halogen atom, a cyano group, a lower alkyl alkane group C3 or a substituent group) α is a selected base), and Α1 represents a general formula CR2 (wherein R2 represents a bonding hand integrated with an atom on an adjacent L1, or a bonding hand which is integrated with an adjacent a2 to form a double bond, and a halogen An atom, a cyano group or a group selected from the substituent group α) Ο or a nitrogen atom, Α2 represents a formula CR3R4 (wherein the substituents R3 and R4 each independently represent a bond with Al when A1 is a formula CR2 Integral, or a binding hand of A3 (A3 itself is a binding to the hand A4) to form a double bond, a dentate atom, a -6-200946528 cyano group or a group selected from the substituent group α, or , R3, R4 become one to form a side oxygen (oxo) group or can be Substituted hydroxyimido), NR5 (R5 represents a bond formed by A1 when Α1 is of the formula CR2, or a bond with A3 (A3 itself is a bond of A4) to form a double bond Binding to a hand, or a group selected from the substituent group α, an oxygen atom, or an oxidizable sulfur atom, Ο Α 3 represents the formula CR6R7 (wherein the substituents R6 and R7 each independently represent an adjacent A2 or The binding hand of A4 is integrated to form a bond of a double bond, a halogen atom, a cyano group or a group selected from the substituent group α, or R6, R7 become a body to form a pendant oxy group or a substituted hydroxy group. Amino group), 〇w Formula NR8 (wherein the substituent R* represents a bonding hand which forms a double bond with a bonding hand of the adjacent human 2 or A4, or a group selected from the substituent group α), An oxygen atom, an oxidizable sulfur atom or a bonding hand, Α4 represents a general formula cW 0 (wherein the substituents R9 and Rig each independently represent a bonding hand with the adjacent A, " a unitary bond that forms a double bond, 200946528 halogen atom, fluorine group or from substitution The group selected by the group α, or R9, R1() is integrated to form a pendant oxy group or a substituted hydroxyimino group), and the formula NR11 (wherein the substituent R11 represents an adjacent A3 (A3) It is a binding hand which forms a double bond in combination with the hand A2), or a group selected from the substituent group α, a helium oxygen atom, or an oxidizable sulfur atom, and L1 represents a general formula - γ^γ2- (wherein Υ1 represents a carbon atom bonded to Α1 and may be substituted with a group selected from the substituent group β, and Υ2 represents a bond bonded to Q1 and may be selected from the group of the substituent group β a substituted 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), and 〇Q1 is represented by the following formula (II) at L^ 6-member ring structure between L2 (* each W does not combine hands)

(wherein the substituent R2G means a halogen atom, a cyano group, a group selected from the substituent group α) or a nitrogen atom, and -8-200946528 z2, z3, Z5 and Z6 each independently represent the formula CR21R22 (wherein The substituents R21 and R22 each independently represent a halogen atom, a cyano group, a group selected from the substituent group α, or R21 and R22 are integrated to form a pendant oxy group or a substituted hydroxyimino group, and L2 represents Formula - γ3_γ4_γ5_ (wherein the Υ3 series and the Ζ4 bonded atom on Q1 represent a side oxy group, and a carbon atom which may be substituted with a group selected from the substituent group δ, may be selected from a substituent The nitrogen atom substituted by the group of the group, ^ may be an oxidized sulfur atom or a bonding hand, Υ4 represents a bonding hand, or may be substituted by a group selected from the substituent group 且 and may form a multiple bond with an adjacent carbon atom a carbon atom, Υ5 represents a bond, a carbon atom which may be substituted with a group selected from the substituent group 且 and which may form a multiple bond with an adjacent carbon atom, and Ο may be substituted by a group selected from the substituent group ε Nitrogen atom, oxygen atom, or oxidizable sulfur atom), Q2 is as follows (III) a heterocyclic structure of a condensed 2-ring type "6-membered ring/6-membered ring" or a "6-membered ring/membered ring" or a single-ring structure having a number of atoms of 5-7 (* indicates a relationship with L2 Combine hands),

(ΙΠ) -9- 200946528 Z8, Z9, Z1(), Z15, Z16, and z" each independently represent a carbon which may be substituted with a group selected from the substituent group η and a lower alkoxy group which may be substituted The atom or the nitrogen atom, 711, 214, 218, and 22 () may each independently be replaced by a nitrogen atom, an oxygen atom, or a sulfonium oxidizable sulfur atom substituted with a group of the substituent group 0, and further These may also form a double bond with the adjacent Ζ12, Ζ13 or Ζ19, and Ζ12, Ζ13, and Ζ19 each independently represent a carbon atom which may be substituted with a group selected from the substituent group η and the pendant oxy group, and may be The nitrogen atom, the oxygen atom, or the oxidizable sulfur atom substituted by the group selected from the substituent group 亦可 may also form a double bond with the adjacent atom, Ζ Ζ 22 ' ζ 24 , Ζ 25 , Ζ 26 , Ζ 27 Ζ 2 8 Ζ 29 Ζ 3 0 Ζ 31 Ζ 32, Ζ 33, Ζ 34, Ζ 3 5, Ζ 36, Ζ 37 and Ζ 38 each independently represent a carbon atom which may be substituted with a group selected from the substituent group 1, may be selected from a substituent a nitrogen atom, an oxygen atom, or an oxidizable sulfur atom substituted by a group of groups, and further, The atom forms a double bond. [Substituent group α]: a hydrogen atom, a lower alkyl group which may be substituted, a lower alkyl group which may be substituted, a monocyclic hydrocarbon ring group or a heterocyclic group which may be substituted, may be protected Or a substituted hydroxy group, a lower alkoxy group which may be substituted, an amine group which may be protected or taken from -10, 2009,465,28, a substituted fluorenyl group, a protected carboxyl group, a substitutable aminocarbonyl group, a substituted lower alkylsulfonyl group, a substituted lower alkylsulfinyl group, and a substituted aminosulfonyl group. [Substituent group β]: a hydrogen atom, a halogen atom, a cyano group, Protected or substituted hydroxy, protected or substituted amine group, protected carboxy group, substituted aminocarbonyl group, substituted lower alkyl sulfonyl group, substituted amino sulfonyl group a pendant oxy group, and a hydroxyimino group which may be substituted. [Substituent group γ]: a hydrogen atom, a lower alkyl group which may be substituted, a lower alkyl fluorenyl group which may be substituted, a substituted aminocarbonyl group , a lower alkoxycarbonyl group which may be substituted, a lower alkylsulfonyl group which may be substituted, and an amine which may be substituted Sulfhydryl. [Substituent group δ]: hydrogen atom, lower alkyl group which may be substituted, lower alkyl alcohol group which may be substituted, protected carboxyl group, substituted aminocarbonyl group, substitutable lower stage Alkylsulfonyl, and optionally substituted aminosulfonyl. [Substituent group ε]: hydrogen atom, lower alkyl group which may be substituted, substituted hydrazine lower alkyl fluorenyl group, protected carboxyl group a substituted aminocarbonyl group, a substituted lower alkylsulfonyl group, and a substituted aminosulfonyl group. [Substituent group]: a hydrogen atom, a halogen atom, a protected or substituted A hydroxy'-substituted lower alkoxy group, a pendant oxy group, and a hydroxyimino group which may be substituted. [Substituent group η]: a hydrogen atom, a _ atom, and a lower alkyl group which may be substituted. [Substituent group Θ]: a hydrogen atom, a lower alkyl group which may be substituted, a hydroxyl group which may be protected by a substitution, and a lower alkoxy group which may be substituted. -11- 200946528 [Substituent group I]: a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted, a lower alkyl group which may be substituted, a protected group or a substituted group, a lower substituted alkoxy group And a cyano group, a protected pendant oxy group, a substitutable perimino group, a protected carboxy group, a substitutable aminocarbonyl group, and a protected or substituted amine group. [Substituent group K]: 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, an amine group which may be substituted a carbonyl group, a substituted aminosulfonyl group, and a lower alkylsulfonyl group which may be substituted; (2) The compound of the above (1) or a pharmacologically acceptable salt thereof, wherein the hydrazine nitrogen atom; (3) The compound of the above-mentioned (1), or a pharmacologically acceptable salt thereof, wherein the compound of any one of the above (1) to (3), or a pharmacologically acceptable salt thereof, wherein Α1 is a nitrogen atom;

The compound according to any one of the above-mentioned items (1) to (3), wherein the oxime 4 is an oxygen atom, or the pharmaceutically acceptable salt of any one of the above (1) to (3). The compound or a pharmacologically acceptable salt thereof, wherein the oxime 1 is a nitrogen atom and the oxime 4 is an oxygen atom, and the compound of any one of (1) to (6) or a pharmacologically acceptable salt thereof, wherein the compound (I) Part of the general formula (la):

(la) -12- 200946528 The structure of the tricyclic structure is as follows (* the combination of the hands with the L 'X, Rla, Rlb, R5, R8 and R11 and the formula (the definition of the substituent in 0) The same),

(8) The compound according to any one of the above (1) to (7) or a pharmacologically acceptable substance thereof

Salt, wherein L1 is -CH2CH2-, -CH2-C(=0)-, -CH2-CH= or -CH2-C(-OH)(-COOH)-; (9) as above (1)~( The compound according to any one of the preceding claims, wherein the Q1 is a 6-membered ring structure between L1 and L2 represented by the following formula (IV) (wherein R23 and R24 each independently represent hydrogen; Atom, hydroxymethyl, methoxy, carboxy, aminocarbonyl, N-(methoxy)aminocarbonyl, N-(methylsulfonyl)aminocarbonyl or pendant oxy; * each represents a binding hand);

The compound or a pharmacologically acceptable salt thereof according to any one of the above items (1) to (9), wherein L2 is -CH2-CH2-, -CH2-CH = CH-, _ch2_C ( = 0) -NH-, -CH2CH2-S--NH-CH2-, -CH2-CH(- OCOCH3)-, -CH2-CH(-OH)-, -CH2-C( = 0). , -C ( = 0)- CH = CH- or -CH2-CH=;

(11) A compound or a pharmacologically acceptable salt thereof according to any one of the above (1) to (10) wherein Q2 is 3-oxo-3,4-dihydro-2H-pyrido[3,2_b ][l,4]噚-6-yl, cycloheptyl, cyclohexyl, 1-hydroxycyclohexyl, 丨_methylsulfonylaminocyclohexyl, 1-cyanocyclohexyl, 2-oxocyclohexyl , U4_ Dioxaspiro[4.5]癸-6-yl, 2-hydroxyiminocyclohexyl, 2-methoxyiminocyclohexyl, 3-oxocyclohexyl, 1,4-dioxaspiro [4.5] 癸-7_yl, 2,2-difluorocyclohexyl, 2-fluoro-1-cyclohexenyl, 2-methylenecyclohexyl, trans-2.hydroxycyclohexyl, cis-2 -hydroxycyclohexyl, trans-2-methoxycyclohexyl, cis-2-methoxycyclohexyl, 2-tetrahydropyranyl, 2-oxooxan-indolyl, cyclopentyl, 2-sided oxocyclopentyl, 2-thienyl, 3-fluorophenyl or 2,5-difluorophenyl; (12) a medicine consisting of any of the above (1) to (11) (13) A compound according to any one of the above (1) to (11) or a pharmacologically acceptable salt thereof for use in medicine production; (14) an antibacterial agent Medicine A compound according to any one of the above (1) to (1), or a pharmacologically acceptable salt thereof, and a therapeutic drug for infectious diseases characterized by containing the above (1)~ (11) A compound according to any one of the above, or a pharmacologically acceptable salt thereof. EFFECT OF THE INVENTION The compound of the formula (I) or a salt thereof is suitable as an antibacterial agent because of its strong antibacterial activity and high safety. Further, the compound of the formula (I) or a salt thereof is excellent in bactericidal property and tissue migration property because it has strong antibacterial activity against drug-resistant bacteria such as MRSA, and thus is suitable as an antibacterial agent. [Embodiment] BEST MODE FOR CARRYING OUT THE INVENTION The compound of the present invention will be described in detail below. In the present specification, the "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom unless otherwise specified. "Lower alkyl" means a straight chain of 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, isopropyl, isobutyl, t-butyl, and t-butyl. Alkyl or branched alkyl. The "lower suspicion group" means a linear or branched alkenyl group having 1 to 6 carbon atoms such as a methylidene, an alkyl group, a 1-propenyl group or a 2-propenyl group. "Lower alkoxy" means a carbon number of methoxy, ethoxy 'n-propoxy, n-butoxy, n-pentyloxy, isopropoxy, isobutoxy, tert-butoxy, etc. a linear or branched alkoxy group of 6. The "lower alkyl fluorenyl group" means a linear or branched alkyl fluorenyl group having 1 to 6 carbon atoms such as an ethyl fluorenyl group, a n-propyl fluorenyl group, a n-butyl fluorenyl group, an isobutyl fluorenyl group or a trimethyl acetyl group. "Lower alkyl sulfinyl" means a methyl sulfinyl group, an ethyl sulfinium-15-200946528 group, a n-propyl sulfinyl alcohol group, an isopropyl sulfene group, and the like having 1 to 6 carbon atoms. A linear or branched alkyl sulfinylene group. "Lower alkylsulfonyl" means a linear chain having a carbon number of 1 to 10 eclipses of 6 or more such as methylsulfonyl, ethyl fluorenyl, n-propylsulfonyl, or isopropylsulfonyl. Or a branched alkylsulfonyl group. "Low-grade home oxygen curtain base" means a linear or branched chain of carbon 胄 2 to 7 such as a methoxy group, an ethoxycarbonyl group, a n-propoxy group, an isopropoxy group or a third butoxy carbon group. Alkoxycarbonyl group. The "lower-grade substituted base" includes an unsubstituted lower alkyl group such as a lower alkyl group substituted by a hydroxyl group, an alkoxy group, an amine group, a carboxyl group, an amine group, a halogen atom or the like, and can be exemplified by a hydroxyl group. Base, methoxymethyl, oxaethyl, 2-methoxyethyl, 1-methoxyethyl, aminomethyl residue methyl, amine methyl hydrazinomethyl, 2-fluoroethyl, 1-fluoroethyl, 2,2,2-trisylethyl, 1,1-difluoroethyl, and the like. The "lower alkenyl group which may be substituted" includes an unsubstituted lower aliphatic group, for example, a lower alkenyl group substituted by a group, an anthracene group, an amine group, a fluorenyl group, an amine group, a halogen atom or the like. Examples thereof include a methylene group, a difluoromethylene group, an ethylene fluorenyl group, a 1-fluorovinyl group, a 2-carboxyvinyl group, a 3-hydroxy-indole-propyl group, a 3-amino-1-propenyl group, and the like. The "lower-substituted alkoxy group" which may be substituted includes an unsubstituted lower-grade alkoxy group, for example, a lower alkoxy group substituted by a thiol group, a oxime group, a halogen atom or the like, and a 2-hydroxyethoxy group may be exemplified. 2-methoxyethoxy 'fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 2,2,2-trifluoroethoxy, and the like. -16- 200946528 "Substitutable lower alkyl fluorenyl group" includes unsubstituted lower alkyl fluorenyl group, for example, lower alkyl fluorenyl group substituted by hydroxy group, alkoxy group, halogen atom or the like, and hydroxyethyl hydrazino group is exemplified. , methoxyethyl fluorenyl, 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, 2 - hydroxyethylsulfinyl, 2-methoxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 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 alkylsulfonyl group substituted by a hydroxyl group, an alkoxy group, a halogen atom or the like, and is exemplified as 2 Hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl and the like. The "substituted aminocarbonyl group" includes an unsubstituted amino group, for example, a methyl group, a 2-hydroxyethyl group, a 2-methoxyethyl group, a 2-fluoroethyl group, an ethyl fluorenyl group, or the like. The substituted aminocarbonyl group can be exemplified by N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, fluorene-(2.methoxy B. Aminocarbonyl, anthracene-(2-fluoroethyl)aminocarbonyl, anthracene-(ethionyl)aminocarbonyl, and anthracene-(methylsulfonyl)aminocarbonyl. "Substitutable aminosulfonyl" includes unsubstituted aminosulfonyl ', for example, methyl, 2-ethyl, 2-methoxyethyl, 2-oxyethyl, -17 - 200946528 Aminosulfonyl group substituted by acetyl group, etc., which can be exemplified as N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2-hydroxyethyl)amine Sulfosyl, N-(2-methoxyethyl)aminosulfonyl, N-(2-fluoroethyl)aminosulfonyl, N-(ethionyl)aminosulfonyl, etc. . The "protected hydroxyl group" includes, in addition to the unprotected hydroxyl group, a hydroxyl group substituted by all the groups which can be used as a usual hydroxy protecting group, and examples thereof include Greene and Woots. Wuts) et al., Protective Groups in Organic Synthesis, 4th Edition, 1 6-3 66, 2006, John Wiley & Sons, Inc. Specifically, 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, and an Sulfhydryl, p-toluenesulfonyl, trimethyldecyl, tert-butyldimethylalkyl, etc. as a protecting group. The so-called "substituted hydroxy", in addition to unsubstituted hydroxy, for example Illustrated by phenyl, pyridyl, aminocarbonyl, aminosulfonyl, etc.

The "protectable amine group" includes, in addition to the unprotected amine group, an amine group substituted with all the groups which can be used as a usual amino group protecting group, and examples thereof include Greene. Wuts et al. (Protective Groups in Organic Synthesis) 4th edition, pp. 696-926, 2006, John Wiley & Sons, Inc. (John Wiley & Sons, Inc. .) The examples described in . Specific examples thereof include a methyl group, an ethyl fluorenyl group, a trifluoroethyl fluorenyl group, a trichloro ethane -18-200946528 group, a trimethyl ethenyl group, a benzamidine group, a benzyl fluorenyl group, and a trisyl group. Benzyl, allyl, benzyl, p-methoxybenzyl, methoxycarbonyl, benzyloxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyloxycarbonyl, methanesulfonyl, p-toluene , benzylidene's diphenylmethylene (methylene), diphenylphosphonium, tert-butylsulfinyl, trimethyldecyl, tert-butyldimethylsulfonyl, etc. As a protection base. The "substituted amino group", in addition to the unsubstituted amino group, may, for example, be exemplified by methyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 2-fluoroethyl, benzene. An amine group substituted with a base, a D group, an amino group, an amine group, or the like. The "protectable carboxyl group" includes, in addition to the unprotected carboxyl group, a carboxyl group which is taken by all the groups which can be used as a usual carboxyl group, and is, for example, Greene, Woot. (Wuts et al., Protective Groups in Organic Synthesis, 4th edition, 5th 3rd - 646th, 2006, 'John Wiley & Sons, Inc. .) The examples described in . Specific examples thereof include a methyl group, an ethyl group, a tert-butyl group, a (9-fluorenyl)methyl group, an allyl group, a benzyl group, a diphenylmethyl group, a trityl group, and a trimethyl decane. The base, the third butyl dimethyl decyl group and the like serve as a protecting group. The "substitutable hydroxyimino group", except for the unsubstituted hydroxyimino group ' can also be exemplified by methyl, difluoromethyl, 2-hydroxyethyl, 2-methoxyethyl, 2 - fluoroethyl, (hydroxycarbonyl)methyl, difluoro(hydroxycarbonyl) sub-oxo-substituted sulfonylamine, carbonylamine, base.醯''''''''' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' Examples of the pendant oxy group substituted by all the groups include, for example, Greene, Wuts, and the like in the organic synthesis (P r 〇tective G r 〇upsi η Ο rganic Synthesis) Examples, pages 43 - 52, page 5, 2006, John Wiley & Sons, Inc. Specific examples thereof include a dimethyl ketal group, a 1,3-dioxanyl group, and a 1,3-didecylalkylene group. The "lower alkoxycarbonyl group which may be substituted", in addition to the unsubstituted lower alkoxycarbonyl group, for example, a lower alkoxy group substituted by a halogen atom, a hydroxyl group, an alkoxy group, a substituted amino group or the like. The carbonyl group may, for example, be 2-hydroxyethoxycarbonyl, 2-methoxyethoxycarbonyl, fluoromethoxycarbonyl, difluoromethoxycarbonyl, trifluoromethoxycarbonyl or the like. The "substituted thiol group" may, for example, be an amidoxime group, a 0-methyl aldehyde oxime group or the like, in addition to the unsubstituted thiol group. 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 constitutes a saturated or unsaturated ring having 3 to 7 G atoms. The substituent may, for example, be phenyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, 12,3-trimethyl, 1,2,4-triazolyl, tetrahydrofuranyl, anthracene The unsubstituted monocyclic substituent such as an oxazolidinyl group, a pyrrolidinyl group or a morpholinyl group may, for example, be a monocyclic substituent substituted with a pendant oxy group, a carboxyl group or an amine formazan group. The "sulfur atom which may be substituted" may, for example, be _s(〇2)_, _s(〇)_ and -S-, and the like. -20· 200946528 Specific examples and preferred examples of the present compound are listed below. X1 and X2 each independently represent a nitrogen atom or a carbon atom to which one hydrogen atom is bonded, preferably a nitrogen atom of X1, and a carbon atom or a nitrogen atom to which one hydrogen atom is bonded to X2, and particularly preferably an X1 system. A nitrogen atom, the X2 system is bonded to a carbon atom of one hydrogen atom. X3 represents a nitrogen atom or a formula CRla (wherein Rla 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), preferably a formula CRla, substituted a group 111:1, a halogen atom, a cyano group, a lower alkyl alkane 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 Hydroxy group, substitutable lower alkoxy group, protected or substituted amino group, decylamino group, substituted fluorenyl group, protected carboxyl group, substituted aminocarbonyl group, substitutable Lower alkylsulfonyl, a lower alkyl sulfinyl group which may be substituted, and an amine sulfonyl group which may be substituted. Here, specific examples of the ruler 1!1 include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, an ethyl sulfonium group, a n-propyl group, a n-butyl group, an isobutyl fluorenyl group, and a trimethyl group. Sulfhydryl, hydroxyethyl, methoxyethyl, aminoethyl, methylaminoethyl, dimethylaminoethyl, fluoroethyl, difluoroethyl, three Fluorinyl, 2-fluoro-2-methylpropenyl, 2,2-difluoropropenyl, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isopropyl, iso Butyl, t-butyl, tert-butyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl , aminomethyl, methylaminomethyl, dimethylaminomethyl, fluorenyl-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2 -Fluoroethylene-21- 200946528

Base, 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, carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-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, vinyl, 1-fluorovinyl, 2-fluorovinyl, 2, 2-difluorovinyl, 1-propenyl, 2-propenyl, 2-nonylethane storage, 2-mercapto-1-air-ethyl storage, 2-residue-2-air-ethyl, 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-pyridine , 6-carboxy-3-pyridyl, thienyl, 4-carboxythienyl, 5-carboxythienyl, 2-thiazolyl, 4-carboxy-2-thiazolyl, 5-carboxy- 2-thiazolyl, 4-thiazolyl, 2-carboxy-4-thiazolyl, 5-thiazolyl, 2-carboxy-5-thiazolyl, 1-pyridyl, 3-carboxy-1-pyrrolyl, 2- Pyrrolyl, 4-carboxy-2-pyrrolyl, 5-carboxy-2-pyridyl, 3-pyrrolyl, 5-carboxy-3-pyrrolyl, 1-pyrazolyl, 3-carboxy-1-pyrazole , 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--22- 200946528 oxooxazolidin-3-yl, 5-carboxy-2-oxooxazolidin-3-yl, 2-oxooxazolidin-4- Base, 2-sided oxyoxazolidin-5-yl, 4-morpholinyl, 2-carboxy-4-morpholinyl, hydroxy, methoxymethyloxy, benzyloxymethyloxy , tetrahydropyranyloxy, trimethyldecyloxy, triethylsulfanyloxy, tert-butyldimethylsilyloxy, tert-butyldiphenylphosphinoalkyl, B Anthraceneoxy, trifluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, p-methoxybenzyloxy, p-nitrobenzyloxy, diphenylmethyloxy , trityloxy, aminocarbonyloxy, methoxy, ethoxy, ^n-propoxy, n-butoxy, n-pentyloxy, isopropoxy, isobutoxy, Tributoxy, 2-hydroxyethoxy, 2-methoxyethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 1-fluoroethoxy 1,1-difluoroethoxy, 2,2,2-trifluoroethoxy, carboxymethyloxy, 2-aminoethoxy, amine, formazanyl, ethylidene Amino, trifluoroacetamidoamine, trichloroacetamidoamine, trimethylethenylamine, benzhydrylamino, phthalicylamino, tritylamino, Allylamino, benzylamine sulfhydryl, p-methoxybenzylamino, methoxycarbonylamino, benzyloxycarbonylamino, (9- Methoxycarbonylamino, allyloxycarbonylamino, methanesulfonylamino, p-toluenesulfonylamino, benzylidene, diphenylmethyleneamino, diphenylphosphine Mercaptoamine, tert-butylsulfinylamino, trimethyldecylamino, tert-butyldimethylalkylamino, methylamino, dimethylamino, ethylamine Base, isopropylamino group, 2-hydroxyethylamino group, 2-methoxyethylamino group, 2-fluoroethylamino group, phenylamino group, pyridylamino group, aminocarbonylamino group, Aminosulfonylamino, guanylamino, decyl, amidino, hydrazine-methyl amidino fluorenyl, fluorenyl-acetamido fluorenyl, carboxy, methoxycarbonyl-23-200946528, B Oxycarbonyl, third butoxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, diphenylmethoxycarbonyl, triphenylmethoxycarbonyl, trimethyldecyloxycarbonyl, Third butyl dimethyl decyloxycarbonyl, (methoxycarbonyloxy)methoxycarbonyl, 1-(methoxycarbonyloxy)ethoxycarbonyl, (t-butoxycarbonyloxy)methoxy Carbonyl, 1-(t-butoxycarbonyloxy)B Carbonyl, (cyclohexyloxycarbonyloxy)methoxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylamine Alkylcarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethinyl) Aminocarbonyl, N-(methylsulfonyl)amine fluorenylcarbyl, methylsulfonyl, ethyl fluorenyl, n-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethyl Sulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonic acid, difluoromethyl acid extension, trimethylmethyl acid extension, 2-fluoroethylsulfonyl, 1,1 -difluoroethylsulfonyl, 2,2,2-tris-ethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonic acid, dimethylaminomethylsulfonyl Methyl, methyl sulfhydryl, ethyl sulfinyl, n-propyl sulfinyl, isopropyl subsynthesis, 2 _ ethyl aryl, 2-methoxyethyl Dimethyl group, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfonium, 2-fluoroethylsulfinyl, U1_digas ethyl Base, 2,2,2-trifluoroethyl sub-bulk, makeup methylsulfinyl, monomethylaminosulfinic acid, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylamino based ortho-based, N-(2-hydroxyethyl)aminosulfonyl, N-(2-methoxyethyl)aminosulfonyl, N-(2- Fluoroethyl)aminosulfonyl, and N-(ethinyl)aminosulfonyl and the like. Preferred examples of Rla include gas atoms and chlorine atoms, and -24-200946528

Cyano, ethyl fluorenyl, n-propyl decyl, n-butyl decyl, isobutyl decyl, trimethyl ethane, hydroxyethyl methoxy, methoxyethyl, trifluoroethyl, 2-fluoro-2- Propyl propyl, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isopropyl, isobutyl, t-butyl, tert-butyl, hydroxymethyl, methoxymethyl , 1-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl, 2-fluoroethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, 1,1- Difluoroethyl, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethoxy , 2-methoxyethoxy, fluorenylfluoro, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy Base, 2,2,2-trifluoroethoxy, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methylsulfonyl)aminocarbonyl Methylsulfonyl, ethyl sulfonate Indenyl, n-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonate , trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, methylsulfin Ethyl, sulfinyl, n-propylsulfinyl, isopropylsulfinyl, 2-hydroxyethylsulfinyl, 2-methoxyethylsulfinyl, fluoromethyl Sulfosyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2, 2, 2-Trifluoroethylsulfinyl, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2-hydroxyethyl)amine Sulfosyl, N-(2-methoxyethyl)aminosulfonyl, N-(2-fluoroethyl)aminosulfonyl, and N-(ethinyl)aminosulfonyl -25- 200946528 and so on. More preferable examples of Rla include a fluorine atom, a chlorine atom, a bromine atom, a cyano group, an ethyl sulfonyl group, a n-propyl fluorenyl group, a trifluoroethane group, a methyl group, an ethyl group, an isopropyl group, and a methyl group. , 1-hydroxyethyl, 2-fluoroethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, 1,difluoroethyl, methoxy, ethoxy, fluoromethoxy , difluoromethoxy, trifluoromethoxy, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, methylsulfonyl, fluoromethylsulfonyl, two Fluoromethylsulfonyl, trifluoromethylsulfonyl, methylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, amine Sulfhydrazinyl, N-methylaminosulfonyl, and N,N-dimethylaminosulfonyl.

A particularly preferred example of Rla is methoxy and cyano. X4 represents a nitrogen atom or a formula CRlb (wherein the ruler "meaning a halogen atom, a cyano group, a lower alkyl alkane group which may be substituted, or a group selected from the substituent group α), preferably a formula CRlb, substituted The group R 2 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 group, a hydroxyl group which may be protected or substituted , a lower alkoxy group which may be substituted, an amine group which may be protected or substituted, a guanamine hydrazine, a substituted fluorenyl group, a protected carboxyl group, a substituted amino group, a substitutable group a lower alkylsulfonyl group, a lower alkylsulfonyl group which may be substituted, and an aminosulfonyl group which may be substituted. Here, specific examples of 1111) include a hydrogen atom, a fluorine atom, and chlorine. Atom, bromine atom, cyano group, ethyl sulfonyl group, n-propyl fluorenyl group, n-butyl fluorenyl group, isobutyl fluorenyl group, trimethyl ethane group, hydroxyethyl methoxy group, methoxy ethoxy group, amino ethyl ketone group, methyl group Aminoethyl hydrazino, dimethylaminoethyl fluorenyl, fluoroethyl hydrazine-26- 200946528 base, difluoroacetinyl, trifluoroacetamidine Base, 2-fluoro-2-methylpropanyl, 2,2-difluoropropenyl, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isopropyl, isobutyl, Second butyl, tert-butyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl, amine Methyl, methylaminomethyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl Base, 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-oxoethyl, vinyl, 1-fluorovinyl, 2-fluorovinyl , 2,2-difluorovinyl, 1-propenyl, 2-propenyl, 2-mercaptoethyl, 2-mercapto-1-pyrene, 2-mercapto-2-ethylene 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-pyridyl, 4-pyridyl, 4-carboxy-2-pyridyl, 5-carboxy-2-pyridyl, 5-carboxy-3-pyridyl, 6 -carboxy-3-pyridyl, thienyl, 4-carboxythienyl, 5-carboxythienyl, 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-pyrrolidyl, 2-pyridyl, 4-carboxy-2 -pyridyl, 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-27- 200946528

, 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-carboxyl -2-tetrahydrofuranyl, 5-carboxy-2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 5-carboxy-3-tetrahydrofuranyl, 2-oxooxazolidin-3-yl, 5-carboxy-2-oxo Ketrazin-3-yl, 2-oxooxazolidin-4-yl, 2-oxooxazolidin-5-yl, 4-morpholinyl, 2-carboxy-4-morpholinyl , hydroxy, methoxymethyloxy, benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecyloxy, triethyldecyloxy, tert-butyldimethylhydrazine Alkyloxy, tert-butyldiphenylphosphonyloxy, ethoxycarbonyl, trifluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, para Oxybenzyloxy, p-nitrobenzyloxy, benzhydryloxy, trityloxy, aminocarbonyl Alkoxy, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethoxy, 2-methoxyethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 2,2,2-trifluoroethoxy, carboxymethyloxy, 2-aminoethoxy, amino, decylamino, ethylamino, trifluoroethylamino, three Chloroethylamino, trimethylethenylamine, benzhydrylamine, phthalicylamino, tritylamino, allylamine, benzylamine, pair Methoxybenzylamino, methoxycarbonylamino, benzyloxycarbonylamino, (9-fluorenyl)methoxycarbonylamino, allyloxycarbonylamino, methanesulfonylamino, p-toluene Mercaptoamine, benzylideneamine, diphenylmethyleneamino-28-200946528, diphenylphosphoniumamino, tert-butylsulfinylamino, trimethylsilyl Amino, tert-butyldimethylmethylalkylamino, methylamino, dimethylamino, ethylamino, isopropylamine , 2-hydroxyethylamino '2-methoxyethylamino, 2-fluoroethylamino, phenylamino, pyridylamino, aminocarbonylamino, aminosulfonylamine , amidino, fluorenyl, amidino, hydrazine-methyl hydrazinyl, fluorenyl-acetamidinyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 9-fluorenyl)methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, diphenylmethyloxycarbonyl, trityloxycarbonylcarbonyl, trimethyldecyloxycarbonyl, tert-butyl Dimethyl decyloxycarbonyl, (methoxycarbonyloxy)methyloxycarbonyl, 1-(methoxycarbonyloxy)ethoxycarbonyl, (t-butoxycarbonyloxy)methyloxy Carbocarbonyl, 1-(t-butoxycarbonyloxy)ethoxycarbonyl, (cyclohexyloxycarbonyloxy)methyloxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, amine Alkylcarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethinyl)aminocarbonyl, N-( Sulfhydryl)aminocarbonyl, methylsulfonyl W, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxy Sulfosyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2 , 2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methylsulfinyl, B Isosulfonyl, n-propylsulfinyl, isopropylsulfinyl, 2-hydroxyethylsulfinyl, 2-methoxyethylsulfinyl, fluoromethylsulfin , difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethyl-29- 200946528, sulfinyl, 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-(B) Yl) amino Sulfonic group.

Preferable examples of R1 include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, an ethyl group, a n-propyl group, a n-butyl group, a n-pentyl group, an isopropyl group, and an isobutyl group. , second butyl, tert-butyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl, amine Methyl, 1-aminoethyl, 2-aminoethyl, 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-carboxyl 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, vinyl, 1-propenyl, 2-propenyl, 1-fluoro Vinyl, 2-fluorovinyl, 2,2-difluorovinyl, 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-carboxyl -3 -pyridyl, thienyl, 4-carboxythienyl, 5-carboxythienyl, 2-thiazolyl, 4-carboxy-2-thiazolyl, 5-carboxy-2-thiazolyl, 4-thiazolyl, 2 -carboxy-4- 30- 200946528 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-carboxyl -3-pyrrolyl, 1-pyrazolyl, 3-carboxy-1-pyrazolyl, 4-carboxy-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-triazol-4-yl, 1,3,4- Triazol-1-yl, 1,3,4-triazol-2-yl, 5-carboxy-1,3,4-triazole-2-O, 2-tetrahydrofuranyl, 4-carboxy-2-tetrahydrofuran , 5-carboxy-2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 5-carboxy-3-tetrahydrofuranyl, 2-oxooxazolidin-3-yl, 5-carboxy-2-oxooxazolidinium -3 -yl, 2-oxooxyoxazolidin-4-yl, 2-oxooxazolidin-5-yl, 4-morpholinyl, 2-carboxy-4-morpholinyl, hydroxy, amine Carbocarbonyloxy, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethoxy , 2-methoxyethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 1-fluoroethoxy, 1,1- Fluorine ethoxylate, 2,2,2-trifluoroethoxy, carboxymethyloxy, 2-aminoethoxy, amine, formazanyl, ethylamino, trifluoro Ethyl mercaptoamine, trichloroacetamidoamine, trimethylethenylamine, benzhydrylamine, phthalnylamino, tritylamino, allylamine , benzylamino, p-methoxybenzylamino, methoxycarbonylamino, benzyloxycarbonylamino, (9-fluorenyl)methoxycarbonylamino, allyloxycarbonylamino, methylsulfonium Amino group, p-toluenesulfonylamino group, benzylidene amine group, diphenylmethyleneamino group, diphenylphosphonium amino group, tert-butylsulfinylamino group, trimethyl Mercaptoalkylamine group, -31- 200946528

Third butyl dimethyl fluorenylalkylamine, methylamino, dimethylamino, ethylamino, isopropylamino, 2-hydroxyethylamino, 2-methoxyethylamine Base, 2-fluoroethylamino group, phenylamino group, pyridylamino group, aminocarbonylamino group, aminosulfonylamino group, mercapto group, amidoxime group, anthracene-methyl amidoxime group , 〇-acetamidohydrazinyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-( 2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methyl Sulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl , Difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonate Methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, 2-hydroxyethylsulfinyl, 2-methoxyethyl Sulfonyl Fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2 , 2,2-trifluoroethylsulfinyl, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2-hydroxyethyl) Aminosulfonyl, N-(2-methoxyethyl)aminosulfonyl, N-(2-fluoroethyl)aminosulfonyl, and N-(ethinyl)amine Sulfonyl and the like. More preferable examples of the ruler 11) include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, an ethyl group, a methylol 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-32- 200946528, 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, vinyl, 2-propenyl, 1-fluorovinyl, 2-fluorovinyl, 2 , 2-difluorovinyl, 2-carboxyvinyl, 2-carboxy-1-hydroxyvinyl, 2-carboxy-2-hydroxyvinyl, 3-hydroxy-1-propanyl, 3-amino-1 - propyl thiol, 3 - fluorenyl base, 2 - ll 11 base, 3 Π 陡 steep base, 4 - 陡 steep base, 4 - residue -2- Π steep base, 5 - fluorenyl -2- turn ratio D-based, 5-carboxy-3-pyridyl, 6-carboxy-3-pyridyl, thienyl, 4-carboxythiophene fluorenyl, 5-carboxyl Benzyl, 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-pyridyl, 5-carboxy-2-pyridyl, 3-pyrrolyl, 5- Carboxy-3-pyridyl, 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- 〇W 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 Ketrazin-3-yl, 2-oxooxazolidin-4-yl, 2-oxooxazolidin-5-yl, 4-morpholinyl, 2-carboxy-4-morpholinyl Hydroxyl group Carbocarbonyloxy, methoxy, 2-hydroxyethoxy, fluoromethoxy, difluoromethoxy, carboxymethyloxy, 2-aminoethoxy, amine, ethenylamine, Methoxy-33- 200946528 carbonylamino, methanesulfonylamino, methylamino, dimethylamino, ethylamino, isopropylamino, 2-hydroxyethylamino, 2-methyl Oxyethylamino group, 2-fluoroethylamino group, pyridylamino group, aminocarbonylamino group, aminosulfonylamino group, mercapto group, amidoxime group, 0-methyl amidoxime group , 0-acetamidoindolyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, methylsulfonyl, methylsulfinyl, aminesulfonate An anthracenyl group, an N-methylaminosulfonyl group, an N,N-dimethylaminosulfonyl group, and an N-(ethinyl)aminosulfonyl group.

Specific examples of Rb. are hydrogen atom, cyano group, methyl group, 2-carboxy-1,2-anthracene dihydroxyethyl group, 2-carboxyvinyl group, 5-carboxythienyl group, fluorenyl group, amidino group , 0-methyl amidoxime, 0-ethylhydrazinyl fluorenyl. A1 represents a general formula CR2 [wherein R2 means a bonding hand (integrated with a bonding hand of an adjacent atom on L1, or a bonding bond with an adjacent A2 to form a double bond), a halogen atom, a cyano group, or an From the group of the substituent group α or the nitrogen atom, preferably a nitrogen atom, and also preferably a compound of the formula CR2, in which case the substituent R2 is selected from the bonding hands (atoms with adjacent L1) The bonding hand is integrated, or integrated with the adjacent Α2 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 alkane 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, decylamino group, substituted sulfhydryl group A protected carboxyl group, a substituted aminocarbonyl group, a lower alkylsulfonyl group which may be substituted, a lower alkylsulfonyl group which may be substituted, and an aminosulfonyl group which may be substituted. -34- 200946528 Here, as a specific example of R2, a bonding hand (combined with a bonding hand of an atom on an adjacent L1 or a bonding bond with an adjacent A2 to form a double bond) and a hydrogen atom are mentioned. , 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, tert-butyl group, hydroxy group Methyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl, aminomethyl, methylaminomethyl, two Methylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, fluorinated 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, 2-amino-2-carboxyethyl, 2-carboxy-1 - pendant oxyethyl, vinyl, 1-fluorovinyl, 2-fluorovinyl, 2,2-difluorovinyl, 1-propenyl, 2-propenyl, 2-carboxyvinyl, 2-carboxyl 1-fluorovinyl, 2-carboxy-2-fluorovinyl, 2-carboxyindole-1,2-difluorovinyl, 2-carboxy-1-hydroxyvinyl, 2-carboxy-2-hydroxyl Vinyl, 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, thienyl, 4-carboxythienyl, 5-carboxythienyl, 2-thiazole Base, 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-35- 200946528, 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-carboxyl -1-imidazolyl, 2-imidazolyl, 4-carboxy-2-imidazolyl, 4-imidazolyl, 2-carboxy-4-imidazolyl, 1,2,3-triazol-1-yl, 4-carboxyl -1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,3,4-triazol-1-yl, 1,3,4-triazole-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-morpholinyl, hydroxy, methoxymethyloxy, benzyloxymethyloxy, tetrahydropyridyl Anthranyloxy, trimethyldecyloxy, triethyldecyloxy, tert-butyldimethylsilyloxy, tert-butyldiphenylphosphinoalkyloxy, ethoxylated, tri Fluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, p-methoxybenzyloxy, p-nitrobenzyloxy, diphenylmethyloxy, trityl Alkoxy, aminocarbonyloxy, methoxy, ethoxy, n-propoxy n-Butoxy, n-pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethoxy, 2-methoxyethoxy, fluoromethoxy, difluoromethyl Oxy, trifluoromethoxy, 2-fluoroethoxy, fluoroacetoxy, 1,1-difluoroethoxy, 2,2,2-trifluoroethoxy, carboxymethyloxy, 2-Aminoethoxy, Amino, Carboxylamido, Ethylamino, Trifluoroethenylamino, Trichloroethenylamino, Trimethylethenylamine, Benzyl Mercaptoamine, phthalnylamino, tritylamino, allylamino, benzylamino, p-methoxybenzylamino, methoxycarbonylamino, benzyloxycarbonylamine , (9-fluorenyl) -36- 200946528 methoxycarbonylamino, allyloxycarbonylamino, methanesulfonylamino, p-toluenesulfonylamino, benzylidene, diphenyl Methyleneamino, diphenylphosphoniumamino, tert-butylsulfinylamino, trimethyldecylamino, tert-butyldimethylalkylamino, methylamino , dimethylamino, ethylamino, isopropylamino, 2-hydroxyethylamino, 2-methoxyethylamine Base, 2-fluoroethylamino group, phenylamino group, pyridylamino group, aminocarbonylamino group, aminosulfonylamino group, decylamino group, fluorenyl group, amidoxime group, fluorene-methyl group Amidoxime, fluorenyl-acetamidohydrazinyl, carboxy, methoxycarbonyl, ethoxycarbonyl hydrazino, tert-butoxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyloxycarbonyl, benzyl Oxycarbonyl, diphenylmethyloxycarbonyl, trityloxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethylalkyloxycarbonyl, (methoxycarbonyloxy) Methyloxycarbonyl, 1-(methoxycarbonyloxy)ethoxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, 1-(t-butoxycarbonyloxy)ethoxylate Carbonyl, (cyclohexyloxycarbonyloxy)methyloxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethyl Aminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methyloxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-( Ethyl carbonyl, N-(methylsulfonyl)aminocarbonyl, methylsulfonate Ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoro Methylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2·trifluoroethylsulfonyl, amine Methylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, Isopropylsulfinyl, 2-hydroxyethyl-37- 200946528 sulfinyl, 2-methoxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl , trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, amine Methylsulfinyl, dimethylaminosulfinyl, 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. Preferable examples of R2 include a bonding hand (integral with a bonding atom of an adjacent atom on L1, or a bonding bond with an adjacent A2 to form a double bond), a hydrogen atom, a fluorine atom, and a cyano group. , methyl, ethyl, n-propyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl, amine Methyl, methylaminomethyl, dimethylaminomethyl, 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-anthracene dihydroxyethyl, 2-amino-1,2-di-oxyethyl, 1-amino-1-carboxylate Methyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, hydroxy, aminocarbonyloxy, methoxy, B Oxyl, 2-hydroxyethoxy, 2-methoxyethoxy, fluoromethoxy, Fluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 2,2,2-trifluoroethoxy, carboxymethyl Oxyl, 2-aminoethoxy, amine, etidylamino, methoxycarbonylamino, methanesulfonylamino, methylamino, dimethylamine-38-200946528, ethyl Amine, isopropylamino, 2-hydroxyethylamino, 2-methoxyethylamino, 2-fluoroethylamino, aminocarbonylamino, aminosulfonylamino, carboxyl , aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)amine Carbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, 2-Hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonate 1,1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethyl Aminomethylsulfonyl, amine Sulfosyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2-hydroxyethyl)aminosulfonyl, N-(2-methoxy Alkyl)aminosulfonyl, N-(2-fluoroethyl)aminosulfonyl, and N-(ethinyl)aminosulfonyl. More preferably, it is a bonding hand (integrated with a bonding atom of an adjacent atom on L1, or a bonding bond with an adjacent A2 to form a double bond), a hydrogen atom, a fluorine atom, a cyano group, a methyl group, an ethyl group. , hydroxymethyl, aminomethyl, formazan W-aminomethyl, 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- 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- side Oxyethyl, hydroxy, aminocarbonyloxy, methoxy, ethoxy, fluoromethoxy, difluoromethoxy, 2-carboxymethyloxy, 2-aminoethoxy, amine- 39- 200946528 base, ethyl mercaptoamine group, methoxycarbonylamino group, methanesulfonylamino group, methylamino group, dimethylamino group, 2-hydroxyethylamino group, 2-fluoroethylamino group Aminocarbonylamino group, amine sulfonate Amino group, mercapto group, carboxyl group, aminocarbonyl group, N-methylaminocarbonyl group, N,N-dimethylaminocarbonyl group, N-(ethinyl)aminocarbonyl group, N-(methylsulfonyl group Aminocarbonyl, methylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonate , dimethylaminomethylsulfonyl, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, and N-(ethenyl) Aminosulfonyl and the like. A particularly good example of R2 is a hydrogen atom. The above A2 represents the above formula CR3R4, NR5, an oxygen atom or a sulfur atom which can be oxidized, but is preferably a compound of the formula CR3R4. When A2 is a general formula CR3R4, R3 and R4 are each independently bonded to the hand [A1 is a carbon atom and integrated with A1, or with A3 (A3 itself is a combination of A4)) Forming 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 or a heterocyclic group which may be substituted, a protected or substituted hydroxyl group, may be substituted Lower alkoxy, protected or substituted amine, guanamine, substituted fluorenyl, protected carboxy, substituted aminocarbonyl, substituted lower alkyl sulfonyl, A lower alkylsulfinyl group which may be substituted, a substituted aminosulfonyl group, or a pendant oxy group or a substituted hydroxyimino group which is formed by R3, R4. Here, as specific examples of R3 and R4, each of them may independently be a bonding hand [A1 is a combination of the formula CR2 and A1, or with -40-200946528 A3 (A3 itself is a combination of hands A4) a combination of hands 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, iso Butyl, 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, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl , Ο 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, 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-hydroxyvinyl, 3-hydroxy-indol-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, thienyl, 4- Carboxythiophenyl, 5-carboxythienyl, 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, 5-carboxy-3-pyridyl, 1-pyrazolyl, 3-carboxy-1-pyrazolyl, 4-carboxy-1 -pyridyl-41- 200946528 oxazolyl, 3-pyrazolyl, 5 -carboxy-3-pyrazolyl, 4-pyrazolyl, 4-pyrazole , 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-side Oxyoxazolidin-4-yl, 2-oxooxazolidin-5-yl, 4-morpholinyl, 2-carboxy-4-morpholinyl, hydroxy, methoxyfluorenylmethyloxy, Benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecyloxy, triethylsulfanyloxy, tert-butyldimethylsilyloxy, tert-butyldiphenyl矽Alkoxy, ethoxycarbonyl, trifluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, p-methoxybenzyloxy, p-nitrobenzyloxy , Diphenylmethyloxy, trityloxy, aminocarbonyloxy, methoxy Ethoxy, n-propoxy, n-butoxy, n-pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethoxy, 2-methoxyethoxy , fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 2,2,2-three Fluoroethoxy, carboxymethyloxy, 2-aminoethoxy, amine, formazanylamine, ethionylamino, trifluoroethenylamino, trichloroacetamidoamine, Trimethylacetamidoamine, benzhydrylamino, phthalnylamino, tritylamino, allylamino, benzylamino, p-methoxybenzylamino , methoxycarbonylamino, benzyloxycarbonylamino, (9-fluorenyl)methoxycarbonylamino, allyloxycarbonylamino, methanesulfonylamino, p-toluenesulfonylamino, -42 - 200946528 benzylideneamine, diphenylmethyleneamino, diphenylphosphoniumamino, tert-butylsulfinylamino, trimethyldecylamino, tert-butyl Methyl decylamino group, methylamino group, dimethylamino group, ethylamino group, isopropylamino group, 2-hydroxyethylamine Base, 2-methoxyethylamino group, 2-fluoroethylamino group, phenylamino group, pyridylamino group, aminocarbonylamino group, aminosulfonylamino group, decylamino group, fluorenyl group , amidoxime, 0-methyl amidoxime, 0-acetamidoxime, carboxyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, (9-fluorenyl)methoxycarbonyl , allyloxycarbonyl, benzyloxycarbonyl, diphenylmethylmethyloxycarbonyl, trityloxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethylsilyloxycarbonyl , (methoxycarbonyloxy)methyloxycarbonyl, 1-(methoxycarbonyloxy)ethoxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, 1-(third Butoxycarbonyloxy)ethoxycarbonyl, (cyclohexyloxycarbonyloxy)methyloxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, aminocarbonyl, N-methylamine Carbocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl Aminocarbonyl, N.(ethinyl)aminocarbonyl, N-(indolyl)amine Carbonyl, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluorocarbon Sulfosyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoro Ethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, positive Propylsulfinyl, isopropylsulfinyl, 2-hydroxyethylsulfinyl, 2-methoxyethylsulfinyl, fluoromethylsulfinyl, difluoromethyl Sulfonyl, -43- 200946528 trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2,2,2·trifluoroethyl Sulfosyl, aminomethylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonate Indenyl, N-(2-hydroxyethyl)aminosulfonyl, N-(2-methoxyethyl)aminosulfonyl, N-(2-fluoroethyl)aminosulfonyl, And N-(ethinyl)amine sulfonate Sulfhydryl, pendant oxy, hydroxyimino, 0-methylhydroxyimino, fluorenyl-(fluoromethyl)hydroxyimino, fluorenyl-(difluoromethyl)hydroxyimino, 0-(three Fluoromethyl)hydroxyimino, 0-(carboxymethyl)hydroxyimino, 0-(difluorocarboxymethyl)hydroxyimino, 〇-(2-carboxyisopropyl)hydroxyindole Amine Wait. As a preferable specific example of R3 and R4, a bonding hand [A1 is a combination with the hand of the formula CR2 and integrated with the hand of the hand, or a combination of a3 (a3 itself is a combination of the hand A4) is used. Integrated to form a double bond], hydrogen atom, fluorine atom, cyano group, methyl group, ethyl group, n-propyl 'hydroxymethyl group, methoxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 2· Methoxyethyl, 丨-methoxyethyl, aminomethyl 'methylaminomethyl, dimethylaminomethyl, ethylethyl, 2-aminoethyl, fluoromethyl , difluoromethyl, trifluoromethyl, fluorene 2-fluoroethyl, 1-fluoroethyl, 2,22 trifluoroethyl, U1•difluoroethyl, 1,2-—ethyl, 1- Amino 2-hydroxyethyl, 2·amino-hydrazine hydroxyethyl, 12·diaminoethyl, fluorenyl-carboxymethyl, κcarboxy-hydroxymethyl, 2·carboxyethyl, 2·carboxyl 1-hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-dihydroxyethyl, 2-amino-1,2-one-oxyethyl, decyl carboxymethyl, hydrazine Amino-2·carboxyethyl, 2-amino-2-carboxyethyl, 2•carboxy-丨-oxyethyl, hydroxyl, aminocarbonyloxy, methoxy, ethoxy, positive Oxy, n-butoxy, n-44- 200946528 pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethoxy, 2-methoxyethoxy, fluoro Methoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 2,2,2-trifluoroethoxy , carboxymethyloxy, 2-aminoethoxy, amino, decylamino, ethionylamino, methoxycarbonylamino, methanesulfonylamino, methylamino, two Methylamino, ethylamino, isopropylamino, 2-hydroxyethylamino, 2-methoxyethylamino, 2-fluoroethylamino, phenylamino, pyridylamine Amino, aminocarbonylamino, aminosulfonylamino, carboxy, aminocarbonyl hydrazine, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl Aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methylsulfonate) Aminocarbonyl, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonate , fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2 -trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methyl sulfinyl, ethyl sulfin Indenyl, n-propylsulfinyl, isopropylsulfinyl, 2-hydroxyethylsulfinyl, 2-methoxyethylsulfinyl, fluoromethylsulfinyl, Fluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2,2,2-trifluoroethyl Sulfosyl, aminomethylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonate Indenyl, N-(2-hydroxyethyl)aminosulfonyl, N-(2-methoxyethyl)aminosulfonyl, N-(2-fluoroethyl)aminosulfonyl, N-(ethinyl)aminosulfonyl, side-45-200946528, 〇·(fluoromethyl)hydroxy(trifluoromethyl)hydroxyloxy, hydroxyimino, 〇·methylhydroxylamine Amino group, 〇- (difluoromethyl)hydroxyimino, hydrazine-fluorocarboxymethyl)hydroxyiminoamine, fluorenyl-(carboxymethyl)hydroxyimino, = base and bis-indole-(2-carboxyisopropyl A hydroxyimino group or the like. As a more specific example of R3 and R4, the binding hand [A1 is a general formula CR2 and Αι A3 (A3 itself is a combined hand A4)), and the binding hand is integrated, or combined. The hand becomes a bond to form a bond], a hydrogen atom, a methyl group, a methylol group, a methoxymethyl 1-hydroxyethyl group,

2-ethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, fluoromethyl, di-methyl, trifluoromethyl, indole, 2-diethyl, bu Amino 2-hydroxyethyl, 2-amino-hydroxyethyl, U2-diaminoethyl, hydrazine-carboxymethyl, carboxy-1-hydroxymethyl, 2-carboxyethyl, 2- Carboxyl-indole-hydroxyethyl, octacarboxy-2_2-amino-1,2-di-oxyethylethyl, 2-carboxy-1,2-dihydroxyethyl, amino-1 -carboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-mercapto-1-yloxyethyl, feecyloxy, amine, Alkylamino, acetamidoamine, methoxyamino, methanesulfonylamino, methylamine

a dimethylamino group, an aminoamino group, an aminosulfonylamino group, a carboxyl group, an amine group, an N-methylamino group, an anthracene, a fluorenyl-dimethylaminocarbonyl group, N·(ethinyl)aminocarbonyl, fluorenyl-(methylsulfonyl)aminocarbonyl, methylsulfonyl, 2-hydroxyethylsulfonyl, fluoromethylsulfonyl 'difluoromethylsulfonate Mercapto, trifluoromethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, 4 dimethylaminomethylsulfonyl, methylsulfinyl, 2- Hydroxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, aminomethylsulfinyl, dimethylaminosulfin Sulfhydryl, aminosulfonyl-46- 200946528 fluorenyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl: ethyl)aminosulfonyl, N-(acetonitrile An aminosulfonyl group, a pendant imine group, a 0-methylhydroxyimino group, a fluorene-(fluoromethyl)hydroxy group, and a fluorenyl-(carboxymethyl)hydroxyimino group. Particularly preferred is a combination of a hand, a hydrogen atom, a methyl group and a pendant oxy group. When A2 is NR5, the substituent R5 is bonded to the hand [Αι is a unitary bond with A1 or integrated with a3 (A3 itself is a bond A4) to form a double bond], a hydrogen atom, a hydrazine Lower alkyl, substitutable lower alkyl fluorenyl, substituted cyclic or heterocyclic, protected or substituted hydroxy, alkoxy, protected or substituted amine, decylamine An amino, sulfonyl group which may be substituted with a carboxylic group, a protected carboxy group, a substituted aminocarbonyl group, a lower alkyl sulfonyl group, or a substituted lower alkyl sulfinyl group. Here, as a specific example of R5, a bonding hand (integrated with A1 in A1 or integrated with A3 (A3 itself is a crucible 4 A4) to form a double bond), a hydrogen atom, may be mentioned. , methyl, n-propyl, n-butyl, n-pentyl, isopropyl, isobutyl, tert-butyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-methoxy Ethyl ethyl, 1-methoxyethyl, aminomethyl, methyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, difluoromethyl, trifluoromethyl Base, 2-fluoroethyl, 1-fluoroethyl, ethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl, 1-amino-2. 2-amino-1- Hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, i'N-(2-oxyl, hydroxyimino, when CR2 is a substituted monocyclic hydrocarbon Lower substituted fluorene substituted, and may be bonded to a carbon atom, ethyl second butyl 2-hydroxyethylaminomethyl, fluoromethyl:, 2,2-trifluorohydroxy 1,1-mercapto-1_-47- 200946528 hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2- two Ethyl, 2-amino-1,2-di-oxyethyl, 1-amino-1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyl Base, 2-carboxy-1-oxoethyl, 2-hydroxy-1-oxoethyl, 2-amino-1-oneoxyethyl, 2-(methylamino)-1- Side oxyethyl, 2-(dimethylamino)-1-oxoethyl, 2,3-dihydroxypropyl, 2·amino-3-hydroxypropyl, 3-amino-2 -hydroxypropyl, 2,3-diaminopropyl, 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-indolyl--ethylenediyl, 2-mercapto-1-yl Ethyl, 2-mercapto-2-ylamino, 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, thienyl, 4 -carboxythiophenyl, 5-carboxythienyl, 2-thiazolyl, 4-carboxy-2-thiazolyl, 5-carboxy-2-thiazolyl, 4-thiazole , 2-carboxy-4-thiazolyl, 5-thiazolyl, 2-carboxy-5-thiazolyl, 1-pyrrolyl, 3-carboxy-1-pyrrolyl, 2-pyrrolyl, 4-carboxy-2-pyridyl Succinyl, 5-carboxy-2-pyrrolyl, 3-pyridyl, 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-triazole- P, 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, -48- 200946528

3-tetrahydrofuranyl, 5-carboxy-3-tetrahydrofuranyl, 2-oxooxazolidin-3-yl, 5-carboxy-2-oxooxazolidin-3-yl, 2-sided oxime Zoxadin-4-yl, 2-oxooxazolidin-5-yl, 4-morpholinyl, 2-carboxy-4-morpholinyl, hydroxy, methoxymethyloxy, benzyloxy Alkoxy, tetrahydropyranyloxy, trimethyldecyloxy, triethylsulfanyloxy, tert-butyldimethylsilyloxy, tert-butyldiphenyldecyloxy , ethoxylated, trifluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, p-methoxybenzyloxy, p-nitrobenzyloxy, diphenyl Alkoxy, trityloxy, aminocarbonyloxy, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, isopropoxy, isobutoxy, Third butoxy, 2-hydroxyethoxy, 2-methoxyethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 1-fluoroethyl Oxyl, 1,1-difluoroethoxy, 2,2,2-trifluoroethoxy, carboxymethyloxy, 2-aminoethoxy, amine, formazanyl, acetamidine base Amino, trifluoroacetamidoamine, trichloroacetamidoamine, trimethylethenylamine, benzhydrylamino, phthalicylamino, tritylamino, Allylamino, benzylamino, p-methoxybenzylamino, methoxycarbonylamino, benzyloxycarbonylamino, (9-fluorenyl)methoxycarbonylamino, allyloxycarbonylamine Base, methanesulfonylamino, p-toluenesulfonylamino, benzylideneamine, diphenylmethyleneamino, diphenylphosphoniumamino, tert-butylsulfinamide Base, trimethyldecylamino group, tert-butyldimethylmethylalkylamino group, methylamino group, dimethylamino group, ethylamino group, isopropylamino group, 2-hydroxyethylamine Base, 2-methoxyethylamino group, 2-fluoroethylamino group, phenylamino group, pyridylamino group, aminocarbonylamino group, aminosulfonylamino group, decylamino group, fluorenyl group , amidoxime, 〇-methyl amidoxime-49- 200946528 base, 〇-acetamidohydrazinyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, (9-fluorenyl) ) methoxycarbonyl, allyloxycarbonyl, oxycarbonyl, diphenylmethyl Carbocarbonyl, trityloxycarbonyl, trimethylsilyloxycarbonyl, tert-butyldimethylsilyloxycarbonyl '(methoxy-oxy)methyloxymethylmethoxy Carbonyloxy)ethoxylated, (t-butoxy oreoxy)methyloxycarbyl, 1-(t-butoxycarbonyloxy)ethoxycarbonyl, (cyclohexyloxycarbonyloxy) Methyloxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, aminocarbonyl, hydrazine-methylaminocarbonyl, hydrazine, hydrazine-dimethylaminocarbonyl, hydrazine-(2 -hydroxyethyl)aminocarbonyl, fluorenyl-(2-methoxyethenyl)aminocarbonyl, fluorenyl-(2-fluoroethyl)aminocarbonyl, fluorenyl-(ethylidene)aminocarbonyl, hydrazine -(Methanesulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxy Ethyl sulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl , 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylamine Methylsulfonyl, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, 2,hydroxyethylsulfinylhydrazine, 2-methyl Oxyethyl sulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-di Fluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, aminomethylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, anthracene Methylaminosulfonyl, hydrazine, hydrazine-dimethylaminosulfonyl, fluorenyl-(2-hydroxyethyl)aminosulfonyl, fluorenyl-(2-methoxyethyl)amine sulfonate Anthracenyl, fluorenyl-(2-fluoroethyl)aminosulfonyl, and fluorenyl-(ethionyl)aminosulfonyl. -50- 200946528 When A2 is an oxidizable sulfur atom, examples thereof may be exemplified by -S(02)-, -S(O)-, and -S-. The above A3 represents a formula CR6R7, a formula NR8, an oxygen atom, an oxidizable sulfur atom or a bonding hand as described above, and is preferably a compound of the formula CR6R7, a formula NR8, an oxygen atom and a bonding hand. When A3 is a compound of the formula CR6R7, the substituents R6 and R7 are each independently bonded to a hand (integral with a conjugated A2 or A4 bond to form a double bond), a hydrogen atom, a halogen atom, a cyano group, a substitutable Lower alkyl, lower alkyl alkane which may be substituted by hydrazine, monocyclic hydrocarbon ring or heterocyclic group which may be substituted, a protected or substituted hydroxy group, a lower alkoxy group which may be substituted, may be protected Or substituted amino, guanylamino, substituted fluorenyl, protected carboxy, substituted aminocarbonyl, substituted lower alkylsulfonyl, substituted lower alkyl The sulfonyl group, the optionally substituted aminosulfonyl group ' or R6, R7 may be an integrally formed pendant oxy group or a substituted hydroxyimino group. q Here, 'specific examples of r6 and R7 each independently include a bonding hand (a double bond is formed integrally with an adjacent A2 or A4 bond), a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, Cyano, methyl, ethyl, n-propyl 'n-butyl, n-pentyl, isopropyl, isobutyl, second butyl, second butyl, hydroxymethyl, methoxymethyl, 1 - hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 1-amine Ethyl ethyl, 2-aminoethyl, fluoromethyl, -fluoromethyl, difluoromethyl, 2-fluoroethyl, _fluoroethyl, 2,2,2-trifluoroethyl, 1, 1-difluoroethyl, 1,2-dihydroxyethyl, amine-2-hydroxyethyl, 2_-51- 200946528

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-indolylmethyl , 1-amino-2-indenyl, 2-amino-2-indenyl, 2-indolyl-1-yloxyethyl, 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-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, thienyl, 4-carboxythienyl, 5-carboxythienyl, 2-thiazolyl, 4-carboxy-2-thiazolyl, 5-carboxy-2-thiazolyl, 4-thiazolyl , 2-carboxy-4-thiazolyl, 5-salrazolyl, 2-carboxy-5-thiazolyl, 1-pyrrolyl, 3-carboxy-1- Rumo, 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-triazole -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- , 2-sided oxy-52- 200946528 oxazolidin-5-yl, 4-morpholinyl, 2-carboxy-4-morpholinyl, hydroxy, methoxymethyloxy, benzyloxymethyl Oxyl, tetrahydropyranyloxy, trimethyldecyloxy, triethylsulfanyloxy, tert-butyldimethylsilyloxy , tert-butyldiphenylphosphonyloxy, ethoxycarbonyl, trifluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, p-methoxybenzyloxy , p-nitrobenzyloxy, benzhydryloxy, trityloxy, aminocarbonyloxy, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy Base, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethoxycarbonyl V, 2-methoxyethoxy, fluoromethoxy, difluoromethoxy, trifluoromethyl Oxyl, 2-fluoroethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 2,2,2-trifluoroethoxy, carboxymethyloxy, 2-amino B An oxy group, an amine group, a decylamino group, an ethenylamino group, a trifluoroethenylamino group, a trichloroacetamidoamine group, a trimethylethenylamino group, a benzhydrylamino group, Benzylamino, tritylamino, allylamino, benzylamino, p-methoxybenzylamino, methoxycarbonylamino, benzyloxycarbonylamino, (9- Mercapto) methoxycarbonylamino, decenylpropoxycarbonylamino, methanesulfonylamino, p-toluenesulfonylamino, benzidine Amino, diphenylmethyleneamino, diphenylphosphoniumamino, tert-butylsulfinylamino, trimethyldecylamino, tert-butyldimethylalkylamine Base, methylamino group, dimethylamino group, ethylamino group, isopropylamino group, 2-hydroxyethylamino group, 2-methoxyethylamino group, 2-fluoroethylamino group, Phenylamino, pyridylamino, aminocarbonylamino, aminosulfonylamino, decyl, decyl, amidino, 0-methylindenyl, 0-ethenyl Amidoxime, carboxyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, diphenyl-53- 200946528 methyl Oxycarbonyl, trityloxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethylsilyloxycarbonyl, (methoxycarbonyloxy)methyloxycarbonyl, i- (methoxycarbonyloxy)ethoxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, i-(t-butoxycarbonyloxy)ethoxycarbonyl, (cyclohexyloxycarbonyl) Oxy)methyloxycarbonyl, 1-(cyclohexyloxy) Carbonyloxy)ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-A Oxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methylsulfonyl Ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoro Methylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, amine Methylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, Isopropylsulfinyl, 2-hydroxyethylsulfinyl, 2-methoxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethyl Isosulfonyl, 2-fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, aminomethylsulfin Sulfhydryl, dimethyl Aminomethylsulfinyl, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2-hydroxyethyl)aminesulfonate Anthracenyl, N-(2-methoxyethyl)aminosulfonyl, N-(2-fluoroethyl)aminosulfonyl, and N-(ethionyl)aminosulfonyl, Sideoxy, hydroxyimino, fluorene-methylhydroxyimino, fluorenyl-(fluoromethyl)hydroxyimino, fluorenyl-(difluoromethyl)-trans-imine, fluorene-(trifluoromethyl) Hydroxyimino group, fluorenyl-(carboxymethyl)hydroxyl 200946528 amine group, 0-(difluorocarboxymethyl)hydroxyimino group, 0-(2-carboxyisopropyl)hydroxyimino group, and the like. Preferred examples of R6 and R7 each independently include a bonding hand (a double bond is formed integrally with a bonding hand of adjacent A2 or A4), a hydrogen atom, a fluorine atom, a cyano group, a methyl group, an ethyl group, N-propyl, 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 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, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, hydroxy, aminocarbonyloxy, methoxy, ethoxy, n-propoxy , n-butoxy, n-pentyloxy oxime, isopropoxy, isobutoxy, third butoxy Base, 2-hydroxyethoxy, 2-methoxyethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 1-fluoroethoxy, 1 , 1_difluoroethoxy, 2,2,2-trifluoroethoxy, carboxymethyloxy, 2-aminoethoxy, amine, formazanyl, ethylamino, Methoxycarbonylamino, methanesulfonylamino, methylamino, dimethylamino, ethylamino, isopropylamino, 2-hydroxyethylamino, 2-methoxyethyl Amino, 2-fluoroethylamino, phenylamino, pyridylamino, aminocarbonylamino, aminosulfonylamino, carboxyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, N -Methylaminocarbonyl, N,N-dimethylaminocarbonyl-55- 200946528, N-(2-hydroxyethyl)amino, N-(2-methoxyethyl)aminocarbonyl , N-(2-fluoroethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, positive Propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoro Sulfosyl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methyl Aminomethylsulfonyl, dimethylaminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, 2 - hydroxyethylsulfinyl, 2-methoxyethylsulfonium sulfonyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2- Fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, aminomethylsulfinyl, dimethylamino Sulfosyl, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2-hydroxyethyl)aminosulfonyl, N -(2-methoxyethyl)aminosulfonyl, N-(2-fluoroethyl)aminosulfonyl, N-(ethinyl)aminosulfonyl, pendant oxy, hydroxy Amino, 0-methylhydroxyimino, fluorenyl-(fluoromethyl)hydroxyimino, fluorenyl-(difluoromethyl)hydroxyimino, fluorene-(trifluoromethyl)hydroxyimino 〇-(carboxymethyl)hydroxyl Group, 〇- (difluoro carboxymethyl) hydroxyimino, O- (2-carboxy-propyl) hydroxyimino like. Further, as a more preferable example of R6 and R7, each of them may be a combination of a hand (A1 is a combination with a hand of the formula CR2 and integrated with a hand of A, or a combination of A3 (A3 itself is a combination of A4)) And forming a double bond], a hydrogen atom, a methyl group, a methylol group, a methoxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, an aminomethyl group, a methylaminomethyl group, a dimethylamine Methyl, fluoromethyl, difluoromethyl-56- 200946528, trifluoromethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyl 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, 1-amino- 2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, aminocarbonyloxy, amine, formazanyl, ethylamino, Methoxycarbonylamino, methanesulfonylamino, methylamino, dimethylamino, aminocarbonylamino, aminosulfonylamino, carboxyl, methoxycarbonyl, oxime ethoxycarbonyl, amine Carbonyl group, N- Methylaminocarbonyl, hydrazine, hydrazine dimethylaminocarbonyl, hydrazine-(ethinyl)aminocarbonyl, hydrazine-(methylsulfonyl)aminocarbonyl, methylsulfonyl, 2-hydroxyethyl Sulfosyl 'fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylamino Methylsulfonyl 'methylsulfinyl, 2-hydroxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, amine Methylsulfinyl, dimethylaminosulfinylhydrazine, aminosulfonyl, fluorene-methylaminosulfonyl, anthracene, fluorenyl-dimethylaminosulfonyl, hydrazine (2-hydroxyethyl)aminosulfonyl, fluorenyl-(ethylidene)aminosulfonyl, pendant oxy, hydroxyimino, fluorene-methylhydroxyimino, fluorene-(fluoromethyl) a hydroxyimino group, a 0-(carboxymethyl)hydroxyimino group, or the like. Particularly preferred are a combination of a hand, a hydrogen atom, a methyl group, a hydroxyl group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group and a pendant oxy group. When Α3 is NR8, the substituent R8 is bonded to a hand (integrated with a bonding hand of Α2 or Α4 to form a double bond), a hydrogen atom, a lower alkyl group which may be substituted, a lower alkyl fluorenyl group which may be substituted, Substitutable monocyclic hydrocarbon-57-200946528 cyclic or heterocyclic group, protected or substituted hydroxy group, hydrazine substituted lower alkoxy group, protected or substituted amine group, decylamino group, Substituted indenyl, protected carboxy, substituted aminocarbonyl, substituted lower alkylsulfonyl, substituted lower alkyl sulfinyl, or substituted amino Sulfonyl. Here, 'specific examples of R8 include a bonding hand (a double bond is formed integrally with an adjacent A2 or A bond), a hydrogen atom, a methyl group, an ethyl group, a n-propyl group, a n-butyl group, and a positive electrode. Pentyl, isopropyl, isobutyl, t-butyl, t-butyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxy Base, 丨-methoxyethyl, aminomethyl, methylaminomethyl, ~methylaminomethyl, oxime-aminoethyl, 2-aminoethyl, fluoromethyl, -fluoro Base, trifluoromethyl, 2-fluoroethyl, fluorofluoroethyl, 222-trisylethyl, 1,1-difluoroethyl, hydrazine, 2-dihydroxyethyl, amidino-2. hydroxy Ethyl, 2-amino-1-hydroxyethyl, -diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyl Ethyl, 2-carboxy-2-hydroxyethyl, 2-residue_1,2·dihydroxyethyl, 2-amino-1,2-di-oxyethyl, 1-amino-poly Methyl, 1-amino-2.carboxyethyl, 2·amino-2·carboxyethyl, 2-carboxyindol-1-yloxyethyl, 2-hydroxy-1-oxoethyl , 2_Amino-丨-side oxyethyl ' 2-(methylamino)_丨_Phenoxyethyl, 2_(dimethylamino)"_ oxiranylethyl, 2,3-dihydroxypropyl, 2-aminohydroxypropyl, 3-amino-2-yl Propyl, 2,3-diaminopropyl, vinyl 'fluorene-fluorovinyl, 2-air-ethyl, 2,2-difluorovinyl, fluorene-propenyl, 2-propenyl, 2_ Carboxylic acid, 2-carboxy-1-fluorovinyl, 2-carboxy-2-fluorovinyl, 2-carboxy-1'2-difluorovinyl, 2-carboxy-1-hydroxyvinyl, 2- Carboxy-2-hydroxy-58- 200946528 vinyl, 3-hydroxy-1-propenyl, 3-amino-1-propenyl, phenyl, 3-carboxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-carboxy-2-pyridyl, 5-resin-2-lead, 5-mercapto-3-D-steep, 6-residue-3-decyl steep, thiophene , 4-carboxythienyl, 5-carboxythienyl, 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-pyrrole , 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- Oxyl oxazolidine W pyridine-4-yl, 2-sided oxyoxazolidin-5-yl, 4-morpholinyl, 2-carboxy-4-morpholinyl, hydroxy, methoxymethyloxy Base, benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecyloxy, triethylsulfanyloxy, tert-butyldimethylsilyloxy, tert-butyl Phenylnonyloxy, ethoxylated, trifluoroethyloxy, trichloroacetoxy, trimethylacetoxy, benzyl , p-methoxybenzyloxy, p-nitrobenzyloxy, benzhydryloxy, trityloxy, aminocarbonyloxy, methoxy, ethoxy, n-propoxy, n-Butoxy, n-pentyloxy, isopropoxy, isobutoxy, tert-59-200946528 oxy, 2-hydroxyethoxy, 2-methoxyethoxy, fluoromethoxy , difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, fluoroacetoxy, 1,1-difluoroethoxy, 2,2,2-trifluoroethoxy, carboxymethyl Alkoxy, 2-aminoethoxy, amine, carbenylamino, etidylamino, trifluoroethenylamino, trichloroacetamidoamine, trimethylethenylamine Base, benzhydrylamino, phthalnylamino, tritylamino, allylamino, benzylamino, p-methoxybenzylamino, methoxycarbonylamino, Benzyloxycarbonylamino, (9-Fertyl) methoxycarbonylamino, allyloxycarbonylamino, methanesulfonylamino, p-toluenesulfonylamino, benzylidene, diphenyl Methyleneamino, diphenylphosphonium phosphonylamino, tert-butylsulfinylamino, trimethyldecane Amino, tert-butyldimethylmethylalkylamino, methylamino, dimethylamino, ethylamino, isopropylamino, 2-hydroxyethylamino, 2-methoxy Ethylamino, 2-fluoroethylamino, phenylamino, pyridylamino, aminocarbonylamino, aminosulfonylamino, decylamino, decyl, amidino, hydrazine -methyl amidoxime, fluorenyl-acetamidofluorenyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyloxycarbonyl, Benzyloxycarbonyl, diphenylmethyloxycarbonyl, trityloxycarbonyl, tri-v-methyldecyloxycarbonyl, tert-butyldimethylsilyloxycarbonyl, (methoxycarbonyl) Oxy)methyloxycarbonyl, i-(methoxycarbonyloxy)ethoxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, i-(t-butoxycarbonyloxy) Ethoxycarbonyl, (cyclohexyloxycarbonyloxy)methyloxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N -dimethylaminocarbonyl, N-(2-hydroxyethyl) Carbonyl group, N- (2- methoxyethyl) aminocarbonyl, N- (2- fluoroethyl) aminocarbonyl, N- (acetyl group) -60-200946528

Aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl , 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoro Ethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, A Isosulfonyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, 2-hydroxyethylsulfinyl, 2-methoxyethylsulfinyl , fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, aminomethylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, N-methylaminosulfonyl, Ν, Ν-dimethylaminosulfonyl, N-(2-hydroxyethyl)aminosulfonyl, N-(2-methoxyethyl)aminosulfonyl, N-(2- Fluoroethyl)aminosulfonyl, and N- (Ethylene) aminosulfonyl and the like. Preferable examples of R8 include a bonding hand (a double bond is formed integrally with an adjacent A2 or A4 bond), a hydrogen atom, a methyl group, an ethyl group, a n-propyl group, and a 2-hydroxyethyl group. 2-methoxyethyl, 2-aminoethyl, 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-oxoethyl, 2-hydroxy-1- side Oxyethyl, 2-amino-1-oneoxyethyl, 2-(methylamino)-1-oxoethyl, 2-(dimethylamino)-1-yloxy Ethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2,3-diaminopropyl, hydroxy, methoxy, Ethoxy, 2-hydroxyethoxy, carboxymethyloxy, 2-aminoethoxy, methoxycarbonyl-61-200946528, ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-Dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)amino Carbonyl, N-(ethionyl)aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, A Sulfosyl, ethylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonate Sulfhydryl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methylamino Methylsulfonyl, dimethylaminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, 2-hydroxy Ethylsulfinyl, 2-methoxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethyl Sulfosyl, 1,1-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, aminomethylsulfinyl, dimethylaminosulfin Base, aminosulfonyl, N-methylaminosulfonyl, anthracene, fluorenyl-dimethylaminosulfonyl, N-(2-hydroxyethyl)aminosulfonyl, N-(2 a -methoxyethyl)aminosulfonyl group, an N-(2-fluoroethyl)aminosulfonyl group, and an N-(ethinyl)aminosulfonyl group. More preferable examples of R8 include a bonding hand (a double bond is formed integrally with a bonding hand of adjacent A2 or A4), a hydrogen atom, a methyl group, a 1-carboxymethyl group, a 2-carboxyethyl group, and 2 -carboxy-2-hydroxyethyl, 2-amino-1,2-dioxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-yloxyethyl, 2- Hydroxy-1-oxoethyl, 2-amino-1-oneoxyethyl, 2-(methylamino)-1-oxoethyl, 2-(dimethylamino)- 1-sided oxyethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2,3-diaminopropyl, hydroxy , methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, amine -62- 200946528 carbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxy Ethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethinyl)aminocarbonyl, N-(A Sulfhydryl)aminocarbonyl, methylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methylsulfinyl, Aminomethylsulfinyl, dimethylamine R8 of sulfinyl, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, and N-(ethinyl)aminosulfonyl A particularly good example is the combination of a hand, a hydrogen atom and a hydroxyl group. When A3 is an oxidizable sulfur atom, for example, _S(〇2)·, ·S(O)-, and -S- may be exemplified. The above A4 represents a formula CR9R1Q, a formula NR11, an oxygen atom or an oxidizable sulfur atom as described above, and is preferably a compound of the formula CR9R1G, a formula NR11 and an oxygen atom. When A4 is a general formula CR9R1G, R9 and R1G are each independently bonded to a hand [in combination with a bonding hand of adjacent A3 (A3 itself is a binding A2) to form a double bond], a hydrogen atom, a halogen atom, a gas. a lower alkyl group which may be substituted, a lower alkyl fluorenyl group which may be substituted, a monocyclic hydrocarbon ring group or a heterocyclic group which may be substituted, a protected or substituted hydroxy group, a lower alkoxy group which may be substituted Protected or substituted amine, guanamine, substituted fluorenyl, protected carboxy, substituted aminocarbonyl, substituted lower alkylsulfonyl, substituted a lower alkylsulfinyl group, a substituted aminosulfonyl group, and a pendant oxy group formed by the combination of r9 and r1(), or a hydroxyimino group which may be substituted. -63- 200946528 Here, as a specific example of R9 and R1(), a bonding hand is formed independently (a double bond is formed integrally with a bonding hand of the adjacent A3 (A3 itself is a bonding hand A2)] , 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, third butyl group , hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl, aminomethyl, methylamino , dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl, 1-decylamino-2-hydroxyethyl, 2-amino-1-hydroxyethyl 1,1,2-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-yloxy Base, vinyl, 1-fluorovinyl, 2-fluorovinyl, 2,2-difluorovinyl, 1-propenyl, 2-propenyl, 2-carboxyvinyl, 2-carboxy-1-fluoroethylene Base, 2-carboxy-2-fluorovinyl, 2-carboxy-1,2-difluorovinyl, 2-carboxy-1-hydroxyvinyl, 2-carboxy-2-hydroxyindolevinyl, 3-hydroxy- 1-propenyl, 3-amino-1-propenyl, phenyl, 3-carboxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-carboxy-2-pyridyl, 5- Mercapto-2 - batch steep base, 5-resin-3-indole ratio B group, 6-residue -3-indolyl group, thienyl group, 4-carboxythienyl group, 5-carboxythienyl group, 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-64- 200946528, 3-pyrrolyl, 5-carboxy-3 -pyrrolyl, 1-pyrazolyl, 3-carboxy-1-pyrazolyl, 4-carboxy-1-pyrazolyl, 3-pyrazolyl, 5-carboxy-3-pyrazolyl, 4-pyrazole Base, 4-pyrazolyl, 1-imidazolyl, 4-carboxyl -1-imidazolyl, 2-imidazolyl, 4-carboxy-2-imidazolyl, 4-imidazolyl, 2-carboxy-4-imidazolyl, 1,2,3-triazol-1-yl, 4-carboxyl -1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,3,4-triazol-1-yl, 1,3,4-triazole-2 -yl, 5-carboxy-l,3,4-triazol-2-yl, 2-tetrahydrofuranyl, 4-carboxy-2-tetrahydrofuranyl, 5-carboxy-2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 5- Carboxy-3-tetrahydrofuranyl, 2-sided oxime oxazolidin-3-yl, 5-carboxy-2-oxooxazolidin-3-yl, 2-oxooxazolidin-4-yl , 2-sided oxyoxazolidin-5-yl, 4-morpholinyl, 2-carboxy-4-morpholinyl, hydroxy, methoxymethyloxy, benzyloxymethyloxy, tetrahydrogen Pyranyloxy, trimethyldecyloxy, triethylsulfanyloxy, tert-butyldimethylsilyloxy, tert-butyldiphenylphosphinoalkyloxy, ethoxylated, Trifluoroethenyloxy, trichloroethyleneoxy, trimethylacetoxy, oxy, p-methoxybenzyloxy, p-nitrobenzyloxy, diphenylmethyloxy, triphenyl Methyloxy, amino-based methoxy, methoxy, ethoxy, n-propoxy oxime , n-butoxy, n-pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethoxy, 2-methoxyethoxy, fluoromethoxy, difluoro Methoxy, trifluoromethoxy, 2-fluoroethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 2,2,2-trifluoroethoxy, carboxymethyloxy Base, 2-aminoethoxy, amino, carbenylamino, etidylamino, trifluoroethenylamino, trichloroacetamidoamine, trimethylethenylamine, Benzylamino, benzyldimethylamino, tritylamino, allylamino, benzylamino, p-methoxybenzylamino, methoxycarbonylamino, benzyloxy Carbonylamino group, (9-Jiangji-65-200946528) methoxycarbonylamino group, allyloxycarbonylamino group, methanesulfonylamino group, p-toluenesulfonylamino group, benzylidene amine group, two Phenylmethyleneamino, diphenylphosphoniumamino, tert-butylsulfinylamino, trimethyldecylamino, tert-butyldimethylalkylamino, methyl Amino, dimethylamino, ethylamino, isopropylamino, 2-hydroxyethylamino, 2-methoxyethylamine Base, 2-fluoroethylamino group, phenylamino group, pyridylamino group, aminocarbonylamino group, aminosulfonylamino group, decylamino group, fluorenyl group, amidoxime group, 0-methyl group Amidoxime, 〇-acetamidoxime, carboxy 'methoxycarbonyl, ethoxycarbonyl 't-butoxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyloxycarbonyl, benzyloxy Carbonyl, diphenylmethyloxycarbonyl, trityloxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethylalkyloxycarbonyl, (methoxycarbonyloxy) A Alkoxycarbonyl, 1-(methoxycarbonyloxy)ethoxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, 1-(t-butoxycarbonyloxy)ethoxycarbonyl , (cyclohexyloxycarbonyloxy)methyloxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethyl Aminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethyl hydrazine Aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methylsulfonyl, Ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethyl Sulfosyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, amine Methylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, iso Propylsulfinyl, 2-hydroxyethyl-66- 200946528 sulfinyl, 2-methoxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, Trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, amine Methylsulfinyl, dimethylaminomethylsulfinyl, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, N- (2-hydroxyethyl)aminosulfonyl, N-(2-methoxyethyl)aminosulfonyl, N-(2-fluoroethyl)aminosulfonyl, N-(ethylidene Aminosulfonyl, pendant oxy, hydroxy Amino, 0-methylhydroxyimino, 0-(fluoromethyl)hydroxyimino, fluorene-(difluorofluorenyl)hydroxyimino, fluorenyl-(trifluoromethyl)hydroxyimino And a fluorenyl-(carboxymethyl)hydroxyimino group, a fluorenyl-(difluorocarboxymethyl)hydroxyimino group, a fluorenyl-(2-carboxyisopropyl)hydroxyimino group, and the like. Preferred examples of R9 and R1() include a bonding hand (a double bond is formed integrally with a bonding hand of adjacent A3 (A3 itself is a bonding hand A2)), a hydrogen atom, and fluorine. Atom, cyano, methyl, ethyl, n-propyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxy Ethyl, aminomethyl, methylaminomethyl, two

Methylaminomethyl, 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-di-ethyl, 2-amino-1,2-oxoethyl, 1-amino-1-indolyl, 1-amino-2-carboxyethyl , 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, hydroxy, aminocarbonyloxy, methoxy, ethoxy, 2-hydroxy-67- 200946528 ethoxy Base, 2-methoxyethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy base,

2,2,2-trifluoroethoxy, carboxymethyloxy, 2-aminoethoxy, amino, decylamino, ethylamino, methoxycarbonylamino, methylsulfonate Amino group, methylamino group, dimethylamino group, ethylamino group 'isopropylamino group, 2-hydroxyethylamino group, 2-methoxyethylamino group, 2-fluoroethylamine Base, phenylamino group, pyridylamino group, aminocarbonylamino group, aminosulfonylamino group, carboxyl group, N-methylaminocarbonyl group, N,N-dimethylaminocarbonyl group, N-( 2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethinyl)aminocarbonyl, N -(Methanesulfonyl)aminocarbonyl, methylsulfonate, ethylsulfonyl, 2-ethylethyl, 2-methoxyethylalkyl, fluoromethylsulfonyl, Difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylanthracene, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethyl , aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, 2-hydroxyethyl Expansion base, 2- Oxyethyl sulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-di Fluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, aminomethylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, N- Methylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2-hydroxyethyl)aminosulfonyl, N-(2-methoxyethyl)aminesulfonate Sulfhydryl, N-(2-fluoroethyl)aminosulfonyl, N-(ethinyl)aminosulfonyl, pendant oxy, hydroxyimino, hydrazine-methylhydroxyimino, hydrazine -(fluoromethyl)hydroxyimino, fluorenyl-(difluoromethyl)hydroxyimino, fluorenyl-(trifluoromethyl)hydroxyimino, fluorenyl-(carboxymethyl)hydroxy-68- 200946528 An imido group, a fluorenyl-(difluorocarboxymethyl)hydroxyimino group, a fluorenyl-(2-hydrazinopropyl)hydroxyimino group, and the like. As R9 and R1. More preferably, each of the specific examples is a bonding hand (a bonding bond with a neighboring A3 (A3 itself is a bonding hand A2) to form a double bond], a hydrogen atom, a fluorine atom, a cyano group, Shengan, ethyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, π-n-methoxymethyl, methylaminomethyl, dimethylaminomethyl, 1_Amino-ethyl, 2-aminoethylhydrazine

, fluoromethyl, difluoromethyl, trifluoromethyl, fluorene, bis, G, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino-1 -hydroxyethyl, 12-diaminoethyl, 1-carboxymethyl, 1-carboxy-indole-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxyl 2-hydroxyethyl, 2-carboxy-1,2-dihydroxy-7, 2-formyl-1,2-dioxyethyl, anthracene-amino-indole-carboxymethyl, anthracene-amine Ethyl ethyl, 2-amino-2-carboxyethyl, 2-carboxy-carboxyl ethyloxy, hydroxy, aminocarbonyloxy, methoxy, 2-hydroxyethoxy, fluoromethyl Oxyl, ~~fluoromethoxy, trifluoromethoxy, carboxymethyloxy, 2-aminoethoxy, amine, formazanyl, ethylamino, methoxycarbonylamino , methanesulfonylamino, methylamino, dimethylamino, ethylamino, 2-hydroxyethylamino, 2-oxyethylamino, aminocarbonylamino, aminosulfonyl Amine, carboxyl, N-methylaminocarbonyl, hydrazine, hydrazine dimethylaminocarbonyl, N-(2-hydroxyethyl)amino thiol, N-(2-methoxyethyl)amine Carbonyl, N-(2-fluoroethyl)amino-based parent group, N_(acetonitrile Aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, 2-hydroxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfanyl, trimethylmethyl Sulfonyl, 2-fluoroethylsulfonyl, aminomethylsulfonylmethylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methyl submineral, -69 - 200946528 2·Hydroxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, amine Methylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, fluorenyl-methylaminosulfonyl, anthracene, fluorenyl-dimethylaminosulfonyl, Ν·(B Amidino)sulfonyl, pendant oxy, hydroxyimino, 0-methylhydroxyimino, fluorenyl (fluoromethyl)hydroxyimino, fluorenyl-(carboxymethyl)hydroxyimino Wait. Particularly preferred are a hydrogen atom, a hydroxyl group, a pendant oxy group, a binding hand, a hydroxyimino group, and a fluorenyl-methylhydroxyimino group. When Α4 is of the formula NR11, the substituent R11 in the formula is bonded to the hand [in combination with the bonding hand of the adjacent Α3 (Α3 itself is the binding 手2), forming a double bond], a hydrogen atom, a substitutable lower Alkyl, substituted lower alkylalkyl, substituted monocyclic hydrocarbon or heterocyclic, protected or substituted hydroxy, substituted lower alkoxy, protected or substituted Amino, amidino, a substituted fluorenyl group, a protected carboxy group, a substituted aminocarbonyl group, a substituted lower alkyl sulfonyl group, a substituted lower alkyl sulfinyl group Or a substituted amine sulfonyl alcohol. Here, as a specific example of R11, a bonding hand (a double bond is formed integrally with a bonding hand of the adjacent Α3 (the Α3 itself is a bonding Α2), a hydrogen atom, a methyl group, an ethyl group, and a positive electrode are mentioned. Propyl, n-butyl, n-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, fluorene-difluoroethyl, 1,2 - Dihydroxyethyl 200946528, 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- side Oxyethyl, 2-hydroxy-1-oxoethyl, 2-amino-1-oneoxyethyl 2-(Methylamino)-1-oxoethyl, 2-(dimethylamino)-1-oxoethyl, 2,3-dihydroxypropyl, 2-amino-3 - Hydroxypropyl, 3-amino-2-hydroxypropyl, 2,3-diaminopropyl, vinyl fluorenyl, 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-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, thiophene , 4-carboxythienyl, 5-carboxythienyl, 2-thiazolyl, 4-carboxy-2-thiazolyl, 5-carboxy-2-thiazolyl, indole-4-thiazolyl, 2-carboxy-4-thiazole , 5-thiazolyl, 2-carboxy-5-salthazolyl, 1-pyrrolyl, 3-carboxy-1-pyrrolyl, 2-pyridyl, 4-carboxy-2-pyrrolyl, 5-carboxy- 2-pyrrolyl, 3-pyridyl, 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-triazole-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-71- 200946528 base-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- Oxyl oxazolidin-4-yl, 2-oxooxazolidin-5-yl, 4-morpholinyl, 2-carboxy-4-morpholinyl, hydroxy, methoxymethyloxy, Benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecyloxy, triethylsulfanyloxy, tert-butyldimethylsilyloxy, tert-butyldiphenyl a decyloxy group, an ethoxycarbonyl group, a trifluoroacetoxy group, a trichloroacetoxy group, a trimethylacetoxy group, Oxyl, p-methoxybenzyloxy, p-nitrobenzyloxy, phthalyloxy, trityloxy, aminocarbonyloxy, methoxy, ethoxy, n-propoxy Base, n-butoxy, n-pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethoxy, 2-methoxyethoxy, fluoromethoxy, di Fluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 2,2,2-trifluoroethoxy, carboxymethyl Oxyl, 2-aminoethoxy, amino, decylamino, ethionylamino, trifluoroethenylamino, trichloroacetamidoamine, trimethylethenylamine , benzhydrylamino, phthalnylamino, tritylamino, allylamino hydrazine, benzylamino, p-methoxybenzylamino, methoxycarbonylamino, Benzyloxycarbonylamino, (9-Jiang) methoxycarbonylamino, allyloxycarbonylamino, methanesulfonylamino, p-toluenesulfonylamino, benzylidene, diphenyl Methyleneamino, diphenylphosphonium, tributylsulfinylamino, trimethyldecylamino, Tributyldimethylammonioamine, methylamino, dimethylamino, ethylamino, isopropylamino, 2-hydroxyethylamino, 2-methoxyethylamino , 2-fluoroethylamino, phenylamino, pyridyl-72- 200946528 Amino, aminocarbonylamino, aminosulfonylamino, decyl, decyl, amidino, hydrazine -methyl amidoxime, oxime-acetamidoxime, carboxyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, (9-Jiang) methoxycarbonyl, allyloxycarbonyl, Benzyloxycarbonyl, diphenylmethyloxycarbonyl, trityloxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethylsilyloxycarbonyl, (methoxycarbonyloxy) Methyloxycarbonyl, 1-(methoxycarbonyloxy)ethoxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, 1-(t-butoxycarbonyloxy)B Oxycarbonyl, (cyclohexyloxycarbonyloxy)methyloxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N- Dimethylaminocarbonyl, N-(2-hydroxyethyl)amine Alkylcarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methylsulfonyl) Aminocarbonyl, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, Fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, _ 1,1 -difluoroethylsulfonyl, 2,2,2 -trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methylsulfinyl, ethylsulfin Indenyl, n-propylsulfinyl, isopropylsulfinyl, 2-hydroxyethylsulfinyl, 2-methoxyethylsulfinyl, fluoromethylsulfinyl, Fluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2,2,2-trifluoroethyl Sulfosyl, aminomethylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonate Sulfhydryl, N-(2-hydroxyl Aminosulfonyl, N-(2-methoxyethyl)aminosulfonyl-73- 200946528, N-(2-fluoroethyl)aminosulfonyl, and N-(acetamidine) A preferred example of R11 is hydrogen atom, methyl n-propyl, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2,2,2- Trifluoroethyl, 1-carboxymethyl, 2-carboxyethyl, 2-ethyl, 2-amino-1,2-di-oxyethyl, 1-amino-1-carboxy-2-carboxyl , 2-carboxy-1-yloxyethyl, 2-hydroxy-yl, 2-amino-1-oneoxyethyl, 2-(methylamino)-1-side 2-(dimethyl Aminoethyl)-1-oxoethyl, 2,3-dihydroxypropan-3-(3-hydroxypropyl), methoxy, 2-hydroxyethoxy, 2-methoxy-2-aminoethoxy, Amine, methanesulfonylamino, methylamine amine, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, N-methyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl) Aminocarbonyl; oxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methylsulfonyl , 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonylhydrazino, difluoromethylsulfonate Sulfhydryl, trifluoromethylsulfonyl, 2-yl, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonylsulfonyl, methylaminomethyl Sulfonyl, dimethylamino, methylsulfinyl, ethylsulfinyl, 2-hydroxyethylmethyleneoxysulfinyl, fluoromethylsulfinyl, difluoro , trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, sulfinyl, 2,2,2-trifluoroethylsulfinyl, amine, dimethylamine a sulfinyl group, an aminosulfonyl group, a N-methylsulfonyl group or the like, an ethyl group, a 2-fluoroethyl 1-carboxy-2-hydroxymethyl group, a 2-amine 1-side oxy group B Oxyethyl, S, 2-amino-ylethoxy, benzyl, dimethylaminocarbonyl S, N-(2-methyl N-(ethenyl), ethyl sulfonate, fluoromethyl Sulfofluoroethylsulfonyl, aminomethylmethylsulfonylsulfonyl, 2-methylsulfinium 1,1-difluoroethylsulfinylsulfonylsulfonyl-74- 200946528 N,N-dimethylaminosulfonyl, N-(2-hydroxyethyl)aminosulfonyl, N-(2-methoxyethyl)aminosulfonyl, N-(2- Fluoroethyl)aminosulfonyl, and N-(ethenyl) Sulfo acyl group and the like. More preferable examples of R11 include a hydrogen atom, a methyl group, an ethyl group, a 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-dioxyethyl, 1-amino-1-carboxymethyl, 2-amino-2-carboxyethyl, 2 -carboxy-ethyloxyethyl, 2-hydroxy-1-oxoethyl, 2-amino-1-oneoxyethyl, 2-(methylamino)-1. fluorene Ethyl, 2-(dimethylamino)_1_sideoxyethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, methoxy, amine, methoxycarbonyl , ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, hydrazine, fluorenyl-dimethylaminocarbonyl, fluorenyl-(2-hydroxyethyl)aminocarbonyl, fluorenyl-(ethenyl)amine Carbonyl, fluorenyl-(methylsulfonyl)aminocarbonyl, methylsulfonyl, 2-hydroxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonate Aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methylsulfinyl, 2-hydroxyethylsulfinyl, fluorocarbon Isosulfonyl, difluoromethylsulfinyl, trifluoro A sulfinyl group, an aminomethylsulfinyl group, a dimethylaminosulfinyl group, an aminosulfonyl group, a fluorenyl-methylaminosulfonyl group, an anthracene, a fluorenyl-dimethylamino group A sulfonyl group, a fluorenyl-(2-hydroxyethyl)aminosulfonyl group, and an anthracene-(ethenyl)aminosulfonyl group. Particularly preferred is a hydrogen atom. When Α4 is an oxidizable sulfur atom, for example, -s(02)-, -s(0)-, and -S- and the like can be exemplified. Here, in the formula (la) of the partial structure of the general formula (Ϊ), in principle, the substituent on the ring-75-200946528 is not particularly limited, and regarding X1 to X4 and A1 to A4, it is shown to be a ring. The specific constituents of the constituent elements are the same as the definition of the substituents in the formula (I).

-76- 200946528 200946528

Among these, as a preferred example of the general formula (la), the following configuration can be cited (* indicates a combined hand with 1/; 乂2, 111!1, ruler 115, ruler 5, 118, and Ruler 11

-78- 200946528

Further, as a more preferable example of the general formula (la), the following structures (* represents a bonding hand with L1; X2, Rla, Rlb, R5, R8, and R11 are substituted with the formula (I)). The definition of the base is the same). -79- 200946528

L1 is a general formula - υ^υ2-,

Wherein y1 is as described above which may be 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, a substituted amine. A carbon atom substituted with a carbonyl group, a substituted lower alkylsulfonyl group, a substituted aminosulfonyl group, a pendant oxy group, and a group of a substituted hydroxyimino group. 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 hydroxyl group, an aminocarbonyloxy group, and a methoxymethyloxy group. Benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecyloxy, triethylsulfanyloxy, tert-butyldimethylsilyloxy, tert-butyldiphenyl矽Alkoxy, ethoxycarbonyl, trifluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, p-methoxybenzyloxy, p-nitrobenzyloxy , Diphenylmethyloxy, Tri-80-200946528 Benzyloxy, Amino, Carboxyamino, Ethylamino, Trifluoroethylamino, Trichloroethenylamine, Trimethylacetamidoamine, benzhydrylamino, phthalnylamino, tritylamino, allylamino, benzylamino, p-methoxybenzylamino , methoxycarbonylamino, benzyloxycarbonylamino, (9-fluorenyl)methoxycarbonylamino, allyloxycarbonylamino, methanesulfonylamino, p-toluenesulfonylamino, benzidine Amino group, diphenylmethylene Base, diphenylphosphonium amino group, tert-butylsulfinylamino group, trimethylsulfonylamino group, tert-butyldimethylsilylalkylamine group, methylamino group, dimethylene Amino group, ethylamino group, isopropylamino group, 2-hydroxyethylamino group, 2-methoxyethylamino group, 2-fluoroethylamino group, phenylamino group, pyridylamino group Aminocarbonylamino, aminosulfonylamino, carboxyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl , diphenylmethyloxycarbonyl, trityloxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethylsilyloxycarbonyl, (methoxycarbonyloxy)methyl Oxycarbonyl, 1-(methoxycarbonyloxy)ethoxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, 1-(t-butoxycarbonylcarbonyl)ethoxycarbonyl (cyclohexyloxycarbonyloxy)methyloxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethyl Aminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl , N-(2-methoxyethyl)aminocarbonyl, Ν(2-fluoroethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methylsulfonyl)amine Carbonyl, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2,methoxyethylsulfonyl, fluorocarbon Sulfosyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethyl-81- 200946528 sulfonyl, 2, 2, 2-Trifluoroethylsulfonic acid 'aminomethylsulfonyl' methylaminomethylsulfonyl, dimethylaminomethylmethyl sulfonyl 'aminosulfonyl, N-methylamine Sulfosyl, N,N-dimethylaminosulfonate, N-(2-ethyl)aminoalkyl, N-(2-methoxyethyl)amine-based, fluorenyl, N-(2-fluoroethyl)aminoalkyl, N-(ethinyl)aminosulfonyl, pendant oxy, hydroxyimino, hydrazine-methylhydroxyimino, 0·(fluorine Methyl)hydroxyimino, fluorenyl-(difluoromethyl)hydroxyimino, fluorenyl-(trifluoromethyl)-trans-iminyl' 〇-(竣methyl)hydroxyimino, 〇-( Difluorocarboxymethyl)hydroxyimino, - (2-carboxy isopropyl) hydroxyimino like. ο. Preferred examples thereof include a hydrogen atom, a cyano group, a hydroxyl group, an aminocarbonyloxy group, an amine group, a decylamino group, an ethyl decylamino group, a methoxycarbonylamino group, and a methanesulfonylamino group. , methylamino, dimethylamino, 2-hydroxyethylamino, 2-fluoroethylamino, aminocarbonylamino, aminosulfonylamino, carboxyl, aminocarbonyl, N- Methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(ethinyl)aminocarbonyl, N-(methylsulfonyl)amine Carbocarbonyl, methylsulfonyl, 2-hydroxyethylsulfonyl, fluoromethylsulfonyl, fluorenyl difluoromethylsulfonyl, trifluoromethylsulfonyl, aminomethylsulfonyl, M-methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl , N-(2-hydroxyethyl)aminosulfonyl, N-(ethinyl)aminosulfonyl, pendant oxy, hydroxyimino, oxime methylhydroxyimino, 0-( Fluoromethyl)hydroxyimino, 0-(difluoromethyl)hydroxyimino, fluorenyl-(trifluoromethyl)hydroxyimino, fluorene-(carboxymethyl) a hydroxyimino group, a fluorenyl-(difluorocarboxymethyl)hydroxyimino group, a fluorenyl-(2-carboxyisopropyl)hydroxyimino group, and the like. -82- 200946528 As a more preferable example, a hydrogen atom, a cyano group, a hydroxyl group, an amino fluorenyloxy group, an amine group, a methoxycarbonylamino group, a methanesulfonylamino group, a methylamino group, and a dimethyl group are mentioned. Amino group, aminocarbonylamino group, aminosulfonylamino group, carboxyl group, aminocarbonyl group, N-methylaminocarbonyl group, N,N-dimethylaminocarbonyl group, N-(ethenyl) Aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl , Aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2-hydroxyethyl)aminosulfonyl, N-(ethylidene Aminosulfonyl®, pendant oxy, hydroxyimino, 0-methylhydroxyimino, fluorenyl-(fluoromethyl)hydroxyimino, fluorenyl-(carboxymethyl)hydroxyimino Etc., especially good for hydrogen atoms. The Y2 group as described above represents a carbon atom which may be substituted, a nitrogen atom which may be substituted, an oxygen atom, or an oxidizable sulfur atom, preferably a carbon atom which may be substituted or a bonding hand. When Y2 is a carbon atom which may be substituted, a substitutable hydrogen atom, a halogen atom, a cyano group, a protected or substituted hydroxyl group, a Q group which may be protected or substituted, may be protected. A carboxy group, a substituted amino group, a lower-grade polyalkyl group which may be substituted, a substituted aminosulfonyl group, a pendant oxy group, and a hydroxyimino group which may be substituted. 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 hydroxyl group, an aminocarbonyloxy group, and a methoxymethyloxy group. Benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecyloxy, triethyldecyloxy, tert-butyldimethylsulfonyloxy, tert-butyldiphenyl Base alkyloxy, ethoxycarbonyl, difluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy-83-200946528, p-methoxybenzyloxy, pair Nitrobenzyloxy, benzhydryloxy, trityloxy, amine, decylamino, ethionylamino, trifluoroethenylamino, trichloroethenylamino , trimethyl ethinylamino, benzhydrylamino, phthalnylamino, tritylamino, allylamino, benzylamino, p-methoxybenzylamine Base, methoxycarbonylamino group, benzyloxycarbonylamino group, (9-fusyl)methoxycarbonylamino group, allyloxycarbonylamino group, methanesulfonylamino group, p-toluenesulfonylamino group, sub Benzylamino, diphenylmethylene Base, diphenylphosphonium amino group, tert-butylsulfinylamino group, trimethylsulfonylamino group, tert-butyldimethylsilylalkylamine group, methylamino group, dimethylene Amino group, ethylamino group, isopropylamino group, 2-hydroxyethylamino group, 2-methoxyethylamino group, 2-fluoroethylamino group, phenylamino group, pyridylamino group Aminocarbonylamino, aminosulfonylamino, carboxyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl , diphenylmethyloxycarbonyl, trityloxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethylsilyloxycarbonyl, (methoxycarbonyloxy)methyl Oxycarbonyl, 1-(methoxycarbonyloxy)ethoxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, 1-(t-butoxycarbonyloxy)ethoxycarbonyl (cyclohexyloxycarbonyloxy)methyloxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethyl Aminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methylsulfonyl)aminocarbonyl , methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl 'fluoromethyl Sulfonyl, difluoromethylsulfonyl-84- 200946528 fluorenyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2 ·Trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, aminosulfonyl, N-methylamine Sulfonyl, N,N-dimethylaminosulfonyl, N-(2-hydroxyethyl)aminosulfonyl, N-(2-methoxyethyl)aminosulfonyl, N -(2-fluoroethyl)aminosulfonyl, N-(ethinyl)aminosulfonyl, pendant oxy, hydroxyimino, 0.methylhydroxyimino, fluorene-(fluoro Hydroxyimino, 〇-(difluoromethyl)hydroxyimino, 0-(trifluoromethyl)hydroxyimino, 0.(carboxymethyl)hydrazine hydroxyimino, 〇-(two Fluorocarboxymethyl)hydroxyimino, 0-( A 2-carboxyisopropyl)hydroxyimino group and a bond capable of forming a double bond with an adjacent carbon atom. Preferable examples of the substitutable group on the carbon atom include a hydrogen atom, a fluorine atom, a cyano group, a hydroxyl group, an aminocarbonyloxy group, an amine group, a decylamino group, an acetamino group, and a group. Oxycarbonylamino, mesylamino, methylamino, dimethylamino, ethylamino, isopropylamino, 2-hydroxyethylamino, 2-methoxyethylamine , 2-fluoroethylamino, aminocarbonylamino, aminosulfonylamino, carboxyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, 〇N-methylaminocarbonyl, N,N - dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N -(ethinyl)aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethyl Sulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2, 2,2-Trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonate , Aminosulfonyl, N-methylaminosulfonyl, N,N- -85- 200946528 Dimethylaminosulfonyl, N-(2-hydroxyethyl)aminosulfonyl, N -(2-methoxyethyl)aminosulfonyl, N-(2-fluoroethyl)aminosulfonyl, N-(ethinyl)aminosulfonyl, pendant oxy, hydroxy Amino group, 0-methylhydroxyimino group, fluorenyl-(fluoromethyl)hydroxyimino group, fluorenyl (difluoromethyl)hydroxyimino group, fluorenyl-(trifluoromethyl)hydroxyimino group, 〇-(carboxymethyl)hydroxyimino, fluorenyl-(difluorocarboxymethyl)hydroxyimino, 0-(2-carboxyisopropyl)hydroxyimino, and double bonds with adjacent carbon atoms The combination of hands and so on. More preferable examples of the substitutable group on the carbon atom include a hydrogen atom, a fluorine atom, a cyano group, a hydroxyl group, an aminocarbonyloxy group, an amine group, a decylamino group, an acetamino group, and Methoxycarbonylamino, methanesulfonylamino, methylamino, dimethylamino, 2-hydroxyethylamino, 2-fluoroethylamino, aminocarbonylamino, aminosulfonate Amino group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, aminocarbonyl group, N-methylaminocarbonyl group, N,N-dimethylaminocarbonyl group, N-(2-hydroxyethyl)aminocarbonyl group, N-(ethenyl)aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methylsulfonyl, 2-hydroxyethylsulfonyl, fluoromethylsulfonyl, aminomethylsulfonate Mercapto, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylamine® Sulfonyl, N-(2-hydroxyethyl)aminosulfonyl, N-(ethinyl)aminosulfonyl, pendant oxy, hydroxyimino, 0-methylhydroxyimino, 〇-(fluoromethyl)hydroxyimino, 0-(carboxymethyl)hydroxyimino, and double with adjacent carbon atoms The bond of the bond or the like is particularly preferably a hydrogen atom, a hydroxyl group, a carboxyl group, a pendant oxy group, and a bonding hand which forms a double bond with an adjacent carbon atom. When Y2 is a nitrogen atom which may be substituted, a hydrogen atom which may be substituted on the nitrogen atom, a lower alkyl group which may be substituted, a lower alkylalkyl group which may be substituted - 86-200946528, a substituted amino group A carbonyl group, a lower alkoxycarbonyl group which may be substituted, a substituted lower alkylsulfonyl group, and a substituted aminosulfonyl group. Here, as a specific example of the substitutable group on the nitrogen atom, a hydrogen atom, an ethyl sulfonyl group, a n-propyl fluorenyl group, a n-butyl fluorenyl group, an isobutyl fluorenyl group, a hydrazinyl group, a hydroxyethyl fluorenyl group, a methoxy acetamyl group may be used. Aminomethylaminomethyl aryl, dimethylaminoethyl fluorenyl, fluoroethylene, difluoro, trifluoroethyl, 2-fluoro-2-methylpropenyl, 2,2_difluoropropionic acid methyl, ethyl, n-propyl, n-butyl, n-pentyl, isopropyl, iso-C), t-butyl, tert-butyl, 2-hydroxyethyl, 2-methoxyethyl, ethylethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, 3-aminopropyl, 2,3-diaminopropyl, 2 -fluoroethyl, 2,2,2-trifluoroethyl 1-carboxymethyl, 2-hydrazinoethyl, 2-resin-2-hydroxyethyl, 2-amino-1,2-oxyethyl , 2-amino-2-indenyl, 2-carboxy-; [_ oxyethyl, carbonyl, ethoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, N-methylcarbonyl, hydrazine, hydrazine - dimethylamino ore, N_(2-hydroxyethyl)aminocarbonyl(2-methoxyethyl)aminoindenyl, N-(2-fluorofluoroethyl)aminocarbonyl, fluorenyl Amine base, N-(methane) Mercapto)carbonylcarbonyl, methylsulfonylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethyl, 2-methoxyethylsulfonyl, fluorine Methylsulfonyl, difluoromethyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, U1_difluoroacetamido, 2,2,2-trifluoroethylsulfonyl , aminomethylsulfonyl, methylmethylmethyl, dimethylaminomethylsulfonyl, aminosulfonylmethylaminocarbonyl, N,N-dimethylamino Sulfhydryl, N_(2-hydroxyaminosulfonyl, N-(2-methoxyethyl)aminosulfonyl, n-(2-fluoro can be exemplified by trimethyl, methyl ethyl, butyl 2 -amino-2-yl, bis-methoxyamino, N-(ethyl...ethyl:sulfonate:sulfonylsulfonylamine: 'N-ethyl)ethyl) -87- 200946528 Aminosulfonic acid And N-(ethinyl)aminosulfonyl group, etc. Preferred examples of the substitutable group on the nitrogen atom include a hydrogen atom, an ethylidene group, a hydroxyethyl group, and a methoxyacetamidine group. Base, aminoethyl thiol, methylaminoethyl hydrazino, dimethylaminoethyl hydrazino, 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, i-carboxymethyl, 2-carboxyethyl, 2-carboxy-2-ethanoethyl, 2-amino-1,2-dioxy Ethyl, 2-amino-2-carboxyethyl, 2-resin-1-sided oxyethyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, hydrazine-methylaminocarbonyl' hydrazine, Ν-Dimethylaminocarbonyl, fluorenyl-(ethionyl)amino, fluorenyl-(methylsulfonyl)aminocarbonyl, methylsulfonyl, 2-hydroxyethylsulfonyl, 2- Methoxyethylsulfonyl, fluoromethylsulfonyl, 2-fluoroethylsulfonic acid, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethyl A sulfonyl group, an aminosulfonyl group, a fluorenyl-methylaminosulfonyl group, an anthracene, a fluorenyl-dimethylaminosulfonyl group, and an anthracene-(ethenyl)aminosulfonyl group. More preferable examples of the substitutable group on the nitrogen atom include a hydrogen atom, an ethyl hydrazino group, a hydroxyethyl fluorenyl group, an aminoethyl fluorenyl group, a methylaminoethyl fluorenyl group, and a dimethylamino group. Ethyl, methyl, 2-hydroxyethyl, 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-side Oxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-oxime-side oxyethyl, methoxycarbonyl, aminocarbonyl, hydrazine-methylaminocarbonyl, hydrazine, hydrazine-dimethyl Aminocarbonyl, fluorenyl-(ethionyl)aminocarbonyl, fluorenyl-(methylsulfonyl)aminocarbonyl, methylsulfonyl, aminosulfonyl, oxime methylamine-88-200946528 A sulfonyl group, an N,N-dimethylaminosulfonyl group, and an N-(ethinyl)aminosulfonyl group. When Y2 is an oxidizable sulfur atom, for example, -S-, -S(O)-, -S(〇2)-, and the like can be exemplified. Here, preferred examples of L1 include -CH2CH2-, -CH2-c(=o)-, -ch2-ch=, or -ch2-c(-oh)(-cooh). Q1 is a 6-membered ring structure between L1 and L2 shown by the following formula (II) as described above.

Z-

Τ—ΐ (Π) Ζ1 and Ζ4 each independently represent the formula CR2() or a nitrogen atom as described above, and when Z1 and Z4 are of the formula cr2(), the substituent r2() is a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group which may be substituted, a lower alkyl fluorenyl 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, a lower alkoxy group which may be substituted Amino group, a protected or substituted amine group, a substituted thiol group, a protected carboxyl group, a substituted aminocarbonyl group, a substituted lower alkylsulfonyl group, a substituted lower alkyl group A sulfinyl group, and a substituted aminosulfonyl group. Here, specific examples of the group R20 include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, an ethyl group, a n-propyl group, a n-butyl group, a n-pentyl group, and an isopropyl group. Isobutyl, t-butyl, tert-butyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxy Base, aminomethyl, methylaminomethyl, dimethylaminomethyl-89-200946528, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, three Fluoromethyl, 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, vinyl, 1-fluoroethylene Base, 2-fluorovinyl, 2,2-difluorovinyl, 1-propenyl, 2-propenyl, 2-carboxyl Alkenyl, 2-carboxy-1-fluorovinyl, 2-carboxy-indole 2-fluorovinyl, 2-carboxy-1,2-difluorovinyl, 2-carboxy-1-hydroxyvinyl, 2-indole Benzyl-2-ylamino, 3-cyano-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, thienyl, 4-carboxythienyl, 5-carboxythienyl, 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-pyrrolidinyl, 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-90- 200946528, 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-morpholinyl, hydroxy, aminocarbonyloxy, methoxymethyloxy, benzyloxy Alkoxy, tetrahydropyranyloxy, trimethyldecyloxy, triethylsulfanyloxy, tert-butyldimethylsilyloxy, tert-butyldiphenyldecyloxy , ethoxylated, trifluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, p-methoxybenzyloxy, hydrazino-nitrobenzyloxy, diphenyl Methyloxy, trityloxy, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, isopropoxy, isobutoxy, tert-butoxy 2-hydroxyethoxy, 2-methoxyethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2·fluoroethoxy '1-fluoroethoxy, 1,1-difluoroethoxy, 2,2,2·trifluoroethoxy, carboxymethyloxy, 2-aminoethoxy, amino, decylamino, ethylamino, trifluoroethylamino, three Chloroethylamino, trimethylethylamino, benzhydrylamine, phthalnylamino, tritylamino, allylamino, benzylamino, P-methoxybenzylamino, methoxycarbonylamino, benzyloxycarbonylamino, (9-fluorenyl)methoxycarbonylamino, allyloxycarbonylamino, methanesulfonylamino, p-toluene Sulfhydrylamino group, benzylidene amine group, diphenylmethyleneamino group, diphenylphosphonium amino group, tert-butylsulfinylamino group, trimethyldecylamino group, Tributyldimethylammonioamine, methylamino, dimethylamino, ethylamino, isopropylamino, 2-hydroxyethylamino, 2-methoxyethylamino , 2-fluoroethylamino, phenylamino, pyridylamino, aminocarbonylamino, aminosulfonylamino, fluorenyl, Amidoxime-91- 200946528, 〇-methyl amidoxime, 〇-acetamidoxime, carboxyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, (9-burial) Methoxymethyl, propylpropoxycarbonyl, benzyloxycarbonyl, diphenylmethyloxy, trityloxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethyl sand Alkyloxycarbonyl, (methoxycarbonyloxy)methyloxycarbonyl, 1-(methoxycarbonyloxy)ethoxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, i -(t-butoxycarbonyloxy)ethoxycarbonyl, (cyclohexyloxycarbonyloxy)methyloxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, aminocarbonyl, N -Methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonylcarbonyl, N-(2-methoxyethyl)aminocarbonyl, N- (2-fluoroethyl)aminocarbonyl, N-(ethinyl)aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, n-propylsulfonate Sulfhydryl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethyl expandase Base, fluoromethylsulfonic acid, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethyl, 2,2, 2 - Digas ethyl aryl, aminomethyl propyl ketone methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, aminosulfonyl, dimethylamino Sulfonyl, methylsulfinyl, ethylsulfinyl, fluorenyl sulfonate, isopropyl stilbene, 2-ethylethyl, 2-methoxy Ethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-difluoro Isosulfonyl, 2,2,2-trifluoroethylsulfinyl, aminomethylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, N-methyl Aminosulfonyl, anthracene, fluorenyl-dimethylaminosulfonyl, N-(2-hydroxyethyl)aminosulfonyl, fluorenyl-(2-methoxyethyl)aminosulfonyl , Ν-(2-fluoroethyl)aminosulfonyl-92- 200946528, and N-(ethinyl)aminosulfonyl group and the like. Preferable examples of R2<) include a hydrogen atom, a fluorine atom, a cyano group, a methyl group, an ethyl group, a n-propyl group, a methylol group, a methoxymethyl group, a 1-hydroxyethyl group, and a 2-hydroxy group. Ethyl, 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-hydroxy Ethyl, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-O 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-hydroxyethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, carboxymethyloxy, amine, ethenylamino, methylsulfonyl Amino, methylamino, dimethylamino, ethylamino, 2-hydroxyethylamino, 2-fluoroethyl Amine, aminocarbonylamino, aminosulfonylamino, carboxyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylhydrazine W-aminocarbonyl, N-(2-hydroxy Ethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, 2-hydroxyethylsulfonyl , fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonate Sulfhydryl, methylsulfinyl, ethylsulfinyl, 2-hydroxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfin Sulfhydryl, 2-fluoroethylsulfinyl, aminomethylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, N-methylaminesulfonyl-93- 200946528 A group, an anthracene, an anthracene-dimethylaminosulfonyl group, an N-(2-hydroxyethyl)aminosulfonyl group, and an N-(ethinyl)aminosulfonyl group. More preferable examples of R20 include a hydrogen atom, a cyano group, a methyl group, a methylol group, an aminomethyl group, a methylaminomethyl group, a dimethylaminomethyl group, a fluoromethyl group, and a difluoromethyl group. Base, trifluoromethyl, 1,2-dihydroxyethyl, amidino-2-ethyl, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxylate Methyl, fluorenyl-carboxy-hydroxymethyl, 1-amino-1-carboxymethyl, hydroxy, aminocarbonyloxy, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy , carboxymethyloxy, amine, etidylamino, methanesulfonylamino, methylamino, dimethylamine decyl, 2-hydroxyethylamino, aminocarbonylamino, Aminosulfonylamino, carboxyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, methylsulfonyl, methylsulfinyl, aminesulfonyl a base, an N-methylaminosulfonyl group, an N,N-dimethylaminosulfonyl group, etc., particularly preferably a hydrogen atom, a hydroxyl group and a carboxy group Z2 'Z3, Z5 and Z6 are each independently represented as described above The general formula C(R21)-R22, the substituents R21 and R22 each independently represent a hydrogen atom, a halogen atom, a cyano group, and may be substituted Lower alkyl, substitutable lower alkane fluorenyl, monocyclic hydrocarbon ring or heterocyclic group which may be substituted, protected hydroxy group, lower alkoxy group which may be substituted, may be protected or substituted Amine, amidino, substituted fluorenyl, protected carboxy, substituted aminocarbonyl, substituted lower alkylsulfonyl, substituted lower alkyl sulfinium a group, and a substituted aminosulfonyl group, or a side oxy group in which R21 and R2 2 are integrated, or a hydroxyimino group which may be substituted. Here, specific examples of R21 and R22 include a hydrogen atom, a fluorocarbon-94-200946528, a chlorine atom, a bromine atom, a cyano group, a methyl group, an ethyl group, a n-propyl group, a n-butyl group, and a n-pentyl group. Base, 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, 1,2-dihydroxyethyl, 1-amine 2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl , 2-hydroxyl-1-ethyl, 2-mercapto-2-ethyl, 2-mercapto-1,2-ethyl, 2-amino-1,2-dioxy 2 , 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, vinyl, 1-fluoroethyl Base, 2-fluorovinyl, 2,2-difluorovinyl, 1-propenyl, 2-propenyl, 2-carboxyvinyl, 2-carboxy-1-fluorovinyl, 2-carboxy-2-fluoro Vinyl, 2-carboxy-1,2-difluorovinyl, 2-carboxy-1-hydroxyvinyl '2-carboxy-2-hydroxyvinyl, 3-hydroxy-1-propene W, 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, thienyl, 4-carboxythienyl, 5-carboxythienyl, 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-pyrrol , 4-carboxy-2-pyrrolyl, 5-carboxy-2-pyrrolyl, 3-pyrrolyl, 5-carboxy-3-pyrrolyl, 1-pyrazolyl, 3-carboxy-1-pyrazolyl, 4-carboxy-1-pyrazolyl, -95- 200946528 3-pyrazolyl, 5-carboxy-3-pyrazolyl, 4-pyrazolyl, 4-pyrazolyl, 1-imidazolyl, 4-carboxyl -1-imidazolyl, 2-imidazolyl, 4-carboxy-2-imidazolyl, 4- Miso, 2-mercapto-4-misomethyl, 1,2,3-trimethyl-1-yl, 4-mercapto-1, 1,2,3-triazol-1-yl, 1,2, 3-triazol-4-yl, 1,3,4-triazol-1yl, 1,3,4-diin-2-yl, 5-resyl-1,3,4-tris-2 -yl, 2-tetrahydrofuranyl, 4-carboxy-2-tetrahydrofuranyl, 5-carboxy-2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 5-carboxy-3-tetrahydrofuranyl, 2-oxooxyoxazolidine-3 -yl, 5-carboxy-2-oxooxyoxazolidin-3-yl, 2-oxooxazolidin-4-yl, 2-oxooxazolidin-5-yl, 4-morpholine , 2-carboxy-4-morpholinyl, hydroxy, aminocarbonylcarbonyloxy, methoxymethyloxy, benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecyl Oxy, triethyl decyloxy, tert-butyldimethyl decyloxy, tert-butyldiphenyl decyloxy, ethoxylated, trifluoroacetoxy, trichloro Anthraceneoxy, trimethylacetoxy, benzyloxy, p-methoxybenzyloxy, p-nitrobenzyloxy, benzhydryloxy, trityloxy, methoxy, B Oxyl, n-propoxy, n-butoxy, n-pentyloxy, isopropoxy , isobutoxy, tert-butoxy, 2-hydroxyethoxy, 2-methoxyethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxycarbonyl, 2-fluoroethyl Oxyl, 1-fluoroethoxy, 1,1-difluoroethoxy, 2,2,2-trifluoroethoxy, carboxymethyloxy, 2-aminoethoxy, amine, A Mercaptoamine, etidylamino, trifluoroethenylamino, trichloroacetamidoamine, trimethylethenylamine, benzhydrylamine, phthalicylamino , tritylamino, allylamino, benzylamino, p-methoxybenzylamino, methoxycarbonylamino, benzyloxycarbonylamino, (9-fluorenyl)methoxycarbonylamine Base, allyloxycarbonylamino group, methanesulfonylamino group, p-toluenesulfonylamino group, -96- 200946528 benzylidene amine group, diphenylmethyleneamino group, diphenylphosphonium group Amino, tert-butylsulfinylamino, trimethyldecylamino, tributyldimethylalkylamino, methylamino, dimethylamino, ethylamino, Isopropylamino, 2-hydroxyethylamino, 2-methoxyethylamino, 2-fluoroethylamino, phenylamino, Pyridylamino, aminocarbonylamino, aminosulfonylamino, guanylamino, decyl, amidino, 0-methylamidino, 0-ethylhydrazinyl, Carboxyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, diphenylmethylmethylcarbonyl, trityl Oxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethylsilyloxycarbonyl, (methoxycarbonyloxy)methyloxycarbonyl, 1-(methoxycarbonyloxy) Ethoxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, 1-(t-butoxycarbonyloxy)ethoxycarbonyl, (cyclohexyloxycarbonyloxy)methyloxycarbonyl , 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(methoxy)aminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-〇V (ethinyl) Aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonate Sulfhydryl, n-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonate , trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonate Sulfhydryl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropyl Sulfonyl, 2-hydroxyethylsulfinyl, 2-methoxyethylsulfinyl, fluoromethylsulfinyl-97- 200946528

Mercapto, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 1,1-difluoroethylsulfinyl, 2,2,2- Trifluoroethylsulfinyl, aminomethylsulfinyl, dimethylaminosulfinyl, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethyl Aminosulfonyl, N-(2-hydroxyethyl)aminosulfonyl, N-(2-methoxyethyl)aminosulfonyl, N-(2-fluoroethyl)amine Sulfonyl, N-(ethinyl)aminosulfonyl, pendant oxy, hydroxyimino, fluorene-methylhydroxyimino, fluorenyl-(fluoromethyl)hydroxyimino, 〇-( Difluoromethyl)hydroxyimino, fluorenyl-(trifluoromethyl)hydroxyimino, fluorenyl-(carboxymethyl)hydroxyimino, fluorenyl-(difluorocarboxymethyl)hydroxyimino, and 〇-(2-carboxyisopropyl)hydroxyimino group and the like.

Preferable examples of R21 and R22 include a hydrogen atom, a fluorine atom, a cyano group, a methyl group, an ethyl group, a n-propyl group, a methylol group, a methoxymethyl group, a 1-hydroxyethyl group, and a 2- Hydroxyethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl 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-di-oxyethyl, 1-amino-1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxyl -1-sided oxyethyl, (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-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--98- 200946528 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, :l,2,3-triazole-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-carboxyl- 2-sided oxyoxazolidin-3-yl, 2-oxooxazolidin-4-yl, 2-oxooxazolidin-5-yl, 4-morpholinyl, 2-carboxy- 4-morpholinyl, hydroxy, aminocarbonyloxy, methoxy, ethoxy, 2-hydroxyethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, carboxymethyl oxygen Base, 2-aminoethoxy, amine, etidylamino, methoxycarbonylamino, methanesulfonylamino, methylamino, dimethyl Amino group, 2-hydroxyethylamino group, 2-methoxyethylamino group, aminocarbonylamino group, aminosulfonylamino group, decylamino group, fluorenyl group, carboxyl group, aminocarbonyl group, N -Methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(methoxy)aminocarbonyl, N-(2-indolylhydroxyethyl)aminocarbonyl, N-(ethinyl) Aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methylsulfonyl, 2-hydroxyethylsulfonyl, fluoromethylsulfonyl, di-methylmethyl, trifluoro | Base-expanding base, 2-air ethyl ore, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, methylsulfinyl, 2-Hydroxyethylsulfinyl, fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, aminomethyl Sulfosyl, dimethylaminosulfinyl, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, N-99-200946528 (2-hydroxyethyl)aminosulfonyl N-(ethionyl)aminosulfonyl, pendant oxy, hydroxyimino, fluorene-methylhydroxyimino, hydrazine a hydroxyimino group, 0-(difluoromethyl)hydroxyimino, 0-(trifluoromethyl)hydroxyimino, 〇-(carboxymethyl)hydroxyimino, fluorene-(difluorocarboxylate) Methyl)hydroxyimino group, and 0-(2-carboxyisopropyl)hydroxyimino group. More preferable examples of R21 and R22 include a hydrogen atom, a fluorine atom, a cyano group, a methyl group, a methylol group, an aminomethyl group, a methylaminomethyl group, a dimethylaminomethyl group, and a fluorine. Methyl, difluoromethyl, trifluoromethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-diamine Ethyl ethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 1-amino-1-carboxymethyl, 2-carboxy-1-yloxyethyl, (2-amino-1 , 2-di- oxyethyl)aminomethyl, (aminosulfonyl)aminomethyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 1-pyrrolyl, 2-pyrrole , 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1,2,3-triazole-1 -yl, 1,2,3-triazol-4-yl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuran Base, 2-oxooxyoxazolidin-3-yl, 2-oxooxazolidin-4-yl, 2-oxooxazolidin-5-yl, 4-morpholinyl, hydroxy, amine Carbocarbonyloxy, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, carboxymethyloxy, 2-Aminoethoxy, Amino, Ethylamino, methoxycarbonylamino, Methanesulfonylamino, Methylamino, Dimethylamino, Aminocarbonylamino, Amine Sulfo Merylamino, guanylamino, carboxy, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(methoxy)aminocarbonyl, N-(ethyl hydrazine Aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methylsulfonyl, methylsulfinyl, aminosulfonyl, N-methyl-100-200946528 Aminosulfonyl , N,N-dimethylaminosulfonyl, N-(ethinyl)aminosulfonyl, pendant oxy, hydroxyimino, 0-methylhydroxyimino, fluorene-(fluoro a hydroxyimino group, a fluorenyl-(carboxymethyl)hydroxyimino group, etc., particularly preferably a hydrogen atom, a methylol group, a methoxy group, a carboxyl group, an aminocarbonyl group, or an N-(methoxy)aminocarbonyl group. , N-(methylsulfonyl)aminocarbonyl and pendant oxy group. L2 is a formula -y3-y4-y5-, wherein, in the above, the oxime 3 is a carbon atom which may be substituted, a nitrogen atom which may be substituted, an oxidizable sulfur atom or a bonding hand, preferably Replace ο with carbon atoms and combine hands. When Υ3 is a carbon atom, a substitutable hydrogen atom on the carbon atom, a lower alkyl group which may be substituted, a lower alkyl alkano group which may be substituted, a protected carboxyl group, a substituted aminocarbonyl group, A lower alkylsulfonyl group which may be substituted, a substituted aminosulfonyl group, and a pendant oxy group. Here, specific examples of the substitutable group on the carbon atom include a hydrogen atom, a methyl group, an ethyl group, a n-propyl group, a n-butyl group, a n-pentyl group, an isopropyl group, an isobutyl group, and a second. 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' 1,2-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-amine-101- 200946528, base-2-carboxyethyl, 2-carboxy-1-yloxyethyl, ethyl hydrazino, n-propyl decyl, n-butyl decyl, iso Butyl, trimethylethenyl, hydroxyethyl, methoxyethyl, amine Sulfhydryl, methylaminoethylidene, dimethylaminoethyl fluorenyl, fluoroethyl fluorenyl, difluoroacetinyl, trifluoroethenyl, 2·fluoro-2-methylpropenyl, 2 , 2-difluoropropanyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, diphenylmethyl Oxycarbonyl 'trityloxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethylsilyloxycarbonyl, (methoxycarbonyloxy)methyloxycarbonyl, 1_( Methoxycarbonyloxy)ethoxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, 1-(t-butoxycarbonyloxy)ethoxycarbonyl, (cyclohexyloxycarbonyloxy) Methyloxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2 -hydroxyethyl)aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethinyl)aminocarbonyl, N- (Methanesulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, n-propylsulfonate Base, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonate Base, 2-fluoroethylsulfonyl, n-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonate Styrene, dimethylaminomethylsulfonyl, aminosulfonyl, N-methylamino acid extended group, N,N-dimethylaminosulfonyl, n-(2-hydroxyethyl) Aminosulfonyl, N-(2-methoxyethyl)aminosulfonyl, N-(2-fluoroethyl)aminosulfonyl, and N-(ethinyl)amine A sulfonyl group, a pendant oxy group, and the like. As a preferable example of the substitutable group on the carbon atom, a hydrogen atom -102-

200946528, methyl, ethyl, n-propyl, hydroxymethyl, methoxymethyl, 2-hydroxy, 2-methoxyethyl, aminomethyl, methylaminomethyl, dimethyl Base, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1,2- Dihydroxyethylamino-2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, methyl, carboxy-1-hydroxymethyl, 2-carboxy , 2-carboxy-1-hydroxyethyl fluorenyl-2-ethyl, 2-mercapto-1,2-ethyl, 2-amino-1,2-methyl-ethyl, 1· Amino-bucarboxymethyl, 1-amino-2-carboxyethyl, 2-amine g ^ carboxyethyl, 2-carboxy-1-oxoethyl, carboxyl, aminocarbonyl, N-amino Carbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)amino, N-(ethionyl)aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, formazan Ethyl, ethylsulfonyl, 2-hydroxyethylsulfonyl, fluoromethylsulfonylfluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyldimethylamine Methylsulfonyl, aminosulfonyl, N-methylaminosulfonate, N,N-dimethyl Sulfo acyl group, N- (2- hydroxyethyl) amino acyl sulfonamide N- (acetyl) amino sulfo acyl, oxo and the like. More preferable examples of the substitutable group on the carbon atom include hydrogen, a methyl group, a methylol group, a methoxymethyl group, an aminomethyl group, a methylamino group, and a dimethylaminomethyl group. Fluoromethyl, difluoromethyl, trifluoromethyl, dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-ylethyl, 1 -carboxymethyl, 1-carboxy-1-hydroxymethyl, 1-amino-1-carboxymethylcarboxy, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylamino, N- (Ethyl)aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, indolyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylethylamino 2- Fluoro-1 -1-carboxy' 2- side oxy i -2-methylcarbonyl sulfonate, 2-yl, fluorenyl, and atomic methyl 1,2-diamine, ¥01 ganol suspension sulfoamine -103- 200946528 Methylsulfonyl, methylaminosulfonyl, particularly preferably a hydrogen atom. When Y3 is a lower carboxyl group which may be substituted by a nitrogen atom, it may be substituted, and may be substituted. As a hydrogen atom, an ethyl hydrazinyl group, a hydroxyaminoethyl group, a group, a trifluoroethylidene group, an ethyl group, a positive group, Dibutyl, bis, 2-hydroxyethyl, 2-methylaminomethyl, fluoromethyl, di-, 2,2,2-trifluoroethyl 3 2-hydroxyethyl, 2-aminopropyl , 2-aminoaminopropyl, 1-carboxy-1_ethyl, 2 ·amino-1,2-dioxy, 2-amino-2-carboxyaminosulfonyl, N a methylamino-based fluorenyl group 'N,N_=, and an N-(ethenyl)aminosulfonyl group, a pendant oxy group, etc., and a pendant oxy group. Substituent, a substitutable hydrogen atom on the nitrogen atom, an alkano group, a lower alkyl group which may be substituted, an amine carbonyl group which may be protected, an amine sulfonate of a lower alkyl sulfonium which may be substituted Specific examples of the substitutable group on the nitrogen atom of the formula are exemplified by n-butyl thiol, n-butyl fluorenyl, isobutyl decyl, trimethyl ethane, methoxy ethoxy, amino acetyl, methyl A Aminomethyl fluorenyl, fluoroethane, difluoroacetic acid, 2-fluoro-2-methylpropenyl, 2,2-difluoropropanyl, propyl, n-butyl, n-pentyl, Isopropyl, isobutyldibutyl, methyl, methoxymethyl, 1-hydroxyethylmethoxyethyl, fluorenyl-methoxyethyl, aminomethyl, -methylamino Methyl, 1-aminoethyl, 2-aminoethyl methyl, difluoromethyl, 2-fluoroethyl, i•fluoroethyl I, 1,1-fluoroethyl, hydrazine, 2· Dihydroxyethyl, decylamino-1-yl-1-ethyl, 12•diaminoethyl, 2,3 dihydroxypropylpropyl, 3-amino-2-hydroxypropyl, 2,3- Dimethyl, 1-carboxy-;!-hydroxymethyl, 2-carboxyethyl, 2-carboxyl-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl 2-ylethyl, 1-amino-1-carboxymethyl, 1-amino-2-carboxyethyl, 2'carboxy-oxime-side oxyethyl, carboxyl, methoxy-104-200946528 carbonyl , ethoxycarbonyl, tert-butoxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, diphenylmethyloxycarbonyl, trityloxycarbonyl, trimethyl Alkyloxycarbonyl, tert-butyldimethylsilyloxycarbonyl, (methoxycarbonyloxy)methyloxycarbonyl, 1-(methoxycarbonyloxy)ethoxycarbonyl, Tributoxycarbonyloxy)methyloxycarbonyl, 1-(t-butoxycarbonyloxy)ethoxycarbonyl, (cyclohexyloxycarbonyloxy)methyloxycarbonyl, 1-(cyclohexyl) Oxycarbonyloxy)ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)amine fluorenylcarbonyl, N-( 2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethinyl)aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methyl Sulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoro Sulfosyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl 'methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, amine ^ Sulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2-hydroxyethyl)aminosulfonyl, N-(2-methoxy Ethyl ethyl)aminosulfonyl, N-(2-fluoroethyl)aminosulfonyl, and N-(ethinyl)aminosulfonyl, etc. as a substitutable group on the nitrogen atom Preferred examples thereof include a hydrogen atom, an ethenyl group, a n-propyl group, a hydroxyethyl group, a methoxyethyl group, an aminoethyl group, a methylaminoethyl group, and a dimethylamino group. Ethyl, fluoroethyl, methyl, ethyl, n-propyl, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-fluoroethyl, 2, 2, 2-Trifluoroethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2,3-diaminopropyl, -105 - 200946528 1-carboxymethyl, 2-carboxyethyl, 2-carboxy- 2-Hydroxyethyl, 2-amino-1,2-di-oxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, methoxycarbonyl, B Oxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-fluoroethyl)amine Carbonyl, N-(ethionyl)aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methylsulfonyl, 2-hydroxyethylsulfonyl, fluoromethylsulfonyl, 2-fluoro Ethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, amine Sulfosyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2-hydroxyethyl)aminosulfonyl, N-(2-fluoroethyl An aminosulfonyl group, an N-(ethinyl)aminosulfonyl group, 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 dimethylamino acetyl group. Base, methyl, ethyl, 2-hydroxyethyl, 2-aminoethyl, 2-fluoroethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, 3-amine 2-hydroxypropyl, 2,3-diaminopropyl, 1-carboxymethyl, 2-carboxyethyl, 2-amino-1,2-di- oxyethyl, 2·amino 2-carboxyethyl, 2-carboxy-1 di-oxyethyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methylsulfonyl, aminomethylsulfonyl, Methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, aminosulfonyl, N-methylaminosulfonyl, anthracene, fluorenyl-dimethylaminosulfonyl, And anthracene-(ethinyl)aminosulfonyl group, etc., particularly preferably a hydrogen atom. When Υ3 is an oxidizable sulfur atom, specifically -S -, -106-200946528 s(o)-, -s(o2)-, and the like can be exemplified. Y4 is a combination of a hand and a substitutable carbon atom which can form a plurality of bonds with adjacent carbon atoms as described above, and is preferably in any case. When Υ4 is a carbon atom, a substitutable hydrogen atom on the carbon atom, a halogen atom, a protected hydroxy group, a lower alkoxy group which may be substituted, a pendant oxy group, and a hydroxyimino group which may be substituted . Here, specific examples of the substitutable group on the carbon atom include a bonding hand (a multiple bond with an adjacent carbon atom), a hydrogen atom, a fluorine atom, a chlorinium atom, a bromine atom, a hydroxyl group, and an aminocarbonyl group. Oxy, methoxymethyloxy, benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecyloxy, triethylsulfanyloxy, tert-butyldimethylsilane Alkoxy, tert-butyldiphenylphosphonyloxy, ethoxycarbonyl, trifluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, p-methoxy Benzyloxy, p-nitrobenzyloxy, benzhydryloxy, trityloxy, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, iso Propoxy, isobutoxy, tert-butoxy, 2-hydroxyethoxy, 2-methoxyethoxy, fluoromethyloxy, difluoromethoxy, trifluoromethoxy, 2 -fluoroethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 2,2,2-trifluoroethoxy, carboxymethyloxy, 2-aminoethoxy, side Oxyl, hydroxyimino, 〇-methylhydroxyimino, 〇-(fluoromethyl Hydroxyimino, fluorene-(difluoromethyl)hydroxyimino, fluorenyl-(trifluoromethyl)hydroxyimino, fluorenyl-(carboxymethyl)hydroxyimino, ρ-(difluorocarboxylate) Methyl)hydroxyimino group, 0-(2-carboxyisopropyl)hydroxyimino group, and the like. Preferred examples of the substitutable group on the carbon atom are bonded hands (multiple bonds with adjacent carbon atoms), hydrogen atoms, fluorine atoms, hydroxyl groups, aminocarbonyloxy groups, -107-200946528 ethoxylated groups, Oxy, ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 1,1 -difluoroethoxy, 2,2,2-trifluoroethoxy, carboxymethyloxy, 2-aminoethoxy, pendant oxy, hydroxyimino, 0-methylhydroxyimino , 0·(fluoromethyl)hydroxyimino, 〇-(difluoromethyl)hydroxyimino, 0-(trifluoromethyl)hydroxyimino, 〇-(carboxymethyl)hydroxyimino , 0-(difluorocarboxymethyl)hydroxyimino group, 0-(2-carboxyisopropyl)hydroxyimino group, and the like. More preferred examples of the carbon atom-substituted group are a bond (a multiple bond with an adjacent carbon atom), a hydrogen atom, a fluorine atom, a hydroxyl group, an aminocarbonyloxy group, an ethoxy group, a methoxy group, or a carboxy group. Alkoxy, 2-aminoethoxy, pendant oxy, hydroxyimino, 0-methylhydroxyimino, 0-(fluoromethyl)hydroxyimino, fluorenyl-(carboxymethyl)hydroxyl The imine group or the like is particularly preferably a combination of a multi-bond formed by a carbon atom adjacent to a carbon atom, a hydroxyl group, an ethoxy group, and a pendant oxy group. Y5 is as defined above as a bonding hand, a substitutable carbon atom capable of forming a plurality of bonds with an adjacent carbon atom, a nitrogen atom which may be substituted, an oxygen atom, or an oxidizable sulfur atom, preferably a bonding hand. When Y5 is a carbon atom, a specific example of the substitutable group on the carbon atom may be a bonding hand (a multiple bond with an adjacent carbon atom) 'hydrogen atom, fluorine atom, chlorine atom, bromine atom, hydroxyl group, aminocarbonyl group Oxy, methoxymethyloxy, benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecyloxy, triethyldecyloxy 't-butyldimethylsilane Alkoxy, tert-butyldiphenylphosphonyloxy, ethoxycarbonyl, trifluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, p-methoxy Benzyloxy, p-nitrobenzyloxy, benzhydryloxy, trityloxy, methoxy, ethyl-108-200946528 oxy, n-propoxy, n-butoxy, n-pentyl Oxyl, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethoxy, 2-methoxyethoxy, fluoromethoxy, difluoromethoxy 'trifluoromethoxy Base, 2-fluoroethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 2,2,2-trifluoroethoxy, carboxymethyloxy, 2-aminoethoxy Base, pendant oxy group, hydroxyimino group, 0-methylhydroxyimino group, 〇-( Methyl)hydroxyimino, fluorene-(difluoromethyl)hydroxyimino, fluorenyl-(trifluoromethyl)hydroxyimino, fluorenyl-(carboxymethyl)hydroxyimino, fluorene-(two Fluorocarboxymethyl)hydroxyimino group, fluorenyl-(2-carboxyisopropyl)hydroxyimino group, and the like. 〇^ A preferred example of a substitutable group on the carbon atom is a bond (a multiple bond with an adjacent carbon atom), a hydrogen atom, a fluorine atom, a hydroxyl group, an aminocarbonyloxy group, an ethoxy group, a methoxy group. , ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 1,1-di Fluoroethoxy, 2,2,2-trifluoroethoxy, carboxymethyloxy, 2-aminoethoxy, pendant oxy, hydroxyimino, hydrazine-methyl hydroxyimino, hydrazine _(fluoromethyl)hydroxyimino, fluorenyl-(difluoromethyl)hydroxyimino, fluorenyl-(trifluoro-Q-methyl)hydroxyimino, 0-(carboxymethyl)hydroxyimino, 〇_(difluorocarboxymethyl)hydroxyimino, fluorenyl-(2-carboxyisopropyl)hydroxyimino group, and the like. More preferred examples of the substitutable group on the carbon atom are a bond (forming a multiple bond to an adjacent carbon atom), a hydrogen atom, a fluorine atom, a thiol group, an amine aryloxy group, an ethoxylated group, a methoxy group. , fluorenylmethyloxy, 2-aminoethoxy, pendant oxy-p-iminoimido, fluorenyl-methyl-transimino, hydrazine-(fluoromethyl)hydroxyimino, hydrazine-( A particularly preferred example of a carboxymethyl)hydroxyimino group is a bond with a hydrogen bond of a contiguous carbon atom. When Y5 is a nitrogen atom, the substituent which may be substituted on the nitrogen atom is, for example, hydrogenogen-109-200946528, ethyl sulfonyl, n-propyl fluorenyl, n-butyl fluorenyl, isobutyl fluorenyl, trimethyl ethinyl, hydroxyacetamidine. , methoxyethyl, aminoethyl, methylaminoethyl, dimethylaminoethyl, fluoroethyl, difluoroethyl, trifluoroethyl, 2 -fluoro-2-methylpropanyl, 2,2-difluoropropenyl, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isopropyl, isobutyl, second 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-trifluoroethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino- 1-hydroxyethyl, 1,2-diaminoethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2,3 -diaminopropyl, 1-carboxymethyl, 1- 1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amine Base-1,2-di-oxyethyl, amidino-1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1 - pendant oxyethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, (9-fluorenyl)methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, diphenylmethyloxy Carbonyl, trityloxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethylsilyloxycarbonyl, (methoxycarbonyloxy)methyloxycarbonyl, 1-(A Oxycarbonyloxy)ethoxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, 1-(t-butoxycarbonyloxy)ethoxycarbonyl, (cyclohexyloxycarbonyloxy) Methyloxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2- Hydroxyethyl)amino-110- 200946528 carbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethinyl) Carbonyl group, N-(methylsulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoro Sulfosyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, amine Sulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2-^hydroxyethyl)aminosulfonyl, N-(2-methoxy Alkyl)aminosulfonyl, N-(2-fluoroethyl)aminosulfonyl, and N-(ethinyl)aminosulfonyl. Preferred examples thereof include a hydrogen atom, an ethenyl group, a n-propyl group, a hydroxyethyl group, a methoxyethyl group, an aminoethyl group, a methylaminoethyl group, and a dimethylamine. Ethylene, fluoroacetamido, methyl, ethyl, n-propyl, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-fluoroethyl, 2,2 , 2-trifluoroethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2,3-diaminopropyl, 1 - carboxymethyl, 2-carboxyethyl, 2-carboxymethyl-2-hydroxyethyl, 2-amino-1,2-dioxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl) Aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methylsulfonyl, 2-hydroxy Ethylsulfonyl, fluoromethylsulfonyl, 2-fluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, aminomethylsulfonic acid, methylaminomethyl Sulfonyl, dimethylaminomethylsulfonyl, aminosulfonyl N-methylaminosulfonyl, N,N-dimethyl-111- 200946528 Aminosulfonyl, N-(2-hydroxyethyl)aminosulfonyl, N_(2-fluoroethyl) An aminosulfonyl group, and an N-(ethinyl)aminosulfonyl group. More preferable examples thereof include a hydrogen atom, an ethyl hydrazide group, a hydroxyethyl fluorenyl group, an aminoethyl fluorenyl group, a methylaminoethyl fluorenyl group, a dimethylaminoethyl fluorenyl group, a methyl group, an ethyl group, and 2 - hydroxyethyl, 2-aminoethyl, 2-fluoroethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2 , 3-diaminopropyl, 1-carboxymethyl, 2-carboxyethyl, 2-amino-1,2-di-oxyethyl, 2-amino-2-carboxyethyl, 2- Carboxy-1-oxoethyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl) Aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl , dimethylaminomethylsulfonyl, aminosulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, and N-(ethinyl) Aminosulfonyl group or the like is particularly preferably a hydrogen atom and a methyl group. When Y5 is an oxidizable sulfur atom, specifically -S-, -S(O)-, -s(o2)-, and the like can be exemplified. Here, as a preferable example of L2, -CH2-CH2-, -CH2-CH=CH-, -CH2-C(=0)-NH-, -CH2CH2-S- > -NH-CH2 - '-CH2-CH(-OCOCH3)-, -CH2-CH(-OH)-, -CH2-C( = 〇).,.C( = 〇)-CH = CH-, -CH2-CH= ' And, -CH2CH2-0- and so on. Q2 is a heterocyclic ring structure of a condensed two-ring type "6-membered ring/6-membered ring" or a "6-membered ring/5-membered ring" represented by the following formula (III), or a single ring having an atomic number of 5-7. The structure is preferably a heterocyclic structure of a condensed two-ring type "6-membered ring/6-membered ring" or "6-membered ring/membered ring". -112- (III) 200946528

Z, z, z, z15, Z16 and Z17 are each independently a nitrogen atom or a carbon atom which may be substituted as described above. a substitutable hydrogen atom or a halogen atom on the carbon atom, which can be taken

I

a lower-grade aristocracy 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, a n-propyl group, a n-butyl group, a n-pentyl group, an isopropyl group, an isobutyl group, a second butyl group, and a 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-fluoroethyl Base, 2,2,2-trifluoroethyl, 1,1_-aeroethyl, 1,2 - _ethyl, 1-amino-2-ethyl, 2-amino 1-hydroxy 1, '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, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy , isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethoxy, 2-methoxyB Base, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 2,2,2-three Fluoroethoxy, carboxymethyloxy, and 2-aminoethoxy. -113- 200946528 Preferred examples are a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a methylol group, a methoxymethyl group, a 2-hydroxyethyl group, an aminomethyl group, a methylaminomethyl group, and a methyl group. Aminomethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl '1-amino 2-hydroxyethyl, 2•amino-1-hydroxyethyl, 1,2-diaminoethyl, 1-carboxymethyl, 丨-carboxy-丨-hydroxymethyl, 2-fluorenylethyl, 2 - Residue-1-ethyl, 2-resin-2-diaethyl, 2-mercapto-1,2-dihydroxyethyl, 2-amino-1,2-di- oxyethyl , amino-bucarboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-yloxyethyl, methoxy, 2-hydroxyl Ethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, carboxymethyloxy, and 2-aminoethoxy. More preferred are hydrogen atom, fluorine atom, chlorine atom, methyl group, aminomethyl group, methylaminomethyl group, dimethylaminomethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 1,2-dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-diaminoethyl, 2·amino-1,2- Bilateral oxyethyl, 2-carboxy-1-oxoethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and 2-aminoethoxy, etc. Preferred are hydrogen atoms, methyl groups and methoxy groups. 〇Z11, Z14, Z18 and Z2G each independently represent a nitrogen atom, an oxygen atom or an oxidizable sulfur atom which may be substituted as described above, and may form a double bond with the adjacent Z12, Z13 or Z19, preferably Z11 and an oxygen atom or a sulfur atom, Z14 and Z2G may be a substituted nitrogen atom or an oxygen atom. Substitutable hydrogen atoms on the nitrogen atom, lower subgroups which may be substituted, protected hydroxyl groups, and lower alkoxy groups which may be substituted. Specific examples thereof include a hydrogen atom, a methyl group, an ethyl group, a n-propyl group, a n-butyl group-114-200946528, a n-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-methoxyethyl, 1-methoxyethyl, aminomethyl, methylaminomethyl, dimethyl Aminomethyl, 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, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2,3-diaminopropyl, 1- Carboxymethyl, 1-carboxy-O 1-hydroxymethyl, 2-carboxyethyl, 2·carboxy-1-hydroxyethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-di Hydroxyethyl, 2-amino-1,2-di-oxyethyl, 1-amino-1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxylate Ethyl, 2-carboxy-1-oxoethyl, hydroxy, aminocarbonyloxy, methoxymethyloxy, benzyloxymethyloxy, Hydropyranyloxy, trimethyldecyloxy, triethylsulfanyloxy, tert-butyldimethylsilyloxy, tert-butyldiphenylphosphinoalkyloxy, ethoxylated , trifluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, p-methoxybenzyloxy, p-nitrosobenzyloxy, diphenylmethyloxy, Trityloxy, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxy Oxyl, 2-methoxyethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 1-fluoroethoxy, 1,1-difluoro Oxy, 2,2,2-trifluoroethoxy, carboxymethyloxy, 2-aminoethoxy, and the like. Preferred examples thereof include 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-trifluoroethyl group, and a 2,3-dihydroxy group. Propyl, 2-amino--115- 200946528 3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2,3-diaminopropyl, 1-carboxymethyl, 2-carboxyethyl , 2-carboxy-2-hydroxyethyl, 2-amino-1,2-dioxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-yloxyethyl, Hydroxy, methoxymethyloxy, methoxy, 2-hydroxyethoxy, 2-methoxyethoxy, carboxymethyloxy, and 2-aminoethoxy. More preferably, 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 - di-oxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, hydroxy, methoxy, 2-hydroxyethoxy, carboxymethyloxy, And 2-aminoethoxy group, etc., particularly preferably a hydrogen atom. When Z11, Z14, Z18 and Z2e are sulfur atoms which can be oxidized, specifically -s-, -s(o)-, -s(o2)- and the like can be exemplified. Z12, Z13 and Z19 each independently represent a carbon atom which may be substituted, a nitrogen atom which may be substituted, an oxygen atom, or a sulfur atom which may be oxidized as described above, and may form a double bond with an adjacent atom, preferably. It is a carbon atom which can be substituted. The base atom which may be substituted 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 n-propyl group, a n-butyl group, a n-pentyl group, an isopropyl group, an isobutyl group, and a second butyl group. Third butyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxyethyl, aminomethyl, methyl Aminomethyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoro B-116- 200946528, 2,2,2-trifluoroethyl, u-difluoroethyl, it dihydroxyethyl, -2-hydroxyethyl, 2-amino-1-hydroxyethyl, I,diaminoethyl, 1-yl, carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, -2-hydroxyethyl, 2-carboxyl - i,2-dihydroxyethyl, 2-amino-1,2-diethyl, 1-amino-1-carboxymethyl, 1-amino-2-carboxyethyl, 2-amino - ethyl, 2-carboxy-1. pendant oxyethyl and pendant oxy. Preferred examples are a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a methyloloxymethyl group, a 2-hydroxyethyl group, a 2-methoxyethyl group, an aminomethyl group, an amine methyl group, and a second group. Methylaminomethyl, 2-aminoethyl, fluoromethyl, methyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, l,l-diyl, 1,2 - _•ethyl, 1-amino-2-ethyl, 2-amino-1-diethyl 1,2-diaminoethyl, 1-carboxymethyl, 2-amino -1,2-di-oxyethyl 2-carboxy-1-oxoethyl and pendant oxy groups. More preferred are hydrogen atom, fluorine atom, methyl group, methylol group, amine group, methylaminomethyl group, dimethylaminomethyl group, fluoromethyl group, difluoromethyltrifluoromethyl group, 1, 2-Dihydroxyethyl, 1-amino-2-hydroxyethyl, 2-amino-indenyl, 1,2-diaminoethyl, 2-amino-1,2-dioxy The ethyl group, the -1-yloxyethyl group and the pendant oxy group are particularly preferably a hydrogen atom, a pendant oxy atom and a methyl group. The substitutable hydrogen atom on the nitrogen atom, a lower 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, a n-propyl group, a benzyl group, an n-pentyl group, an isopropyl group, an isobutyl group, a second butyl group, a third butylmethyl group, and a methoxymethyl group. - hydroxyethyl, 2-hydroxyethyl, 2-methoxy 1-amine carboxymethyl 2-carboxyoxy 2-carboxy, methyl difluorofluoroethyl, benzyl, methyl, .1-hydroxy 2- Carboxy, fluoroalkane, n-butyl, hydroxyethyl-117- 200946528

, 1-methoxyethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, 2,3-dihydroxypropane Base, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 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-hydroxyl Ethyl, 2-carboxy-2-hydroxyethyl, 2-carboxy-1,2-dihydroxyethyl, 2-amino-1,2-di-oxyethyl, 1-amino-1-carboxylate Methyl, 1-amino-2-carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, hydroxy, aminocarbonyloxy, methoxymethyl Oxy, benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecyloxy, triethylsulfanyloxy, tert-butyldimethylsilyloxy, tert-butyl Diphenyldecyloxy, ethoxycarbonyl, trifluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy , p-methoxybenzyloxy, p-nitrobenzyloxy, benzhydryloxy, trityloxy, methoxy, ethoxy, n-propoxy, n-butoxy, positive Pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethoxy, 2-methoxyethoxy, fluoromethoxy, difluoromethoxy, trifluoromethyl Oxyl, 2-fluoroethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 2,2,2-trifluoroethoxy, carboxymethyloxy, 2-amino B Oxyl and the like. Preferred examples are hydrogen atom, methyl group, ethyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 2-aminoethyl group, 2,3-dihydroxypropyl group, 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-amine-118- 200946528 yl-1,2-di- oxyethyl, 2-amino-2-carboxyethyl, 2-carboxy- 1-sided oxyethyl, hydroxy, methoxy, ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, carboxymethyloxy, 2-aminoethoxy, and the like. More preferred examples are 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 group-2. -hydroxypropyl, 2,3-diaminopropyl '2-fluoroethyl, 2-amino-1,2-di-oxyethyl, 2-carboxy-1-yloxyethyl, hydroxy , methoxy, 2-hydroxyethoxy, 2-aminoethoxy, and the like. Ο When Ζ12, Ζ13 and Ζ19 are oxidizable sulfur atoms, specifically, -S-, -S(O)-, -S(〇2)- and the like can be exemplified. Z21, Z22, Z23, Z24, B25, χ26% χ27, χ28, χ29, ζ30, Ζ3 1 , Ζ32, Ζ3 3, Ζ34, Ζ35, ζ36, Ζ37 and ζ38 are each independently represent a substitutable A carbon atom, a nitrogen atom which may be substituted, an oxygen atom, or an oxidizable sulfur atom may also form a double bond with an adjacent atom. Substitutable hydrogen atom on the carbon 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 hydroxyl group which may be protected, 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 substitutable hydroxyimino group. 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, a n-propyl group, a n-butyl group, and a n-pentyl group. Base, isopropyl, isobutyl, t-butyl, t-butyl, hydroxymethyl, methoxymethyl, 1-ethyl, 2-ethyl, 2-methoxyethyl, 1-methoxyethyl, aminomethyl, methylaminomethyl-119- 200946528, 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-dioxy Ethylethyl, 1-amino-1-indenylmethyl, 1-amino-2-indoleethyl, 2-amino-2-residylethyl, 2-indolyl-1_yloxyethyl, sub Methyl, fluoromethylene, difluoromethylene, vinyl, 1-fluorovinyl, 2- Vinyl, 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, Hydroxy, methoxymethyloxy, benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecyloxy, triethylsulfanyloxy, tert-butyldimethylalkyl Oxy, tert-butyldiphenylphosphonyloxy, ethoxycarbonyl, trifluoroethyloxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, p-methoxy Benzyloxy, p-nitrobenzyloxy, benzhydryloxy, trityloxy, aminocarbonyloxy, methoxy, ethoxy, n-propoxy, n-butoxy, positive Pentyloxy, isopropoxy, isobutoxy, tert-butoxy, 2-hydroxyethoxy, 2-methoxyethoxy, fluoromethoxy, difluoromethoxy, trifluoromethyl Oxyl, 2-fluoroethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 2,2,2-trifluoroethoxy, carboxymethyl Oxyl, 2-aminoethoxy, amino, decylamino, ethionylamino, trifluoroethenylamino, trichloroacetamidoamine, trimethylethenylamine , benzhydrylamino, benzene-120-200946528 formamylamino, tritylamino, allylamino, benzylamino, p-methoxybenzylamino, methoxycarbonyl Amine, benzyloxycarbonylamino, (9-fluorenyl) methoxycarbonylamino, allyloxycarbonylamino, methanesulfonylamino, p-toluenesulfonylamino, benzylideneamine, Diphenylmethyleneamino, diphenylphosphoniumamino, tert-butylsulfinylamino, trimethyldecylamino, 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, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group, (9-fluorenyl)methoxycarbonyl group, allyl group Oxycarbonyl, benzyloxycarbonyl, diphenylmethyloxycarbonyl, tri Methyloxycarbonyl, trimethyldecyloxycarbonyl, tert-butyldimethylbenzyloxycarbonyl, (methoxycarbonyloxy)methyloxycarbonyl, 1-(methoxycarbonyloxy) Ethyloxycarbonyl, (t-butoxycarbonyloxy)methyloxycarbonyl, 1-(t-butoxycarbonyloxy)ethoxycarbonyl, (cyclohexyloxycarbonyloxy)methyloxy Carbocarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl Aminocarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methylsulfonate) Aminocarbonyl, pendant oxy, 1,3-dioxoalkyl-2-yl, 1,3-dioxan-2-yl, 1,1-dimethoxy, 1,1-di Oxyl, 1,3-dithiazolidine-2yl, 1,3-dithiaalkyl-2-yl, 1,1-dimethylthio, 1,1-diethylthio, 1, 3-oxathiolan-2-yl, 1,3-oxathian-2-yl, hydroxyimino, 0.methylhydroxyimino, 0-(fluoromethyl)hydroxyimino] 0 -(difluoromethyl)hydroxyimino, 〇-( Trifluoromethyl)hydroxyimino, 〇-(carboxymethyl)-121- 200946528 Hydroxyimino, fluorene-(difluorocarboxymethyl)hydroxyimino, 〇-(2-carboxyisopropyl) Hydroxyimino group and the like. Preferred examples of the substitutable group on the carbon atom may be a hydrogen atom, a fluorine atom, a cyano group, a methyl group, an ethyl group, a methylol group, a methoxymethyl group, a 2-hydroxyethyl group or a 2-methoxy group. Ethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-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-dioxyethyl, 1-amino-1-carboxymethyl, 1-amino-2- Carboxyethyl, 2-amino-2-carboxyethyl, 2-carboxy-1-oxoethyl, methylene, fluoromethylene, difluoromethylene, 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, hydroxy, aminocarbonyloxy, methoxy, ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy , fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 1,1-difluoroethoxy, 2,2,2-trifluoroethoxy, carboxymethyl Oxyl, 2-aminoethoxy, amino, decylamino, ethylamino, methoxycarbonylamino, methanesulfonylamino, methylamino, dimethylamino, Ethylamino, isopropylamino, 2-hydroxyethylamino, 2-methoxyethylamino, 2-fluoroethylamino, aminocarbonylamino, aminosulfonylamino Carboxy, methoxycarbonyl, ethoxycarbonyl, amine-122- 200946528 carbonyl, hydrazine methylaminocarbonyl, N,N-dimethylaminocarbonyl, n-(2-hydroxyethyl)aminocarbonyl , N-(2-methoxyethyl)aminocarbonyl, N-(2-fluoroethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methylsulfonyl)amine Carbonyl, pendant oxy, 1,3-dioxoalkyl-2-yl, 1,3-dioxan-2-yl, 1,1-dimethoxy, hydroxyimino, 0-methylhydroxy Imino group, 〇_(fluorine Hydroxyimino-p-(difluoromethyl)hydroxyimino, fluorenyl-(trifluoromethyl)hydroxyimino, fluorenyl-(carboxymethyl)hydroxyimino, fluorene-(difluoro Carboxymethyl)hydroxyimino, fluorenyl-(2-carboxyisopropyl)hydroxyimino, and the like. Further, a more preferable example of the substitutable group on the carbon atom may be a hydrogen atom, a fluorine atom, a cyano group, a methyl group, a methylol group, a 2-hydroxyethyl group, an aminomethyl group, a methylaminomethyl group, or a second group. Methylaminomethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 12-dihydroxyethyl, 1-amino-2-hydroxyethyl , 2-amino-buhydroxyethyl, iota, 2-diaminoethyl, 2-amino-1,2-dioxyethyl, 2-carboxy-1-yloxyethyl, Methylene, fluoromethylene, difluoromethylene, hydroxy, aminocarbonyloxy, methoxy, 2-hydroxyethoxy, q-fluoromethoxy, difluoromethoxy, trifluoromethoxy Base, 2-aminoethoxy, amino, decylamino, ethylamino, methoxycarbonylamino, methanesulfonylamino, methylamino, dimethylamino, 2 - hydroxyethylamino, 2-methoxyethylamino, aminocarbonylamino 'aminosulfonylamino, carboxyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, N-methylamine Carbonyl group, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methylsulfonyl)amine Carbocarbonyl, pendant oxy, 1,3-dioxoalkyl-2-yl, 1,3-dioxan-2-yl, hydroxyimino, fluorene-methyl hydroxyimino, fluorene Methyl)hydroxyimino, 0-(carboxymethyl)hydroxyimino, etc., particularly preferred examples -123- 200946528 are nitrogen atom, gas atom, cyano 'methylene group, hydroxyl group, methoxy group, A A sulfonylamino group, a pendant oxy group, a 1,3-dioxane-2 group, a hydroxyimino group, a fluorene-methylhydroxyimino group, and the like. Substitutable hydrogen group on a nitrogen atom, lower alkyl alkane group which may be substituted, lower alkyl group which may be substituted, protected hydroxyl group, lower substituted oxycarbonyl group which may be substituted, substituted aminocarbonyl group A lower alkylsulfonyl group which may be substituted, and an aminosulfonyl group which may be substituted. Here, specific examples of the substitutable group on the nitrogen atom include a hydrogen atom, an ethenyl group, a n-propyl group, a n-butyl group, an isobutyl group, a trimethylethyl group, a hydroxyethyl group, and a group. Oxidyl, aminoethyl, methylaminoethyl, dimethylaminoethyl, fluoroacetamido, difluoroacetinyl, trifluoroethenyl, 2-fluoro- 2-methylpropenyl, 2,2-difluoropropenyl, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isopropyl, isobutyl, t-butyl, 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-fluoroethyl Base, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1,2-dihydroxyethyl, 1-amino-2.hydroxyethyl, 2-amino-1-hydroxyl Ethyl, 1,2-diaminoethyl, 1-carboxymethyl, 1-carboxy-1-hydroxymethyl, 2-carboxyethyl, 2-carboxy-1-hydroxyethyl, 2-carboxy-2 -hydroxyethyl, 2-carboxy-1,2-dihydroxy , 2-amino-1,2-di-oxyethyl, 1-amino-1-carboxymethyl, 1-amino-2-carboxyethyl '2-amino-2-carboxyethyl , 2-carboxy-1-oxoethyl, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2,3-diamine Propyl group, hydroxyl group, -124- 200946528 Ο

Methoxymethyloxy, benzyloxymethyloxy, tetrahydropyranyloxy, trimethyldecyloxy, triethylsulfanyloxy, tert-butyldimethylsilyloxy , tert-butyldiphenylphosphonyloxy, ethoxycarbonyl, trifluoroacetoxy, trichloroacetoxy, trimethylacetoxy, benzyloxy, p-methoxybenzyloxy , p-nitrobenzyloxy, benzhydryloxy, trityloxy, aminocarbonyloxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, guanidine-methyl Aminocarbonyl, hydrazine, hydrazine-dimethylaminocarbonyl, hydrazine-(2-hydroxyethyl)aminocarbonyl, fluorenyl-(2-methoxyethyl)aminocarbonyl, hydrazine-(2-fluoro Ethyl)aminocarbonyl, anthracene-(ethionyl)aminocarbonyl, anthracene-(methylsulfonyl)aminocarbonyl, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso Propylsulfonyl, 2-hydroxyethylsulfonyl, 2-methoxyethylsulfonyl, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2 -fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, amine Sulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, aminosulfonyl, fluorene-methylaminosulfonyl, anthracene, fluorenyl-dimethylamino Sulfonyl, fluorenyl-(2-hydroxyethyl)aminosulfonyl, fluorenyl-(2-methoxyethyl)aminosulfonyl, fluorenyl-(2-fluoroethyl)aminosulfonyl And Ν-(ethinyl)aminosulfonyl group and the like. Preferred examples of the substitutable group on the nitrogen atom may be a hydrogen atom, an ethyl fluorenyl group, a hydroxyethyl fluorenyl group, a methoxyethyl fluorenyl group, an aminoethyl fluorenyl group, a methylaminoethyl fluorenyl group, or a dimethyl group. Aminoethylene, fluoroethyl, methyl, ethyl, n-propyl, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-fluoroethyl, 2, 2,2-Trifluoroethyl, 1-carboxymethyl, 2-carboxy-2-hydroxyethyl, 2-amino-1,2-di-oxyethyl, 2-amino-2-carboxyl Base, 2-carboxy-1-sidedoxyethyl-125- 200946528 base, 2,3-dihydroxypropyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2 , 3-diaminopropyl, hydroxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N- (2-hydroxyethyl)aminocarbonyl, N-(ethionyl)aminocarbonyl, N-(methylsulfonyl)aminocarbonyl, methylsulfonyl, 2-hydroxyethylsulfonyl, fluorine Methylsulfonyl, 2-fluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, aminosulfonyl, N-methylaminosulfonyl, N , N-dimethylaminosulfonyl, N-(2-hydroxyethyl)aminosulfonyl, and N-(ethinyl)aminosulfonyl. More preferred examples of the substitutable group on the nitrogen atom may be a hydrogen atom, an ethyl hydrazino group, a hydroxyethyl fluorenyl group, an aminoethyl fluorenyl group, a methylaminoethyl fluorenyl group, a dimethylaminoethyl fluorenyl group, or a fluorine group. Ethyl, methyl, ethyl, 2-hydroxyethyl, 2-aminoethyl, 2-fluoroethyl, 2-amino-1,2-di-oxyethyl, 2,3-di Hydroxypropyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2,3-diaminopropyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, N- Methylaminocarbonyl, N,N-dimethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, methylsulfonyl, 2-hydroxyethylsulfonyl, fluoromethylsulfonate Base, 2-fluoroethylsulfonyl, aminomethylsulfonyl, methylaminomethylsulfonyl, dimethylaminomethylsulfonyl, aminosulfonyl, N-methyl Aminosulfonyl group, and N,N-dimethylaminosulfonyl group and the like. When Z21, Z22, Z23, Z24, Z25, Z26, Z27, Z28, Z29, Z30, Z31, Z32, Z33, Z34, Z35, Z36, Z37 and Z38 are oxidizable sulfur atoms, specifically exemplified - S-, -s(〇)-, -s(o2)-, etc. When Z21, Z22, Z23, Z24, Z25, Z26, Z27, Z28, Z29, Z30-126-200946528, Zn, θ' θ' Z34' Z35' Z36' z37, and z38 are oxidizable sulfur atoms' Specifically, -s-, -s(0)-, -S(〇2)_, and the like can be exemplified. Specific examples of Q2 include [1,2,3]thiadiazolo[5,4_b]pyridine-6-yl, 1Η-Π比略和[2,3-b]tI ratio steep-2 - 1,2,3-di.hydro[1 4]dioxy[2,3-b]pyridin-6-yl, 2,3-dihydro[1,4]dioxy[2,3- b]pyridine-7-yl, 2,3-dihydro[1,4]dioxy[2,3-c]pyridin-7-yl, 2,3-dihydrobenzo[1,4]dioxime Plough-6-yl, 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][l,4]indole-7-yl, 2-sided oxygen-2,3- Dihydro-1H-pyrido[2,3_b][1,4] 噻 thia s-7-yl, 3,4-dihydro-2H-benzo[1,4]fluorene-6-yl' 3 - Methyl-2-oxo-2,3-dihydrobenzoxazol-6-yl, 3·sideoxy-3,4-dihydro-2H-benzo[1,4]indole-6-yl , 8-methoxy-3-oxo-oxy-3,4-dihydro-2H-benzo[1,4]indole-6-yl, 8-methyl-3-oxo- 3,4-di Hydrogen·2Η-benzo[1,4]噚哄-6-yl, 5-methyl-3-oxo-3,4-dihydro-2Η-benzo[1,4]fluorene-6-yl , 7-methyl-3-oxo-3,4-dihydro-2-indole-benzopyrene, 4]indole-6-yl, 2-methyl-3-oxo-3,4-dihydro- 2Η-benzo[1,4]曙耕-6-yl, 2-fluoro-3-oxo-3,4-dihydro-2-indole-benzo[1,4]fluorene-6-yl, 3- Lateral oxygen-3,4-dihydro-2-indole Pyridoindole [3,2-b][l,4]non-6-yl, 8-methoxy-3-oxooxy-3,4-dihydro-2-indole-pyrido[3,2-b ][l,4]曙耕-6-yl, 7-methyl-3-oxo-oxy-3,4-dihydro-2-indole-pyrido[3,2-b][l,4]曙哄-6 -yl, 7-chloro-3-oxo- 3,4-dihydro-2Η-卩 ratio steep and [3,2-1>][1,4]曙哄-6-yl, 7-fluoro-3 - side oxygen-3,4-dihydro-211-pyrido[3,2-1)][1,4]non-6-yl, 2-methyl-3-oxo-3,4-di Hydrogen-211-la-deep [3,2-b][l,4]噚耕-6-yl, 2-fluoro-3-oxo-3,4-dihydro-2-indole-pyridine[3,24 ][1,4]曙哄-6-yl, 3-oxo-3,4-monohydro-211-benzo[1,4]thiazol-6-yl, 8-methoxy-3- side Oxy-3,4-dihydro-2-indole-benzo[1,4]thia trap-6-yl, -127- 200946528 7-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] tidal-6-yl, 2-methyl-3-oxo-oxo-3,4-dihydro-2H-benzo[1,4]thia trap-6-yl, 2-fluoro-3 - side oxygen - 3,4-dihydro-2H-benzo[1,4]thracycline-6-yl, 4-oxo-4H-pyrido[l,2-a]pyrimidin-2-yl, 6 -nitro-benzo[1,3]dioxan-5-yl, 7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]indole-6-yl , 8-hydroxy-1-oxo-1,2-dihydro-isosialrin-3-yl, 8-hydroxyquinoline-2- Benzo, benzo[1,2,3]thiadiazol-5-yl, 1,3-benzothiazol-5-yl,[1,3]---[-[beta]-[beta]-b]pyridine-6- Base, 2-oxo-2,3-dihydro-1H-pyrido[3,4-b][l,4]indole-7-yl, 2-sided oxy-2,3-dihydro-1H -pyrido[3,4-b][l,4]thia trap-7-yl, 3-oxooxy-3,4-dihydro-2H-pyrido[3,2-b][l,4] Thio-6-yl, 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]salt-6-yl, 7-fluoro- 3-sided oxygen·3,4·dihydro-2Η-pyrido[3,2-b][l,4]thienyl-6-yl, 8-methoxy-3-oxo-3,4- Dihydro-2-indole-pyrido[3,2-b][l,4]thinyl-6-yl, 7-methyl-3-oxo-3,4-dihydro-2-indolyl[3, 2-b][l,4]thiat-6-yl, 2-methyl-3-oxo-3,4-dihydro-211-pyrido[3,2-15][1,4]thiazide Plow-6-yl, 2-fluoro-3-oxo-3,4-dihydro-2Η-pyrido[3,2-b][l,4]thinyl-6-yl, 6-side oxygen- 6,7-Dihydro-5Η-嗒 and [3,4-b][l,4]噚--3-yl, 6-side oxy-6,7-dihydro-5Η-嗒耕[3 ,4-b][l,4]thin-3-yl, 7-side oxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl, 7-chloro-3- Side Oxygen-3,4-dihydro-2H-pyrido[3,2-bni,4]indole-6-yl, (38)-2,3-dihydro-[1,4]dioxy [2,3-15] Arid-3-yl,[1,3]indolo[5,4-c]pyridin-6-yl,3,4-dihydro-2H-pyrano[2,3-c]pyridine-6- , 2,3-dihydro[1,4]indolo[2,3-c]pyridin-7-yl, 5-aero-2,3-carbo-1,4-benzodoxy -7-yl, 2,3-dihydro-1-benzofuranyl, 2,3* dihydro[1,4]indolo[2,3-b]pyridin-7-yl, 6,7- Dioxan, 4] sulfonium-128- 200946528 [3,2-c]indol-3-yl, 6,7-dihydro[1,4]indole thio[2,3-cry- 3-based, 6,7-dihydro[1,4]dioxy[2,3-c]indole-3-yl, 2,3-dihydro[2,3-c]pyridine-5 -yl, 5-oxo-1,2,3,5-tetrahydroindol-7-yl, 6,7-dihydro-5H-pyrano[2,3-c]indole-3- , 7-hydroxymethyl-6,7-dihydro[1,4]dioxy[2,3-c]indole-3-yl, 5,6-dihydro[2,3-c嗒 -3-yl, cycloheptyl, 2-azapaki, 2-oxopaki, 3-oxopaki, 2-thiopa, 3-thiopa, cyclohexyl, 1-hydroxycyclohexyl , 1-methylcyclohexyl, 1-methylsulfonylaminocyclohexyl, 1-cyanocyclohexyl, 2-oxocyclohexyl, 1,4-dioxaindole [4.5]癸-6- Base, 2-hydroxyiminocyclohexyl, 2-methoxyiminocyclohexyl, 3-sided oxycyclohexane , 1,4-dioxaspiro[4.5]dec-7-yl, 3-hydroxyiminocyclohexyl, 3-methoxyiminocyclohexyl, 2,2-difluorocyclohexyl, 3, 3-difluorocyclohexyl, 4,4-difluorocyclohexyl, trans-2-fluorocyclohexyl, cis-2-fluorocyclohexyl, trans-3-fluorocyclohexyl, cis-3-fluorocyclo Hexyl, trans-4-fluorocyclohexyl, cis-4-fluorocyclohexyl, 2-fluoro-1-cyclohexenyl, 2-methylenecyclohexyl, 2-methyl-1-cyclohexenyl , trans-2-methylcyclohexyl, cis-2-methylcyclohexyl, trans-3-methylcyclohexyl, cis-3-methyl

Cyclohexyl, trans-4-methylcyclohexyl, cis-4-methylcyclohexyl, trans-2-hydroxycyclohexyl, cis-2-hydroxycyclohexyl, trans-3-hydroxycyclohexyl ,cis-3-hydroxycyclohexyl, trans-4-hydroxycyclohexyl, cis-4-hydroxycyclohexyl, trans-2-methoxycyclohexyl, cis-2-methoxycyclohexyl, Trans-3-methoxycyclohexyl, cis-3-methoxycyclohexyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 1-piperidinyl, 2-sided oxy-1 - piperidinyl, 2-piperidinyl, N-methyl-2-piperidinyl, 3-oxo-2-piperidinyl, N-methyl-3-oxo-2-piperidinyl, 2 -Phenoxy-3-piperidinyl, N-methyl-2-oxo-3-piperidinyl-129- 200946528, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, cyclopentyl , 1-hydroxycyclopentyl, 1-methylcyclopentyl, 1-methylsulfonylaminocyclopentyl, 1-cyanocyclopentyl, 2-oxocyclopentyl, 1,4- Dioxaspiro[4.4]fluoren-6-yl, 2-hydroxyiminocyclopentyl, 2-methoxyiminocyclopentyl, 3-oxocyclopentyl, 1,4-dioxo Heterospiro[4.4]壬-7-yl, 3-hydroxyiminocyclopentyl, 3-methoxyiminocyclopentyl, 2,2-di Cyclopentyl, 3,3-difluorocyclopentyl, trans-2-fluorocyclopentyl, cis-2-fluorocyclopentyl, trans-3-fluorocyclopentyl, cis-3-fluoro Cyclopentyl, 2-fluoro-1-cyclopentenyl, 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-pyridinyl, 2- Pyrrolidinyl, N-methyl-2-pyridylidene, 3-oxo-2-pyrrolidinyl, N-methyl-3-oxo-2-pyrrolidinyl, 2-oxo-3- Pyrrolidinyl, N-methyl-2-oxo-3-pyrrolidinyl, 2-thienyl, 3-fluoro-2-thienyl, 4-fluoro-2-thienyl, 5-fluoro-2-thiophene , 3,4-difluoro-2-thienyl, 3,5-difluoro-2-thienyl, 4,5-difluoro-2-thienyl, 3-chloro-2-thienyl, 4-chloro 2-thienyl, 5-chloro-2-thienyl, 3,4-dichloro-2-thienyl, 3,5-dichloro-2-thienyl, 4,5-dichloro-2-thienyl , 3-chloro-4-fluoro-2-thienyl, 3- 5-5-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-difluoro Phenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-three-130- 200946528 fluorophenyl, 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-di Chlorophenyl, 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.

Preferred examples of Q2 include 2,3-dihydro[1,4]dioxy[2,3-b]pyridine-7-yl and 2,3-dihydro[1,4] Oxo[2,3-c]pyridine-7-yl, 2,3-dihydrobenzo[1,4]dioxane-6-yl, 3-oxo-oxy-3,4-dihydro-2H -Benzo[1,4]fluorene-6-yl, 3-oxo-3,4-dihydro-2H-pyrido[3,2-1?][1,4]non-6-yl , 3-oxo-3,4-dihydro-211-benzo[1,4]sain-6-yl, 2-oxo-2,3-dihydro-1H-pyrido[3,4- b][l,4]噚耕-7-yl, 2-oxo-2,3-dihydro-1H-pyrido[3,4-b][l,4]thiado-7-yl, 3 - side oxy-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiat-6-yl, cycloheptyl, 2-oxopyl, cyclohexyl, 1-hydroxyl Cyclohexyl, 1-methylcyclohexyl, 1-methylsulfonylaminocyclohexyl, 1-cyanocyclohexyl, 2-oxocyclohexyl, 1,4-dioxaspiro[4.5]indole-6 -yl, 2-hydroxyiminocyclohexyl, 2-methoxyiminocyclohexyl, 3-oxocyclohexyl, 1,4-dioxaspiro[4.5]dec-7-yl, 3- Methoxyiminocyclohexyl, 2,2-difluorocyclohexyl, 3,3-difluorocyclohexyl, trans-2-fluorocyclohexyl, cis-2-fluorocyclohexyl, trans-3- Fluorocyclohexyl, cis-3- Cyclohexyl, 2-fluoro-1-cyclohexenyl, 2-methylenecyclohexyl, 2-methyl-1-cyclohexenyl, trans-2-methylcyclohexyl, cis-2-yl Cyclohexyl, trans-3-methylcyclohexyl, cis-3-methylcyclohexyl, trans-2-hydroxy-131- 200946528 cyclohexyl, cis-2-hydroxycyclohexyl, trans-2 -Methoxycyclohexyl, cis-2-methoxycyclohexyl, trans-3-methoxycyclohexyl, cis-3-methoxycyclohexyl, 2-tetrahydropyranyl, 2- Sideoxy-1_piperidinyl, 2-piperidinyl, N-methyl-2-piperidinyl, cyclopentyl, 1-hydroxycyclopentyl, 1-methylcyclopentyl, 1-methylsulfonate Aminocyclopentyl, 1-cyanocyclopentyl, 2-oxocyclopentyl, 1,4-dioxaspiro[4.4]dec-6-yl, 2-hydroxyiminocyclopentyl , 2-methoxyiminocyclopentyl, 1,4-dioxaspiro[4.4]dec-7-yl, 2,2-difluorocyclopentyl, 3,3-difluorocyclopentyl, Trans-2-fluorocyclopentyl, cis-2-fluorocyclopentyl, trans-3-fluorocyclopentyl, cis-3-fluorocyclopentyl, 2-fluoro-1-cyclopentenyl , 2-methylenecyclopentyl, 2-methyl-1-cyclopentyl, trans-2-methylcyclopentyl, cis-2-methylcyclopentyl, 3-methylcyclopentyl, cis-3-methylcyclopentyl, trans-2-hydroxycyclopentyl, cis-2-hydroxycyclopentyl, 2-tetrahydrofuranyl, hydrazine pyrrolidine Base, 2_ side oxygen arbitrage, 2_ lysole, N-methyl-2_shame steep, 2-thienyl, 3·fluoro-2-thienyl, 4-fluoro-2-thiophene , 5_fluoro-2-thienyl, 3_nonyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2'4-difluoro Phenyl, 2,5·difluorophenyl, 2,6-diphenyl, 3,4·digas-based, gas-based, 2-chlorophenyl, 3-oxophenyl, 4-chlorobenzene Base, 2,3 "" monochloro, 2,4-chlorophenyl, 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 and the like. As a preferable example of Q2, 2,>dichloro[1,4]dioxy[2,3·-132-200946528 C]pyridine-7-yl, 2,3-dihydrobenzo[ 1,4] diterpene-6-yl, 3-oxo- 3,4-dihydro-2H-benzopyrene, 4]indole-6-yl, 3-oxo-oxy-3,4-dihydrogen · 2Η-啦陡和[3,2-b][l,4]噚耕-6-yl, 3-sided oxygen-3,4-dihydro-2Η-benzo[丨,4]thia trap-6 -3,3-oxo- 3,4-dihydro-2H-D ratio steeply [3,2-b][l,4]thiazol-6-yl, cycloheptyl, cyclohexyl, 1-hydroxyl Cyclohexyl, methylcyclohexyl, 1-methylsulfonylaminocyclohexyl, 1-cyanocyclohexyl, 2-oxocyclohexyl, l54_dioxaspiro[4·5]non-6-yl, 2 -hydroxyiminocyclohexyl, 2-methoxyiminocyclohexyl, 3-oxocyclohexyl, 1,4-dioxaspiro[4.5]indole-7-ylindole, 3-methoxy Iminocyclohexyl, 2,2-difluorocyclohexyl, 3,3-difluorocyclohexyl, trans-2-fluorocyclohexyl, cis-2-fluorocyclohexyl, trans-cyclohexyl, cis 3-fluorocyclohexyl, 2-fluoro-1-cyclohexenyl, 2-methylenecyclohexyl, 2-methyl-1-cyclohexyl, trans-2-methylcyclohexyl, cis _2_methylcyclohexyl, trans 3-methylcyclohexyl, cis-3-methylcyclohexyl, trans-2-hydroxycyclohexyl, cis-2-hydroxycyclohexyl, trans-2-methoxycyclohexyl, cis- 2-methoxycyclohexyl, trans-3-methoxycyclohexyl, cis_3_methoxycyclohexyl, 2-tetrahydropyridylpyranyl, 2-oxo-oxy-1-peptidyl, ring Pentyl^, 1-hydroxycyclopentyl, 1-methylcyclopentyl, 1-methylsulfonylaminocyclopentyl, 1-cyanocyclopentyl, 2-oxocyclopentyl, 1, 4-dioxaspiro[4.4]non-6-yl, 2-hydroxyiminocyclopentyl, 2-methoxyiminocyclopentyl, 2,2-difluorocyclopentyl, trans- 2-fluorocyclopentyl, cis-2-fluorocyclopentyl, 2-fluoro-1-cyclopentenyl, 2-methylenecyclopentyl, 2-methyl-1-cyclopentenyl, counter 2-methylcyclopentyl, cis-2-methylcyclopentyl, trans-2-hydroxycyclopentyl, cis-2-hydroxycyclopentyl, 2-tetrahydrofuranyl, 2-thienyl , 3-fluoro-2-thienyl, 4-fluoro-2-thienyl, 5-fluoro-2-thienyl, 3-thienyl, 2-fluorobenzene-133- 200946528, 3-fluorophenyl, 4 -fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl And 3,4-difluorophenyl, 3,5-difluorophenyl, 2,5-dichlorophenyl, and 2-chloro-5-fluorophenyl. As a particularly preferable example of Q2, it can be mentioned that side oxygen_3,4_-hydrogen-2H-D]iD is combined with [3,2-bHl,4]non-6-yl, cyclopentyl, cyclohexyl, 1-hydroxycyclohexyl, 1-methanesulfonylaminocyclohexyl, 丨-cyanocyclohexyl, 2-oxoxycyclohexyl, 1,4-dioxaspiro[4.5]癸-6-yl, 2 -hydroxyiminocyclohexyl, 2-methoxyiminocyclohexyl, 3-formoxycyclohexyl, anthracene, 4-dioxaspiro[4·5]non-7-yl, 2,2- Difluorocyclohexyl, 2-fluoro-1-cyclohexenyl, 2-methylenecyclohexyl, trans-2-ylcyclohexyl, cis-2-ylcyclohexyl, trans-2-methyl Oxycyclohexyl, cis-2-methoxycyclohexyl, 2-tetrahydropyranyl, 2-oxo-1-piperidinyl, cyclopentyl, 2-oxocyclopentyl, 2_ Thienyl, 3-fluorophenyl, and 2,5-difluorophenyl. Here, preferred examples of the compound represented by the formula (1) include {2-[1-(2-cyclohexylethyl)piperidinyl]ethyl}ethyl}_9-methoxy - 2,3_Dihydro-1H-[1,4]indolo[2,3-c]quinoline, 1-{2-[1-(2-cyclohexylethyl) vendor steep _ 4-yl Ethyl}-9-methoxybenzo[h]-l,6-naphthyridin-2(1H)-one, (2-cyclohexylethyl)piperidine-4-yl]ethyl b-9_ Methoxy-2,3·dihydrobenzo[h]-l,6-naphthyridin-4(1H)-one, 1-{2-[1-(2-cyclohexylethyl)piperidine-4 -yl]ethyl b-9-methoxy-2,3-dihydrobenzo[h]-l,6-naphthyridin-4(1H)-one oxime, {2-[l-(2-cyclohexyl) Ethyl)piperidin-4-yl]ethyl}-3-hydroxy-9-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione, 1-{2- [1-(2-cyclohexylethyl) acridin-4-yl]ethyl}-9-methoxy-4-oxo-1,4-dihydrobenzo[h]-l,6-naphthalene Pyridine-3-carboxylic acid, 1-(2-{1-[2-(1,4-dioxaspiro[4.5]fluoren-6-yl)ethyl;]pipe-134- 200946528 pyridine-4-yl }Ethyl)-9-methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinoline, 2-(2-{4-[2-( 9-Methoxy 2,3-dihydro-1H-[1,4]indole and [2,3-c]quinolin-1-yl)ethyl]piperidine-l-yl}ethyl) Cyclohexanone, 9-A丨_丨_(2_ {1-[2-(2·Sideoxycyclohexyl)ethyl]piperidine _4_yl oxime ethyl)·1Η_ [1,4]0§哄[2,3- <:] Quinoline-2(311)-one, 2-(2-{4-[2-(9-methoxy-2.3-dihydro-111-[1,4]噚[[, 34]quinolin-1-yl)ethyl]piperidine-1_yl}ethyl)cyclopentanone, 1-{2-[1-(2-cyclopentylethyl)piperidin-4-yl] Ethyl}-9-methoxy-2,3-dihydro-1 Η - [ 1,4 ] 噚 and [2,3 - c ] quinine, 1 - { 2 - [ 1 - (2- ^ Cycloheptylethyl)piperidin-4-yl]ethyl}-9-methoxy-2,3-dihydro-1Η-[1,4]indole and [2,3-c]quinoline, 1-{2-[1-(2-Cyclohexylideneethyl)piperidin-4-yl]ethyl}-9-methoxy-2,3-dihydro-1H-[1,4]fluorene And [2,3-c]quinoline, 1-(2-{1-[2-(2,2-difluorocyclohexyl)ethyl]piperidin-4-yl}ethyl)-9-methoxy Benzyl-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinoline, 9-methoxy-1-(2-{1-[2-(tetrahydro-) 2H-pyran-2-yl)ethyl]piperidin-4-yl}ethyl)-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline, N-[l-(2-{4-[2-(9-methoxy-2.3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl) Ethyl] piperidine-l-yl} oxime ethyl)cyclohexyl]methanesulfonamide, 1- (2-{4-[2-(9-Methoxy-2,3-dihydro-111-[1,4]indole[2,3-£:]quinolin-1-yl)ethyl) Piperidin-1-yl}ethyl)cyclohexanecarbonitrile, 1-{2-[1-(2-cyclohexylethyl)piperidin-4-yl]ethyl}-8-methoxy-2.3 - Dihydro-1H-pyrrolo[3,2-c]quinoline, 1-{2-[1-(2-cyclohexylethyl)piperidin-4-yl]ethyl}-9-methoxy -2,3-dihydro-1H-[1,4]indole and [2,3-c]quinoline-3-carboxylic acid methyl ester, 1-(2-{1-[(2Ε)-3- (2,5-difluorophenyl)-2-propan-1-yl]indole-4-yl}ethyl)-9-methoxy·2,3-diaza-1H-[1,4 ]噚哄[2,3-c]quinoline, 1-{2-[1-(2-cyclohexylethyl)piperidin-4-yl]ethyl b-135- 200946528 9-methoxy- 7-Methyl-2,3-dihydro-1 Η - [ 1,4 ] Df Cultivated [2,3 - c ]quinoline, 1-{2-[l-(2-cyclohexylethyl)per Pyridin-4-yl]ethyl b-9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]-l,5-chattle, (2Ε) -3-(1-{2-[1-(2-cyclohexylethyl)piperidin-4-yl]ethyl}-9-methoxy-2,3-dihydro-1H-[1,4噚[[,3-〇]Salanta-7-yl)acrylic acid, 6-[({1-[2-(9-methoxy-2,3-dihydro- IH-[1,4]噚 并 and [2,3-c]quinolin-1-yl)ethyl]piperidine _4-yl} Methyl]-2H-pyrido[3,2-b][l,4]indole-3(4H)-one, 1-cyclohexyl-2-{4-[2-(9-A) Oxy-2,3-dihydro-1Η·[1,4]indole[2,3-c]quinolin-1-yl)ethyl]piperidin-1-yl}ethyl ester, 1- Cyclohexyl-2-{4-[2-(9-methoxy-2,3-dihydro-lH-[l,4]Df哄[2,3-c]salin-1-yl)B Benzyl pi-1-yl}ethanol, 1-cyclohexyl-2-{4-[2-(9-methoxy-2,3-dihydro-1H-[1,4] fluorene and 2,3-c]quinolin-1-yl)ethyl]piperidin-1-yl}ethanone, 9-methoxy-1-(2-{1-[2-(2-methylene ring) Hexyl)ethyl]piperidine-4-yl}ethyl)-2,3-dihydro-1H-[1,4]indolo[2,3-c]quinoline, 1-(2-{1 -[2-(2-Fluorocyclohex-1-en-1-yl)ethyl]piperidin-4-yl}ethyl)-9-methoxy- 2,3-dihydro-1H-[1 , 4] 噚耕和[2,3-c]quinoline, N-(3-fluorophenyl)-2-{4-[2-(9-methoxy- 2,3-dihydro-1H- [1,4]噚 and [2,3-c] sialolin-1-yl)ethyl]piperidin-1-yl}acetamide, N-(2,5-difluorophenyl)-2 -{4-[2-(9-Methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl)ethyl]piperidine -丨-yl}acetamide, 1-{2-[1-(2-cyclohexylethyl)-3-methoxypiperidin-4-yl]ethyl}-9- Benzyl-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinoline, 2-(2-{3-methoxy-4-[2-(9-A) Oxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinolin-1-yl)ethyl]piperidine-l-yl}ethyl)cyclohexanone , (2RS, 4RS)-l-(2-cyclohexylethyl)-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]曙[[, 3-c]quinoline--136- 200946528 1-yl)ethyl]piperazine-2-residual acid, {(RS)-l-(2-cyclohexylethyl)_4-[2-(9-A) Oxy-2,3-monohydro-1H-[1,4]indolo[2,3-c]quinoline·indoleyl)ethyl]piperidin-2-yl}methanol, 2-(2 -{(RS)-2-hydroxymethyl-4-[2-(9-methoxy-2,3-dihydro-lH-[l,4]Df-trap[2,3-c]quinoline -1-yl)ethyl]piperazin-1_yl}ethyl)cyclohexanone, {(2SR,4RS)-l-(2-cyclohexylethyl)-4-[2-(9-methoxy -2.3-Dihydro-1H-[1,4]indole and [2,3-c]quinolin-1-yl)ethyl]piperidine_2-yl} Methanol, 1-{2-[1 -(2-cyclohexylethyl)piperidin-4-yl]ethyl b-9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c] Quinoline, 1-(2-cyclohexylethyl U )-4-[1-yl-2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[ 2,3-c] sialolin-1-yl)ethyl]indole-4-ol, (E)-3-(2,5-di Phenyl)-i-{4-[2-(9-methoxy- 2,3-dihydro-1H-[1,4]indolo[2,3-c] sialolin-1-yl) Ethyl] piperidine-l-yl}acetone, {(3SR,4RS)-l-(2-cyclohexylethyl)-4-[2-(9-methoxy- 2,3-dihydro-1H -[1,4] 噚耕和[2,3-c]quinolin-1-yl)ethyl]piperidin-3-yl}methanol, (3SR, 4RS)-l-(2-cyclohexylethyl -4-[2-(9-methoxy-2.3-dihydro-111-[1,4]indole and [2,3-(:]quinolin-1-yl)ethyl]piperidine- 3-carboxyacid, (3RS, 4RS)-l-(2-cyclohexylethyl)-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole Plowing [2,3-c] sialolin-1-yl)ethyl]piperidine-3-carboxylic acid, (3311,4118)-1-[2-(2-fluorocyclohex-1-ene-1 -yl)ethyl]-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl) Ethyl]piperidine-3-carboxylic acid, (3SR, 4RS)-l-(2-cyclohexylethyl)-4-[2-(9-methoxy-2,3-dihydro-1Η-[ 1,4]Π§[2,3-c]quinolin-1-yl)ethyl]piperidine-3-carboxamide, (3SR,4RS)-l-(2-cyclohexylethyl) -4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-<:]quinolin-1-yl)ethyl]- :^-(methylsulfonyl)piperidin-3-indoleamine, (3SR, 4RS)-l-(2- Cyclohexylethyl)-N-methoxy-4-[2-(9-methyl-137- 200946528 oxy-2,3-dihydro-1H-[1,4] fluorene and [2,3- c]quinolin-1-yl)ethyl]piperidine-3-indolyl, 1-(2-{1_[trans-3-(2,5-difluorophenyl)propane-2-ene-1 -yl]piperidin-4-yl}ethyl)-9-methoxy-4-oxo-1,4-dihydrobenzo[h]-l,6-naphthyridin-3-carboxylic acid, and ,9-methoxy-1-(2-{1-[2-(2-thienylthio)ethyl]piperidin-4-yl}ethyl)-2,3-dihydro-1H-[1 4] 噚耕和[2,3-c]quinoline and the like. A more preferable example of the compound represented by the formula (I) is 1 - { 2 - [ 1 -(2-cyclohexylideneethyl)piperidin-4-yl]ethyl}-9-methoxy Benzyl-2,3-dihydro-111-[1,4]indole and [2,3-c] porphyrin, (2Ε)-3-(1-{2-[1-(2-cyclohexyl) Piperidin-4-yl]ethyl}-9-methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinolin-7-yl) Acrylic acid, 1-(2-{1-[2-(2-fluorocyclohex-1-en-1-yl)ethyl]piperidin-4-yl}ethyl)-9-methoxy-2, 3-Dihydro-1H-[1,4]indole and [2,3-c]quinoline, 1-{2-[1-(2-cyclohexylethyl)piperidin-4-yl]B }}-9-methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c] porphyrin, {(3SR,4RS)-l-(2-cyclohexyl Ethyl)-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl)ethyl] Piperidin-3-yl}methanol, (3SR, 4RS)-l-(2-cyclohexylethyl)-4-[2-(9-methoxy-2,3-dihydro-lH-[l, 4] Bf and [2,3-c]quinolin-1-yl)ethyl]piperidine-3-carboxylic acid, (3SR, 4RS)-l-(2-cyclohexylethyl)-4-[ 2-(9-Methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinolin-1-yl)ethyl]piperidine-3-carboxyindole Amine, and 9-methoxy-1-(2-{1-[2-(2-thiophene) Yl) ethyl] piperidin-4-yl} ethyl) -2,3-dihydro -1H- [1,4] and eosin coax [2,3-c] quinoline and the like. Next, the method for producing the compound of the present invention will be described. The compound of the present invention represented by the formula (I) (hereinafter referred to as the compound (1), and the compound of the other formulae are also abbreviated as the same) can be produced by various methods - 138 - 200946528 Compound (1) can be produced by Scheme 1. For example, when A and N are used, the compound (1) can be produced from a compound of the formula (2).

〇 Scheme 1 Here, the LG1 system in the formula (3 a) is followed by a substitution on the reactive atom in the L1 structure bonded to the A1 group, and may remain in the compound of the formula (4) after the reaction. It may not remain. Further, when the reactivity of the reactive atom is sufficiently high, the LG1 system may not be present. Examples of LG1 include chlorine, bromine, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. The PG1 in the general formulae (3a), (3b), and (4) is a substituted protecting group on the reactive atom in the Q1 structure bonded to L2, and the reactivity of the reactive atom is in the production formula. When the compound of (4) is not affected, the protecting group may not be present. The methylene chain in the L11-based L1 structure in the formula (3b) has a short structure of only one part. The formula (3b) is not only the acid shown, but also a carbonyl compound (3c) such as a ketone. -139- 200946528

The LG2 in the formula (6a) may be substituted with a substituent on the reactive atom in the L2 structure bonded to Q1, and may remain in the compound of the formula (I) after the reaction, or may not remain. Further, when the reactivity of the reactive atom is sufficiently high, the LG2 system may not be present. As an example of LG2, chlorine, bromine, and iodine are mentioned.

The methylene chain in the L21 -based L2 structure in the formula (6b) has a short structure of only one part. The formula (6b) is not only the aldehyde shown, but also a carbonyl compound (6c) such as a ketone.

〇 In order to produce a compound of the formula (4), for example, an amine derivative of the formula (2) can be reacted with a compound of the formula (3a) in the presence of a base and an intended iodide. This reaction can be described by Advanced Organic Chemistry, 5th edition (by Michael B. Smith and Jerry March), pages 499 to 500, pages 513 to 515, 2001, John Wiley & Sons, Inc. The method or method according to it is carried out. -140-200946528 The solvent used in the reaction may be any solvent, and examples thereof include alcohols such as methanol, ethanol, 2-propanol and n-butylglycol-2-propanol. , chloroform and i, 2_dichlorohalogen hydrocarbons, aromatic hydrocarbons such as benzene, toluene and xylene, ketones such as butanone and tbutyl butyl ketone, diethyl ether, di- or tert-butylmethyl Ethers such as ether, dioxane, tetrahydrofuran, anisole ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and ethylene diether, hydrazine, etc. And esters such as butyl ketone, guanidine, dimethyl hydrazine, phthalamide such as N,N-dimethyl 1-methyl-2-pyrrolidone, water, etc. . The base to be used in the reaction may, for example, be triethylaminoethylamine, imidazole, pyridine, dimethylaminopyridine or hexa-1,5-diazabicyclo[4.3.0]non-5-ene. 1,8-diazabicyclo-7-ene, 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine butylimido-2- Monoethylamino-1,3-methyl-all-gas-1,3,2-. hydrazine, lithium diisopropyl decylamine, n-butyl lithium, hexamethyldifluoride lithium dinitrate And an organic base such as hexamethyldiazine potassium nitride, an inorganic base such as sodium carbonate, potassium carbonate, carbonic acid, potassium phosphate, potassium hydroxide, sodium hydride or potassium hydride. Further, examples of the iodide to be used include potassium iodide and lithium iodide. In addition, the relevant mobile catalyst may be coexisted as needed, and the catalyst may be activated, for example, tetra-n-butylammonium chloride, triethyl chloride adversely affecting acetone, 2-acetone, etc. Ether, diphenyl alcohol, monomethylacetic acid, triethylamine, and the like, diisopropylmethyl hydrazine, [5,4, fluorene] decene, 2-third diazaphosphine, hexamethyl Sodium hydrogencarbonate, sodium iodide hydroxide, related benzyl ammonium chloride, -141-200946528 18-crown-6, and the like. The amount of the base used in the reaction may be 1 to 10 moles per mole of the compound of the formula (2), and the iodide may be 0.01 to 10 moles. The relevant mobile catalyst can be 0.01 to 10 times moles. The reaction temperature may be -100 to 25 ° C, preferably -80 to 150 ° C, and the reaction time is in the range of 1 Torr to 24 hours. Further, for example, when the general formula (3a) is an epoxide, the amine derivative of the formula (2) and the compound of the formula (3a) can be reacted as desired in the presence of a base or a Lewis acid. The compound of the formula (4) is produced. This reaction can be carried out by the method described in Advanced Organic Chemistry, 5th Edition (by Michael B. Smith and Jerry March), page 5 04, 2001, published by John Wiley & Sons, Inc., or the like. The method is carried out. Further, for example, when the general formula (3a) is a Michael acceptor, the amine derivative of the formula (2) and the compound of the formula (3a) can be present in the presence of a base or a Lewis acid as desired. The reaction is carried out to produce a compound of the formula (4). This reaction can be carried out by the method described in Advanced Organic Chemistry, 5th edition (by Michael B. Smith and Jerry March), pages 1022-1024, 2001, John Wiley & Sons, Inc., or the like. Come on. Further, for example, when the general formula (3a) is similar to a mercapto halide, a mixed acid anhydride or the like, the amine derivative of the formula (2) and the compound of the formula (3a) can be present in an alkali as desired. The reaction is carried out to produce a compound of the formula (4). Further, when the formula (3a) is a carboxylic acid or the like, the amine derivative of the formula (2) and the compound of the formula (3a) can be produced by reacting a condensing agent with a desired base in the presence of a base. -142- 200946528 A compound of the formula (4). This reaction can be based on the methods described in Advanced Organic Chemistry, 5th Edition (Michael B_ Smith and Jerry March), pp. 516-512, 2001, John Wiley & Sons, Inc., etc. The method described in the experiment (Izumi, et al.), pages 89 to 142, 1985, and the publication of Nine-Good, or the method according to the method. 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, n-butanol, and 2-methylpyridyl-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 t-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 diol monomethyl ether, sub-millings such as dimethyl hydrazine, esters such as ethyl acetate and t-butyl acetate, hydrazine, hydrazine-dimethylformamide, N, N - guanamines such as dimethylacetamide H and 1-methyl-2-pyrrolidone, water, and the like may be mixed and used. Examples of the hydrazino halide, the mixed acid anhydride, and the like include hydrazine halides such as mercapto chloride, mercapto bromide, and mercaptofluoro, and carboxylic acid and ethyl chlorocarbonate, and isobutyl chlorocarbonate in the presence of an organic base. a mixed acid anhydride obtained by reacting an ester or a trimethylethenyl group, a p-nitrophenyl ester of a carboxylic acid, N-hydroxysuccinimide, N-hydroxybenzylidene imide, and five Fluorophenyl ester, 1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole, 3,4-dihydro-3-hydroxy-4· sideoxy-1,2,3-benzene The activity of tri-trap ester, hydroxy-7-azabenzotriazole ester, etc. -143-200946528 ester, and the like. These are similar to those of a mercapto halide, a mixed acid anhydride, etc., and may be synthesized from a carboxylic acid of a precursor or the like without using separation. The base to be used in the reaction may, for example, be triethylamine, diisopropylethylamine, imidazole, pyridine, dimethylaminopyridine, hexamethylguanidine or 1,8-diazabicyclo[5. , 4,0] eleven-7-ene, 1,3,4,6,7,8-hexahydro-211-pyrimido[l,2-a]pyrimidine, 2-tert-butylimido- 2-Diethylamino-1,3-dimethyl·perhydro-1,3,2-diazaphosphine, lithium diisopropyl decylamine, n-butyl lithium, hexamethyldifluoride An organic base such as sodium hexamethyldisulfonate or potassium hexamethyldifluoride, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, carbonic acid planing, potassium phosphate, sodium hydroxide, potassium hydroxide or sodium hydride. An inorganic base such as potassium hydride or the like is used as a condensing agent used in the reaction, and examples thereof include ruthenium, osmium-dicyclohexylcarbodiimide and oxime-ethyl-Ν'-(3-dimethylamino). a carbodiimide such as carbodiimide or diisopropylcarbodiimide; a carbonyl group such as carbonyldiimidazole; a fluorenyl azide such as diphenylphosphonium azide; and diethylphosphonium Acid cyanide such as cyanide, 1-[bis(dimethylamino)methylene]-1Η-benzotriazole gun six Phosphate 3-oxide, 1-[bis(dimethylamino)methylene]-1Η-benzotriazole tetrafluoroborate 3-oxide, 1-[bis(dimethylamino) )methylene]-5-chloro-1Η-benzotriazole gun hexafluorophosphate 3_oxide, 1_[bis(dimethylamino)methylene]-5-chloro-1Η-benzotrien Oxime salt such as oxazolium tetrafluoroborate 3-oxide, 0-(7-azabenzotriazol-1-yl)-1 1,1,3,3-tetramethylurea hexafluoro Phosphate ester, tris(pyrrolidinyl) hexafluorophosphate, benzotriazol-1-yloxytris(pyrrolidinyl)phosphonium hexafluorophosphate, 2-chloro-1,3-dimethyl- 2-imidazole pyridine hexafluorophosphate, ν, ν - bis (2- oxo 3- 144 - 200946528 oxazolidinyl) phosphino chloride. The amount of the base and the condensing agent used in the reaction may be from 0. 01 to 50 moles, preferably from 1 to 5 moles, per mole of the formula (2). The reaction temperature may be -80 to 150 ° C, preferably -20 to 120 ° C, and the reaction time is completed in the range of 1 minute to 48 hours. The compound of the formula (4) can be produced by reacting an amine derivative of the formula (2) with a carbonyl compound of the formula (3b) in the presence of a reducing agent. This reaction can be carried out by WO2007/081597, WO2007/071936, or Advanced Organic Chemistry, fifth edition (by Michael Smith Smith and Jerry March), pages 1187 to 1189, 2001, John Wiley & Sons The method described in, or published by, Inc., or the method according to the method. 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, n-butanol, and 2-methyl-2-propanol. Halogen hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; diethyl hydrazine ether, diisopropyl ether, and tert-butylmethyl Ethers such as ether, dioxane, tetrahydrofuran, anisole, diphenyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and ethylene glycol monomethyl ether, dimethyl hydrazine, etc. Esters of anthraquinones, ethyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrole Examples of the guanamine such as ketone and water and the like as the reducing agent used in the reaction include hydrogenation of lithium aluminum hydride, sodium borohydride, sodium triethoxy borohydride, sodium cyanoborohydride, and the like. 145- 200946528 The wrong compound 'boron, sodium and sodium amalgam, etc. Further, contact reduction using Raney nickel, platinum oxide or palladium black, and reduction using zinc and acid may be used. The amount of the reducing agent used in this reaction may be 1 to 20 moles, preferably 1 to 5 moles per mole of the compound of the formula (2). The reaction temperature may be -50 to 200 ° C, preferably -10 to 100. (: The reaction time is completed in the range of 10 minutes to 72 hours. To produce the compound of the formula (5), for example, when the reactive atom on Q1 of the compound of the formula (4) is a nitrogen atom, PGi is a nitrogen protection The base group may be classified according to the kind of the protecting group, for example, Greene, Wuts, etc., Protective Groups in Organic Synthesis, 4th edition, pp. 696-926, 2006. The method described in the year, John Wiley & Sons, Inc. or according to the method thereof. Next, 'for the production of the compound of the formula (I), for example, when the formula (5) When the reactive atom on Q1 of the compound is a nitrogen atom, the same method as in the case of reacting the compound of the formula (2) with the compound of the formula (3a) to obtain a compound of the formula (4) The compound of the formula (5) is produced by reacting a compound of the formula (6a). Further, a compound of the formula (4) can be obtained by reacting a compound of the formula (2) with a compound of the formula (3b). The same method, the compound of the formula (5) and the formula (6b) In the above manufacturing method, among all the compounds, the compound of the compound: the substituent of the stomach, the functional group can be suitably protected by the protecting group, and can be deprotected at an appropriate stage. - 200946528 Further, the compound of the formula (I) can also be produced from the compound of the formula (2) via the scheme 2

LG1—LMa1—L-Q5 7a Η Ο 7b Scheme 2 ie, the compound of the formula (4) can be obtained by reacting a compound of the formula (2) with a compound of the formula (3a) or (3b). A method of reacting a compound of the formula (2) with a compound of the formula (7昀 or (7b). In this case, the formula (7b) is not only the aldehyde shown, but also a ketone or the like. A carbonyl compound (7c) or the like.

The compound of the formula (2) can be produced, for example, by the scheme 3. -147- 200946528

Scheme 3 Here, LG3 and LG4 in the general formulae (8), (1〇), and (11) are exfoliated, and LG4 may remain in the compound of the formula (1〇) or (2) after the reaction. Can not remain. Further, each of LG3 and LG4 may be converted to LG3 or LG4 by an appropriate precursor functional group at an appropriate stage of the following production method, and LG4 may not be present when the reactivity of the A2 atom is sufficiently high. Examples of LG3 and LG4 include chlorine, bromine, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. In the general formula (9), (10), and (11), the PG2, PG3 is an amino group protecting group or hydrogen. When the amine group is protected, for example, Greene, Wuts, and the like are mentioned. An example described in Protective Groups in Organic Synthesis, 4th edition, pp. 696-926, 2006, John Wiley & Sons, Inc. One or both of PG2 and PG3 may be hydrogen-148-200946528 as long as the reaction is not hindered. The compound of the formula (2) can be produced from the compound of the formula (8) via the compound of the formula (1). . That is, the compound of the formula (8) and the compound of the formula (9) can be obtained by the same method as the method of producing the compound of the formula (4) from the compound of the formula (2) and the compound of the formula (3a). The compound is reacted to produce a compound of the formula (10). At this time, the compound of the formula (9) can also be replaced with a metal azide. In this case, the guanamine group can be reduced to an amine after the reaction (both PG2 and PG3 in the compound of the formula (10) are Hydrogen), which is then used in the reaction. The nucleophilic substitution reaction by azide ion used in this case is carried out in the presence of a desired compound, and can be obtained by Advanced Organic Chemistry, 5th edition (by Michael B. Snith and Jerry March), pp. 515~ The method described in 516 pages, 2001, John Wiley & Sons, Inc., or the like, or the method according thereto. The solvent used for the azidation reaction may be any one which does not adversely affect the reaction, and examples thereof include alcohols such as methanol, ethanol, 2-propanol, n-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 t-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 An ether such as diol monomethyl ether, an anthracene such as dimethyl hydrazine, an ester such as ethyl acetate 't-butyl acetate, N,N-dimethylformamide, N,N - guanamines such as dimethylacetamide and 1-methyl-2-pyrrolidone, water, and the like may be used in combination. -149-200946528 The iodide used may be, for example, potassium iodide or sodium iodide as the azide ion to be used, and examples thereof include sodium azide and trimethyl sand-based azide. The amount of the iodide used in the reaction may be 0.1 to 10 moles per mole of the compound of the formula (8), and the azide ion may be 1 to 10 times the mole of the compound of the formula (8). ear. The reaction temperature may be from 〜200 ° C, preferably from 20 to 120 ° C, and the reaction time is from 5 minutes to 48 hours. Examples of the reduction of the azide compound to be produced include a hydrogenation-based reduction reagent such as contact hydrogenation of palladium carbon as a reducing agent, lithium aluminum hydride or sodium borohydride, mercaptan, triphenylphosphine, and trihydrobenzene. Hexane, polymethylhydroquinone and a catalytic amount of hexabutylstannene. The solvent to be used in the reduction reaction may be any one that does not adversely affect the reaction, and examples thereof include alcohols such as methanol, ethanol, 2-propanol, n-butanol, and 2-methyl-2-propanol. 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 methyl ether, dioxane, tetrahydrofuran, anisole, diphenyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and ethylene glycol An ether such as monomethyl ether, an anthracene such as dimethyl hydrazine, an ester such as ethyl acetate or t-butyl acetate, N,N-dimethylformamide, N,N-di Amidoxime such as methylacetamide or 1-methyl-2-pyrrolidone, water, or the like may be used in combination. The amount of the reducing agent used in this reaction may be from 1 to 150 to 200946528 to 1 〇 imomol relative to the azide compound. The reaction temperature may be 〇~200°c, preferably 〇~12 (TC, and the reaction time is completed in the range of 5 minutes to 48 hours. Next, when both PG2 and PG3 are not hydrogen, one of them is used. After deprotection or both, when one or both of PG2 and PG3 are hydrogen, the compound of the formula (10) is allowed to be in the base or iodine as desired, after deprotection of the protecting group as it is. The reaction is carried out in the presence of a compound or a catalyst, and when both PG2 and PG3 are hydrogen, the chemical complex of the compound (2) can be produced by deprotecting the amine protecting group. This reaction can be carried out by Advanced Organic. Chemistry 5th Edition (by Michael Smith Smith and Jerry March), pp. 513-515, 864-866, 2001 1 John Wiley & Sons, Inc. or Meta 1 · Cata 1 yzed C ross - C oup 1 ing R eacti ο ns Volume 2, 2nd Edition (Armin de meijere et al.), 699-760, 2004 WILEY-VCH Verlag GmbH & Co·KGaA Publishing, etc. Or according to the method thereof. As the solvent used in this reaction, as long as the reaction is not The adverse effects may be, for example, alcohols such as methanol, ethanol, 2-propanol, n-butanol, and 2-methyl-2-propanol, dichloromethane, chloroform, and 1,2-dichloro Halogen hydrocarbons such as ethane, aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone, 2-butanone and tert-butyl methyl ketone; diethyl ether, diisopropyl ether, and Ethers such as tributyl methyl ether 'dioxane, tetrahydrofuran, anisole, diphenyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and ethylene glycol monomethyl ether, dimethyl Athene of Aachen et al., esters of ethyl acetate, acetate-151-200946528 tributyl ester, etc. 'N,N-dimethylformamide, hydrazine, hydrazine-dimethylacetamide and 1 - a guanamine such as methyl-2 - succinone or the like, water, or the like may be used in combination. The base to be used in the reaction may, for example, be triethylamine or diisopropylethylamine. , imidazole, pyridine, dimethylaminopyridine, hexamethylguanidine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5,4,〇 Eleven-7-ene, 1,3,4,6,7,8-hexahydro-2Η-pyrimido[l,2-a]pyrimidine 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphine, lithium diisopropyl decylamine, n-butyl An organic base such as lithium 'hexamethyldiazine lithium nitride, hexamethyldifluoride sodium nitride or hexamethyldiazine potassium nitride, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, carbonic acid, potassium phosphate, hydrogen An inorganic base such as sodium oxide, potassium hydroxide, sodium hydride or potassium hydride, a metal alkoxide such as potassium third potassium oxylate, sodium methoxide or sodium ethoxide. Further, examples of the iodide to be used include potassium iodide, sodium iodide, and lithium iodide. As the catalyst to be used, for example, palladium acetate (II), a palladium carbon catalyst, bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), dichloride can be used. Bis(acetonitrile) (II) and others and by Metal-Catalyzed Cross-Coupling Reactions Volume 2, 2nd Edition (edited by Armin de meijere et al.), page 705, 2004, WILEY-VCH Verlag GmbH & Co. A catalyst adjusted in advance by a ligand such as KGaA, or a catalyst generated in the reaction system, or Metal-Catalyzed Cross-Coupling Reactions Volume 2, 2nd Edition (Armin de meij ere Edit), page 707, 2004, WILEY-VCH Verlag GmbH & -152- 200946528

Catalysts and the like described in the publication of Co. KGa A. Further, the related mobile catalyst may be coexisted as needed, and examples of the related mobile catalyst include tetra-n-butylammonium chloride, triethylbenzyl chloride chloride, and 18-crown-6. The amount of the base used in the reaction may be 丨~" 倍莫耳' iodide may be 〜. 〇1~10 times mole relative to the formula (1〇). The amount of palladium catalyst used is relative to Gutong. The formula (1〇) may be 0.005~1〇Mool. The related mobile catalyst may be 0.01~10 times Mo. The reaction temperature may be -100~250 °c, preferably 20~150 °c. The reaction time is completed in the range of 1 minute to 72 hours. Further, the compound of the formula (2) can also be produced from the compound of the formula (8) via the compound of the formula (11).

That is, in the intermolecular reaction, a compound of the formula (2) can be reacted with a compound of the formula (9) in the same manner as in the case of producing a compound of the formula (2) from the compound of the formula (10). a compound of formula (11). Further, at this time, the compound of the formula (9) may be replaced with a metal azide. In this case, the guanamine group may be reduced to an amine after the reaction (both PG2, PG3 in the compound of the formula (1 1)) All are hydrogen) and then used in the reaction. Next, the compound of the general formula (η), when both PG2 and PG3 are not hydrogen, deprotect one or both, or when one or both of PG2 and PG3 is hydrogen, as it is Or after the deprotection of the protecting group, the same method as in the production of the compound of the formula (4) from the compound of the formula (2) and the compound of the formula (3 a) can be introduced to the formula (2). compound of. Further, when PG3 is hydrogen, the compound of the formula (2) can also be directly produced from the compound of the formula (8), -153 to 200946528, and the compound of the formula (9). That is, the same method as the method of producing the compound of the formula (1 1) from the compound of the formula (8) and the compound of the formula (9) can be directly guided from the compound of the formula (8) to the formula Compound of (2). The compound of the formula (4) can also be produced from the compound of the formula (8) via the scheme 4. That is, when PG2 is hydrogen, the compound of the formula (8) can be obtained by the same method as the method of producing the compound of the formula (10) from the compound of the formula (8) and the compound of the formula (9). A compound of the formula (12) is used to synthesize a compound of the formula (13), and then PG2 is deprotected, and a compound of the formula (4) is produced by the same method as the production of the compound of the formula (2) from the compound of the formula (10). )compound of. Alternatively, the compound of the formula (8) and the compound of the formula (12) can be produced by the same method as the compound of the formula (9) and the compound of the formula (9). The compound of the formula (14) is synthesized, and then PG2 is deprotected, and a compound of the formula (4) is produced by the same method as the production of the compound of the formula (2) from the compound of the formula (11). -154- 200946528

When PG2 is hydrogen, the compound of the formula (8) can be obtained by the same method as the method of directly producing the compound of the formula (2) from the compound of the formula (8) and the compound of the formula (9). The compound of the formula (12) is reacted to produce a chemical Q compound of the formula (4). Further, the compound of the formula (4) can also be produced from the compound of the formula (8) to the compound of the formula (10) or via the compound of the formula (11). That is, in the compound of the formula (1), when both of PG2 and PG3 are not hydrogen, one or both of them are deprotected, or when one or both of PG2 and PG3 are hydrogen, as it is. After deprotection of the protecting group, the same method as the compound of the formula (2) and the compound of the formula (3 a) or (3 b) can be used to produce the compound of the formula (4). a compound of formula (13). Next, the pG2 is deprotected, and the compound of the formula (4) can be produced by the same method as the production of the compound of the formula (2) from -155 to 200946528 from the compound of the formula (1). Further, in the compound of the formula (11), when both of PG2 and PG3 are not hydrogen, one or both of them are deprotected, or when one or both of PG2 and PG3 are hydrogen, as it is Or, after deprotecting a protecting group, it can be guided to the general formula by the same method as the compound of the formula (2) and the compound of the formula (3 a) or (3b). (1 4) compound. Next, PG2 is deprotected, and a compound of the formula (4) can be produced by the same method as the production of the compound of the formula (2) from the compound of the formula (11). A more specific example of the above manufacturing method is shown in the scheme 5.

Scheme from compound (15) and compound (16), by Journal of Medicinal

Compound (8a) is produced by the method described in Chemistry, Vol. 33, No. 5 27- 5 3, and 990, and then saturated with compound-156-200946528 (8a) and ammonia by heating in a sealed tube. The solvent (9a) can produce the compound (2a). Further, the compound (17) can be produced by heating the compound (8 &) and 2,4-dimethoxyanisidine (9b) in the presence of a palladium catalyst and a base, followed by 2,4-dimethyl Compound (2a) can also be produced by deprotection of oxybenzyl. Further, 'potassium phthalimide (9(;) is applied to compound (8a) to produce compound (10a), and then deprotected to be a compound (l〇b) by protecting the phthalic acid group. Compound (2a) can also be produced by heating in the presence of a base. Further, 'compound (10b) can also be synthesized by reacting sodium azide with compound (8a) to synthesize compound (i〇c)' followed by triphenylphosphine/ The water is produced by reducing a guanamine group. The compound (2a) ' obtained as described above can be reacted with an iodide (3aa) in the presence of a base, as shown in Scheme 6, and guided to the compound (4a). After the Boc group is deprotected to form the compound (5a), for example, an amination reaction with a reduction of the aldehyde (6b a), the object (I)-a can be produced.

Further, as shown in Scheme 7, by reacting the compound (8a) with the compound (12a), for example, in the presence of a base, or reacting the compound (10b) with (3ab), for example, in the presence of a base, Compound (13a) is produced, and then compound (4a) can be produced by adding heat of -157 to 200946528 in the presence of a base or heating in the presence of an inert catalyst. Further, the compound (4a) 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 4a can be introduced to the compound of the formula (I) by the aforementioned method or the like. Further, by condensing the compound (1 〇b) with the compound (3 ac) to synthesize the compound (13b), the obtained compound (13b) is heated in the presence of a base or heated in the presence of a palladium catalyst and a base. Compound (4b) was produced. The compound (4b) can be introduced to the compound of the formula (I) by the aforementioned method or the like.

Scheme 7 Another specific example is shown in Scheme 8. -158- 200946528

Ethyl 32 acid Ph,p. l,CI.TEa/DMF heating

COOEt

THAiDMSO heating

ΊΕΑ/DMSO heating

N-Boe Scheme 8 o Compound (18) described in Chemical Pharmaceutical Bulletin, Vol. 55, 821_824, 2007, etc., can be iodinated to compound 19, followed by chlorination using phosphorus oxychloride to obtain a compound (2〇) ). The compound (20) can be reacted with a hexyl acrylate (Heck) to produce a compound (sb). The compound (14a) can be produced by heating a mixture of the obtained compound (8b) and the compound (12a) in the presence of a test, and then the compound (4c) can be produced by heating in the presence of a base. The compound (4c) can be introduced to the compound of the formula (0) by the aforementioned method or the like.

In program 9, it is no longer ~ specific 〇

-159- 200946528 Scheme 9 The obtained citric acid compound (22) can be obtained by hydrolyzing the compound (21) described in Journal of Medicinal Chemistry, Vol. 36, No. 1 6 69-1 673, 1993, etc. The compound (23) is introduced by the method described in Organic Process Research and Development, Vol. 11, No. 389-398, 2007, and the like. The compound (8c) can be synthesized by using the ethyl orthoformate and acetic anhydride as the obtained compound (23), and then the compound (12a) is allowed to act to produce the compound (13c). The compound (4d) can be produced by heating in the presence of a base. The compound (4d) can be guided to the compound of the formula (1) by the aforementioned method or the like. A further specific example is shown in the scheme 10.

The compound (25) can be produced by allowing phosphorus oxychloride to act on the compound (18) to synthesize the compound (24), followed by the action of 2-aminoethanol. By the action of bromine in acetic acid on the obtained compound (25), a compound (26) having a bromine atom selectively introduced at a position can be produced. Compound (2b) can be produced by heating in the presence of a base or heating in the presence of a copper catalyst and a base. The compound of the formula (I) can be produced from the compound (2 b) by the same method as described in the above -160-200946528. In the compound of the formula (I), the compound A4 is a compound such as a nitrogen atom or an oxygen atom, and can also be produced by the scheme of the formula (11). Here, the LG5 group is a leaving group, and the compound of the formula (8) can remain after the reaction. In it, it can also be residual. When the reactivity of the A3 atom is sufficiently high, etc., LG5 may not exist. Examples of LG5 include chlorine, bromine, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. The general formulae (28b) and (29b) are not only the aldehyde shown, but also a carbonyl compound such as a ketone or an a-ketoester of the formula (3c), (6c) or (7c).

That is, when A4 is a nitrogen atom which may be substituted, the same method as in the case of producing a compound of the formula (4) from a compound of the formula and a compound of the formula (3 a) or (3b) The compound of (27) is reacted with a compound of the formula (28 & or (281)) to produce a compound of the formula (8). Then, the compound of the formula (I) can be produced by the aforementioned method or the like. Similarly, a compound of the formula (13) can be produced from a compound of the formula (27) and a compound of the formula (29a) or (29b)-161-200946528, from the compound of the formula (13) by the aforementioned Process to produce a compound of formula (I). When A4 is an oxygen atom, the compound of the formula (27) can be obtained by a method similar to the method of producing a compound of the formula (4) from the compound of the formula (2) and the compound of the formula (3a). The compound of (28a) is reacted to produce a compound of the formula (8). For example, the method described in Advanced Organic Chemistry, 5th edition (by Michael Smith Smith and Jerry March), pages 477 to 48 8 , 2001, published by John Wiley & Sons, Inc, or the method according thereto Come on. Then, the compound of the formula (1) can be produced by the aforementioned method or the like. Similarly, a compound of the formula (13) can be produced from a compound of the formula (27) and a compound of the formula (29a), and a compound of the formula (13) can be produced from the compound of the formula (13) by the aforementioned method. compound of. A more specific example of the above manufacturing method is shown in the scheme 12.

Alternatively, the compound (31) can be produced by allowing a third butanol and a diphenylphosphoric acid azide to act on the compound (22) and heating. The compound (8d) can be produced by deprotecting the compound (31) to -162-200946528 to form a compound (3 2) and then reacting the chloroethyl chloro group. Next, the compound (13d) is obtained by heating the compound (8d) and the compound (12a) together with a base, and heating is continued to produce the compound (4e). The compound (4e) can be introduced to the compound of the formula (1) by the aforementioned method or the like. When A1 is a substitutable carbon atom in the configuration of the compound of the formula (I), it can be produced, for example, by the scheme 13.

Here, 'RA11 is LLq^I^-Q2 itself, or a substituent which can be introduced later, or a substituent which can be converted into I^-Qi-L^-Q2, and the substitutable substitution of RA12 on carbon A1, Or later converted to a functional group taking a Q group. Further, in the case where either or both of RA11 and RA12 are electron-withdrawing substituents, the methylene group between RA11 and RA12 of the compound (22) can be deprotonated in the presence of a base. The electron-withdrawing substituent may, for example, be a ketone group, an ester group, a nitrile group, a nitro group, a carboxyl group, an anthracene, a maple or a sulfonate. Namely, a compound of the formula (34) can be produced first by reacting a compound of the formula (8) with a compound of the formula (33), for example, in the presence of a base. This reaction can be achieved, for example, by Advanced Organic Chemistry, 5th Edition (by Michael B Smith and Jerry March), 548~5 5 6th, 2001, John-163-200946528

The method described in the publication of Wiley & Sons, Inc., et al., or the method according thereto. Next, a compound of the formula (3 5) can be produced by reacting a compound of the formula (34) as desired in the presence of a base or a catalyst. This reaction can be achieved, for example, by Advanced Organic Chemistry, 5th Edition (by Michael B. Smith and Jerry March), pp. 869-870, 2001, published by John Wiley & Sons, Inc, or Chemical Reviews, Vol. 106, No. 26. The method described in 5 1 -27 1 0, 2006, etc., or according to the method therefor. 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, n-butanol, and 2-methyl-2-propanol. 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 methyl ether, dioxane, tetrahydrofuran, anisole, diphenyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and ethylene glycol An ether such as monomethyl ether, a flavonoid such as dimethyl sulfoxide, an ester such as ethyl acetate or t-butyl acetate; hydrazine, hydrazine-dimethylformamide, N, N-di The guanamines such as methyl acetamide and methyl-2-pyrrolidone, water, and the like 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-2H-pyrimidine [l,2-a]pyrimidine, 2-third-164- 200946528 butylimido-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazo An organic base such as a heterophosphine, lithium diisopropyl decylamine, n-butyl lithium, hexamethyldiazine lithium nitride, hexamethyldifluoride sodium nitride, and hexamethyldifluoride potassium nitride, sodium hydrogencarbonate An inorganic base such as 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 (palladium), palladium carbon catalyst, bis(dibenzylideneacetone)palladium (ruthenium), and tris(dibenzylideneacetone)dipalladium (ruthenium). , a catalyst prepared in advance such as a ligand such as a ligand such as diphenyl bis(acetonitrile)palladium (II) or BINAP or Tol-BINAP, as described in 'O Chemical Reviews, Vol. 106, No. 2658-2659, 2006, etc. Or a catalyst generated in the reaction system. The amount of the base used in the reaction may be 0.1 to 10 moles per mole of the compound of the formula (34), and the catalyst may be 0.001 to 10 moles. The reaction temperature may be from 0 to 200 ° C, preferably from 0 to 120 ° C, and the reaction time is completed in the range of from 5 minutes to 72 hours. Further, the compound of the formula (3), in the case of the compound of the formula (I) itself, can also be chemically converted to either or both of RA11 and RA12 to produce a compound of the formula (I). When RA12 of the compound of the formula (35) is an ester group, a carboxyl group or the like, the compound of the formula (36) can be produced by deesterification or decarbonation by an appropriate method. The compound of the formula (36) is also present in the case of the compound of the formula (I), and the compound of the formula (1) can be produced by chemically converting Raii, and the compound of the formula (I) can also be used according to the scheme. 14 to manufacture. -165- 200946528

4β Scheme 14 Here, the oxime 1 is hydrogen or an electron-withdrawing substituent which is susceptible to aromatic nucleophilic substitution reaction, and examples thereof include a carboxyl group, an ester group, a cyano group, and a nitro group. The Υ2 system can be converted by Υ1, and later converted to a substituent having a cyclic structure of -Α^Α2-Α3-Α4- together with Υ3 or the like. Similarly, the Υ3 system is substituted with A1 to constitute a main atom, and later converted to a substituent having a cyclic structure of -A'A2-A3-A4- together with Y2 or the like. Υ4 and Y5 may also be hydrogen, which may later be converted into substituents of RA11 and RA12. EWG1 is easy to deprotonate adjacent methylene or methine groups, and is susceptible to aromatic nucleophilic substitution reaction or cross-coupling reaction between the compound of the formula (37) and the compound of the formula (43). An electron withdrawing substituent. That is, the compound of the formula (37) can be first reacted with the compound of the formula (9) by the same method as the production of the compound of the formula (2) from the compound of the formula (10) to produce a general formula. (38) compounds. Next, the compound of the formula (38) is suitably subjected to an operation of converting γ1 into γ2 and deprotecting the protecting group PG2 to introduce Y3, whereby the compound of the formula (39) can be produced. -166- 200946528 Then, a compound of the formula (40) can be produced by adding an appropriate cyclization reaction to the compound of the formula (39), and the compound of the formula (40) can be obtained by the same method as described above. The compound of the formula (2) is introduced to the compound of the formula (I). As a suitable cyclization reaction for guiding the compound of the formula (39) to the compound of the formula (40), for example, an etherification reaction, an esterification reaction, a guanylation reaction, or a urethanation reaction can be mentioned. , urealation, amination, reduction of amination, aldol reaction, Mannich reaction, Knoevenagel reaction, Dieckmann cyclization, other 0 carbon-carbon Key generation reaction, Woody reaction, Horner-Emmons reaction, Peterson reaction, Grgnard reaction, other Barbier type reaction, Refo Matts Reformatsky reaction, Baylis-Hillman reaction, cross-coupling reaction, metathesis reaction, etc., each of which can be subjected to etherification reaction: Advanced Organic Chemistry, 5th edition (Michael Β· Smith And Jerry March), 477~482 '996~997, 1180 _~1183 pages, 2001, published by John Wiley & Sons, Inc, esterification Ο Reaction: same as 482~49 0, 997~998 pages, Amidoxime reaction: same as pages 506~514, 1001~1002 Aminoation reaction: same as 482~493, 1182~1183, urealation reaction: same as page 1191, amination reaction: same as 49-9~505, reduction of amination reaction: same 1187 ~ 1189 pages, aldol reaction: same as pages 1218~1224, Mannich reaction: same as pages 1189~1191, Dickman cyclization reaction · · 569~571, Knoevenagel Reaction: same as the 1225~1228, other carbon-carbon bond formation reaction: the same as the 536th to 573th page, Michael Plus-167-200946528 Reaction: the same as the 996~1002, 1022~1030 pages, Bellis Hill Mann reaction: with the 1212th, Woody reaction, Hena Emmons reaction: the same as the 1231~1237, Peterson reaction: the same as the 1228~1229, Gliner reaction, other Barbary type reaction: Same as 1 20 5~1211, Revelmatsky reaction: same as page 1212, cross-coupling reaction: Metal-Catalyzed Cro ss -Coup 1 ing Reactions Volume 1, Volume 2, Second Edition (Armin de meijere Et al., 2004, WILEY-VCH Verlag GmbH & Co. KGaA Publishing, Metathesis Reaction: Angewante Che The method described in mie International Edition of English, Vol. 44, No. 4490-4527, 2005, etc., or the method according thereto. Further, the compound of the formula (37) and the formula (12) can be produced by the same method as the compound of the formula (3) from the compound of the formula (37) and the compound of the formula (9). The compound of the formula (41) can be produced by a compound of the formula (38), a compound of the formula (40), a compound of the formula (2) The compound of the formula (I) is produced by the same method as the compound of the formula (I), and the compound of the formula (I) is produced from the compound of the formula (41), the compound of the formula (42), and the compound of the formula (4). Further, when A1 is a carbon atom which may be substituted, a compound of the formula (37) and a formula can be obtained by the same method as the method of producing a compound of the formula (3) from the compound of the formula (34). The compound of the formula (43) can be used to produce the compound of the formula (44), which can be obtained from the compound of the formula (38), the compound of the formula (39), the compound of the formula (40), and the formula. The compound of the formula (2) is produced by the same method as the compound of the formula (U), and the compound of the formula (44) is produced by the compound of the formula (45), the compound of the formula (35), and the compound of the formula (3). (Ι) compound. A more specific example of the above method is shown in the scheme 15.

Scheme 15 化合物 Compound (4 la) can be produced by heating a mixture of compound (21) and compound (12 a) in dimethyl hydrazine in the presence of triethylamine. Next, the ester moiety of the compound (41a) is hydrolyzed to form the compound (41b), and then condensed with 0-benzylhydroxylamine to be guided to the compound (42a). Then, the compound (4f) can be produced by reacting with triphosgene in the presence of sodium hydride. The compound (4f) can be introduced to the compound of the formula (I) by the same method as described above.

Another specific example is shown in the scheme 16.

In the sixth embodiment, the compound (4la) is reduced to the alcohol (41c) by lithium hydride, and then oxidized by manganese dioxide to produce an acid (41d). For this, a compound (41e) can be produced by using a dijin reaction of -169-200946528 chloroperbenzoic acid. The compound (4g) can be produced by subjecting ethyl bromoacetate to the compound (41e) in the presence of potassium carbonate to form a compound (42b), followed by heating in isopropanol. The compound (4g) can be introduced to the compound of the formula (1) by the same method as described above. A specific example is shown in the scheme 17.

Scheme 17 A compound (4 If) can be produced by allowing hexamethyldiazine potassium nitride and allyl bromide to act on the compound (4 la). The compound (4 lf) is reduced to an alcohol (4 1 g) with lithium aluminum hydride, followed by oxidation with manganese dioxide to produce an aldehyde body (41 h) » This is subjected to a Woody reaction to become a compound (42c) Compound (4h) can be produced by performing a metathesis reaction on (42c) using Grubbs second generation catalyst. Compound (4h) can be introduced to the compound of the formula (I) by the same method as described above. A specific example is shown in the scheme 18. -170- 200946528

N^V®00" 21

NaCP'DMSO heating Ο 1 Scheme 18 The compound (12b) can be produced from the compound (3 aa) and ethyl acrylate by the method shown in Tetrahedron Letters, Vol. 38, No. 5 8 3 1 - 5 8 3 4, and the like. ). Compound (42d) can be produced by heating (12b) and compound (21) obtained in the presence of triethylamine in dimethyl hydrazine. Next, the compound 4i can be produced by heating the compound (42d) in ethanol in the presence of sodium ethoxide to cause a Dickman cyclization reaction. Next, the compound (4j) and the compound (4d) can be produced, for example, by heating in a dimethyl ray in the presence of sodium chloride Q. The compounds (4i) and (4j) can be introduced to the compound of the formula (1) by the same method as described above. The compound of the formula (I) of the present invention, when having a basic group such as an amine group, can be converted into a salt by reacting with an alkali by reacting with an acid or when having an acidic group such as a carboxyl group. a basic base-based salt such as a hydrochloride, a hydrogen bromide, a hydrocyanide-like hydrohalide, a nitrate, a perchlorate, a sulfate, a phosphate, or the like. Salt; meta-sulfonate, trifluoromethanesulfonate, ethylsulfonate-171- 200946528 acid-like lower alkanesulfonate, besylate, p-toluenesulfonate-like aryl salt, acetate , malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc.; or glycinate, lysate, fine Amino acid salt of aminate, alanine, glutamate, aspartate. On the other hand, the salt based on an acidic group is, for example, a metal salt such as a sodium salt, a potassium salt, an alkali metal salt such as a lithium salt, a calcium salt, an alkaline earth metal salt such as a magnesium salt, an aluminum salt or an iron salt; Ammonium salt-like inorganic salt, third octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl vine salt, ethylenediamine salt, N-methylglucamine salt , guanidinium salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procain salt, diethanolamine An amine salt such as a salt, an N-benzylphenethylamine salt, a piperazine salt, a tetramethylammonium salt or a tris(hydroxymethyl)aminomethane salt-like organic salt, or a glycinate or an lysine Salt, arginine, alanine, glutamate, aspartate-like amine salts. When the compound of the formula (I) of the present invention or a salt thereof has an asymmetric carbon atom in the molecule, a R-coordination or an S-coordination stereoisomer exists, and each of them or any of these compounds is present in any ratio. It is included in the present invention. As such a stereoisomer, for example, the compound (I) can be synthesized by using an optically isolated raw material compound, or the synthesized compound (1) can be optically isolated by a usual optical separation or separation method as desired. In the compound of the formula (I) or a salt thereof of the present invention, the presence of an optical isomer, 'each optical isomer and a mixture of such optical isomers are included in the present invention-172-200946528 The compound of the formula (1) or a salt thereof is a case where it is placed in the atmosphere or absorbs water due to recrystallization, and adsorbs water to form a hydrate. Thus, the aqueous compound and salt are also included in the present invention. in. Since the compound (I) of the present invention has strong antibacterial activity and high safety, it can be used as a medicine for humans, animals, fish, and the like, or as a preservative for pesticides and foods. When the compound (I) of the present invention is used as a medicine, the dosage varies depending on the age, sex, symptoms, and the like of the patient, and the adult daily dose is from 50 mg to lg, more preferably from 100 mg to 800 mg. In addition, the amount of 〇v administered by animals differs depending on the purpose of administration, the size of the animal to be treated, the type and extent of the pathogen of the infection, and in terms of the amount of the day, Img is used per 1 kg of body weight of the general animal. To 200 mg, more preferably 5 mg to 100 mg. The amount of this day is once a day, or 2 to 4 times. Furthermore, the amount of one day may also exceed the above amount as needed. In the pharmaceutical of the present invention, the compound (I), the salt thereof or the hydrate of the present invention is used as an active ingredient, and the administration form is not particularly limited, and may be appropriately selected, for example, as a tablet, a powder, or the like. Non-oral preparations for granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, etc. for oral or solid preparations; liquid preparations; injections, suppositories, etc.; fine granulated powders, liquid sprays An inhalant such as a preparation; an external preparation, an eye drop, a patch, or the like. These administration forms can be formulated with a pharmaceutically acceptable carrier in a preparation method of various preparations which are usually used. The solid preparation ' can contain the compound (1) and a pharmaceutically acceptable carrier. Examples of the carrier include, for example, chelating agents, extenders, binders, disintegrating agents, solution accelerators, wetting agents, lubricants, and the like -173-200946528. Examples of the liquid preparation include a solution, a suspension, an emulsion, and the like. As the additive, a suspending agent, an emulsifier or the like may be contained. As the injection, a stabilizer, a preservative, a solution adjuvant, or the like may be used in the preparation, or a solution containing the auxiliary agent may be stored in a container, and then a solid preparation may be formed by freeze-drying or the like, and the preparation prepared when it acts. . Further, a single dose may be stored in a container, or a plurality of doses may be accommodated in the same container. Examples of the external preparation include a solution, a suspension, an emulsion, a soft palate, a gel, a cream, a lotion, a spray, and the like. In addition to the compound (I) of the present invention, the pharmaceutical composition of the present invention may contain other clinically useful antibacterial agents (for example, a macrolide system, a quinolinone system, a β-endoyamine or an amino glucoside system). And/or other known drugs of one or more selected from anti-infective drug substances (for example, antifungal triazole or amphotericin), or are also administered together. As the above-mentioned known drugs, carbapenems such as merpenpenem or imipenem can be mentioned, and the therapeutic effectiveness can be expanded. Further, in order to improve the activity against Gram-negative bacteria and the resistance of the bacteria to the antibacterial agent, the compound of the present invention may contain or be administered together with a bactericidal transdermal protein (BPI) product or a discharge pump inhibitor. The invention will be described in more detail below with reference to the examples and examples, but the invention is not limited thereto. [Reference Example 1] 3-(hydroxymethylene)tetrahydropyran-2-one sodium salt a - cxo

NaO^-174-200946528 Sodium hydride (oily, containing 60%, 14.48 g, 0.36 mol) was washed with n-hexane under a nitrogen atmosphere, suspended in dehydrated ether (360 mL), and ice-cooled. A mixture of δ-valerolactone (24.96 g, 0.25 m·l) and ethyl formate (27.75 g, 0.37 mol) was added dropwise over 2 hours and 45 minutes, and then stirred at room temperature. After 1 hour and 30 minutes passed after the start of the room temperature stirring, the reaction liquid solidified due to the precipitation of crystals. Therefore, dehydrated ether (3 60 mL) was added and stirred for 40 minutes. Then, after stirring overnight at 4 ° C, the volatiles were evaporated under reduced pressure to give 29.4 g of the crude compound as a white solid.

^-NMRCSOOMHz, CD3〇D) δ : 1.7 3 - 1 . 7 9 ( 2 H m), 2.32 (2H, t, J = 6.4 Hz), 4.12 (2H, t, J = 5.1 Hz), 8.91 (1H , s).

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

To a suspension of the crude product of 3-(hydroxymethylene)tetrahydropyran-2-one obtained in Reference Example 1 (28.7 g) in ethanol (8 80 mL), p-aniline hydrochloride was added. (36.02 g, 0.22 mol), stirred at 70 ° C for 2 hours. Immediately after the reaction was stopped, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. Ethyl ether and n-hexane were added to the obtained crude product, and the solid thus obtained was filtered to give 25.18 g (44%) of the title compound as a brown solid. ^-NMRCSOOMHz, CDC13) δ : 1. 9 4 - 2.0 2 (2 H, m), 2.41 (2H, td, J = 6.6, 1.7Hz), 3.79(3H, s), 4.28(2H, t, J = 5.2 Hz), 6.26 (1H, -175- 200946528 d, J = 13.9 Hz), 6.82-6.98 (4H, m), 8.07 (1H, dt, J = 13.9, 1.7 Hz). MS(FAB)m/ z: 234 (M + H) +.

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

In the 3-{[(4-methoxyphenyl)amino]methylene}tetrahydrofuran-2-one (5.00 g, 21 mmol) obtained in Reference Example 2, phosphorus chlorochloride (21 mL) was added. Reflux for 2 hours. The reaction solution was ice-cold, poured into ice, and then warmed to boiling. The resulting black insolubles were filtered off and the filtrate was cooled to 0 °C. The solid which precipitated was filtered, crystallized from diethyl ether and water to yield 3.93 g (68%) of W-NMROOOMHz, CDC13) δ: 2.14 - 2.23 (2H, m), 3.11 (2H, t, J = 7.5 Hz), 3.60 (2H, t, J = 6.4 Hz), 3.98 (3H, s), 7.36 ( 1H, dd, J = 9.1, 2.7Hz), 7.45(1H, d, J = 2.7Hz), 7.98(1H, d, J = 9.1Hz), 8·61(1Η, s). MS(FAB)m /z:270, 27 1, 272(M + H) + .

[Reference Example 4] methoxy-1,2,3,4-tetrahydrobenzo[11][1,6]naphthyridine

4-Chloro-3-(3-chloropropyl)-6-methoxyquinoline (3.00 §, 11.1111111〇1) and phenol (6.〇〇§) obtained in Reference Example 3 were placed in a high pressure cylinder' The solution was brought to a state of 45 - 176 - 200946528 ° C, and ammonia gas was blown in. After the plug was sealed, it was stirred at 160 ° C for 2 hours. The reaction solution was cooled, and 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with methylene chloride and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was purified by column chromatography (chloroform:methanol = 20:1 - 5:1) to give 83 0 mg (3 5 %) Labeled compound, which is a pale yellow solid. ❹ *Η-ΝΜΚ(300ΜΗζ, CDC13) δ: 2.02 (2Η, quint, J = 6.0 Hz), 2.85(2H, t, J = 6.0Hz), 3.57(2H, m), 3.90(3H, s), 5.69(1H, brs), 7.03(1H, d, J = 2.7 Hz), 7.22(1H, dd, J = 9.2, 2.7Hz), 7.85(1H, d, J = 9.2Hz), 8.16(1H, s MS(FAB)m/z: 2 15(M + H) + .

[Reference Example 5] 4-[2-(9-Methoxy-3,4-dihydro-2H-benzo[h][l,6]naphthyridin-i-yl)ethyl]piperidine-l -carboxylic acid tert-butyl ester

9-methoxy·1,2,3,4-tetrahydrobenzo[h][l,6]naphthyridine (1.00 g, 4.67 mmol) of N,N-dimethyl ester obtained in Reference Example 4. In a solution of carbamide (50 mL), sodium hydride (oily, containing 60%, 〇.37 g, 9.3 3 mmo 1) was added under a nitrogen atmosphere, and after stirring at room temperature for 20 minutes, 4-(2-iodine) was added. A solution of tert-butyl (ethyl)piperidine-1-carboxylate (3.16 g, 9.33 mmol) in N,N-dimethylformamide (20 mL) was stirred overnight. To the reaction mixture, baking soda water was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. After drying under anhydrous magnesium sulfate, the residue was purified by hydrazine gel column chromatography (chloroform: methanol - 177 - 200946528 = 20:1) to give 9 〇 5 mg (46%). A labeled compound which is a yellow oil. W-NMROOOMHz, CDC13) δ:1.ΐ3]·27(2Η,m), 1.46(9H's)' 1.64-1 .91 (7H, m), 2.66(2H, t, J = 12.1Hz), 2.87(2H, t, J = 5.7Hz), 3.14-3.25(4H, m), 3.92(3H, s), 4.10(2H, brs), 7.13(1H,d,J = 2.8Hz),7.22-7.26 (1H, m), 7_89 (1H, dd, J = 9.2, 1.5 Hz), 8.34 (1 H, s). MS (FAB) m/z: 426 (M + H) + .

[Example l] l-{2-[l-(2-cyclohexylethyl)piperidin-4-yl]ethyl-9-methoxy-1,2,3,4-tetrahydrobenzo[ Hni,6]naphthyridine

4-[2-(9-Methoxy-3,4-dihydro-2H-benzo[h][l,6]naphthyridin-1-yl)ethyl]piperidine obtained in Reference Example 5 - To a solution of hydrazine-carboxylic acid tert-butyl ester (279 ng, 0.66 mmol) in dichloromethane (3 mL), EtOAc. After the reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in dichloromethane (6 mL). Under nitrogen atmosphere and ice-cooling, cyclohexyl acetaldehyde (124 mg, 0.98 mmol) and hydrogenated triethoxy hydride boron were added. Sodium (214 mg, 0.98 mmol) was stirred at room temperature for 2 h. Further, cyclohexylacetaldehyde (42 mg, 0.3 mmol) and hydrogenated sodium triethoxyborohydride (72 mg, 0.33 mmol) were added under ice cooling, and stirred at room temperature for 2 hr. Saturated sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with brine. After drying under anhydrous magnesium sulfate, -178-200946528, the residue was purified by column chromatography (chloroform: methanol = 40:1 to 20:1 - 10:1) to give 183. Milligram (64%) of the labeled compound, which is a brown oil. 158 mg of this was dissolved in chloroform (1 - 5 mL), and 4 N of hydrogen chloride / dioxane solution (.33 mL) was added thereto, and the mixture was stirred for 5 minutes, and then concentrated under reduced pressure. Ethyl ether was added thereto, and the solid was collected by filtration, and dried to give 148 mg of the title compound of the title compound as a yellow solid, W-NMROOO, (CDC13, in free form) δ:0·89-1_31 (7 Η, m), 1 . 6 7 - 2.3 3 ( 1 5 Η,m), 2 · 74 - 3 _ 0 0 (6 Η,m),3 · 5 1 - 3 · 5 5 (4H,m), 3.78(2H, t , J = 8.0Hz), 3.96(3H, s), 7.11(1H, d, J = 2.4Hz), 7.34(1H, dd, J = 9.3, 2.4Hz), 8.06(1H, s), B.34 (1H, d, J = 9.3 Hz). MS (FAB) m/z: 43 6 (M + H) + .

[Reference Example 6] 2-[(6-Methoxysulfin-4-yl)amino]ethanol

4-chloro-6-methoxyporphyrin (B i 〇〇r ganic & Medic inal Chemistry Letters, 2006, Vol. 16, No. 20, 5 3 84- 5 3 8 8 , 20.0 g, 0.103 Mol) was suspended in 2-aminoethanol (i〇〇mL) and stirred with heating at 120 °C for 17 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform: methanol: water = 2 〇 : 3:1, and washed with water. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give <1> -179- 200946528 1H-NMR (400MHz, CDC13) δ: 3.52 (2Η, q, J = 5.3Hz), 3.94(3H, s), 4.03(2H, t, J = 5.3Hz), 5.16(1H, brs ), 6.45(1H, d, J=5.4Hz), 6.99( 1 H, d, J = 2.7Hz), 7.3 1 (1 H, dd, J = 9.2, 2.8Hz), 7.92(1H, d, J = 9.3 Hz), 8.46 (1H, d, J = 5.1 Hz). MS (ESI) m/z: 219 (M + H) +.

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

The acetic acid (190 mL) was dissolved in 2-[(6-methoxyquinolin-4-yl)amino]ethanol (H94g, 86.78 mm) obtained in Reference Example 6, and bromine was added at room temperature (4·4). 5 mL), stirred for 8 hours. The solvent was distilled off under reduced pressure, and water was added, and then 5 The extract was extracted with a lower solvent of chloroform:methanol:water = 7:3:1 and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then suspended in ethyl acetate-hexane at 40. (: The slurry was stirred. After standing at room temperature, a solid was collected by filtration to give 23.29 g (yield: 90%) of the title compound as a brown solid. 'H-NMR (400 MHzs CDCI3) δ: 3.73 - 3.67 (2 Η, m ), 3.86(2H, t, j==5.〇Hz), 3.93(3H, s), 4.89(1H, s), 7.32(1H, dd, J = 9.3, 2-4Hz), 7.38(1H, d, J = 2.9 Hz), 7.92 (1H, d, J = 9.〇Hz), 8.61(1H, s).

Ms (ESl) m/z: 297, 299 (M + H) + .

[Reference Example 8] 9-methoxy-2,3-dihydro-111-[1,4]indolo[2,3-(:]quinoline-180- 200946528

2-[(3-Bromo-6-methoxyquinolin-4-yl)amino]ethanol (22.30 g, 7 5.05 mmol) obtained in Reference Example 7 was dissolved in hydrazine, hydrazine-dimethylformamide (2 50 mL), a third potassium pentoxide (12.63 g, 112.57 mmol) was added under ice cooling, and the mixture was stirred at 16 (TC for 13 hours). After the solvent was evaporated under reduced pressure, the residue was dissolved in dichloromethane. The mixture was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness, and purified by silica gel column chromatography (chloroform-methanol) to give 5.90 g (3 6%). It is a brown solid. 1H-NMR (400MHz, CDCI3) δ: 3.66-3.70 (2 Η, m), 3.92 (3H, s), 4.33 (2H, t, J = 4.4 Hz), 4.59 (1H, brs), 6.83(1H, d, J = 2.7Hz), 7.19(1H, dd, J = 9.3, 2.7Hz), 7.87(1H, d, J = 9.0Hz), 8.31(1H, s). MS(ESI)m /z:217(M + H) + .

[Reference Example 9] 1-(Tertidinoxycarbonyl)-4_[2_(9-methoxy-2,3-dihydro-1H_[1,4]噚[[,3,3-c]quinoline -1-yl)ethyl]piperidine

The 9-methoxy-2,3-dihydro-1H-[1,4]D§ trap[2,3-c]salthene (100 mg, 〇462ιηιηο1) obtained in Reference Example 8 was dissolved in n, N. Add dimethyl hydride (oily, containing 55%, 22.2 mg, 〇-5 0 8 mmol) in dimethylformamide (5 mL). After stirring for 3 minutes, add 4_(2_ at the same temperature. Iodoethyl) -181- 200946528 Piperidine-1-carboxylic acid tert-butyl ester (188 mg, 0.55 5 mmol). After stirring for 24 hours while warming to room temperature, water was added and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. Purification by hydrazine gel column chromatography (hexane-ethyl acetate) afforded the title compound (87.5 mg, 44%) as an orange oil. 1H-NMR (400MHz, CDC13) δ : 1.0 7 -1 . 3 1 (2 Η , m), 1.46 (9H, s), 1.64- 1.73 (2H, m), 1. 8 3 -1 . 9 1 ( 2 H, m), 2.6 3 - 2.7 4 (2 H, m), 3.09-3.15(2H, m), 3.23(2H, t, J = 4.3Hz), 3.71(1H, q> J = 5.4Hz) , 3.93(3H, s), 4.0 3 - 4.1 6 (2 H, m), 4.21(2H, t, J = 4.4Hz), 7.09(1H, d, J = 2.7Hz), 7.18(1H, dd, J = 9.2, 2.8 Hz), 7.90 (1H, d, J = 9.0 Hz), 8.39 (1H, s).

[Reference Example l] 9-Methoxy-1-(2-piperidin-4-ylethyl)-2,3-dihydro-1H-[1,4]fluorene[2,3-c ]quinoline

The 1-(t-butoxycarbonyl)-4-[2-(9-methoxy-2,3-hydrogen·ιη·[1,4]曙哄[2,3-] obtained in Reference Example 9 was obtained. c]Quinolin-1-yl)ethyl]Small (87.5 mg, 0.205 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.5 mL) was added under ice cooling, and stirred for 2 hr. After distilling off the solvent under reduced pressure, saturated sodium bicarbonate was added under ice cooling to make it alkaline, and then extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was evaporated. 'Η-ΝΜΚ(400ΜΗζ, CDC13) δ : 1 . 1 9 -1 . 3 0 (2 Η , m), j 44(ΐΗ -182- 200946528 brs), 1.71(2Η, d, J=11.7Hz), 1 . 8 4 - 1 . 8 9 (2 Η, m), 2.59 (2Η, t, J= 1 2.1 Hz), 3.04-3. 1 4(4H, m), 3,24(2H, t, J = 4.4 Hz), 3.93 (3H, s), 4.21 (2H, t, J = 4.3 Hz), 7.11 (1H, d, J = 2.7 Hz), 7.17 (1H, dd, J = 9.2, 2.8 Hz), 7.89 (1H, d, J = 9.3 Hz), 8.39 (1H, s).

[Example 2] 1-{2-[1-(2-cyclohexylethyl)piperidin-4-yl]ethyl}-9-methoxy- 2,3-dihydro-1H-[1, 4] 噚耕和[2,3-c] 奎琳

Ο

9-methoxy-1-(2-piperidin-4-ylethyl)·2,3-dihydro-1^1-[1,4]indole [2,3] obtained in Reference Example 10. -. Quinoline (58.8111 §, 0.18 〇 111111 〇 1), cyclohexyl ketone (34.1 mg, 0.270 mmol) was dissolved in dichloromethane (3 mL), and acetic acid (〇.012 mL, 0.216 mmol) was added at room temperature. Sodium triethoxyborohydride (48.2 mg, 0.216 mmol) was hydrogenated and stirred for 9 hours. The solvent was distilled off under reduced pressure, and 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 under reduced pressure and purified by silica gel column chromatography (chloroform:methanol: water = 7:3:1 under solvent). 4 equivalents of chlorinated gas/diterpenoid solution (〇.135 mL) was added and trituration was carried out, diethyl ether was added, and the resulting solid was collected by filtration to give 61.6 mg (62%) of Light yellow solid. j-NMRHOOMHz, CDC13, in free form) δ: 0.85-1·96 (22Η, m), 2.35 (2H, brs), 2.9 1 - 3.0 2 (2 Η, m), 3.07-3. 1 4 (2Η , m), 3.23(2Η, t, J = 4.3Hz), 3.92(3H, s), 4.20(2H, t, J = 4.3Hz), -183- 200946528 7.09(1H, d, J = 2.7Hz) , 7.17(1H, dd, J = 9.0, 2.7Hz), 7.89(1H, d, J = 9.0Hz), 8.38(1H, s). MS(ESI)m/z:43 8(M + H)+ .

[Reference Example 11] 3-iodo-6-methoxysinor-4-ol

To a solution of 6-methoxyquinolin-4-ol (1. g, 5.70 mmol) in MeOH (40 mL), EtOAc (t. Stir at 35 ° C for 22 hours. Then, the precipitated crystals were filtered off using methanol cooled to 5 ° C to give 1.69 g (98%) of the title compound as a brown crystalline material. 1H-NMR (400 MHzj DMSO-D6) 6:3, 83 (3H, s), 7.33 (1H, dd, J = 9.0, 2.9 Hz), 7.49 (1H, d, J = 2.9 Hz) s 7.55 (1H, d, J = 9.0 Hz), 8.44 (1H, s), 12.17 (1H, brs). MS (ESI) m/z: 302 (M + H) +.

[Reference Example 12] 4-chloro-3-iodo-6-methoxyquinoline

To a solution of 3-B-6-methoxyquinolin-4-ol (〇5 g, 1.66 mmol) in N,N-dimethylformamide (5 mL) obtained in Reference Example 11 Phosphorus (0.191111, 1.911111111〇1)' is at 50. (: stirring for 30 minutes. Then, the reaction liquid was developed in ice water. The precipitated crystals were filtered with water to give -184-200946528 0.46 g (86%) of the title compound as a brown crystalline material. 1H-NMR (400 MHz , DMSO-D6) δ: 3.95 (3Η, s), 7.51 (2H, dt, J = 17.1, 6.0 Hz), 8.00 (1H, d, J = 9.3 Hz), 9.01 (1H, s). MS (ESI) ) m / z: 320 (M + H) + .

[Reference Example 13] (2 E)-3-(4-Chloro-6-methoxyindoline-3-yl)acrylic acid ethyl ester

o Addition of 4-chloro-3-iodo-6-methoxyquinoline (0.46 g, 1.44 mmol) in N,N-dimethylformamide (1 〇m L) obtained in Reference Example 12 Ethyl acrylate (0.25 mL, 2.30 mmol), triethylamine (〇.32 mL, 2.30 mmol), lithium chloride (〇.18 g, 4.32 mmol), triphenylphosphine (〇.〇20 g, 0.07 mmol), palladium acetate (0-030 g, 0.14 mmol), stirred at 85 ° C for 6 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and then evaporated. The obtained residue Q was dissolved in n-hexane:ethyl acetate = 1:1, and insoluble crystals were collected by filtration. The filtrate was purified as it was by gel column chromatography (n-hexane: ethyl acetate = 1:1) to form a 0.35 g (83%) labeled compound with the crystals just filtered. It is a brown crystalline material. 1 H-NMR (400MHz, CDC13) δ: 1.38 (3Η, t, J = 7.2Hz), 4.00(3H, s), 4.33(2H, q, J = 7.1Hz), 6.66(1H, d, J= 16.1 Hz), 7.43 (1H, dd, J = 9.3, 2.7 Hz), 7.51 (1H, d, J = 2.9 Hz), 8.00 (1H, d, J = 9.0 Hz), 8.22 (1H, d, J= 16.1 Hz), 8.93 (1H, s). MS (ESI) m/z: 2 92 (M + H) + 185 - 200946528 [Reference Example 14] 4-[2-({3_[(1e)-3 -Ethoxy-3-oxo-propyl-indenyl-ene-]-yl]-6-methoxyquinolin-4-ylindolyl)ethyl]piperidine-1-carboxylic acid tert-butyl ester

A solution of ethyl (2Ε)-3-(4-chloro-6-methoxyindoline-3-yl)acrylate (〇.24 g, 〇.83 mmol) obtained in Reference Example 13 in dimethylhydrazine (15 mL) Add 3-(2-Aminoethyl)piperidine-1-carboxylic acid tert-butyl ester (〇.57g, 2.54mmol) and triethylamine (〇.69mL, 4.98mmol) at 80°C Stir for 20 hours. Next, the same amount of tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate was further added, and the mixture was stirred at 80 ° C for 22 hours. Then, the reaction solution was dispersed in ethyl acetate and water, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced vacuo. The residue obtained was purified by hydrazine gel column chromatography (ethyl acetate) to afford 0.32 g (yield: 80%) of the title compound.

1H-NMR (400MHz, DMSO-d6) δ: 1.00 (2Η, t, J = 5.7Hz), 1.18(3H, t, J = 7.1Hz), 1.38(9H, s), 1. 5 4 -1.6 4 (4 H, m), 2.58-2.69 (2H, m), 3.4 1 - 3.5 0 (2 H, m), 3.8 5 - 3.9 2 ( 6 H, m), 4.20 (2H, q, J = 7.1Hz ), 6.47 (1H, d, J = 15.6 Hz), 6.74 (1H, s), 7.32 (1H, dd, J = 9.2, 2.6 Hz), 7.66- 7.70 ( 1 H, m), 7.74 ( 1 H, d, J = 9.0 Hz), 7.96 (1H, d, J = 15.9 Hz), 8.57 (1H, s). MS (ESI) m/z: 484 (M + H) + [Reference Example 15] 4-[ 2-(9-Methoxy-2-oxooxybenzo[h]-l,6-naphthyridine--186- 200946528 1(2H)-yl)ethyl]piperidine-1-carboxylic acid III Butyl ester

4-[2-({3-[(1Ε)-3-ethoxy-3-oxoethoxypropan-1-yept-1-yl]-6-methoxyquinoline) obtained in Reference Example 14 4-yl}amino)ethyl]piperidine-;[-carboxylic acid terpene vinegar (O.lg, 0.21 mmol) in anhydrous ethanol (8 mL), sodium sulphate (〇.〇6g, 0.88) Methyl)'s heated to reflux for 3 hours. After distilling off the solvent, the residue was dissolved in chloroform and washed twice with water and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced vacuo. The residue obtained was purified by hydrazine gel column chromatography (ethyl acetate-dichloromethane:methanol=10··1) to give 0.03 9 g (4 3%) of the labeled compound as a brown foamy substance. 1H-NMR (400MHz, CDC13) 5: 1.24- 1 .3 8 (2H, m), 1.47 (9H, s), 1-50- 1.65 (4H, m), 1.6 5 - 1. 8 3 ( 2 H, m), 2 . 〇7 - 2.1 8 ( 1 H, m), 2.68-2.81 (lH, m), 4.00 (3H, s), 4.04-4.19 ( 1H, m), 4.58-4.66 (2H , m), 6.84(1H, d, J = 9.3Hz), 7.4 3 - 7.5 1 (1 H, m), 7.79-7.85(2H, m), 8.0 9 - 8 . 1 8 ( 1 H, m) , 8.7 2 - 8.8 1 (1H, m). MS (ESI) m/z: 43 8 (M + H) + [Ref. 16] 9 methoxy-1-(2-piperidin-4- Benzyl)benzo[h]-l,6-naphthyridin-2(1 Η)-one-187- 200946528

4-[2_(9-Methoxy-2-oxobenzobenzo[11]-1,6-naphthyridin-1(2H)-yl)ethyl]piperidine-carboxylic acid obtained in Reference Example 15 A solution of tributyl ester (0.071 g, 〇. 16 mmol) in dichloromethane (5 mL) was evaporated. After distilling off the solvent, a saturated aqueous solution of sodium hydrogencarbonate was added and extracted with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was evaporated to dryness tolulululululululululululululululululululululululululululululululu (2H, m), 1.66-1.79(1 H, m), 1. 80- 1.89(2H, m), 2.11- 2.18(2H, m), 2.69(2H, td, J=12.1, 2.4Hz), 3 .1 5 - 3.2 3 (2 H, m), 4_00(3H, s), 4.62(2H, t, J = 7.9Hz), 6.83(1H, d, J = 9.3Hz), 7.47(1H, dd , 5 = 9.2, 2.6 Hz), 7.8 0 - 7.8 4 (2 H, m), 8.1 1 (1H, d, J = 9.0 Hz), 8.76 (1H, s).

[Example 3] 1-{2-[1-(2-cyclohexylethyl)piperidin-4-yl]ethyl}-9-methoxybenzo[h]-l,6-naphthyridine- 2(1H)-ketone

9-Methoxy-1-(2-piperidin-4-ylethyl)benzo[h]-l,6-naphthyridin-2(1H)-one obtained in Reference Example 16 (〇.〇47g , 〇.14mmol) in dichloromethane (5niL) -188- 200946528 solution, adding cyclohexyl acetaldehyde (〇.〇33g, 0.26mmol) and hydrogenated sodium triethoxyborohydride (〇.〇59g, 0.28mmol) ), stirring at room temperature for 3 hours and a half. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and extracted with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by EtOAc EtOAc EtOAc EtOAc It is a pale yellow solid substance. 1H-NMR (400MHz, CDC13) δ : 0.8 5 -0.99(3 Η, m), 1.11- 1.30(6Η, m), 1. 3 8-2.1 7( 1 3 Η, m), 2.3 3 - 2.4 8 (2 Η, m), 2.93-Ο 3.08(2Η, m), 3.97(3Η, s), 4.60(2Η, t, J = 7.8Hz), 6.82 1Η, d J = 9.6Hz), 7.45(1H, Dd, J = 9.2, 2.3 Hz), 7.7 8 - 7.8 3 (2 H, m), 8.10 (1H, d, J = 9.2 Hz), 8.75 (1H, s). MS (ESI) m/z: 448 (M + H) + [Reference Example 17] 4-(2-{[3-(3-ethoxy-3-oxopropyl)-6-methoxysin-4-yl]amino group }Ethyl piperidine-1-carboxylic acid tert-butyl ester

4- 4-[2-({3-[(1Ε)-3-ethoxy-3-oxooxyprop-1-en-1-yl]-6-methoxy group obtained in Reference Example 15 with nitrogen a solution of quinoline-4-yl}amino)ethyl]piperidine-1-carboxylic acid tert-butyl ester (〇.21g, 0.44mmol) in absolute ethanol (5inL), 10% palladium carbon catalyst (M, About 50% water, 〇.〇3 g). A balloon containing hydrogen was attached and stirred at room temperature for 3 hours. An equal amount of 10% carbonaceous catalyst was added and stirred at room temperature for 15.5 hours, and the same amount of 1% palladium carbon catalyst was added thereto, and the mixture was stirred at room temperature for 1 hour at -189-200946528. After filtering off the palladium carbon catalyst, the reaction liquid was distilled off under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc) elute 1H-NMR (400MHz, CDC13) δ : 1. 1 0 -1.2 8 (5 Η, m), 1.45(9H, s), 1.51-1.62(1H, m), 1.63 - 1. 72(4H, m) , 2.63 -2.73 (4H, m), 3.06(2H, t, J = 7.2Hz), 3.42(2H, t, J = 7.3Hz), 3.93(3H, s), 4.02-4.1 7(4H, m) , 4.2 4 - 4.3 9 ( 1 H, m), 7.2 6 - 7.3 0 (2 H, m), 7.91 (1H, d, J = 8.8Hz), 8.42(1H, s). MS(ESI)m/ z: 486 (M + H) + [Reference Example 18] 4-[2-(9-methoxy-2-oxo-3,4-dihydrobenzo[h]-l,6-naphthyridine- 1(2 Η)-yl)ethyl]piperidine·1-carboxylic acid tert-butyl ester

4-(2-{[3-(3-ethoxy-3-oxopropyl)-6-methoxyquinolin-4-yl]amino}ethyl)piperidyl obtained in Reference Example To a solution of pyridine-1-carboxylic acid tert-butyl ester (〇18 g, 0.36 mmol) in anhydrous ethanol (10 mL), EtOAc (EtOAc (EtOAc) After distilling off the solvent, the residue was dissolved in chloroform and washed twice with water and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced vacuo. The residue obtained was purified by hydrazine gel column chromatography (dichloromethane:methanol = 1:1: 1) to afford 0.10 g (64%) of the title compound as a pale yellow foam. 1H-NMR (400MHz, CDC13) δ : 0.9 5 -1.0 7 (2 Η, m), 1.23- -190- 200946528 1·35(2Η,m), 1.41(9Η, s), 1.4 4 - 1. 6 8 (4 Η , m), 2.4 9 - 2.6 1 (2 Η, m), 2.66-2.73 (2H, m), 2.94-3.0 1 (2H, m), 3.93 (3H, s), 3.94-4.04 ( 1Η,m),4·20-4·27(2Η,m), 7·08(1Η,d,J=2.7Hz), 7.37(1Η,dd,J=9.3,2.7Ηζ),8·04( 1Η, d, J = 9.3 Hz), 8·58 (1Η, s)· MS (ESI) m/z: 440 (M + H) + [Reference Example 19] 9-methoxy-1-(2- Piperidin-4-ylethyl)-3,4-dihydrobenzo[h]-l,6-naphthyridin-2(1H)-one

4-[2-(9-Methoxy-2-oxooxy-3,4-dihydrobenzo[h]-l,6-naphthyridin-1(2H)-yl)B obtained in Reference Example 18. To a solution of tert-butyl piperidin-1-carboxylic acid (30 mL) in dichloromethane (5 mL) was added trifluoroacetic acid (0.5 mL). A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was evaporated. After drying over anhydrous magnesium sulfate, the solvent was evaporated. 1H-NMR (400MHz, CDC13) δ : 1 _ 0 0 -1 . 1 2 (2 Η, m), 1.21- 1.33(2H,m), 1.4 5- 1.54(3 H,m), 2.13-2.28( 2H,m),2.42-2.53(2H, m), 2.6 5 - 2.7 2 (2 Η, m), 2.9 4 - 3.0 3 (3 Η, m), 3.93(3H, s), 4.1 9-4.27( 2H, m), 7.08 (1H, d, J = 2.9 Hz), 7.35 (1H, dd, J = 9.3, 2.7 Hz), 8.01 (1H, d, J = 9.3 Hz), 8.58 (1H, s).

[Example 4] 1-{2-[1-(2-cyclohexylethyl)piperidin-4-yl]ethyl}-9-methoxy-191- 200946528-based-3,4-dihydrobenzo [11]-1,6-naphthyridine-2(111)-one

9-Methoxy-1-(2-piperidin-4-ylethyl)-3,4-dihydrobenzo[11]-1,6-naphthyridin-2 (111) obtained in Reference Example 19. - a solution of ketone (0.0728, 0.21111 1 1 〇1) in dichloromethane (5 mL), EtOAc (EtOAc: EtOAc (EtOAc) The mixture was stirred at room temperature for 3.5 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was extracted with methylene chloride. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. Dichloromethane:methanol = 10:1) EtOAc (EtOAc: EtOAc: EtOAc) 1.09- 1·27(6Η, m), 1.32- 1.37(2Η, m), 1.4 7 - 1.5 3 (4 Η, m), 1.57-!·69(6Η, m), 1.74-1.84(2Η, m ), 2.2 6 - 2.3 4 ( 2 Η , m), 2.65-2·72 (2Η, m), 2.81-2.89 (2Η, m), 2.9 4 - 3.0 0 (2 Η, m), 3.92 (3Η, s)> 4.23(2Η, t, J = 7.6Hz), 7.08(1Η, d, J = 2.8Hz), 7.34(1Η, dd> J = 9.2, 2.3Hz), 8.00(1H, d, J = 9.6 Hz), 8.57 (1H, s). Ms (ESI) m/z: 45 0 (M + H) + [Reference Example 20] 4-({2-[l-(Third Carbonyl) piperidin-4-yl] ethyl} amino) -6-methoxy-quinoline carboxylate -192-200946528 _3_

COOEt

^Boc

OMe COOEt

, Boc was heated and stirred on an oil bath at 80 ° C to ethyl 4-chloro-6-methoxyquinoline-3-carboxylate (1.446 g, 5.44 mmol), 4-(2-aminoethyl)piperidine. A mixture of tert-butyl 1-carboxylic acid (1.242 g, 5.44 mmol), triethylamine (i.516 mL, 10.88 mmol) and dimethyl br The reaction mixture was diluted with ethyl acetate (150 mL), washed with water and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (chloroform: ethyl acetate = 2:1 - 1:1) to give 2.20 g (88%). It is a pale yellow solid. 1H-NMR (400MHz, CDC13) δ: 1. 1 1 -1.22(2H, m), 1.43(3H, t, J = 7.1Hz), 1.45(9H, s), 1.4 5 - 1.7 8 ( 5 H, m), 2.69(2H, m), 3.84(2H, dd, J=12.2, 7.1Hz), 3.91(3H, s), 4.10(2H, m), 4.39(2H, q, J = 7.2Hz), 7.36{1H, dd, J = 9.2, 2.8Hz), 7.54(1H, d, J = 2.9Hz), 7.90(1H, d, J = 9.3Hz), 7.66(1H, d, J = 8.3Hz), 〇 9.00 (1H, s). MS (ESI) m/z: 45 8 (M + H) + .

[Reference Example 21] 4-(allyl {2-[l-(t-butoxycarbonyl)piperidin-4-yl]ethyl}amino)-6-methoxyquinoline-3-carboxylic acid Ethyl ester

4-({2-[1-(Tertidinoxyl)piperidin-4-yl]-193- 200946528 ethyl}amino)-6-methoxyquinoline-3 obtained in Reference Example 20. A solution of ethyl carboxylate (3.38 g, 7.39 mmol) in tetrahydrofuran (15 mL), EtOAc (EtOAc) After stirring at the same temperature for 30 minutes, allyl bromide (1.92 mL, 22.2 mmol) was added and stirred at room temperature for 3 hr. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The mixture was washed with water and brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue obtained was purified by gel column chromatography (hexane: ethyl acetate = 9:1 - 4:1 - 2:1) to give 1.36 g (3) 7%) a labeled compound which is a tan gum gum solid. 1H-NMR (400MHz, CD C13 : CD 3 〇D = 1 : 1) δ : 1.0 1 - 1 . 0 9 (2 H, m), 1.27- 1.5 8(1 7H, m), 2.60(2H, m ), 3.3 4 - 3 . 3 9 ( 2 H, m), 3.87-4.08 (7H, m), 4.47 (2H, q, J = 7.1Hz), 5.2 3 - 5.3 6 (2 H, m), 5.94 -6.04 ( 1 H, m), 7.420-7.57 (3H, m), 7.92-7.99 (1H, m). MS (ESI) m/z: 498 (M + H)+.

[Reference Example 22] 4-(2-{Allyl[3-(hydroxymethyl)-6-methoxyquinolin-4-yl]amino}ethyl)piperidine-1-carboxylic acid tert-butyl ester

4-(Allyl {2_tl_(t-butoxycarbonyl)piperidin-4-yl]ethyl}amino)·6·methoxyquinolinecarboxylic acid ethyl ester (16 g, obtained in Reference Example 21) 3.22 mmol) of tetrahydrofuran (30 mL) was added to a solution of lithium aluminum hydride (244 mg, 6.43 mmol) for 5 minutes under ice cooling. After stirring at the same temperature for 3 minutes, water (〇. 2 3 ml) was added in a cautious manner. 1 5 % aqueous sodium hydroxide - 194 - 200946528 (0.23 mL), water (〇. 69 mL). After stirring at room temperature for 2 hours, anhydrous magnesium sulfate was added, filtered over Celite, and the filtrate was washed with ethyl acetate. After the hydrazine was combined with the washing liquid, the solvent was evaporated under reduced pressure, and the residue was dissolved in chloroform:methanol = 9:1 mixture solvent and filtered. The filtrate was concentrated under reduced pressure to give 1.86 g (yield) of the title compound as an orange gum solid 1H-NMR (400 MHz, CDCh) δ: 1.03 (2 Η, m), 1. 3 0 - 1.6 0 ( 1 4 Η, 〇m), 2.58(2Η, m), 3.36(2Η, m), 3.8 0-4 . Ο 5 ( 7 Η , m), 4.87(2Η, s), 5.14-5.22(2Η, m) , 5.8 5 - 5.9 5 ( 1 Η, m), 7.3 1 - 7.3 6 (2 Η, m), 7.99 (1Η, d, J = 9.0Hz), 8.69(1Η, s). MS(ESI)m/ z:456(M + H)+.

[Reference Example 23] 4-(allyl{2-[1-(t-butoxycarbonyl)piperidin-4-yl]ethyl}amino)-6-methoxyquinoline-3-carbaldehyde

(4-(2-{Allyl[3-(hydroxymethyl)-6-methoxysin-4-yl]amino}ethyl)piperidine-1-carboxylate obtained in Reference Example 22 A solution of the acid tert-butyl ester (1.86 g, 3-22 mmol) in dichloromethane (40 mL) was added with EtOAc (3. The filtrate was washed with a mixed solvent of chloroform:methanol=9:1. The filtrate was combined with the washing liquid, and concentrated under reduced pressure to obtain a gel column chromatography (hexane: ethyl acetate = 4). :1—2:1—1:1— 1:3) The residue was purified to give 1.27 g (8 7%) of the title compound as a yellow gum solid. -195- 200946528 1H-NMR (400 MHz, CDC13) δ ············································ 7.6 Hz), 3.96- 4.12 (7H, m), 5.2 3 - 5.3 0 ( 2 H, m), 5.7 9 - 5.8 9 ( 1 H, m), 7.37 (1H, d, J = 2.8Hz), 7.46 (1H, dd, J = 9.2, 2.8 Hz), 8.06 (1H, d, J = 9.2 Hz), 9.00 (1H, s), 10.35 (1H, s). MS (ESI) m/z: 45 4 ( M + H) + .

[Reference Example 24] (4-{2-[allyl(6-methoxy-3-vinylquinolin-4-yl)amine]ethyl}piperidine-1-carboxylic acid tert-butyl ester

A solution of methyltriphenylphosphonium iodide (1.752 g, 4.33 mmol) in tetrahydrofuran (9 mL) was added at room temperature for 5 min to afford n-butyllithium/hexane (1.57M, 2.76mL, 4.33mmol). After stirring at the same temperature for 30 minutes, it was ice-cooled, and the 4-(allyl{2·[t-(t-butoxycarbonyl)piperidin-4-yl]ethyl}amine obtained in Reference Example 23 was added dropwise over 5 minutes. A solution of 6-methoxyquinoline-3-carbaldehyde (1.31 g, 2.89 mmol) in tetrahydrofuran (6 mL). After stirring at room temperature for 2.5 hours, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and ethyl acetate was evaporated. The extract was washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue obtained was purified by gel column chromatography (hexane·ethyl acetate = 4:1 - 2:1) to give 11.1 g (8 5 %) A labeled compound which is a colorless, transparent, gummy solid. 1H-NMR (400MHz, CDC13) δ: 1.04(2Η, m), 1.4 2 - 1.7 3 (1 4 Η , -196- ' 200946528 m), 2.57(2H, m), 3.35(2H, m), 3 8 7 - 4.0 5 (7 H, m), 5.13- 5.23(2H, m), 5.44(1H, d, J=11.4Hz), 5.78(1H, d, J=17.9Hz), 5.86(1H, m), 7.03 (1H, dd, J = 17.7, 11.2 Hz), 7.2 7 - 7.3 2 (1 H, m), 7.38 (1H, s), 7.97 (1H, d, J = 9.2 Hz), 8.80 ( 1H, s). MS (ESI) m/z: 452 (M + H) + .

[Reference Example 25] 4-[2-(9-Methoxybenzo[h]-l,6-naphthyridin-1(2H)-yl)ethyl]piperidine-1-carboxylic acid tert-butyl ester

The 4-(2-[2-[allyl(6-methoxy-3-vinylquinolin-4-yl)amino]ethyl}piperidine-1-carboxylate obtained in Reference Example 24 was stirred at 40 °C. A solution of the acid tert-butyl ester (1.08 g, 2 - 39 mmol) and Grubbs second generation catalyst (2 〇 3 mg, 0.24 mmol) in toluene (30 mL) for 2 hours, followed by the addition of Grubbs second generation catalyst (203 mg, 0.24 mmol) The mixture was stirred at 50 ° C for 3 hours, and stirred at Q 60 ° C for 14 hours. Further, Grubbs second generation catalyst (203 mg, 0.24 mmol) was added, and the mixture was stirred at 60 ° C for 2 hours, and the solvent was evaporated under reduced pressure. In order of 矽 gel column chromatography (1st, chloroform: methanol = 98:2 - 95:5; 2nd, dichloromethane · acetone = 4:1 - 2:1) and preparative The residue was purified by a thin layer chromatography (EtOAc, EtOAc: EtOAc: EtOAc: EtOAc). C13) δ : 1.0 9 - 1.9 3 ( 1 6 H, m), 2.60 (2H, m), 3.29 (2H, m), 3.92-4.15 (7H, m), 5.78 (1H, m), 6.58 (1H , d, J = 9.2Hz), 7.22-7.27(2H, m), 7.89(1H, d, J = 9.2Hz), 8.36(1H, -197- 200946528 s). MS(ESI)m/z:424 (M + H) + .

[Reference Example 26] 4-[2-(3-hydroxy-9-methoxy-3,4-dihydrobenzo[11]-1,6-naphthyridin-1(2H)-yl)ethyl] Piperidine-i-carboxylic acid tert-butyl ester

4-[2-(9-Methoxybenzo[h]-1,6-naphthyridin-1(2H)-yl)ethyl]piperidine-1-carboxylic acid tertidine obtained in Reference Example 25. A solution of the ester (279 mg, 0.659 mmol) in THF (2 mL), EtOAc (EtOAc m. The reaction solution was ice-cooled, and 4N aqueous sodium hydroxide (1. 65 mL) was added, followed by 30% hydrogen peroxide (1.49 mL), and then stirred at room temperature overnight. After adding water to the reaction mixture, the mixture was extracted with ethyl acetate, and the extract was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, and filtered, and the solvent was evaporated under reduced pressure, and the residue obtained was purified by gel column chromatography (chloroform:methanol = 98:2 - 95:5) to yield 170 mg (58%). A crude product of the labeled compound, which is a yellow gum-like solid. 1H-NMR (400MHz, CDC13) δ : 1 .1 0 -1 . 9 5 (1 6 Η, m), 2.60- 3.65(7H, m), 3.9 1 - 4.0 7 (7 H, m), 7.1 0 - 7.1 5 (1 H, m), 7.27 (1H, m), 7.3 6-7.40 (lH, m), 8.67 (1H, d, J = 9.6 Hz). MS (ESI) m/z: 442 (M + H) + .

[Example 5] 1-{2-[1-(2-Cyclohexylethyl)piperidin-4-yl]ethyl}-9-methoxy-1,2,3,4-tetrahydrobenzo [h]-l,6-naphthyridin-3-ol-198- 200946528

丨〆 Boc OMe

OMe 4-[2-(3-hydroxy-9-methoxy-3,4-dihydrobenzo[h]-l,6-naphthyridin-1(211)-yl)B obtained in Reference Example 26. a solution of the crude product of pyridine pyridine-1 -carboxylic acid, butyl succinate (162 mg, EtOAc) (3 mL), EtOAc (3 mL) hour. The solvent was evaporated under reduced pressure. After a saturated aqueous solution of sodium hydrogencarbonate was added to the residue, the mixture was extracted with chloroform:methanol = 9:j 0 mixed solvent and dried over anhydrous sodium sulfate. The obtained residue was dissolved in a mixed solvent of a crude product of cyclohexylacetaldehyde (content: 54%, 103 mg, 441.441 mmol) and dichloromethane (3 mL) and methanol (0.3 mL). Sodium triethoxy borohydride (156 nig, 0-736 mm 〇l) was stirred at the same temperature for 14 hours. After adding a saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture, it was extracted with a mixed solvent of chloroform:methanol = 9:1. The combined extract was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated evaporated. Preparation of thin layer chromatography (矽 gel, first time, chloroform: methanol: triethylamine = 95:5:0.5; second, chloroform: methanol: triethylamine = 95 · · 5: 0.5) After refining the residue, it was pulverized in diethyl ether to give the title compound 48 mg (29%), which was white powder. 1H-NMR (400MHz, CDC13) δ: 〇·91(2Η, m), 1 · 1 0 - 1.4 2 (1 0 Η, m), 1.66(7Η, tn), 1.87(3Η, m), 2.34 ( (2H, m) . 3 5 - 3 . 5 0 (2 H, m), 3.91 (3H, s), 4.26(1H, m), -199- 200946528 7.10(1H, d, J = 2.3Hz), 7.24(1H, m ), 7.89 (1H, d, J = 9.2 Hz), 8.31 (1H, s). MS (ESI) m/z: 452 (M + H) + .

[Reference Example 27] 3-[N-(2,4-Dinitrophenylsulfonyl)amino]propionic acid ethyl ester

A solution of P-alanine ethyl ester hydrochloride (23.5 3 g, 153.2 mmol), 2,6-lutidine (41.04 mL, 3 52.4 mmol) in dichloromethane (800 mL). 2,4·Dinitrobenzenesulfonyl chloride (43.76 g, 160.8 mmol) was added in minutes. After stirring at room temperature for 2.5 hours, the solvent was concentrated under reduced pressure to give about 300 mL, ethyl acetate (1200 mL) was added, and washed with water, 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate. 1H-NMR (400MHz, CDCh) δ: 1.25 (3Η, t, J = 7.1Hz), 2.61(2H, t, J = 6.0Hz), 3.41(2H, t, J = 5.7Hz), 4.1 4(2H , q, J = 7.2Hz), 6·13(1Η, brs), 8.36(1H, d, J = 8.3Hz), 8.56(1H, dd, J = 8.5, 2.1Hz), 8.68(1H,d, J = 2.3Hz).

[Reference Example 28] 3-(N-{2-[l-(T-Butoxycarbonyl)piperidin-4-yl]ethyl}amine)ethyl propionate

3-[N-(2,4-dinitrophenylsulfonyl)amino group obtained in Reference Example 27] 200946528 ethyl propionate (37.75 g, 108.7 mmol), 4-(2-iodoethyl)peroxide A solution of pyridine-1-carboxylic acid tert-butyl ester (36.87 g, 108.7 mmol) in N,N-dimethylformamide (300 mL) was added with iced water (16-53 g, 119.6 mmol). Stir for 23 hours. The reaction solution was poured into an equivalent of hydrochloric acid, and the combined extract was extracted with ethyl acetate, and then washed with water and saturated brine. After drying over anhydrous sodium sulfate, the mixture was filtered and evaporated.

The obtained residue was dissolved in N,N-dimethylformamide (300 mL), and potassium carbonate (3 7.5 6 g, 271.8 mmol) and ethyl mercaptoacetate (9.1 mL, 13 1 ·0ιηιηο1) were added. Stir at room temperature for 1 · 5 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. After the extract was combined, it was washed with water and brine, dried over anhydrous sodium sulfate and filtered and evaporated. The residue obtained was purified by hydrazine gel column chromatography (chloroform:methanol = 9 8:2 - 95:5 - 9 〇:1 〇) to afford 16-06 g (45%) of oil. 1H-NMR (4〇〇MHz, CDC13) δ: 1.05-1 .1 5(2H, m), 1.25(3H, t, J = 7.1Hz), 1.40- 1.50(12H, m), 1.6 1 -1.6 5 (2 H, m), 2.50 (2H, t, J = 6.4 Hz), 2.62-2.65 (4H, m), 2.87 (2H, t, J = 6.4 Hz), 4.05 (2H, m)> 4.1 3(2H, q, J = 7.3 Hz). MS (ESI) m/z: 329 (M + H) + .

[Reference Example 29] 4-[{2-[l-(Tertidinoxycarbonyl)piperidin-4-yl]ethyl}(3-ethoxy-3-oxopropyl)amino]- Ethyl 6-methoxyquinoline-3-carboxylate

200946528 Ethyl 4-chloro-6-methoxyquinoline-3-carboxylate (10.83 g, 40.8 mmol) was stirred and stirred on an oil bath at 80 °C, and 3-(Ν-{2- [1-(Tertidinoxycarbonyl)piperidin-4-yl]ethyl}amino)propionic acid ethyl ester (I6.06 g, 48.9 mmol), triethylamine (14.2 mL, 1 Ο 1 · 9 mm ο I) and a mixture of dimethyl hydrazine (8 OmL) for 22 hours. After the reaction mixture was stirred at room temperature, water was added and extracted with ethyl acetate. After the extract is combined, it is washed with water and saturated saline. Drying with anhydrous sodium sulfate, filtering, and distilling off the solvent under reduced pressure, and purifying the column by column chromatography (hexane: ethyl acetate = 4:1 > 2:1 - 1:1 - chloroform: acetic acid Ester = 2 : 1 - 1 : 1 - 1 : 2) The obtained residue was purified to give 7.2 g (3 2%) of the title compound as a red oil. 1H-NMR (400MHz, CDC13) δ: 1.01 (3Η, t, J = 7.1 Η z), 1.0 0- 1 - 1 5(2H, m), 1.3 0- 1.85( 1 7H, m), 2.5 3 - 2.6 0 (4 H, m), 3.35 (2H, t, J = 7.6Hz), 3.66(2H, t, J = 7.1Hz), 3.8 9 - 4.0 5 (7 H, m), 4.43 (2H , q, J = 7.2Hz), 7.3 7 - 7.4 0 (2 H , m)5 7.9 8 ( 1 H, d, J = 9.2Hz), 8.87(1H, s). MS(ESI)m/z: 558 (M + H) + .

[Reference Example 30] 1-{2-[T-(t-butoxycarbonyl)piperidin-4-yl]ethyl b- 9-methoxy-4-oxo-oxo-1,2,3,4-tetra Hydrogen benzo[h]-1,6-naphthyridine-3-carboxylic acid ethyl ester

4-[{2-[1-(Tertidinoxycarbonyl)piperidine-4-yl]ethyl}(3-ethoxy-3-oxopropyl)amino) obtained in Reference Example 29] Ethyl -6-methoxyquinoline-3-carboxylate (7.23 g, 12.96 mmol) in ethanol (200 mL), ethoxylated 200946528

Sodium (1.058 g, 15.55 mmol) was stirred and heated on a 40 ° C oil bath for 7 hours. After the reaction mixture was allowed to reach room temperature, it was poured into ice-cooled 3N hydrochloric acid (300 mL), and the obtained mixture was concentrated under reduced pressure to about 300 mL. The obtained aqueous solution was washed with ethyl acetate (300 mL), and after adding sodium hydrogencarbonate to make it alkaline, 1,4-dioxane (300 mL) and dibutyl succinate (5 · 66 g, 2 5.93 mmol), stirred at room temperature for 5 hours. The reaction mixture was extracted with ethyl acetate, and the combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. After filtered, the solvent was evaporated under reduced pressure. Methanol = 9 8 : 2 9 5 : 5 - 9 0 : 1 0 ) The resulting residue gave 4.65 g (yield: 70%) of the title compound as an orange-brown gum solid. 1H-NMR (400MHz, CDC13) δ: 1.1〇-ΐ.85(18Η, m), 1.90- 2.00(1H, m), 2.55-2.70(2H, m), 3 . 3 5 - 3.4 5 ( 1 H , m), 3.60-3.70(1H, m), 3.8 5-4.5 0( 1 OH, m), 7.2 1 - 7.2 6 ( 1 H, m), 7.35-7.42( 1 H, m), 7.9 5 - 8.0 2 ( 1 H, m), 8.9 5 - 9.0 3 ( 1 H, m). MS (ESI) m/z: 5 1 2 (M + H)+.

[Reference Example 31] 4-[2-(9-Methoxy-4-oxo-3,4-dihydrobenzo[h]-l,6-naphthyridin-1(2H)-yl)ethyl ] piperidine-1-carboxylic acid tert-butyl ester, and tert-butoxymethylpiperazin-4-yl]ethyl}-9-methoxy-4-oxo-1,4-dihydrobenzene And [h]-l,6-naphthyridine-3-carboxylic acid ethyl ester

1-{2-[1-(Tertidinoxycarbonyl)piperidin-4-yl]ethyl}-9-methoxy-4-oxo-1,2,3,4 obtained in Reference Example 30 - tetrahydrophenyl hydrazine [h, i.e., 6-naphthoquinone-3-cyan-203- 200946528 acid vinegar (2.68 g, 5.24 mmol) in dimethyl hydrazine (50 mL), sodium chloride (4 60 mg) , 7.86 mmol), and the mixture was heated and stirred for 6 hours on a 13 (TC oil bath. After the reaction mixture was allowed to reach room temperature, a saturated aqueous solution of sodium hydrogencarbonate and water was added, and extracted with ethyl acetate. The extract was washed with water and saturated brine. Drying with anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. residue was purified by gel column chromatography (chloroform: ethyl acetate = 4:1 - 2 ··1 - 1 : 1 ). 1.6 g (34%) of 4-[2-(9-methoxy-4-oxo-3,4-dihydrobenzo[h]-l,6-naphthyridin-1 (2H)) a tert-butyl ester of ethyl]piperidine-1-carboxylate as a red-orange gum-like solid and 0.25 g (9%) of 1-{2-[1-(t-butoxycarbonyl)piperidine Ethyl 4-methoxy]ethylmethoxy-4-oxo-1,4-dihydrobenzo[h]-1,6-naphthyridin-3-carboxylate as a tan solid gum. 4-[2-(9-methoxy-4-sideoxy-3,4-chlorobenzene) [h]-l,6-Caishen-1(2H)_yl)ethyl]piperidine-1-carboxylic acid tert-butyl ester: 1H-NMR (40 0MHz, CDC13) δ : 1.2 0 - 1. 3 5 (2 Η, m), 1.46(9H, s), 1.60- 1.90(3 H,m), 1.91-1.97(2H, m), 2.62-2,75(4H,m), 3.59-3.63 (2H , m), 3.6 7 - 3.7 0 (2 H, m), 3.94 (3H, s), 4.11(2H, m), 7.22 (1H, d, J = 2.8Hz), 7.40(1H, dd, J = 9.2, 2.8 Hz), 7.96 (1H, d, J = 9.2 Hz), 9.06 (1H, s). MS (ESI) m/z: 440 (M + H) +. 1-{2-[1-( Third butoxycarbonyl)piperidin-4-yl]ethyl}-9-methoxy-4-oxo-1,4-dihydrobenzo[h]-l,6-naphthyridin-3-carboxylate Ethyl acetate: 1H-NMR (400MHz, CDC13) δ: 1.2 3 - 1.2 8(2H, m), 1.43- 1.46(1 2Η, m), 1. 5 5 -1 · 7 0 (3 Η, m) , 1 . 9 8 - 2.0 3 (2 Η, m), 2.67(2Η, m), 3.99(3Η, s), 4 · 1 2 (2 Η, m), 4 · 4 5 (2 Η, q, -204- 200946528 J = 7.2Hz), 4.58(2H, m), 7.5 2 - 7.5 7 (2 H, m), 8.21(1H, d, J = 9.2Hz), 8.52(1H, s), 9.66( 1H, s). MS (ESI) m/z: 5 1 0 (M + H) + .

[Reference Example 32] 4-[2-(4-Hydroxy-9-methoxy-3,4-dihydrobenzo[11]-1,6-naphthyridin-1(2H)-yl)ethyl] Piperidine-1-carboxylic acid tert-butyl ester

4-[2-(9-Methoxy-4-oxo-3,4-dihydrobenzo[h]-l,6-naphthyridin-1(2H)-yl) obtained in Reference Example 31 A solution of ethyl iodide-1-carboxylic acid tert-butyl ester (89 mg, 0.20 mmol) in MeOH (4 mL)EtOAc. After adding a saturated aqueous solution of sodium hydrogencarbonate and water to the reaction mixture, the mixture was extracted with chloroform and then chloroform:methanol = 9:1. The combined extract was dried over anhydrous sodium sulfate, filtered, and evaporated. The resulting residue was purified by preparative thin layer chromatography (EtOAc, EtOAc:EtOAc:EtOAc:EtOAc Solid. 'H-NMR (400MHz, CDC13) δ: 1.15 - 1.25 (2Η, m), 1.46 (10H, m), 1.60-1, 70 (2H, m), 1. 8 5 - 2.0 0 (4 H, m ), 2.6 5 - 2.7 1 (2 H, m), 3.24-3.3 7(4H, m), 3.91(3H, s), 4.09(2H, m), 4.89(1H, m), 7.12(1H, d , J = 2.8Hz), 7 · 2 7 - 7 · 2 9 (1 H, m), 7.8 9 (1 H,d, J = 9.2Hz), 8.48(1H, s).

[Example 6] 1-{2-[1-(2-cyclohexylethyl)piperidin-4yl]ethyl}-9-methoxy-1,2,3,4-tetrahydrobenzo [h]-1,6-naphthyridine-4-oil-205- 200946528

4-[2-(4-Hydroxy-9-methoxy-3,4-dihydrobenzo[h]-l,6-naphthalene-stham-1(2H)-yl)ethyl group obtained in Reference Example 32 A solution of piperidd-l-decanoic acid terpene vinegar (82 mg, 0.186 mmol) in dichloromethane (2 mL). The solvent was evaporated under reduced pressure. EtOAc (EtOAc)EtOAc. The combined extract was dried over anhydrous sodium sulfate, filtered, and then evaporated. The obtained residue was dissolved in a mixed solvent of crude cyclohexylacetaldehyde (35 mg, 0.27 7 mmol) and dichloromethane (2 mL) and methanol (2 mL), and triethylhydrazine was added at room temperature. Sodium borohydride (79 mg, 0.373 mmol) was stirred at the same temperature for 15 hours. After adding a saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture, it was extracted with a mixed solvent of chloroform:methanol = 9:1. The combined extract was dried over anhydrous sodium sulfate, filtered, and then evaporated. The residue was purified by preparative thin layer chromatography (purine gel, chloroform:methanol: triethylamine = 300:50:3) and then pulverized in dichloromethane and diethyl ether to give 45 mg (54%). A labeled compound which is a white powder. 1H-NMR (400MHz, CDC13) δ : 0 · 8 5 - 0 · 9 5 (2 Η, m), 1.05- 1.50(1 OH, m), 1.55- 1.75(6H, m), 1.85-2.05 (6H, m), 2.38(2H, m), 2.98(2H, m), 3.2 0 - 3.4 5 (4 H , m), 3.90(3H, s), 4.88(1H, m), 7.12(1H, m), 7 · 2 7 (1 H, m), 7.8 8 (1 H, d, J = 9.2 Hz), 8.47 ( 1 H, s). -206- 200946528 MS (ESI) m/z: 452 ( M + H) + .

[Example 7] 1-{2-[1-(2·cyclohexylethyl)piperidin-4-yl]ethyl}-9-methoxy-2,3-dihydrobenzo[1!] -1,6-naphthyridin-4(111)-one

^0

1-{2-[1-(2-Cyclohexylethyl)acridin-4-yl]ethyl}-9-methoxy·1,2,3,4-tetrahydrobenzene obtained in Reference Example 32 And [h]-l,6-naphthyridin-4-ol (548 mg, 1.213 mm 〇l) in dichloromethane (12 mL), sodium bicarbonate (3 06 mg, 3.64 mmol), followed by Days-Ma Dess-Martin periodinane (796 mg, 1.820 mmol) was stirred at room temperature for 5 hours. Further, Dess-Martin periodinane (796 mg, 1.820 mmol) was added, and after stirring for 16 hours, a 5% aqueous sodium thiosulfate solution (20 mL) and a saturated aqueous The mixture was extracted with a mixed solvent of chloroform:methanol = 9:1. The combined extract was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and purified by column chromatography (chloroform: methanol: triethylamine = 9 8:2:1 - 9 5:5: 1) The residue obtained by crude refining. Thus, a crude product of 431 mg (7 9%) of a labeled compound was obtained as a reddish brown gum solid. Preparative thin layer chromatography (矽 gel, chloroform: methanol: triethylamine = 95:5:1) followed by reverse phase high speed liquid chromatography (Develosil, 2 cm <|) x 10 cm, containing 0.1% formic acid After purifying a part (90 mg, 〇. 200 mmol) of acetonitrile-water mixed solvent, it was pulverized in diethyl ether using 4 equivalents of hydrogen chloride / dioxane as a hydrochloride. 10 mg (10%) of the title compound was obtained as a white powder. -207- 200946528 !Η-ΝΜΚ(400ΜΗζ, CD3OD) 5:0.95 - 1 .0 5 (2Η, m), 1 .20- 1.45(4Η, m), 1.6 3 -1 · 8 5 (1 0 Η, m), 2.09(2Η, m), 2.17(2Η, m), 2.89(2Η, m), 2.99(2Η, m), 3.13(2Η, m), 3.62(2Η, m), 4.02-4.08(7Η , m), 7.57 (1Η, d, J = 2.3Hz), 7.71(1H, dd, J = 9.4, 2.5Hz), 7.89(1H, d, J = 9.6Hz), 8.78(1H, s). MS (ESI) m/z: 450 (M + H)+.

[Example 8] l-{2-[1-(2-cyclohexylethyl)piperidin-4yl]ethyl}-9-methoxy-2,3-diazabenzo[h]- l,6-chao steep - 4 (1H)-嗣

1-{2-[1-(2·Cyclohexylethyl)piperidin-4-yl]ethyl}-9-methoxy-2,3-dihydrobenzo[h] obtained in Example 7. -1,6-naphthyridin-4(1H)-one crude product (234 mg, 0.520 mm 〇l) in pyridine (2.5 mL), hydroxyamine hydrochloride (4 7 mg, 0.676 mmol) Stir for 16 hours. Further, a hydroxylamine hydrochloride (47 mg, 0.676 mmol) was added, and the mixture was stirred for 2 hours, and the solvent was evaporated evaporated evaporated. The extract was combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give a preparative thin layer chromatography (1 g, chloroform: methanol: triethylamine = 60:6:1 The second time, chloroform: methanol = 10:1) the residue obtained by purification. Then, it was pulverized in isopropyl alcohol-diethyl ether to obtain 10 mg (4%) of the title compound as a yellow-white powder. 1H-NMR (400MHz, CD C13 : CD 3 Ο D = 2 : 1) δ : 0.9 0 - 1.0 0 (2 H, m), 1 · 10-1.30(4H, m), 1.4 5 -1 · 9 5 (1 6 Η, m), 2.49(2Η, m), -208- 200946528 2.82(2H,m),2·91(2Η,m), 3.25-3.50(2H,m),3·73(2Η, m), 3.95(3H, s), 7.22 (1H, s), 7.32 (1 H, d, J = 8.7 Hz), 7.87 (1 H, d, J = 8.7 Hz), 9.12 (1H, s). MS (ESI) m/z: 465 (M + H) + .

[Example 9] 1-{2-[1-cyclohexylethyl)piperidin-4-yl]ethyl}-9-methoxy-2,3-dihydrobenzo[h]- l,6-naphthyridine-4(1H)-one 0-methyloxime

1-{2-[1-(2-Cyclohexylethyl)piperidin-4-yl]ethyl}-9-methoxy-2,3-dihydrobenzo[11] obtained in Example 7. -1,6-naphthyridin-4(114)-one crude product (107 mg, 0.23 8 mm) in pyridine (1.2 mL) Stir at room temperature for 16 hours. Further, hydrazine-methylhydroxylamine hydrochloride (26 mg, 0.311 mmol) was added, and after stirring for 2 hours, the solvent was distilled off under reduced pressure to prepare a thin layer chromatography (purified gel, chloroform: methyl alcohol: triethyl) Amine = 100: 5: 1) Purified residue. Using 4 equivalents of a hydrogen chloride / dioxane solution to give the hydrochloride salt, which was obtained from EtOAc (EtOAc) 1H-NMR (400MHz, CD3〇D) 6:0.9 5 - 1.05(2H, m), 1.15- 1.40(6H, m), 1.60- 1.80(8H, m), 2.00-2.15 (4H, m), 2.99 (4H, m), 3.12(2H, m), 3.5 8 - 3.7 4 ( 4 H, m), 3.9 1 - 4.0 2 (8 H, m), 7.45(1H, s), 7.64 (1H, d, J = 8.7 Hz), 7.89 (1H, d, J = 9.2 Hz), 8.86 (1 H, s). -209- 200946528 MS (ESI) m/z: 479 (M + H) + .

[Reference Example 33] 4-{2-[l-(t-butoxycarbonyl)piperidin-4-yl]ethylamino}-6-methoxyquinoline-3-carboxylic acid

Ethyl 4-{2-[1-(t-butoxycarbonyl)piperidin-4-yl]ethylamino}-6-methoxysinolate-3-carboxylate obtained in Reference Example 20 (500 mg To a solution of 1.09 mmol of tetrahydrofuran (4.95 mL), 2N aqueous sodium hydroxide (1. 65 mL) was added, and the mixture was stirred at room temperature for 16 hours and stirred at 50 ° C for 16 hours. After cooling, the tetrahydrofuran was distilled off under reduced pressure, and the residue was diluted with water. After washing with ethyl acetate, it was neutralized by adding 0.5 equivalent of hydrochloric acid to the aqueous layer (pH = 7). The precipitated solid was collected by filtration and dried overnight at 50 <0>C under reduced pressure to afford <3> 1H-NMR (400MHz, DMSO-d6) δ : 0.9 5 -1 .1 0 (2 Η, m), 1.36 (9H, s), 1.60-1.71 (5H, m), 2.5 7 - 2.7 4 (2 H , m), 3 . 8 6 - 3.9 8 ( 7 H , m), 7.48 (1H, d, J = 9.2 Hz), 7.6 9 - 7.7 7 (2 H, m), 8.71 (1H, s). MS (ESI) m/z: 430 (M + H) +.

[Reference Example 34] 4-[2-({3-[(benzyloxy)aminocarbamoyl]-6-methoxyquinolin-4-yl}amino)ethyl]piperidine-1-residic acid Tributyl ester

-210- 200946528 4-{2-[1-(Tertidinoxycarbonyl)piperidin-4-yl]ethylamino}-6-methoxyquinolin-3-carboxylic acid obtained in Reference Example 33 (50〇mg,

Ο N,N-dimethyl ketone: in the amine (20mL) solution 'Add Ν, Ν·diisopropylamine (262μί, 2 · 32 2mmol), 0-(7-azabenzotriazine) 1 _ _)) 1,1,3,3-tetramethylurea hexafluorophosphate (530 mg, 1.39 mmol), 0·benzyl benzylamine (930 mg, 5.83 mmol), triethylamine (812 μί, 5.83 mmol) ), stirring at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine, 1N hydrochloric acid, 10% aqueous sodium carbonate and brine, and dried over magnesium sulfate. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc: · W-NMRHOOMHz, CDC13) δ: 1.06-1.21 (2Η, m), 1.45 (9H, s), 1.64-1 .71 (5H, m), 2.6 0 - 2.7 5 (2 H, m), 3.73 ( 2H, t, J = 6.9Hz), 3.90(3H, s), 4.08(2H, brs), 5.06(2H, s), 7.2 7 - 7.4 8 (9 H, m), 7.83(1H, d, J = 9.2 Hz), 8.39 (1H, s). MS (ESI) m/z: 535 (M + H) + .

[Reference Example 35] 4-[2-(3-Benzyloxy-9-methoxy-2,4-di-oxy-3,4-dihydro-2H-pyrimido[5,4-c] Quinol-1-yl)ethyl]piperidine-1-carboxylic acid tert-butyl ester

The 4-[2-( {3- -211- 200946528 [(benzyloxy))aminomethane]-6-methoxyquinolin-4-yl group obtained in Reference Example 34 was cooled in an ice water bath under an argon atmosphere. Amino)ethyl]piperidine-1- 1-resin acid butyl vinegar (377 mg, 0.71 mmol) in tetrahydrofuran, sodium hydride (oily, containing 55%, 67.7 mg, 1.55 mmol), stirred at the same temperature 10 minutes. Triphosgene (251 mg, 0.8 5 mmol) was added thereto and stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, and a 1% aqueous sodium carbonate solution was carefully added, and the organic layer was separated. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure, and then subjected to column chromatography (the first time, chloroform: methanol = 100:1; second, n-hexane: ethyl acetate = 3: 1 - 1:1-> 1:2) The obtained residue was purified to give 100 mg (25%) of the title compound as a pale yellow crystal free solid. 1H-NMR (400MHz, CDC13) δ: 1.18-1.34(2Η, m), 1.47(9H, s), 1·59(2Η, s), 1.70(1H, d, J=12.4Hz), 1.9 8 - 2.0 8 ( 2 H, m), 2- 63-2.77(2H, m), 3.98(3H, s), 4.0 2 - 4.1 8 (2 H, m), 4.40- 4-48(2H, m), 5.26(2H, s), 7.3 7 - 7.4 4 (3 H, m), 7.5 2 - 7.5 7 (2 H, m)» 7.60-7.66(2H, m), 8.1 2 - 8.1 6 ( 1 H, m ), 9.34 (1H, s). Ms (ESI) m/z: 561 (M + H) + .

[Reference Example 36] 3·Benzyloxy- l-{2-[1-(2-cyclohexylethyl)piperidin-4-yl]ethyl}-9-methoxy-1H-pyrimidine[5 ,4-c]salolin-2,4-dione

4-[2-(3-Benzyloxy-9-methoxy-2,4-di-oxo- 3,4-dihydro-2H-pyrimido[5,4-c] obtained in Reference Example 35 ]Sialolin-1-yl)ethyl]piperidine-1-carboxy-212- 200946528 Acidic tert-butyl ester (100 mg, 0.19 mmol) in dichlorocarbyl (2 mL) solution, added trifluoroacetic acid (〇. 2 mL), stirred at room temperature for 1 hour. After diluting the reaction mixture with methylene chloride, a 10% aqueous sodium carbonate solution was added to adjust to pH = 10. The mixture was extracted with chloroform and dried over anhydrous magnesium sulfate.

Ο The obtained residue was dissolved in dichloromethane (2 mL), and cyclohexylacetate (30.7 mg, 0.24 mmol), acetic acid (23.6 pL, 0.41 mmol) and hydrogenated sodium triacetoxyborate (45.9 mg) were added. , 0.21 mmol), stirred at room temperature for 6 hours. The reaction mixture was diluted with methylene chloride, washed with saturated aqueous sodium hydrogen sulfate and dried over anhydrous magnesium sulfate. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc) IH-NMR (400 MHz, CDC13) δ : 0.8 5 - 0 · 9 7 (2 Η, m), 1.15- 1.23 (3H, m), 1. 3 5 - 1.4 5 (5 H, m), 1.5 9 - 1.7 2 (8 H, m), 1.82- 1.92(2H, m), 1.97-2.04(2H, m), 2.32(2H, t, J = 8.1Hz), 2.93(2H, d, J=11.0 Hz), 3.97(3H, s), 4.3 9 - 4.4 6 (2 H, m), 5.26(2H, s), 7.3 8-7.43(3H, m), 7.5 1 - 7.5 6 ( 2 H, m) , 7.62- 7.64 (2H, m), 8.12 (1H, d, J = 9.0 Hz), 9.34 (1H, s). MS (ESI) m/z: 57 1 (M + H) + .

[Example l] l-{2-[1-Cyclohexylethyl)piperidin-4-yl]ethyl}-3-hydroxy-9-methoxy-111-pyrimidine[5, 4-(:]quinoline-2,4-dione

-213- 200946528 3-Benzyloxy_1-{2-[1-(2-cyclohexyl-ethyl)-piperidin-4-yl]-ethyl}-9-methoxy obtained in Reference Example 36 a solution of keto-1H-pyrimido[5,4-c]salofol-2,4-dione (65 mg, 0.114 mmol) in methanol (50 mL), 10% palladium carbon catalyst (M, containing 50% water, 32 mg), contact hydrogenation at room temperature for 2 hours. The catalyst was filtered off, and the filtrate was washed with a mixed solvent of chloroform:methanol:water = 8:3:0.5. After the combined filtrate and the washing liquid, the solvent was concentrated under reduced pressure, and the residue obtained was purified by preparative thin layer chromatography (chloroform·methanol: water=8··3:0.5) to obtain 38 mg (7 0). %) A labeled compound which is a colorless solid. !Η-ΝΜΚ(400ΜΗζ, CDC13) δ : 0 · 7 9 - 0.9 3 (2 Η, m), 1.02- 1·42 (9Η, m), 1.52- 1.69 (6H, m), 1.77- 1.9 8 ( 3H,m), 2.27(2H, brs), 2.76-2.89(2H, m), 3.96(3H, s), 4.35(2H, brs), 7.56-7.6 4 (2 H, m), 8.04 (1H, d, J = 9.6 Hz), 9.1 0 (1 H, s). MS (ESI) m/z: 48 1 (M + H) +.

[Reference Example 37] 3-(4-Chloro-6-methoxyquinolin-3-yl)-3-oxopropionic acid ethyl ester

Stir monoethyl malonate monopotassium salt (1.226 g, 7.20 mmol), magnesium chloride (1.029 g, 10.81 mmol), triethylamine (2.51 mL, 18.0 mm 〇l) and acetic acid on an oil bath at 50 °C A mixture of ethyl ester (15 mL) was applied for 19 hours (solution A). Next, a solution of 4-chloro-6-methoxyquinoline-3-carboxylic acid (International Publication No. 2004/05 8 1 44, 856 mg, 3.60 mmol) in tetrahydrofuran (15 mL) under ice cooling Carbonyldiimidazole (759 mg, 4.68 mmol) was added and stirred at room temperature for 214-200946528 for 4 hours (solution B). The solution B was added to the solution A under ice cooling, and then stirred at 50 ° C for 26 hours. After adding 1 equivalent of hydrochloric acid to the reaction mixture, the mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the mixture was filtered, and the solvent was evaporated evaporated evaporated]]]]]] %) A labeled compound which is a white solid. 1H-NMR (400MHz, CDC13) δ : 1.2 5 (0.7 5 Η, t, J = 7.1 Hz),

1.3 7 (2.25H, t, J = 6.9Hz), 4.00(3 H, s), 4 · 1 6 (0.5 H, s), 4.21 (0.5H, q, J = 6.6Hz), 4.32(1, 5H, q, J = 6.9Hz), 5.64(0.75H, s), 7.44-7.52 (1 H, m), 7.5 5 - 7.5 6 ( 1 H , m), 8.02-8.06(1H, m), 8.82 (0.75H, s), 8.8 5 (0.25H, s).

[Reference Example 38] 4-(2-{[3-(4-Chloro-6-methoxyquinolin-3-yl)-2-(ethoxycarbonyl)-3-oxopropane-1-ene -1-yl]amino}ethyl)piperidine-1-carboxylic acid tert-butyl ester

The ethyl 3-(4-chloro-6-methoxyquinoline-3-yl)-3-oxopropanoate obtained in Reference Example 37 was heated under reflux in an oil bath at 120 ° C (2.89 g, 9.3 6 mmol). A mixture of triethyl orthoformate (18 niL) and acetic anhydride (9 mL) for 3.5 hours. After distilling off the solvent under reduced pressure, azeotropy was carried out using toluene to remove residual solvent. The residue obtained was dissolved in dichloromethane (50 mL) with EtOAc (EtOAc (EtOAc) Stir under 16 hours. The reaction solution was diluted with ethyl acetate, and washed with 1-215-200946528 equivalent of hydrochloric acid, water and saturated brine. After drying over anhydrous sodium sulfate, the mixture was filtered, and the solvent was evaporated evaporated evaporated. 1.60 g (31%) of crude product of the labeled compound was obtained as an orange gum solid. The obtained crude product was used in the next reaction without performing purification other than this. [Reference Example 3 9] 1-{2-[T-(t-butoxycarbonyl)piperidin-4-yl]ethyl}-9-methoxy-4-oxo-1,4-dihydrobenzene And [h]-l,6-naphthyridine-3-carboxylic acid ethyl ester

4·(2-{[3-(4-Chloro-6-methoxyquinolin-3-yl)-2-(ethoxycarbonyl)-3-oxopropane-1- obtained in Reference Example 38 a crude solution of tert-butyl ester of alkenyl-1-amino]ethyl)piperidine-1-carboxylate (1.60 g, 2.93 mmol) in hydrazine, hydrazine-dimethylformamide (30 mL), Potassium carbonate (526 mg, 3.81 mmol) was heated and stirred on an oil bath of 50 °C for 18 hours. After distilling off the solvent under reduced pressure, 1% aqueous hydrochloric acid was added to the residue and ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine and dried over anhydrous sodium sulfate. The residue was suspended in a mixed solvent of ethyl acetate:hexane = 1:1, and the insoluble material was filtered to give 626 mg (42%) of the title compound as a red-yellow powder. 1H-NMR (400MHz, CDC13) δ: 1.23-1.28 (2Η, m), 1.43- 1.46 (1 2H, m), 1. 5 5 - 1.7 0 ( 3 Η, m), 1.9 8 - 2.0 3 ( 2 Η, m), 2.67(2Η, m), 3.99(3Η, s ), 4 · 1 2 ( 2 Η, m), 4 · 4 5 ( 2 Η, q, J = 7.2Hz), 4.58(2Η, m), 7.5 2 - 7.5 7 (2 Η, m), 8.21 (1Η, d, -216- 200946528 J = 9.2Hz), 8.52(1H, s), 9.66(1H, s). MS(ESI)m /z:5 1 0(M + H) + .

[Example ll] 1-{2-[1-cyclohexylethyl)piperidin-4-yl]ethyl b-9-methoxy-4-oxo-1,4·dihydrobenzo [h]-l,6-naphthyridine-3-carboxylic acid ethyl ester

1-{2-[1-(Tertidinoxycarbonyl)piperidine-4-yl]ethyl}-9-methoxy-4-oxo-1,4-dihydrobenzene obtained in Reference Example 39 And [h]-l,6-naphthyridine-3-carboxylic acid ethyl vinegar (2 5 0 mg, 0 · 4 9 1 mm ο 1) in a solution of dichlorocarbyl (4 m L), add three under ice cooling Fluorineacetic acid (2 mL) was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure. EtOAc (EtOAc) The combined extract was dried over anhydrous sodium sulfate, filtered, and evaporated. The obtained residue was dissolved in a mixture of crude cyclohexylacetaldehyde (93 mg, Q 〇.737 mmol) and dichloromethane (3 mL) and methanol (0.3 mL), and hydrogenated triethylhydrazine was added at room temperature. Sodium borohydride (208 mg, 0.981 mmol) was stirred at the same temperature for 15 hours. After adding a saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture, it was extracted with a mixed solvent of chloroform:methanol = 9:1. The combined extract was dried over anhydrous sodium sulfate, filtered, and then evaporated. The residue was purified by preparative thin-layer chromatography (EtOAc, EtOAc:MeOH:EtOAc:EtOAc To a portion (41 mg, 0.079 mmol) was added ethanol (5 mL), followed by 4N hydrogen chloride / dioxane solution (1 mL) to afford 2 - hydrochloric acid - 217 - 200946528 salt. The solvent was distilled off under reduced pressure and then azeotroped with ethanol (2 times). The residue was pulverized in diethyl ether to give 25 mg (yield: 53%). 1H-NMR (400MHz, CD3〇D) δ: 1.01 (2Η, m), 1. 6 6 -1.4 3 (9 Η, m) 1.63 - 1.95 ( 1 OH, m), 2.05-2.20 (4H, m), 2.97(2H, m), 3.12(2H, m), 3.61(2H, m), 4.11(3 Ή,s), 4.42(2H, q, J = 7.2Hz), 7.91(1H, d, J = 9.2 Hz), 7.94 (1H, s), 8.26 (1H, d, J = 8.7 Hz), 8.92 (1H, s), 9.56 (1H, s). MS (ESI) m/z: 520 (M + H) + .

[Example 12] 1-{2-[1-cyclohexylethyl)piperidin-4-yl]ethyl}-9-methoxy-4-oxo-1,4-dihydrobenzene And [h]-1,6-naphthyridine-3-carboxylic acid

1-{2-[1-(2-Cyclohexylethyl)piperidin-4-yl]ethyl}-9-methoxy-4-oxo-i,4-dihydrofurate obtained in Example 11. A solution of benzo[h]-l,6-naphthyridin-3-carboxylic acid ethyl ester (153 mg, 0.294 mmol) in methanol (2 mL) and THF (2 mL) ), stirred at room temperature for 40 minutes. After adding the equivalent of hydrochloric acid (0.88 mL, 0.88 mmol) to the reaction mixture, the solvent was evaporated under reduced pressure, and water was added to the residue, and the mixture was extracted with chloroform:methanol = 9:1. The combined extract was dried over anhydrous sodium sulfate, filtered, and then evaporated. The residue obtained was purified by preparative thin layer chromatography (EtOAc, EtOAc: EtOAc: EtOAc: EtOAc) -218- 200946528 1H-NMR (400MHz, CDC13) δ : 0.8 7 - 0.9 6 (2 Η, m), 1.13- 1.24(4H, m), 1.4 0 - 1.7 5 ( 1 2 H, m), 1.95 ( 2H, m), 2.11 (2H, m), 2.38(2H, m), 2.99(2H, m), 4.01(3H, s), 4.69(2H, t, J = 8.3Hz), 7.60-7.65(2H , m), 8.28 (1H, d, J = 9.2 Hz), 8.82 (1H, s), 9.67 (1H, s). MS (ESI) m/z: 492 (M + H) + .

[Reference Example 40] 2-Chloro-N-(4-chloro-6-methoxy-quinolin-3-yl)acetamide

A solution of 4-chloro-6-methoxysalthrin-3-ylamine (International Publication No. 2004/05 8 144, 300 mg, 1.44 mmol) in dichloromethane (22 mL) was added in an ice water bath, and potassium carbonate was added. Aqueous solution (_5 37 mg, 3.89 mmol / 15 mL) and chloroethyl chloride (0.154 mL, 1.94 mmol) were stirred at the same temperature for 30 min. Further, an aqueous potassium carbonate solution (268 mg, 0.97 mmol / 2 mL) and chloroacetic acid Q-chloride (yield: 77 mL, 0.927 mmol) were added and stirred at the same temperature for 30 minutes. After separating the aqueous layer, the organic layer was dried over magnesium sulfate and evaporated. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc) 1H-NMR (400MHz, CDCI3) δ: 3.99 (3Η, s), 4.32(2H, s), 7.33-7.40(2H, m), 8.01(1H, d, J = 8.3Hz), 8.93(1 H, Brs), 9.62 (1H, s). MS (ESI) m/z: 285 (M + H) + .

[Reference Example 41] 4-[2-(9-Methoxy-3-oxooxy-3,4-dihydro-2H-pyrido--219-200946528 [2,3-c]quinoline-1- Tert-butyl)ethyl]piperidine-1-carboxylic acid

In the 2-chloro-N-(4-chloro-6-methoxysalthrin-3-yl)acetamide (300 mg, 1.05 mmol) obtained in Reference Example 40, hydrazine, dimethyl-dimethylformamide was dissolved. (6 mL), add potassium carbonate (160 mg, 1.16 mmol) and tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (324 mg, 1.42 mm 〇1), stir at room temperature night. The reaction mixture was diluted with ethyl acetate, washed with brine, aq. The residue obtained was purified by hydrazine gel column chromatography (chloroform: methanol = 70:1) to give 3 96 mg of 2-{2-[1-(t-butoxycarbonyl)piperidin-4-yl. ]Ethyl}amino-N-(4-chloro-6-methoxy-quinolin-3-yl)acetamide as a pale brown solid. The obtained solid was dissolved in N,N-dimethylacetamide (10 mL) and heated at 1 ° C for 5 hours. After cooling, it was diluted with ethyl acetate, washed with a 10% aqueous sodium carbonate solution and brine, dried over magnesium sulfate, and evaporated. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc) 1H-NMR (400MHz, CDC13) δ : 1.0 3 -1 . 1 8 (2 H, m), 1.24- 1.40 (2H, m), 1.44 (9H, s), 1. 5 2 - 1 . 72 (4H , m), 2.5 4 - 2.6 9 (2 H , m), 3.29-3.34(2H, m)} 3.86(2H, s), 3.95(3H, s), 3.98- 4.14(1H,m), 7.22( 1H,d,J = 2.8Hz), 7.25-7.31(1H,m), -220- 200946528 7.96(1H, d, J = 9.2Hz), 8.31(1H, brs), 8.35(1H, s). MS (ESI) m/z: 441 (M + H) +.

[Example 13] 1-{2-[1-(2-cyclohexylethyl)piperidin-4yl]ethyl}-9-methoxy-1,4-dihydro-2H-pyridane [2,3-c]quinolin-3-one

〇

4-[2-(9-Methoxy-3-oxo-3,4-dihydro-2H-pyrido[2,3-c]quinolin-1-yl)B obtained in Reference Example 41 The tert-butyl piperidine-l-carboxylic acid tert-butyl ester (120 mg, 0.27 mmol) was dissolved in dichloromethane (2.7 mL), and trifluoroacetic acid (0.3 mL) was added and stirred at room temperature for 1 hour. A 10% aqueous sodium carbonate solution was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (purified gel, chloroform:methanol:water = 8:3:0.5) to give 60.3 mg (66%) of 9-methoxy-1-[2- (峨t-4-yl)ethyl]-3-oxo-3,4-diaza 2H-pyridin[2,3-c]quinoline, which is a colorless solid. The obtained solid was dissolved in chloroform (2.5 mL) and methanol (1. 〇mL), and cyclohexyl acetaldehyde (29 mg, 0.23 mmol) and acetic acid (3 〇.3 μί, 0.5 3 1 mmol) were added thereto. Stir for 1 hour. Sodium triethoxyborohydride (43.4 mg, 0.195 mmol) was added and stirred at room temperature for 2 days. An aqueous solution of 1% by weight of sodium carbonate was added to the reaction mixture, and the organic material was extracted with a mixed solvent of chloroform:methanol = 5:1. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. The residue obtained was purified by preparative thin-layer chromatography (EtOAc: EtOAc:EtOAc:EtOAc: 1H-NMR (400MHz, DMSO-d6) δ: 0.75-0.89 (2Η, m), 0.97- -221- 200946528 1.30 (10H, m), 1.41-1.80 (1 1H, m), 2.20 (1H, brs) , 2.75(1H, brs), 3. 19-3.27(3H, m), 3.74(2H, s), 3.88(3H, s), 7.14- 7.24(2H, m), 7.81(1H, d, J = 9.2 Hz), 8.31 (1H, s), 10.72 (1H, s)_ MS (ESI) m/z: 45 1 (M + H) + .

[Reference Example 42] 4-Ethoxycarbonyl-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline- 1-butyl)ethyl]piperidine-1-carboxylic acid tert-butyl ester

Dissolving 9-methoxy-2,3-dihydro-1H-[1,4]indolo[2,3-c]quinoline (400 mg, 1.85 mmol) in N,N-dimethylformamidine Add sodium hydride (oily, containing 55%, 161 mg, 3.70 mmol) in an amine (10 mL). After stirring for 1 hour, add 4-ethoxycarbonyl-4-(2-iodoethyl)piperate at the same temperature. Tributyl hydride of pyridine-1-carboxylate (described in International Publication No. 1 999/052895, 913 mg, 2.22 mmol). After stirring for 16 hours while warming to room temperature, water was added and extracted with a solvent of chloroform:methanol:water = 20:3:1. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. Purification by gel column chromatography (1st, hexane-ethyl acetate; 2nd, chloroform-methanol) afforded 56.3 mg (7%) of the title compound as an orange oil. h-NMRHOOMHz, CDC13) δ: 1.19 (3Η, t, J = 7.1Hz), 1.46(11H, m), 2.09- 2.1 8(4H, m), 2.84-3.06(4H, m), 3,20( 2H, t, J = 4.4Hz), 3.95 (5H, m) , 4.1 4 (2 H , q , J = 7.2Hz), 4.1 9(2H, t, J = 4.3Hz), 7.03(1H, d, J = 2.7 Hz), 7.18 (1 H, dd, J = 9., 2, -222- 200946528 2.8 Hz), 7.91 (1H, d, J = 9.3 Hz), 8.38 (1H, s). MS (ESI) ) m / z: 500 (M + H) + .

[Reference Example 43] 4-[2-(9-Methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl)ethyl Ethyl piperidine-4-carboxylate

The 4-ethoxycarbonyl-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indolo[2,3-c]quinidine obtained in Reference Example 42 was obtained. Tert-butyl-1-yl)ethyl]piperidine-l-carboxylic acid (56_3 mg, 0.113 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (0.5 mL) hour. The solvent was distilled off under reduced pressure. After saturated sodium bicarbonate was added under ice-cooling to afford basics, the mixture was extracted with chloroform: methanol: water = 20:3:1. After drying over anhydrous sodium sulfate, the solvent was evaporated. 1H-NMR (400MHz, CDC13) 5:1.20 (3H, t, J = 7.1Hz), 1.25(2H, s), 1.44-1 .5 1 (2H, m), 2.0 9 - 2.2 4 (4 H, m), 2.6 5 - 2.7 4 (2 H, m), 2-94-3 .05 (2H, m), 3.19 (2H, t, J = 4.4Hz), 3.96(3H, s), 4.13(2H , q, J = 7.1Hz), 4.18(2H, t, J = 4.4Hz), 7.05(1H, d, J = 2.9Hz), 7.17(1H, dd, J = 9.0, 2.7Hz), 7.89(1H , d, J = 9.〇Hz), 8.38(1H, s).

[Reference Example 44] 1-(2-cyclohexylethyl)_4_[2-(9-methoxy-2,3-dihydro-1H-[1'4]fluorene[2,3-c] Sodium sulfin-1-yl)ethyl]piperidine-4-carboxylate-223- 200946528

4-[2-(9-Methoxy-2,3-dihydro-1H-[1'4]ophilic [2,3-c]quinoline-i-yl) B obtained in Reference Example 43 Ethyl hydrazide- 4 carboxylic acid ethyl ester (37.6 mg, 〇, 094 mmol), cyclohexyl acetaldehyde (18.0 mg, 0.141 mmol) was dissolved in dichloromethane (1 mL), and acetic acid (0.007 mL, 0.113 mmol), sodium triethoxyborohydride (25_2 mg, 0.113 mmol), stirred for 16 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform:methanol:water = 20:3:1 under solvent. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and purified to silica gel column chromatography (chlorobenzene:methanol=100:1) to give the title compound 44.6 mg (93%) as yellow oil. . 1H-NMR (400MHzJ CD C13) δ : 0.8 5 - 0.9 7 (2 H, m), 1 . 0 8 -1 · 2 9 (9 Η , m), 1.51-1.72 (10Η, m), 1. 9 7 - 2 · 2 5 ( 5 Η, m.), 2 · 3 4 (1 Η, br s), 2.77 (1 Η, brs), 2.9 7 - 3.0 3 (2 Η, m), 3.18 (2 Η, t , J = 4.3Hz), 3.95(3Η, s), 4.12(2Η, q, J = 7.1Hz), 4.18(2H, t, J = 4.2Hz), 7.04(1H, d, J = 2.7Hz), 7.17 (1H, dd, J = 8.9, 2.6 Hz), 7.89 (1H, d, J-9.0 Hz), 8.38 (1H, s). MS (ESI) m/z: 5 1 0 (M + H)+ .

[Example 14] 1-(2-cyclohexylethyl)-4-[2-(9-methoxy- 2,3-dihydro-1H-[1,4]曙 till [2,3- c]quinolin-1-yl)ethyl]piperidine-4-carboxylic acid

-224- 200946528 1-(2-cyclohexylethyl)-4-[2-(9-methoxy-2,3-dihydro-111-[1,4] hydrazine obtained in Reference Example 44 Ethyl [2,3-(:]quinolin-1-yl)ethyl]piperidine-4-carboxylate (44.6 mg, 0.088 mmol) was dissolved in ethanol (3 mL). The sodium aqueous solution (1 ml) was stirred for 2 hours at 1 ° C. The solvent was evaporated under reduced pressure, and then 1N aqueous hydrochloric acid was added to the mixture to adjust to pH 7.4 under ice-cooling: chloroform:methanol:water=7:3 The solvent of the lower layer was extracted 6 times, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was obtained from ethyl acetate and hexane, and the solid was collected to give 1 9.0 mg (43%). The compound is a white solid. 1H-NMR (400MHz, DMSO-d6) δ: 0.8 1 - 0.9 4 (2 Η, m), 1.07- 1.38 (7H, m), 1.44- 1 . 5 5 (2H, m), 1. 5 6 -1.7 1 ( 5 H, m), 1.93-2.13(6H, m), 2.2 0-2.2 9 (2 H, m), 2.6 1 - 2.7 0 (2 H, m), 2.92-3.01(2H, m), 3.14-3.21(2H, m), 3.92(3H, s), 4.1 6 - 4.2 4 (2 H, m), 7.03(1H, d, J = 2.7Hz ), 7.16 (1H, dd, J = 9.3, 2.7 Hz), 7.78 (1 H, d, J = 9.0 Hz), 8.29 (1 H, s).

MS (ESI) m / z: 482 (M + H) + .

[Example 15] 1-(2-{1-[2-(1,4-Dioxaspiro[4.5]癸-6-yl)ethyl]piperidin-4-yl}ethyl)-9- Methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c] saliva

9-Methoxy-b[2-(piperidin-4-yl)ethyl]-2,3-dihydro-111-[1,4]噚[[3,3-] obtained in Reference Example 10. (:) Quinoline (1〇〇«^, 0.305111111〇1) -225- 200946528 in dichloromethane solution (10 mL), added (1,4-dioxaspiro[4.5]癸-6-yl) Aldehyde (68 mg, 0.367 mmol) and hydrogenated sodium triethoxyborohydride (i 2 mg, 0.458 mmol) were stirred for 1 hour. Water (2 mL) was added and stirred for 30 minutes, then 1N aqueous sodium hydroxide solution was added to the reaction mixture. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 10:1). The title compound was obtained as a colorless oil 〇1H-NMR (400MHz, CDC13) δ: 1.21-1.36 (5 Η, m), 1.43- U64 (6H, m), 1,72- 1.77(4H,m),1.84.1.92(3H,m),2·00(2Η, m), 2.42(2H, m), 3.03(2H, brd, J=10.8Hz), 3.09(2H, m) , 3.22(2H, brt, J = 4.4Hz), 3.92(3H, s), 3.9 1 - 3.9 7 (4 H, m), 4.19(2H, brt, J = 4.4Hz), 7.07(1H, d5 J = 2.7 Hz), 7.15 (1H, dd, J = 2.7, 9.0 Hz), 7.87 ( 1H, d, J = 9.0 Hz), 8.36 (1H, s). The above-obtained l-(2-{l-[2-(l,4-dioxaspiro[4·5]癸-6- Ethyl]piperidin-4-yl}ethyl)-9-methoxy- 2,3·dihydro-1Η-[1,4]噚[[,,,,,,,,, A hydrogen chloride/ethanol solution (1 equivalent, 0.61 mL) was added to ethanol (5.0 mL), and the mixture was stirred for 1 minute, and the reaction mixture was concentrated under reduced pressure. After pulverization, the mixture was dried at 40 ° C under reduced pressure to give 137. </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; m)5 2.72(2Η, m), 3.03(2Η, m), 3.5 2 - 3.7 Ο (6 Η , brm), 3.74(3Η, s), 3.99(4Η, m), 4.32(2Η, brm), 7.09 (1Η, d, J = 2.4Hz), 7.34(1 Η, dd, J = 2.4, 9.3Hz), 8.18(1Η, brm), -226- 200946528 8.45(1 H, d, J = 9.3Hz) , 12.0 (1H, brs). HRMS (ESI) m/z: 496.3 1 483 (calculation of C29H42N3〇4: 496.3 1 7 5 3 ).

[Example 16] 2-(2-{4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-indole]quinoline- 1-yl)ethyl]piperidin-1-yl}ethyl)cyclohexanone

Ο

1-(2-{1-[2-(1,4-Dioxaspiro[4.5]癸-6-yl)ethyl]piperidin-4-yl}ethyl)-9 obtained in Example 15 -Methoxy-2,3·dihydro-1H-[1,4]indolo[2,3-&lt;:]quinoline hydrochloride (10 211^, 0.17 9111111〇1) in tetrahydrofuran (10 mL) In the solution, 1N hydrochloric acid (3.0 mL) was added and stirred for 36 hours. After neutralizing with a saturated aqueous solution of sodium hydrogencarbonate, a 1 N aqueous solution of sodium hydroxide was added to the mixture, and the organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (EtOAc, EtOAc: EtOAc: EtOAc: EtOAc) 1H-NMR (400MHz, CDC13) δ : 1 . 3 2 -1 . 5 1 (5 Η , m), 1.63- 1.75 (4Η, m), 1. 8 3 - 1 . 9 0 (3 Η, m) , 1. 9 6 - 2.1 4 ( 5 Η, m), 2.27- 2.45(5Η, m), 3 · 0 0 (2 Η, m), 3 · 0 8 (2 Η, m), 3.21 (2 Η, t, J = 4.4Hz), 3.92(3Η, s), 4.19(2Η, t, J = 4.4Hz), 7.07(1Η, d, J = 2.7Hz), 7.1 5(1H, dd, J = 2.7, 9.1 Hz), 7.87 (1H, d, J = 9. 1 Hz), 8.36 (1H, s). 2-(2-{4-[2-(9-methoxy-2,3-) Dihydro-1H--227- 200946528 [1,4] 曙耕和[2,3-£:]Salolin-1-yl)ethyl]piperidin-1-yl}ethyl)cyclohexanone is dissolved in Dichloromethane (10 mL) was added with a hydrogen chloride / ethanol solution (1 eq, 456 μΙ〇, stirred for 1 minute. The reaction mixture was concentrated under reduced pressure, diethyl ether and pulverized, and the supernatant was removed by decantation. Drying was carried out at 40 ° C under reduced pressure to give 85.5 mg (yield) of the hydrochloride salt of the labeled compound. 1H-NMR (400 MHz, CDC13) δ: 1. 1 9 - 2.3 8 (1 9 Η, m), 2.53 (1Η, m), 2.68(2Η, m), 2.95(1Η, brm), 3.06(1Η, brm), 3.52- 3.71(4Η, brm), 3.98(3Η, s), 4.31(2Η, brs), 7.08(1Η, brs), 7.36(1Η, br d, 9.5 Hz), 8.21 (1 Η, brm), 8.51 (1 Η, d, J = 9.5 Hz), 12.1 (1 Η, brs). HRMS (ESI) m/z : 452.29 1 23 (calculation of C27H38N303: 452.29 1 3 2).

[Reference Example 45] 4-(2-{[3-(Hydroxymethyl)-6-methoxyquinolin-4-yl]amino}ethyl)piperidine-1-carboxylic acid tert-butyl ester

Ethyl 4-({2-[1_(t-butoxycarbonyl)piperidine-4-yl]ethyl}amino)-6-methoxyquinoline-3-carboxylate obtained in Reference Example 20 ( 2 94g, 6.43mm 〇 1M § In a solution of tetrahydrofuran (35 mL), lithium aluminum hydride (488 mg, l2.8 5 mmol) was added under ice cooling, and stirred for 7 hours. Water (5 mL) and 5 eq. Sodium aqueous solution (〇. 5mL), water (i_5mL), stir at room temperature for 14 hours, add diethyl ether, and carry out the ultrasonic wave. Add anhydrous magnesium sulfate to dry -228-200946528, filter, distill off under reduced pressure Solvent, resulting in 2.53 g (95%) of the title compound as a yellow foam. 1H-NMR (400 MHz, CDC13) δ: 1.0 9 -1.2 2 (2 Η, m), 1.45 (9H, s), 1.62-1 .7 1 (5H, m), 2.6 1 - 2.7 4 (2 H, m), 3 . 5 7 - 3.6 5 (2 H, m), 3.93 (3H, s), 4.08 (2H, brs ), 4.80(2H, d, J = 3.7Hz), 4.99(1H, brs), 7.34-7.27(2H, m), 7.90( 1H, d, J = 9.3Hz), 8.28(1 H, d, J = 9.3Hz).

[Reference Example 46] 4-{2-[(3-Methylamino-6-methoxyquinolin-4-yl)amino]ethyl}piperidinecarboxylic acid tert-butyl ester

4-(2-{[3-(hydroxymethyl)-6-methoxyquinolin-4-yl]amino}ethyl)piperidine-1-carboxylic acid tert-butyl ester obtained in Reference Example 45 (3.06 g, 7.3 6 mm 〇l) was dissolved in dichloromethane (73 mL), and manganese dioxide (7.51 g, 〇73·6 mm 〇l) was added at room temperature, and stirred for 1 hour. After filtering the reaction mixture with diatomaceous earth, the solvent was evaporated under reduced pressure. Purification by hydrazine gel column chromatography (chloroform-methanol) gave 2.68 g (8 8%) of the title compound as a yellow amorphous solid. A-NMRHOOMHz, CDC13) δ: 1_13-1·27 (2Η, m), 1.46 (9H, s), 1-63-1, 75 (4H, m), 1.80 (2H, q, J = 6.8Hz) , 2.6 4 - 2.7 8 (2 H, m), 3-92 (3H, s), 3.95-4.01 (2H, m), 4.11 (1H, brs), 7.41 (1H, dd, J&amp;9-3, 2.7 Hz), 7.67 (1H, d, J = 2.7 Hz), 7.91 (1H, d, J = 9.〇Hz), 8*49(1H, s), 9.87(1H, s), 10.13-10.19( 1H, m).

[Reference Example 47] 4-{2-[(3-Hydroxy-6-methoxyquinolin-4-yl)amino]ethyl} -229- 200946528 Tetbutyl pyridine carboxylic acid

4-{2-[(3-Methyl fluorenyl-6-methoxyquinolin-4-yl)amino]ethyl}piperic acid third butyl vinegar (180 mg, 〇.) obtained in Reference Example 46. 435 mmol) was dissolved in a mixed solvent of methanol:dichloromethane = 1 : 1 (4 mL), and potassium carbonate (75 mg, 0.544 mmol) and m-chloroperbenzoic acid (94 mg, After an hour, the temperature was raised to room temperature and stirred for 19 hours. Potassium carbonate (75 mg, 0.544 mmol) and m-chloroperbenzoic acid (9 4 mg, 〇.5 44 mmol) were added under ice cooling, and stirred at room temperature for 4 hr. The addition of saturated baking soda water was extracted with a lower solvent of chloroform:methanol:water = 7:3:1, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol: water = 7:3: 1 solvent) to give 10 mg (63%) of Crystalline solid. 1H-NMR (400MHz, CDC13) δ:1.10-1.31 (2Η, m), 1.45(9H, s), 1 -60-1.77(5H, m), 2.6 2 - 2.7 5 ( 2 H, m), 3.77 (2H, t, J = 7.0Hz), 3-9l(3H, s), 4.08(2H, m), 7.16(1H, d, J = 8.3Hz), 7.31(1H, s), 7.92(1H, d, J = 9.3Hz), 8.14(1H, s).

[Reference Example 48] 4-(2-{[3-(2-ethoxy-2-oxoethoxyethoxy)-6-methoxyquinolin-4-yl]amino}ethyl)piperidin Pyridin-1-carboxylic acid tert-butyl ester-230- 200946528

4-{2-[(3-Hydroxy-6-methoxyquinolin-4-yl)amino]ethyl}piperidine-1-carboxylic acid tert-butyl ester 0.274 mm〇l obtained in Reference Example 47 Dissolved in N,N-dimethylformamide (1 _5 mL), and added potassium carbonate (45 mg, 0.329 mmol), ethyl acetate (〇.〇32 mL, 0.288 mm 〇l) under ice cooling, and warmed up. Stir for 9 hours at room temperature. Add ether and wash with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated, evaporated, mjjjjjjj 1H-NMR (400MHz, CDC13) δ : 1.0 8 -1.2 1 (2 H, m), 1.30 (3H, t, J = 7.1Hz), 1.45(9H, s), 1.60-1 . 72(4H, m ), 2.6 1 - 2.7 5 (2 H, m), 3.5 6-3.64 (2H, m), 3.93 (3H, s), 3.9 9 - 4.1 6 (2 H, m), 4.27 (2H, q, J = 7.2 Hz), 4.73 (2H, s), 4.8 2-4.8 9 (1 H, m), 7.2 6 - 7.2 Ο (2H, ◎ m), 7.88 (1H, d, J = 9.0Hz), 8.37 ( 1H, s). MS (ESI) m/z: 48 8 (M + H) + .

[Reference Example 49] 4-[2-(9-Methoxy-2-oxo-2,3-dihydro-1H-[1,4]indole[2,3-c]salostyl-1 -ethyl)ethyl]piperidine-1-carboxylic acid tert-butyl ester

-23 1- 200946528 4-(2-{[3-(2-ethoxy-2-oxoethoxyethoxy)-6-methoxyquinolin-4-yl]amine obtained in Reference Example 48 The tert-butyl ethyl hydrazide-hydrazine-carboxylic acid tert-butyl ester (82.9 mg, 0.170 mmol) was dissolved in ethanol (3 mL) and heated to reflux for 42 hours. Isopropanol (10 mL) was added, and the mixture was heated under reflux for 3 days. After standing to cool, the solvent was evaporated under reduced pressure. Purification by gel column chromatography (hexane-ethyl acetate) gave 60.7 mg (yield: 81%) of 1H-NMR (400MHz, CDC13) δ : 1 . 0 1 -1 . 1 〇(2 H , m), 1.24- 1.39(2H, m), 1.43(9H, s), 1.4 8 - 1.6 8 (3 H , m), 2.5 3 - 2.6 5 (2 H, m), 3.94 (3H, s), 3.9 5 - 4.0 8 (2 H, m), 4.25 (2H, t, J = 7.6Hz), 4.60 (2H , s), 7.11(1H, d, J = 2.4Hz), 7.31(1H, dd, J = 9.3, 2.7Hz), 8.00-8.04(1 H, m), 8.58(1H, s).

[Reference Example 50] 9-Methoxy-l-[2-(acridin-4-yl)ethyl]-1H-[1,4]indole and [2,3-c]salin-2 ( 3H)-ketone

4-[2-(9-Methoxy-2-oxo-2,3-dihydro-111-[1,4]indole and [2,3-(^quinoline-) obtained in Reference Example 49 Tri-butyl 1-ethyl)ethyl]piperidine-1-carboxylate (60.7 mg, 137. 137 mmol) was dissolved in dichloromethane (1.5 mL), trifluoroacetic acid (0.5 mL) 2 hours. After distilling off the solvent under reduced pressure, &lt;&lt;&gt;&lt;&apos;&gt;&gt; A compound which is a colorless oil. -232- 200946528 1H-NMR (40 0MHz, CDC13) δ : 1.0 2 -1 .1 4 (2 Η, m), 1.23- 1.39(1H, m), 1.50 - 1.64(4H, m), 2.4 5 - 2.5 4 (2 H, m), 2.96- 3.03(2H, m), 3.94(3H, s), 4.24(2H, t, J = 7.6Hz), 4.60( 2H, s), 7.13 (1H, d, J = 2.7 Hz), 7.30 (1H, dd, J = 9.3, 2.7 Hz), 8.01 (1H, d, J = 9.3 Hz), 8.58 (1H, s).

[Reference Example 51] 1-(1-{l-[2-(l,4-Dioxaspiro[4-5]indole-6-yl)ethyl]piperidin-4-yl}ethyl)-9- methoxy-1H-[1,4]indole and [2,3-c]quinoline-2(3H)-

The 9-methoxy-1-(2-piperidin-4-ylethyl)-1Η-[1,4]indole obtained from Reference Example 50 was cultivated and [2,3-c]saltholin-2 (3H) )-ketone (47mg, 0.137mmol), (1,4-dioxaspiro[4.5]癸-6-yl)acetaldehyde (3 3!1^, 0.178111111〇1) dissolved in dichlorocarbyl (3mL) Acetic acid (〇.〇〇9 mL, 0,164 mmol) and hydrogenated sodium triethoxyborohydride (37 mg, 0.164 mmol) were added at room temperature, and stirred for 17 hours. The solvent was saturated under reduced pressure, dissolved in chloroform, and washed with saturated baking soda. After drying over anhydrous sodium sulfate, the solvent was evaporated. 1H-NMR (400MHz, CDC13) δ: 1. 1 3 -1 . 3 8 (6 H , m), 1.42- 1.66 (13H, m), 1.71-1.92 (3H, m), 2.32 (1H, brs) , 2.89(1H, brs), 3.89-3.97(7H, m), 4.2 1 - 4.2 9 (2 H, m), 4.60(2H, s), 7.10-7.14(1H, m), 7.2 8 - 7.3 3 ( 1 H, m), 8.00 (1H, d, J = 9.3 Hz), -233- 200946528 8.57 (1H, s). MS (ESI) m/z: 5 10 (M + H) + .

[Example 17] 9-methoxy-1-(2-(1-[2-(2-oxocyclohexyl)ethyl]piperidin-4-yl}ethyl)-1Η-[1, 4] 噚耕和[2,3-c]Salanta-2(3H)-one

1-(2-{1-[2-(1,4-Dioxaspiro[4.5]癸-6-yl)ethyl]piperidin-4-yl}ethyl)-9 obtained in Reference Example 51 -Methoxy-1H-[1,4]indolo[2,3-c]quinolin-2(3H)-one (42.3 mg, 0.0831]1111〇1) was dissolved in tetrahydrofuran (61111^) 1N hydrochloric acid (2 mL) was added at room temperature, and the mixture was stirred for 6 hours. After adding saturated sodium bicarbonate to make it alkaline, it was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (chloroform-methanol). Then, 4 equivalents of a hydrogen chloride/dioxane solution (0.034 mL) was added. After the ultrasonic treatment, ethanol was added, and the mixture was stirred at 4 ° C for 1 Torr. The solvent was distilled off under reduced pressure. diethyl ether was added, and the mixture was subjected to ultrasonication, and the solid was filtered to afford 23 mg (yield: 48%) of the title compound as a pale yellow solid. 1H-NMR (4〇〇MHz, CDC13) δ : 1 .1 3 -1.4 5 (5 Η, m), 1.48· 1.74(9H, m), 1. 9 3-2.1 3 (3 H, m), 2.2 1 - 2.4 3 ( 5 H, m), 2.77- 2.93(2H, m), 3.94(3H, s), 4.2 0 - 4.2 8 (2 H, m), 4.60(2H, s), 7 · 1 2 (1 H,d,J = 2.4 H z ),7 · 3 0 (1 H,dd,J = 9 · 2,2.6 H z),8 · 0 0 (1 H, d, J = 9.3 Hz) , MS (ESI) m/z: 466 (M + H) + . -234 - 200946528 [Reference 52] l-{2-[1-(T-butoxycarbonyl)piperidine Methyl 4-ethyl]ethyl}-9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline-3-carboxylate

4-{2-[(3-Hydroxy-6-methoxysin-4-yl)amino]ethyl}piperidine-1-carboxylic acid tert-butyl ester obtained in Reference Example 47 (100 mg, 0.249) Methyl acetate in N,N-dimethylformamide (2 mL), potassium carbonate (103 mg, 0-747 mmol), methyl 2,3-dibromopropanoate (0.047 mL, 0.374 mmol) Stir at 2.5 ° C for 2.5 hours. Water was added under ice cooling, and extracted with ethyl acetate. Washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated to dryness crystalljjjjjjjjjjjjj 1H-NMR (400MHz, CDCh) δ: 1.16-1.34 (3Η, m), 1.46(9H, s), 1·62(2Η, brs), 1.6 7 - 1 . 7 6 ( 2 H, m), 1 8 6 - 1.9 6 ( 2 H, m), 2.62- Q 2-76(2H, m), 3 . 1 5-3.23(1H, m), 3 . 3 6 - 3.4 7 ( 1 H, m) , 3.57- 3·65(1Η, m), 3.89(3H, s), 3.93(3H, s), 4.0 5 - 4.1 9 ( 1 H, m), 4·6〇 (1 H, dd, J = 8.4, 2.6 Hz), 7.07 (1H, d, J = 2.9 Hz), 7.21 (1H, dd&gt; J = 9.2, 2.8 Hz), 7.92 (1H, d, J = 9.0 Hz), 8.53 (1H, s) .

[Reference Example 53] 9-Methoxy-l-[2-(piperidin-4-yl)ethyl]-2,3-dihydro-1H-[1,4]indole[2,3- (^quinoline-3-carboxylic acid methyl ester

200946528 The third butoxycarbonyl) piperidinyl-4-yl]ethyl}-9-methoxy-2,3-dihydro-1H-[1,4] hydrazine obtained in Reference Example 52 [2, 3-c]Sodium porphyrin-3-carboxylate (103 mg, 213. 213 mmol) was dissolved in dichloromethane (3niL). The solvent was distilled off under reduced pressure, and saturated sodium bicarbonate was added under ice cooling to become alkaline. The extract was extracted with chloroform. The title compound was evaporated. 1H-NMR (400MHz, CDC13) δ : 1.20- 1. 3 6(2Η, m), 1.41- 1.53(1Η, m), 1.69- 1.77(2Η, m), 1. 8 6 - 1.9 5 (2 Η, m), 2.55- 2.66(3Η, m), 2.8 1 - 2.8 8 (1 Η, m), 3.0 6 - 3.1 4 (2 Η, m), 3.18(1Η, dd, J=14.3 , 8.9Hz), 3 . 3 7 - 3.4 8 ( 1 Η, m), 3.61 (1Η, dd, J=13.9, 2.4Hz), 3.89(3Η, s), 3.93(3Η, s), 4.60(1Η , dd, J = 8.7, 2.6Hz), 7.09(1H, d, J = 2.7Hz), 7.20(1H, dd, J = 9.3, 2.7Hz), 7.92(1H, d5 J = 9.0Hz), 8.54( 1H, s).

[Reference Example 54] 1-(2-{1-[2-(1,4-Dioxaspiro[4.5]fluoren-6-yl)ethyl]piperidin-4-yl}ethyl)-9- Methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinoline-3-carboxylic acid methyl ester

9-Methoxy-1-[2-(piperidin-4-yl)ethyl]-2,3-dihydro-1H-[1,4]indole obtained in Reference Example 53 and [2,3 -c] methyl quinoline-3-carboxylate (72 mg, 〇.187111111〇1), (1,4-dioxaspiro[4.5]fluoren-6-yl)acetaldehyde (4511^, 〇-243 mmol) The solution was dissolved in dichloromethane (5 mL). EtOAc - EtOAc - EtOAc (EtOAc) The solvent was distilled off under reduced pressure, and dissolved in a solvent mixture of chloroform:methanol:water=7:3:1 and washed with saturated sodium bicarbonate. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc It is a pale orange bubble. 1H-NMR (400MHz, CDC13) δ : 1 . 1 8 - 1.9 7 (2 0 Η, m), 2.23 -

2.41(2H, m), 2.7 8 - 2.8 9 ( 1 H, m), 2.9 0 - 3.0 0 (2 H , m), 3.17 (1H, dd, J=14.5, 8.7Hz), 3.3 7 - 3.4 6 ( 1 H, m), 3 . 5 7 - 3.6 3 ( 1 H , m), 3.89 (3H, s), 3.90-4.00 (7H, m), 4.6 1 - 4.5 7 (1 H , m), 7.07 (1H, d, J = 2.7Hz), 7.20(1H, dd, J = 9.3, 2.7Hz), 7.91(1H, d, J = 9.0Hz), 8.53(1H, s). MS(ESI)m/ z: 554 (M + H) +.

[Example 18] 9-methoxy- l-(2-{l-[2-(2-o-oxycyclohexyl)ethyl]piperidin-4-yl}ethyl)-2,3-di Hydrogen-1H-[1,4]噚 and [2,3-c]quinoline-3-carboxylic acid

1-(2-U_[2-(l,4-Dioxaspiro[4.5]癸-6-yl)ethyl]piperidin-4-yl}ethyl)-9-A obtained in Reference Example 54 Oxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]salpin-3-carboxylic acid methyl ester (86.9 mg, 0.157 mmol) were dissolved in tetrahydrofuran (12 mL) 1N hydrochloric acid (4 mL) was added at room temperature and stirred for 4 hours. After adding saturated baking soda water and making it alkaline, it is extracted with chloroform in -237-200946528. After drying with anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, and purified by hydrazine gel column chromatography (chloroform-methanol). 56.9 mg (71%) of the title compound was obtained as a pale yellow oil. 4 parts of hydrogen chloride / dioxane solution (0.02 mL) and diethyl ether were added to one part of the obtained oil (19.4 mg, 0.038 mmol), and the mixture was subjected to ultrasonic treatment, and the solid was collected by filtration to obtain 1 mg (3). 9%) Labeled compound hydrochloride, which is a yellow solid. 1H-NMR (400MHz, CDC13) δ : 0.8 5 - 0.9 1 (2 Η, m), 1.22- 1.47 (6H, m), 1.6 3 - 1.7 6 (3 H, m), 1. 8 1 -1.9 5 (4H, m), 1.98-

2.16(3H, m), 2.2 3 - 2.44 (4 H, m), 2.7 6 - 3.0 0 (3 H, m), 3.18 (1H, dd, J-14.2, 8.5Hz), 3 · 3 5 - 3 · 4 6 ( 1 H, m), 3.60 (1H, d, J = 13.4 Hz), 3.89 (3H, s), 3.93 (3H, s), 4.5 6 - 4.6 2 (1 H, m), 7.07 ( 1H, s), 7.20(1H, d, J = 9.3Hz), 7.92(1H, d, J = 9.3Hz), 8.53(1H, s). MS(ESI)m/z:5 1 0 (M + H)+.

[Example 19] 9-methoxy- l-(2-{l-[2-(2-o-oxycyclohexyl)ethyl]piperidin-4-yl}ethyl)-2,3-di Hydrogen-1H-[1,4]噚[[,3,3-c]quinoline-3-carboxylic acid

The 9-methoxy-1-(2-{1-[2-(2-oxocyclohexyl)ethyl]piperidin-4-yl}ethyl)-2,3- obtained in Example 18 was obtained. Methyl dihydro-1H-[1,4]D§[2,3-c]quinoline-3-carboxylate (42.2mg, 0.083mmol) was dissolved in methanol (imL) and added 1 in ice cold Equivalent sodium hydroxide aqueous solution (0.166 mL, 0 · 1 66 mmol) was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the mixture was neutralized with iced cold -23 8- 2009465. The solvent was distilled off under reduced pressure, and ethanol was added and subjected to ultrasonic treatment. The insoluble matter was filtered off, and the solvent was evaporated under reduced pressure. Ethyl alcohol-hexane was added, and the slurry was stirred at 40 °C. After standing to cool, the solid was filtered to give &lt 1H-NMR (400MHz, DMSO-d6) δ : 1.2 6 - 1 . 3 8 (1 Η, m), 1.48- Ο 2.10(14Η, ra), 2.1 8 - 2.5 5 (3 Η, m), 2.7 9 - 2.9 0 ( 2 Η, m), 2.92-3·〇2(2Η, m), 3.19(1Η, brs), 3.4 0 - 3.6 7 (5 Η, m), 3.76-3.84(1Η, m), 3.95(3Η, s), 5.03(1Η, brs), 7.18(1Η, s), 7.45-7.52(1Η, m), 7.98(1Η, d, J = 9.3Hz), 8.66(1Η, s). MS (ESI) m/z: 496 (M + H) + .

[Reference Example 55] 1-(2-{1-[2-(1,4-Dioxaspiro[4.4]keto-6-yl)ethyl]piperidin-4-yl}ethyl)-9- Methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline

9-Methoxy-1-[2-(piperidin-4-yl)ethyl]-2,3-dihydro-111-[1,4] hydrazine obtained in Reference Example 10 [2,3 -£:]Quotaline (0.1 (^, 0.30111111〇1) in dichloromethane (10 mL) in solution 'add (1,4-dioxaspiro[44]keto-6-yl) Ethyl (0.10 g, 0.61 mmol) and sodium triethoxysulfonium hydride (0.13 g, 0.61 mmol) were stirred at room temperature for 18 hours. Then, acetic acid (0'018 mL, (K2 8 mmol)' was stirred at room temperature for 48 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was evaporated to methylene chloride. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give a column chromatography (dichloromethane: -239 - 200946528 methanol = 10: 1) Purification of the residue to give 0.060 g (yield: 41%) of the title compound as a yellow oily material. 1H-NMR (400 MHz, CDC13) δ:1 .1 9 - 2.3 4 (2 2 Η , m), 3.06- 3.14(3Η, m), 3.2 0 - 3.2 5 (3 Η, m), 3.8 3 - 3.8 5 ( 2 Η, m), 3.93(3Η, s), 4.17-4.22(2Η, m), 7.0 7 - 7.1 1 (1 Η, m), 7.1 4 - 7.1 9 (1 Η, m), 7.89 (1Η, d, J = 9.0Hz), 8.38(1Η, s). MS(ESI)m/z:482( M + H) + [Example 20] 2-(2-{4-[2-(9-methoxy-2) ,3-dihydro-1Η-[1,4]indolo[2,3-c]quinolin-1-yl)ethyl]piperidine-l-yl}ethyl)cyclopentanone

1-(2-{1-[2-(1,4-Dioxaspiro[4.4] keto-6-yl)ethyl]piperidin-4-yl}ethyl)-9 obtained in Reference Example 55 -Methoxy-2,3-dihydro-1 Η-[1,4] hydrazine and [2,3-c]quinoline (0.060 g, 0.12 mmol) in tetrahydrofuran (6 mL), 1 HCl (2 mL), stirred at room temperature for 24 hours. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and then partitioned between two aqueous layers of aqueous sodium hydroxide and methylene chloride. The hydrazine extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by gel column chromatography (dichloromethane:methanol = 1 :1) to give 0.036 g. A yellow turbid oily substance. The obtained compound was dissolved in dioxane (3 mL), and 4 eq. of hydrogen chloride / EtOAc (O.lmL, 0.25 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hr. 0.03 0 (47%) of the labeled compound of -240-200946528 hydrochloride was obtained as a yellow foamy material. 1H-NMR (400MHz, CDC13) δ : 1 .1 9 -1.9 0 (1 6 H, m), 1.93- 2.33(5H, m), 3.0 8 - 3 . 1 2 (2H, m), 3.2 0 - 3.2 5 (3 H, m), 3.93(3H, s), 4.18-4.22(2H, m), 7.09(1H, d, J = 2.7Hz), 7.17(1H, dd, J = 9.2, 2.8Hz) , 7.89 (1H, d5 J = 9.0 Hz), 8.38 (1H, s). MS (ESI) m/z: 43 8 (M + H) + [Example 21] l-{2-[l-(2 -cyclopentylethyl)piperidin-4-yl]ethyl}-9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline

9-Methoxy-1-[2-(piperidin-4-yl)ethyl]-2,3-dihydro-111-[1,4]indole and [2,3) obtained in Reference Example 10. -&lt;:] Quinoline (0.05 (^, 0.15111111〇1) in dichloromethane (5 mL), cyclopentyl acetaldehyde (0.034 g, 0.30 mmol) and sodium triethyl sulfonium hydride (0.065) g, 0.31 mmol), and stirred at room temperature for 3 hours. A saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted with methylene chloride w. After drying over anhydrous magnesium sulfate, the solvent was evaporated in vacuo. The residue was chromatographed (dichloromethane:methanol = 10:1) to give 0.054 g of the title compound as a yellow oily material. The obtained compound was dissolved in dioxane (3mL) The dioxane solution (0.095 mL, 0.38 mmol) was stirred at room temperature for 10 minutes, then evaporated and evaporated, evaporated, evaporated, evaporated. 1H-NMR (400MHz, CDCI3) δ : 1. 〇7 -1.2 0 ( 2 Η, m), 1.52- -241- 200946528 1.94(12H, m), 2.0 0-2.0 8 (2 H, m) , 2.2 6 - 2.4 0 (2 H, m), 2.61-2.75 (2H, m), 2.8 9 - 2.9 9 (2 H, m), 3 . 5 3 - 3.6 1 (4H, m), 3.61- 3.69(2H, m), 3.99(3H, s), 4.2 9 - 4.3 4 (2 H, m), 7.0 8 - 7 · 1 1 (1 H, m), 7.34 (1H, dd, J = 9.2, 2.3 Hz), 8 .1 7 - 8.2 2 (1 H , m), 8.49 (1H, d, J = 9.6Hz MS (ESI) m / z: 424 (M + H) + [EXAMPLE 22] 1·{2-[2-(2-cycloheptylethyl)piperidin-4-yl]ethyl}- 9-methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinoline

9-Methoxy-1-[2-(piperidin-4-yl)ethyl]-2,3-dihydro-111-[1,4 mouth Qin [2,3-] obtained in Reference Example 10. (:) a solution of quinoline (0.0508, 0.15111111〇1) in dichloromethane (5 mL), adding cycloheptylacetaldehyde (0.026 g, 0.19 mmol) and sodium triethyloxyborohydride (〇.〇65g, After stirring at room temperature for 3 hours, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was extracted with methylene chloride. After drying over anhydrous magnesium sulfate, the solvent was evaporated in vacuo. (Dichloromethane:methanol = 10:1). The residue was purified to give EtOAc EtOAc EtOAc EtOAc EtOAc The dioxane solution (011 mL, 0.4 2 mmol) was stirred at room temperature for 10 minutes, then evaporated and evaporated. 1H-NMR (400MHz, CDC13) δ : 1 · 1 7 -1 · 2 9 (3 Η, m), 1.37_ -242- 200946528 1.73(UH, m), 1.7 8 - 1.9 0 ( 4H, m), 1.9 9 - 2.0 9 (2 H, m), 2.26-2.38 (2H, m), 2.5 9 - 2.7 0 ( 2 H, m), 2.9 0 - 2.9 8 (2 H, m), 3.52-3.60 (4H, m), 3.6 0 - 3.6 8 (2 H, m), 3.99 (3H, s), 4.2 9 - 4.3 4 (2 H, m), 7.08-7.1 1(1H, m), 7.36(1H, dd, J = 9.6, 2.3Hz), 8.20-8.24(1H, m), 8.52(1H, d , J = 9.2 Hz). MS (ESI) m/z: 452 (M + H) + [Example 23] l-(2-{4-[2-(9-methoxy-2,3 -2) Hydrogen-1H-[1,4]indole and [2,3-c]quinolin-1-yl)ethyl]piperidine-l-yl}ethyl)cyclohexanol, and ι·{2-Ο [1-(2-Cyclohexylideneethyl)acridin-4-yl]ethyl}-9-methoxy-2,3-dihydro-111-[1,4]哔 and [2,3 -(:]quinoline

+ h〇9c 9·methoxy-l-[2-(piperidin-4-yl)ethyl]-2,3-hydrogen-1 Η-[ 1,4 ]曙哄 obtained in Reference Example 10. And [2,3 - c ] sormine (5 0 · 0 mg, 0 · 1 5 3 mm ο 1) in dichloromethane (3 mL), (1-hydroxycyclohexyl)acetaldehyde (26.1 mg, 0.183 mmol) of dichloromethane (〇. 2 mL) and hydrogenated sodium triethoxyborohydride (48.5 mg, (K229 mmol), stirred for 3 hours. After adding water (1 mL) and stirring for 30 minutes, 0.1 equivalent of the reaction solution was added. Aqueous sodium hydroxide solution was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and then filtered, and the filtrate was concentrated under reduced pressure. :1—10:1) and preparative thin layer chromatography (矽 gel, chloroform: methanol: water = 20:3:1 lower solvent) to refine the residue, respectively, to obtain 17.8 mg-243- 200946528 (2 6 %) 1-(2-{4-[2-(9-methoxy-2,3-dihydro_1^[1,4]噚[[3_{;] quinolin-1-yl)) Benzylpyridin-1-yl}ethyl)cyclohexanol and 171 mg (26°/.) 4-{2-[1-(2-cyclohexylideneethyl)piperidin-4-yl]ethyl I 9 methoxy-2,3- Hydrogen-1H-[1,4]indolo[2,3-c]quinoline, each as a pale yellow oil. 1-(2-{4-[2-(9-methoxy-2, 3-Dihydro·iHqu] 噚耕和[2 3 (;]quinolin-1-yl)ethyl]piperidine-l-yl}ethyl)cyclohexanol: !Η-ΝΜΚ(400ΜΗζ, CDC13) δ : 1.2 5 - 1.7 5 ( 1 7 Η, m), 1.81 - 1.98(4Η, m), 2.10(1Η, m), 2.57(1Η, m), 3.0 2 - 3.1 1 (5 Η, m), 3.2 1 (2Η, m), 3.92(3 Η, s), 4.1 9 (2Η, m) , 7.07(1 Η, d, J = 2.7Hz), 7.15(1Η, dd, J = 2.7, 9.3Hz), 7.87(1Η, d, J = 9.3Hz), 8.36(1Η, s). MS(ESI) m/z: 454(M + H) + 4-{2-[l-(2-cyclohexylethyl) Piperidine_4_yl]ethyl}_9_methoxy-2,3-dihydro-lH-[l,4]Df culti[2,3-c]quinoline: 1H-NMR (400 MHz, CDC13) δ: 1.36 (1Η, m), 1. 5 0 - 1.6 3 (6 Η, m), 1.75 (2Η, brd, J = 11.7Hz), 1. 8 5 - 1.9 7 (6 Η , m) , 2.05(2Η, brt, J=11.2Hz), 2.20(2Η, brm), 2.51(2Η, brm), 3.0 5 - 3 . 1 2 (4 Η, m), 3.22(2Η, t, J = 4.2 Hz), 3.92(3Η, s), 4.19(2Η, t, J = 4.2Hz), 5.43(1H, brm), 7.07(1H, d, J = 2.7Hz), 7.15(1H, dd, J = 2.7 , 9.2 Hz), 7.8 7 ( 1 Η, d, J = 9.2 Hz), 8.3 6 (1 Η, s). MS ( ESI) m/z: 43 6 (M + H) + l_(2-{4-[2-(9-methoxy-2,3-dihydroindole[2,3-c]quinoline- 1-(Ethyl)ethylidenepiperidine-l-yl}ethyl)cyclohexanol hydrochloride-244-200946528 The above-obtained 1-(2·{4-[2-(9-methoxy-2) , 3-dihydro-1H-[1,4]indole and [2,3-c]quinolin-1-yl)ethyl]piperidine-l-yl}ethyl)cyclohexanol dissolved in dichloro A methylene chloride/ethanol solution (1 equivalent, 98 μM) was added to methane (4 mL), and after stirring for 1 minute, the reaction mixture was concentrated under reduced pressure. After the mixture was pulverized by adding diethyl ether to the residue, the supernatant was removed by decantation, and dried under reduced pressure at 40 ° C to obtain 20.6 mg (quant.) of the labeled compound. 1H-NMR (400MHz, CD3OD) δ : 1. 3 0 - 1.9 2 ( 1 5 Η, m), 2.04- 2.08(4Η, m), 2.27(1Η, m), 2.98(2Η, m), 3.23( 2Η, m),

3.62 (2Η, brd, J=11.7Hz), 3.82(2H, m), 4.01(3H, brs), 4.37(2H, m), 7.35(1H, brs), 7.55(1H, brm), 7.87(1H , dd, J = 1.2, 9.3 Hz), 8.35 (1H, brd, J = 1.2 Hz). HRMS (ESI) m/z : 4 5 4.3 0 7 5 7 (C 2 7 Η 4 〇N 3 O 3 Calculated 値: 454.3 0697). 1-{2-[1-(2-Cyclohexylideneethyl)piperidin-4-yl]ethyl}-9-methoxy-2,3-dihydro-1H -[1,4]indolo[2,3-c]quinoline hydrochloride gives 1-{2-[1-(2-cyclohexylideneethyl)piperidin-4-yl]B obtained above }}-9-methoxy-2,3-dihydro-1H-[1,4] hydrazine and [2,3-c]quinoline dissolved in dichloromethane (5 mL), adding hydrogen chloride / ethanol solution (1 eq., 98 μM, stirred for 1 minute, and the reaction mixture was concentrated under reduced pressure. EtOAc was evaporated and evaporated, and then evaporated, and the mixture was removed by decantation and dehydrated at 40 ° C under reduced pressure. Dry to give 20.3 mg (quantitative) of the labeled compound. 1H-NMR (400 MHz, CD3 〇〇) δ: 1. 5 7 - 1.6 9 (5 Η, m), 1.80 (2 Η, brm), 1.99-2.1 〇 ( 8Η, m), 2.39(2Η, m), 2.99(2Η, brt, J=11.7Hz), 3.16(2H, m), 3.61(2H, brd, J=11.7Hz), 3.73(2H, -245- 200946528 m),3.81(2H,m),4 · 01 (3Η, s), 4.36 (2H, m), 5·59 (1Η, brs), 7.35 (1H, d = 2.3Hz), 7.55 (1H, dd, J = 2.3, 9.2Hz), 7.87 ( 1H, d, J = 9.2Hz), 8.47(1 H, s). HRMS(ESI)m/z : 436.29737 (calculation of C27H38N3〇2: 436.29640).

[Example 24] 1-(2-{l-[2-(2,2-difluorocyclohexyl)ethyl]piperidin-4-yl}ethyl)_9-methoxy- 2,3-di Hydrogen-1H-[1,4]曙 and [2,3-c]quinoline

9-Methoxy-1-[2-(piperidin-4-yl)ethyl]-2,3-dihydro-1^1-[1,4]indole[2] obtained in Reference Example 10. , (3)-(2,2-difluorocyclohexyl)acetaldehyde obtained in Reference Example 1〇5, was added to a dichloromethane solution (3 mL) of quinoline (50.0 «1, 0.153111111〇1). 2 9.7 mg, 0.183111111〇1) of dichloromethane (0.11111 〇 solution and hydrogenated sodium triethoxy borohydride (48.5 mg, 0.229 mmol), stirred for 3 hours. After adding water (1 mL) and stirring for 30 minutes, the reaction solution The organic layer was dried over anhydrous sodium sulfate and the desiccant was filtered off. The filtrate was concentrated under reduced pressure. =20:1 - 10:1) and preparative thin layer chromatography (矽 gel, chloroform: methanol: water = 20:3:1 lower solvent) to purify the residue to give 48.5 mg (6 7%) of the labeled compound It is a pale yellow oil. 1H-NMR (40 〇 MHz, CDC13) δ : 1.2 1 - 2.0 9 (2 0 Η, m), 2.38 (2H, m), 2.94 (2H, brd, J=11.5 Hz), 3.09(2H, m), 3.22(2H, t, J = 4.4Hz), 3.92(3H, s), 4.19(2H, t, J = 4.4Hz), 7.08(1H, d, -246- 2 00946528 J = 3.0Hz), 7.15(1H, dd, J = 3.0, 9.0Hz), 7.87(1H, d, J = 9.0Hz), 8.36(1 H, s). l-(2-{l-[ 2-(2,2-Difluorocyclohexyl)ethyl]piperazin_4_yl}ethyl)_9_methoxy- 2,3-dihydro-1Η·[1,4]噚耕和[2 , 3-c]quinoline hydrochloride, 1-(2-{1-[2-(2,2-difluorocyclohexyl)ethyl]piperidin-4-yl}ethyl)-9 obtained above -Methoxy-2,3-dihydro-11^-[1,4]曙 and [2,3-(:]quinoline dissolved in dichloromethane (8 mL), hydrogen chloride / ethanol solution (1 Equivalent, 23 0 μΙ〇' After stirring for 1 minute, the reaction mixture was concentrated under reduced pressure. After diethyl ether was added to the residue and pulverized, the supernatant was removed by decantation, under reduced pressure at 40 °C. Drying gave 54.3 mg (97%) of the title compound as the hydrochloride salt. 1H-NMR (400 MHz, CD3 〇D) δ: 1. 2 8 - 2.1 8 (1 8 Η, m), 2.99 (2 Η, brt, J = 12.0 Hz), 3.19 (2H, brt, J = 9.0 Hz), 3.61 (2H, brd, J = 12.0 Hz), 3.73 (2H, m), 3.82 (2H, m), 4.00 (3H, s) , 4.36(2H, m), 7.34(1H, brs), 7.54(1H, brd, J = 9.3Hz), 7.86(1H, d, ▲ J = 9.3Hz), 8.34(1H, s). 〇HRMS( ESI)m/z : 474.29397 (C27H38F2N3〇2) Zhi: 474.29321).

[Example 25] 9-methoxy-l-(2-{l-[2-(tetrahydro-2H-pyran-2-yl)ethyl]indole-4-yl}•ethyl)- 2,3 -diaza-1H-[1,4]indolo[2,3-c] porphyrin

-247- 200946528 9-Methoxy-l-[2-(piperidin-4-yl)ethyl]-2,3-dihydro-111-[1,4]11 § ploughed in Reference Example 10. And [2,3-(:]quinoline (0.05 (^, 0.15111111〇1) in dichloromethane (5 mL), (tetrahydro-2H-pyran-2-yl)acetaldehyde (0.03 9 g) , 0.30 mmol) and sodium triethyl sulfonium hydride hydride ( 〇 〇 g g g g g g g g g g g g 〇 g 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 3 3 3 饱和After the magnesium was dried, the solvent was evaporated under reduced pressure, and the residue was purified to silica gel column chromatography (dichloromethane:methanol = 10:1) to give 0.062 g of the title compound as a yellow oily material. The compound was dissolved in dioxane (3 mL), and 4 equivalents of chlorinated gas / bismuth solution (O.11 mL, 0.42 mmol) was added, and the mixture was stirred at room temperature for 1 hr. 〇· 〇 5 7 g (72%) of the hydrochloride salt of the labeled compound, which is a pale yellow foamy substance. 1H-NMR (400 MHz, DMSO-d6) δ: 1. 1 1 -1.2 7 (2 Η, m), 1.37- 1.95(15H, m), 2.7 6 - 2.9 0 (2 H, m), 2.9 4 - 3.2 2 (2 H, m), 3.31-3.71(5H, m), 3.8 0 - 3 . 8 9 (2 H, m), 3.96(3H, s), 4.2 9 - 4.3 5 (2 H, m), 7.20-7.25 (lH , m), 7.55 (lH, dd, J = 9.2, 2.3 Hz), 8.02 - 8. 10 (1 H, m), 8.60 (1H, s). MS (ESI) m/z: 44 0 (M + H) + [Example 26] 1^-[1-(2-{4-[2-(9-methoxy-2,3-dihydro-111-[1,4] 曙耕和[2, 3-c] sialolin-1-yl)ethyl]piperate-l-yl}ethyl)cyclohexyl]methylammonium

248-200946528 9 9-methoxy-1_[2_(piperidin-4-yl)ethyl]-2,3-hydrogen-1Η-[1,4]噚[[ 2,3-c]Quinoline (〇.〇5〇g, 〇.i5mmol) in dichloromethane (5mL), added Ν-[1-(2·-oxyethyl)cyclohexyl]methane The decylamine (〇. 〇 67 g, 0.31 mmol) and sodium triethyl sulfonium hydride (0.065 g, 0.3 1 mmol) were stirred at room temperature for 3 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture to extract with dichloromethane. After drying over anhydrous magnesium sulfate, the residue was purified by silica gel column chromatography (dichloromethane:methanol = 1 :1) to afford 0.032 g (3 9%) of . 1H-NMR (400MHz, CDC13) δ : 1 .1 6 -1 . 8 1 (2 Ο Η, m), 1.84- 2.00 (2Η, m), 2.01-2.19 (2Η, m), 2.9 8 - 3 . Ο 2 (4 Η, m), 3.06-3.13(3Η, m), 3.2 Ο - 3.2 5 (2 Η, m), 3.94(3Η, s), 4.1 8 - 4.2 2 (2 Η, m), 7.07 -7.1 0(1 Η, m), 7.1 4 - 7.2 Ο (1 Η, m), 7.89 (1Η, dd, J = 9.0, 3.2Hz), 8.38(1Η, s). MS(ESI)m/z :53 1(M + H) + [Example 27] 1-(2·{4-[2-(9-methoxy- 2,3-dihydro-1Η-[1,4]噚哄[ 2,3-c]quinolin-1-yl)ethyl]piperidine-hydrazinyl}ethyl)cyclohexanecarbonitrile

9-Methoxy-1-[2-(piperidin-4-yl)ethyl]-2,3-dihydro-1^1-[1,4]indole obtained in Reference Example 1 Add a solution of 2,3-〇]pitaline (0.05 (^, 〇.15111111〇1) in dichloromethane (5 mL) with 1-(2-o-oxyethyl)cyclohexanecarbonitrile-249-200946528 ( 0.028 g, 0.18 mmol) and sodium triethoxysulfonium hydride (65 g, 0.3 1 mmol), stirred at room temperature for 2 hours, and then allowed to stand at room temperature for 3 days. Saturated sodium hydrogencarbonate was added to the reaction mixture. The aqueous solution was extracted with methylene chloride. After dried over anhydrous magnesium sulfate, the solvent was evaporated to dryness, and the residue was purified by column chromatography (dichloromethane:methanol = 10:1) to give 0.052 g ( 6 9%) labeled compound, which is a yellow oily substance. Dissolve dioxane (3 mL) in the obtained compound, add 4 equivalents of hydrogen chloride / dioxane solution (0.061 mL, 0.24 mmol), stir at room temperature After 10 minutes, it was evaporated under reduced pressure and evaporated tolulululululululululululululululululululululululululululululululululu , m), 1.33- 1.47(4H, m), 1.59-1.76(6H, m), 1.84- 1.99(6H , m), 2.03- 2.1 3(2H, m), 2.84-2.96(2H, m), 3 . 1 2-3.29(2H, m), 3.3 8- 3.73(6H, m), 3.97(3H, s ), 4.30-4.36(2H, m), 7.2 1-7. 25(1 H, m)s 7.56(1H, dd, J = 9.4, 2.5Hz), 7.9 7 - 8 . 1 〇(1 H , m ), 8.62 (1H, s) · MS (ESI) m/z: 463 (M + H) + [Example 28] l-(2-{l-[2-(l,4-dioxaspiro[ 4,5]癸-7-yl)ethyl]piperazin-4-yl}ethyl)-9-methoxy- 2,3-dihydro-1H-[1,4]ophilic [2, 3-c]quinoline

-250- 200946528 9-methoxy-l-[2-(piperidin-4-yl)ethyl]-2.3-diox-111-[1,4] obtained in Reference Example 10 , 3-(;) quinine (10〇11^, 0.3051111]1〇1) in dichloromethane (10mL), added (1,4-dioxaspiro[4.5]癸-7-yl) Aldehyde (68 mg, 0.367 mmol) and sodium triethoxysulfonium hydride (102 mg, 0.458 mmol) were stirred for 36 hours. After adding water (2 mL) and stirring for 30 minutes, 1N aqueous sodium hydroxide solution was added to the reaction solution, The organic layer was dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 10:1). 133 mg (88%) of the title compound are obtained as a colorless oil. 1H-NMR (400 MHz, CDC13) δ: 0.87 (1 Η, m), 1. 1 5-1.92 (1 9H, m), 2.33 ( 2H, m), 2.93(2H, brd, J=11.2Hz), 3.07(2H, m), 3.20(2H, t, J = 4.3Hz), 3.91(3H, s), 3.92(4H, m), 4.17(2H, t, J = 4.3Hz), 7.06(1H, d, J = 2.7Hz), 7.14(1H, dd, J = 2.7, 9.0Hz), 7.86(1H, d, J = 9.0Hz), 8.35(1H, s). ow 1-(2-{1-[2-(1,4-Dioxaspiro[4.5]癸-7 -yl)ethyl]piperidin-4-yl}ethyl)-9-methoxy-l-[2-(piperidin-4-yl)ethyl]-2,3-dihydro-1H-[1 , 4] 噚耕和[2,3_c]quinoline hydrochloride to give 1-(2-{1-[2-(1,4-dioxaspiro[4.5]癸-7-yl)) Benzylpiperidin-4-yl}ethyl)-9-methoxy-1-[2-(piperidin-4-yl)ethyl]-2.3-dihydro-111-[1,4] And [2,3-〇]quinoline was dissolved in dichloromethane (1〇1111〇, hydrogen chloride / ethanol solution (1 equivalent, 〇. 6 7 mL) was added, stirred for 1 minute -251-200946528, concentrated under reduced pressure The reaction solution was pulverized by adding diethyl ether, and the supernatant was removed by decantation, and dried under reduced pressure at 40 ° C to obtain 166 mg (quant.) of the hydrochloride salt of the labeled compound. 1H-NMR (400MHz, CDC13) δ : 0 9 3 - 2.4 2 ( 1 6 H, m), 2.77 (2H, brm), 2.98 (2H, brm), 3 . 5 7 - 3 . 8 0 (8 H , m) , 3.92(4H, brm), 3.99(3H, s), 4.32(2H, brs), 7.08(1H, brs), 7.29(1H, brd, J=10.0Hz), 8. 1 3(1H, brd, J = 4.6 Hz), 8.38 (1H, brm), 12.1 (1H, brs). HRMS (ESI) m/z: 496.32054 (calculation of C29H42N3O4: 496.3 1 7 5 3 ).

[Example 29] 3-(2-{4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline- 1-yl)ethyl]piperidine-l-yl}ethyl)cyclohexanone

1-(2-{1-[2-(1,4-Dioxaspiro[4.5]]-7-yl)ethyl]piperidin-4-yl}ethyl)-9 obtained in Example 28. -Methoxy-2,3-dihydro-1H-[1,4] hydrazine and [2,3-c]quinoline hydrochloride (108 mg, 0.189 mmol) in tetrahydrofuran (12 mL), 1 Equivalent hydrochloric acid (4.0 mL) was stirred for 36 hours. After neutralizing with a saturated aqueous sodium hydrogencarbonate solution, 0.1N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by preparative thin-layer chromatography (EtOAc: EtOAc:EtOAc:EtOAc:EtOAc - 200946528 1H-NMR (400MHz, CDC13) δ : 1 . 3 0 -1.9 1 (1 3 Η, m), 2.03(2Η, m), 2.21-2.47(7Η, m), 2.91(2Η, brd, J =11.5Hz), 3.09(2H, m), 3.22(2H, t, J = 4.4Hz), 3.91(3H, s), 4.19(2H, t, J = 4.4Hz), 7.07(1H, d, J = 2.7 Hz), 7.15 (1H, dd, J = 2.7, 9.3 Hz), 7.87 (1H, d, J = 9.3 Hz), 8.36 (1H, s). 3-(2-{4-[2-( 9-Methoxy-2,3-dihydro-111-[1,4]indole[2,3-(;]quinolin-1-yl)ethyl]piperidinyl-ethyl}ethyl) Cyclohexanone hydrochloride

3-(2-{4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-indole]quinolin-1) obtained above -Ethyl)piperidin-1-yl}ethyl)cyclohexanone was dissolved in dichloromethane (4 mL), and a hydrogen chloride / ethanol solution (1 eq, 395 μM) was stirred for 1 min. The reaction solution was pulverized by adding diethyl ether, and the supernatant was removed by decantation, and dried under reduced pressure at 40 ° C to obtain 86.6 mg (quant.) of the hydrochloride salt of the labeled compound. 1H-NMR ( 400MHz, CD3OD) δ : 0.9 1 -1.7 6 ( 1 2 Η, m), 2.01 - 2·06(6Η, m), 2·96(2Η, brt, J=12.0Hz), 3.13(2H, m) , 3.59(2H, brd, J=12.0Hz), 3.74(2H, t, J = 4.4Hz), 3.82(2H, m), 4.00(3H, s), 4.36(2H, t, J = 4.4Hz) , 7.35(1H, d, J = 2.6Hz), 7.55(1H, dd, J = 2.6, 9.5Hz), 7.86(1H, d, J = 9.5Hz), 8.34(1H, s). HRMS(ESI) m/z : 4 5 2.2 8 9 9 0 (calculation of C 2 7 H3 8N 3 O 3 452: 452.29132).

[Example 30] trans-9-methoxy-1-(2-(1-[2-(2-methoxycyclohexyl)ethyl]piperidin-4-yl}ethyl)-2, 3-dihydro-1H-[1,4]indole[2,3-c]quinoline-253- 200946528

9-Methoxy-l-[2-(piperidin-4-yl)ethyl]-2,3-dihydro, 111-[1,4]噚 and [2,3) obtained in Reference Example 10. -. To a solution of quinoline (50.〇11^, 0.153111111〇1) in dichloromethane (3 mL), di-(2-methoxycyclohexyl)acetaldehyde (28.6 mg, 0.183 mmol) A solution of methane (〇. 2 mL) and sodium triethyl sulfonium hydride (48, 5 mg, s. 229 mmol) was stirred for 16 hours. After adding water (1 mL) and stirring for 30 minutes, an aqueous solution of hydrazine. The organic layer was dried over anhydrous sodium sulfate, and then filtered and evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc 1H-NMR (400MHz, CDC13) δ : Ο . 9 7 -1. 8 1 ( 1 4 Η, m), 1.90 (2Η, m), 2.00-2.1 4(2Η, m), 2.1 8 - 2.2 4 ( 2 Η , brm), 2.6 2 - 2.6 9 (2 Η, m), 2.77 (1Η, dt, J = 4.2, 10.0Hz), 3.09(2Η, m), 3.18- 3.23(4Η, m), 3.32( 3Η, s), 3.93(3Η, s), 4.19(2Η, t, J = 4.4Hz), 7.07(1H, d, J = 2.7Hz), 7.16(1H, dd, J = 2.7, 9.3Hz), 7.88 (1H, d, J = 9.3 Hz), 8.37 (1H, s). trans-9-methoxy-1-(2-{1·[2·(2-methoxycyclohexyl)ethyl) Piperidine-4_yl}ethyl)-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline hydrochloride gives the trans-9-A obtained above Oxy-^(2-(1-1:2-(2-methoxycyclohexyl)ethyl]piperidin-4-yl}ethyl)-2,3-dihydro-1H-[1,4 ] 噚耕和[2,3-c] Quinoline was dissolved in dichloromethane (4 mL), and a hydrogen chloride/ethanol solution was added (1 when -254-200946528, 44 9 μΙ〇, stirred for 1 minute, concentrated under reduced pressure) The reaction solution was dried under reduced pressure at 40 ° C to give 50.5 mg (yield) of the hydrochloride salt of the labeled compound. 1H-NMR (400 MHz, DMSO-d6) δ: 0.9 5 - 2.1 1 (1 9 Η, m), 2.79(2H, m), 3.01(2H, m), 3.25(3H, s), 3.44(2H, m), 3.6 7 - 3.7 2 (4 H, m), 3.97(3H, s), 4.32(2H, brs), 7.24(1H, d, J = 2.5Hz), 7.56(1H, dd, J = 2.5 , 9.3 Hz), 8.10 (1H, d, J = 9.3 Hz), 8.61 (1H, s).

HRMS (ESI) m/z: 468.32 1 63 (calculated for C28H42N303: 468.32262).

[Reference Example 56] trans- l- [2-(l-{2-[2-(t-butyldimethylmethyloxyalkyl)cyclohexyl]ethyl}piperidin-4-yl)ethyl] -9-methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinoline

9-Methoxy-1-[2-(piperidin-4-yl)ethyl]-2,3-dihydro-111-[1,4]indole[2,3 obtained in Reference Example 10. - 〇 〇 porphyrin (50. 〇 111 §, 0.153111111 〇 1) in dichloromethane solution (3 mL), add trans-[2-(t-butyldimethyl oxalate)cyclohexyl] A solution of (20.9 mg, 198. 198 mmol) in dichloromethane (1 mL) and hydrogenated sodium triacetoxyborate (48.5 mg, 0.229 mmol) was stirred for 18 hours. After adding water (1 mL) and stirring for 30 minutes, a 1 N aqueous solution of sodium hydroxide was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by gel column chromatography (dichloromethane: methanol = 20:1 -&gt; 10:1) to give (76.2 mg, 0·134ιηιη〇1, 88%). A compound which is a pale yellow oil. 4-Amount 11 (4001^112, €0 (:13) 3:0.05 (611,3), 0_89 (eye 8), 0.87-2.05 (21H, m), 2.25 (1H, dt, J = 5.5, 10.6 Hz), 2.44 (1H, dt, J = 4.9, 11.7Hz), 2.94(2H, m), 3.09(1H, m), 3 . 1 7 - 3.2 3 (3 H, m), 3.92(3H, s ), 4.19(2H, t, J-4.2Hz), 7.08(1 H, d, J = 2.7Hz), 7.1 5(1H, dd, J = 2.7, 9.0Hz), 7.87(1 H, d, J = 9.0Hz), 8.36(1H, s).

[Example 3 1] trans-2-(2-{4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-called Quinoline-1-yl)ethyl]piperidin-1-yl}ethyl)cyclohexanol

The trans-l-[2-(l-{2-[2-(t-butyldimethylsilyloxy)cyclohexyl]ethyl}piperidin-4-yl)ethyl group obtained in Reference Example 56 a solution of 9-methoxy-2,3-dihydro-111-[1,4]indolo[2,3-(^quinoline (7511^, 0.132111111〇1) in tetrahydrofuran (10 mL), Add tetrabutylammonium fluoride / tetrahydrofuran solution (1M, 198 μιη, 0.19 8mm 〇l), stir at room temperature for 4 hours. Add tetrabutylammonium fluoride / tetrahydrofuran solution (1M, 462kL, 0-462mmol), stir at 40 ° C 72 hours. Add 1 当量 aqueous sodium hydroxide solution to the reaction solution, extract with dichloromethane, dry the organic layer with anhydrous sodium sulfate, filter the desiccant, concentrate the filtrate, and purify the gel column chromatography. (dichloromethane: methanol = 10:1) and preparative thin layer chromatography (矽 gel, chloroform: methanol: water = 20:3:1 lower layer - 256-200946528) to refine the residue obtained 49.1 mg (82%) of the title compound are obtained as a pale yellow oil. 1H-NMR (400 MHz, CDC13) δ: 1.0 3 - 1.8 8 (1 9 Η, m), 2.02 (1H, m), 2.13 ( 1H, m), 2.34 (1H, ddd, J = 2.3, 5.0, 12.9Hz), 2.49(1H, m), 2.89(1H, brd, J=11.7Hz), 3.0 6 - 3.2 2 (6 H, m), 3.92(3H, s), 4.19(2H, t, J = 4.4Hz), 7.08(1H, d, J = 2.7 Hz), 7.16 (1H, dd, J = 2.7, 9.1 Hz), 7.88 (1H, d, J = 9.1 Hz), 8.35(1H, s). O trans -2-(2-{4- [2-(9-Methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl)ethyl]piperidine-l-yl }ethyl)cyclohexanol hydrochloride gives trans- 2-(2-{4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]fluorene) obtained above Plowing [2,3-(;]quinolin-1-yl)ethyl]piperidin-1-yl}ethyl)cyclohexanol dissolved in dichlorocarbyl (1 OmL), adding hydrogen chloride / ethanol solution (1 eq., 271 μΙ〇, stirring for 1 minute, the reaction mixture was concentrated under reduced pressure. After the residue was added to diethyl ether and pulverized, the supernatant was removed by decantation, under reduced pressure at 40 Drying to give 54.0 mg (95%) of the title compound as the hydrazine hydrochloride. 1 H-NMR (400 MHz, CD3 〇D) δ : 1.0 3 - 2.0 7 (1 9 Η, m), 2.95 (2 Η, m), 3.17(2Η, m), 3.60(2Η, m), 3.7 1 - 3.8 3 ( 5 Η , m), 4.00(3Η, s), 4.36(2Η, t, J = 4.2Hz), 7.34( 1Η, d, J = 2.4Hz), 7.54(lH, dd, J = 2.4, 9.3Hz), 7 .85 (1H, d, J = 9.3 H z), 8.3 4 (1 H, s). MS (FAB) m/z: 454 (M + H) + [Example 32] cis-9-methoxy 4- 4-(1-{l-[2-(2-methoxycyclohexyl)ethyl]piperazin-4-yl}ethyl)-2,3-diaza-1H-[1,4]曙哄[2,3-c]porphyrin-257- 200946528

9-Methoxy-4-[2-(piperidin-4-yl)ethyl]-2,3 -mononitro-1H-[1,4]D% obtained in Reference Example 10 [2, 3-c]Quinine (5〇.〇mg, 0.153mmol) in dichloromethane (3 mL) was added 'cis-(2-methoxycyclohexyl)acetaldehyde (2 8.6 mg, 0.1 83 mmol) A solution of methylene chloride (〇. 9 mL) and sodium hydrogen triacetoxyborate (48.5 mg, 0.229 mmol) were mixed for 4 hours. Water (1 mL) was added and stirred for 30 minutes, and then 0.01 equivalent of aqueous sodium hydroxide solution was added to the reaction mixture to extract with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and then filtered and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc 1H-NMR (400MHz, CDC13) δ : 1.2 1 -1.7 5 (1 5 Η, m), 1.84- 1.90 (3H, m), 1.98 (2H, brt, J=ll, 6Hz), 2.40(2H, m ), 3.02(2H, brd, J= 1 0.8Hz), 3.08(2H, m), 3.2 1 (2H, t, J = 4.4Hz), 3.25(1H, m), 3.29(3H, s), 3.91 (3H, s), 4.18(2H, t, J = 4.4Hz), 7.07(1H, d, J = 2.7Hz), 7.15(1H, dd, J = 2.7, 9.3Hz), 7.87(1H, d, J = 9.3 Hz), 8.35 (1H, s). cis-9-methoxy-4·(2-{l-[2-(2-methoxycyclohexyl)ethyl]piperidine-4-yl }Ethyl)-2,3-dihydro-111-[1,4]indole and [2,3-&lt;:]quinoline hydrochloride gave the above-obtained cis-9-methoxy-4 -(2-{l-[2-(2-methoxycyclohexyl)ethyl]piperazin-4-yl}ethyl)-2,3-dihydro-lH-[l,4]Df哄[2,3-c] Quinoline was dissolved in dichloromethane (4 mL), and a solution of hydrogen chloride in ethanol (1 - 258 - 200946528 equivalent, 3 37 μ Ι〇, stirred for 1 min, concentrated under reduced pressure Drying under reduced pressure at 4 Torr gave 73.8 mg (quant.) of the hydrochloride salt of the labeled compound. 1H-NMR (400 MHz, DMSO-d6) δ: 1 . 0 5 -1.9 1 (1 8 Η, m), 2.83(2Η, m), 2.96(2Η, m), 3.18-3, 22(2Η, m), 3.22(3Η, s), 3.42- 3.66 (5Η, brm), 3.96(3Η, s), 4.31(2Η, brs), 7.22(1Η, brs), 7.55(1Η, d, J = 7.8Hz), 8. 1 1 ( 1H, d, J = 7.8 Hz), 8.59 (1 H, s), 10.6 (1H, brs). 〇HRMS(ESI) m/z : 46 8.3 2 1 6 3 (calculation of C28H42N3 O3: 468.32262).

[Reference Example 57] cis-1-[2-(1-{2-[2-(t-butyldimethylsilyloxy)cyclohexyl]ethyl}piperidin-4-yl)ethyl] -9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline

9-Methoxy-4-[2-(piperidin-4-yl)ethyl]-2,3-dihydro-111-[1,4] hydrazine obtained in Reference Example 10 [2,3 -(:) Quinoline (50.011^, 0.153111111〇1) in dichloromethane (3 mL) was added cis-[2-(t-butyldimethylsilyloxy)cyclohexyl]acetaldehyde ( 50.9 mg, 0.198 mmol) of dichloromethane (1.0 mL) and hydrogenated sodium triethoxyborohydride (48.5 mg, 0.229 mmol), stirred for 4 hours. After adding water (1 mL) and stirring for 30 minutes, the reaction solution Add 1 Torr of aqueous sodium hydroxide solution and extract with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and then filtered, and then evaporated. The filtrate was concentrated under reduced pressure. 矽-259-200946528 gel column chromatography (Dichloromethane:methanol = 50:1 -&gt; 20:1). The residue was purified to give 76.5 mg (8 8%) of the title compound as a colorless oil. 1H-NMR (400 MHz, CDC13) δ: 0.03 (3Η, s), 0·05(3Η, s), 0.90(9Η, s), 1.20- 1.46( 1 OH, m), 1. 5 8 - 1 . 73 (6H, m), 1.84- 1.93( 4H, m), 2.36(2H, m), 2.96(2H, brt, J=1 1.0Hz), 3.09(2H, m), 3.22(2H, t, J = 4.4Hz)s 3.78(1H, m) , 3.92(3H, s), 4.19(2H, t, J = 4.4Hz), 7.08 (1HS d, J = 2.7Hz), 7.16(1H, dd, 5 = 2.7, 9.3Hz), 7.88(1H, d, J = 9.3Hz), 8.37(1H, s).

[Example 33] cis-2-(2-{4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]fluorene[2,3-c]] Quinoline-1·yl)ethyl]piperidine-1-yl}ethyl)cyclohexanol

Cis-1-[2-(1-{2-[2-(t-butyldimethylsilyloxy)cyclohexyl]ethyl}piperidin-4-yl)ethyl group obtained in Reference Example 57 ]-9-Methoxy-2,3-dihydro-lH-[l,4]Df-trap and [2,3-c]salin (75 mg, 0.132 mmol) in tetrahydrofuran (10 mL) A solution of tetrabutylammonium/tetrahydrofuran (1 M, 660 pL, 0.660 mmol) was stirred at 40 ° C for 64 hours. To the reaction liquid, 0.1N aqueous sodium hydroxide solution was added, and extracted with dichloromethane. Dry the organic layer with anhydrous sodium sulfate, filter off the desiccant, and concentrate the filtrate by hydrazine gel column chromatography (dichloromethane: methanol = 2 0:1 - 8:1) and preparative thin layer The residue obtained was purified by chromatography (EtOAc, EtOAc:EtOAc:EtOAc:EtOAc: -260- 200946528 lH-NMR (400MHz, CDC13) δ : 1.2 5 -1 · 7 3 ( 1 7 H, m), 1. 8 4 (2 H, m), 1.94 (2H, brt, J=U. 5Hz), 2.26(1H, m), 2.42(1H, m), 3.00(2H, brt, 11.5Hz), 3.07(2H, m), 3.19(2H, brt, 4.4Hz), 3.74(1H, s) , 3.91(3H, s), 4.17(2H, t, J = 4.4Hz), 7.06(1H, d, J = 2.7Hz), 7.1 5(1H, dd, J = 2.7, 9.0Hz), 7.87(1H , d, J = 9.0Hz), 8.35(1H, s). cis- 2-(2-{4-[2-(9-methoxy- 2,3-dihydro-1H-[1,4噚[[,3,3-c]quinolin-1-yl)ethyl]piperidine-1-yl}ethyl)cyclohexanol hydrochloride

The above-obtained cis-2-(2-{4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]噚][2,3-c] saliva Phenyl-1-yl)ethyl]piperidine-1-yl}ethyl)cyclohexanol was dissolved in dichloromethane (10 mL), and a solution of hydrogen chloride/ethanol (1 eq. The reaction solution was concentrated under reduced pressure. After the residue was added to diethyl ether and then pulverized, the supernatant was removed by decantation, and dried under reduced pressure at 40 ° C to obtain 62.8 mg (quant. Hydrochloride. 1H-NMR (400MHz, CD3〇D) δ : 1. 3 Ο - 2 . Ο 8 ( 1 9 Η, m), 2.96 (2Η, ο brt, J = 12.0Hz), 3 · 1 2 ( 2 Η,m),3 · 6 0 (2 Η,brd,J = 1 2 · Ο Hz), 3.72(2H, t, J = 4.1Hz), 3.7 7 - 3.8 1 (3 H, m) , 4.00(3H, s), 4.35(2H, t, J = 4.1 Hz), 7.34(1H, d, J = 2.4Hz), 7.54(1H, dd, J = 2.4, 9.5Hz), 7.85(1H, d, J = 9.5 Hz), 8.34 (1H, s). HRMS (ESI) m/z : 4 5 4.3 0 6 7 1 (calculation of C 2 7 H4 〇N 3 〇3 : 454.30697).

[Example 34] 1-(2-{4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline- 1-yl)ethyl]piperidine-1-yl}ethyl)piperidin-2-one-261- 200946528

OHC

9-Methoxy-1·[2-(piperidin-4-yl)ethyl]-2,3 -hydrogen-1Η-[1,4]曙哄[2,3 obtained in Reference Example 10. -c]a solution of quinoline (〇.〇5g, 0.15mmol) in dichloromethane (5mL), (2-trioxypiperidin-1-yl)acetaldehyde (0.043g, 0-30mmol) and triethyl hydrogenhydride Sodium borohydride (〇.〇65g, 0.3 1 mmol) was stirred at room temperature for 18 hours. A saturated aqueous solution of saturated sodium hydrogencarbonate was added to the mixture and the mixture was evaporated. After drying over anhydrous magnesium sulfate, the residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to afford y. The obtained compound was dissolved in dioxane (3 mL), and 4N aqueous hydrogen chloride / dioxane (yield: 51 mL, 0.20 mmol) was added thereto, and the mixture was stirred at room temperature for 10 minutes, and then evaporated under reduced pressure and dried. 0.036 g (45%) of the hydrochloride salt of the title compound was obtained as a yellow foamy material. 1H-NMR (400MHz, DMSO-d6) δ: 1.22- 1.28( 1 H, m), 1.52- 1.80(7Η, m), 1.83- 1.96(3Η, m), 2.2 0 - 2.2 9 ( 2 Η, m), 2.82- 2.95(1Η, m), 3.1 2 - 3 .1 9 ( 1 Η, m), 3.2 2 - 3.3 5 (3 Η, m), 3.47- 3.71(8Η, m), 3.97(3Η, s), 4.0 5 - 4.0 7 ( 1 Η, m), 4.3 0 - 4.3 6 (2 Η, m), 7.22-7.27( 1Η, m), 7.5 3 - 7.5 9 ( 1 Η, m ), 7.9 9 - 8.0 7 (1 Η, m), 8.62 (1 Η, s). MS (ESI) m/z: 45 3 (M + H) + [Example 35] 2-(2_{4- [2-(9-Methoxy-2,3-dihydro-lH-[l,4]Bf-[2,3-c]quinolin-1-yl)ethyl]piperidine-l-yl }Ethyl)cyclohexanone oxime-262- 200946528

Add 2-Hydroxylamine hydrochloride (11. -{4-[2-(9-Methoxy-2,3-dihydro-1H-[1,4]indolo[2,3-c]quinolin-1-yl)ethyl]indole A solution of 1-ethylidene ethyl)cyclohexane (46.7 mg, 0.1 mmol) in ethanol (4 mL) was stirred at 60 ° C for 9 hours, then 0.1 N aqueous sodium hydroxide was added to the reaction mixture to dichloride. Methane extraction. The organic layer was combined, dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by gel column chromatography (dichloromethane: methanol = 20:1 - 10:1 - chloroform:methanol: water = 20:3:1) to give 38.6 mg (8 0) %, a mixture of cis, trans isomers) a labeled compound which is a pale yellow oil. Major isomer = *Η-ΝΜΚ(400ΜΗζ, CD C13) δ : 1 . 3 2 - 2.6 0 (2 3 H, m), 3.03- 3.09(4H, m), 3.20(2H, m), 3.90 ( 3H, s), 4.18(2H, m), 7.06(1 H, d, J = 2.7Hz), 7.15(1H, dd, J = 2.7, 9.3Hz), 7.90(1 H, d, J = 9.3Hz ), 8.37(1H, s). Minor isomer: iH-NMRMOOMHz, CDC13)S: 3.92(s). (only for methoxy-rich peaks) 2-(2-{4-[2-( 9-Methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinolin-1-yl)ethyl]piperidine-l-yl}ethyl) Cyclohexanone oxime hydrochloride gives 2-(2-{4-[2-(9-methoxy-2,3-dihydro-1H-[1,4] 噚 till [2,3] obtained above) -(:]quinolin-1-yl)ethyl]piperidin-1-yl}ethyl)cyclohexanone-263- 200946528 肟 dissolved in dichloromethane (8 mL), adding hydrogen chloride / ethanol solution (1 equivalent After stirring at 207 μM for 1 minute, the reaction mixture was concentrated under reduced pressure. After diethyl ether was added to the residue and pulverized, the supernatant was removed by decantation, and the mixture was dehydrated at 40 ° C under reduced pressure. Drying gave 45.6 mg (quant.) of the hydrochloride salt of the labeled compound. 1H-NMR (400 MHz, CD3OD) δ: 1. 3 9 - 2.4 2 (1 8 Η, m), 2.93- 3.21 (5 Η, m), 3.60 (2Η, brt, Jl 1 , ΟΗζ), 3.73(2H, m), 3.82(2Η, m), 4.00(3Η, s), 4.36(2Η, m), 7.34(1Η, brs), 7.54(1Η, Brd, J = 9.3 Hz), 7.86 (1H, 9.3 Hz), 8.34 (1H, brs). HRMS (ESI) m/z: 467.29983 (calculation of C27H39N403: 467.3022 1 ).

[Example 36] 2-(2-{4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline- 1-yl)ethyl]piperidine-l-yl}ethyl)cyclohexanone 0-methylindole

To a solution of the methoxyamine hydrochloride (13-9 mg, 0.17 mmol) and sodium acetate (10.Omg, 0.12 mmol) in water (1 mL)-ethanol (5 mL) 4-[2-(9-Methoxy-2,3-dihydro-1H-[1,4]indole[2,3-(:]quinolin-1-yl)ethyl]piperidine- A solution of 1-yl}ethyl)cyclohexanone (50.0 mg, O.llmmol) in ethanol (4 mL) was stirred at 60 ° C for 9 hr. Methane extraction. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and then filtered, and the filtrate was concentrated under reduced pressure. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Methylene chloride: methanol = 2 0:1 - -264 - 200946528 10 : 1) Purification of the residue to give 44.0 mg (83%, mixture of cis, trans isomers) of the title compound as white amorphous. Main isomer: 1H-NMR (400MHz, CDC13) δ : 1 2 9 - 2.0 2 ( 1 8 H, m), 2.22(1H, m), 2.3 3 -2.5 2(3 H, m), 3.00(2H, brd, J=11.0Hz), 3.19(2H, m ), 3.22(2H, t, J = 4.0Hz), 3.80(3H, s), 3.92(3H, s), 4.20(2H, t, J = 4.0Hz), 7.08(1H, d, J = 2.7Hz ), 7.1 6(1H, dd, J = 9.3, 2.7Hz), 7.88(1H, d, J = 9.3Hz), 8.38(1H, s),

Minor isomer: 1H-NMR (400MHz, CDC13) δ : 3 · 7 8 (s). (Only the peak of methyl group belonging to 〇-methyl oxime) 2-(2-{4-[2- (9-Methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinolin-1-yl)ethyl]piperidine-l-yl}ethyl Cyclohexanone oxime-methyl hydrazine hydrochloride gives the 2-(2-{4-[2-(9-methoxy-2,3-dihydro-1H-[1,4] fluorene) obtained above And [2,3-c] sialolin-1-yl)ethyl]piperidine-1-yl}ethyl)cyclohexanone oxime-methyl oxime was dissolved in dichloromethane (8 mL), and hydrogen chloride/ethanol was added. The solution (1 equivalent, 229 μM, stirred for 1 minute, the reaction mixture was concentrated under reduced pressure. After the residue was added to diethyl ether, the residue was removed, and the supernatant was removed by decantation. The residue was dried to give 50. 0 mg (yield: 99%) of the title compound as the hydrochloride salt. 1H-NMR (400 MHz, CD3 〇D) δ: 1. 3 9 - 2.2 9 (1 7 H, m), 2.93- 3.02(3H, m), 3 · 1 8 (2 H,m),3 · 6 1 (2 H,m),3 · 7 4 - 3.8 4 (7 H,m), 4.01(3H, s), 4.36(2H, m), 7.35(1H, brs), 7.54(1H, brd, J = 9.5Hz), 7.86( 1H, d, J = 9.5Hz), 8.34(1H, s). -265- 200946528 HRMS (ESI)m/z: 48 1 ·3 1 98 1 ( Calculation of C28H41N403: 48 1.3 1 786).

[Reference Example 58] {1-[2-(l,3-di-oxy-1,3-dihydro-2H-isoindol-2-yl)ethyl]piperidin-4-yl}amino group Tert-butyl formate

N-(2-bromoethyl)benzonitrile (699 mg, 2.75 mmol), piperidin-4-ylaminocarbamic acid terpene vinegar (500 mg, 2.50 mmol) was dissolved in N,N-dimethyl Potassium carbonate (449 mg, 3.25 mmol) was added to carbamide (10 mL) and stirred at 70 ° C for 12 hours. Ethyl acetate was added, and the mixture was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. Purification by gel column chromatography (chloroform-methanol) gave 701 mg (75%) of !Η-ΝΜΚ(400ΜΗζ, CDC13) δ : 1.2 6 - 1 . 3 8 (2 Η, m), 1.43(9Η, s), 1. 84- 1.92(2Η, m), 2 . 1 Ο - 2.1 9 (2 Η, m), 2.61 (2Η, t, J = 6.6Hz), 2.84-2.91 (2Η, m), 3.44(1Η, brs), 3.80(2Η, t, J = 6.7Hz), 4.37 (1H, brs), 7.6 9 - 7.7 3 (2 H, m), 7.8 5 - 7.8 3 (2 H, m).

[Reference Example 59] [1-(2-Aminoethyl)piperidin-4-yl]carbamic acid tert-butyl vinegar

The {1-[2-(1,3-di- oxy-1,3-dihydro-2H-isoindol-2-yl)ethyl]piperidin-4-yl}amino group obtained in Reference Example 58 was obtained. The tert-butyl formate (492, 1, 32 mm) was dissolved in ethanol (10 mL), and hydrazine 1 hydrate 200946528 (0.32 mL, 5.28 mmol) was added at room temperature and stirred at 40 ° C for 19 hours. After standing to cool, ethanol was added and the insoluble material was filtered off, and the solvent was evaporated under reduced pressure to give 388 mg (yield) of the title compound as white solid. 1H-NMR (400MHz, CDC13) δ: 1.44 (9Η, s), 1.6 9 -1.8 7 (4 Η, m), 1.92 (2Η, d, J = 10.7Hz), 2.09 (2Η, t, J =i〇7Ηζ), 2.39(2Η,t, J = 6.2Hz), 2.77(4H, m), 3.47(1H, brs), 4.43(1H, brs).

[Reference Example 60] {l-[2-(9-Methoxy-3,4-dihydrobenzo[h]-16·naphthyridin-1(2H)-yl)ethyl]piperidin-4- Amino acid carboxylic acid

4-Chloro-3-(3-chloropropyl)-6-methoxyquinoline (311 mg, 1.15 mmol) obtained in Reference Example 3, [1-(2-aminoethyl) obtained in Reference 59 The piperidin-4-ylaminocarbamic acid tert-butyl ester (2 80 mg, 1.15 mmol) was dissolved in acetonitrile (10 mL), and potassium carbonate (350 mg, 2.53 mmol) was added at room temperature and stirred at 80 ° C for 2 days. N,N-dimethylformamide (10 mL) was added, and the mixture was stirred at 130 ° C for 3 days. Water was added, and the mixture was extracted with ethyl acetate and washed with brine. After drying over anhydrous sodium sulfate, the solvent was evaporated, evaporated, mjjjjjjj 1H-NMR (400MHz, CDC13) δ : 1. 3 3 -1.42( 1 H, m), 1.44(9H, s), 1.86- 1.95(4H, m), 2.1 3 - 2.2 1 (1 H, m) , 2.8 2 - 2.9 0 (6 H, m), 3.23 -3.3 6(4H, m), 3.4 0 - 3.5 2 ( 2 H, m), 3.94 (3H, s), 3.96-4.00 (1H, m) , 4.36-4.47(lH, m), 7.2 2 - 7.2 5 ( 2 H , m), 7.88- -267- 200946528 7.92(1H, m), 8.34(1H, s). Hydroquinone [h]-l ,6-naphthyridine_ [Reference Example 61] l-[2-(9-Methoxy_3,4_bis1(2H)-yl)ethyl]piperidin-4-ylamine

Let { 1 - [ 2 - (9) obtained in Reference Example 60

(72 mg, 0.162 mm of 〇I) was dissolved in dichloromethane (2 mL), and difluoroacetic acid (.5 mL) was added under ice cooling, and stirred for 1 hour. The solvent was distilled off under reduced pressure to dissolve the chloroform:methanol:water = 7 : 3 : 1 solvent and washed with saturated sodium bicarbonate. After drying over anhydrous sodium sulfate, the solvent was evaporated. 1H-NMR (400MHz, CDC13) δ : 1.2 2 - 1.2 7 (1 H, m), 1.34- 1.40 (2H, m), 1.77- 1.84 (2H, m), 1. 8 7 - 1.9 5 (2 H, m), 2.08- 2.16(2H, m), 2.6 2 - 2.7 2 (1 H , m), 2.8 4 - 2.9 1 (7 H, m), 3.25- 3.29 (2H, m), 3.2 9 - 3 . 3 5 (2 H, m), 3.95 (3H, s), 7.2 2 - 7.2 6 (2 H, m), 7.87-7.91 (lH, m), 8.35 (1H, s).

[Example 37] 6-[({l-[2-(9-methoxy-3,4-dihydrobenzo[h]-l,6-naphthyridin-1(2-yl)ethyl) ]piperidin-4-yl}amino)methyl]-211-pyrido[3,2-b][l,4]indole-3(4H)-one

-268- 200946528 1-[2-(9-Methoxy-3,4-dihydrobenzo[h]-l,6-naphthyridin-l(2H)-yl)ethyl group obtained in Reference Example 61 Piperidin-4-ylamine (47 mg, 0·138 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]IIf-well-6-formaldehyde (International Publication No. 2004/05 8 1 44, 27 mg, 0.152 mmol) was suspended in dichloromethane: methanol = 1:1 mixed solvent (4 mL), and acetic acid (〇.〇12 mL, 0.207 mm〇) was added under ice cooling. l), sodium cyanoborohydride (10 mg, 152. 152 mm 〇l), and stirred at room temperature for 13 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 distilled off under reduced pressure, and purified by preparative thin layer chromatography (purified gel, chloroform:methanol = 7:3:1 lower solvent). The obtained crude product was taken up in dichloromethane-diethyl ether and filtered to afford 6 to 4 mg (yel. 1H-NMR (400MHz, CDC13) δ: 1.26 (1Η, brs), 1. 3 6 - 1.4 8 (2 Η, m), 1.85- 1.95(4H, m), 2.11(1H, m), 2.48-2 57(2H, m), 2.82-2.94(6H, m), 3.25 -3.3 0(2H, m), 3.31-3. 37(2H, m), 3 .8 1 (2H, s), 3, 94(3H, s), 4.63(2H, s), 6 • 92(1 H, d, J = 8. 1Hz), 7.19(1H, d, J-8.1Hz), 7.23- 7.25(2H ,m) , 7.89-

7.93 (1 Η, m), 8.34 (1 Η, s). MS (ESI) m/z: 503 (M + H) + .

[Reference Example 62] [1-(Chloroethyl)piperidin-4-yl]aminocarboxylic acid tert-butyl ester

The piperidin-4-ylaminocarbamic acid tert-butyl ester (500 mg, 2.50 mmol) was dissolved in tetrahydrofuran (15 mL), and triethylamine (0 3 83 mL, -269 - 200946528 2.75 mmol) was added under ice cooling. Chloroacetyl chloride (0.219 mL, 2.75 mmol) was stirred for 2 hours. After distilling off the solvent under reduced pressure, ethyl acetate was added and washed with water and brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate·hexane) to afford 726 mg (quant. . 1H-NMR (400MHz, CDC13) δ : 1 . 3 2 - 1.4 5 ( 1 1 Η , m), 2.02 (2Η, m), 2.81 (1H, t, J = 12.6Hz), 3.20(1H, t, J = 12.8 Hz), 3.69 (1H, s), 3.82 (1H, d, J = 13.9 Hz), 4.06 (2H, q, J = 11.8 Hz), 4.39-4.49 (2H, m).

[Reference Example 63] {1-[(9-Methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c] sialolin-1-yl)ethenyl) Tert-butyl piperidin-4-yl}carbamic acid

9-Methoxy-2,3-dihydro-1H-[1,4]indolo[2,3-c]quinoline (200 mg, 〇.925 mmol) obtained in Reference Example 8 was dissolved in N, N. - Add dimethyl hydride (oily, containing 55%, 42.4 mg, 〇· 971 mmol) in dimethylformamide (5 mL) under ice-cooling for 20 min. The terp-(chloro(indenyl)piperidin-4-yl]carbamic acid tert-butyl ester (384 mg, 1.38 mmol) obtained in Reference Example 62 was added, and the mixture was stirred for 17 hours while warming to room temperature. Ethyl acetate was added and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (chloroform-methanol) to afford 422 mg (yield) of the title compound as an orange oil. 1h-NMR (CDC13) δ: 1.16-1.39 (2Η, m), 1.45(9H, s), 1.93--270- 200946528 2.1 0(2H, m), 2.84(1H, t, J=12. 2Hz), 3.07(1H, t, J=1 1. 1Hz), 3.40-3.49(2H, m), 3.5 7-3.76(2H, m), 3.86(3H, s), 3.9 1- 4.09(2H, m), 4.21 - 4.29 (2H, m), 4.46 (1H, brs), 4.58- 4.69 (1 H, m), 7.10 (1H, d, J: = 2.7 Hz), 7.17 (1H, dd, J = 9.2, 2.8 Hz), 7.90 (1H, d, J = 9.3 Hz), 8.39 (1H, s). MS (ESI) m/z: 457 (M + H) + .

[Reference Example 64] 1-[(9-Methoxy-2,3-dihydro-1H-[1,4]D§ cultivating [2,3-c]quinoline-1-yl)ethenyl Piperidin-4-amine

The {1·[(9-methoxy-2,3-dihydro_1Η_[1,4]indolo[2,3-c] sialolin-1-yl)ethylidene obtained in Reference Example 63 was obtained. The tert-butyl ester of hydrazino-4-yl}aminocarbamate (248 mg, 0-543 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added and the mixture was stirred for 1 hour. The solvent was distilled off under reduced pressure, and saturated sodium bicarbonate was added under ice cooling to be basic. The mixture was extracted with EtOAc (EtOAc)EtOAc. iH-NMRHOOMHz, CDC13) δ: 1.14-1·36 (2Η, m), 1.86 (2H, m), 2.80-3.09 (4H, m), 3.40-3.46 (2H, m), 3.5 9-3.69 ( 1 H,m), 3.85(3H, s), 4.00(2H, d, J = 6.6Hz), 4.24(2H, t, J = 4.4Hz), 4.58(1H, d, J=13.4Hz), 7.11( 1H, d, J = 2.9Hz), 7.16(1H, dd, J = 9.2, 2.8Hz), 7.89(1H, d, J = 9.0Hz), 8.39(1H, s).

[Example 38] 6-[({l-[(9-methoxy-2,3-dihydro-1H-[1,4]曙 并-271- 200946528 [2,3-c]quinoline -1-yl)ethinyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][l,4]indole-3(4H)-one

1-[(9-Methoxy-2,3-dihydro-1H-[1,4]indolo[2,3-(:]quinolin-1-yl)acetamidine obtained in Reference Example 64 Benzylpyridin-4-amine (57.91118, 0-1621»111〇1), 3-sided oxy-3,4-dihydro-211-pyrido[3,2-15][1,4]噚-6-formaldehyde (31.8 mg, 0.179 mmol) was suspended in methanol: dichloromethane = 1:1 mixed solvent (2 mL), and acetic acid (〇·〇 14 mL, 0.243 mmol), sodium cyanoborohydride ( 11.8 mg, 0.179 mmol), and stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure, and then dissolved in chloroform·methanol: water = 7:3:1, and washed with water. After drying, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (chloroform:methanol: water = 7:3:1 under solvent). The solid was collected by filtration to give 45.0 mg (yield: 52%) ofyield as pale orange solid. 1H-NMR (400 MHz, CDC13) δ: 1. 2 2 - 1.4 6 (3 Η , m), 1.83- 2.02 (2H , m), 2.73-2.81(lH, m), 2.86-2.95(lH, m), 2.99 3.08(1H, m), 3.4 1 -3.45(2H, m), 3.60-3.68(lH, m), 3.74 3.87(6H, m), 4.01(1H, d, J = 9.3 Hz), 4.24(2H, t, J = 4.4Hz), 4.50-4.58(lH, m), 4.6 2 - 4.6 7 ( 3 H, m), 6.92 (1H, d, J = 8.1Hz), 7.11( 1H, d, J = 2.7Hz), 7.16(1H, dd, 5 = 9.2, 2.8Hz), 7.21(1H, d, J = 8.1Hz), 7.89(1H, d, J = 9.0Hz), 8.39( 1H, s). MS (ESI) m/z: 5 1 9 (M + H) + . -272 - 200946528 [Reference 65] 3-(hydroxymethylene)dihydro-2(3H)-furanone Sodium salt

In a suspension of sodium hydride (oily, containing 55%, 10.6 g, 0.244 mol) in hexane (200 mL), γ-butyrolactone (20 g, 0.232 mol) was added dropwise at 〇 ° C for 1 hour under a nitrogen atmosphere. A mixture with ethyl formate (18.1 g, 0.244 mol). On the way, when about 20% was dropped, ethanol (〇.5tnL) was added. After the end of the dropwise addition, the mixture was heated to reflux. The precipitated solid was collected by filtration, and the solid was washed with hexane. Drying under reduced pressure gave 30.9 g (yield: 98%) of the title compound as a white solid. 1H-NMR (400MHz, CD3OD) δ: 2.78 (2Η, m), 4.20 (2H, t, J = 9.0Hz), 8.52 (1H, brs).

[Reference Example 66] 3-[l-(4-Methoxyphenylamino)methylene]dihydrofuran-2-one

To a suspension of 3-(hydroxymethylene)dihydro-2(3Η)-furanone sodium salt (27.2 g, 0.20 mol) in toluene (500 mL) obtained in Reference Example 65, was added to anisidine hydrochloride. (31.9 g, 0.20 mol), using a Dean-Stark apparatus, heated to reflux for 24 hours while removing water. Ethanol (20OmL) was added, and the mixture was further heated under reflux for 6 hours, and then concentrated under reduced pressure until the reaction mixture became a slurry. The solid was collected by filtration and dried <RTI ID=0.0> -273- 200946528 1H-NMR (400MHz, CDC13) δ : 2 _ 8 3 (2 Η, dt, J = 2.2,7 · 6 Hz), 3.70(3H, s), 4.26(2H, t, J = 7.6 Hz), 6.87(2H, m), 7.08(2H, m), 7.56(1H, brs), 8.90(1H, brs).

[Reference Example 67] 4-Chloro-3-(2-chloroethyl)-6-methoxyquinoline

3-[l-(4-Methoxyphenylamino)methylene]hydrofuran-2-one (21.9 g, 100 mmol) obtained in Reference Example 66 was dissolved in trichloromethane (100 mL). Heat to reflux for 4 hours. After distilling off the phosphorus oxychloride under reduced pressure, water (100 mL) and 1N aqueous sodium hydroxide (5OmL) were sequentially added to the residue under ice cooling, and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by hydrazine gel column chromatography (dichloromethane: ethyl acetate = 40:1 - 10:1) to afford 6-49 g (25%) of the title compound as a dark blue solid. 1H-NMR (400MHz, CDCI3) δ: 3.41 (2Η, t, J = 7.1Hz), 3.83(2H, J = 7.1Hz), 3.98(3H, s), 7.39(1H, dd, J = 2.7, 9.3 H), 7·45 (1Η, d, J = 2.7Hz), 7.99(1H, d, J = 9.3Hz), 8.62(1H, s). [Ref. 68] 2-[2-(4·Cl3) -6-methoxyquinolin-3-yl)ethyl]isoindole-13-dione

-274- 200946528 4-Chloro-3-(2-chloroethyl)-6-methoxyquinoline (2.00 g, 7.81 mmol) obtained in Reference 67 (N,N-dimethylformamide) To a solution of 40 mL), potassium phthalimide (2.17 g, 11.7 mmol) was added, and the mixture was stirred at 100 ° C for 4 hours under a nitrogen atmosphere. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated, and methanol was added to the obtained residue to obtain a slurry. The solid was collected by filtration to give 1.09 g (3. V 1H-NMR (400MHz, CDC13) δ: 3.35 (2Η, t, J = 7.1Hz), 3.98(3H, s), 4.08(2H, t, J = 7.1Hz), 7.37(1H, dd, J = 2.7, 9.3 Hz), 7.46 (1H, d, J = 2.7 Hz), 7.70 (2H, m), 7.81 (2H, m), 7.95 (1H, d, J = 9.3 Hz), 8.54 (1H, s) .

[Reference Example 69] 2-(4-Chloro-6-methoxyquinolin-3-yl)ethylamine

2-[2-(4-Chloro-6-methoxyquinolin-3-yl)ethyl]isoindole-1,3-dione (4.26 g, 8.79 mmol) obtained in Reference Example 68 To a solution of ethanol (10 mL), hydrazine 1 hydrate (1.7 mL, 35.2 mmol) was added and heated under reflux for 27 hours. Methanol was added to dissolve the precipitated solid, and the mixture was further heated under reflux for 7 hours. The reaction mixture was concentrated under reduced pressure, and the obtained solid was dissolved in methylene chloride and 1N aqueous sodium hydroxide. After drying the organic layer with anhydrous sodium sulfate, the desiccant was filtered off and the filtrate was concentrated - 275-200946528. The residue obtained by purifying the obtained residue by gel column chromatography (dichloromethane: methanol = 10:1 - chloroform:methanol:water = 7:3:1 lower solvent) 1-23 g (59%) of the labeled compound as a white solid. 1H-NMR (400MHz, CDC13) δ: 3.09 (4Η, m), 3.98 (3H, s), 7.36 (1H, dd, J = 2.7, 9.0 Hz), 7.46 (1H, d, J = 2.7 Hz), 7.98 (1H, d, J = 9.0Hz), 8.56 (1Η, s).

[Reference Example 70] 8-Methoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline

2-(4-Chloro-6-methoxyquinolin-3-yl)ethylamine (1, 23 g, 5-20 mmol) obtained in Reference Example 69 was dissolved in N,N-methylacetic acid amine (10 mL). Stir at 120 ° C for 24 hours. After cooling to room temperature, the solid which precipitated was collected by filtration to give 79 5 mg (76%) of 1H-NMR (400 MHz &gt; CDCb) δ: 3.26 (2 Η, t, J = 7.0 Hz), 3.85 (2H, t, J = 7.0 Hz), 3.89 (3H, s), 4.65 (1H, brs), 6.81 ( 1H, d, J = 2.9Hz), 7.24(1H, dd, J = 2.9, 9.3Hz), 7.88(1H, d, J = 9.3Hz), 8.41(1H, s).

[Reference Example 71] 4-[2-(8-Methoxy-2,3-dihydropyrano[3,2-c]quinoline-1-yl)ethyl]piperidine-l-carboxylic acid Third butyl ester

8-Methoxy-2,3-dihydro-1H-pyrrolo[3,2--276-200946528 c]quinoline (147 mg, O.734 mmol) of N,N-dimethyl ester obtained in Reference Example 70 Sodium hydride (oily, containing 55%, 48 mg, 1.0 mmol) was added to a solution of carbamide (10 mL) and stirred for 20 min. Add a solution of 3-(2-iodoethyl)piperidine-1-carboxylic acid tert-butyl ester (3 74 mg, 1.0 mmol) in N,N-dimethylformamide (2 mL), stir

2 hours. After a saturated aqueous solution of ammonium chloride was added to terminate the reaction, the reaction mixture was made basic with 1N aqueous sodium hydroxide and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by hydrazine gel column chromatography (dichloromethane:methanol = 1:1: chloroform: methanol: water = 7:3:1 solvent) to afford 234 mg (78%) of It is a light brown oil. 1H-NMR (400MHz, CDC13) δ:1·20(2Η,m), 1.46(9H,s), 1.54(1H, m), 1.68- 1.74(3 H, m), 2.70(2H, brt , J=12.0Hz), 3.13(2H, t, J = 9.4Hz), 3.63(2H, m), 3.72(2H, t, J = 9.4Hz), 3.87(3H, s), 4.10(3H, brs ), 7.18(1H, d, J = 2.7Hz), 7.23(1H, dd, J = 2.7, 9.3Hz), 7.90(1H, d, J = 9.3Hz), 8.30(1H, s).

[Reference Example 72] 8-methoxy-1-(2-piperidin-4-ylethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline

Further, it is more than 4-[2-(8-methoxy-2,3-dihydropyrrolo[3,2-c]quinolin-1-yl)ethyl]piperidine-1-carboxylate obtained in Reference Example 71. A solution of the acid tert-butyl ester (100 mg, 〇. 243 mmol) in dichloromethane (9.0 mL) was added trifluoroacetic acid (1 mL) and stirred for 1 hour. The reaction mixture was made alkaline with a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layer was washed with a 1N aqueous sodium hydroxide solution and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated to give 72.3 mg (yield: 96%). 1H-NMR (400MHz, CDC13) δ : 1.2 0 - 1 . 3 0 (3 H, m), 1.52 (1H, m), 1.67- 1.75 (4H, m), 2.62 (2H, dt, J = 2.4, 12.2Hz), 3.10- 3.14(4H, m), 3.60(2H, m), 3.70(2H, t, J = 9.5Hz), 3.87(3H, s), 7.19(1H, d, J = 2.7 Hz), 7.22 (1H, dd, J = 2.7, 9.3 Hz), 7.87 (1H, d, J = 9.3 Hz), 8.30 (1H, s).

[Example 39] l-{2-[1-(2-Cyclohexylethyl)piperidin-4-yl]ethyl}-8-methoxy-2,3-dihydro-1H-pyrrolidine [3,2-c]quinoline

8-methoxy-1-(2-piperidin-4-ylethyl)-2,3-dihydro-111-pyrrolo[3,2-(:]quinoline (7211) obtained in Reference Example 72 ^, 0.231111111〇1) in a solution of dichloromethane (5.0 mL), sequentially adding cyclohexyl acetaldehyde (44 mg, 〇.347111111〇1), acetic acid (16 01, 〇.277111111〇1) and hydrogenated triethylene hydride Sodium borohydride (62 mg, 0.277 mmol) was stirred for 24 hours. A saturated aqueous solution of sodium hydrogencarbonate was added and stirred for 1 hour, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate.矽 Gel column chromatography (dichloromethane: methanol = 10 · · 1 - chloroform: methanol · water = 7 : 3 : 1 lower solvent) Purification residue 'hydrogen chloride / ethanol solution (1 equivalent The obtained pale yellow amorphous form was dried to give 64.5 mg (yield: 61%) of the title compound - 278 - 200946528 as a pale yellow solid. 1H-NMR (400 MHz, CDC13) δ: 0.92 ( 2Η, m), 1 . 1 2 -1 . 2 6 (4 Η, m), 1.42-1 · 52(5Η, m), 1. 6 2 - 1.7 9 (9Η, m), 2.04(2Η, brt , J=10.4Hz), 2.44(2H, m), 3.05(2H, brd, J=11.2Hz), 3.16( 2H, t, J = 9.3Hz), 3.69(2H, m), 3.81(2H, t, J = 9.3Hz), 3.88(3H, s), 7.19(1H, d, J = 3.4Hz), 7.27( 1H, dd, J = 3.4, 10.3 Hz), 8.02 (1H, d, J = 1 0.3 Hz), 8.21 (1H, s). MS (ESI) m/z: 422 (M + H) + . Example 40] l-{2-[1-(2-Cyclohexylethyl)piperidin-4-yl]ethyl}-9-methoxy-2,3-dihydro-1H-[1,4 ]噚耕和[2,3-c]Sodium porphyrin-3-carboxylate

9 9-methoxy-1-(2-piperidin-4-ylethyl)-2,3-dihydro-1^[1,4]噚 and [2,3-] obtained in Reference Example 53 〇]Quinolin-3-carboxylic acid methyl ester (188.2!118, 〇.48 8 mmol), cyclohexyl ketone (92.4 mg, 0.732 mmol) was dissolved in dichloromethane (3 mL), and acetic acid (0-034 mL, 0.586 mmol) Hydrogenated sodium triethoxyborohydride (131 mg, 0.586 mmol) was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure. Add saturated sodium bicarbonate and extract with chloroform. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (chloroform-methanol). Add 4 equivalents of hydrogen chloride / dioxane solution to a portion of 42.8 mg (0.086 mmol) of the obtained orange oil, and the resulting solid was filtered to give 26.0 mg (32%) of It is a yellow solid. -279- 200946528 1H-NMR (400MHz, CDC13) δ : 0 · 8 5 - 0 _ 9 7 (2 H, m), i &quot; 1.29(5H, m), 1. 3 0 - 1.4 8 (5 H , m), 1 .6 1 -1.7 6 (6 H, m), i.8l

1.96 (4H, m), 2.33 (2H, brs), 2.79-2.8 9 ( 1 H, m), 2.95 (2H

Brs), 3 .1 4-3.22( 1 H, m), 3.3 6 - 3.4 7 ( 1 H , m), 3 . 5 7 - 3.6 3 ( j H m), 3.89 (3H, s), 3.92 ( 3H, s), 4·57·4·61 (1Η, m), 7.08 (1 hd J = 2.7 Hz), 7.20 (1H, dd, J = 2.7, 9.1 Hz), 7.91 (1H, d J = 9.1 Hz), 8.53 (1H, s). MS (ESI) m/z: 495 (M + H) + .

[Example 41] 1-{2-[1-(2-Cyclohexylethyl)piperidin-4-yl]ethyl}·9-methoxy- 2,3-chloro-1Η-[1, 4]曙哄[2,3-c]Salina-3-cyanate

1-{2-[1-(2-Cyclohexylethyl)piperidin-4-yl]ethyl}-9-methoxy-2,3-dihydro-1Η·[1] obtained in Example 40 , 4] hydrazine and [2,3-c]quinoline _3_residic acid methyl ester (84.9 mg, 0.171 mmol) was dissolved in methanol (2 mL), and i eq sodium hydroxide aqueous solution (0.343 mL, 0.343 mmol) was added. ), stir 1 small _. The solvent was distilled off under reduced pressure, and dissolved in a solvent mixture of chloroform:methanol:water = 7:3:1. The solvent was extracted with a solvent of chloroform:methanol:water = 7:3:1 and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and hexane was applied and purified, and the resulting solid was filtered to afford 4 1 0 mg (4 6%) of the title compound as a pale brown solid. 1H-NMR (400MHz, DMSO-d6) δ : 0.8 1 - 0.9 5 (3 Η, m), 1.05- 1.30 (5Η, m), 1.34-1.54 (5Η, m), 1. 5 6 - 1.7 0 ( 3 Η, m), 1.74- -280- 200946528 1.85(3H, m), 1 . 8 5 - 1 . 9 5 ( 1 H, m), 2.3 1 - 2.5 0 (2 H, m), 2.62- 2.78 (2H, m), 2.8 9 - 2.9 9 ( 1 H, m), 3.0 1 - 3.0 9 ( 1 H, m), 3.12 - 3.39 (4H, m), 3.4 3 - 3.5 1 (1 H, m) , 3.89(3H, s), 4.3 5-4.42 (1 H, m), 7.05(1H, s), 7.1 4 - 7.1 9 (1 H, m), 7.7 8 - 7.8 2 (1 H, m), 8.34 (1H, s). MS (ESI) m/z: 482 (M + H) + .

[Example 42] 1-(2-{1-[(2£)-3-(2,5-difluorophenyl)_2-propenyl-1-yl]piperidin-4-yl}ethyl)- 9-methoxy-2,3-dihydro-111_[1,4]indole[23_(;]quinoline

9-methoxy-helium plant piperidin-4-ylethyl 2,3-dihydro-111-[1,4] hydrazine and [2,3-(:] quinine obtained in Reference Example 1 Porphyrin (5〇.〇111§, 〇.154111111〇1), (2E)-3-(2,5-difluorophenyl)propanil (34.〇mg, 0.200mmol) dissolved in dichloromethane ( To 2 ml), acetic acid (O.oiim L, 185.185 mmol) and hydrogenated sodium triethyloxyacetate (41.3 mg, 0-185 mmol) were added, and the mixture was stirred at room temperature for 21 hours. The solvent was evaporated under reduced pressure and saturated sodium bicarbonate was added. The extract was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and purified by EtOAc EtOAc (EtOAc). 'Addition of 4 eq. of hydrogen chloride / dioxane solution, and the resulting solid was filtered to give 50.0 mg (5 4%) of the title compound as a pale yellow solid. 1H-NMR (400 MHz, CDC13) δ : 1 . 3 1 -1.47(3 Η, m), 1.71- -281- 200946528 1.79(2H, m), 1 . 8 4 - 1 . 9 2 (2 H, m), 1 . 9 3 - 2.0 2 (2 H, m), 2.94- 3.02 (2H, m), 3.0 7 - 3 . 1 4 (2 H, m), 3 . 1 4 - 3 . 1 8 (2 H, m), 3.22- 3.25 (2H, m), 3.93(3H, s), 4.1 9 - 4.2 2 (2 H, m), 6.3 0 - 6.3 9 ( 1 H , m), 6.59-6.66 (lH, m), 6.8 4 - 6.9 1 (1 H, m), 6.9 4 - 7.0 1 ( 1 H, m), 7.07-7.20 (3H, m), 7.89 (1H, d, J = 9.0 Hz), 8.38 (1H, s). MS (ESI) m/z: 480 (M + H) + .

[Reference Example 73] {[(4-Methoxy-2-methylphenyl)amino]methylene}malonic acid diethyl ester

4- Dissolve 4-methoxy-2-methylaniline (20.0g, 146.146mol), diethyl ethoxymethylenemalonate (35.4mL, 0.175111〇1) in toluene (1001111〇, The mixture was heated under reflux for 6 hours. After standing to cool, the solvent was evaporated to dryness to give the title compound (yield: &lt;RTI ID=0.0&gt;&gt; = 7.2Hz), 1.38(3H, t, q J = 7.2Hz), 2.34(3H, s), 3.80(3H, s), 4.24(2H, q, J = 7.2Hz), 4.3 1 (2H, q , j = 7.2 H z ) , 6 · 7 6 - 6 · 7 8 ( 2 H, m), 7.1 3 ( 1 H, d, J = 8.5 Hz), 8.43 (1H, d, J = 13.7 Hz), 1 0.9 9 - 1 1.0 7 (1 H, m).

[Reference Example 74] Ethyl 4-hydroxy-6-methoxy-8-methylquinoline-3-carboxylate

-282- 200946528 The {[(4-methoxy-2-methylphenyl)amino]methylene}malonic acid diethyl ester (64.75 g, 0.146 mol) obtained in Reference Example 73 was suspended in Ito The reagent (100 mL) was stirred at 90 ° C for 26 hours. After the reaction mixture was ice-cooled, it was gradually added to an aqueous solution (1 L) in which sodium carbonate (150 g) was dissolved while maintaining an internal temperature of l 〇 ° C or less. The resulting solid was collected by filtration and washed with water. Ethyl ether: hexane = 1 : 3 was mixed with a solvent to suspend, and after the slurry was stirred, the solid was collected by filtration. After resuspending in diethyl ether and stirring, the solid was filtered to give 24.36 g (yield: 64%). 1H-NMR (400MHz, CDC13) δ: 1.47 (3Η, t, J = 7.1Hz), 2.73(3H, s), 3.94(3H, s), 4.51 (2H, q, J = 7.1 Hz), 7.30 ( 1H, d, J = 2.9Hz), 7.43(1H, d, J = 2.9Hz), 9.04(1H, brs), 12.14(1H, s).

[Reference Example 75] Ethyl 4-chloro-6-methoxy-8-methylquinoline-3-carboxylate

Phosphorus oxychloride (7.1 mL) was added to ethyl 4-hydroxy-6-methoxy-8-methyls-phenyl- phenyl-3-carboxylate (l.Og, 3.83 tnmol) obtained in Reference Example 74. Stir at 95 °C for 4 hours. After chilling, it is sent to ice water. Stir under ice cooling, and add 28% ammonia water to make it alkaline. The precipitated solid was collected by filtration, washed with water, and purified by hydrazine gel column chromatography (hexane: ethyl acetate = 4:1) to give 725.3 mg (68%) of White solid. 'Η-ΝΜΚ(400ΜΗζ, CDC13) δ: 1.46(3Η, t, J = 7.2Hz), 2.77(3H, s), 3.97(3H, s), 4.49(2H, q, J = 7.2Hz), 7.3 3 - 7.3 5 ( 1 H, m), -283- 200946528 7.47 (1H, d, J = 2.9Hz), 9.06(1H, s).

[Reference Example 76] 4-({2-[l-(Tertidinoxycarbonyl)piperidin-4-yl]ethylguanidino)-6-methoxy-8-methylquinolinone-3 -carboxylic acid ethyl vinegar

4-Chloro-6-methoxy-8-methylquinoline_3-residic acid ethyl ester (725_0 mg, 2.59 mmol) obtained from Reference Example 75, 4-(2-aminoethyl)piperidine-oxime The carboxylic acid first vinegar (710 mg, 3.11 mmol) was dissolved in EtOAc (3 mL), EtOAc (EtOAc) After standing to cool, diethyl ether was added, and the mixture was washed with water and saturated brine. The solvent was evaporated under reduced pressure. EtOAc EtOAc (EtOAc) 1H-NMR (40 0MHz, CDC13) δ: 1.08-1,20(2H, m), \.2A- 1·29(1Η, m), 1.41(3H, t, J = 7.2Hz), 1.45(9H , s), 1.62- 1.74(3H, m), 2.61-2.71(3H, m), 2.72(3H, s), 3.7 6 - 3.8 2 (2 H , m), 3.89(3H, s), 4.0 0 - 4.1 5 (2 H, m), 4.38 (2H, q, J = 7.2 Hz), 7.23 -7.25 (lH, m), 7.3 5 - 7.3 7 ( 1 H, m), 8.7 1 - 8.7 6 (1 H , m), 9.〇7(lH, s).

[Reference Example 7 7] 4-(2-{[3-(Hydroxymethyl)-6-methoxy-8-methylquinolin-4-yl]amino}ethyl)piperidine-1-carboxylate Tert-butyl acid

-284- 200946528 Butyloxycarbonyl)piperidine-4-yl]-3-carboxylic acid ethyl ester (1.15 g, hydrogenation under ice cooling to give 4_({2_π_(triethyl}amino))) 6. Methoxymethylquinolinone (2.44 mmol) was dissolved in tetrahydrofuran (15 mL). Lithium (185 mg, 4.88 mmol) was stirred for 4 hours. Water (0.25 mL) was added sequentially under ice-cooling. (〇25 mL) and water (0.75 mL) were stirred for 2 hours. After adding magnesium sulfate and drying over Celite, the solvent was evaporated under reduced pressure to give 194.2 mg (19%) of Ο 1H-NMR (400MHz, CDC13) δ : 1. 〇7 -1.2 2 (3 Η, m)5 1.45(9Η, s), 1.62- 1.72(3 Η, m), 1. 8 3 - 1 . 8 8 (2H, m), 2.6 1 - 2.7 2 (2 H, m), 2.73 (3H, s), 3.53-3.60(2H, m), 3.91(3H, s), 4.0 2 - 4.1 6 (2 H, m), 4.83(2H, s), 4.8 4 - 4.9 1 (1 H, m), 7.1 2 - 7.1 5 ( 1 H, m), 7.18-7.21 (1H, m), 8.39 (1H, s ).

[Reference Example 78] 4-{2-[(3-Mercapto-6-methoxy-8-methylquinolin-4-yl)amino]ethyl}piperidine-1-carboxylic acid III Ethyl ester

ο 4-(2-{[3-(Hydroxymethyl)-6-methoxy-8-methylsin-4-yl]amino}ethyl)piperidine-bucarboxylate obtained in Reference Example 77 The acid tert-butyl ester (194 2 mg, hydrazine, 452 mmol) was dissolved in dichloromethane (3 rnL), EtOAc (462 mg, 5. 31 mmol). After filtration through diatomaceous earth, the solvent was evaporated under reduced pressure and purified by EtOAc EtOAc (EtOAc) eluting 200946528 1H-NMR (400MHz, CDC13) δ : 1.1 1 -1.24(2H, m), 1.45(9H, s), 1.65- 1.73(3H, m), 1. 7 4 -1 . 8 1 (2 H, m), 2.6 5 - 2.7 6 (5 H, m), 3.90 (3H, s), 3.92-3.99 (2H, m), 4.0 3 - 4.1 6 ( 2 H, m), 7.28- 7.31 (1H, m ), 7.49-7.5 1 (1H, m), 8.53 (1H, s), 9.88 (1H, s), 9.99 (1H, brs).

[Reference Example 79] 4-{2-[(3-Hydroxy-6-methoxy-8-methylquinolin-4-yl)amino]ethyl}piperidine-1-carboxylic acid tert-butyl ester

4-{2·[(3·Mercapto-6-methoxy-8-methylquinolin-4-yl)amino]ethyl}piperidine-1-carboxylic acid obtained in Reference Example 78 A 3-stage ethyl ester (125.5 mg, 0.294 mmol) was dissolved in a methanol··dichloromethane=1:1 mixed solvent (4 mL), and potassium carbonate (50.9 mg, 〇.368 mmol) and m-chloroperbenzene were added under ice cooling. Formic acid (63.5 mg, 0-368 mmol) was stirred for 6 hours. Further, potassium carbonate (5 〇.9 mg, 0.368 mmol), m-chloroperbenzoic acid (63.5 mg, 0.368 mmol) was added, and after stirring for 13 hours, saturated baking soda water was added to chloroform:methanol:water=7:3:1 Lower solvent extraction. After drying over anhydrous sodium sulfate, the solvent was evaporated. 1H-NMR (400MHz, CDCI3) δ: 1. 1 0-1.24(2H, m), 1.45(9H, s), 1. 5 8- 1.73 (6H, m), 2.6 2 - 2.7 3 (6 H, m), 3.70(2H, t, J = 7.3Hz), 3.90(3H, s), 4.01-4.15(2H, m), 7.05(1H, m), 7.14(1H, m), -286- 200946528 8.3 5 (1 Η, s).

[Reference Example 80] 4-[2-(9-Methoxy-7-methyl-2,3-dihydro-1Η-[1,4]indole[2,3-c]quinoline-oxime] -ethyl)ethyl]piperidine-carboxylic acid tert-butyl ester

4-{2-[(3-Hydroxy-6-methoxy-8-methylquinolin-4-yl)amino]ethyl}piperidine-carboxylic acid tert-butyl ester obtained in Reference Example 79 (469 6mg, Ο dissolved in dimethylformamide (6rnL), added potassium carbonate (625 mg, 4.52mmol), 1,2-dibromoethane (〇.195mL, 2.26mmol) at room temperature The mixture was stirred at 80 ° C for 15 hours. After standing to cool, ethyl acetate was added, and the mixture was washed with water, saturated sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. Trituration (hexane-ethyl acetate) to give 23 3.4 mg (47%) of

1H-NMR (400MHz, CDC13) δ: 1. 1 6-1 . 3 0(4Η, m), 1.46(9Η, s), 1.64-1, 73(2Η, m), 1. 8 3 - 1 . 9 0 (2 Η, m), 2.72(3Η, s), 3.06- 3.12(2H,m), 3.23(2H,t,J = 4_3Hz), 3.91(3H,s),4.06-4.16(3Η, m ), 4.21 (2Η, t, J = 4.3Hz), 6.96(1H, d, J = 2.9Hz), 7.05(1H, d, J = 2.9Hz), 8.42(1H, m).

[Reference Example 81] 9-methoxy-7-methyl-1-(2-piperidin-4-ylethyl)-2,3-dihydro-1H-[1,4] 噚耕和[2 ,3-c]quinoline

-287- 200946528 4-[2-(9-Methoxy-7-methyl-2,3-dihydro-1H-[1,4]噚[[,3,3-c] obtained in Reference Example 80 ] Quinolin-1-yl)ethyl]piperidine-decanoic acid tert-butyl ester (100 mg, 0.226 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added under ice-cooling and stirred. 2 hours. The solvent was distilled off under reduced pressure, and saturated sodium bicarbonate was added under ice-cooling to make it basic. Extraction with chloroform was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 92.8 mg (yield) of the title compound as a yellow oil. 1H-NMR (400MHz, CDC13) δ: 1.19·1·32 (2Η, m), 1.37- 1.51 (2Η, m), 1. 6 7- 1 .7 5 (2Η, m), 1.82 - 1.90(2Η, m), 2.55- 2.63(2Η, m), 2.72(3Η, s), 3.0 5 - 3 . 1 2 (4 Η, m), 3.23(2Η, t, J = 4.3Hz), 3.91(3Η, s), 4.21(2Η, t, J = 4.3Hz), 6.97(1H, d, J = 2.9Hz), 7.05(1H, d, J = 2.7Jz), 8.41(1H, s).

[Example 43] 1-{2-[1-(Cyclohexylethyl)piperidin-4-yl]ethyl b- 9-methoxy-7-methyl-2,3-dihydro-1H -[1,4] 噚耕和[2,3-c]quinoline

The 9-methoxy-7-methyl-1-(2-piperidin-4-ylethyl)-2,3-dihydro-1H-[1,4] obtained from Reference Example 81 was cultivated and [ 2,3-c]quinoline (92.8 mg, 〇. 226 mmol), cyclohexyl-ethyl-yield (42.8 mg, 0.339 mmol) was dissolved in dichloromethane (5 mL), and acetic acid (〇.〇i6 mL, 0.271 mmol), Sodium triethoxyborohydride (60.5 mg, 0.271 mmol) was hydrogenated and stirred at room temperature for 16 h. The solvent was distilled off under reduced pressure, and saturated sodium bicarbonate was added, and the solvent was extracted with chloroform:methanol:water =7:3:1. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure -288-200946528, and purified by gel column chromatography (chloroform·methanol). To the obtained orange oil, 4 N of hydrogen chloride / dioxane solution was added, and the resulting solid was filtered to give 29.0 mg (yield: 22%) of the title compound as a pale yellow solid. 1H-NMR (400MHz, DMSO-d6) δ : 0.8 5 - 0.9 8 (2 Η, m), 1.07- 1.32(4H, m), 1. 5 3 - 1.7 0 (9 H , m), 1. 8 0 - 1.9 3 (4 H , m), 2.65 (3H, brs), 2.74-2.87 (2H, m), 2.9 5 - 3.0 2 (2 H, m), 3.4 0 - 3.6 2 (5 H, 〇m ), 3.6 7-3.88 (2H, m), 3.93(3H, s), 4.2 8 - 4.3 3 ( 2 H, m), 7.04-7.07(1H, m), 7.37(1H, brs), 8.38(1H , s), 10.20 (1H, brs). MS (ESI) m/z: 452 (M + H)+.

[Reference Example 82] {[(6-Methoxypyridin-3-yl)amino]methylene}malonate diethyl ester

6-Methoxypyridin-3-amine (7.86 g, 63.3 2 mmol), ethoxymethylenemalonic acid diacetic acid (15.35 ml, 75.98 mmol) was dissolved in toluene (40 mL) and heated to reflux 2 5 hour. After standing to cool, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (H.sub.-ethyl acetate) to give 21.07 g (quant.) of the title compound as a pale yellow solid. 1H-NMR (400MHz, CDC13) δ: 1.32 (3Η, t, J = 7.2Hz), 1.38(3H, t, J = 7.1Hz), 3.94(3H, s), 4.24(2H, q, J = 7.2 Hz), 4.31(2H, q J = 7.1Hz), 6.78(1H, d, J = 8.8Hz), 7.43(1H, dd, J = 2.8, 8.8Hz), 8.03(1H, d, J = 2.8Hz ), 8.37 (1H, m), 10.93 (1H, m). -289- 200946528 [Reference Example 83] 4-Hydroxy-6-methoxy-1,5-naphthyridine-3-carboxylic acid ethyl ester

The {[(6-methoxypyridyl)amino]methylene)malonate (1 8.7 3 g, 6 3 _ 6 4 mm ο 1 ) obtained in Reference Example 82 was added to the addition. Stir at 20 ° C for 20 minutes in a mixture of Dowtherm (mixture of biphenyl and biphenyl oxide) A (100 mL). After standing to cool, the solvent was evaporated under reduced pressure. The mixture was stirred with hexanes and the solid was collected by filtration. It was further added to Dowtherm A (100 mL) heated to 260 ° C, and heated under reflux for 6 hours. After standing to cool, hexane (300 mL) was added and subjected to ultrasonication, and the solid was filtered to give 7.9 g (50%) of the title compound as a brown solid. 1H-NMR (400MHz, CDC13) δ: 1.49 (3Η, t, J = 7.2Hz), 4.15(3H, s), 4.53(2H, q, J = 7.2Hz), 7.2 1 ( 1 H,d,J = 9.0 H z), 8.1 6 ( 1 H,d, J = 9.0 Hz), 9.05 (1H, s), 12.06 (1H, s).

[Reference Example 84] 4-chloro-6-methoxy-1,5-naphthyridine-3-carboxylic acid ethyl ester

Phosphorus oxychloride (9 mL) was added to 4-hydroxy-6-methoxy-1,5-naphthyridine-3-carboxylic acid ethyl ester (1. g, 4.03 mmol) obtained in Reference Example 83. 5 (TC stirring for 1.5 hours. After ice-cooling, it is sent to ice water. Stir under ice cooling, add 28% ammonia water to make alkaline, extract with dichloromethane. Dry with anhydrous sulfuric acid-290-200946528 The solvent was evaporated, and purified by silica gel column chromatography (hexane-ethyl acetate) to give 66 3.7 mg (yield of 61%) as a white solid. 1H-NMR (400 MHz, CDC13) δ : 1.47 (3Η, t, J = 7.2Hz), 4.17(3Η, s), 4.51(2H, q, J = 7.2Hz), 7.23(1H, d, J = 9.0Hz), 8.23(1H, d, J = 9.0Hz), 9.05(1H, s).

[Reference Example 85] 4-({2-[l-(Tertidinoxycarbonyl)piperidin-4yl]ethyl)amino)-6-methoxy-1,5-naphthyridine-3- Ethyl carboxylate

Ethyl 4-chloro-6-methoxy-1,5-naphthyridin-3-carboxylate (663.7 mg, 2.47 mmol), 4-(2-aminoethyl)piperidine obtained in Reference Example 84. The 1-carboxylic acid tert-butyl ester (677 mg, 2.96 mmol) was dissolved in dimethyl sulfoxide (13 mL), and triethylamine (〇.447 mL, 3.2 1 mmol) was added and stirred at 80 ° C for 3 days. After standing to cool, add water to Q' and wash with water and saturated brine. The solvent was evaporated under reduced pressure and purified with EtOAc EtOAc (EtOAc) 1H-NMR (400MHz, CDCI3) δ: 1 . 12-1 .24(3H, m), 1.42 (3H, t, J = 7.2Hz), 1.46(9H, s), 1. 5 9 - 1.7 5 ( 7 H, m), 2.6 6 - 2.7 6 (2 H, m), 4.00 (3H, s), 4.04-4.15 (2H, m), 4.38 (2H, q, J-7.2Hz), 7.07 (1H, d, J = 9.0 Hz), 8.04 (1H, d, J = 9.0 Hz), 8.96 (1H, s).

[Reference Example 86] 4-(2-{[3-(Hydroxymethyl)-6-methoxy-1,5-naphthyridin-4-yl]amino}ethyl)piperidine-1-carboxylic acid Third butyl ester-291- 200946528

Rocr was added to a solution of lithium aluminum hydride (98.8 mg, 2.60 mmol) in tetrahydrofuran (1 mL), and 4-({·[1-(t-butoxycarbonyl)piperidine-4) was added to the obtained Example 85 under ice cooling. A solution of ethyl 2-ethyl}amino)-6-methoxy-1,5-naphthyridine-3-carboxylate (993.3 mg, 2.44 mmol) in THF (5 mL) Water (0.1 OmL), 5 equivalents of sodium hydroxide aqueous solution (0.1 mL), and water (0.30 mL) were added in this order under ice cooling, and stirred for 2 hours. Ether-methanol was added, anhydrous sodium sulfate was added and stirred overnight. After filtration over celite, the solvent was evaporated to dryness crystals eluted eluted eluted elution elution 1H-NMR (400MHz, CDC13) δ : 1. 1 4 -1 . 2 7 (2 Η, m), 1.45(9H, s), 1.60-1.7 7(6H,m),2·62-2·74 (2Η,m),3.8 3 - 3.90(2H, m), 4.03(3H, s), 4.09(2H, brs), 4.80(2H, s), 6.4 7 - 6.5 3 (1 H , m), 7.05 (1H, d, J = 9.0Hz), 8.05(1H, d, J = 9.0Hz), 8.22(1H, s).

[Reference Example 87] 4-{2-[(3-Methylamino-6-methoxy-i,5-naphthyridinyl-4-yl)amino]ethyl}piperidine-1-carboxylic acid III Butyl ester

4-(2-{[3-(Hydroxymethyl)-6-methoxy-i,5-naphthyridin-4-yl]amino}ethyl)piperidine-1-carboxylic acid obtained in Reference Example 8 The third butyl ester (775 mg, 1.86 mmol) was dissolved in dichloromethane (10 mL). After filtration over celite, the solvent was evaporated to dryness crystals eluted eluted eluted elution 1H-NMR (400MHz, CDC13) δ: 1.1 1-1.26(2H, m), 1.46(9H, s), 1 -58(2H, brs), 1.68- 1.78(5H, m), 2.6 2 - 2.7 9 ( 2 H , m), 4-〇〇(3H, s), 4.10(1H, brs), 4.4 2 - 4.4 9 (2 H , m), 7.13(1H, d, J = 9.〇Hz ), 8.06 (1H, d, J = 9.0 Hz), 8.49 (1H, s), 9.91 (1H, s). ^ [Reference 88] 4-{2-[(3-hydroxy-6-methoxy) -1,5-naphthyridin-4-yl)amino]ethyl}piperidine-1-carboxylic acid tert-butyl ester

4-{2-[(3-Methylamino-6-methoxy-1,5-naphthalen-4-yl)amino]ethyl}piperidine-1-carboxylic acid obtained in Reference Example 87 Tributyl ester (622.9 mg, 1.50 mm 〇l) was dissolved in a mixed solvent of methanol: dichloromethane = 1:1 (15 mL), and potassium carbonate (260 mg, 1.88 mmol) and m-chloroperbenzoic acid were added under ice cooling ( 324 mg, 1.88 m mol), stirred for 2 hours. Further, after adding potassium carbonate (50.9 mg, 368.368 mmol) and m-chloroperbenzoic acid (63.5 mg, 0.368 mmol) twice, stirring was carried out for 5 hours, and then saturated baking soda water was added thereto, and chloroform:methanol:water=7 : 3 : 1 lower solvent extraction. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (chloroform-methanol) to afford 404.4 mg (67%) of 1H-NMR (400MHz, CDCI3) δ: 1.12 - 1.25 (2 Η, m), 1.45 (9H, s), 1-56- 1.77 (6H, m), 2.6 2 - 2.7 4 (2 H, m), 4.0 2 - 4.1 0 ( 8 H, m), -293- 200946528 6.94 (1 H, d, J = 9.0 Hz), 8.10 (1H, d, J = 9.0 Hz), 8.42 (1H, s). [Reference example 8 9] 4-[2-(9-Methoxy-2,3-dihydro 4]indole-[2,3-c]-1,5-naphthyridin-1-yl)ethyl]piperidine 1-carboxylic acid tert-butyl ester

The 4-{2-[(3-hydroxy-6-methoxy-1,5-naphthyridin-4-yl)amino]ethyl}piperidine·1·carboxylic acid tributyl group obtained in Reference Example 88 The ester (4 04.4 mg, 1.0 mmol) was dissolved in dimethylformamide (5 mL) and potassium carbonate (5 5 3 mg, 4.00 mmol) and 1,2-dibromoethane (〇) · 1 72 mL, 2.00 mmol), stirred at 80 ° C for 4 hours. After standing to cool, diethyl ether was added, and the mixture was washed with water, saturated sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and purified by silica gel column chromatography (chloroform-methanol) to afford 1 13.6 g (27%) of the title compound as an orange oil. 1H-NMR (400MHz, CDC13) δ : 1.0 9 -1.2 8 (2 Η, m), 1.45(9Η, s), 1.52- 1,75 (6Η, m), 2.5 9 - 2.7 8 (2 Η, m ), 3.44 (2Η, t, J = 4.3Hz), 3.99-4.10(6Η, m), 4.23(2Η, t, J = 4.3Hz), 6.95(1H, d, J = 8.8Hz), 8.09(1H , d, J = 9.0Hz), 8.32(1H, s).

[Reference Example 90] 9-methoxy-1-(2-piperidin-4-ylethyl)-2,3-dihydro-1H-[1,4]indole and [2,3-c] -l,5-naphthyridine

4-[2-(9-Methoxy-2,3-dihydro-1H--294-200946528 [1,4] 曙[[,3-c]-l,5 obtained in Reference Example 89 -Naphthyridin-1-yl)ethyl]piperidine-hydrazine-residual acid tert-butyl ester (113.6 mg, 0.265 mmol) was dissolved in dichloromethane (5 nL), and diacetic acid (1 mL) was added under ice cooling. Spoiled for 1 hour. The solvent was distilled off under reduced pressure, and saturated sodium bicarbonate was added under ice-cooling to afford. It was extracted with chloroform:methanol.water = 7:3:1 lower solvent. The solvent was evaporated under reduced pressure to give EtOAc (EtOAc): 1H-NMR (400MHz, CDC13) δ : 1.1 1 -1.2 7 (2 H , m), ι59· 1.81 (6Η, m), 2.52-2.61 (2Η, m), 3.0 2 - 3 . 1 2 (2 Η , m), 3.43 (2Η, t, J = 4.3Hz), 3.96-4.02(2Η, m), 4.04(3Η, s), 4.23(2Η, t, J = 4.3Hz), 6.94(1Η, d, J = 9.0 Hz), 8.07 (1H, d, J = 9.0 Hz), 8.32 (1 H, s).

[Example 44] 1-{2-[1-(2-Cyclohexylethyl)piperidin-4-yl]ethyl b- 9-methoxy- 2,3-dihydro-1H-[1,4噚 并 and [2,3-&lt;;]-1,5-naphthyridine

9-Methoxy-1-(2-piperidin-4-ylethyl)-2,3-hydrogen-1 η-[ 1,4 ] 曙明 1 and [2,3] obtained in Reference Example 90 - c ] -1,5-naphthalene (6 2 · 9m g, 0.192mmol), cyclohexyl ketone (36.3mg, O.288mmol) dissolved in dichloromethane (3mL), adding acetic acid (〇.〇i3mL) , 0.23 0 mmol), sodium hydrogen triethoxyborohydride (51.4 mg, 0.230 mmol), stirred at room temperature for 19 hr. The solvent was distilled off under reduced pressure, and saturated sodium bicarbonate was added, and the mixture was extracted with chloroform:methanol:water = 7:3:1. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure of -295-200946528, and purified by gel column chromatography (chloroform-methanol). To the obtained orange oil, 4 N of hydrogen chloride / dioxane solution was added, and the resulting solid was filtered to give 38.0 mg (yield of 37%) of the title compound as a pale orange solid. 1H-NMR (400MHz, DMSO-d6) δ: 〇. 8 0 - 0 · 9 7 (2 Η, m), 1. 1 2 ' 1.30 (5H, m), 1.51-1.91 (12H, m), 2.7 3 - 2.8 8 (2 H, m), 2.90-3.01 (2H, m), 3.34-3.45(2H, m), 3.82(2H, t, J = 4.2Hz), 3.99(3H, s), 4.32( 2H, t, J = 4.2Hz), 4.4 8 - 4.5 7 (2 H, m), 7.41 (1H, d, J = 9.3Hz), 8.38 (1H, d, J = 9.3Hz), 8.48(1H, s), 10.44 (1H, brs). MS (ESI) m/z: 43 (M + H) + .

[Reference Example 91] {[(2-Bromo-4-methoxyphenyl)amino]methylene}malonate diethyl ester

2-Bromo-4-methoxyaniline (The Journal of Organic

Chemistry, 2005, Vol. 70, No. 7, 2870-2873, 13.89g, 68.75mmol), diethyl ethoxymethylenemalonate (16.67mL, 82.5 0mmol) dissolved in toluene (150mL) In the heating, reflux for 11 hours. After leaving to cool, the solvent was distilled off under reduced pressure, and hexane: ethyl acetate = 3:1 mixed solvent was added, and the mixture was dissolved in 4 (TC for 30 minutes by slurry stirring. Ultrasonic treatment was carried out. The crystals were formed and allowed to stand at room temperature for 1 hour. The crystals were collected by filtration and washed with hexane: ethyl acetate = 3:1 solvent to give 14.63 g (5 7%) of the title compound as white cotton crystals. Further, after concentrating the filtrate -296-200946528, hexane was added, and ultrasonication was carried out, and the resulting solid was collected by filtration to give 7.62 g (30%) of the title compound as a pale brown solid. 1H-NMR (400 MHz, CDC13) δ: 1.33 (3Η, t, J = 7.1Hz), 1.38(3H, t, J = 7.2Hz), 3.81(3H, s), 4.25(2H, q, J = 7.2Hz), 4.34(2H , q, J = 7.2Hz), 6.92(1H, dd, J = 2.8, 8.9Hz), 7.1 5(1H, d, J = 7.2Hz), 7.21(1H, d, J = 8.8Hz), 8.41( 1H, d, J=13.7Hz), 1 1.18(1H, d, J=15.1Hz).

[Reference Example 92] Ethyl 8-bromo-4-hydroxy-6-methoxyquinoline-3-carboxylate

The {[(2-bromo-4-methoxyphenyl)amino]methylene}malonate diethyl ester (7.62 g, 2 0.47 mmol) obtained in Reference Example 91 was suspended in an Ito reagent (30 mL). ) Stir at 24 〇C for 24 hours. After the reaction mixture was ice-cooled, it was gradually added to an aqueous solution (200 mL) in which sodium carbonate (23.9 g, 225.1 7 mmol) was dissolved, while maintaining the internal temperature 〇 10 ° C or less. The resulting solid was collected by filtration and washed with water. The obtained solid was dissolved in a chloroform-methanol mixed solvent and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, hexane-diethyl ether was added and the mixture was taken. The resulting solid was filtered, washed with hexanes and dried tolululu 1H-NMR (400MHz, CDCI3) δ: 1.46 (3Η, t, J = 7.1Hz), 3.95(3H, s), 4.49-4.5 1 (2H, m), 7.61(1H, brs), 7.77(1H, Brs), 9 〇9(lH, brs).

[Reference Example 93] Ethyl 8-bromo-4-chloro-6-methoxysorphyrin-3-carboxylate -297- 200946528

Phosphorus oxychloride (20 mL) was added to ethyl 8-bromo-4-hydroxy-6-methoxyquinoline-3-carboxylate (4.0 g, 12.26 mmol) obtained in Reference Example 92. 2 hours. After ice-cooling, it is sent to ice water. It is made alkaline by adding 28% ammonia water while stirring under ice cooling. The solid which can be precipitated is filtered off, washed with water, and dissolved in chloroform to give anhydrous sulfuric acid. The mixture was dried over sodium sulfate. -NMR (400MHz, CDC13) δ: 1.46 (3Η, t, J = 7.2Hz), 4.00(3H, s), 4.50(2H, q, J = 7.2Hz), 7.63(1H, d, J = 2.7Hz ), 7.86 (1H, d, J = 2.7Hz), 9.15 (1H, s).

[Reference Example 94] 8-bromo-4-({2-[1-(t-butoxycarbonyl)piperidin-4-yl]ethyl}amino)-6-methoxyquinoline-3-carboxylate Ethyl acetate

Ethyl 8-bromo-4-chloro-6-methoxysinolate-3-carboxylate (1.70 g, 4.93 mmol) obtained in Reference Example 93, 4-(2-aminomethyl)piperidine-1 The carboxylic acid tert-butyl ester (1.35 g, 5.92 mmol) was dissolved in dimethyl hydrazine (25 mL), triethylamine (1.03 mL, 7.40 mmol) was added, and the mixture was stirred at 80 ° C for 11 hours. After leaving to cool, diethyl 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 purified by EtOAc EtOAc EtOAc EtOAc. 1H-NMR (400MHz, CDC13) δ: 1 . 0 8 -1 . 2 1 (2 Η, m), 1.4l (3H, t, J = 7.1Hz), 1.45(9Η, s), 1. 5 8 - 1 . 7 5 (5 Η , m), 2.6 2 - 2.7 3 (2 Η, m) 3.76-3.83(2Η, m), 3.91(3Η, s), 4.0 1 - 4.1 4 (2 Η , m) } 4.39 (2Η, q, J_7.1Hz), 7.53 (1Η, d, J = 2.7Hz), 7.74(1Η, d, J = 2 7Hz) 8.93-8.97( 1 H, m), 9.13(1H, s ).

[Reference Example 95] 4-(2-{[8-Bromo-3-(hydroxymethyl)-6-methoxyquinolin-4-yl]aminoindenyl}ethyl)piperidine-1-carboxylic acid Third butyl ester

8-Bromo-4-({2-[l-(t-butoxycarbonyl)piperidin-4-yl]ethyl}amino)-6-methoxyquinoline-3- obtained in Reference Example 94 Ethyl acetate (2.3 〇g, 4.29 mmol) was dissolved in tetrahydrofuran (40 mL), and lithium aluminum hydride (195 mg, 5.15 mmol) was then added and stirred for 3 hr. Further, lithium hydride (195 mg, 5.15 mmol) was added. After stirring for 1 hour, water (0.40 mL), 5 equivalents of aqueous sodium hydroxide solution (〇.4〇mL), and water (i.20 mL) were sequentially added under ice cooling. Stir overnight. The solvent was distilled off under reduced pressure, and chloroform was added and subjected to ultrasonic treatment to remove insoluble materials. The solvent was evaporated under reduced pressure and purified with EtOAc EtOAc (EtOAc) 1H-NMR (400MHz, CDC13) δ: 1.0 9 -1.2 1 (2 Η, m), 1.45(9Η, s), 1.58- 1.70(5Η, m), 1. 8 2 - 1. 8 9 ( 1 Η , m), 2.6 2 - 2.7 3 (2 Η, m), -299- 200946528 3.5 5-3.62(2H, m), 3.92(3H, s), 4.0 0 - 4.1 6 (2 H, m), 4.84 (2H, brs), 5.01-5.08(1H, m), 7.29(1H, d, J = 2.7Hz), 7.71(1H, d, J = 2.7Hz), 8.47(1H, s).

[Reference Example 96] 4_{2-[(8-Bromo-3-carbamimido-6-methoxyquinolin-4-yl)amino]ethyl}piperidine-1-carboxylic acid tert-butyl ester

4-(2-{[8-bromo-3-(hydroxymethyl)-6-methoxyquinolin-4-yl]amino}ethyl)piperidine-bucarboxylic acid obtained in Reference Example 95 Tributyl ester (99 4 mg, 2- 〇l mmol) was dissolved in dichloromethane (1 (1,11 mmol), added manganese dioxide (2.06 g, 2 〇·1 mmol), and stirred at room temperature for 4 hours. After filtration of the soil, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (chloroform-methanol) to give 696 mg (7%) of the title compound as a yellow solid. 1H-NMR (400 MHz, CDCI3) δ: 1.20- 1 , 3 3 (3 H, m), 1.45 (9H, s), 1 83-1, 97 (4Hj m), 2 · 6 4 - 2.7 8 (2 H, m), 3 . 79(2H, brs), 3- 9l(3H, s), 4.04-4.1 9(2H, m), 7.67(1H, d, J = 2.8Hz), 7·8〇(1Η, d, J = 2.8 Hz), 8.61(1H, s), 9.90(1H, s), 10.17(1H, brs).

[Reference Example 97] 4-{2-[(8-Bromo-3-hydroxy-6-methoxyquinolin-4-yl)amino]ethyl}piperidine-1-carboxylic acid tert-butyl ester

4-{2-[(8-Bromo-3-carbamimido-6-methoxyquino-300-200946528 phenyl-4-yl)amino]ethyl}piperidine-1T carboxylate obtained in Reference Example 96 The acid tert-butyl ester (695.7 mg, 1.4 lmmol) was dissolved in a mixed solvent of methanol: dichloromethane = 1:1 (14 ml), and potassium carbonate (293 mg, 2.12 mmol) was added while stirring at 〇 °C. Chloroperbenzoic acid (3 66 mg, 2.12 mmol) was stirred at -2 °C for 3 days. Add saturated baking soda under ice and stir for another 2 hours. The extract was extracted with a solvent of chloroform:methanol:water = 7:3:1 and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified tolululululululululululululu 1H-NMR (400MHz, CDC13) δ: 1.0 5 -1.2 2 (2 Η, m), 1.45 (9Η, s), 1.54-1.72 (6Η, m), 2.5 8 - 2.7 5 ( 3 Η, m), 3.5 2 - 3.5 9 (2 Η, m), 3.91 (3Η, s), 4.00-4.14(2Η, m), 7.20(1Η, d, J = 2.4Hz), 7.51(1Η, d, J = 2.4Hz ), 8.30(1H, s).

[Reference Example 98] 4-[2-(7-Bromo-9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1- Tert-butyl)ethyl]piperidine-1-carboxylic acid

4-{2-[(8-Bromo-3-hydroxy-6-methoxysin-4-yl)amino]ethyl}piperidine-1-carboxylic acid tert-butyl ester obtained in Reference Example 97 (l.OOg, 2.14 mmol) was dissolved in dimethylformamide (5 mL). Potassium carbonate (226 mg, 1.63 mmol) and 1,2-dibromobenzene (0.070 mL, 0.82 mmol) were added at room temperature. Stir at 80 °C for 1 7 hours. After standing to cool, saturated sodium bicarbonate was added, extracted with chloroform, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified by EtOAc EtOAc EtOAc (EtOAc) 1H-NMR (400MHz, CDC13) δ: 1. 1 5 -1 .2 8 (2 Η, m), 1.46 (9Η, s), 1.64- 1.73 (2Η, m), 1. 8 1 -1 . 8 9 (2 Η, m), 2.6 1 - 2.7 4 (2 Η, m), 2.96 (1 Η, s), 3.05-3 . 1 1 (2Η, m), 3.2 3 ( 2 Η, t, J = 4 · 3 Hz), 3.92 (3Η, s), 4.04-4.1 7(2Η, m), 4.22(2Η, t, J = 4.3Hz), 7.10(1Η, d, J = 2.7Hz), 7.57(1H , d, J = 2.7Hz), 8.50(1H, s).

[Reference Example 99] 4-(2-{7-[(lE)-3-ethoxy-3-oxopropen-1-yl]-9-methoxy-2,3-dihydro-1H -[1,4]噚 and [2,3-c]quinoline-l-yl}ethyl)piperidine-1·carboxylic acid tert-butyl ester

4-[2-(7-Bromo-9-methoxy-2,3-dihydro-1H-indole, 4]indole obtained from Reference Example 98 and [2,3-c]quinolin-1- Tert-butyl)ethyl]piperidine-1-carboxylate (1 0 1.9 mg, 0.201 mmol.l), potassium carbonate (55.6 mg, 0.402 mmol), tetrabutylammonium bromide (130.9 mg, 0.402 mmol) Dissolved in N,N-dimethylacetamide (2.25 mL), and added ethyl acrylate (0.055 mL, 503.503 mmol), dichlorobistriphenylphosphine palladium (11) (14.4 mg, 0.020) under a nitrogen atmosphere. Mm). The nitrogen substitution operation was carried out three times, and the mixture was stirred at 120 ° C for 7 hours. After standing to cool, add water and extract with chloroform. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and purified to silica gel column chromatography (hexane-ethyl acetate) to give 59.5 mg (62%) of . 1H-NMR (40 〇 MHz, CDCI3) δ: 1. 1 5-1 .30 (3H, m), 1.36 (3H, t, J = 7.1 Hz), 1.46 (9H, s), 1.6 5 - 1 . 7 3 (2 Η, m), 1 . 8 2 -1.9 0 (2 Η, m), -302- 200946528 2.62-2.73 (2H, m), 3.0 5 - 3 . 1 2 (2 H, m), 3.23(2H, t, J = 4.3Hz), 3.94(3H, s), 4.05-4.16(2H, m), 4.22(2H, t, J = 4.3Hz), 4.30(2H, q, J = 7.1Hz ), 6.69 (1H, d, J = 16.4 Hz), 7.18 (1H, d, J = 2.7 Hz), 7.44 (1H, d, J = 2.7 Hz), 8.44 (1H, s), 8.81 (1H, d , J= 1 6,4Hz).

[Reference Example 100] (2E)-3-[9-methoxy-1-(2-piperidin-4-ylethyl)_2,3-dihydro-1H-[1,4]噚[ 2,3-c]salin-7-yl]ethyl acrylate

〇

4-(2-{7-[(1Ε)-3-ethoxy-3-oxopropen-1-yl]-9-methoxy-2,3-dihydro-- obtained in Reference Example 99 1H-[1,4]indolo[2,3-c]quinolin-1-yl}ethyl)piperidine-1-carboxylic acid tert-butyl ester (59.5 mg, 0.113 mmol) dissolved in methyl chloride (3 mL), trifluoroacetic acid (〇5 mL) was added under ice cooling and stirred for 1 hour. The solvent was distilled off under reduced pressure, and saturated sodium bicarbonate was added under ice-cooling to make it. The mixture was extracted with a solvent of chloroform:methanol:water = 7:3:1 and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give &lt;RTIgt;5&lt;/RTI&gt; 1H-NMR (400MHz, CDC13) δ: 1.21-1,, 1 · J〇(3H, m), 1.36(3H, t, J = 7.2HZ), 1.68-1·74(1Η,m)' L.83_l 89(2H, (4), 2 36(ih,s), 2.55-2.63(2H, m), 3.0 5 - 3 .1 1 (4 H, m), 3.24(2H, t, J = 4.3Hz ), 3.94(3H, s), 4.22(2H, t, J = 4.3Hz), 4 ^ 4-30(2H, q, J = 7.1Hz), 6 · 69( 1 H, d, J= 1 6.1 Hz), 7 · 1 5-7.2 〇〇u , UUH, m), 7.43(1H, d, J = 2.7Hz), 8.44(1H, s), 8.80(1H,d,J:=l6 1Hz) - 303- 200946528 [Reference Example 1〇1](2Ε)-3-(1-{2-[1-(2-Cyclohexylethyl)piperidine-4-yl]ethyl}-9-methoxy· 2,3-Dihydro-1H-[1,4]D§ cultivating ethyl [2,3-c]pipelin-7-yl)acrylate

(2E)-3-[9-Methoxy-1-(2-piperidin-4-ylethyl)-2,3-dihydro-1H-[1,4]D§ obtained in Reference Example 100 Oxide [2,3-c]quinolin-7-yl]-propionic acid ethyl ester (51.0 mg, 0.120 mmol), cyclohexylacetaldehyde (22.7 mg, 〇.l8〇mmol) was suspended in the second chamber ( In 3 mL), acetic acid (〇〇〇8 mL, 0.144 mmol) and hydrogenated sodium triacetoxyborate (32.1 mg, 0.14 mmol) were added under ice cooling, and stirred at room temperature for 12 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 under reduced pressure. Purification by hydrazine gel column chromatography (chloroform-methanol) gave 52.1 mg (yield: 81%) of the title compound as a yellow foam. *H-NMR (400MHz, CDC13) δ: 0 · 8 5 - 0.9 7 (2 Η, m), 1.12- 1.26(4Η,m), 1.28- 1.46(7Η, m), 1. 63 - 1.76(9H , m), 1.81-1.93 (3H, m), 2.2 7 - 2.3 8 ( 2 H, m), 2.8 9 - 2.9 9 ( 2 H , m), 3.04-3.11 (2H, m), 3.23 (2H, t, J = 4.1Hz), 3.93(3H, s), 4.22(2H, t, J = 4.1 Hz), 4.30(2H, q, J = 7.2Hz), 6.69(1H, d, J=16.1Hz) , 7.18(1H, d, J = 2.7Hz), 7.43(1H, d, J = 2.7Hz), 8.44(1H, s), 8.80(1H, d, J = 1 6.1Hz).

[Example 45] (2E)-3-(l-{2-[l-(2-cyclohexylethyl)piperidin-4-yl]ethyl-304- 200946528 }-9-methoxy-2 ,3-dihydro-1H-[1,4]噚 and [2,3-c]sal-7-yl)acrylic acid

〇

(2Ε)-3-(1-{2-[1-(2-cyclohexylethyl)piperidin-4-yl]ethyl}-9-methoxy·2,3- obtained in Reference Example 101 Dihydro- lH-[l,4]Df and [2,3-c]quinolin-7-yl)ethyl acrylate (52.1 mg, 0.097 mmol) was suspended at 90 ° /. Aqueous 20% aqueous sodium hydroxide solution (0.058 ml, 0.485 mmol) was added to aq. EtOAc (2 mL), and the mixture was stirred at room temperature for 2 hours and at 50 °C for 2 hours. After standing to cool, the solvent was evaporated under reduced pressure, dissolved in water, and neutralized with 1 N aqueous hydrochloric acid under ice cooling. The mixture was extracted with a solvent of chloroform:methanol:water = 7:3:1 and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained solid was suspended in dichloromethane-hexane, and subjected to ultrasonic treatment. The solvent was concentrated under reduced pressure, and hexane was added to carry out ultrasonic treatment. The solid was filtered to give 44 mg (yield: 69%) of MS (ESI) m / z: 508 (M + H) +.

[Reference Example 102] {1-[2-(9-Methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c] sialolin-1-yl)) Tert-butyl ester of piperidin-4-yl}carbamic acid

[1,4] Hydrazine and [2,3-c]quinolin-1-yl)ethinyl]piperidin-4-yl}carbamic acid tert-butyl ester (739.8 mg, 1.62 mmol) dissolved in tetrahydrofuran (i〇mL), -305-200946528 A borane-tetrahydrofuran complex/tetrahydrofuran solution (0.99 M, 4·9 lml, 4.86 mmol) was added dropwise under ice cooling, and the mixture was stirred for 23 hours while warming to room temperature. After distilling off the solvent under reduced pressure, a 90% aqueous solution of ethanol (20 mL) and triethylamine (2 mL) were added and the mixture was refluxed for 4 hours. After the solvent was distilled off under reduced pressure, ethyl acetate was added and washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated, evaporated, mjjjjjjjj 1H-NMR (400MHz, CDC13) 5:1.3 2- 1.46( 1 1 H, m), 1.86- 1.97(2H, m), 2.12-2.22(2H, m), 2.7 9 - 2.8 5 ( 2 H, m ), 2.85-2.91(2H, m), 3. 18-3.29(4H, m), 3.45(1H, brs), 3.92(3H, s), 4.20(2H, t, J = 4.3Hz), 4.39( 1H, brs), 7.1 2 - 7.1 9 (2 H, m), 7.88 (1H, d, J-9.0Hz), 8.36(1H, s).

[Reference Example l〇3] l-[2-(9-Methoxy-2,3-dihydro-lH-[l,4]Bf culti[2,3-c]quinolin-1-yl) Ethyl]piperidin-4-amine

The {1-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole-[2,3-£:] sialolin-1-yl group obtained in Reference Example 102) was obtained. Ethyl]piperidin-4-yl}carbamic acid tert-butyl ester (242.5 mg, 0.548 mmol) was dissolved in dichloromethane (10 mL). The solvent was distilled off under reduced pressure to dissolve in water and washed with ethyl acetate. Under ice cooling, saturated baking soda water was added to the aqueous layer to adjust to alkaline, and the solvent was extracted with chloroform:methanol:water -306-200946528 = 7:3:1. After drying over anhydrous sodium sulfate, the solvent was evaporated. 1H-NMR (400MHz, CDC13) δ : 1. 3 1 -1 ·42 (2Η, m), 1.76- 1.84(2H, m), 2.0 8 - 2.1 6 (2 H, m), 2.6 3 - 2.7 2 ( 1 H, m), 2.81-2.86 (2H, m), 2.8 7 - 2.9 3 (2 H, m), 3.2 0 - 3.2 9 (4 H, m), 3.93 (3H, s), 4.20 (2H , t, J = 4.4 Hz), 7.1 3-7.2 5 (4H, m), 7.87 (1H, d, J-9.0Hz), 8.36( 1H, s). Λ W [Example 46] 6-[( {l-[2-(9-Methoxy-2,3•dihydro-1H-[1,4]indole and [2,3-indolyl]quinolin-1-yl)ethyl]piperidine- 4-yl}amino)methyl]-211-pyrido[3,2-b][l,4]indole-3(4H)-one

1-[2-(9-Methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl)B obtained in Reference Example 103 Benzylpyridin-4-amine (196·4m g, Ο w 0.574111111〇1), 3-sided oxy-3,4-dihydro-211-pyrido[3,2-15][1,4]噚The well-6-formaldehyde (113.0 mg, 0.63 2 mmol) was suspended in a methanol: dichloromethane = 1:1 mixed solvent (6 mL), and acetic acid (〇. 〇 49 mL, 0.861 mmol) and sodium cyanoborohydride were added under ice cooling. (41.8 mg, 〇. 63 2 mmol), stirred at room temperature for 19 hr. After distilling off the solvent under reduced pressure, the solvent was dissolved in a solvent mixture of chloroform:methanol:water = 7:3:1, and washed with saturated sodium bicarbonate. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (chloroform-methanol). The obtained crude product was triturated with ethyl acetate-hexane, and the solid was filtered to afford 1 17.0 m - 307 - 200946528 g (3 7%) of the title compound as white solid. 1H-NMR (400MHz, CDC13) δ : 1 . 3 7 -1 · 4 9 (2 Η, m), 1.85- 1.93(2H, m), 2.0 7 - 2.1 6 (2 H, m), 2.4 7 - 2.5 7 (2 H, m), 2.83 (2H, t, J = 7.2Hz), 2.90-2.96(2H, m), 3.22-3.3 0(4H, m), 3.78(2H, s), 3.92(3H , s), 4.20(2H, t, J = 4.3Hz), 4.62(2H, s), 6.91(1H, d, J = 8.0Hz), 7.13-7.21(3H, m), 7.88(1H, d, J = 8.8 Hz), 8.36 (1H, s). MS (ESI) m/z: 5 05 (M + H)+.

[Example 47] 1-cyclohexyl_2-{4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]噚 till [2,3-(: Quinoline-1-yl)ethyl]piperidin-1-yl}ethyl ester

9-Methoxy-1-[(2-(piperidin-4-yl)ethyl)-2,3-dihydro-1H-[1,4]indole obtained in Reference Example 10 under a nitrogen atmosphere. Plowing [2,3-c]quinoline (120 mg, 0.3 67 mm 〇l) with cyclohexyl-2-epoxyethyl acetate (Organic Letters, 1 999, Vol. 1, No. 3, 411-414) In a solution of 88 mg, 0.476 mmol) in dichloromethane (12 mL), hydrogenated sodium acetoxyborate (117 mg, 0.550 mmol) was added at room temperature. After stirring at the same temperature for 6 hours, the reaction solution was poured into a 0.1N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate, filtered, and evaporated. The obtained residue was purified by EtOAc EtOAc (MeOH:MeOH: 20:1 - 10:1). -308- 200946528 1H-NMR (400MHz, CDC13) δ: 1.0 0 -1.3 4 (8 H, m), 1.56 (1H, m), 1.64-1, 75 (7H, m), 1 · 80- 1 . 86(3 H,m),2 . Ο 1 (1 H,m), 2 02(3H, s), 2.40(1H, dd, J = 4.1, 13.4Hz), 2.46(1H} dd, J = 7.8 , 13.4 Hz), 2.79 (1 H, brd, J = 10.5 Hz), 2.94 (1 H, brd, J = 9.8 Hz), 3.04-3.08 (2H, m), 3.20 (2H, dd, J = 4.1, 4.2Hz), 3.91(3H, s), 4.17(2H, dd, J = 4.1, 4.4Hz), 4.90(1 H, m), 7.07(1H, d, J = 2.7Hz), 7.15(1H, dd , 3 = 2.7, 9.3Hz), 7.87(1H, d, J = 9.3Hz), 8.36( 1H, s).

MS (ESI) m/z: 495 (M + H) + .

[Example 48] 1-Cyclohexyl-2-{4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quina Phenyl-1-yl)ethyl]piperidine- l-yl}ethanol

1-cyclohexyl·2-{4-[2-(9-methoxy-2,3-dihydro-1Η-[1,4]噚 till [2,3-c] obtained in Example 47 Sodium methoxide (6.0 mg) was added to a solution of quinolin-1-yl)ethyl]piperidin-1-yl}ethyl ester (80 mg, 0.161 mmol) in methanol (10 mL). After stirring at the same temperature for 6 hours, it was stirred for further 48 hours while heating to 40 °C. The reaction solution was poured into a 0.1 equivalent aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate. The obtained residue was purified by gel column chromatography (dichloromethane: methanol = 20:1 - 10:1), followed by preparative thin layer chromatography (矽 gel, chloroform:methanol:water). =7:3:1 lower layer solvent) was purified to give 68.9 mg (94%) of the title compound as pale yellow - 309 - 200946528 amorphous. 1H-NMR (400MHz, CDC13) δ : 0 9 7 -1 · 4 9 (9 Η, m), 1.61- 1.77 (6Η, m), 1. 8 3 - 1.9 2 (4 Η, m), 2.2 5 - 2.3 8 (3 Η , m), 2.83 (1Η, brd, J = 1 1.5 Hz), 3.0 3 - 3.1 〇( 3 Η,m), 3 · 2 1 (2 Η, dd, J = 4.1, 4.2 Hz), 3.42 (1Η, m), 3.92 (3Η, s), 3.98 (1Η, br), 4·18 (2Η, dd, J = 4.1, 4.4Hz), 7.07(1H, d, J = 2.7 Hz), 7.15 (1H, ddd, J = 0.5, 2.7, 9.3 Hz), 7.87 (1H, d, J = 9.3 Hz), 8.36 (1H, d, J = 0.5 H z). MS(ESI) m/ z: 454 (M + H) +.

[Example 49] 1-cyclohexyl-2-{4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quina Phenan-1-yl)ethyl]piperidine- l-yl}ethanone

Under a nitrogen atmosphere, dimethyl sulfoxide (19 μί, 0.270 mmol) of dichloromethane was added dropwise to a solution of chloroform (12 μί, 0.135 mmol) in dichloromethane (0.2 mL) at -70 ° C for 5 minutes. 〇. 2mL) solution. After stirring at the same temperature for 5 minutes, the 1-cyclohexyl-2-{4-[2-(9-methoxy- 2,3-dihydro-1H-[1,4] obtained in Example 48 was added over 7 minutes. A solution of [2,3-c]quinolin-1-yl)ethyl]piperidine-1-yl}ethanol (40.8 mg, 0_0899 mmol) in dichloromethane (1. 5 mL). After stirring at the same temperature for 40 minutes, a solution of triethylamine (0.063 mL) in methylene chloride (0.2 mL) was added, and then warmed to room temperature and stirred for 20 minutes. The reaction solution was poured into 0.1N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate, and then filtered, and then evaporated. The obtained residue was purified by preparative thin layer chromatography (purified gel, chloroform:methanol·water = 7:3:1 solvent) to give 23.4 mg (5 8%) of Amorphous. 1H-NMR (400MHz, CDC13) δ : 1.1 8-1.40 (6H, m), 1.48 (2H, ddt, J = 3.4, 12.0, 12.2Hz), 1.6 7 -1.7 9 (7 H, brm), 1.87 ( 2H, dt, J = 9.0, 7.1Hz), 2.00(2H, t, J=10.5Hz), 2.40(1H, m), 2.88(2H, brd, J=11.2Hz), 3.09(2H, m), 3 · 2 2 ( 2 H, dd, J = 4.1, 4, 2Hz), 3.23(2H, s), 3.92(3H, s), 4.19(2H, dd, J = 4.1, 4.5Hz), 7.08(1H , d, J = 2.7 Hz), 7.15 (1H, dd, J = 2.7, 9.0 Hz), 7.87 (1H, d, J = 9.0 Hz), 8.36 (1H, s). MS (ESI) m/z: 452 (M + H) + .

[Example 50] 9-methoxy-1-(2-{1-[2-(2-methylenecyclohexyl)ethyl]piperidin-4-yl}ethyl)-2,3-di Hydrogen-1H-[1,4]噚 and [2,3-c] porphyrin

9-Methoxy-1_[(2-(piperidin-4-yl)ethyl)-2,3-dihydro-1H-[1,4]噚 obtained in Reference Example 10 under a nitrogen atmosphere Plowing [2,3-c]quinoline (52.4 mg, 0.160 mmol) with (2-methylenecyclohexyl)acetaldehyde (The Journal of Organic Chemistry, 1985, Vol. 50, No. 25, 5193-5199) A solution of 28.7 mg, 0,208 mmol of dichloromethane (4.0 mL) was added, and sodium hydrogen acetoxyborate (50.9 mg, 0.240 mmol) was added at room temperature. After stirring at the same temperature for 3 hours, the reaction solution was poured into a 0.1 N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate -311 - 200946528. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was purified by hydrazine gel column chromatography (dichloromethane:methanol = 20:1) to give 39.7 mg (55%) of the title compound as pale yellow amorphous. 1H-NMR (400MHz, CDC13) δ: 1. 2 5 - 1.7 5 ( 1 2 Η, m), 1.80- 2.07(7H, m), 2.21(1H, m), 2.35(2H, m), 3.00( 2H, brd, J = 1 1.5Hz), 3.09(2H, m), 3.22(2H, dd, J = 4.1, 4.4Hz), 3.92(3H, s), 4.19(2H, dd, J = 4.1, 4.3 Hz), 4.57(1H, brs), 4.64(1H, brs), 7.07(1H, d, J = 2.7Hz), 7.15(1H, dd, J = 2.7, 9.1Hz), 7.87(1H, d, J = 9.1 Hz), 8.36 (1H, s). MS (ESI) m/z: 450 (M + H) + .

[Reference Example 104] 2-(2,2-difluorocyclohexyl)ethanol, 2-(2-fluorocyclohex-1-enyl)ethanol, 2-(2-fluorocyclohex-2-enyl)ethanol

Ethanol (0.379 mL, 6.49) was added sequentially at 0 ° C in a solution of (2- oxocyclohexyl)ethyl acetate (5.98 g, 32.5 mmol) in dichloromethane (35 mL). Methyl) bis(2-methoxyethyl)aminothiotrifluoride (10.2 mL, 55.2 mmol). After stirring at the same temperature for 30 minutes, it was slowly cooled to room temperature and stirred for another 3 hours. The reaction solution was carefully poured into ice-cold saturated aqueous sodium hydrogen carbonate and extracted with diethyl ether. The organic layer was combined, washed with brine, dried over anhydrous sodium sulfate, and then filtered and evaporated. The obtained residue was purified by hydrazine gel column chromatography (hexane·ethyl acetate = 20:1 - 10:1) to give 4.78 g of the fluorinated ester-312-200946528 mixture which was colorless. Oily. This mixture was used as it is in the next reaction. A sodium hydrogenated bis(methoxyethoxy)aluminum/toluene solution (65%, 17.4 mL, 57.9) was added to a solution of the obtained colorless oil in toluene (3OmL). Methyl), while stirring slowly to room temperature, stirring for 18 hours. The reaction solution was cooled to 〇 ° C, and a 10% Rochelle salt aqueous solution (30 mL) was carefully added, and stirred for 2 hours. The reaction solution was then extracted with diethyl ether. The organic layer was combined, washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained was purified by hydrazine gel column chromatography (hexane: ethyl acetate = 4:1 - 3:1 - 2:1) to give a colorless oil of 8.0 g. 0%) 2 - (2,2-difluorocyclohexyl)ethanol and 1.12 g (24%) of 2-(2-fluorocyclohex-1-enyl)ethanol, 2-(2-fluorocyclohex-2- Alkenyl) a mixture of ethanol. 2-(2,2-Difluorocyclohexyl)ethanol: 1H-NMR (400MHz, CDC13) δ : 1.2 3 -1.3 4 (2H, m), 1.42- ◎ 1.76(5H, m), 1. 7 9 - 1.9 7 (2 H, m), 1.9 9 - 2 . 1 2 (3 H, m), 3.67 (1H, dt, J=l〇.5, 7.1Hz), 3.74(1H, ddd, J = 5.9 , 6.6, 10.5 Hz). A mixture of about 7:3 of 2-(2-fluorocyclohex-1-enyl)ethanol, 2-(2-fluorocyclohex-2-enyl)ethanol 1H-NMR (400 MHz , CDCI3) 6:1.24-2.1 8(9.4H, m), 2.3 1- 2.34(1H, m), 2.46(0.3H, br), 3.66(1.4H, t, J = 6.7Hz), 3.71(〇 .6H, m), 5.18 (0.3H, ddt, J=1.0, 18.3, 4.1Hz).

[Reference Example 105] (2,2-Difluorocyclohexyl)acetaldehyde -313- 200946528

Adding a solution to the solution of 2-(2,2-difluorocyclohexyl)ethanol (164 mg, 1.0 mmol) obtained in Reference Example 104 in dichloromethane (5.0 mL) - Martin High Iodine (636 mg, 1.50 mmol). While slowly heating to room temperature, stir for 2 hours. The reaction solution was poured into a 1% aqueous sodium thiosulfate solution and extracted with diethyl ether. 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 to give crude title compound as a colorless oil. This compound was used in the next reaction as it was without purification. 1H-NMR (400MHz, CDC13) δ : 1.2 5 - 1 . 3 9 ( 2 H, m), 1.48- 1.85 (5H, m), 2.11 (1H, m), 2.32 (1H, m), 2.40 (1H , m), 2. 89(1 H, m), 9.78(1 H, s).

[Reference Example 10 6] (2-Fluorocyclohex-1-enyl)acetaldehyde, (2-fluorocyclohex-2-enyl)acetaldehyde

F F

a mixture of about 7:3 of 2-(2-fluorocyclohex-1-enyl)ethanol and 2-(2-fluorocyclohex-2-enyl)ethanol obtained in Reference Example 104 under a nitrogen atmosphere ( 144 mg, 1.0 mmol) in dichloromethane (5.0 mL) EtOAc. 〇 Add Days-Martin High Iodine (551mg, 1.30mmol). I slowly heated up to room temperature and stayed for 2 hours. The reaction solution was poured into a 1% aqueous sodium thiosulfate solution to extract with acetic acid. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and brine, and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give crude titled compound. This compound was used as it is for the next reaction without further purification [Example 51] 1-(2-{1-[2-(2-Fluorocyclohex-1-en-1-yl)B Piperidin-4-yl}ethyl)-9-methoxy-2,3-diar-1H-[1,4]indolo[2,3-c] porphyrin

9-Methoxy-1-[(2-(piperidin-4-yl)ethyl)-2,3-dinitro-1H-[1,4]indole obtained in Reference Example 10 under a nitrogen atmosphere. [2,3-c]quinoline (48.0 mg, 0.147 mmol) and the crude product of (2-fluorocyclohex-1-enyl)acetaldehyde obtained in Reference Example 106 (31.3 mg, 0.220 mmol, and A mixture of 2-fluorocyclohex-2-enyl)acetaldehyde was used as it was in dichloromethane (4.0 mL), and hydrogenated sodium acetoxyborate (46.6 mg, 0.220 mmol) was added at room temperature. After stirring at the same temperature for 16 hours, the reaction solution was poured into a 0.1 N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate, and then filtered, and evaporated. The obtained residue was purified by preparative thin layer chromatography (purified gel, chloroform:methanol: water = 7:3:1 solvent) to give 20.5 mg (31%) of Crystal form. 1H-NMR (400MHz, CDC13) δ : 1.2 5 - 2.0 0 ( 1 7 Η, m), 2.13(1H, brrn), 2.23-2.42(3H, m), 2.9 5 - 3.0 0 (2 H, brm) , 3.09(2H, m), 3.22(2H, dd, J = 3.9, 4.6Hz), 3.92(3H, s), 4.20(2H, dd, J = 4.0, 4.6Hz), 7.09(1H, d, J = 2.7 Hz), 7.16 (1H, dd, J = 2.7, -315- 200946528 9.0 Hz), 7.88 (1H, d, J = 9.0 Hz), 8.37 (1H, s). MS (ESI) m/z: 454 (M + H) + .

[Example 52] N-(3-fluorophenyl)-2-{4-[2·(9-methoxy-2,3-dihydro-1H-[1,4]fluorene[2, 3-c]quinolin-1-yl)ethyl]piperidine-oxime-yl}acetamide

9-Methoxy-1-[(2-(piperidin-4-yl)ethyl)-2,3-dihydro-1H-[1,4]噚 obtained in Reference Example 10 under a nitrogen atmosphere Plowing [2,3_c] porphyrin (50.0 mg, 0.153 mmol) with N,N-diisopropylethylamine (〇·〇5 3 m L, 0.305 mmol) in toluene (1.0 mL)-dichloro In a solution of ethane (〇.5 mL), 2-gas-N-(3-phenylphenyl)etheneamine was added at room temperature (Bioorganic &amp; Medicinal Chemistry, 2004, Vol. 12, No. 1, 3, 3 4 7 1 - 3 4 8 3 items, 28.6 mg, 0.153 mmol). After stirring at the same temperature for 20 minutes, it was heated to 50 ° C and stirred for another 15 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate, filtered, and evaporated. The resulting residue was purified by preparative thin layer chromatography (EtOAc, methylene chloride:methanol = 20:1) to give 63.7 mg (8 7%) of the title compound as pale yellow amorphous 1H- NMR (400MHz, CDC13) δ: 1.32-1.47 (3Η, brxn), 1.78-1.80(2H, brm), 1. 8 6 -1 . 9 1 (2 H, m), 2.24(2H, brt, J= 10.0 Hz), 2.90 (2H, brd, J = 1 .5 Hz), 2.08 (2H, s), 3.10 (2H, m), 3.23 (2H, dd, J = 4.1, 4.4 Hz), 3.94 (3H, s), 4.20(2H, t, J = 4.4Hz), 6.79(1H, ddt, J = 0.7, 2.4, 8.3Hz), 7.10(1H, d, -316- 200946528 J-2.7Hz), 7.15-7.27 (3Η, m), 7.51(1Η, dt, J=10.7, 2.4Hz), 7.89(1 Η, d, J = 9.0Hz), 8.3 7(1 Η, s), 9.20(1Η, br). MS (ESI) m/z: 479 (M + H) + .

[Example 53] N-(2,5-difluorophenyl)-2-{4-[2-(9-methoxy- 2,3-dihydro-1H-[1,4] [2,3-c]quinolin-1-yl)ethyl]piperidine- l-yl}acetamide

Ο

9-Methoxy-1-[(2-(piperidin-4-yl)ethyl)-2,3-dihydro-1H-[1,4] obtained in Reference Example 1 under a nitrogen atmosphere. Indole [2,3-c]quinoline (50.0 mg, O.153 mmol) and N,N-diisopropylethylamine (〇. 〇53 mL, 0.305 mmol) in toluene (1.0 mL) To a solution of ethyl chloride (0.5 mL), 2-chloro-N-(2,5-difluorophenyl)ethonamide (31.4 mg, 0.153 mmol) was added at room temperature. After stirring at the same temperature for 20 minutes, it was heated to 50 ° C and stirred for another 24 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was combined, washed with brine and dried over anhydrous sodium sulfate. The residue obtained was purified by hydrazine gel column chromatography (ethyl acetate:hexane = 1:1^2:1 - 4:1) to give 62.0 mg (82%) of Amorphous. iH-NMRHOOMHz, CDC13) δ:1·3 9- 1.48 (3 Η,m), 1.79 (2H,brd, J= 10.OHz), 1.91(2H, m), 2.27(2H, brt, J=11.2 Hz), 2.90(2H, brd, J=11.2Hz), 3.11(2H, m), 3.13(2H, s), 3.24(2H, dd, J = 4.3, 4, 4Hz), 3.95(3H, s) , 4.20 (2H, dd, J = 4.1, 4.4 Hz), 6.72 (1H, m), 7.05 (1 H, ddd, 4.9, 9.3, 1 0.2 Hz), 7.09 (1H, d, -317- 200946528 J = 2.7 Hz), 7.16 (1H, dd, J = 2.7, 9.3 Hz), 7.89 (1H, d, J = 9.3 H z), 8.2 1 (1 H,ddd, J = 3 · 2 , 6 · 3,1 〇· 2 H z ), 8.3 7 (1 H, s), 9.67 (1H, br). MS (ESI) m/z: 495 (M + H) + .

[Example 54] N-(3-fluorophenyl)-2-{4-[2-(9-methoxy-2,3·dihydro-1H-indole, 4] 噚耕和[2,3 -c]quinolin-1-yl)ethyl]piperidine-l-yl}-N-methylacetamide

9-Methoxy-1-[(2-(indol-4-yl)ethyl)-2,3-dihydro-1H-[1,4]曙 obtained in Reference Example 10 under a nitrogen atmosphere Indole [1,3-c]quinoline (50,0 mg, 0.153 mmol) and N,N-diisopropylethylamine (〇. 〇5 3 m L, 〇.305 mmol) of toluene (1.0 mL) 2-Chloro-N-(3-phenylphenyl)-N-methylethanoamine (30.8 mg, 〇-153 mmol) was added to a solution of dichloromethane. After stirring at the same temperature for 20 minutes, the mixture was heated to 50 ° C and stirred for another 15 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, and then filtered and evaporated. The residue obtained was purified by preparative thin layer chromatography (m.p., methylene chloride:methanol = 20:1) to afford 42.6 mg (5 7%) of the title compound as pale yellow amorphous. J = 3.3, 12.2, 12.0 Hz), 1.63 (2H, brd, J = 12.0 Hz), 1.84 (2H, m), 1.98 (2H, t, J = 10.8 Hz), 2.83 (2H, brd, J = 10.8) Hz), -318- 200946528 2.94(2H, br), 3.06(2H, m), 3.21(2H, dd, J = 4.2, 4.4Hz), 3.26(3H, brs), 3.91(3H, s), 4.18 (2H, dd, 5 = 4.2, 4.4 Hz), 6.95-7.06 (3H, m), 7.07 (1H, d, J = 2.7 Hz), 7.15 (1H, dd, J = 2.7, 9.0 Hz), 7.36 ( 1H, dt, J = 6.4, 8.0 Hz), 7.87 (1H, d, J = 9.0 Hz), 8.36 (1H, s). MS (ESI) m/z: 493 (M + H)+.

[Reference Example l7] 4-Allyl-3-hydroxypiperidine-l-carboxylic acid benzyl ester

Benzyl 4-allyl-3-oxoxypiperidine-1-carboxylate (Synthesis, 1 999, No. 10, 1814-1818, 3.60 g, 13.2 mmol) of methanol under nitrogen atmosphere In a (30 mL) solution, sodium borohydride (249 mg, 6.59 mmol) was added at 0 °C. After stirring slowly to room temperature for 30 minutes, a saturated aqueous ammonium chloride solution (15 mL) was added to terminate the reaction. Most of the methanol component of the reaction mixture was distilled off under reduced pressure, and the residue was poured into two layers of saturated brine and extracted with ethyl acetate. The organic layer was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered and evaporated. The residue obtained was purified by hydrazine gel column chromatography (hexane: ethyl acetate = 4:1 - 3:1 - 2:1) to give 585 mg of the labeled compound as a polar isomer. 5 6 g of highly polar isomer and 1.6 g of these mixtures, each being a colorless oil. The total output was 3.21 g (89%). Low polar isomer: W-NMRHOOMHz, CDC13) δ: 1.44-1.62 (3H, brm), 2·04 (1Η, dt, J=13.9, 6.8 Hz), 2.21 (1H, dt, J=13.9, - 319- 200946528 6.6Hz), 2.52-2.89(3H, brm), 3.79(1H, br), 4.20(2H, brm), 5.01-5.10(4H, m), 5.78(1H, m), 7.2 5 - 7.3 7 ( 5 H , m). Highly polar isomer · · lH-NMR (400MHz, CDC13) δ: 1.21 (1Η, br), 1.49 (1H, m), 1·75 (1Η, brd, J=13 , 2Hz), 1.89(1H, brm), 2.01(1H, dt, J=14.4, 7.6Hz), 2.46(1H, br), 2.65(1H, t, J=11.4Hz), 2.77(1H, br) , 3.36(1H, br), 4.06(1H, br)3 4.23(1H, br), 5.04-5.1 1(4H, m), 5.81(1H, m), 7.3 0 - 7.3 8 (5 H , m ) .

[Reference Example l-8] 4-Allyl-3-methoxypiperidine-1-carboxylic acid benzyl ester 〇

4-Allyl-3-hydroxypiperidine-1·carboxylic acid benzyl ester (highly polar isomer, 760 mg, 2.76 mmol) obtained in Reference Example 107 and iodocarbane (0.258 mL, 4.14) Sodium hydride (oily, containing 55%, 181 mg, 4.14 mmol) was added at room temperature to a solution of EtOAc (4 mL). A saturated aqueous solution of ammonium chloride was added under ice cooling to stop the reaction. The reaction solution was poured into saturated brine and extracted with ethyl acetate. The organic layer was combined, washed with brine and dried over anhydrous sodium sulfate. The residue obtained was purified by hydrazine gel column chromatography (hexane: ethyl acetate _ =1 9 : 1 - 9 ··1 - 6 : 1) to give 671 mg (84%) of It is a colorless oil. With respect to the low polar isomer, from the 485 mg (i.76 mmol) of the starting material _-320-200946528, the same reaction was carried out to give 344 mg (yield: 68%) of the title compound as a colorless oil. From the highly polar isomer: h-NMRMOOMHz, CDC13)S: 1.19 (1H, br), 1.52 (1H, br), 1.76 (1H, brd, J = 11.2 Hz), 1.94 (1H, dt, J = 13.9) , 8.1Hz), 2.50(1H, brm), 2.61(1H, br), 2.79(1H, t, J=12.1Hz), 2.83(1H, br), 3.40(3H, brs), 4.01(1H, brd , 〇J=13.4Hz), 4.34(1H, brm), 5.0 1 - 5.0 5 (2 H, m), 5.13(2H, brs), 5.75(1H, m), 7.2 9 - 7.3 6 ( 5 H, m). MS (ESI) m/z: 290 (M+H) +. from low polar isomer: h-NMRHOO MHz, CDC 13)S: 1.40 (1H, br), 1.56 (1H, br), 2.03 ( 1H, m), 2.20(1H, br), 2.6 7 - 2.8 3 (3 H, brm), 3. 1 7-3.40(4H, brm), 4.0 0 - 4.4 9 (2 H, brm), 5.01- 5.18(4H, m), 5.75(1H, m), 7.2 9 - 7.3 5 ( 5 H, m). MS (ESI) m/z: 290 (M + H) + .

[Reference Example 109] 4-(2-Hydroxyethyl)-3-methoxypiperidine-1-carboxylic acid benzyl ester

A solution of 4-allyl-3-methoxypiperidine-1-carboxylic acid benzyl ester (highly polar isomer, 670 mg, 2.32 mmol) in dichloromethane (30 mL) Ozone gas was blown in at 70 °C for 30 minutes. After 1.5 hours of nitrogen gas blowing at the same temperature, methanol (15 mL) and sodium borohydride (5 25 mg, 1 3 ·9ιηιηο1) were added in this order. After heating to room temperature, it was stirred at the same temperature for 96 hours. After adding a saturated aqueous solution of ammonium chloride under ice cooling to stop the reaction, the solution was poured into saturated brine and extracted with ethyl acetate. The organic layer was combined, washed with brine and dried over anhydrous sodium sulfate. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc With respect to the low polar isomer, from 285 mg (〇.985 mmol) of the starting material, 171 mg (yield: 59%) of the title compound was obtained as a colorless oil. From the highly polar isomer: j-NMRHOOMHz, CDC13) δ: 1.26 (1Η, brm), 1.47-1.60 (2H, m), 1.7 4 - 1. 8 4 (2 H, m), 2.10 (1H, br ), 2.54(1H, br), 2.77(1H, brt, J=12.9Hz), 2.87(1H, br), 3.43(3H, brs), 3.63(1H, m), 3.72(1H, m), 4.08 (1H, br), 4·47(1Η, brm), 5.13(2H, brs), 7.3 0 - 7.3 8 ( 5 H, m). From low polar isomer: iH-NMRHOOMHz, CDC13) δ: 1.42 (1Η, bO,1·47_1·82(4Η,m), 2.57(1H,br),2·76-2·91(2Η,m), 3.21-3.49(4H, brm), 3.6 1 - 3.7 5 (2 H, m), 4.0 7 - 4.4 6 ( 2 H, brm), 5·14(2Η, m), 7.3 0-7.3 8 (5 H, m).

[Reference Example 110] 4-(2-Iodoethyl)-3-methoxypiperidine-1-carboxylic acid benzyl ester

4-(2-Hydroxyethyl)-3-methoxypiperidine-1-carboxylic acid benzyl ester (highly polar isomer, 500 mg, 1.70 mmol) obtained in Reference Example 109 under nitrogen atmosphere - 322 - 200946528 To a solution of triethylamine (0.356 mL, 2.56 mmol) in dichloromethane (10 mL), m. After stirring at the same temperature for 10 minutes, borneol was added to stop the reaction. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was combined, washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give a crude methanesulfonate matrix. The obtained crude form of the methanesulfonamide substrate was dissolved in acetone (20 mL), sodium iodide (511 mg, 3.41 mmol) was added, and the mixture was heated under reflux for 7 hours. The reaction solution was poured into a 1% aqueous solution of sodium thiosulfate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by gel column chromatography (hexane: ethyl acetate = 2: 1-1:1) to give 634 mg (92%). A labeled compound which is a pale yellow oil. With respect to the low polar isomer, 172 mg (74%) of the title compound was obtained from 168 mg (0.597 mmol) of material, which was obtained as a colorless oil. 〇_ from the highly polar isomer: h-NMRHOOMHz, CDC13) δ: 1. ΐ5 (1Η, brm), 1.55 (1H, br), 1.66 (1H, m), 1.77 (1H, brd, J=12. 〇Hz), 2.32(1H, m), 2.57(1 H, br), 2.79(1H, brt, J=12.6Hz), 2.85(1H, br), 3.16(1H, m), 3.28(1H, m ), 3.38(3H, brs), 4.05(1H, brd, J=12.0Hz), 4.41(1H, brm), 5.12(2H, brs), 7.24-7.37(5H, m). from low polar isomers :W-NMRGOOMHz, CDC13) δ:1·ΐ3_1·94(4Η,m), 2.29-2.84(3H,m),3·12-3·38(6Η,m),4.04--323- 200946528 4.53 (2H, brm), 5.0 7 - 5 .1 7 (2 H, m), 7.2 6 - 7.3 5 ( 5 H, m).

[Reference Example 111] 3·Methoxy-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]salin- I-yl)ethyl]piperidine-1-carboxylic acid benzyl ester

9-Methoxy-2,3-dihydro-1H-[l,4]Bf-trap and [2,3-c]quinoline (108 mg, 0.499 mmol) obtained in Reference Example 8 under a nitrogen atmosphere. In a solution of N,N-dimethylacetamide (1.5 mL), sodium hydride (oily, 55%, 57 mg, 1.30 mmol) was added at room temperature and stirred for 1.5 hours. The N,N 4-(2-iodoethyl)-3-methoxypiperidine-1-carboxylic acid benzyl ester (from the highly polar isomer, 262 mg, 0.649 mmol) obtained in Reference Example 110 was added dropwise over 20 min. A solution of dimethylacetamide (0.5 mL) was stirred at the same temperature for 3 hours. A saturated aqueous ammonium chloride solution (3.0 mL) was added under ice cooling to stop the reaction, and the mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate, filtered and evaporated. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc From a low polar isomer compound, also from 72.3 mg (0.334 mmol) of 9-methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinoline and 170 </RTI> </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; It is a light brown oil. From highly polar isomer: W-NMRHOOMHz, CDC13) δ: 1.26 (1Η, -324- 200946528 br), 1.46(1 Η, m), 1.6 9 - 1.7 8 (2 Η, m), 2.39 (1 Η , brt, J = 1 3.2Hz), 2.5 1 (1 H, br), 2.74 (1H, brt, J=1 1.0Hz), 2.92(1H, m), 3.02(1H, m), 3.18(1H, m), 3.2 0 - 3.2 9 (2 H , m), 3.41(3H, brs), 3.92(3H, s), 4.10(1 H, br), 4.20(2H, dd, J = 4.2, 4.4Hz) , 4.49(1 H, brm), 5. 14(2H, brs), 7.10(1H, d, J = 2.7Hz), 7. 17(1H, dd, J = 2.7, 9.3Hz), 7.3 0 - 7.3 7 (5 H, m), 7.90 (1H, d, J = 9.3 Hz), 8.38 (1H, s). MS (ESI) m/z: 492 (M + H) + .

From the lower polar isomer: W-NMRHOOMHz, CDC13) δ: 1.44 (1Η, br), 1.72 (1H, m), 1 , 88 (1H, m), 2.09 (1H, br), 2.39- 3.41 (11H , m), 4.23(3H, s), 4.0 8 - 4.2 2 (3 H , m), 4.42(1H, brm), 5. 1 1(1H, d, J=12.4Hz), 5.16(1H, d , J = 12.4 Hz), 7.09-7.17 (2H, m), 7.2 9 - 7.3 5 (5 H, m), 7.88 (1H, d, J = 9.0 Hz), 8.37 (1H, s). MS (ESI) m/z: 492 (M + H) + .

[Example 55] 1-{2-[1-(2-Cyclohexylethyl)-3-methoxypiperidin-4-yl]ethyl}-9-methoxy-2,3-dihydro -111-[1,4]噚 and [2,3-(:]quinoline

3-methoxy-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4] oxime from the highly polar isomer obtained in Reference Example 111 [2,3-c]quinolin-1-yl)ethyl]piperidine-1-carboxylic acid benzyl ester (193 mg, 0-393 mmol) in methanol (5.0 mL), 10% palladium carbon catalyst at room temperature (about 50% aqueous, 50 mg). -325- 200946528 After replacing the inside of the reaction vessel with hydrogen, it was stirred at the same temperature for 96 hours. Filtration of the catalyst The filtrate was concentrated under reduced pressure to give 208 mg of 9-methoxy-i-[2-(3-methoxypiperidin-4-yl)ethyl]-2,3-dihydro-1H. -[1,4] The crude form of [2,3-c]quinoline. 62.3 mg (0.118 mmol) of the obtained amine was dissolved in dichloromethane (2.0 mL) under nitrogen atmosphere, and cyclohexylacetaldehyde (88.0 mg, 0.697 mmol) was added at room temperature. Methyl chloride (0.5 mL) solution and hydrogenated sodium triethoxyborohydride (73.0 mg, 0.344 mmol). After stirring at the same temperature for 65 hours, the reaction liquid was poured into 0. 1 equivalent of an aqueous sodium hydroxide solution, and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and filtered and evaporated. The residue obtained was purified by hydrazine gel column chromatography (dichloromethane:methanol = 49:1 - 19:1 - 9:1) to give 41.1 mg (75%) of Amorphous. Regarding 3·methoxy-4-[2-(9-methoxy-2,3-dihydro-111-[1,4]噚-[2,3- from low polar isomers Benzyl quinolin-1-yl)ethyl]piperidine-1-carboxylate (134 mg, 0.273 mmol) was obtained in the same procedure as above to give 20.0 mg (31%) of Amorphous. From the highly polar isomer: W-NMRHOOMHz, CDC13) δ: 0.92 (2Η, dt, J = 10.3, 10.7Hz), 1. 1 0-1.42 (9H, m), 1. 6 2 - 1 . 8 7 (8 H, m), 2.37-2.44(3H, m), 2.85(1H, brd, J=11.0Hz), 2.9 2 - 3.0 6 (2 H, m), 3 .17-3.29(4H, m) , 3.40(3H, s), 3.93(3H, s), 4.15- 4.22(2H, m), 7.11(1H, d, J = 2.7Hz), 7.15(1H, dd, J = 2.7, 9.0Hz)7.88 (lH, d, J = 9.0 Hz), 8.37 (1H, s). MS (ESI) m/z: 46 8 (M + H) + . -326 - 200946528 From low polar isomer: W-NMRHOOMHz, CDC13) δ: 0.91 (2Η, dt, J=10.5, 10.7Hz), 1.10-1.25(5H,m), 1,40(2H, m), 1.52(2H, m), 1.62- 1.83(5H , m), 1.90(2H, m), 2.0 3 - 2.1 8 (2 H, m), 2.29 (1H, ddd, J = 5.4, 10.2, 12.2Hz), 2.42 (1H, ddd, J = 6.1, 10.4 , 12.2Hz), 2.82(1H, brd, J=10.0Hz), 2.99- 3.15(3H, m), 3.2 3 - 3.2 5 (3 H, m), 3.33(3H, s), 3.94(3H, s ), 4. 17-4.23(2H, m), 7. 1 4 - 7 . 1 7 (2 H, m), 7.88 (1H, d, J=10.0Hz), 8.38(1H, s). O MS (ESI) m/z: 468 (M + H) + .

[Reference Example 112] 1-(1-{l-[2-(l,4-dioxaspiro[4.5]indole-6-yl)ethyl]-3-methoxypiperidin-4-yl} Ethyl)-9-methoxy- 2,3-dihydro-1H-[1,4]D§[2,3-c]quinoline

92.3 mg (〇.118 mmol) of 9-methoxy-1-[2-(3-methoxypiperidin-4-yl)ethyl]- from the highly polar isomer obtained in Example 55 2,3-Dihydro-1H-[1,4]indole and [2,3-c]quinoline in dichloromethane (2.0 mL) in hexanes. 65.0 mg, 0.353 mmol) in dichloromethane (0.5 mL) and hydrogenated sodium triacetoxyborate (49.4 mg, 0.233 mmol). After stirring at the same temperature for 19 hours, the reaction solution was poured into a 0.1 N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate. The residue obtained from -327-200946528 was purified by hydrazine gel column chromatography (dichloromethane:methanol = 4 9:1 - 19:1 - 9:1) to give 33.6 mg (54%) of It is white amorphous. 1H-NMR (400MHz, CDC13) δ : 1 . 2 2 - 1 . 8 8 ( 1 7 H, m), 2.35- 2.45 (3H, m), 2.86 (1H, br), 2.9 7 - 3.0 5 (2 H , m), 3 .1 6 - 3.3 1 (4 H, m), 3.40 (3H, s), 3.9 0 - 3.9 9 (7 H, m), 4.1 5 - 4.2 3 (2 H, m), 7.11(1H, d, J = 2.7Hz), 7.16(1H, dd, J = 2.7, 9.0Hz), 7.88(1H, d, J = 9.0Hz), 8.38(1H, s). MS(ESI)m /z:526(M + H) + .

[Example 56] 2-(2-{3-methoxy-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]噚[[,3,3] -(:]quinolin-1-yl)ethyl]piperidin-1-yl}ethyl)cyclohexanone

1-(1-{1-[2-(l,4-Dioxaspiro[4.5]癸-6-yl)ethyl]-3-methoxypiperidin-4-yl obtained in Reference Example 112 }Ethyl)-9-methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinoline (33.6 mg, 0.0639 mmol) in tetrahydrofuran (9.0 mL) In the solution, 1N hydrochloric acid (3.0 mL) was added at room temperature, and stirred for 17 hours. After adding a saturated aqueous solution of sodium hydrogencarbonate and neutralizing, the reaction mixture was poured into a 0.1 N aqueous sodium hydroxide solution and extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by hydrazine gel column chromatography (dichloromethane:methanol = 49:1 &gt; 19:1 - 9:1) to give 28.6 mg (93%) of Yellow amorphous. 1H-NMR (400MHz, CDC13) δ : 1.2 5 -1.4 5 (4 H, m), 1.65- -328- 200946528 1.78(5Η, m), 1.85(2Η, m), 2.0 1-2.1 2 (3 Η , m), 2.2 7 - 2.4 2 (6 Η, m), 2.84 (1Η, brt, J=ll.lHz), 2.9 7 - 3.0 5 (2 Η, m), 3.15- 3.30(4H, m), 3.39(3H, d, J = 3.2Hz), 3.94(3H, s), 4.16- 4.22(2H, m), 7.12(1H, d, J = 2.7Hz), 7.16(1H, dd, J=2.7, 9.0 Hz), 7.88 (1 Η, d, J = 9.0 Hz), 8.37 (1 Η, s). MS (ESI) m/z: 48 2 (M + H) + .

[Reference Example 1 13] (2RS, 4SR)-4-(2-iodoethyl)piperidine-1,2-dicarboxylic acid 1-t-butyl ester 2-ethyl ester

((2RS,4SR)-4-(2-Hydroxyethyl)piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester under nitrogen atmosphere (Journal of Medicinal Chemistry, 1989) Year, 32 volumes, No. 9, 2171-2178, 2.04g, 6.77mmol) and triethylamine (1_42mL, 1〇.2111111〇1) in dichloromethane (3〇1111〇 solution, at 〇°C Methanesulfonium chloride (0.576 mL, ' 7.45 mmol) was added and stirred at the same temperature for 2 hours. After adding borneol and stirring for 30 minutes, the reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium sulfate and dried over anhydrous sodium sulfate. The mixture was heated to reflux for 8 hours, and the reaction mixture was poured into aq. After subtraction -329- 200946528, the concentrated filtrate was pressed and subjected to gel column chromatography (hexane: ethyl acetate = 49:1 - 19: 1 9:1) The residue obtained was purified to give 2.61 g (yield: 94%) ofyield as a colorless oil. 1H-NMR (400 MHz, CDC13) δ: 1.29 (3 Η, t, J = 7.1 Hz) , 1.42(1H, m), 1.44(9H, s), 1.7 4 - 2.0 1 (6 H,m),3 . 1 8 (2 H,dd,J = 6 · 8, 7.3Hz), 3.29(1H , brm), 3.64(1H, br), 4.19(2H, q, J = 7.1Hz), 4.38(1H, dd, J = 5.6, 6.1Hz).

[Reference Example 1 14] (2RS, 4SR)-4-[2-(9-methoxy-2,3-dihydro_1H_[1,4]indole[2,3-c]sarin-1 -ethyl)ethyl]piperidine-1,2-dicarboxylic acid i_t-butyl ester

9-Methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline (913 mg, 4.22 mmol) obtained in Reference Example 8 under a nitrogen atmosphere. In a solution of N,N, dimethylacetamide (10.0 mL), sodium hydride (oily, containing 5 5 %, 5 5 3 mg, 1 2 · 7 mm ο 1 ) was added at room temperature, and the mixture was stirred for 1 hour. 5 minutes at 0 °C: (2RS, 4SR)-4-(2-iodoethyl)piperidine-1,2-dicarboxylic acid 1-t-butyl ester 2-ethylate obtained in Reference Example 1 13 A solution of the ester (2.60 g, 6.33 mmol) in N,N-dimethylacetamide (5. (mL)) was stirred for 2.5 hours while warming to room temperature. Saturated aqueous ammonium chloride solution was added under ice cooling to stop the reaction, and the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with dichloromethane. The aqueous layer was made basic with 1N aqueous sodium hydroxide solution and then extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate, and then filtered, and then evaporated to dryness. The obtained residue was purified by gel column chromatography (dichloromethane: methanol = 4 9:1 - 19:1 - 9:1), followed by reverse phase high-speed liquid chromatography (〇6乂61). 〇3 (1, 2 £: 111 (|) &gt; 10 (; 111, acetonitrile-water mixed solvent containing 0.1% formic acid) was purified to give 250 mg (13%) of the title compound as pale yellow amorphous 1H-NMR (400MHzJ CDC13) δ: 1.21 (1Η, m), 1. 3 7- 1.46 (1 1 Η,

m), 1.67(1Η, brm), 1. 8 5 - 1 . 8 7 (2 Η, m), 2.31(1Η, m), 2.94-3.10(1Η,brm),3.38(4Η,br),3 · 89(3Η, s), 3.95 -4.07( 1 Η,m), 4.20(2Η, brm), 4.7 7-4.9 2 (1 Η, m), 7.05(1Η, d, J = 2.2Hz), 7.20 (1Η, dd, J = 2.2, 9.3Hz), 8.01(1Η, d, J = 9.3Hz), 8.35(1Η, s), 8.42(1Η, br). MS(ESI)m/z:472(M + H) + .

[Example 57] (2RS, 4RS)-l-(2-cyclohexylethyl)-4-[2-(9-methoxy-2,3-dihydro-111-[1,4]噚 well [2,3-(:]quinolin-1-yl)ethyl]piperidine-2-carboxylic acid

(2RS,4SR)-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline obtained in Reference Example 114 -1-yl)ethyl]piperidine-1,2.dicarboxylic acid 1-t-butyl ester (250mg, 0.5311«111〇1) in dichloromethane (1〇.〇1111^) solution, in the room 4 equivalents of hydrogen chloride/dioxane solution (5.0 mL) were added thereto, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to give 223 mg (2RS, 4SR) -4-[2-(9-methoxy-2,3-dihydro-111-[1,4] oxime and [2, 3-(:]Salanta-1-yl)-331- 200946528 Ethyl]piperidine-2-carboxylic acid as a crude brown solid. (2RS, 4SR) -4-[2 -(9-methoxy-2,3-dihydro-IH-[1,4]indole and [2,3-c]salolin-1-yl)ethyl]piperidine-2-carboxylic acid The crude product (1781118, 0.424111111〇1) was dissolved in methylene chloride (8. 〇1111〇-methanol (1. 〇1111〇 mixture was added at room temperature in order to add diethylamine (〇.167mL, 1.20mmol) and Cyclohexyl acetaldehyde (202 mg, 1.60 mmol) and sodium triethyl sulfonium hydride (3 3 9 mg, 1 · 60 ιηιηο1) were stirred at the same temperature for 1 hour. The reaction solution was poured into a phosphate buffer (ΡΗ6.0). The mixture was extracted with dichloromethane, and the organic layer was combined and dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The column was subjected to column chromatography (dichloromethane: methanol = 49:1) ~^19:1-&gt;9:1-&gt;6:1) The obtained residue was purified to give 151 mg (yield: 74%) ofyield as white solid. 1H-NMR (40 〇 MHz, CD3OD) δ : 0 ·9 8-1 · Ο2(2Η, m), 1.17- 1.33(5H,brm), 1.60- 1.95(1 3H,brm), 2.29(lH,br),3.14· 3.31(7H, m) , 3.83(1H, br), 3.93(3H, s), 4.22(2H, brs), 7_12(1H,brd, J = 2.0Hz), 7.18(1H, dd, J = 2.0, 9.0Hz), 7.77( 1H, d, J = 9.〇Hz), 8.21(1H, s). MS(ESI) m/z: 482(M + H) + . * [Reference Example 115] (2RS, 4SR)-4-[ 2-(Third butyl dimethyl decyloxy) ethyl] piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester

Under nitrogen atmosphere '(2RS,4SR)-4-(2-hydroxyethyl)piperidine_U2_di-332- 200946528

Carboxylic acid 1-t-butyl ester 2-ethyl ester (9.52 g, 31_6 mm 〇l) and imidazole (4.30 g, 63.2 mmol) in dichloromethane (80 mL)-N,N-dimethylformamide (20 mL) In the solution, chlorotributyl dimethyl decane (5.43 g, 36.0 mm 〇l) was added at room temperature, and stirred at the same temperature for 30 minutes. After adding borneol and stirring for 30 minutes, the reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was extracted with ethyl acetate and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered and evaporated. The obtained residue was purified by hydrazine gel column chromatography (hexane: ethyl acetate = 20:1 - 10: 1-&gt; 5:1) to afford 12.4 g (9 5%) of It is a colorless oil. 1H-NMR (400MHz, CDC13) δ: 0.36(6Η, s), 0.88(9H, s), 127(311, t, J = 7.0Hz), 1.44(9H, s), 1.4 5 -1 · 5 1 ( 3 H,m),1.71-1-86(3H, m), 1.99(1H, m), 3.33(1H, br), 3.60(1H, br), 3-62(2H, t, J = 6.3 Hz) 4.17 (2H, q, J = 7.0Hz), 4.43(1H, t, J==5.8Hz).

[Reference Example 116] (7311, 8 &amp; 118)-7-[2-(Tertiary butyl dimethyl decyloxy) Q ethyl] hexahydrooxazolo[3,4-a]pyridine-3_ ketone

(2RS,4SR)-4-[2-(D-butyl dimethyl decyloxy)ethyl]piperidine-1,2-dicarboxylic acid 1-dimer obtained in Reference Example 115 under a nitrogen atmosphere After adding a solution of 2-ethyl ester (6.00 g, 14.4 mmol) in tetrahydrofuran (100 mL), lithium borohydride (629 mg, 28.9 mmol) was added at room temperature, and then heated to reflux for 3 - 333 - 200946528 hr. The reaction solution was carefully poured into a saturated aqueous solution of ammonium chloride. When the generation of the gas is stopped, the mixture is extracted with ethyl acetate, and the organic layer is combined and washed with saturated brine. The extract was dried over anhydrous sodium sulfate, and then filtered and evaporated. The residue obtained was purified by hydrazine gel column chromatography (hexane: ethyl acetate = 10:1 - 2:1 - 1:1) to give 3.99 g (92%) of Shape. 1H-NMR (400MHz, CDC13) δ: 0.00(3Η, s), 〇.49(3H, s), 〇.84(9H, s), 1.03(1H, dt, J=11.7, 11.8Hz), 1.12 (1H, m), 1-41-1.47(2H, m), 1. 6 0 - 1 . 7 0 (2 H, m), 1.83 (1H, m), 2.81 (1H, dt, J = 3.1, 13.2Hz), 3.62(2H, t, J = 6.2Hz), 3.65(1H, m), 3.82(2H, m), 4.35(1H, t, J = 8.3Hz). MS(ESI)m/z: 3 00 (M + H) + .

[Reference Example 117] (78 ft, 83118)-7-(2-hydroxyethyl)hexahydrooxazolo[3,4-&amp;]pyridin-3-one, (7SR,8aSR)-7-(2 -hydroxyethyl)hexahydroindolo[3,4-a]pyridin-3-one

(7SR,8aRS)-7-[2-(Tertiary butyldimethylstannoxy)ethyl]hexahydrocarbazolo[3,4-a obtained in Reference Example 1丨6 under a nitrogen atmosphere. A solution of pyridine-3-ketone (3.98 g, 13.3 mmol) in tetrahydrofuran (30 mL) was added EtOAc (4M, 17.3 mL, 17.3 mmol). Stir for 3 hours. After adding saturated ammonium chloride water-dissolved -334-200946528 solution (10 mL) and stirring for a minute, the reaction solution was poured into water. The organic layer was extracted with methylene chloride and washed with saturated brine (5OmL). The mixture was dried over anhydrous sodium sulfate, filtered and evaporated. The residue obtained was purified by hydrazine gel column chromatography (ethyl acetate:methanol = 100:0 - 95:5) to give 2.42 g (98%, 3:2 stereoisomer mixture) labeled compound. It is a colorless oil. Ο 1H-NMR (400MHz, CDC13) δ: 1.07 (0.6Η, dt, J = 12.6, 11.5Hz), 1.18 (0.6H, ddt, J=1.2, 5.1, 12.6Hz), 1. 5 3 -1.6 3 (2 H, m), 1.68-1.79 (2.8H, m), 1.90 (0.6H, m), 2.18 (0.4H, m), 2.87 (0.6H, dt, J = 3.4, 13.4Hz), 3.06 ( 0.4H, dt, J = 3.4, 13.4Hz), 3.66- 3.76(3H, m), 3.8 4-3.9 2 (2 H, m), 4.37- 4.43(1H, m).

[Reference Example 118] (7 811, 8 &amp; 118)-7-(2-iodoethyl)hexahydrooxazolo[3,4-pyridin-3-one, (7SR,8aSR)-7-(2 -iodoethyl)hexahydrooxazolo[3,4-a]pyridin-3-one

(7SR,8aRS)-7-(2-ethylidene)hexahydroindole[3,4-a]D than steep-3-ketone and (7SR,8aSR) obtained in Reference Example 117 under a nitrogen atmosphere a solution of 7-(2-ethyl)ethyl hexachloroindole[3,4-a]U in a mixture of steep-3-indole (2j2g, 13.1 mmol) in dichloromethane (30 mL) Triethylamine (2_70 mL, 19.6 mmol) and methanesulfonium chloride (1.11 mL, 14.4 mmol) were added in this order, and the mixture was stirred for 15 hours while warming to room temperature. The reaction solution was poured into saturated aqueous solution of -335-200946528 and sodium bicarbonate, and extracted with ethyl acetate (2 mL). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in acetone (4 mL). Sodium iodide (3.92 g, 26.1 mmol) was added and the mixture was heated to reflux for 15 hours. The reaction solution was poured into a 10% aqueous sodium thiosulfate solution 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, and the residue obtained was purified by gel column chromatography (ethyl acetate:hexane = 1:1 -&gt; 2:1) to give 3.31 g (86). %, a 3:2 mixture of stereoisomers) a labeled compound which is a pale yellow oil. 1H-NMR (400MHz, CDC13) δ: 1.06 (0.6Η, dt, J=12.4, 11.5Hz), 1.17 (0.6H, ddt, J=1.2, 5.1, 12.4Hz), 1. 5 6 - 1.6 3 ( 1 H , m), 1.66-1 .88 (3.6H, m), 1.9 6 - 2.0 8 (0.8 H, m), 2.15 (0.4H, m), 2.90 (0.6H, dt, J = 3.4, 13.4 Hz), 3.00 (0.4H, dt, J = 3.4, 13.4Hz), 3.20-3.24(2H, m), 3.6 8 - 3.9 5 (3 H , m), 4.38- 4.44(1 H, m). MS (ESI) m/z: 296 (M + H) + .

[Reference Example 119] (311)-7-[2-(9-Methoxy-2,3-dihydro-111-[1,4]indole[2,3-indole]quinoline-1- Ethyl]ethyl]hexahydrooxazolo[3,4-&amp;]pyridin-3-one

9-Methoxy-2,3-dihydro-lH-[l,4]Df 哄[2,3-c]quinoline (i"8g, 5-47mmol) obtained in Reference Example 10 under a nitrogen atmosphere. N,N-di-336-200946528 In a solution of methyl acetamide (27.0 mL), sodium hydride (oily, 55%, 477 mg, 10.9 mmol) was added at room temperature and stirred for 1 hour. The (7SR,8aRS)-7-(2-iodoethyl)hexahydrooxazolo[3,4-a]pyridin-3-one obtained with Reference Example 118 was added at 5 °C for 5 minutes and (7SR, 8aSR) a mixture of 7-(2-iodoethyl)hexahydrooxazolo[3,4-a]pyridin-3-one (2.42 g, 8.20 mmol) of N,N-dimethylacetamide (3.0) The solution was stirred at the same temperature for 3 hours, then warmed to room temperature and stirred for additional 50 hours. The reaction was stopped by adding a saturated aqueous solution of ammonium chloride under ice cooling, and the mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate, and then filtered, and evaporated. The residue obtained was purified by hydrazine gel column chromatography (dichloromethane:methanol = 19:1 - 9:1) to give 1.90 g (yield: 91%) of crude compound as a pale brown oil. Things. This compound was used in the next reaction without further purification. MS (ESI) m / z: 3 84 (M + H) + .

[Example 58] {(118)-1-(2-cyclohexylethyl)-4-[2-(9-methoxy-2,3-dihydrol-lH-[l,4] Df-trap And [2,3-c]quinolin-1-yl)ethyl]piperidin-2-yl}methanol

(SR)-7-[2-(9-Methoxy-2,3-dihydro-1H-[1,4]indole[2,3-(:]quinoline-) obtained in Reference Example 119 a solution of 1-yl)ethyl]hexahydrooxazolo[3,4-&amp;]pyridin-3-one (2.50 g, 6.52 mmol) in tetrahydrofuran (50.0 mL) Potassium butoxide (2.19 g, 19.6 mmol), while stirring slowly to room temperature for 24 hours, heated to 50 ° C, and stirred for another 24 hours - 337 - 200946528. Add 1 equivalent of hydrogen chloride / ethanol solution under ice cooling After (4 OmL), the reaction mixture was concentrated under reduced pressure to give 3.97 g of <RTIgt;((s) </RTI> <RTIgt; Indole [2,3-c]indol-1-yl)ethyl]piperidin-2-yl} Methanol crude, which is a pale yellow solid. 1.64 mmol) was suspended in dichloromethane (20.OmL)-methanol (2.0 mL), and triethylamine (0.597 mL), cyclohexylacetaldehyde (541 mg, 4.28 mmol), Sodium borohydride (1.36 g, 6.4 3 mmol) was stirred at the same temperature for 30 hours. The reaction solution was poured into 0.1N aqueous sodium hydroxide solution and extracted with dichloromethane. After drying over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure, and purified by gel column chromatography (dichloromethane: methanol = 49:1 - 19:1 - 9:1). The residue was purified by preparative thin layer chromatography (purified gel, chloroform:methanol: water = 7 : 3 : 1 solvent) to afford 270 mg (35%) of 1H-NMR (400MHz, CDC13) δ : Ο . 9 2 - Ο . 9 8 (2 Η , m), 1.12- 1.30 (4Η, m), 1.45 - 1 , 93 ( 1 4Η, m ) 2.5 8 ( Ο . 5 Η , dt, J = 2.7, 12.3 Hz), 2.73 (0.5 Η, m), 2.8 6 - 2.9 4 (2 Η, m), 3 . Ο 1 - 3 . 1 6 (3 Η, m) , 3.20-3.3 2(2.5Η, m), 3.30(0.5Η, m), 3.56(0.5Η, dd, J = 3.2, 12.7Hz), 3.60(0.5H, dd, J = 4.7, 11.7Hz), 3.83 (0.5H, dd, J = 7.8, 1 1.7 Hz) 3,92 (3H, s), 3 · 9 9 (0.5 H, dd, J = 2.9, 12.7 Hz), 4.17-4.22 (2H, m) , 7.06(1 H, d, J = 2.7Hz), 7. 16(0.5H, dd, J = 2.7, 9.0Hz), 7.17(0.5H, dd, J = 2.7, 9.0Hz), 7.88(0.5H , d, J = 9.0 Hz), 7.89 (0.5H, d, J = 9.0 Hz), 8.36 (1H, s) · -338- 200946528 MS (ESI) m/z: 468 (M + H) + .

[Reference Example 120] {l-[2-(l,4-dioxaspiro[4.5]indole-6-yl)ethyl]-4-[2-(9-methoxy-2,3-di) Hydrogen-lH-[l,4]Df哄[2,3-c]salolin-1-yl)ethyl]piperidin-2-yl}methanol

{{(RS)-4-[2-(9-Methoxy-2,3-dihydro-1H-indole,4]indolo[2,3-c]quinoline obtained in Example 58 A suspension of crude (l.OOg, 1.64 mmol) in dichloromethane (20.0 mL) eluted with EtOAc (EtOAc) , 4.07 mmol), 1,4-Dioxaspiro[4.5]indole-6-ylacetaldehyde (500 mg, 2.71 mmol) and sodium triethoxysulfonium hydride (8 62 mg, 4.0 7 mmol) at the same temperature Stir for 15 hours. The reaction solution was poured into 0.1N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate, and then filtered and evaporated. The residue obtained was purified by hydrazine gel column chromatography (dichloromethane:methanol = 9:1 - 6:1) to yield 400 mg (46%) of the title compound as pale yellow amorphous. MS (ESI) m / z: 5 26 (M + H) + .

[Example 59] 2-(2-{(foot 8)-2-hydroxymethyl-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4] 噚And [2,3-c]quinolin-1-yl)ethyl]piperidine-1-yl}ethyl)cyclohexanone-339- 200946528

{1-[2-(1,4-Dioxaspiro[4.5]癸-6-yl)ethyl]-4-[2·(9-methoxy- 2,3-) obtained in Reference Example 120 Dihydro-1H-[1,4]indolo[2,3-c]quinolin-1-yl)ethyl]piperidin-2-yl}methanol (10011^, 0.190111111〇1) in tetrahydrofuran (15 In a solution of .OmL), 1N hydrochloric acid (5.0 mL) was added at room temperature, and stirred at the same temperature for 6 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate, filtered, and evaporated. The obtained residue was purified by preparative thin layer chromatography (purine gel, chloroform:methanol:water = 7:3:1 under solvent) to give 9 1·6 mg (quant.) of the labeled compound. Yellow amorphous. MS (ESI) m / z: 482 (M + H) + .

[Reference Example 121] (2SR, 4SR)-4-[2-(t-butyldimethylsilyloxy)ethyl]-2-hydroxymethylpiperidine-1-carboxylic acid tert-butyl ester

(2RS, 4SR)-4-[2-(Tertiary butyldimethylsilyloxy)ethyl]piperidine-1,2-dicarboxylic acid 1-first obtained in Reference Example 115 under a nitrogen atmosphere Add a solution of sodium ethoxide (6.00 g, 14.4 mmol) in ethanol (150 mL), and add sodium sulphate/ethanol solution (1M, 3.61 mL, 3.61 mmol) at room temperature, and add to 40 °C. Stir for 3 hours. The reaction mixture was concentrated under reduced pressure and dichloromethane was evaporated. After extracting with ethyl acetate, the organic layer was combined, washed with brine and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give a white oil. The obtained colorless oil was dissolved in tetrahydrofuran (100 mL) under nitrogen atmosphere, and lithium boronhydride (448 mg, 20.6 mmol) was added at room temperature.

Heat to reflux for 22 hours. After the saturated ammonium chloride aqueous solution (i〇mL) was added under ice cooling to stop the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution. After extracting with ethyl acetate, the organic layer was combined, washed with brine and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated, and the residue obtained was purified by gel column chromatography (ethyl acetate:hexane = 1:19 - 1:4-&gt; 2:3) to give 4.23 g. (98%) labeled compound which is a colorless oil. 1H-NMR (400MHz, CDC13) δ: 0.05 (6H, s), 1.02 (9H, s), i-lOCIH, dt, J = 4.3, 13.2Hz), 1.27(1H, dt, J = 5.8, 13.2Hz ), 1 · 39-1.46(2H, m), 1.47(9H, s), 1.6 2 -1.7 4 (3 H, m), 2.19(1H, br), 2.80(1H, dt, J = 2.1, 13.4 Hz), 3.54(1H, dd, J = 5.6, 1 1 0Hz), 3.60(2H, t, J = 6.4Hz), 3.77(1H, dd, J = 9.7, ^•OHz), 3.99(1H, brd , J=11.4Hz), 4.36(1H, m).

[Reference Example 122] (2 SR, 4SR)-4-(2-hydroxyethyl)-2-hydroxymethylpiperidine-1-carboxylic acid tert-butyl ester

-341-200946528 (2SR,4SR)-4-[2-(Tertiary dimethyldimethyl-decyloxy)ethyl]-2-hydroxymethylpiperidine obtained in Reference Example 121 under a nitrogen atmosphere. A solution of 1-carboxylic acid tert-butyl ester (4.22 g, 11.3 mmol) in tetrahydrofuran (30 mL) was added with a solution of tetrabutylammonium fluoride/tetrahydrofuran (1 M, 18.3 mL, 18.3 mmol) at 0 ° C. Stir for 3 hours at room temperature. The reaction solution was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was combined, washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the residue obtained was purified by gel column chromatography (ethyl acetate: methanol = 100: 〇 - 95: 5) to give 2.60 g (quant.). A compound which is a colorless oil. 1H-NMR (400MHz, CDC13) δ: 1.09 (1H, ddt, J = 4.4, 12.9, 1 3.0Hz), 1.28(1H, m), 1.46(9H, s), 1.6 8 - 1.7 8 (5 H, m), 2.84 (1H, brt, J = 13.4 Hz), 3.61 (1H, dd, J = 6.1, 10.9 Hz), 3.70 (2H, t, J = 6.5 Hz), 3.79 (1H, 9.3, 10.9 Hz) , 4.04 (1H, brd, J = 12.0 Hz), 4.39 (1H, br). MS (ESI) m/z: 260 (M + H) + .

[Reference Example 123] (7SR, 8aSR)-7-(2-hydroxyethyl)hexahydrooxazolo[3,4-a]pyridin-3-one

(2SR,4SR)-4-(2-hydroxyethyl)-2-hydroxymethylpiperidine-1-carboxylic acid tert-butyl ester (2.50 g, 9.64 mmol) obtained in Reference Example 122 under nitrogen atmosphere. Sodium hydride (oily, containing 200946528 55%, 92 5 mg, 21.2 mmol) was added to a solution of tetrahydrofuran (50 mL), and stirred for 18 hours while warming to room temperature. The reaction was stopped by adding a saturated aqueous ammonium chloride solution (10 mL) under ice cooling. The reaction solution was poured into water and extracted with a mixed solvent of dichloromethane:methanol = 10:1. The organic layer was combined, dried over anhydrous sodium sulfate, filtered, dried, filtered, evaporated, evaporated, evaporated, evaporated. The residue gave 1.34 g (75%) ofyy. ❹ 1H-NMR (400MHz, CDC13) δ: 1.5 5 - 1.63(2Η, m), 1.68-1.81(4H, m), 2.18(1H, m), 3.05(1H, dt, J = 3.4, 13.4Hz) , 3.70-3.77(3H, m), 3.83(2H, m), 4.39(1H, m). [Reference 124] (78 ft, 8 &amp; 811)-7-(2-iodoethyl)hexahydro Oxazo[3,4-3]pyridin-3-one

I

(7SR,8aSR)-7-(2-hydroxyethyl)hexahydrooxazolo[3,4-a]pyridin-3-one (1.34 g, 7.23 mmol) obtained in Reference Example 123 under a nitrogen atmosphere. Triethylamine (1.50 mL, l〇.9 mmol) and methanesulfonium chloride (0.616 mL, 7.96 mmol) were added to a solution of dichloromethane (20 mL) at 0 ° C, and then warmed to room temperature. Stir for 18 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 saturated brine and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in acetone (4O mL). Sodium iodide (2.17 g, 14.5 mmol) was added and heated to reflux for 2.5 hours. The reaction solution was poured into an aqueous solution of -343-200946528 1 〇% sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. In addition to the desiccant, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by hydrazine gel column chromatography (ethyl acetate: hexane = 1: 4 - 1:2 - 1:1) to give 1.85 g. (87%) labeled compound as a pale yellow oil. 1H-NMR (400MHz, CDC13) δ: 1. 5 6 - 1.6 3 (2 H, m), 1.68- 1.77 (2H, m), 1.96-2.08 (2H, m), 2.15 (1H, m), 3.00 (1H, dt, J = 3.4, 13.4Hz), 3 . 1 7-3.26(2H, m), 3.7 3 - 3.8 7 (3 H, m), 4.40(1H, t, J = 7.8Hz). MS (ESI) m/z: 296 (M + H) + .

[Reference Example 125] (7SR, 8aSR)-7-[2-(9-methoxy-2,3-dihydro-1H-[1,4]噚[[,][2]3-(:]quinoline -1-yl)ethyl]hexahydrooxazolo[3,4-cis-pyridin-3-one

9-methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinoline (904 mg, 4.18 mmol) obtained in Reference Example 10 under a nitrogen atmosphere. To a solution of N,N-dimethylacetamide (15.OmL), sodium hydride (oily, 55%, 3, 5 5 mg, 8. 6 mmol) was added at room temperature and stirred for 1 hour. The (7SR, 8aSR)-7-(2-iodoethyl)hexahydrooxazolo[3,4-a]pyridin-3-one (l_85g, 6.27 mmol) obtained in Reference Example 124 was added dropwise at 0 °C for 5 minutes. The solution of N,N-dimethylacetamide (5.0 mL) was stirred at the same temperature for 3 hours, then warmed to room temperature and stirred for 17 hours. The reaction was stopped by adding a saturated aqueous solution of ammonium chloride (5.0 mL) -344 - 200946528, and the mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate, and then filtered, and evaporated. The residue thus obtained was purified by EtOAc EtOAc (EtOAc:MeOHMeOHMeOHMeOH This compound was used in the next reaction without performing purification other than this. 1H-NMR (400MHz, CDC13) δ : 1 · 6 0 -1 · 6 9 ( 2 Η, m), 1.74-

1.83(2H, m), 2.06-2.1 2 (3 H, m), 3.1 1 - 3.2 1 ( 3 H, m), 3.28 (2H, t, J = 4.4Hz), 3.77(1H, dd, J= 1.7, 5.4Hz), 3.87(1H, m), 3.91(3H, s), 3.97(1H, m), 4.24(2H, m), 4.43(1H, t, 8.0Hz), 7. 14(1 H , d, J = 2.7 Hz), 7.21 (1H, dd, J = 2.7, 9.3 Hz), 7.96 (1H, d, J = 9.3 Hz), 8.37 (1H, s). MS (ESI) m/z: 3 84 (M + H) + .

[Example 60] {(2 811,4113)-1-(2-cyclohexylethyl)-4-[2-(9-methoxy-2,3-dihydro-111-[1,4]噚耕和[2,3-&lt;:] porphyrin-1-yl)ethyl]piperidin-2-yl} methanol

(7SR,8aSR)-7-[2(9-methoxy·2,3·dihydro-111-[1,4]噚[2,3-(^]quinoline) obtained in Reference Example 125 a solution of -1-yl)ethyl]hexahydroindolo[3,4-pyridin-3-one as a crude product (1.56 g, 3.81 mmol) in ethanol (50.0 mL) An aqueous solution of lithium chloride (10.2 mL, 40.8 mmol) was heated under reflux for 27 hours. The reaction solution was poured into water and extracted with methylene chloride -345-200946528. The organic layer was combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give K52 g ((2SR, 4RS)-4-[2-(9-methoxy-2,3-dihydro-11^[1,4]) till [2,3 -£:]Quinolin-1-yl)ethyl]piperidin-2-yl} Methanol of crude 'which is pale yellow amorphous. The resulting {(2SR, 4RS)-4-[2-( 9-Methoxy-2,3-dihydro-1H-[1,4]indolo[2,3-£:]salolin-1-yl)ethyl]piperidin-2-yl}methanol 1.02 g (2.56 mmol) in the crude was dissolved in dichloromethane (30.0 mL), and cyclohexylacetaldehyde (5 5 6 mg, 4.4 1 mmol) and sodium triethoxysulfonate hydrogenate were added sequentially at room temperature. (1.25 g, 5.88 mmol), stirred at the same temperature for 20 hours. The organic layer was dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure. Methane:methanol = 19:1 - 9 : 1) The obtained residue was purified by preparative thin layer chromatography (矽 gel, chloroform:methanol:water = 7:3:1 lower solvent). 1.01 g (8 5%) of a labeled compound which is pale yellow amorphous. 1H-NMR (400 MHz, CDC13) δ: 0.8 7-0.96 (2 Η , m), 1.12- 1.29 (4H, m), 1.4 3 -1 . 7 0 ( 1 2 H, m), 1. 8 0 - 1 . 8 5 ( 2 H , m), 2.74-2.93 (4H, m), 3·02-3·10 (3Η, m), 3.20 (2H, dd, J = 4.2, 4.4 Hz), 3.51 (1H, dd, J = 5.4, 11.0 Hz), 3.75 (1H, dd, J = 8.4, 11.0 Hz), 3.91 (3H, s), 4.17 ( 2H, dd, J = 4.2, 4.4Hz), 7.05(1H, d, J = 2.7Hz), 7.1 5(1 H, dd, J = 2.7, 9.0Hz), 7.87(1H, d, J = 9.0Hz ), 8.34 (1H, s). MS (ESI) m/z: 468 (M + H) + .

[Example 61] (2 511, 4 Han 8)-1-(2-cyclohexylethyl)-4-[2-(9-methoxy--346- 200946528 2,3-dihydro-1H- [1,4]indolo[2,3-c]quinolin-1-yl)ethyl]piperidine-2-decanoic acid

〇 醯 醯 醯 醯 醯 〇 〇 (〇 〇 mL mL mL mL 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 ( ( ( ( ( ( 2 2 2 2 2 2 OmL) solution. After stirring at the same temperature for 5 minutes, the {(2SR,4RS)-l-(2-cyclohexylethyl)-4-[2-(9-methoxy-2) obtained in Example 60 was added dropwise for 1 minute. 3-Dihydro-1H-[1,4]indole-[2,3-c]quinolin-1-yl)ethyl]piperidine-2-yl}methanol (180 mg, 0.385 mmol) in dichloromethane (3.0 mL) solution. After stirring at the same temperature for 1 hour, a solution of triethylamine (0.322 mL, 2.31 mmol) in dichloromethane (2 mL) was added, and the mixture was stirred for 45 minutes while warming to room temperature. The reaction solution was poured into a 0.1 N aqueous solution of sodium hydroxide and extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate, filtered, and evaporated. The obtained residue was dissolved in a mixture of tetrahydrofuran (5.0 mL)-t-butanol (5.0 mL)-2-methyl-2-butene (〇-54 mL), and sodium chlorite was added under ice cooling. A solution of (87 mg, 0.770 mmol) and sodium dihydrogen phosphate 2 hydrate (3 60 mg, 2 - 31 mm) in water (2.0 mL). After stirring for 2 hours while gradually heating to room temperature, the reaction solution was poured into a water solution of sodium thiosulfate. After extracting with dichloromethane, the organic layer was combined and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by gel column chromatography (chloroform:methanol:water=7:3:1 under solvent), followed by -347-200946528 Thin layer chromatography (矽 gel, chloroform:methanol:water = 7:3:1 lower solvent) was purified to give 32.6 mg (18%) of the title compound as pale yellow amorphous. 1H-NMR (400MHz, CDC13) δ : 0.8 9 · 0.9 7 (2 Η, m), 1.08- 1.22(5H, m), 1.6 3 - 1. 8 9 (1 2H, m), 2.40 (1H, brd , J = 8.8Hz), 2.61(1H, brm), 2.91(1H, brm), 3.09(2H, t, J = 4.1Hz), 3.15-3.22(2H, m), 3.3 8 - 3.4 4 (2 H , m), 3.68 (1H, brd, J = 12.2 Hz), 3.91 (3H, s), 4.14-4.21 (2H, m), 7.02 (1H, d, J = 2.7 Hz), 7.16 (1H, dd, J = 2.7, 9.3 Hz), 7.89 (1H, d, J = 9.3 Hz), 8.36 (1H, MS (ESI) m/z: 482 (M + H) + .

[Reference Example 126] {(2811,41^)-1-[2-(1,4-Dioxaspiro[4.5]癸-6-yl)ethyl]-4-[2-(9-methoxy -2,3-dihydro-1H-[1,4]indolo[2,3-c]quinolin-1-yl)ethyl]piperidin-2-yl}methanol

The {(2SR,4RS)-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quina obtained in Example 60 was obtained. 500 mg (i.25 mmol) in the crude form of phenyl-1-yl)ethyl]piperidin-2-yl}methanol was dissolved in dichloromethane (15.0 mL). Dioxaspiro[4.5]non-6-ylacetaldehyde (51511^ 2.79 mmol) and hydrogenated sodium triethoxyborohydride (889 mg, 4.20 mmol) were stirred at the same temperature for 18 hours. The reaction solution was poured into 当量·1 NaOH aqueous solution -348-200946528, and extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate, and then filtered and evaporated. The obtained residue was purified by gel column chromatography (dichloromethane:methanol = 19:1 - 9:1), followed by preparative thin layer chromatography (矽 gel, chloroform:methanol:water) =7:3:1 lower solvent) Purified to give 627 mg (95%) of the title compound as pale yellow amorphous. 1H-NMR (400MHz, CDC13) δ: 1.27-1.86 (18Η, m), 2.20-

3.12(4H, br), 3.0 3 - 3 .1 4 (2 H, m), 3.23(2H, dd, J = 4.2.4.4Hz), 3.45(1H, br), 3.75(1H, br), 3.9 1 - 3.9 9 (9 H, m), 4.21 (2H, dd, J = 4.2, 4.4 Hz), 7.08 (1H, d, J = 2.7), 7.18 (1H, dd, J = 2.7, 9.3 Hz), 7.90 (1H, d, J = 9.3 Hz), 8.38 (1H, s). MS (ESI) m/z: 526 (M + H) + .

[Reference Example 127] (2811, 4118)-1-[2-(1,4-Dioxaspiro[4.5]fluoren-6-yl)ethyl]-4-[2-(9-methoxy- 2,3-dihydro-lH-[l,4]Df-and-[2,3-c]quinolin-1-yl)ethyl]piperidine-2-carboxylic acid hydrazine

A solution of dimethyl sulfoxide (0.418 mL, 5.90 mmol) in dichloromethane (1. 5 mL) was then evaporated. After stirring at the same temperature for 10 minutes, the {(2SR, 4RS)-l-[2-(l,4-dioxaspiro[4.5]癸-6-yl)ethyl] obtained in Reference Example 126 was added dropwise over 5 minutes. -4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinolin-1-yl)ethyl]piperidine- A solution of 2-methyl}methanol (620 mg, 1.18 mmol) in dichloromethyl-349-200946528 (3.0 mL). After stirring at the same temperature for 1 hour, a solution of triethylamine (0.822 mL, 5.90 mmol) in dichloromethane (1.5 mL) was added, and the mixture was stirred for 30 minutes while warming to room temperature. The reaction solution was poured into an aqueous solution of sodium hydroxide in an equivalent amount, and extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate, filtered, and evaporated. The obtained residue was dissolved in a mixture of tetrahydrofuran (1 OmL)-t-butanol (10 mL)-2-methyl-2-butene (2.0 mL), and sodium chlorite (267 mg) was added under ice cooling. , 2.36 mmol) and a solution of dihydro sodium dihydrogen dihydrate (1.10 g, 7.07 mmol) in water (2.0 mL). The mixture was stirred for 1 hour while gradually warming to room temperature, and then the reaction solution was poured into a 10% aqueous sodium thiosulfate solution. After extracting with dichloromethane, 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 was purified by gel column chromatography (dichloromethane: methanol = 19:1 - 9:1 - 6:1) to yield 210 mg ( 3 3%) labeled compound, which is light yellow amorphous. MS (ESI) m/z: 540 (M + H) + .

[Example 62] (2SR, 4RS)-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-&lt;:] quin Polin-1-yl)ethyl]-1-[2-(2-oxocyclohexyl)ethyl]piperidine-2-carboxylic acid

(2SR, 4RS)-l-[2-(l,4-Dioxaspiro[4.5]癸-6-yl)ethyl]-4-[2-(9-methoxy) obtained in Reference Example 127 -2,3-dihydro-1H-[1,4]indolo[2,3-c]quinolin-1-yl)ethyl]piperidine-2-carboxylic acid (10 mg, 0.195 mmol) To a solution of -350-200946528 in tetrahydrofuran (15.0 mL), 1N hydrochloric acid (5 mL) was added at room temperature. After stirring at the same temperature for 12 hours, the reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate, and then filtered and evaporated. Purified by reverse phase high-speed liquid chromatography (〇6乂61〇8丨1,2&lt;;111&lt;|&gt;&gt;10 (;111, acetonitrile-water mixed solvent containing 0.1% formic acid) The residue gave 5 8.8 mg (6 1 %) of the title compound as white solid.

1 H_NMR (400MHz, CD3OD) δ : 1.4 4 - 2 · 6 5 (2 1 Η, m), 3.22- 3.31(5H, m), 3.85(1H, br), 3.95(3H, s), 4.24(2H , dd, J-4.0, 4.2Hz), 7.16(1H, d, J = 2.7Hz), 7.20(1H, dd, J = 2.7, 9.0Hz), 7.78(1H, d, J = 9.0Hz), 8.23 (1H, s). MS (ESI) m/z: 496 (M + H)+.

[Reference Example 128] 4-(2-hydroxyethylidene)piperidine-l-carboxylic acid tert-butyl ester 7.2 0m mol) in toluene (30 mL) was added, and the hydrogenated isobutyl aluminum was added at -70 t for 10 minutes. /toluene solution (0.99 M, 15.3 mL, 15.1 mmol) was stirred at the same temperature for 3 hours. After carefully dropping a saturated aqueous ammonium chloride solution (5 niL) at the same temperature, the mixture was stirred for 15 hours while gradually warming to room temperature. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was combined and washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure -351-200946528, and the obtained residue was purified by gel column chromatography (hexane: ethyl acetate = 2:1 - 1:1 - 1:2). I.54 g (94%) of the title compound was obtained as a colorless oil. 1H-NMR (400MHz, CDC13) δ: 1.47 (9Η, s), 2.18 (2H dd J = 5.4, 5.9 Hz), 2.26 (2H, dd, J = 5.6, 5. 9Ηζ), 3·39-3· 44(4η m), 4.17(2H, d, J = 7.1Hz), 5.48(1H, t, J = 7.1Hz).

[Reference Example 129] 4-(2-bromoethylidene)piperidine-1-carboxylic acid terpene vinegar

4-(2-hydroxyethylidene)piperidine-1-carboxylic acid tert-butyl ester (1.53 g, 6.73 mmol) obtained in Reference Example 128 and triphenylphosphine (1.94 g, 7.40 mmol) In a solution of methylene chloride (l〇_〇mL), in 〇. (: A solution of carbon tetrabromide (2.46 g, 7.40 mmol) in dichloromethane (5. 〇mL) was added, and the mixture was stirred for 2 hours while gradually warming to room temperature. The concentrated reaction liquid was reduced under reduced pressure to give a sand. The residue obtained was purified by gel column chromatography (dichloromethane-hexane: ethyl acetate = 5:1 - 4:1) to give 356 mg (19%) of 1H-NMR (400MHz, CDCI3) δ: 1,47(9H, s), 2.20(2H, t, J = 5.6Hz), 2.29(2H, t, J = 5.6Hz), 3.43(2H , dd, J = 5.6, 5.8 Hz), 3.44 (2H, dd, J = 5.6, 5.8 Hz), 4.00 (2H, d, J = 8.5 Hz), 5.61 (1H, t &gt; J = 8.5 Hz).

[Reference Example 130] 4-[2-(9-Methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl)-ethylidene Tert-butyl piperidine-1-carboxylic acid tert-butyl ester-352- 200946528

9-Methoxy-2,3-dihydro-1 Η-[ 1,4 ] 曙明:[2,3 - c ]quinoline (3 5 4 mg) obtained in Reference Example 8 under a nitrogen atmosphere A solution of 1 _ 6 4 mm ο 1) in N,N-dimethylacetamide (6.0 mL) was added sodium hydride (oily, 55%, 178 mg, 4.09 mmol) at room temperature and stirred for 1 hour. N,N-dimethyl B, 4-(2-bromoethylidene)piperidine-1-carboxylic acid tert-butyl ester (3 65 mg, 1.26 mmol) obtained in Reference Example 129 was added dropwise over 5 min. A solution of guanamine (1.0 mL) was stirred at the same temperature for 20 hours. The reaction was stopped by adding a saturated aqueous ammonium chloride solution (5.0 mL) under ice-cooling, and the mixture was poured into a 0.1% aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate. The residue obtained was purified by hydrazine gel column chromatography (dichloromethane:methanol = 49:1 - 19:1 - 9:1) to give 595 mg (8 6%) of Oily. 1H-NMR (400MHz, CDC13) δ : 1.4 7 ( 9 Η, s), 2.2 2 (2 Η, brs), 2.28 (2H, brs), 3.19 (2H, brdd, J = 3.6, 4.4 Hz), 3.39 (2H, br), 3.47(2H, brdd, J=5.1, 5.8Hz), 3.74(2H, d, J = 6.3Hz), 3.90(3H, s), 4.18(2H, brdd, J = 3.6, 4.6 Hz), 5.65(1H, t, J = 6.3Hz), 7.13-7.1 6(2H, m), 7.87(1H, d, J=10.OHz), 8.37(1 H, s). MS(ESI) m/z: 426 (M + H) + .

[Example 63] 1-{2-[1-(2-Cyclohexylethyl)piperidinyl-4-yl]ethyl}-9-methoxy-2,3-dihydro-1H-[1 , 4] 噚耕和[2,3-c]quinoline-353- 200946528

4-[2-(9-Methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl) y. Ethyl] piperidine-carboxylic acid tert-butyl ester (5 95 mg, 1.40 mmol) in dichloromethane (1 mL) was added 4 eq. hydrogen chloride / dioxane solution (5 〇 niL) at room temperature. Stir for 20 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained solid was suspended in diethyl ether (10 mL) and then filtered to afford 9 methoxy-1 - [2-(piperidin-4-yl)ethyl ]-2,3-Dihydro-111-[1,4]噚 and [2,3-(:]quinoline crude (58911^), which is a pale yellow solid. Oxy-1-[2-(ipiperidin-4-yl)ethyl]-2,3-dihydro-1H-[1,4]D§哄[2,3-c]porphyrin (589mg Suspended in dichloromethane (10 mL), and added triethylamine (〇.563 mL, 4.04 mm 〇1) and cyclohexylacetaldehyde (340 mg, 2.69 mmol) and hydrogenated triethoxycarbonyl at room temperature. Sodium borohydride (570 mg, 2.69 mmol) was stirred at the same temperature for 6 hours. The reaction solution was poured into 0.1 N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered to remove desiccant. The filtrate was concentrated under reduced pressure, and the residue obtained was purified by EtOAc EtOAc (MeOH:MeOH: EtOAc: EtOAc: Compound, which is pale yellow amorphous. 1H-NMR (400 MHz, DMSO-d6) δ: Ο . 9 1 - Ο . 9 5 ( 2 Η, brm) , 1.16-1.30(5Η, m), 1.60- 1.72(8Η, br), 2.6 8 - 2.8 6 (4 Η, m), 3.07(2Η, br), 3.02-3.22(4Η, br) , 3.91(3Η, s), 4.2 3 - 4.4 2 (4 Η, br), -354- 200946528 5.79(1H, br), 7.30(1H, brs), 7.53(1H, brd, J = 9.3Hz), 8.02 (1H, d, J = 9.3 Hz), 8 · 5 8 ( 1 H, br s). MS (ESI) m/z: 43 6 (M + H) + .

[Example 64] l-(2·cyclohexylethyl)-4-[l-hydroxy-2-(9-methoxy-2,3-dihydro-1H-[1,4]噚 till [[ 2,3-c]quinolin-1-yl)ethyl]piperidin-4-ol

1-{2-[1-(2-Cyclohexylethyl)piperidin-4-yl]ethyl}-9-methoxy-2,3-dihydro-1H- obtained in Example 63. [1,4] N-methylmorpholine was added to a solution of [2,3-c]quinoline (66.0 mg, 0.152 mmol) in acetone (2.0 mL)-water (1.0 mL) at room temperature -N-Oxide (35.0 mg, 0.303 mmol) and tetraoxide (ca · 1 mg) were stirred at the same temperature for 16 hours. After adding 10% aqueous sodium thiosulfate solution (5 mL), the mixture was stirred for 1 hour, and then poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate (MgSO4), filtered and evaporated. The residue obtained was purified by hydrazine gel column chromatography (dichloroform: methanol = 19:1 9 : 1 6 : 1) to give 48.5 mg (68%) of Crystal form. 1H-NMR (400MHz, CDC13) 6 : 0.8 6 - 0.9 4 ( 2 H, m), 1·〇8_ 1.25(5H, m), 1. 3 8 - 1.4 3 ( 2 Η, m), 1.54 (1Η , brd, J=12.9Hz), 1.62- 1.69(5Η, m), 1.83 - 1.85(2Η,m),2.3 0-2.43 (4Η,m), 2.46(1Η, br), 2.79(2Η, brdd, J=12.2, 17.3Hz), 2.88(1H, d, J=13.6Hz), 3.15-3.25(2H, m), 3.63(1H, dd, J=ll.〇, 13.2Hz) -355- 200946528 3.80( 1H, d, J = 9.0Hz), 3.88(3H, s), 4.06(1H, dd, J = 8.6, 9.0Hz), 4.28(1H, d, J=1 1.0Hz), 4.39(1H, br) , 7.12 (1H, dd, J = 2.7, 9.0 Hz), 7.61 (1H, d, J = 2.7 Hz), 7.88 (1H, d, J = 9.0 Hz), 8.35 (1H, s). MS (ESI) m/z: 470 (M + H)+.

[Reference Example 13 1] [1-(2-Cyclohexylethyl)-2-oxopiperidin-4-yl]acetic acid ethyl ester

Ethyl (2-oxopiperidin-4-yl)acetate in a nitrogen atmosphere (Pharmaceutical Journal, 1959, 79, 71 1-716, 500 mg, 2.70 mmol) and (2) -Bromoethyl)cyclohexane (0.761 mL, 4.86 mmol) in tetrahydrofuran (10.0 mL)-N-N-dimethylformamide (2.0 mL). %, 141 mg, 3.24 mmol), stirred for 20 hours. After a saturated aqueous ammonium chloride solution (5.0 m L) was added thereto under ice cooling to terminate the reaction, the reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate to ethyl acetate. The organic layer was combined, washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc: . 1H-NMR (400MHz, CDC13) δ : 0 · 8 8 - 0.9 7 (2 Η, m), 1.12- 1.26(4H, m), 1.27(3H, t, J = 7.1Hz), 1 · 3 8 - 1.4 6 (2 H,m), 1.52(1H,m),1.62- 1.76(5H,m), 1.97(1H,brd,J=13.4Hz), -356- 200946528 2.06(1H, dd, J=10.0 , 16.8Hz), 2.2 6 - 2.3 3 (3 H , m), 2.56 (lH, ddd, J = 2.2, 2.6, 16.8Hz), 3.24-3.39(4H, m), 4.14(2H, q, J = 7.1Hz).

[Reference Example 132] 1-(2-Cyclohexylethyl)-4-(2-hydroxyethyl)piperidin-2-one

Π_(2_Cyclohexylethyl)-2-oxooxypiperidine. 4-yl]acetate (522 mg, 1.77 mmol) in tetrahydrofuran (15.0 mL) obtained in EtOAc m. Lithium borohydride (77 mg, 3.53 mm 〇l) was added to the solution at room temperature and stirred for 18 hours. After adding 1 equivalent of hydrochloric acid (5. 〇mL) under ice cooling and stopping the reaction, the reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by hydrazine gel column chromatography (dichloromethane:methanol = 49:1 &gt; 19:1 - 9:1) to give 355 mg (7 9%) of the title compound. It is a colorless oil. H-NMR (400MHz, CDC13) δ: 0.8 8-0.97(2Η, m), 1.12- 1'26(4H&gt; m), 1.36-1.74(1 OH, m), 1 · 9 2 - 2.0 6 (3 H, m), 2.53 (1H, m), 3, 24-3.30 (2H, m), 3.36 (2H, t, J = 8_0Hz), 3.7l (2H, m).

[Reference Example 133] 1-(2-Cyclohexylethyl)-4-(2-iodoethyl)piperidin-2-one

1-(2-Cyclohexylethyl-357-200946528)-4-(2-hydroxyethyl)piperidin-2-one (352 mg, 1.39 mmol) obtained in Reference Example 132 under a nitrogen atmosphere and triethyl A solution of the amine (0.387 mL, 2.78 mmol) in dichloromethane (10 mL) was stirred at room temperature. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then filtered and evaporated. The obtained residue was dissolved in acetone (30.OmL), sodium iodide (416 mg, 2.78 mmol) was added at room temperature, and the mixture was refluxed for 6 hours. It was purified by hydrazine gel column chromatography (hexane: ethyl acetate = 1:1 - 1:2 - 1:9) to give 450 mg (yield: 9%) of the title compound as a colorless oil. !Η-ΝΜΚ(400ΜΗζ, CDC13) δ : Ο . 8 8 - Ο . 9 6 (2 Η , m), 1.12- 1.26(4Η, m), 1 .3 6 - 1 . 5 2 ( 3 Η, m ), 1 . 5 9 - 2 . Ο Ο ( 1 Ο Η, m), 2.51 (1Η, m), 3 .1 7-3.23(2Η, m), 3.2 4 - 3.3 1 ( 2 Η, m), 3.32-3.40 (2Η, m).

[Example 65] 1-(2-cyclohexylethyl)-4-[2-(9-methoxy-2,3-dihydro-111-[1,4]indole[2,3- c]quinolin-1-yl)ethyl]piperidin-2-one

9-methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinoline (204 mg, 0.942 mmol) obtained in Reference Example 8 under a nitrogen atmosphere. In a solution of N,N-dimethylacetamide (3.0 mL), sodium hydride (oily, 55%, 74 mg, 1.70 mmol) was added at room temperature and stirred for 2 hours. 1-(2-Cyclohexylethyl)-4-(2-iodoethyl)piperidine--358-200946528 2-one (445 mg, 1.23 mmol) obtained in Reference Example 133 was added dropwise at 0 °C for 30 min. A solution of hydrazine, hydrazine-dimethylacetamide (5.0 mL) was stirred for 15 hours while gradually warming to room temperature. The reaction was stopped by adding a saturated aqueous solution of ammonium chloride (5.0 mL), and the mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue obtained was purified by hydrazine gel column chromatography (dichloromethane:methanol = 1:1 · 1 -&gt; 9 : 1 ) to afford 275 mg (65%) of Shape. Ο ❹ 1H-NMR (400MHz, CDC13) δ : 0.8 8 - 0 · 9 7 (2 Η, m), 1.12- 1.27(4H, m), 1. 3 6 - 1.4 4 (2 H, m), 1 5 1 -1 . 7 4 (6 H , m), 1.84- 1.97 (4H, m), 2.09 (1H, dd, J = 10.3, 17.3 Hz), 2.55 (1H, ddd, J = 2.0, 4.9, 17.3Hz), 3.07-3.1 6(2H, m), 3.2 3 (2 H, dd, J = 4.2, 4.4Hz), 3.28(2H, dd, J = 3.6, 8.1Hz), 3.36(2H, t, J = 8.1 Hz), 3.92 (3H, s), 4.20 (2H, dd, J = 3.9, 4.2 Hz), 7.07 (1H, d, J = 2.8 Hz), 7.1 7 ( 1 H, dd, J = 2.8 , 9.3 Hz), 7.90 ( 1 H, d, J = 9.3 Hz), 8.37 (1 H, s). MS (ESI) m/z: 452 (M + H) + .

[Example 66] 2-cyclohexyl-l-{4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]噚 and [2,3-(〇 Polin-1-yl)ethyl]piperidin-1-yl}ethanone

/〇/0 9-methoxy-bromo-piperidin-4-ylethyl)-2,3-dihydro-1H-[1,4] hydrazine obtained in Reference Example 10 under a nitrogen atmosphere And [2,3-C]quinoline (67 7 mg -359- '200946528 0.2 07 mmol) and cyclohexylacetic acid (32.3 mg, 0.227 mmol) in dichloromethane (5.0 mL) (7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea gun hexafluoroborate (86.5 mg, 0.227 mmol) was stirred at the same temperature for 20 hours. Inject the reaction solution into saturated sodium bicarbonate solution

In the solution, extract with dichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate. The obtained residue was purified by hydrazine gel column chromatography (dichloromethane: methanol = 4 9:1 - 19:1 - 9:1) to give 54.1 mg (58%) of Light yellow amorphous. 1H-NMR (400MHz, CDC13) δ : 0.9 2 - 1.0 1 (2 H , m), 1.12- 1.32 (5H, m), 1. 54- 1.89 ( 1 1 H, m), 2.20 (2H, d, J = 6.9 Hz), 2.51 (1H, dt, J = 2.2, 12.9 Hz), 2.98 (1H, brt, J = 12.0 Hz), 3.11 (2H, m), 3.22 (2H, dd, J = 4.2 , 4.4Hz), 3.89(1H, brd, J=13.4Hz), 3.9 1 (3H, s), 4.19(2H, dd, J = 4.2, 4.4Hz), 4.65(1 H, brd, 1 3,4Hz ), 7.07 (1 H, d, J = 2.7 Hz), 7.17 (1H, dd, J = 2.7, 9.0 Hz), 7.90 (1H, d, J = 9.0 Hz), 8.37 (1 H, s). MS (ESI) m/z: 452 (M + H) + .

[Example 67] (Ugly)-3-(2,5-difluorophenyl)-1-{4-[2-(9-methoxy-2,3-dihydro-1H-[1,4 [2,3-c]quinolin-1-yl)ethyl]piperidine- l-yl}acetone

Under the nitrogen atmosphere, 9-methoxy-1·(2-piperidin-4-ylethyl)-2,3-dihydro-1Η-[1,4] obtained from Reference Example 10 was cultivated and [2] , 3-c] quinoline (78.5 mg, 0.240 mm 〇l) and (E)-3-(2,5-difluorophenyl)acrylic acid (48.6 mg, -360-200946528 0.264 mmol) of dichloromethane (5.0 mL) solution, adding 0-(7-azabenzotriazol-1-yl)-indole, hydrazine, hydrazine, Ν'-tetramethylurea gun hexafluoroantimonate (100 mg) at room temperature , 0.2 64 mmol), stirred at the same temperature for 20 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 obtained was purified by hydrazine gel column chromatography (dichloromethane:methanol = EtOAc: EtOAc: EtOAc: EtOAc: Amorphous.

1H-NMR (400MHz, CDC13) δ: 1.30 (2H, ddt, J = 3.9, 12.2, 12.4 Hz), 1.64 (1H, m), 1. 8 2 - 1.92 (4H, m), 2.66 (1H, br ), 3.08-3.1 5(3H, m), 3.23(2H, dd, J = 4.1, 4.4Hz), 3.92(3H, s), 4.09(1H, brd, J=11.7Hz), 4.21(2H, dd , J = 4.1, 4.4 Hz), 4.73 (1H, brd, J = J = 11.7 Hz), 6.9 6-7.0 6 (3 H, m), 7.08 (1 H, d, J = 2.7 Hz), 7.17 ( 1H, dd, J = 2.7, 9.0 Hz), 7.19 (1H, m), 7.64 (1H, d, J = 14.6 Hz), 7.91 (1H, d, J = 9.0 Hz), 8.37 (1H, s). MS (ESI) m / z: 494 (M + H) +.

[Reference Example 134] 4-[1-(Bromomethyl)vinyl]piperidine-1-carboxylic acid tert-butyl ester

T-butyl 4-[1-(hydroxymethyl)vinyl]piperidine-1-carboxylate under nitrogen atmosphere (Heterocycles, 1994, Vol. 38, No. 8, pp. 1889-1896, 1.44g 5,97. The methyl chloride (5.0 mL) solution was stirred for 15 hours while gradually warming to room temperature. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (dichloromethane-hexane: ethyl acetate = 5:1 - 4:1) The residue obtained was purified to give 1.59 g (yield: 87%) of the title compound as a colorless oil. 1H-NMR (400 MHz, CDC13) δ: 1.36 (2 Η, ddt, J = 4.4, 12.4, 13.0 Hz), 1.46 (9H, s), 1.79 (2H, brd, J = 13.0 Hz), 2.32 (1H, tt, J=3.1, 12.0 Hz) 2.73 (2H, dt, J = 2.4, 13.0 Hz), 4.01 (2H, s), 4.18 (2H, brd, J = 13.4 Hz), 4.99 (1H, s), 5.22 (1H, s).

[Reference Example 135] 4-{l-[(9-Methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl) A Vinyl}piperidine-i-carboxylic acid tert-butyl ester

9·Methoxy-2,3-dihydro-1H-[1,4]indolo[2,3-c]quinoline (1.09 g, 5.05 mmol) obtained in Reference Example 8 under a nitrogen atmosphere. To a solution of N,N-dimethylacetamide (20.0 mL) was added sodium hydride (oily, 55%, 441 mg, 10.1 mmol) at room temperature and stirred for 2 hours. 4-(1-(Bromomethyl)vinyl]piperidine-1-carboxylic acid tert-butyl ester (1.72 g, 6.57 mmol) obtained in Reference Example 134 was added dropwise hydrazine, hydrazine-dimethyl hexane. A solution of decylamine (5.0 mL) was stirred at the same temperature for 20 hours. The reaction was stopped by adding a saturated aqueous solution of ammonium chloride (10.OmL) under ice-cooling, and the mixture was poured into a solution of hydrazine-l. The organic layer was combined, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue obtained was purified by hydrazine gel column chromatography (2-362-200946528 chloromethane:methanol = 19:1 - 9:1) to afford 2.05 g (92%) of Crystal form. 1H-NMR (400MHz, CDC13) δ: 1,46(9H, s), 1.50(2H, m), 1.76(2H, brd, J=12.7Hz), 2.05(1H, m), 2.70(2H, brt , J = 12.3 Hz), 3.22 (2H, t, J = 4.2 Hz), 3.78 (2H, brs), 3.80 (3H, s), 4.21 (2H, brm), 4.22 (2H, dd, J = 4.2, 4.4 Hz), 5.23 (1H, brs), 5.72 (1H, brs), 7.13 (1H, d, J = 2.7 Hz), 7.17 (1H, dd, J = 2.7, 9.3 Hz), 7.96 (1H, d, J = 9.3 Hz), 8.37 (1H, s). MS (ESI) m/z: 440 (M + H) + .

[Reference Example 136] 4-[1-hydroxy-1-hydroxymethyl-2-(9-methoxy-2,3-dihydro-1 fluorene-[1,4] hydrazine and [2,3- c] quinoline-1-yl)ethyl]piperidine-1-carboxylic acid tert-butyl ester

4-{1-[(9-Methoxy-2,3-dihydro-1H-[1,4]indolo[2,3-(:]quinolin-1-) obtained in Reference Example 135 Addition of N-methyl]vinyl}piperidine-1-carboxylic acid tert-butyl ester (1.82g, 4.14mmoI) in acetone (20.0mL)-water (10.OmL) at room temperature Methylmorpholine-N-oxide (849 mg, 7.25 mmol) and tetrazoic acid (ca. 7 mg) were stirred at the same temperature for 60 minutes. Add 10% aqueous sodium thiosulfate solution (1 mL) and stir for 1 hour. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and then filtered, and the filtrate was concentrated under reduced pressure. (Dichloromethane:methanol = 49:1 - 19:1 - -363 - 200946528 9:1) The obtained residue was purified to give 1.77 g (yield: 90%) of the title compound as pale brown amorphous. 1H-NMR (400MHz, CDC13) δ : 1.2 1 -1 . 3 9 (2 Η, m), 1.42(9H, s), 1.44(1H, m), 1.72-1 .8 1 (3H, m), 2.89 (2H , brm), 3.24- 3 · 3 8(4H, m), 3.85(1H, brd, J=14.1Hz), 3.93 (3H, s), 3.94(1H, d, J=11.2Hz), 4.14 (1H, d, J=11.2Hz), 4.16(2H, br m), 4.24 (1H, ddd, J = 2.6, 5.3, 11.4 Hz), 4.33 (1H, ddd, J = 2.4, 7.3, 11.4 Hz), 7.17 (1H, dd, J = 2.7, 9.3 Hz), 7.49 (1H, brd, J = 2.7 Hz), 7.93 (1H, d, J = 9.3 Hz), 8.34 (1H, s). MS (ESI) m/z: 474 (M + H) + .

[Reference Example 137] 2-[1-(Tertidinoxycarbonyl)piperidin-4-yl]-2-hydroxy-3-(9-methoxy-2,3-dihydro-1H-[1, 4] 噚耕和[2,3-c]quinolin-1-yl)propionic acid

Dichloromethane (〇.l〇5 mL, 1.48 mmol) of dichloromethane was added dropwise at -78 °C in a solution of chlorine (〇.〇63 mL, 0.739 mmol) in dichloromethane (3.0 mL). 2.OmL) solution. After stirring at the same temperature for 5 minutes, the 4-[1-hydroxy-1-hydroxymethyl-2-(9-methoxy-2,3-dihydro-1H-[1] obtained in Reference Example 136 was added dropwise over 10 minutes. , 4] dichloromethane (3.0 mL) of tert-butyl [2,3-c]quinolin-1-yl)ethyl]piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.211 mm 〇l) Solution. After stirring at the same temperature for 1.5 hours, a solution of triethylamine (0.206 mL, 1.48 mmol) in methylene chloride (2.OmL) was added, and the mixture was stirred for 15 minutes while warming to room temperature. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane - 364 - 200946528. The organic layer was combined, dried over anhydrous sodium sulfate, filtered, and filtered, and evaporated. The obtained residue was dissolved in a mixture of tetrahydrofuran (5. 〇mL)-t-butanol (5.0 mL)-2-methyl-2-butene (1.0 mL), and then added to the mixture. A solution of sodium (48 mg, 0-422 mmol) and sodium dihydrogen phosphate 2 hydrate (198 mg, 1.27 mmol) in water (1. The mixture was stirred for 30 minutes while gradually warming to room temperature, and then the reaction solution was poured into a mixed solution of a 1% by weight aqueous sodium thiosulfate solution and a phosphate buffer (ρΗ7·2). After extracting with dichloromethane, 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 was purified by silica gel column chromatography (dichlorobenzene: methanol = 10:1 - 4:1) to give 67.3 mg (65%). A labeled compound which is a pale yellow solid. 1H-NMR (400MHz, DMSO-d6) δ : 1. . . . . . . . . . 11.2Hz), 1.95(1H, m), 2.62(2H, br), 2.96(1H, m), 3.23(1H, d, J=13.6Hz), 3.56(1H,

Od, J=13.6Hz), 3.87-3.99(6H, m)5 4.2 3 - 4.2 8 (2 H, m), 5.29(1H, br), 7.13(1H, dd, J = 2.7, 9.0Hz), 7.75 (1H, d, J = 9.0 Hz), 7.91 (1H, d, J = 2.7 Hz), 8.28 (1H, s). MS (ESI) m/z: 48 8 (M + H) + .

[Example 68] 2-[1-(2-Cyclohexylethyl)piperidin-4-yl]_2-hydroxy-3-(9-methoxy- 2,3-diamino-1H-[1, 4]indolo[2,3-c]quinoline-i-yl)propionic acid

Ο ΌΗ 0 '-365- 200946528 2-[1-(Tertidinoxycarbonyl)piperidin-4-yl]-2-hydroxy-3-(3-methoxy-2,3) obtained in Reference Example 137 - dihydro-1H-[1,4] indole and [2,3-c]quinoline-1-yl)propionic acid (100 mg, 0.205 mmol) in dichloromethane (10 mL) Trifluoroacetic acid (2.0 mL) was added and stirred at the same temperature for 20 hours. The reaction solution was concentrated under reduced pressure to give 2-(piperidin-4-yl)-2-hydroxy-3-(9-methoxy-2,3-dihydro-1H-[1,4] And [2,3-c] sialolin-1-yl)propanoic acid as a crude brown oil. The resulting 2-(piperidin-4-yl)-2-hydroxy-3-(9-methoxy-2,3-dihydro-1H-[1,4]indole and [2,3- c]Quinolin-1-yl)propionic acid was dissolved in dichloromethane (10.OmL), and triethylamine (〇.〇86 mL, 〇.615 mmol) and cyclohexylacetaldehyde (52.0 mg) were added sequentially at room temperature. , 0.410 mmol) and sodium triethoxysulfonium hydride (87.0 mg, 0.410 mmol) were stirred at the same temperature for 3 hours. The reaction solution was poured into a phosphate buffer (pH = 6.0), and extracted with a mixture of dichloromethane:methanol (1:1). The organic layer was combined, dried over anhydrous sodium sulfate, and then filtered and evaporated. The residue obtained was purified by hydrazine gel column chromatography (dichloromethane:methanol = 9:1 - 6 :1 - 4 : 1) to give 5 2.2 mg (5 1 %) of Amorphous. 1H-NMR (400MHz, CD3〇D) δ: 1.〇4-1.37(7Η, m), 1.66(2H, brt, J = 13.9Hz), 1.7 7 - 2.1 9 ( 8 H, m), 2.68 ( 1H, brs), 2.88- 3.70(1〇h, m), 3.94(3H, s), 4.20(1H, m), 4.28(1H, m), 7.16-7.19(2H, m), 7.76(1H, d, J = 9.3 Hz), 8.20 (1H, s). MS (ESI) m/z: 498 (M + H) + .

[Reference Example 13 8] 3-({[T-butyl(dimethyl)decyl)oxy}methyl)-4-(2-ethoxy-2-oxooxyethylidene)piperidine- 1-carboxylic acid tert-butyl ester-366- 200946528

二 Under a nitrogen atmosphere, in a solution of sodium hydride (oily, containing 55%, 53 7 mg, 12.3 mmol) in tetrahydrofuran (30 mL), diethylphosphonium thioacetate (2.53 mL) was added for 5 minutes at 〇 °C. A solution of 12.8 mm (1 mL) in tetrahydrofuran (10 mL) was stirred at the same temperature for 30 min. Add 3-({[Tertiary butyl(dimethyl)decyl)oxy}methyl)-4-oxooxypiperidin-1-decanoic acid tert-butyl vinegar at the same temperature for 5 minutes (Bioorganic &amp; Medicinal Chemistry Letters, 2005, 15 volumes, 5, 1 375 - 1 3 7 8 , 3.13 g, 9.11 mmol) in tetrahydrofuran (10 mL), stirred for 30 minutes while warming to room temperature. . After the reaction was stopped by adding a saturated aqueous solution of ammonium chloride (10 mL) under ice-cooling, the reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was combined, washed with brine and dried over anhydrous sodium sulfate. The residue obtained was purified by hydrazine gel column chromatography (hexane: ethyl acetate = 19: 1-6: 1) to give 3.39 g (E: Z: = 5:1). It is a colorless oil. h-NMRHOOMHz, CDC13, only the peak of the main product (E body) is recorded. 5: 0.03 (3H, s), 0.05 (3H, s), 0.88 (9H, s), 1.28 (3H, t, J = 7) 1Hz), 1.46(9H, s), 2.3 9 - 2.4 9 ( 1 H , brm), 2.72(1H, m), 3 . 12-3.26(2H, m), 3.41(1H, dd, J = 3.9 , 13.1Hz), 3.61- 3.72(4H, m), 4.15(2H, m), 5.69(1H, brs).

[Reference Example 139] (3SR, 4RS)-3-({[T-butyl(dimethyl)decylalkyl]oxy-367- 200946528 yl}methyl)-4-ethoxycarbonylmethylpiperidine-1 - tert-butyl carboxylate, (3811, 43 ft)-3-({[t-butyl(dimethyl)decyl)oxy}methyl)-4-ethoxycarbonylmethylpiperidine-1 -carboxylic acid tert-butyl ester

3-({[T-butyl(dimethyl)decyl)oxy}methyl)-4-(2-ethoxy-2-oxooxyethylidene) piperidine obtained in Reference Example 138 A solution of tert-butyl-1-carboxylate (3.12 g, 7.54 mmol) in ethanol (30 mL) was added at room temperature with a platinum carbon catalyst (about 50% aqueous, 700 mg). The inside of the reaction vessel was replaced with hydrogen and stirred at the same temperature for 3.5 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by gel column chromatography (hexane: ethyl acetate = 9 5:1) to give 2.99 g ((3SR, 4RS). : (3SR, 4SR) 体 = 4:1) Labeled compound, which is a colorless oil. 1H-NMR (400MHz9 CDCI3, only the peak of the main product ((3SR, 4RS)))) δ: 0·03 (3Η, s), 0.04 (3H, s), 0.88 (9H, s), 1.25 ( 3H,t, J = 7.1Hz), 1.42(1H, m), 1.43(9H, s), 1.52(1H, m), 1.85(1H, br), 2.25-2.3 1 (2H, m), 2.40( 1H, brt, J = 9.8Hz), 3.04(1H, brm), 3 . 1 0(1 H, dd, 3 = 3.2, 1 3 · 4Hz), 3.5 1 - 3 · 6 1 (2 H,m) , 3-76(2H5 br), 4.0 9 - 4.1 5 (2H, m). MS (ESI) m/z: 41 6 (M + H)+.

[Reference Example 14 0] (38 ft, 4 sec 3)-3-({[T-butyl(dimethyl)decyl)oxy}methyl)-4-(2-hydroxyethyl)piperidine Tert-butyl 1-carboxylic acid, (3SR, 4SR)-3_({[T-butyl(dimethyl)decyl]oxy}methyl)-4-(2-hydroxyethyl)pipea- 368- 200946528

(3SR, 4RS)-3-({[T-butyl(dimethyl)decyl)oxy}methyl)-4-ethoxycarbonylmethylpiperidine-1-carboxylic acid obtained in Reference Example 139 Third butyl ester with (3SR, 4SR)-3-({[t-butyl(dimethyl)decyl)oxy}methyl)_4_ φ ethoxycarbonylmethylpiperidine·1-carboxylic acid third Add a solution of sodium hydride bis(methoxyethoxy)aluminum/toluene (65°/., 6.20 mL, 20.7 mmol) to a solution of butyl ester (2.87 g, 6.91 mmol) in toluene (50 mL). ), stirring at the same temperature for 1 hour. A 10% aqueous solution of Rochelle salt (10 mL) was carefully added and stirred for 2 hours. The reaction solution was poured into a 10% aqueous solution of Rochelle salt, and extracted with ethyl acetate. The organic layer was combined, washed with brine and dried over anhydrous sodium sulfate. The residue obtained was purified by hydrazine gel column chromatography (hexane: ethyl acetate = 2:1 - 1:1) to give 2.55 g (9 9%) of the title compound as a colorless oil. . iH-NMRHOOMHz, CDC13, only the peak of the main product ((3SR, 4RS))) δ: 0·05 (3Η, s), 0.06 (3H, s), 0.89 (9H, s), 1.36- 1 -57(1 1 H, m), 1.61-1.75(2Η, m), 1 · 8 Ο -1. 8 8 (2 Η, m), 3.00(1Η, brm), 3.02(1Η, dd, J = 2.9, 13.2Hz), 3 . 5 4 - 3.8 1 (7 Η, m ).

[Reference Example 141] (3SR, 4RS)-3-({[T-butyl(dimethyl)decyl)oxy}methyl)-4-(2-iodoethyl)piperidine-1-carboxylate Acidic butyl butyl ester, (3SR, 4SR) - -369- 200946528 3-({[T-butyl(dimethyl)decylalkyl]oxy}methyl)-4-(2-iodoethyl)per Pyridin-1-carboxylic acid tert-butyl ester

(3SR, 4RS)-3-({[Tertiary butyl(dimethyl)decyl)oxy}methyl)-4-(2-hydroxyethyl) obtained in Reference Example 140 under a nitrogen atmosphere Piperidine-1-carboxylic acid tert-butyl ester with (3811,48 ft)-3-({[t-butyl(dimethyl)decyl)oxy}methyl)-4-(2-hydroxyethyl) a mixture of tert-butyl piperidine-1-carboxylic acid tert-butyl ester (2.55 g, 6.83 mmol) and triethylamine (1.43 mL, 10.2 mmol) in dichloromethane (30.0 mL) Sulfonyl chloride (〇.581mL, 7.5 1 mmo 1) 'Stirred for 2 hours. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was combined and washed with saturated brine. After drying over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue thus obtained was dissolved in acetone (70.0 mL), sodium iodide (2.05 mg, 13.7 mm) was added at room temperature, and the mixture was heated to reflux for one hour. The reaction solution was poured into a 1% aqueous solution of sodium thiosulfate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by gel column chromatography (ethyl acetate: hexane = 7:1 - 4:1) to yield 2 82 g (86% ) a labeled compound which is a pale yellow oil. ^-NMRHOOMHz, CDC13, only the peak of the main product ((3SR, 4RS) body) δ : 0.0 4 (3 Η, s ), 0.0 5 (3 Η, s ), 0 · 8 9 ( 9 Η, s),1.4 4 ( 2 Η,m), 1.45(9Η,s),1·75-1·91(4Η,m),2·97(1Η,br),2·99(1Η,dd, - 370- 200946528 J = 3.2, 13.4Hz), 3 . 1 8-3 .3 1 (2H, m), 3.55(2H, d, J = 6.3Hz), 3.85(2H, brd, J=1 1.5Hz) .

[Reference Example 142] (38 ft, 431 〇-3-({[t-butyl(dimethyl)decyl)oxy}methyl)-4-[2-(9-methoxy-2, 3-Dihydro-111-[1,4]indole and [2,3-(:]quinolin-1-yl)ethyl]piperidine-1-carboxylic acid tert-butyl ester, (3SR, 4RS) -3-({[T-butyl(dimethyl)decyl)oxy}methyl)-4-[2-(9-methoxy-2,3-dihydro-1Η_[1,4] Tillering and [2,3-c]quinolin-1-yl)ethyl]piperidine-1-carboxylic acid tert-butyl ester

9-methoxy-2,3-dihydro-1H-[1,4] oxime and [2,3-c] porphyrin (85 3 mg, 3 -95 mmol) obtained in Reference Example 8 under a nitrogen atmosphere. Sodium hydride (oily, containing 55%, 3 10 mg, 7.10 mmol) was added to a solution of N,N-dimethylacetamide (10.0 mL), and stirred for 2 hours. (TC drops reference example

(3SR,4RS)-3-({[T-butyl(dimethyl)decyl)oxy}methyl)-4-(2-iodoethyl)piperidine-1-carboxylic acid Tributyl ester with (3SR, 4SR)-3-({[T-butyl(dimethyl)decyl)oxy}methyl)-4-(2-iodoethyl)piperidine-1-carboxylic acid A solution of a mixture of the third butyl ester (2.48 g, 5.13 mmol) in N,N-dimethylacetamide (5.0 mL) was stirred at the same temperature for 20 hours. The reaction was stopped by adding a saturated aqueous solution of ammonium chloride (5.0 mL), and the mixture was poured and evaporated. The organic layer was combined and dried over anhydrous sodium sulfate. The residue obtained by -37-200946528 was purified by gel column chromatography (dichloromethane:methanol = 4 9:1 19:1-9:1) to give 1.88 g (83 %) a labeled compound which is a pale yellow amorphous "W-NMRHOOMHz, CDC13, only the peak of the main product ((3SR, 4SR) body)) δ: 0.05 (3 Η, s), 0.06 (3H, s), 0.90 (9H, s), 1.45 (9H, s), 1.46 (2H, br), 1.54 (1H, brm), 1.74-2.0 1 (4H, m), 2.94- 3.08 (3H, m), 3.2 2 - 3.3 3 (3 H, m), 3.63 (2H, d, J = 6.6Hz), 3.87(1H, br), 3.92(3H, s), 4.1 6 - 4.2 6 (2 H, m), 7.09(1H, d, J = 2.7 Hz), 7.19 (1H, dd, J = 2.7, 9.0 Hz), 7.98 (1H, d, J = 9.0 Hz), 8.36 (1H, s). MS (ESI) m/z: 572 (M + H) + .

[Reference Example 143] (3SR, 4SR)-3-(hydroxymethyl)-4-[2-(9-methoxy- 2,3-dihydro-1H-[1,4] 曙耕和[2 ,3-c]quinoline-1-yl)ethyl]piperidine-1-carboxylic acid tert-butyl ester, (3SR, 4RS)-3-(hydroxymethyl)-4-[2-(9-A Oxy-2,3-dihydro-1H-[1,4]indole-[2,3-c]salolin-1-yl)ethyl]piperidine-1-carboxylic acid tert-butyl ester

(3SR,4SR)-3-({[Tertiary butyl(dimethyl)decyl)oxy}methyl)-4-[2-(9-A) obtained in Reference Example 142 under a nitrogen atmosphere Oxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinoline-1-yl)ethyl]piperidine-1-carboxylic acid tert-butyl ester with ( 3SR, 4RS)-3-({[T-butyl(dimethyl)decyl)oxy}methyl)-4-[2-(9-methoxy- 2,3-dihydro-1H- [1,4] A mixture of tert-butyl [2,3-c]salolin-1-yl)ethyl]piperidine-1-carboxylic acid (1.87 g, 3.27 mmol) in tetrahydrofuran (25. To a solution of OmL), tetrabutylammonium fluoride/tetrahydro-372-200946528 furan solution (1 Torr, 4.86 mL, 4.86 mmol) was added at room temperature and stirred for 15 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane. After the organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by hydrazine gel column chromatography (dichloromethane:methanol = 49:1 - 19:1 - 9:1) to give 1.12 g (75%) of 3SR, 4SR) and 361 mg (24%) (3SR, 4RS) bodies, each of which is light yellow amorphous. Ο

(3SR,4SR)-3-(hydroxymethyl)-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]噚[[,3,3-c] T-butyl quinolin-1-yl)ethyl]piperidine-1-carboxylate: 'Η-ΝΜΚ(400ΜΗζ, CDC13) δ : 1 · 4 4 -1 · 4 8 (1 1 Η,m), 1.7 9 (2H, br), 1.93 (2H, br), 2.7 2 - 2.8 6 (2 H, brm), 3.1 2 - 3 . 3 3 ( 5 H, brm), 3.51 (1H, br), 3.67 ( 1H, br), 3.92(3H, s), 4.10(1H, br), 4.17-4.26(3H, m), 7.08(1H, d, J = 2.7Hz), 7.20(1H, dd, J = 2.7, 9.3Hz), 7.99(1H, d, J = 9.3Hz), 8.35(1H, s). MS(ESI) m/z:45 8(M + H) + . (3吕11,4113)-3- (hydroxymethyl)-4-[2-(9-methoxy-2,3-dihydro-111-[1,4]indole[2,3-c]quinolin-1-yl)B Benzylpyridine-1-carboxylic acid tert-butyl ester··1H-NMR (400MHz, CDC13) δ: 1.27(1 H, m), 1.45(9Η, s), 1.47(1 Η, m), 1.60(1Η, m), 1.72(1Η, m), 1.82- 1.88(2Η, m), 2.27(1Η, m), 2.92(2Η, br), 3.2 5 - 3.3 8 (4 Η, brm) , 3.72(2Η, br), 3.91-3.97(5Η, m), 4.24(2Η, t, J = 4.4Hz), 7.12(1Η, d, J = 2.7Hz), 7.24(1H, dd, J = 2.7 , 8.0Hz), 8. 14(1H, brd, J = 8.0Hz), 8.30(1H, s). MS(ESI)m/z:45 8(M + H)+. -373- 200946528 Example 69] {(3SR,4RS)-l-(2-cyclohexylethyl)-4-[2-(9-methoxy-2,3-dihydro-111-[1,4]噚And [2,3-(:]quinolin-1-yl)ethyl]piperidin-3-yl}methanol

(3SR,4SR)-3-(hydroxymethyl)-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]噚[[4] a solution of 2,3-c]quinolin-1-yl)ethyl]piperidine-carboxylic acid tert-butyl ester (28811^, 0.629111111〇1) in dichloromethane (1〇.〇1111^) 4 equivalents of hydrogen chloride / diterpenoid solution (1. 〇 mL) was added at room temperature, and stirred at the same temperature for 20 hours. The reaction solution was concentrated under reduced pressure to give {(38 s, 4113) -4-[2-(9-methoxy-2,3-dihydro-111-[1,4] hydrazine and [2, 3-(:] quinoxalyl-1-yl)ethyl]piperidin-3-yl}methanol as a crude red-brown solid, which gave the obtained {(3SR, 4RS)-4-[2-( Thickness of 9-methoxy-2,3-dihydro-1H-[1,4]indolo[2,3-c]quinolin-1-yl)ethyl]piperidin-3-yl}methanol The solution was dissolved in dichloromethane (10. OmL), and triethylamine (0.263 mL, l_89 mmol) and cyclohexylethane (159 mg, 1.26 mmol) and hydrogenated sodium triacetoxyborohydride (334 mg) were added sequentially at room temperature. The mixture was stirred at the same temperature for 3 hours. The reaction mixture 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. The filtrate was purified by gel column chromatography (dichloromethane: methanol = 9:1 - 6: 1-4:1), followed by preparative thin layer chromatography (矽 gel). , chloroform:methanol:water = 7:3:1 lower solvent) was purified to give 69.5-374-200946528 mg (24%) of the labeled compound, which was white amorphous. 'Η-ΝΜ (400ΜΗζ, CDC13) δ : 0.8 5 - 0.9 4 (2 Η , m), 1.11- 1.27(5H, m), 1.3 6- 1.46(2H, m), 1.62- 1 , 69(8H, m) , 1.94- 2.06(4H, m), 2.26-2_36(3H, m), 2.97-3,05(2H, m), 3.12- 3.20(2H, m), 3.24(2H, t, J = 4.2Hz) , 3.90 (1H, brd,

J = 10.7 Hz), 3.93 (3H, s), 4.03 (lH, brd, J = l 〇.7 Hz), 4.l4-4.24 (2H, m), 7.11 (1H, d, J = 2.7 Hz), 7.15 (1H, dd, J = 2.7, 9.0 Hz), 7.87 (1H, d, J = 9.0 Hz), 8.36 (1H, s). MS (ESI) m/z: 468 (M + H) + .

[Reference Example 144] (3SR, 4SR)-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinoline- 1-yl)ethyl]piperidine-1,3-dicarboxylic acid 1-t-butyl ester

Dimethyl hydrazine (〇.814 mL, 11.5 mmol) in dichloromethane (2 mL) was added dropwise to a solution of dichloromethane (〇.591 mL, 6.88 mmol) in dichloromethane (1 〇. 〇 mL) at -78 °C. .OmL) solution. After stirring at the same temperature for 5 minutes, (3SR, 4SR)-3-(hydroxymethyl)-4-[2-(9-methoxy-2,3-dihydro) obtained in Reference Example 143 was added dropwise for 1 minute. -111-[1,4] Dihydrochloride of 2,3-(:]quinoxa-1-yl)ethyl]piperazin-1-decanoate tert-butyl ester (1.058, 2.29191111〇1) Methane (7. 1111〇 solution. After 1 hour of temperature disturbance, a solution of diethylamine (1.60 mL, 11.5 mmol) in dichloromethane (2.0 mL) was added while stirring slowly to room temperature. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate, and extracted with dichloromethane-375-200946528. The organic layer was combined and dried over anhydrous sodium sulfate, and then filtered and evaporated. The residue was dissolved in tetrahydrofuran (15.0 mL)-t-butanol (15.0 mL)-2-methyl-2-butene (3.0 mL), and sodium chlorite (519 mg, 4.59 mmol) And a solution of sodium dihydrogen phosphate 2 hydrate (2.15 g, 13.8 mm 〇l) in water (3.0 mL). After stirring for 30 minutes while gradually warming to room temperature, the reaction solution was poured into 1 〇% thiosulfuric acid. Sodium solution in phosphate buffer (pH 7.2). After extracting with methylene chloride, the organic layer was combined and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give a gel column chromatography (dichloroform: methanol = 49:1 &gt; 19:1 - 9:1) The residue obtained was purified to give 960 mg (yield: 89%) of the title compound as pale yellow amorphous. 1H-NMR (400 MHz, CDC13) δ: 1.45 (9 Η, s) , 1.63(1H, m), 1.87(1H, m), 2.0 1-2.1 6(3H, m), 2.67(1H, m), 3 .1 9-3.27(4H, m), 3.36(1H, m ), 3.59(2H, dd, J = 3.2, 13.5Hz), 3.88(1H, m) 3.90(3H, s), 4.14(2H, dd, J = 3.9, 4.2Hz), 7.04(1H, d, J = 2.7 Hz), 7.08 (1H, dd, J = 2.7, 9.0 Hz), 7.90 (1H, d, J = 9.0 Hz), 8.29 (1H, s). MS (ESI) m/z: 472 (M + H) + .

[Example 7〇] (3311, 4 尺 8)-1-(2-cyclohexylethyl)_4_[2_(9-methoxy-2,3-dihydro-111-[1,4]fluorene And [2,3-〇]quinolin-1-yl)ethyl]piperidine-3-carboxylic acid-376- 200946528

(3SR,4SR)-4-[2-(9-Methoxy-2,3_dihydro-1H-[1,4]indole[2,3-c]quinoline obtained in Reference Example 144 a solution of 1-hexyl)ethyl]piperidine-13-dissidic acid 1-tributyl ester (10 mg, 0.212 mmol) in dichloromethane (5. 〇mL). Acetic acid (1.0 mL) was stirred at the same temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give (3SR, 4RS)-4-[2-(9-methoxy-2,3_0 dihydro-1H-[1,4]indole and [2,3- The crude form of c]quinolin-1-yl)ethyl]piperidine-3-decanoic acid as a light brown oil. The obtained (3SR, 4RS)-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole and [2,3-c]quinoline-b The crude solution of ethyl]ethylidenepiperidine-3-carboxylic acid was dissolved in dichloromethane (10.OmL), and triethylamine (0.089 mL, 0.636 mm oi) and cyclohexyl ketone (54.0) were added sequentially at room temperature. Mg, 〇. 424 mmol) and sodium triethoxyborohydride (99.0 mg, 0.467 mmol) were stirred at the same temperature for 2.5 hours. The reaction solution was poured into a phosphate buffer (ΡΗ7·2) and extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue obtained was purified by reverse phase high-speed liquid chromatography (Develosil, 2 cm (|) &lt; 10 cm, acetonitrile-water mixed solvent containing 0.1% formic acid) to give 67.7 mg (67%) of a labeled compound. It is a white solid. 1H-NMR (400MHz, CD3OD) δ : 0 · 9 9 -1 · 0 7 (2 Η, m), 1.19- 1.39(5H, m), 1.58(1H, m), 1.6 8 - 2.2 8 ( 1 0 Η, m), 3.07- 3·28(6Η, m), 3.48(1Η, brd, J=12.4Hz), 3·74(2Η, t, -377- 200946528 J = 4.4Hz), 3.87( 1H, brd, J=12.5Hz), 3.98(1H, m), 4.01(3H, s), 4.37-4.40(2H, m), 7.37(1H, d, J = 2.4Hz), 7.55(1H, dd , 3 = 2.4, 9.3 Hz), 7.87 (1H, d, J = 9.3 Hz), 8.37 (1H, s). MS (ESI) m/z: 482 (M + H) + .

[Reference Example 145] (3RS, 4SR)-4-[2-(9-methoxy-2,3·dihydro-1H-[1,4]indolo[2,3-c]quinoline- 1-yl)ethyl]piperidine-1,3-dicarboxylic acid 1-t-butyl ester

A solution of dimethyl sulfoxide (0.279 mL, 3.93 mmol) in dichloromethane (2.0 mL) was added dropwise to a solution of dichloromethane (?? After stirring at the same temperature for 5 minutes, the (3RS, 4SR)-3-(hydroxymethyl)-4-[2-(9-methoxy-2,3-dihydro-) obtained in Reference Example 143 was added dropwise over 10 minutes. 1H-[1,4]噚[[2,3-c]quinolin-1-yl)ethyl]piperidine-1-carboxylic acid terpene vinegar (360 mg, 0.787 mmol) in dichlorocarbyl ( 5.0 mL) solution. After stirring at the same temperature for 1 hour, a solution of triethylamine (0.548 mL, 3.93 mmol) in methylene chloride (2.OmL) was added, and the mixture was stirred for 30 minutes while warming to room temperature. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate, filtered, and filtered, and evaporated. The obtained residue was dissolved in a mixture of tetrahydrofuran (10.OmL)-t-butanol (10.0 mL)-2-methyl-2-butene (1.0 mL). 200946528 A solution of sodium sulphate (178 mg, 1.57 mmol) and sodium dihydrogen phosphate 2 hydrate (736 g, 4.72 mmol) in water (2.0 mL). After slowly raising the temperature to room temperature for 30 minutes, the reaction solution was poured into a mixture of 1 〇% aqueous sodium thiosulfate solution and phosphate buffer (pH 7.2). After extracting with dichloromethane, the organic layer was combined and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by gel column chromatography (dichloromethane: methanol = 4 9:1 - 19:1 - 9:1 - 7:1). There was obtained 275 mg (74%) of a labeled compound which was pale brown amorphous.

1H-NMR (400MHz, CDC13) δ: 1.31 (1Η, m), 1.47 (9H, s), 1 _ 7 6 (1 H, brd, J = 1 1 · 7 H z ), 1. 8 4 -1.8 8 (2 H,m ),2.1 6 (1 H,m), 2.31(1H, m), 2.73(1H, brm), 2.89(1H, br), 3 .1 1 - 3.3 7 (4 H, m ), 3.90(3H, s), 4.0 8 - 4.1 8 ( 3 H, m), 4.35(1H, br), 6.98- 7.01(2H, m), 7.82(1H, d, J = 9.0Hz), 8.26 (1H, s). MS (ESI) m/z: 472 (M + H) + .

[Example 71] (3118, 4113)-1-(2-cyclohexylethyl)-4-[2-(9-methoxy- 2,3-dihydro-111-[1,4] And [2,3-(:]quinolin-1-yl)ethyl]piperidine-3-carboxylic acid

(3118,4811)-4-[2-(9-Methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline obtained in Reference Example 145 -1-yl)ethyl]piperidine-u·didecanoic acid 1-t-butyl ester (275 mg, 0.583 mmol) in a solution of dichlorocarbyl (5. 〇mL) 'add 4 equivalents of hydrogen chloride at room temperature/ The second broth solution (〇.583 mL) was stirred at the same temperature as -379-200946528 for 4 hours. The reaction solution was concentrated under reduced pressure to give (3RS, 4RS)-4,[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3- c] crude of quinoline-1-yl)ethyl]piperidine-3-carboxylic acid as a light brown oil. The obtained (3RS, 4RS)-4-[2-(9-methoxy-2,3-dihydro-1Η-[1,4]噚[[,3-c]quinoline-1] The crude solution of ethyl-ethyl]piperidine-3-carboxylic acid was dissolved in dichloromethane (10 mL), and triethylamine (0.244 mL, 1.75 mmol) and cyclohexylacetaldehyde were added sequentially at room temperature. 147 mg, 1.17 mmol) and sodium triethyl borohydride (309 mg, 1.46 mmol) were stirred at the same temperature for 1 hour. The reaction solution was poured into a phosphate buffer (pH 7.2, 10 mL), and extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate, filtered, and evaporated. The obtained residue was purified by reverse phase high-speed liquid chromatography (Develosil, 2 〇 111 &lt;|) &lt; 10 (; 111, acetonitrile-water mixed solvent containing 0.1% formic acid) to obtain 174 mg (62%). ) a labeled compound which is a white solid. 1 H-NMR (400MHz, CD3OD) 5:0.97- 1.06(2H, m), 1_19-

1.34(4H, m), 1. 6 3 - 1 . 7 7 ( 8 H, m), 1 . 9 8 - 2.0 2 (2 H , m), 2.16 (1H, brd, J=13.2Hz), 2.31 (1H, brm), 2.74(1H, brm), 2.99(1H, brt, J=12.0Hz), 3.06(1H, t, J = 12.5Hz), 3. 16 - 3.2 0 (2 H , m) , 3.62 (1H, brd, J = 12.5 Hz), 3.7 0 - 3.7 6 (4 H, m), 3.90 (1H, m), 4.0 1 (3 H, s ), 4.3 5 - 4.3 9 (2 H, m), 7.2 9 ( 1 H,d,J = 2 · 2 H z), 7.53 (1H, dd, J = 2.2, 9.3 Hz), 7.86 (1H, d, J = 9.3 Hz), 8.37 (1H, s). MS (ESI) m/z: 482 (M + H) + .

[Example 72] (3311, 4 ft 3)-1-[2-(2-fluorocyclohex-1-en-1-yl)ethyl]_4_-380- 200946528 [2-(9-methoxyl) -2,3-dihydro-1H_[1,4]indole[2,3-c]quinolin-1-yl)ethyl]piperidine-3-carboxylic acid

(3811,4311)-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline obtained in Reference Example 144 Add 1-trifluoroacetic acid (1 - yl)ethyl]piperidine-i,3-dicarboxylic acid 1-tributyl ester (100 mg, 0.212 mmol) in dichloromethane (5.0 mL) .OmL), stirred at the same temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give (3SR, 4RS)-4-[2-(9-methoxy-2,3-dihydro-lH-[l,4]0f till [2,3- The crude form of c]quinolin-1-yl)ethyl]piperidine-3-carboxylic acid as a light brown oil.

The obtained (3SR, 4RS)-4-[2-(9.methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline-1 was obtained. The crude solution of ethyl-ethyl]piperidine-3-carboxylic acid was dissolved in dichloromethane (8.0 mL), and triethylamine (〇. 〇 89 mL, 0.636 mmol) was added to the mixture at room temperature. 6 (2-fluorocyclohex-1-en-1-yl)acetaldehyde obtained in the crude (55.〇11^, 〇.371111111〇1) dichlorocarbyl (2.〇1111〇 solution and hydrogenation Sodium diethyl ethoxide (90.0 mg, 0.424 mmol) was stirred at the same temperature for 5 hours. The reaction solution was poured into a phosphate buffer (pH 7.2) and extracted with dichloromethane. The organic layer was combined with anhydrous sulfuric acid. After the sodium was dried, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by gel column chromatography (dichloromethane:methanol = 19:1 - 9:1 - 7:1). 100 mg (95%) of the title compound are obtained as a pale yellow amorphous. 1H-NMR (400 MHz, CDC13) δ: 1.4 6-2.3 6 (1 8H, m), 2.57--381- 200946528 2.65 (3H, m ), 3 . 1 2 - 3.2 3 (5 H, m), 3.35 (1H, m), 3.92 (3H, s), 4.17 (1H, m), 4.25 (1H, m), 7.10 (1H, d, J = 2.7 Hz), 7.15 (1H, dd, 5 = 2.1, 9.0 Hz), 7.87 (1H, d, J = 9.0 Hz), 8.36 (1H, s). MS (ESI) m/z: 498 (M + H) + .

[Reference Example 146] (3811, 48 ft) 3-aminocarbazyl-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4] 噚耕和[2 , 3-c]quinolin-1-yl)ethyl]piperidine-1-carboxylic acid tert-butyl ester

(3SR,4SR)-4-[2-(9-Methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline obtained in Reference Example 144 -1-yl)ethyl]piperidine-i,3-dicarboxylic acid 1-tert-butyl ester (100 mg, 0.212 mmol) in dichloromethane (2. 〇mL) in solution 'add ammonia/room at room temperature Decane solution (0.5 Μ, 2.97 mL, 1.48 mmol) and 〇-(7-azabenzotriazol-1-yl)-N,N,N,N,-tetramethylurea hexafluoroboron The ester (96.7 mg, 0.254 mmol) was stirred at the same temperature for 72 h. The reaction solution was poured into an aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was purified by sand-gel column chromatography (Methylene chloride: methanol = 49:1 - 19:1 - 9:1) to give 8 4.8 mg (85%) of Light yellow amorphous. Η -NM R(4 Ο Ο Μ H z, CD C13) δ : 1.4 6 (9 Η, s), 1 5 7 (1 H m) 1·73-1·80(2Η,m),1·96 (1Η,m), 2.17(1H,m), 2.49(1H,m), -382- 200946528 3.02-3.18(5H, m), 3.28(1H, ddd, J = 2.4, 4.8, 14.2Hz), 3.84 (1H, m), 3.91(3H, s), 4.04(1H, m), 4.1 1-4.2 1 (2 H , m), 6.00(1H, br), 6.46(1H, br), 7.09(1H, d, J = 2.7 Hz), 7.13 (1H, dd, J = 2.7, 9.0 Hz), 7.85 (1H, d, J = 9.0 Hz), 8.33 (1H, s). MS (ESI) m/z: 47 1 (M + H)+ .

[Example 73] (3SR, 4RS)-l-(2-cyclohexylethyl)-4-[2-(9-methoxy-2,3-dihydro-lH-[l,4] And [2,3-C]quinoline-l-yl)ethyl]piperidine-3-carboxamide

(3SR,4SR)-3-Aminomethylmercapto-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]噚[[4,4] , 3-c]quinolin-1-yl)ethyl]piperidine·1-carboxylic acid tert-butyl ester (84.811^, 0.18〇111111〇1) in dichloromethane (1〇.〇«11〇 solution Trifluoroacetic acid (2.0 mL) was added at room temperature, and stirred at the same temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to give (3SR, 4RS)-4-[2-(9-methoxy) a crude form of 2,3-dihydro-1H-[1,4]indole[2,3-c]quinolin-1-yl)ethyl]piperidine-3-carboxamide, which is Light brown oil. The resulting (3SR, 4RS)-4_[2-(9-methoxy-2,3-dihydro-1H-[1,4]噚 and [2,3-c The crude product of quinolin-1-yl)ethyl]piperidine-3-carboxamide was dissolved in dichloromethane (15.0 mL), and triethylamine (0.0754 mL, 0-541 mm·l) was added sequentially at room temperature. Stirring with cyclohexylacetaldehyde (45.5 mg, 0.360 mmol) and sodium triethoxysulfonium hydride (76_4 mg, 0.360 mmol) at the same temperature for 1 hour. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate to dichloro- 383- 200946528 Methane extraction. Combined organic layer, dried with anhydrous sodium sulfate, filtered The desiccant was concentrated and reduced under reduced pressure. The obtained residue was purified by gel column chromatography (Methylene chloride: methanol = 4 9:1 - 19:1 - 9:1) to obtain 86.6 mg. (Quantitative) labeled compound, which is a pale yellow amorphous 》 *Η-ΝΜΚ(400ΜΗζ, CDC13) δ : 0.8 6 - 0.9 4 ( 2 Η, m), l.u_ I. 25(4Η, m), 1.2 8 -1.4 1 (2 Η, m), 1.6 0 -1.7 1 (8 Η, m), 1.85(1Η, m), 1.94(1Η, brt, J=10.6Hz), 2.0 3 - 2.1 Ο (2 Η , m), 2.33 (2Η, t, J = 7.6Hz), 2.50(1Η, brs), 2.97(1Η, brd, J=11.2Hz), 3.07-3.19(2Η, m), 3.21(2Η, t, J = 8.3 Hz), 3.37 (1H, ddd, J = 2.2, 4.1, 14.0 Hz), 3.92 (3H, s), 4.16 (1H, ddd, J = 2.2, 7.8, II. 0Hz), 4.25 (1H, m), 5.89 (1H, d, J = 4.4 Hz), 7.11 (1H, d, J = 2.7 Hz), 7.13 (1H, dd, J = 2.7, 9.0 Hz), 7.86 (1H, d, J = 9.0) Hz), 8.35 (1H, s), 8.76 (1H, br). MS (ESI) m/z: 48 1 (M + H) + .

[Reference Example 147] (3SR, 4SR)-4-[2-(9-Methoxy-2,3-dihydro-1H-[1,4]indolo[2,3-c]salin- 1-butyl)ethyl]-3-[(methylsulfonyl)amine-carbamoyl]piperidine-1-carboxylic acid tert-butyl ester

(3311,4811)-4-[2-(9-Methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline obtained in Reference Example 144 1-yl)ethyl]piperidine-i,3-dicarboxylic acid 1-tert-butyl ester (100 mg, 〇.212 mmol) and mesylamine (22.0 mg, -384-200946528 0.23 3 mmol) and hydrazine, Ν-Dimethylaminopyridine (28.0 mg, 0.23 3 mmol) in dichloromethane (3.0 mL)-N,N-dimethylformamide (1.0 mL) -Methylaminopropyl)-indole-ethylcarbodiimide hydrochloride (4.5 g, 0.23 3 mmol), stirred at the same temperature for 18 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 obtained was purified by hydrazine gel column chromatography (dichloromethane:methanol = 49:1 - 19:1 - 9:1) to give 87.2 mg (75%) of Crystal Form 1H-NMR (400MHz, CDC13) δ:1·45(9Η, s), 1·48(1Η, m), 1. 86-1 ·98(3Η,m), 2 . Ο 9 (1 Η , m), 2.6 4 ( 1 Η, m), 2 · 9 Ο - 3 · Ο 4 (2 Η, ιη), 3.11-3.18(3Η, m), 3.24(1Η, m), 3.26(3Η, s ), 3.83(1Η, m), 3.86(3Η, s), 4 . Ο 7 - 4.2 Ο (3 Η, m), 6.96(1Η, d, J = 2.7Hz), 7. 12(1Η, dd, J = 2.7, 9.3 Hz), 7.88 (1 Η, d, J = 9.3 Hz), 8.04 (1 Η, br), 8.32 (1 Η, s). MS (ESI) m/z: 549 (M + H) +.

[Example 74] (3SR, 4RS)-l-(2-cyclohexylethyl)-4-[2-(9-methoxy-2,3-dihydro-lH-[l,4]IIf And [2,3-c]quinoline·l-yl)ethyl]-N-(methylsulfonyl)piperidin-3-indenylamine

(3SR,4SR)-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-c]quinoline obtained in Reference Example 147 -1-yl)ethyl]-3-[(methylsulfonyl)-385- 200946528 Aminomethylmercapto]piperidine-1-carboxylic acid tert-butyl ester (87.2 mg, 0.159 mmol) in dichloromethane (5.0 mL), trifluoroacetic acid (1.0 mL) was added at room temperature, and stirred at the same temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give (3SR, 4RS)-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3- c] quinolin-1-yl)ethyl]-N-(methylsulfonyl)piperidin-3-indolamine as a crude brown oil. The resulting (3SR, 4RS)-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole[2,3-(:]quinoline- The crude solution of 1-yl)ethyl]-&amp;(methylsulfonyl)piperidin-3-indolamine was dissolved in dichloromethane (10. OmL), and triethylamine was added sequentially at room temperature. _ 〇 66 mL, 0.477 mmol) and cyclohexyl acetaldehyde (40.0 mg, 0.318 mmol) and sodium triethoxy borohydride (67.0 mg, O.318 mmol) were stirred at the same temperature for 62 hours. The reaction solution was poured into saturated carbonic acid. The organic layer was extracted with methylene chloride. 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. 49:1 - 19:1 - 9:1) The obtained residue was purified to give 78.8 mg (yield: 89%) of the title compound as white amorphous. 1H-NMR (400 MHz, CDC13) δ: 0.92 (2 Η, dt , J=10.7, 12.0Hz), 1.12-1.32(4H, m), 1.48(2H, dt, J = 7.3, 7.4Hz), 1.63- 1.75(7H, m), 1. 8 4 - 1.9 3 (2 H, m), 2.07(1H, m), 2.31(2H, brm), 2.52-2.64(3H, m), 3 .1 2 - 3.2 8 (8 H, m), 3.35 (1H, ddd, J = 2.2, 4.4, 14.4Hz), 3.93(3H, s), 4.16(1H, Ddd, J = 2.2, 7.8, 12.0 Hz), 4.27 (1H, ddd, J = 2.4, 4.4, 12.0 Hz), 7.09 (1H, d, J = 2.7 Hz), 7.15 (1H, dd, J = 2.7, 9.0 Hz), 7.88 (1H, d, J = 9.0 Hz), 8.35 (1H, s). -386- 200946528 MS (ESI) m/z: 5 5 9 (M + H) + .

[Reference Example 148] (3811, 4811)-3-(methoxyaminemethanyl)-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]fluorene Cultivated tert-butyl [2,3-c]quinolin-1-yl)ethyl]piperidine-1-carboxylic acid

(3SR,4SR)-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4]indole and [2,3_c]quinoline-) obtained in Reference Example 144 1-yl)ethyl]piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (100 mg, 0.212 mmol) and hydrazine-methylhydroxylamine hydrochloride (19_0 mg, 0.23 3 mmol) and triethylamine ( 〇_〇59mL, 0.424mmol) in dichloromethane (3.0mL), added 0-(7-azabenzotriazol-l-yl)-N,N,N',N'- at room temperature Tetramethylurea hexafluoroborate (89.0 mg, 0.23 3 mmol) was stirred at the same temperature for 3 hours. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate and filtered. The residue obtained was purified by hydrazine gel column chromatography (dichloromethane:methanol = 49:1 - 19:1 - 9:1) to give 99.4 mg (94%) of . 1H-NMR (400MHz, CDC13) δ: 1.47 (9Η, s), 1.58 (1H, m), 1.96 (1H, m), 2.24 (1H, br), 2.47-2.79 (3H, br m), 2.94- 3.22(5H, m), 3.35(1H, brd, J=12.5Hz), 3,75(3H, s), 3.91(3H, s), 3.92(1H, m), 4.1 2 - 4.2 3 ( 3 H, m), 7.08 (1H, d, J = 2.7 Hz), 7.14 (1 H, dd, J = 2.7, 9.0 Hz), 7.87 (1H, d, -387- 200946528 J = 9.0 Hz), 8.33 (1H, s), 9.63 (1H, br). MS (ESI) m/z: 501 (M + H) + .

[Example 75] (38 ft, 4 -8)-1-(2-cyclohexylethyl)-&gt; 1-methoxy-4-[2-(9-methoxy-2,3-di Hydrogen-1H-[1,4]indole and [2,3-c]quinolin-1-yl)ethyl]piperidin-3-indenylamine

(3SR,4SR)-3-(methoxyaminemethanyl)-4-[2-(9-methoxy- 2,3-dihydro-1H-[1,4] obtained in Reference Example 148 a solution of tert-butyl [2,3-c]quinolin-1-yl)ethyl]piperidine-1-carboxylic acid (99.4 mg, 0.199 mmol) in dichloromethane (5.0 mL) Trifluoroacetic acid (1.1 mL) was added at room temperature and stirred at the same temperature for 3 hours. The reaction solution was concentrated under reduced pressure to give (3SR, 4RS)-N-methoxy-4-[2-(9-methoxy- 2,3-dihydro-1H-[1,4]] And [2,3-c]quinolin-1-yl)ethyl]piperidine-3-indolamine as a crude brown oil. The resulting (3311,4118)-:^-methoxy-4-[2-(9-methoxy-2,3-dihydro-1H-[1,4] ploughed [2,3 -c]Quinolin-1-yl)ethyl]piperidine-3-indolamine was dissolved in dichloromethane (10. OmL), and triethylamine (0.083 mL, 0.596 mmol) was added at room temperature. With cyclohexylacetaldehyde (50.0 mg, 0.397 mmol) and hydrogenated sodium triethoxyborohydride (84.0 mg, 0.397 x nmol), stirred at the same temperature for 64 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane. The organic layer was combined, dried over anhydrous sodium sulfate and filtered and evaporated. The obtained residue was purified by hydrazine gel column chromatography (dichloromethane: methanol = 49··1 - 19:1 - 9:1) to give 45.7 s - 3 88 - 200946528 g (4 5 ° / .) A labeled compound which is white amorphous. 1H-NMR (400MHz, CDC13) δ : 0.8 7 - 0.9 7 (2 Η, m), 1.13- 1.45(6Η, m), 1.5 8 - 1 . 7 2 (8 Η, m), 1.87(1Η, m ), 1.9 3 - 2.1 1 (3 Η, m), 2.37 (2Η, t, J = 7.4Hz), 2.59(1Η, brs), 3.00(1Η, brd, J=12.7Hz), 3.03(1Η, brd , J=13.7Hz), 3.14(1H, ddd, J = 2.4, 8.5, 14.2Hz), 3.20-3.26(2H, m), 3.44(1H, ddd, 5 = 2.2, 3.6, 14.2Hz), 3.80( 3H, s), 3.92(3H, s), 4.18(1H, ddd, J = 2.2, 8.3, 12.5Hz), 4.30(1H, dt, J = 2.4, 12.5Hz), 7.11(1H, d, Ο J = 2.7 Hz) 7.15 (1H, dd, J = 2.7, 9.0 Hz), 7.88 (1H, d, J = 9.0 Hz), 8.37 (1 H, s), 1 1.4 (1H, br). MS (ESI) m/z: 5 1 1 (M + H) + .

[Example 76] 1-(2-{1-[2-(2,2-difluorocyclohexyl)ethyl]piperidin-4-yl}ethyl)-9-methoxy-4-side oxygen -1,4-dihydrobenzo[h]-l,6-naphthalene-deep-3-acid

o 1-{2-[1-(Tertidinoxycarbonyl)piperidin-4-yl]ethyl}-9-methoxy-4-oxo-1,4-dihydrofurate obtained in Reference Example 39 a solution of benzo[h]-l,6-naphthyridin-3-carboxylic acid ethyl acetate (10 2 mg, 0.20 mmol) in dichloromethane (1 mL), trifluoroacetic acid (0.5 mL) Stir for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was evaporated. The combined extract was dried over anhydrous sodium sulfate, filtered, and then evaporated. The obtained residue was dissolved in 2,2-difluoro-389-200946528 cyclohexylacetaldehyde crude product (65 mg, 0.30 mmol) obtained in Reference Example 105, and dichloromethyl (imL) and methanol (0.2 mL). Sodium triethoxyborohydride (85 mg, 0.40 mmol) was added at room temperature and stirred at the same temperature for 16.5 hours. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (eluent gel, chloroform: methanol: triethylamine = 200:1:0:5) to afford ethyl ester of 31 mg of the title compound. Light yellow gum solid. To the obtained ester solution of methanol (〇. 6 mL) and tetrahydrofuran (〇. 6 mL), 1N aqueous sodium hydroxide solution (〇.3〇1^, 0_3〇111111〇1) was added and stirred at room temperature for 1 hour. . Add 1 equivalent of hydrochloric acid (〇.30mL, 0.30mm〇l) to the reaction solution, and distill off the solvent under reduced pressure to prepare a thin layer chromatography (矽 gel, chloroform:methanol:water=7:3:1 lower solvent) The residue obtained was purified to give 24 mg (2 3%) of the title compound as pale yellow powder. 1H-NMR (400MHz, CD3〇D) δ: 1.30(2Η, m), 1 · 5 0 - 2 · 0 5 (1 6 Η, m), 2.69(2H, m), 2.97(2H, m), 3.42(2H, m), 4.0 2 (3 H, s), 4.76(2H, m), 7.61(1H, m), 7.70(1H, m), 8.07(1H, m), 8.79(1 H, m ), 9.40 (1H, s). MS (ESI) m/z: 528 (M + H) + .

[Reference Example 149] 1-(2-{l-[trans-3-(2,5-difluorophenyl)propan-2-ene-1-yl]piperidin-4-yl}ethyl)- 9-Methoxy-4-oxo-l,4-dihydrobenzo[h]-l,6-naphthyridine-3-carboxylic acid ethyl ester

1-{2-[1-(Tertidinoxycarbonyl)piperidin-4-yl]-390- 200946528 ethyl}-9-methoxy-4-oxo-oxy-1,4 obtained in Reference Example 39 a solution of dihydrobenzo[h]-l,6-naphthyridin-3-carboxylic acid ethyl acetate (25 5 mg, 〇.50 mmol) in dichloromethane (2 mL) with trifluoroacetic acid (1 mL) ) 'Stir at room temperature for 1 hour. The solvent was distilled off under reduced pressure and the mixture was azeotroped twice with toluene.

The residue obtained was dissolved in trans-3-(2,5-difluorophenyl)propan-2-acid (84 mg, 0.50 mmol), triethylamine (0.14 mL, 1.00 mmol) and dichloromethane. In a mixed liquid of (5 mL) and methanol (1 mL), sodium hydrogen triacetate borohydride (212 mg, 1.0 mmol) was added at room temperature, and stirred at the same temperature for 40 hours. After adding water to the reaction mixture, it was extracted with a mixed solvent of chloroform:methanol = 9:1. The combined extract was dried over anhydrous sodium sulfate, filtered, and then evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol: 98:2 - 95:5) to yield 252 mg (90%) of the title compound as an orange gum gum solid. 1H-NMR (400MHz, CDC13) δ : 1.4 3 -1.4 6 (6 Η, m), 1.69- 1.72(2H, m), 1. 9 4 - 2.0 2 (4 H, m), 2.98(2H, m ), 3 · 1 6 (2H, d, J = 6.4Hz), 3.98(3H, s), 4.45(2H, q, J = 6.9Hz), 4.57(2H, t, J = 8.0Hz), 6.33( 1H, m), 6.63(1H, d, J = 16.0Hz), 6.88(1H, m), 6.99(1H, m), 7.13(1H, m), 7.53(1H, d, J = 9.2Hz), 7.57(1H, s), 8.20(1H, d, J = 9.2Hz), 8.53(1H, s), 9.67(1H, [Example 77] 1-(2-{1-[trans-3-( 2,5-Difluorophenyl)propan-2-en-1-yl]cycloazin-4-yl}ethyl)-9-methoxy-4-oxo-1,4-dihydrobenzo[ h]-1,6-naphthyridine-3-carboxylic acid-391- 200946528

1-(2-{1-[trans-3-(2,5-difluorophenyl)propan-2-en-1-yl]piperidin-4-yl}ethyl) obtained in Reference Example 149 -9-methoxy-4-oxo-1,4-dihydrobenzo[h]-l,6-naphthyridine-3-carboxylic acid ethyl ester (242 mg, 0.43 mmol) in methanol (2.6 mL) A solution of tetrahydrofuran (2.6 mL) was added 1N aqueous sodium hydroxide (1 - 29 mL, 1.29 mmol) and stirred at room temperature for 32 hr. 1N hydrochloric acid (1.29 mL, 1.29 mmol) was added to the reaction mixture, and the solvent was concentrated under reduced pressure, and the obtained aqueous residue was extracted with chloroform:methanol = 9:1 mixture solvent. The extract was combined and dried over anhydrous sodium sulfate. The obtained residue was purified by preparative thin layer chromatography (purine gel, chloroform:methanol:water = 7:3:1 under solvent) to afford 1 18 mg (5 1 %) of Yellow powder. 1H-NMR (400MHz, CDC13) δ:1·49(3Η, m), 1.75(2H, m), 2.03(2H, m), 2.13(2H, m), 3.02(2H, m), 3.20(2H , d, J = 6.4Hz), 4.01(3H, s), 4.70(2H, t, J = 8.0Hz), 6.35(1H, m), 6.65(1 H, d, J=16.0Hz), 6.89( 1H, m), 6.99(1H, m), 7.14(1H, m), 7.61(1H, dd, J = 9.2, 2.8Hz), 7.65(1H, d, J = 2.3Hz), 8.27(1 H, d, J = 9.2 Hz), 8.83 (1H, s), 9.66 (1H, s). MS (ESI) m/z: 5 3 4 (M + H) + .

[Example 78] 9-Methoxy-1-(2-{1-[2-(2-thienylthio)ethyl]piperidin-4-yl}ethyl)-2,3-dihydro- 1H-[1,4] 噚耕和[2,3-c]quinoline-392- 200946528

The 9-methoxy-1-(2-piperidin-4-ylethyl)-2,3-dihydro-111-[1,4]indole obtained in Reference Example 10 was [2,3-( :] porphyrin (7〇11^, 0.214111111〇1), 2-[(2-chloroethyl)thio]thiophene (60mg, 0.3 3 6mm〇l) dissolved in hydrazine, hydrazine-dimethylformamide (5 mL), potassium carbonate (90 mg, 0.651 mmol) and sodium iodide (20 mg, 0.133 mmol) were added at room temperature, and after stirring for 1 hour, the temperature was raised to 60 ° C 0 and stirred for 22 hours. Ethyl acetate and water were washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the column was subjected to column chromatography (the first time was ethyl acetate; the second time) It is purified by chloroform·methanol = 10:1). After dissolving in 1,4-dioxane (5 ml), 4 equivalents of hydrogen chloride / dioxane solution (0. 〇 5 mL) is added and the solution is filtered. The resulting solid was obtained as 29.8 mg (26%) of the title compound as the salt of the title compound as a yellow foamy solid. 1H-NMR (400 MHz, DMSO-d6) δ: 1 5 1 -1 · 6 7 (2 Η,m),ι .80-O 1.95(4H, m), 2.8 1 - 2.9 3 (2 H, m), 3.2 0 - 3.2 1 ( 4 H, m), 3.33-3.73 (7H, m), 3.95 (3H, s), 4.2 8 - 4.3 5 (2 H , m), 7.0 8 - 7.1 4 (1 H , m), 7.19-7.26 (1H, m), 7.2 9 - 7.3 4 ( 1 H , m), 7.5 0 - 7.5 6 ( 1 H, m), 7.71 (1H, dd, J = 5.4, 1.2 Hz), 7.9 5 - 8.0 5 ( 1 H, m), 8.60 ( 1 H, s) · MS (ESI) m/ z: 470 (M + H) + o &lt;Test Example&gt; Antibacterial Activity -393- 200946528 By following the guidelines of CLSI (Clinical Laboratory Standards Association): "M7-A7 aerobic dilution method is sensitive to antimicrobial drugs The test method; the approved standard, the seventh edition, the micro-liquid dilution method, measures the antibacterial activity of the compound of the present invention. The strain uses Staphylococcus aureus (s. Aureus) FDA209P strain. The results are shown in Table 1. [Table 1 Example No. MIC (pg/mL) 1 0.125 3 0.125 37 2 Industrial Applicability The compound (I) of the present invention has antibacterial activity against bacteria which are causes of various infectious diseases, and can treat, prevent or alleviate such diseases. A disease caused by a pathogen. Examples of the bacteria which are effective as the compound (I) of the present invention include Staphylococcus, Streptococcus pyogenes, Streptococcus hemolyticus, Enterococcus, Pneumococcal, Neisseria, Coliform citrobacter, Shigella ( Shigella), Klebsiella, Enterobacter, genus Serratia, Proteus, Pseudomonas aeruginosa, influenza, Acinetobacter, genus mycoplasma . Examples of the diseases caused by such pathogens include deciduous sputum, sputum, sputum, erysipelas, cellulitis, lymphangiogenesis, fingertip abscess, subcutaneous abscess, sweat gland inflammation, cluster acne, and infectivity. Superficial secondary infection of powder tumor, abscess around the anus, mastitis, trauma, thermal injury, surgical trauma, etc., throat pharyngitis, acute bronchitis, tonsillitis, chronic bronchitis, and bronchus -394-200946528 Symptoms, diffuse pan-bronchitis, secondary infections of chronic respiratory diseases, pneumonia, pyelonephritis, cystitis, prostatitis, epididymisitis, gonococcal urethritis, non-gonococcal urethritis, cholecystitis, cholangitis , bacterial red sputum, enteritis, uterine appendage inflammation, intrauterine infection, Badolin's gland inflammation, eyelid inflammation, stye, tendinitis, meibomitis, corneal ulcer, otitis media, paranasal inflammation, periodontitis, Periorbital inflammation, tendinitis, peritonitis, endocarditis, sepsis, meningitis, skin infections, etc. [Simple description of the diagram] 〇 No. [Main component symbol description] None. ❹ 395-

Claims (1)

200946528 VII. Patent application scope 1. A compound represented by formula (I), a pharmacologically acceptable salt thereof or a compound thereof, In the formula, X1 and X2 each independently represent a nitrogen atom or a carbon atom to which one hydrogen atom is bonded; Οχ3 represents a nitrogen atom or a formula CRla (wherein Rla represents a halogen atom, a cyano group, and a substitutable lower group) An alkane group or a group selected from the group of substituents α), X4 represents a nitrogen atom or a formula CRlb (wherein Rb represents a halogen atom, a cyano group, a lower alkyl alkane group which may be substituted or a group of substituents α The selected base), Ο Α1 represents the general formula CR2 (wherein R2 represents a bond with the bonding atom of the adjacent L1, or a bonding hand of the adjacent Α2 to form a double bond, a halogen atom , cyano or a group selected from the substituent group α) or a nitrogen atom, -396- 200946528 A2 represents a formula CR3R4 (wherein the substituents R3 and R4 each independently represent a combination of Al and the formula CR2 with Al The hand becomes a body, or a binding hand of A3 (A3 itself is a binding hand a4) forms a bond of a double bond, a halogen atom, a cyano group or a group selected from the substituent group α, or R3 and R4 are integrated to form a side oxygen (0Χ0) group or a substituted hydroxyimino group, NR5 (R5 represents a combination of a bond with Al when Al is a formula CR2) or a bond with A3 (A3 itself is a bond A4) a bond of a double bond, or a group selected from the substituent group α, an oxygen atom, or an oxidizable sulfur atom, Α3 represents a formula CR6R7 (wherein the substituents R6 and R7 are each independently represented and contiguous The binding hand of A2 or A4 is integrated to form a bond of 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 a substituted hydroxy group. Imino), Formula NR8 (wherein the substituent R8 represents a bond with a contiguous A2 or A4 which is a bond formed by the addition of -397-200946528 to form a double bond, or a group selected from the substituent group α) , an oxygen atom, an oxidizable sulfur atom or a bonding hand, Α4 represents a formula CR9R1 0 (wherein the substituents R9 and R1Q each independently represent a bonding hand with an adjacent Α3 (Α3 itself is a binding Α2) a bond that forms a double bond and a halogen atom a cyano group or a group selected from the substituent group α, or, r9, R1() are integrated to form a pendant oxy group or a substituted hydroxyimino group), and a formula NR11 (wherein the substituent R11 represents a combination of adjacent A3 (A3 itself is a binding to the hand A2) which forms a double bond, or a group selected from the substituent group α, an oxygen atom, or an oxidizable sulfur atom, L1 represents a general formula - γ^γ2. (wherein Υ1 represents a carbon atom bonded to Αι and may be substituted with a group selected from the substituent group ρ, and γ2 represents a bond with Q1 and may be selected from substitution a carbon atom substituted by a group of the group β, a nitrogen atom + 'oxygen atom which may be substituted with a group selected from the substituent group γ, or an oxidizable sulfur atom), and Q1 is a compound of the following formula (II) The 6-membered ring structure shown between L1 and L2 (* each -398-200946528 self-representing the combined hand), Z1 and z4 each independently represent the formula CR20 (wherein the substituent R2G means a halogen atom, a cyano group, a group selected from the substituent group α) or a nitrogen atom, and z2, z3, Z5 and Z6 each independently represent Cr21r22 (wherein the substituents R21 and R22 each independently represent a halogen atom, a cyano group, a group selected from the substituent group α, or R21 and R22 are integrated to form a pendant oxy group or a substituted hydroxy group. Amino group), L2 represents a formula - γ3-γ4-γ5- (wherein the Υ3 series is bonded to the Ζ4 bonded atom on Q1, which represents a side oxy group) and can be substituted by a group selected from the substituent group δ a carbon atom, a nitrogen atom which may be substituted with a group selected from the substituent group ε, an oxidizable sulfur atom or a bonding hand, Υ4 represents a bonding hand, or may be substituted by a group selected from the substituent group ζ And may form a multi-bond carbon atom with an adjacent carbon atom, and Υ5 represents a bonding hand, a carbon atom which may be substituted with a group selected from the substituent group ζ and which may form a multiple bond with an adjacent carbon atom, and may be selected from a nitrogen atom, an oxygen atom, or a -399-20094 substituted with a group of a substituent group ε 6528 is a sulfur atom which can be oxidized), and Q2 is a heterocyclic structure of a condensed two-ring type "6-membered ring/6-membered ring" represented by the following formula (III) or "6-membered ring/5 member ring j" or a single-ring structure with an atomic number of 5-7 (* indicates a binding hand with L2), ο ο Z8, Z9, ZlG, Z15, Z16, and Z17 each independently represent a carbon atom or a nitrogen atom which may be substituted with a group selected from the substituent group η and the lower alkoxy group which may be substituted, Ζ11, Ζ14, Ζ18, and Ζ2&lt;) each independently may be selected from a nitrogen atom, an oxygen atom, or an oxidizable sulfur atom substituted with a substituent of the substituent group 0. Further, these may also be adjacent to Ζ12, Ζ13 or Ζ19 form a double bond, and Ζ12, Ζ13, and Ζ19 each independently represent a carbon atom which may be substituted with a group selected from the substituent group η and the pendant oxy group, and may be selected from the group of substituents. a nitrogen atom, an oxygen atom, or an oxidizable sulfur atom substituted by a group 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, -400-200946528, a carbon atom which may be substituted with a group selected from the substituent group I, may be selected from the group of the substituent group K Substituted nitrogen atom, oxygen atom, or oxidizable sulfur atom, , these may also form a double bond with an adjacent atom; [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 which may be substituted or Heterocyclic group, protected or substituted hydroxy group, substituted lower alkoxy group, protected or substituted neck group, substituted fluorenyl group, protected carboxyl group, substituted amino group carbonyl group a lower alkylsulfonyl group which may be substituted, a lower alkylsulfonyl group which may be substituted, and an aminosulfonyl group which may be substituted; [Substituent group β]: a hydrogen atom, a halogen atom, a cyano group , a protected or substituted hydroxy group, a protected or substituted amine group, a protected carboxy group, a substituted aminocarbonyl group, a substituted lower alkyl sulfonyl group, a substituted amino sulfonate a mercapto group, a pendant oxy group, and a substituted hydroxyimino group; [Substituent group γ]: a hydrogen atom, a lower alkyl group which may be substituted, a lower alkyl alkane group which may be substituted, a substituted amino group a carbonyl group, a lower alkoxycarbonyl group which may be substituted, a lower alkyl sulfonyl group which may be substituted, and Aminosulfonyl group; [Substituent group δ]: a hydrogen atom, a lower alkyl group which may be substituted, a lower alkyl fluorenyl group which may be substituted, a protected carboxyl group, a substituted amino group, a lower alkyl sulfonyl group which may be substituted, and a substituted amine group -401-200946528 fluorenyl group; [Substituent group ε]: a hydrogen atom, a lower alkyl group which may be substituted, a lower alkyl group which may be substituted a mercapto group, a protected carboxyl group, a substituted aminocarbonyl group, a substituted lower alkylsulfonyl group, and a substituted aminosulfonyl group; [substituent group]: a hydrogen atom, a halogen An atom, a protected or substituted hydroxy group, a substituted lower alkoxy group, a pendant oxy group, and a substitutable hydroxyimino group; [Substituent group η]: a hydrogen atom, a halogen atom, and a lower alkyl group which may be substituted; [Substituent group Θ]: a hydrogen atom, a lower alkyl group which may be substituted, a hydroxyl group which may be protected or substituted, and Substituted lower alkoxy; [Substituent group hydrogen atom, halogen atom, lower alkyl group which may be substituted, lower alkenyl group which may be substituted, hydroxyl group which may be protected or substituted, lower alkoxy group which may be substituted a cyano group, a protected pendant oxy group, a substituted hydroxyimino group, a protected carboxy group, a substituted amino group, and a protected or substituted amine group; κ]: 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, a substituted aminocarbonyl group, Substituted aminosulfonic acid groups, and lower alkylsulfonyl groups which may be substituted. 2. A compound as claimed in claim 1 or a pharmacologically acceptable salt thereof, wherein X1 is a nitrogen atom. 3. The compound of claim 1 or a pharmacologically acceptable salt thereof, wherein X4 is CH in -402-200946528. 4. A compound according to any one of claims 1 to 3, wherein the A1 is a nitrogen atom, or a pharmacologically acceptable salt thereof. 5. A compound according to any one of claims 1 to 3, wherein the A4 is an oxygen atom, or a pharmacologically acceptable salt thereof. 6. A compound according to any one of claims 1 to 3, wherein the A1 is a nitrogen atom and the A4 is an oxygen atom, or a pharmacologically acceptable salt thereof. 7. The compound of any one of claims 1 to 6 or a pharmacologically acceptable salt thereof, wherein the formula (la) is a partial structure of the formula (I): The three-ring structure shown is of the following formula (* represents the binding hand to L1; X2, Rla, Rlb, R5, R8 and R11 are the same as defined in the formula (I)), and: -403 - 200946528 8. A compound according to any one of claims 1 to 7, which is a pharmacologically acceptable salt or a hydrate thereof, wherein L1 is -CH2CH2-, _CH2_C(=0), and -CH2-CH = Or -ch2-c(_oh)(-cooh)·. 9. The compound of any one of claims 1 to 8 or a pharmacologically acceptable salt thereof, wherein Q1 is a 6-membered ring structure between L1 and L2 represented by the following formula (IV) (wherein R23 and R24 each independently represent a hydrogen atom and a hydroxyl group. a group, a methoxy group, a carboxyl group, an aminocarbonyl group, an N-(methoxy)aminocarbonyl group, an N-(methylsulfonyl)aminocarbonyl group or a pendant oxy group; 10. The compound of any one of claims 1 to 9 or a pharmacologically acceptable salt thereof, wherein L2 is -ch2-ch2-, -CH2-CH = CH., -ch2-C(=0)- NH-, -CH2CH2-S-, -NH-CH2-, -CH2-CH(- OCOCH3)-, -CH2-CH(-OH)- &gt; -CH2-C(= O)-, -C( = 0)- -404- 200946528 CH = CH- or -CH2-CH=. 11. A compound according to any one of claims 1 to 10, wherein the Q2 is 3-oxo-oxy 3,4-dihydro-2H-pyrido[3,2-b], or a pharmacologically acceptable salt thereof. [l,4] Df-trap-6-yl, cycloheptyl, cyclohexyl, 1-hydroxycyclohexyl, 1-methylsulfonylaminocyclohexyl, 1-cyanocyclohexyl, 2-oxocyclohexyl , 1,4-Dioxaspiro[4.5]dec-6-yl, 2-hydroxyiminocyclohexyl, 2-methoxyiminocyclohexyl, 3-oxocyclohexyl, 1,4- 2 • '-V .'. ·* Oxospiro[4.5]癸-7-yl, 2,2-difluoro-domain 2-fluoro-1-cyclohexenyl, 2-methylene (methylidene) cyclohexyl , trans-2-hydroxycyclohexyl, cis-2-hydroxycyclohexyl, trans-2-methoxycyclohexyl, cis-2-methoxycyclohexyl, 2-tetrahydropyranyl, 2 - oxo-1-piperidinyl, cyclopentyl, 2-oxocyclopentyl, 2-thienyl, 3-fluorophenyl or 2,5-difluorophenyl. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof. 13. The use of a compound according to any one of claims 1 to 3, or a pharmacologically acceptable salt thereof, for use in the manufacture of a medicament. An antibacterial agent which comprises a compound according to any one of claims 1 to 11 or a drug thereof, 'if*: a permissible salt. A therapeutic agent for an infectious disease, which comprises a compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof. -405- 200946528 IV. Designation of Representative Representatives: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the representative figure: Μ 〇 j\w Ο 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: