TW201412749A - Amino group-containing pyrrolidinone derivative - Google Patents

Abstract

To provide a drug having excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria and also being excellent in terms of safety. A compound represented by the following formula (I) or a salt thereof: wherein R represents hydrogen atom; m represents an integer of 1 or 2; n represents an integer of 0 or 1 Ar1 represents a bicyclic heterocyclic group represented by the following formula: wherein: Aa represents nitrogen; Ab and Ac represent CH; R1 represents a methoxy group, a difluoromethoxy group, a halogen atom, or a cyano group; R2represents a hydrogen atom or a halogen atom; Ar2 represents a bicyclic heterocyclic group represented by the following formula.

Description

Amino-containing pyrrolidone derivative

The present invention relates to a novel compound which is excellent in antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, and which is excellent in safety, a salt thereof or a hydrate thereof, and an antibacterial agent containing the same.

To date, various antibiotics and synthetic antibacterial agents have been used in the medical field to treat infectious diseases. However, in recent years, resistant bacteria have emerged, such as anti-xylene penicillin Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), anti-penicillin Streptococcus pneumoniae (PRSP), anti-quinolinone Escherichia coli , (Carbapenems) resistant K. pneumoniae, or multiple drug resistant Pseudomonas aeruginosa. Because these bacteria are resistant to many existing antibiotics and antibacterial agents, the treatment of patients infected with these bacteria has become a global issue.

Accordingly, there is a need to develop different types of antibacterial agents having structures different from those of existing antibacterial agents.

As for the different kinds of antibacterial compounds per se, a group of compounds having two aromatic rings which may be a heterocyclic ring and including a heterocyclic ring which is a structural moiety linking these aromatic rings to each other is known, for example. Oxazolidinone (see, for example, Patent Documents 1 to 13). However, it is considered that compounds having such a structure must be improved in safety for use in the therapeutic field. With respect to the above compounds, there is currently no known compound having a structure in which pyrrolidone is contained in a linking structure of a diaromatic ring.

Reference list

Patent document

[Patent Document 1] International Publication No. WO 2002/50040

[Patent Document 2] International Publication No. WO 2004/50036

[Patent Document 3] International Publication No. WO 2008/26172

[Patent Document 4] International Publication No. WO 2008/126024

[Patent Document 5] International Publication No. WO 2008/126034

[Patent Document 6] International Publication No. WO 2009/77989

[Patent Document 7] International Publication No. WO 2009/104147

[Patent Document 8] International Publication No. WO 2009/104159

[Patent Document 9] International Publication No. WO 2010/15985

[Patent Document 10] International Publication No. WO 2010/41194

[Patent Document 11] International Publication No. WO 2010/41218

[Patent Document 12] International Publication No. WO 2010/41219

[Patent Document 13] International Publication No. WO 2013/21363

There is a need to develop a pharmaceutical agent that exhibits broad and powerful antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, and drug-resistant bacteria, and has excellent safety.

According to the results of the present invention, the inventors have found a compound represented by the formula (I), a salt thereof, or a hydrate thereof, which has two heteroaryl groups at both ends of the molecule, and The pyridyl ketone is included in the structural moiety in which the groups are linked to each other, and thus exhibits broad and strong antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, and has excellent safety, thereby achieving the present invention.

In particular, the invention of the present application includes the following [1]:

[1] A compound represented by the following formula (I) or a salt thereof: Wherein R represents a hydrogen atom; m represents an integer of 1 or 2; n represents an integer of 0 or 1; and Ar ¹ represents a bicyclic heterocyclic group represented by the following formula: R ¹ represents a methoxy group, a difluoromethoxy group, a halogen atom, or a cyano group; R ² represents a hydrogen atom or a halogen atom; A ^a represents nitrogen; A ^b and A ^c represent CH; and Ar ² represents represented by the following formula; Bicyclic heterocyclic group: [Formula 3]

Further, the invention of the present application includes the following [2] to [11].

[2] The compound according to [1] or a salt thereof, wherein the sum of m and n is 1, 2 or 3.

[3] according to [1] or [2] The compound or a salt thereof, wherein, R ¹ stands methoxy.

[4] The compound according to [1] or [2] or a salt thereof, wherein R ¹ represents a difluoromethoxy group.

[5] The compound according to [1] or [2] or a salt thereof, wherein R ¹ represents a cyano group.

[6] The compound according to [1] or [2], wherein R ¹ and R ^{2 each} represent a halogen atom, or a salt thereof.

[7] The compound according to [1] or [2], wherein R ¹ and R ^{2 each} represent a fluorine atom, or a salt thereof.

[8] A compound according to [1] or a salt thereof, which is selected from the group consisting of 3-oxo-4-(3-{[(3R)-5-sideoxy-1-(3-oxo-3), 4-dihydro-2H-pyrido[3,2-b][1,4] -6-yl)pyrrolidin-3-yl]amino}propyl)-3,4-dihydroquine Benzene-6-carbonitrile; 3-oxo-4-[3-({[(3R)-5-sideoxy-1-(3- side oxy-3,4-dihydro-2H-pyrido[3] ,2-b][1,4] -6-yl)pyrrolidin-3-yl]methyl}amino)propyl]-3,4-dihydroquine Benzene-6-carbonitrile; 6-[(4R)-4-({3-[7-(difluoromethoxy)-2-oxoquine Porphyrin-1(2H)-yl]propyl}amino)-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4] -3(4H)-one; 6-[(4R)-4-[({3-[7-(difluoromethoxy)-2-oxyquine Porphyrin-1(2H)-yl]propyl}amino)methyl]-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4] -3(4H)-one; 6-[(4R)-4-{[4-(6,7-difluoro-2-oxoquine Porphyrin-1(2H)-yl)butyl]amino}-2-oxopyrrolidin-1-yl]-3,4-dihydro-2H-pyrido[3,2-b][1,4] 2-ketone; 6-[(4R)-4-{[4-(7-methoxy-2-oxoquine) -1(2H)-yl)butyl]amino}-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4] -3(4H)-one; and 6-[(4R)-4-{[4-(7-difluoromethoxy-2-oxoquine) -1(2H)-yl)butyl]amino}-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4] -3(4H)-one.

[9] An agent comprising the compound according to any one of [1] to [8] or a salt thereof as an active ingredient thereof.

[10] A therapeutic agent for infectious diseases comprising the compound according to any one of [1] to [8] or a salt thereof as an active ingredient thereof.

[11] A method for treating an infectious disease, which comprises administering a compound according to any one of [1] to [8] or a salt thereof.

The compound of the invention of the present application, a salt thereof, or a hydrate thereof, that is, has two heteroaryl groups at both ends of the molecule, and pyrrolidone is included in the structural moiety in which these groups are linked to each other. A compound that exhibits broad and powerful antibacterial activity against Gram-positive and Gram-negative bacteria with excellent safety. Accordingly, the compounds of the present invention are expected to exhibit excellent effects in the treatment and/or prevention of infectious diseases and are therefore useful.

The compound having the structure (I) includes a bicyclic aromatic heterocyclic substituent (heteroaryl group; in the present invention, each may be simply referred to as Ar ¹ or Ar ² ), and the two heteroaryl groups at both ends of the molecule. It is connected by a substructure unit containing a pyrrolidinone group.

In the case of Ar ¹ , this would contain a guanamine structure at its 1 and 2 positions, which is a cyclic guanamine structure having a 2-sided oxy group. The nitrogen atom in the indoleamine structure is a position to which Ar ² is bonded.

In the case of Ar ² , this includes a cyclic guanamine structure in which the guanamine structure is composed of a 3-sided oxy group at positions 3 and 4. Ar ² is directly attached to the pyrrolidone moiety present in the linking moiety at the 6 position, and further to the nitrogen atom of the pyrrolidone (the calculation of these position numbers is based on A ^{a in} Ar ¹ A ^c is CH and when Ar ² is 1,4-benzene Structure).

Further, Ar ¹ has a substituent R ¹ and R ² , wherein R ¹ represents a methoxy group, a difluoromethoxy group, a halogen atom, or a cyano group; and R ² represents a hydrogen atom or a halogen atom. When R ¹ or R ² is a halogen atom, a chlorine atom or a fluorine atom is preferred, and a fluorine atom is more preferred.

Next, a structure in which Ar ¹ and Ar ^{2 are} connected to each other will be described.

One of the compounds of the present invention is characterized in that the structure comprises pyrrolidone. The pyrrolidone is preferably 2-pyrrolidone. The preferred structure of the pyrrolidone is that Ar ² is attached to the nitrogen atom of the structure. Further, Ar ¹ is bonded to the structure at one carbon atom of the pyrrolidone ring via another linking moiety. On the 2-pyrrolidone ring, the linking position to the linking portion of Ar ¹ is preferably the fourth position. Further, depending on the mode of attachment at the 4th position of the pyrrolidone, two isomers may be produced, and all such isomers are included in the present invention.

The linking portion to Ar ¹ is characterized in that it contains an amine group. Preferably, the amine group is attached directly to the 4th position of the 2-pyrrolidone or via a methylene group. The linking moiety from this amine group to Ar ¹ is composed of a methylene chain containing 3 to 4 carbon atoms.

Therefore, the following structure is constituted: Ar ¹ -CH ₂ -CH ₂ -CH ₂ -NH-(2-pyrrolidone-1-Ar ² -4-yl)Ar ¹ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -NH-(2-pyrrolidone-1-Ar ² -4-yl)Ar ¹ -CH ₂ -CH ₂ -CH ₂ -NH-CH ₂ -(2-pyrrolidone-1-Ar ² -4- Yl) Ar ¹ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -NH-CH ₂ -(2-pyrrolidone-1-Ar ² -4-yl)[(2-pyrrolidone-1-Ar ² -4-yl) indicates that the fourth position is the position of attachment of the 2-pyrrolidone, and the position of Ar ^{2 in} combination with 2-pyrrolidone is in the first position]

The present invention includes the following compounds, but is not limited: 3-oxo-4-(3-{[(3R)-5-oxo-l-(3-oxo-3,4-dihydro-2H-pyridine) And [3,2-b][1,4] -6-yl)pyrrolidin-3-yl]amino}propyl)-3,4-dihydroquine Benzene-6-carbonitrile; 3-oxo-4-[3-({[(3R)-5-sideoxy-1-(3- side oxy-3,4-dihydro-2H-pyrido[3] ,2-b][1,4] -6-yl)pyrrolidin-3-yl]methyl}amino)propyl]-3,4-dihydroquine Benzene-6-carbonitrile; 6-[(4R)-4-({3-[7-(difluoromethoxy)-2-oxoquine Porphyrin-1(2H)-yl]propyl}amino)-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4] -3(4H)-one; 6-[(4R)-4-[({3-[7-(difluoromethoxy)-2-oxyquine -1(2H)-yl]propyl}amino)methyl]-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4] -3(4H)-one; 6-[(4R)-4-{[4-(6,7-difluoro-2-oxoquine Porphyrin-1(2H)-yl)butyl]amino}-2-oxopyrrolidin-1-yl]-3,4-dihydro-2H-pyrido[3,2-b][1,4] 2-ketone; 6-[(4R)-4-{[4-(7-methoxy-2-oxoquine) -1(2H)-yl)butyl]amino}-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4] -3(4H)-one; 6-[(4R)-4-{[4-(7-difluoromethoxy-2-oxoquine) -1(2H)-yl)butyl]amino}-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4] -3(4H)-one, its salt or its solvate.

Next, a method for producing the compound of the present invention will be described.

The compound represented by the formula (1) of the present invention (abbreviated as Compound 1, and other structural compounds having different numbers are also abbreviated in the same manner) is produced by various methods. For example, it can be produced by the following method.

For example, the compound represented by the formula (1) of the present invention can be produced by performing a reductive alkylation reaction (reductive amination reaction) between the compound 2 as an aldehyde compound and the compound 3 as an amine compound. (plan 1). That is, as long as the imine compound or the iminium compound is reduced as it is produced from the reaction between the compound 2 and the compound 3, it can be converted into the compound 1. The reaction can be carried out in a one-pot reaction or a stepwise reaction.

This reaction can be carried out by the method described by John Wiley & Sons Co., Ltd., Advanced Organic Chemistry, 4th Edition (written by Jerry March), pages 898-900, or by et al. Implemented by the method of righteousness. As the reducing agent used in this reaction, a hydrogenated complex compound can be preferably used. The boron-containing compound is suitable as such a hydrogenated complex compound, and such a boron-containing compound includes, for example, sodium borohydride, sodium triethoxysulfonate borohydride, and sodium cyanoborohydride. Further, it is preferred to use a catalytic reaction using a metal catalyst such as palladium carbon, nickel stellate, platinum oxide or palladium black. The reduction using the hydroboration-containing compound can be carried out simply as a reduction reaction, and therefore it is preferred to use this reaction.

Regarding the reaction temperature, both the imine/imine oxime formation reaction and the reduction reaction can be carried out at a temperature ranging from -100 ° C to 150 ° C, preferably between -20 ° C and 50 ° C.

As desired, the various functional groups of compounds 2 and 3 can be protected by a suitable protecting group during this reaction. Such a functional group is deprotected after completion of the reaction, and therefore, the compound can be induced to the compound 1.

Further, the compound 1 can also be reacted by reacting the compound 5 with the compound 4 having a leaving group, and in the amine group of the pyrrolidone compound. It was prepared by performing an alkylation reaction as described below (Scheme 2).

This reaction can be carried out by the method described by John Wiley & Sons Co., Ltd., Advanced Organic Chemistry, 4th Edition (written by Jerry March), pages 411-413 and 425-427. Or by the method described in pages 353-359 of Chemical Communications published in 2004, or by equivalent methods. This reaction is usually carried out in the presence of a base. Examples of useful bases include: inorganic bases such as potassium carbonate or cesium carbonate; organic bases such as triethylamine or N,N-diisopropylethylamine; and sodium hydride, lithium N,N-diisopropylamine, and hexamethyl Lithium hexamethyldisilazide, hexamethyldiazoxide sodium and hexamethyldiazoxide.

This reaction can be carried out at a temperature ranging from -100 ° C to 250 ° C, preferably between -20 ° C and 150 ° C.

P ¹ may be hydrogen or a protecting group. Examples of such protecting groups include: aralkyl type protecting groups such as benzyl, benzhydryl and trityl; sulfhydryl (alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, etc.) type protecting groups , for example, a mercapto group, a trifluoroethenyl group, and a trichloroethenyl group; an alkoxycarbonyl- and an aralkoxycarbonyl-type protecting group, such as a benzyloxycarbonyl group and a third butoxycarbonyl group; and other protecting groups For example, toluenesulfonyl, p-nitrophenylsulfonyl, tert-butylsulfinyl and sulfo groups. After the current alkylation reaction is completed, such a protecting group is removed under appropriate conditions, and thus, the compound can be induced to the compound 1. Examples of the leaving group L ¹ include a leaving group such as a methylsulfonyloxy group, a toluenesulfonyloxy group, a trifluoroacetoxy group, and a trifluoromethanesulfonyloxy group, and a halogen atom.

As desired, the various functional groups of compounds 4 and 5 can be protected by a suitable protecting group during this reaction. In this case, such a functional group is deprotected after completion of the reaction, and therefore, the compound can be induced to the compound 1.

Further, the compound 1 can also be produced by carrying out a cross-coupling reaction between the indoleamine compound 6 and the compound 7, and thus an aromatic ring is introduced onto the nitrogen atom of the indoleamine compound (Scheme 3).

This reaction can be performed by Elsevier Co., Ltd. (Strategic Applications of Name Reactions in Organic Synthesis) (edited by L. Kuerti et al.), 70-71, WILEY-VCH Verlag GmbH & Co., the second edition of the KGaA Publishing Company published in 2004, Metal-Catalyzed Cross-Coupling Reactions (Edited by Armin de meijere et al), Volume 2, 699-760 The method described in the page, or the Journal of The American Chemical Society, Vol. 124, No. 25, pp. 7421-7428, 2002, or by an equivalent method.

X ¹ may be tosyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy or the like, and may be a halogen atom such as chlorine, bromine or iodine.

As desired, the various functional groups of compounds 6 and 7 can be protected by a suitable protecting group during this reaction. After completion of the reaction, such a functional group is deprotected, and therefore, the compound can be induced to the compound 1.

This coupling reaction can be carried out in the presence of a catalyst compound composed of a metal atom and a ligand compound. Examples of such a metal constituting the catalyst include palladium and copper. These metals may be added to the reaction in the form of palladium (II) acetate, dibenzylideneacetone dipalladium (0), copper (I) iodide or the like. When the catalyst metal is exemplified as palladium, the ligands constituting the catalyst compound include BINAP and S-Phos. When the catalyst metal is exemplified by copper, the ligand constituting the catalyst compound includes N,N'-dimethylethylenediamine and trans-1,2-cyclohexanediamine. The catalyst compound can be prepared by mixing a catalytic metal and a ligand compound before the start of the reaction. Alternatively, the catalyst metal and the ligand compound may be separately added to the reaction mixture so that a catalyst compound may be produced in the reaction mixture. This coupling reaction is preferably carried out in the presence of a base and the catalyst compound. Examples of useful bases include inorganic bases such as potassium carbonate, cesium carbonate and potassium phosphate.

This reaction can be carried out at a temperature ranging from 0 ° C to 250 ° C, preferably between 50 ° C and 150 ° C.

Furthermore, the cross-coupling reaction may also be carried out between the compound 6 and the compound 8 having a single ring structure, replacing the compound 7 having a fused ring structure, and the functional groups R11 and R12 are subsequently converted, thereby constructing a fused ring structure, and then the compound Compound 1 is introduced (Scheme 4, wherein A ^d is N). R11 may be a nitro group, a halogen atom or the like, which may then be converted to an amine group. R12 can be, for example, hydrogen, a suitable protecting group, an alkoxycarbonylmethyl group or the like. For example, when R11 is a nitro group and R12 is an alkoxycarbonylmethyl group, the compound can be converted to the compound 1 by performing heat treatment in the presence of iron/acetic acid or by catalytic reduction reaction.

Further, the compound 1 can also be obtained by subjecting the compound 9 to the reaction with the compound 10 to carry out an alkylation reaction on the nitrogen atom of the cyclic guanamine, as described below (Scheme 5).

This reaction can be advanced organic by John Wiley & Sons Co., Ltd. in 1991. Chemistry) The method described in the fourth edition (written by Jerry March) on pages 425-427, or an equivalent method.

This reaction can be carried out in the presence of a base. Examples of the usable base include: an inorganic base such as potassium carbonate, cesium carbonate or potassium phosphate; an organic base such as triethylamine or N,N-diisopropylethylamine; and sodium hydride, lithium N,N-diisopropylamine, Lithium hexamethyldiazoxide, sodium hexamethyldiazoxide, and potassium hexamethyldisodium.

This reaction can be carried out at a temperature ranging from -100 ° C to 200 ° C, preferably between -20 ° C and 150 ° C.

Examples of the leaving group L ² include a leaving group such as a methylsulfonyloxy group, a toluenesulfonyloxy group, a trifluoroethenyl group, and a trifluoromethanesulfonyloxy group, and a halogen atom.

The various functional groups of compounds 9 and 10 can be protected by a suitable protecting group during this reaction. In this case, such a functional group is deprotected after completion of the reaction, and therefore, the compound can be induced to the compound 1.

Further, when n = 1, the compound 1 can be produced by carrying out a reductive alkylation reaction (reductive amination reaction) between the compound 11 as an amine compound and the compound 12 as an aldehyde compound, as described below. Further, the compound 1 can also be produced by an alkylation reaction between the compound 13 protected by the protective group P ² and the compound 14 having the leaving group L ³ (Scheme 6). This reductive alkylation reaction (reductive amination reaction) can be carried out by the same method as the production of the compound 1 from the above compound 2 and the amine compound 3. Further, the amination reaction is carried out by the same method as the production of the compound 1 from the compound 4 and the compound 5. Here, P ² may be hydrogen, and it may also be an aralkyl type protecting group such as a benzyl group, a diphenylmethyl group or a trityl group; a fluorenyl type protecting group such as a formazan group or a trifluoroacetic acid group. And trichloroethenyl; alkoxycarbonyl- and aralkyloxycarbonyl-type protecting groups, such as benzyloxycarbonyl and tert-butoxycarbonyl; and other protecting groups such as toluenesulfonyl, p-nitro Benzosulfonyl, tert-butylsulfinyl and sulfo groups. Upon completion of the current alkylation reaction, such a protecting group will be removed under appropriate conditions so that the compound can be induced to the compound 1. Examples of the leaving group L ³ include a leaving group such as a methylsulfonyloxy group, a toluenesulfonyloxy group, a trifluoroacetoxy group, and a trifluoromethanesulfonyloxy group, and a halogen atom.

As desired, the various functional groups of compounds 11, 12, 13 and 14 can be protected by a suitable protecting group during this reaction. Such a functional group is deprotected after completion of the reaction, and therefore, the compound can be induced to the compound 1.

Further, the compound can be obtained by a reaction between the compound 15 as an oxirane compound and the compound 16 as an amine compound protected by a protecting group P ³ as described below (Scheme 7). This reaction can be performed by the method described on page 416 of Advanced Organic Chemistry, 4th edition of Advanced Organic Chemistry, published by John Wiley & Sons, Inc. in 1991, or by equivalent The method is implemented.

This reaction can be carried out in the presence or absence of a suitable solvent. In addition, suitable reagents are added to the reaction system. Solvents include: alcohols such as methanol, ethanol and isopropanol; ethers such as tetrahydrofuran, 1,4-two Alkanes and 1,2-dimethoxypropane; aromatic hydrocarbons such as toluene and benzene; esters such as ethyl acetate; water; N,N-dimethylformamide; and acetonitrile. Further, these solvents may also be used in the form of a mixed solvent. Examples of the reagent which can be added to the reaction system include: Brinell, such as hydrochloric acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid; a base such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate, and cesium carbonate; a Lewis acid such as four Lithium fluoroborate, lithium perchlorate, cerium (III) triflate, cerium (III) chloride and zinc (II) chloride; and strong bases such as sodium hydride, lithium diisopropylamide, hexamethyl Nitrogen lithium, hexamethyldiazoxide sodium, hexamethyldiazepine potassium and P4-phosphazene.

This reaction can be carried out at a temperature ranging from -100 ° C to 200 ° C, preferably between -80 ° C and 150 ° C.

Here, P ³ may be hydrogen, and it may also be an aralkyl type protecting group such as benzyl, diphenylmethyl or trityl; fluorenyl protecting group such as formazan or trifluoroacetate And trichloroethenyl; alkyl- or aralkoxycarbonyl-type protecting groups, such as benzyloxycarbonyl or tert-butoxycarbonyl; and other protecting groups such as toluenesulfonyl, p-nitrobenzenesulfonate Mercapto, tert-butylsulfinyl or sulfo group. After the current reaction is completed, such a protecting group is removed under appropriate conditions, and thus, the compound can be induced to the compound 1.

As desired, the various functional groups of compounds 15 and 16 can be protected by a suitable protecting group during this reaction, such functional groups being deprotected upon completion of the reaction, and thus, the compound can be induced to compound 1.

The hydroxyl group present in this compound can be converted to a methylene group by a suitable known synthetic organic chemical method.

Next, a method of producing each of the synthetic intermediate compounds will be described.

[Compound 2]

Compound 2 can be produced by the method described in International Publication No. WO 2009/104159, or by an equivalent method, for example (Scheme 8). That is, for example, a compound in which a mercapto group is protected by a protecting group (for example, dimethyl acetal) and a compound 9 are subjected to an alkylation reaction, and then the carbenyl-protecting group is subjected to an alkylation reaction. The obtained Compound 18 was removed to give the Compound 2. The leaving group L ⁴ may be a halogen atom or may be a leaving group such as a methylsulfonyloxy group, a toluenesulfonyloxy group, a trifluoroacetoxy group or a trifluoromethanesulfonyloxy group.

Further, the compound 19 in which the hydroxyl group is protected by the protecting group P ⁴ and the compound 9 are subjected to a monoalkylation reaction. Thereafter, the protecting group P ^{4 is} then removed from the obtained compound 20, and the hydroxyl group is oxidized to a monomethyl group, thereby producing the compound 2. As desired, the various functional groups of compounds 9, 17, 18, 19 and 20 can be protected by appropriate protecting groups during these reactions. The protection base can be removed at an appropriate stage.

Further, for example, the alkylation reaction of the compound 9 is carried out by the compound 21, 23 and an analog thereof which is an unsaturated compound. Thereafter, hydroboration/oxidation is carried out on the unsaturated bond of the obtained compound 22, or a reaction such as conversion to diol/oxidative fission is carried out on the compound 24, and therefore, the compound 2 can also be produced (Scheme 9). Here, each of R13 and R14 may be hydrogen, an alkyl group or the like. As desired, the various functional groups of compounds 9, 21, 22, 23 and 24 can be protected by appropriate protecting groups during these reactions, while the protecting groups can be removed at an appropriate stage.

[Formula 12]

The compound 9 in the scheme 9 can be produced by a method described in International Publication No. WO2006/134378, International Publication No. WO2006/137485, International Publication No. WO2009/1126, or the like, or by an equivalent method.

Some of the compounds 17, 19, 21 and 23 are commercially available, and thus they can be used. In addition, non-commercially available compounds can be produced by synthetic organic chemistry methods generally known.

[Compound 3]

Compound 3 can be produced by performing a cross-coupling reaction between Compound 25 and Compound 8, and then converting the functional groups R11 and R12 of Compound 26 obtained. Alternatively, the compound 3 can be produced by performing a cross-coupling reaction between the compound 25 and the compound 7 (Scheme 10). Here, each of the protecting groups P ⁵ and P ⁶ may be hydrogen or a protecting group. When they are protecting groups, they can be removed at the appropriate stage. As the reaction conditions for these cross-coupling reactions, the same reaction conditions as those for the production of the compound 1 from the compounds 6 and 7 or the reaction conditions for the production of the compound 1 from the compounds 6 and 8 are also applicable. As desired, the various functional groups of compounds 7, 8, 25 and 26 can be protected by appropriate protecting groups during these reactions, while the protecting groups can be removed at an appropriate stage.

Compounds 7 and 8 can be produced by the methods described in International Publication No. WO2010/41194, International Publication No. WO2007/118130, International Publication No. WO2007/16610, etc., or by equivalent methods.

When n = 0 (compound 28), compound 25 is commercially available, and the compound 28 can also be produced by the method described in International Publication No. WO 2004/022536. Alternatively, the compound 25 can also be induced from commercially available 4-hydroxy-2-pyrrolidone derivatives, such as, for example, Compound 27 (Scheme 11). In particular, a series of reactions, such as methanesulfonation, azide, and reduction of an azide group, can be carried out on compound 27, and thus, can be induced to compound 28. Where appropriate, the indoleamine moiety of the commercially available 4-hydroxy-2-pyrrolidone derivative used as a starting material can be protected, and such a protecting group can be removed at an appropriate stage. Further, the 4-hydroxy-2-pyrrolidone derivative may be an optically active substance, and the optically active compound 1 can be produced by using the optically active substance. Further, the compound 28 can be synthesized from the compound 29 as the main amine and the itaconic acid 30, and then carboxylated. The base is converted to an amine group. As desired, the various functional groups of compounds 28, 29, 30 and 31 can be protected by appropriate protecting groups during these reactions. The protecting group can be removed at an appropriate stage.

As such a compound 29, it is preferred to use 4-methoxyaniline or benzylamine in which the P ⁷ moiety acts as a protecting group which can be removed later, or optically active 1-phenylethylamine, 1-(4-A) Oxyphenyl) ethylamine and the like. Further, with such an optically active compound of the compound 29, a stereoisomer can be easily isolated at a stage of, for example, a compound 31, an ester compound or the like according to the stereo configuration of the 4th position of the pyrrolidone. . Even in the case where the compound used is not optically active, the stereoisomer can be separated by column chromatography using a column capable of separating optical isomers. In order to synthesize compound 31 from compounds 29 and 30, a mixture of compounds 29 and 31 is heated, or such a compound is heated together with a suitable solvent such as benzene, toluene, water or alcohol. During such processing, a suitable catalyst, such as toluenesulfonic acid, may coexist. In addition, when a Dean-Stark device or the like is utilized, water generated by the reaction can be removed. The carboxyl group of compound 31 can be converted to an amine group, for example, by performing a series of reactions such as acid azide synthesis/Curtius rearrangement/urethane synthesis (using benzyl alcohol and tert-butanol) Benzyloxycarbonyl protection, or synthesis of Boc protected amine groups) / deprotection. In addition, after the carboxyl group has been converted to the guanamine group, it can be converted to an amine group by Huffman rearrangement or the like. For example, when the P ⁷ group is 4-methoxyphenyl, 1-(4-methoxyphenyl)ethyl or the like, deprotection can be carried out by using cerium (IV) diammonium nitrate or the like. Under the conditions, or under acidic conditions using trifluoroacetic acid or the like, or under other conditions. When it is a benzyl group, a 1-phenylethyl group or the like, deprotection can be carried out under reducing conditions for Birch reduction or the like.

Compound 25 is commercially available when n = 1 (compound 33). Alternatively, the compound 25 can also be induced from commercially available 4-(hydroxymethyl)-2-pyrrolidone derivatives, such as compound 32, for example (Scheme 12). In particular, a series of reactions such as methanesulfonation, azide, and reduction of an azide group can be carried out on the compound 32, and thus, it can be induced to the compound 33. The indoleamine moiety of the commercially available 4-(hydroxymethyl)-2-pyrrolidone derivative, which is used as a starting material, may be protected, if appropriate, and such a protecting group may be removed at an appropriate stage. Further, the 4-(hydroxymethyl)-2-pyrrolidone derivative may be an optically active substance, and the optically active compound 1 can be produced by using the optically active substance. Compound 32 is commercially available, and it can also be obtained by synthesizing Compound 31 from Compound 29 as the main amine and itaconic acid 30, followed by reduction of the carboxyl group. The reduction reaction can be carried out under the usual reduction conditions for converting a carboxyl group to a methylol group, or the carboxyl group can also be carried out by a carboxylate compound. Restored as a medium.

Further, the compound 3 can be produced by performing a cross-coupling reaction between the protected hydroxy compound 34 and the compound 7 or the compound 8, and then converting the hydroxy group to an amine group at an appropriate stage (Scheme 13). Here, the protecting group P ⁸ is hydrogen or a protecting group, and when the protecting group P ⁸ is a protecting group, it can be removed at an appropriate stage. As the reaction conditions for these cross-coupling reactions, the same reaction conditions as those for the production of the compound 1 from the compounds 6 and 7 or the reaction conditions for the production of the compound 1 from the compounds 6 and 8 are also applicable. As desired, the various functional groups of compounds 7, 8, 34, 35 and 36 can be protected by appropriate protecting groups during these reactions, while the protecting groups can be removed at appropriate stages.

Some compounds 34 are commercially available. Alternatively, the non-commercially available compound 34 can be produced by generally known synthetic organic chemistry methods, using compounds 31, 32 or the like, or using commercially available reagents.

[Formula 16]

[Compound 4]

Compound 4 can be produced by a method similar to the method for producing Compound 2 (Scheme 14). That is, for example, reduction of the deacetalization/aldehyde functional group will be carried out on the synthesis intermediate compound 18 of the compound 2, thus converting the compound 18 to the compound 37 which is an alcohol compound. Thereafter, the hydroxyl group of the compound 37 is converted into a leaving group, thereby producing the compound 4. The production of the compound 37 promotes the production of the compound 4 or the compound 37 can also be obtained by deprotecting the hydroxyl group of the compound intermediate compound 20 of the compound 2. Further, the compound 37 can also be synthesized by performing hydroboration on the synthesis intermediate compound 22 of the compound 2, or by performing ozone oxidation/reduction treatment on the synthesis intermediate compound 24 of the compound 2, or by The diol/oxidation fission/reduction to the aldehyde group is synthesized, and on the other hand, the compound 4 can also be produced by subjecting the compound 38 having the two leaving groups to a selective alkylation reaction on the compound 9.

During a series of reactions, each of the various functional groups of these compounds can be protected by a suitable protecting group, after which the protecting group can be removed at an appropriate stage.

Some of the compounds 34 of Scheme 14 are commercially available. another In addition, the non-commercially available compound 38 can be produced by generally known synthetic organic chemistry methods using commercially available reagents.

[Compound 5]

Compound 5 may be Compound 3 itself, or it may be produced by a method similar to the method for producing Compound 3, or simply induced from Compound 3.

[Compound 6]

Compound 6 can be produced by performing reductive amination (reductive alkylation) between a protected pyrrolidone derivative, such as compound 39, and compound 2, which can also be carried out by performing compound 4 and compound 39 or Manufactured by an alkylation reaction between the likes (Scheme 15). P ⁹ and P ¹⁰ are protecting groups, and they may be hydrogen unless they affect the reaction. P ^{10 is} preferably an indenyl group, an alkoxycarbonyl group, a benzyl group, a substituted benzyl group, a 1-phenylethyl group, a 1-(substituted) phenylethyl group or the like, which can be removed later. P ⁹ is an aralkyl type protecting group such as a benzyl group. When compound 39 is used in the alkylation reaction, P ⁹ may be various types of protecting groups capable of stabilizing anions, such as a mercapto group, an alkoxycarbonyl group, a sulfonyl group or a sulfinyl group. As desired, during each of these reactions, the various functional groups of all of these compounds can be protected by a suitable protecting group, after which the protecting group can be removed at the appropriate stage.

Similarly, the compound 6 can be produced by performing a reaction such as reductive alkylation or alkylation between the pyrrolidone compound 39 or a similar compound which can be protected and a suitable compound such as the compound 38, 41, 42 or 43. Next, if necessary, removal of a protecting group, conversion to a leaving group, and the like are performed, thereby inducing it to the compound 44, and then performing an alkylation reaction of the compound 44 with the compound 9 (Scheme 16). P ¹¹ may be an alcohol protecting group, and it may also be hydrogen unless it affects the reaction. As desired, the various functional groups of all of these compounds can be protected by appropriate protecting groups during these reactions. The protecting group can then be removed at the appropriate stage.

The compound 39 in the schemes 15 and 16 may be the above-mentioned compound 25 itself, or it may be synthesized from the compound 25 or may be synthesized by a method similar to the method of synthesizing the compound 25. In addition, some of compounds 41, 42 and 43 are commercially available. In addition, non-commercially available compounds can be produced by generally known synthetic organic chemistry methods using commercially available reagents.

Further, when n=1, the compound 6 can be subjected to a reductive alkylation (reductive amination) reaction between the compound 11 and the compound 46, or an alkylation reaction between the compound 13 and the compound 47. And manufactured (Scheme 17). Each of the various functional groups of these compounds can be protected by a suitable protecting group, and thereafter, the protecting group can be removed at an appropriate stage.

[Formula 20]

Further, when n = 1, the compound 6 can be subjected to a reductive alkylation (reductive amination) reaction between the compound 46 and the compound 48 or the compound 49, thereby obtaining the compound 44, and then similarly to the scheme 16 Manufactured by the method (Scheme 18). This compound 44 can also be produced by subjecting reductive alkylation between compound 47 and compound 48 or compound 49, and then, if necessary, removal of a protecting group, conversion of a hydroxyl group to a leaving group or the like. Each of the various functional groups of these compounds can be protected by a suitable protecting group, and thereafter, the protecting group can be removed at an appropriate stage.

Compounds 46 and 47 in Schemes 17 and 18 can be Known synthetic organic chemistry methods are obtained from the above-mentioned compounds 31, 32 and 34, and the like. Some of the compounds 48 and 49 are commercially available. Non-commercially available compounds can be made by generally known synthetic organic chemistry methods using commercially available reagents.

[Compound 10]

Compound 10 can be produced by performing an alkylation reaction between Compound 5 and a suitable compound such as Compound 38 or 42, followed by, if necessary, performing a protective removal, conversion to a leaving group, etc. (Scheme 19). Alternatively, the compound 10 may be subjected to a reaction such as reductive alkylation between the compound 5 and a suitable compound such as the compound 41 or 43, and then, if necessary, performing removal of a protecting group, conversion to a leaving group, or the like, as described above. Said (Scheme 19). The leaving group L ⁴ may be the same as or different from L ² . When the leaving group L ^{4 is} different from L ² , L ⁴ may be converted to L ² later. During these reactions, the various functional groups of all of these compounds can be protected by appropriate protecting groups, as described above, and thereafter, the protecting groups can be removed at the appropriate stage.

[Formula 22]

Further, the compound 10 can also be prepared by removing the protecting group P ¹⁰ from the compound 44 or 45, followed by the cross-coupling reaction of the compound 44 or 45 with the compound 7 or the compound 8, and then converting various functional groups (if necessary). (Scheme 20). During these reactions, the various functional groups of all of these compounds can be protected by appropriate protecting groups, as described above, and thereafter, the protecting groups can be removed at the appropriate stage.

Further, when n = 1, the compound 10 can be subjected to a reductive alkylation reaction between the compound 12 and the compound 48 or the compound 49, or by performing an alkane between the compound 14 and the compound 48 or the compound 49. a base reaction, and then, if necessary, a protecting group Or manufactured by conversion of functional groups (Scheme 21). During these reactions, the various functional groups of all of these compounds can be protected by appropriate protecting groups, as described above, and thereafter, the protecting groups can be removed at the appropriate stage.

Some of the compounds 48 and 49 of Scheme 21 are commercially available, and non-commercially available compounds can be made by generally known synthetic organic chemistry methods using commercially available reagents.

[Compounds 11 and 13]

Compound 11 or 13 can be produced by subjecting ammonium acetate to reductive alkylation on compound 2, or by performing such reductive alkylation on compound 2 with benzylamine, followed by removal of benzyl or the like. Got it. Further, the compound 11 or 13 can also be produced by subjecting the azide/reduction reaction to the compound 4 (Scheme 22). Further, the compound 11 or 13 can also be produced by subjecting an alkylation reaction between the compound 9 and the compound 50 having a protective amine functional group. P ¹² and P ¹³ are protecting groups for the amine. P ¹² and P ¹³ may be hydrogen unless they affect the reaction. During these reactions, the various functional groups of all of these compounds can be protected by appropriate protecting groups, as described above, and thereafter, the protecting groups can be removed at the appropriate stage.

Some of the compounds 50 of Scheme 22 are commercially available. Non-commercially available compounds can be made by generally known synthetic organic chemistry methods using commercially available reagents.

[Compounds 12 and 14]

Compounds 12 and 14 can be produced from compounds 35, 36 and the like by a generally known synthetic organic chemical method.

[Compound 15]

Compound 15 can be synthesized by epoxidizing the olefin structure of compound 22, for example. Further, the compound 15 can also be converted to a dihydroxy group (compound 52) by converting the olefin structure of the compound 22, followed by selectively converting the primary alcohol to the leaving group L ⁵ (compound 53), and then allowing the appropriate base to be on the compound. Synthesis by reaction (Scheme 23). Further, the compound 15 can also be synthesized by subjecting an alkylation reaction between the compound 9 and the compound 54 having an ethylene oxide structure. Further, the compound 15 can also be synthesized by carrying out an alkylation reaction between the compound 9 and the compound 55 in which the two hydroxyl groups are appropriately protected, and then by the compounds 56, 52 and 53. During these reactions, the various functional groups of all of these compounds can be protected by appropriate protecting groups, as described above, and thereafter, the protecting groups can be removed at the appropriate stage.

Some of the compounds 54 or 55 of Scheme 23 are commercially available. Non-commercially available compounds can be made by generally known synthetic organic chemistry methods using commercially available reagents.

[Compound 16]

Compound 16 may be compound 3 or 5 itself, or it may be prepared from compound 3, 5 or the like by a synthetic organic chemical method generally known. Alternatively, compound 16 can be obtained by a method similar to the method of producing compounds 3, 5 and the like.

According to the general knowledge in this technical field, the protecting groups used in the above reaction may be selected from the group below.

The protecting group for the amine group is not particularly limited as long as it is a usual user in the art. Such protecting groups for the amine group include: alkoxycarbonyl groups such as a third butoxycarbonyl group and a 2,2,2-trichloroethoxycarbonyl group; an aralkoxycarbonyl group such as a benzyloxycarbonyl group or a p-methoxybenzyloxy group. a carbonyl group, and a p-nitrobenzyloxycarbonyl group; an anthracenyl group such as an acetamyl group, a methoxyethyl group, a trifluoroethyl group, a chloroethyl group, a trimethylethyl group, a methyl group, and a benzamidine group Alkyl or aralkyl, such as tert-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, triphenylmethyl; ethers, such as methoxymethyl, tert-butoxymethyl , tetrahydropyranyl, and 2,2,2 trichloroethoxymethyl; (alkyl and/or aralkyl) substituted fluorenyl, such as trimethyl decyl, isopropyl dimethyl decyl, third Butyl dimethyl decyl, tribenzyl sulfonyl, and tert-butyl diphenyl fluorenyl; aryl sulfonyl, such as p-toluenesulfonyl, phenylsulfonyl, and 2-nitrophenylsulfonyl (p-Nitrophenylsulfonyl); sulfinyl, such as phenylsulfinyl, p-toluenesulfinyl, and tert-butylsulfinyl; and sulfo and propenyl. The thiol group may be an alkylcarbonyl group, an arylcarbonyl group, or an aralkylcarbonyl group.

The protecting group for the hydroxyl group is not particularly limited as long as it is a usual user in the art. Such a protective package for a hydroxyl group Including: alkyl groups such as tert-butyl and allyl groups; aralkyl groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-nitrobenzyl, diphenylmethyl And triphenylmethyl; 1-(alkoxy)alkyl or 1-(aralkyloxy)alkyl, such as methoxymethyl, 2-(trimethylindenyl)ethoxymethyl, tetrahydroper Meryl, 1-ethoxyethyl, tert-butoxymethyl, and benzyloxymethyl; (alkyl and/or aralkyl) substituted fluorenyl, such as trimethyl decyl, triethyl decyl, triiso Propyl, tert-butyldimethylalkyl, and tert-butyldiphenylalkyl; fluorenyl, such as formazan, ethyl fluorenyl, chloroethyl, trichloroethyl, trifluoro Anthracenyl, trimethylethenyl, benzhydryl, and 2,4,6-trimethylbenzylidene; oxycarbonyl, such as methoxymethyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsulfonyl)ethoxycarbonyl, isobutoxycarbonyl, allyloxycarbonyl, p-nitrophenyloxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxy Carbonyl, p-nitrobenzyloxycarbonyl; sulfonyl, such as methylsulfonyl, and p-toluenesulfonyl. When two hydroxyl groups are adjacent to each other and have a 1,2- or 1,3 relationship, the two hydroxyl groups can be simultaneously protected. Examples of such protecting groups include: cyclic acetals/ketals such as methylene, tert-butylmethylene, isopropylidene, benzylidene; and orthoesters such as methoxymethylene.

The protecting group for the carbonyl group is not particularly limited as long as it is a usual user in the art. Such protecting groups for the carbonyl group include: acyclic acetals/ketals such as dimethyl acetal groups; cyclic acetals/ketals such as 1,3- two Alkane, 1,3-dioxolane, palmitic or non-palm 4,5-dimethyl-1,3-dioxolane, palmitic or non-palm 4,5-diphenyl-1, 3-dioxolane, and trans-1,2-cyclohexanediol ketal; thioacetal/thioketal, such as dimethyl dithioacetal, 1,3-dithiacyclohexane, 1 3-dithiazide Cyanohydrin, such as O-tridecyl cyanohydrin, and O-acetonitrile; hydrazine, such as N, N-dimethyl hydrazine, and toluene sulfonate; and hydrazine, such as O-methyl hydrazine, and O- Benzyl hydrazine.

The protecting group for the carboxyl group is not particularly limited as long as it is usually used in the art. Such protecting groups for the carboxyl group include: alkyl esters such as methyl ester, ethyl ester, tert-butyl ester, 9-fluorenyl methyl ester, cyanomethyl ester, cyclohexyl ester, allyl ester, Methoxymethyl ester, tetrahydrobenzylidene ester, 2-(trimethyldecyl)ethoxymethyl ester, benzyloxymethyl ester, trimethylacetoxymethyl ester, benzamidine methyl ester, 2 , 2,2-trichloroethyl ester, and 2-(trimethyldecyl)ethyl ester; aralkyl esters such as benzyl ester, diphenylmethyl ester, triphenylmethyl ester, 2, 4, 6-trimethylbenzyl ester, o-nitrobenzyl ester, p-nitrobenzyl ester, and p-methoxybenzyl ester; aryl esters such as phenyl ester, 2,6-dimethylphenyl ester, 2 , 6-di-tert-butyl-4-methylphenyl ester, and pentafluorophenyl ester; a decyl alkyl ester such as a trimethyl decyl methacrylate, a triethoxy decyl ester, a triisopropane decyloxy ester, and Tert-butyldimethyloxyl ester; orthoester such as triethoxymethyl ester.

The protecting group for the N-mono-substituted sulfhydryl group is not particularly limited as long as it is usually used in the art. Such protecting groups for N-mono-substituted amide groups include substituted alkyl groups such as allyl, tert-butyl, methoxymethyl, benzyloxymethyl, 2,2,2-trichloroethane , butyl dimethyl decyl oxymethyl, trimethyl ethoxymethyl, and cyanomethyl; aralkyl, such as benzyl, 4-methoxybenzyl, 2,4-dimethyl Oxybenzyl, o-nitrobenzyl, triphenylmethyl, (R)-1-phenylethyl, (S)-1-phenylethyl, (R)-1-(4-methoxy Phenyl)ethyl, and (S)-1-(4-methoxyphenyl)ethyl; substituted aryl such as 4-methoxyphenyl, 3,4-dimethoxyphenyl; alkyl /aralkyloxy, such as methoxy, and benzyloxy; substituted decyl, Such as triisopropyl sulfonyl, and tert-butyldimethyl dimethyl alkyl; urethanes such as tert-butyloxycarbonyl, benzyloxycarbonyl, and methoxycarbonyl; and sulfonyl, such as p-toluene醯基.

According to the general knowledge in this technical field, the base used in the above reaction may be selected from the group consisting of the following. In particular, examples of such bases include: alkali metal or alkaline earth metal hydrides (such as lithium hydride, sodium hydride, potassium hydride, and calcium hydride); alkali metal or alkaline earth metal amides (such as lithium amination, sodium amination, Lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldiazoxide, sodium hexamethyldiazoxide, and potassium hexamethyldiazoxide; lower alkane of alkali or alkaline earth metal Oxides (such as sodium methoxide, sodium ethoxide, potassium butoxide); alkali metal or alkaline earth metal hydroxides (such as sodium hydroxide, potassium hydroxide, lithium hydroxide, or barium hydroxide); alkali metals Alkaline earth metal or silver carbonate (such as sodium carbonate, potassium carbonate, cesium carbonate, and silver carbonate); alkali metal hydrogencarbonate (such as sodium hydrogencarbonate, and potassium hydrogencarbonate); alkyl lithium (such as n-butyl lithium) Or an alkyl Grignard (such as methylmagnesium bromide); an inorganic base such as silver oxide or an amine (such as triethylamine, diisopropylethylamine, N-methyl) Morpholine); an organic base such as a basic heterocyclic compound (eg 4-dimethylaminopyridine, imidazole, 2,6-dimethylpyridine, Colin base, 1,8-diguanidine) [5,4, 0] eleven-7-ene, 1,5-dioxabicyclo[4,3,0]non-5-ene, and 1,4-dioxabicyclo[2,2,2]octane; and phosphine Nitroene, such as P4-phosphazene.

According to the general knowledge in this technical field, the solvent used in the above reaction may be selected from the group consisting of the following. Examples of such a solvent include alcohol solvents, ether solvents, halogen solvents, aromatic solvents, nitrile solvents, guanamine solvents, ketone solvents, hydrazine solvents, and water. These solvents can be Two or more of them are used in combination.

The compounds of the invention may be free compounds or acid addition salts. Examples of such acid addition salts include: acid salts such as hydrofluoric acid salts, hydrochlorides, hydrobromides, and hydroiodides; inorganic acid salts such as hydrochlorides, nitrates, and perchlorides. Acid salts, sulfates, and phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as besylate, and Tosylate; and organic acid salts such as acetate, malate, lactate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate and maleate .

It is possible that the compound of the present invention contains water molecules in its crystallization, or its absorbed content and has adsorbed water, and thus, for example, it is retained during the crystallization generating step, or during the purification step, or by being retained It becomes a hydrate in the atmosphere. Such hydrates are also included in the salts of the present invention.

The compounds of the invention have one or more asymmetric carbon atoms in their molecule and optical isomers are present. These isomers and mixtures of these isomers are represented by a single molecular formula, that is, the general formula (I). Accordingly, the compounds of the present invention include all such optical isomers and mixtures containing optical isomers in any ratio.

The invention also includes compounds wherein one or more of the compounds of the invention are substituted with isotopes of the atoms. There are two types of isotopes, namely, radioisotopes and stable isotopes. Examples of such isotopes include: hydrogen isotopes ( ² H and ³ H), carbon isotopes ( ¹¹ C, ¹³ C and ¹⁴ C), nitrogen isotopes ( ¹³ N and ¹⁵ N), oxygen isotopes ( ¹⁵ O, ¹⁷ O and ¹⁸⁾ O), and the fluorine isotope ( ¹⁸ F). A composition including a compound labeled with an isotope can be used, for example, as a therapeutic agent, a prophylactic agent, a research reagent, a test reagent, a diagnostic agent, a diagnostic imaging agent in vivo, or the like. Compounds labeled with isotopes are also included in the compounds of the invention, and mixtures comprising compounds in such proportions labeled as isotopes are also included in the compounds of the invention. The isotope-labeled compound of the present invention can be produced by a method known in the art, for example, by using an isotopically labeled starting material in place of the starting material used in the production method of the present invention, as will be described later.

Since the salts and/or crystals of the present invention have a strong antibacterial action, they can be used as a medicament for humans, animals and fish, or as a preservative for agricultural chemicals or foods. When the compound of the present invention is used as a medicament for human body, the dose is set to be 100 mg to 10,000 mg, preferably 300 to 5000 mg per day per adult. On the other hand, the dose of the compound of the present invention when used in animals varies depending on the purpose of administration, the size of the animal to be treated, the type of pathogen of the infection, and the degree of symptoms. Usually, the dose is set to 1 to 200 mg, preferably 5 to 100 mg per kg of animal weight per day. Such a daily dose is such that the animal is taken once a day or divided into 2 to 4 doses. It should be noted that the daily dose may exceed the previously mentioned amount.

The salts and/or crystals of the present invention are active against a wide range of microorganisms which cause various types of infectious diseases. Thus, the salts and/or crystals of the present invention are capable of treating, preventing or ameliorating the diseases caused by these pathogens. Examples of bacteria or bacterial-like microorganisms which can produce potency of the compounds of the present invention include Staphylococcus, Streptococcus pyogenes, Hemolytic chain balls Bacteria, Enterococcus, Pneumococci, Streptococcus pneumoniae, Gonococci, Escherichia coli, Citrobacter, Shigella, Klebsiella pneumoniae, Enterobacter, Enterobacter, Proteus, Pseudomonas aeruginosa , Haemophilus influenzae, Acinetobacter, Mycobacterium, Mycoplasma, and Chlamydia trachomatis.

Examples of diseases caused by these pathogens include folliculitis, sputum, sputum, erysipelas, cellulitis, lymphangitis (lymphitis), sputum, subcutaneous abscess, sweat gland inflammation, polymeric acne, infectious atheroma, anal Secondary infection of abscess, mastitis, trauma/scald/surgical wound, pharyngitis, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, secondary infection of chronic respiratory disease, Pneumonia, pyelonephritis, cystitis, mastitis, epididymitis, gonorrhea urethritis, non-gonococcal urethritis, cholecystitis, cholangitis, bacillary dysentery, enteritis, uterine annexitis, intrauterine infection, large vestibular gland Inflammation, blepharitis, stye, dacryocystitis, meibomian gland inflammation, corneal ulcer, otitis media, sinusitis, periodontal ulceration, pericardial periodontitis, jaw inflammation, peritonitis, endocarditis, sepsis, meningitis And skin infections.

Further, examples of the acid-tolerant bacteria capable of producing the compounds of the present invention include Mycobacterium tuberculosis group (Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium tuberculosis), Atypical Mycobacteria (Mycobacterium sinensis, Sea Mycobacterium, Mycobacterium phlei, Mycobacterium tuberculosis, Mycobacterium intracellulare, Mycobacterium phlei, Mycobacterium tuberculosis, and Mycobacterium marinum. Based on pathogenic microorganisms, mycobacterial infections caused by these pathogens can be broadly classified into three types of infections, namely, tuberculosis, atypical mycobacteria, and leprosy. Tuberculosis can be in the chest, trachea/bronchus, Lymph nodes, whole body, bone joints, meninges/brains, digestive organs (intestine/liver), skin, breast, eyes, middle ear/pharyngeal, urethra, male genitalia, female genitalia, and lungs were observed. The main organ infected with atypical mycobacteria (non-tuberculous mycobacterial infection) is the lung, and other organs that infect the disease include regional lymph nodes, skin soft tissues, joints of bones, and whole body.

Furthermore, the salts and/or crystals of the present invention can be used for various microorganisms causing infectious diseases of animals, such as Escherichia, Salmonella, Pasteurella, Haemophilus, Bordetella, and grapes. Coccidia, Mycoplasma. Examples of specific diseases infecting avians include colibacillosis, ferrets, poultry paratyphoid, poultry cholera, infectious rhinitis, staphylococcal disease, and mycoplasma infection. Examples of specific diseases infecting pigs include Escherichia coli, Salmonella, Pasteurella, Haemophilus infection, atrophic rhinitis, exudative dermatitis, and Mycoplasma infection. Examples of specific diseases in which a cow is infected include colibacillosis, salmonellosis, hemorrhagic septicaemia, mycoplasma infection, infectious bovine pleuropneumonia, and mastitis. Examples of specific diseases infecting dogs include E. coli sepsis, Salmonella infection, hemorrhagic sepsis, uterine empyema, and cystitis. Examples of specific diseases infecting cats include exudative pleurisy, cystitis, chronic rhinitis, Haemophilus infection, cat diarrhea, and mycoplasma infection.

An agent comprising a salt and/or a crystal of the present invention as an active ingredient is preferably provided as a pharmaceutical composition comprising an additive for a medicament using the salt and/or crystal of the present invention as an active ingredient and one or two or more types. Form of matter. The agent of the present invention is not particularly limited in terms of administration, and it can be administered orally or parenterally.

Depending on the usual method of preparing the various types of agents, the salts comprising the salts and/or crystals of the invention may be prepared by the selection of the appropriate agent depending on the method of administration. Dosage forms including the antibacterial agents of the compounds of the present invention as main agents include tablets, powders, granules, capsules, solutions, syrups, elixirs, and oily or aqueous suspensions. In the case of an injection, a stabilizer, a preservative, a solubilizer, a pH adjuster, an isotonizing agent, or the like can be added to the medicament. A solution which may include the aforementioned agent is placed in a container and then freeze-dried to prepare a solid preparation which is an agent prepared at the time of use. Alternatively, a single dose of the medicament can be presented in a container or a plurality of doses of the medicament can be presented in a container. Examples of the external preparation include a solution, a suspension, an emulsion, an ointment, a gel, a cream, a liquid, and a spray. In the case of a solidifying agent, it may include pharmaceutically acceptable additives, as well as the active compound. Examples of such additives include fillers, binders, disintegrants, solution promoters, wetting agents, and lubricants. Examples of liquid agents include solutions, suspensions, and emulsions. Such liquid agents may include suspending agents, emulsifiers, and the like as additives.

[Example]

The invention will be described in more detail in the following examples and the like, however, these examples are not intended to limit the scope of the invention.

[Reference Example 1] 4-chloro-3-nitrobenzonitrile

4-Chloro-3-nitrobenzonitrile (4 g, 29.2 mmol) was dissolved in dry acetonitrile (40 mL) and EtOAc (t. The reaction mixture was stirred at room temperature 20 hour. The reaction mixture was poured into ice water. The precipitated white solid was collected by filtration, and the filtrate was washed with water and dried. The compound thus obtained (4.0 g, 75.47%) was used in the next step without purification.

[Reference Example 2] N-(4-cyano-2-nitrophenyl)glycine ethyl ester

Dissolve 4-chloro-3-nitrobenzonitrile (4 g, 21.98 mmol) and ethyl glycinate (4.6 g, 32.97 mmol) in dry acetonitrile (40 mL) in a microwave vial. And diisopropylethylamine (10.9 ml, 65.94 mmol), and the mixture was irradiated at 125 ° C for 30 minutes. The solvent was removed under reduced pressure. The residue obtained was purified by silica gel column chromatography (ethyl acetate /hexane) to yield the desired compound 4.0 g (73.13%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.33 (t, J = 7.2Hz, 3H), 4.13 (d, J = 5.2Hz, 2H), 4.32 (q, J = 7.2Hz, 2H), 6.77 ( d, J = 9.2 Hz, 1H), 7.65 (dd, J = 9.2, 2.0 Hz, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.81 (s, 1H).

[Reference Example 3] N-(2-Amino-4-cyanophenyl)glycine ethyl ester

Ethyl N-(4-cyano-2-nitrophenyl)glycine (1.0 g, 4.02 mmol) was dissolved in dry methanol (30 mL) and palladium carbon (0.3 g, 30% w/) w). The reaction mixture was stirred under a hydrogen atmosphere for 1.5 hours. After the consumption of the starting materials was completed, the reaction mixture was filtered and washed with methanol. The filtrate and washings were concentrated under reduced pressure to give crude material (yield: EtOAc,

[Reference Example 4] 3-sided oxygen-1,2,3,4-tetrahydroquine Porphyrin-6-carbonitrile

[Equation 27]

Ethyl N-(2-amino-4-cyanophenyl)glycine (Reference Example 3, 0.88 g) was dissolved in ethanol (10 ml), and acetic acid (1.0 ml) was added. The reaction mixture was heated at 80 ° C for 1 hour. The solvent was removed under reduced pressure to yield crude material (0.75 g) which was used directly in the next step.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 3.90 (d, J = 1.6Hz, 2H), 6.68 (d, J = 8.4Hz, 1H), 6.94 (d, J = 2.0Hz, 1H), 7.16 (dd, J = 8.4, 2.0 Hz, 1H), 10.50 (s, 1H).

MS (-ve mode): 172 (M-H).

[Reference Example 5] 3-sided oxygen-3,4-dihydroquine Porphyrin-6-carbonitrile

Dissolve 3-oxo-1,2,3,4-tetrahydroquine in dry methanol (25 mL) Porphyrin-6-carbonitrile (0.55 g, 3.18 mmol). Potassium carbonate (0.66 g, 4.77 mmol) and iodine (0.97 g, 3.82 mmol) were added thereto at room temperature, and stirred at the same temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in water and then quenched with aqueous sodium dithiosulfinate, until iodine color disappeared. The aqueous layer was extracted with ethyl acetate (x3), and then evaporated.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 7.64 (d, J = 1.6 Hz, 1H), 7.70 (dd, J = 8.4, 2.0 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H) ), 8.31 (s, 1H), 12.70 (s, 1H).

MS (-ve mode): 170 (M-H).

[Reference Example 6] 4-(3-bromopropyl)-3-oxo-oxy-1,2,3,4-tetrahydroquina Porphyrin-6-carbonitrile

Dibromopropane (2.5 ml, 24.85 mmol) and potassium hydroxide (0.33 g, 5.96 mmol) were placed in dry dimethyl hydrazine (10 ml). And adding 3-oxo-3,4-dihydroquine in portions to the above reaction mixture at 0 °C Porphyrin-6-carbonitrile (Reference Example 5, 0.85 g, 4.97 mmol). The reaction mixture was stirred at room temperature for 2.0 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The obtained crude product was purified by silica gel column chromatography (ethyl acetate /hexane) to yield 0.3 g (20.69%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.18 (t, J = 7.2 Hz, 2H), 3.66 (t, J = 7.2 Hz, 2H), 4.30 (t, J = 7.2 Hz, 2H), 7.79 (dd, J = 8.4, 1.6 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 8.25 (d, J = 1.2 Hz, 1H), 8.36 (s, 1H).

[Reference Example 7] [(3R)-5-Phenoxypyrrolidin-3-yl]carbamic acid benzyl carbamate

Trifluoroacetic acid and dichloromethane (1:2, 30 ml) were placed in a two-necked round bottom flask (100 ml) and cooled to 5-10 ° C. [(3R)- 3-Butoxypyrrolidin-3-yl]carbamic acid tert-butyl ester (20 g, 0.1 mmol). The reaction temperature was slowly raised to room temperature and stirred for 6 hours. After the completion of the consumption of the starting materials, the reaction mixture was concentrated, and the excess trifluoroacetic acid was removed using a high vacuum pump to yield a crude ( 4R )-4-aminopyrrolidin-2-one. Oily residue (11 g).

(4R)-4-Aminopyrrolidin-2-one (11 g, 0.11 mol) was dissolved in tetrahydrofuran and water (1:1, 100 mL), and the mixture was cooled to 5-10 °C. Solid sodium bicarbonate was added to the solution until foaming ceased and the pH of the reaction mixture was neutral. Thereafter, benzyl chloroformate (44.88 ml in 50% toluene, 0.132 mol) was added dropwise to the reaction mixture at the same temperature. The reaction mixture was slowly warmed to room temperature and stirred for 8 hours. After the consumption of the starting amine was completed, the reaction mixture was extracted with ethyl acetate (x3), and the organic layer was dried over anhydrous sodium sulfate. The extract was concentrated to give a semi-solid compound which was crystallised from diethyl ether and hexanes (50%, 250 mL) to yield 20 g (85%)

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.22 (m, 1H), 2.69 (m, 1H), 3.27 (m, 1H), 3.72 (m, 1H), 4.48 (bs, 1H), 5.10 (bs , 2H), 5.71 (bs, 2H), 7.30 (m, 5H).

MS: 235 (M+H) ⁺ .

[Reference Example 8] ({6-[(4R)-4-{[(benzyloxy)carbonyl]amino}}-2-oxopyrrolidin-1-yl]-2- nitropyridine-3- Ethyl acetate

[(3R)-5-Phenoxypyrrolidin-3-yl]carbamic acid benzyl ester (10 g, 0.042 mol) and [(6-bromo-2-nitropyridin-3-yl)oxy]acetic acid Ethyl ester (20.8 g, 0.068 mol) was placed in a three-necked round bottom flask (1 liter) and added to 1,4- argon under argon alkyl. To the reaction vessel were added cuprous iodide (6.5 g, 0.034 mol), cesium carbonate (42 g, 0.128 mol), and N,N'-dimethylethylenediamine (3.4 ml, 0.034 mol). Then, it was degassed with argon for 10 minutes. The reaction mixture was then refluxed at 100-110 °C for 3 h then evaporated to dryness eluted eluted The organic layer was washed with water (x2), dried over anhydrous sodium sulfate, filtered, and then concentrated to give a brown oily crude compound by Combiflash flash column chromatography (ethyl acetate /hexane) Purified to yield 11.5 g (61%) of the desired compound.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.32 (m, 2H), 2.65 (m, 1H), 3.12 (m, 1H), 3.75 (s, 3H), 3.92 (m, 1H), 4.35 (m , 1H), 4.5 (bs, 1H), 4.77 (bs, 2H), 5.20 (s, 3H), 7.33 (m, 5H), 7.50 (d, 9.2 Hz, 1H), 8.60 (d, 9.2 Hz, 1H) ).

MS: 459 (M+H) ⁺

[Reference Example 9] [(3 R )-5-sideoxy-1-(3- side oxy-3,4-dihydro-2 H -pyrido[3,2- b ][1,4] Benzyl-6-yl)pyrrolidin-3-yl]carbamate

({6-[(4R)-4-{[(benzyloxy)carbonyl]amino}}-2-oxopyrrolidin-1-yl]-2-nitropyridin-3-yl}oxy)acetic acid Ethyl ester (10 g, 0.021 mol and iron powder (6 g, 0.109 mol) was placed in a three-neck round bottom flask (1 L). Acetic acid (100 ml) and ethanol (500 ml) were added to this reaction vessel. And vigorously stirred at 70-80 ° C for 3 hours. After the consumption of the starting material was completed, the reaction mixture was evaporated, and cold water (250 ml) was added to the residue, then the mixture was cooled to 10-15 ° C, and Sodium bicarbonate was added thereto until the pH of the solution was neutral. Thereafter, the mixture was extracted with dichloromethane and ethyl acetate (x5), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. An off-white solid compound was obtained which was triturated with diethyl ether (100 mL) to yield 9 g (98%)

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 2.46 (m, 2H), 2.92 (m, 1H), 3.82 (m, 1H), 4.11 (m, 1H), 4.15 (bs, 1H), 4.60 (s, 2H), 5.03 (s, 2H), 7.35 (m, 5H), 7.85 (m, 2H), 11.17 (s, 1H).

MS: 383 (M+H) ⁺

[Reference Example 10] 6-[(4R)-4-amino-2-oxooxypyrrolidin-1-yl]-2H-pyrido[3,2- b ][1,4] -3(4 H )-ketone

[Formula 33]

[(3 R )-5- side oxo-1-(3- side oxy-3,4-dihydro-2 H -pyrido[3,2- b ][1,4] Benzyl-6-yl)pyrrolidin-3-yl]carbamate (10 g, 0.026 mol) was placed in a round-bottomed flask (500 mL), and methanol (250 mL) was then added, followed by palladium Carbon (5 g, 50% w/w) was stirred at room temperature for 2 hours under a hydrogen balloon. After the consumption of the starting material was completed, the reaction mixture was filtered through a Buchner funnel and washed with methanol (500 mL). The organic layer was evaporated to give an off-white solid which was purified eluting with diethyl ether (50 ml) to yield 6 g (98%) of desired compound.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 0.93 (m, 1H), 2.25 (m, 1H), 2.76 (m, 1H), 3.63 (m, 4H), 3.97 (m, 1H), 4.60 (s, 2H), 7.39 (d, 8.8 Hz, 1H), 7.84 (d, 8.8 Hz, 1H).

MS: 249 (M+H) ⁺

[Reference Example 11]

6-[(4 R )-4-(Aminomethyl)-2-oxopyryrrolidin-1-yl]-2 H -pyrido[3,2- b ][1,4] -3( 4H )-one (7.7g) utilizes benzyl {[( 3R )-5-oxooxypyrrolidin-3-yl]methyl}carbamate (12g) in a similar manner and Prepared for similar yields.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 2.45 (m, 2H), 2.63 (m, 3H), 3.67 (m, 1H), 4.01 (m, 1H), 4.60 (s, 2H), 7.39 (d, 8.8 Hz, 1H), 7.81 (d, 8.8 Hz, 1H).

MS: 263 (M+H) ⁺

[Example 1] 3-oxo-4-(3-{[(3 R )-5-sideoxy-1-(3- side oxy-3,4-dihydro-2 H -pyrido[3,2] - b ][1,4] -6-yl)pyrrolidin-3-yl]amino}propyl)-3,4-dihydroquine Porphyrin-6-carbonitrile

Dissolve 4-(3-bromopropyl)-3-oxo-l,2,3,4-tetrahydroquine in dry N,N-dimethylformamide (2.0 ml) Porphyrin-6-carbonitrile (Reference Example 6, 0.150 g, 0.51 mmol), 6-[(4 R )-4-amino-2-oxopyrrolidin-1-yl]-2 H -pyridine [3,2- b ][1,4] -3( 4H )-one (Reference Example 10, 0.127 g, 0.51 mmol), and diisopropylethylamine (0.3 mL, 1.02 mmol). The reaction mixture was stirred at 50 ° C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The crude product obtained was purified by preparative thin layer chromatography (methanol / dichloromethane) to yield 20 mg (8.48%) of the desired compound.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.79 (bs, 2H), 2.37 (m, 1H), 2.61 (bs, 2H), 2.79 (m, 1H), 3.38 (d, J = 6.8Hz , 2H), 3.74 (bs, 1H), 4.01 (bs, 1H), 4.26 (bs, 2H), 4.60 (s, 2H), 7.39 (d, J = 8.8 Hz, 1H), 7, 78 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 8.27 (s, 1H), 8.36 (s, 1H), 11.16 (bs, 1H).

MS: 460 (M+H) ⁺ .

[Example 2] 3-oxo-4-[3-({[(3 R )-5-sideoxy-1-(3- side oxy-3,4-dihydro-2 H -pyrido[3, 2- b ][1,4] -6-yl)pyrrolidin-3-yl]methyl}amino)propyl]-3,4-dihydroquine Porphyrin-6-carbonitrile, in a manner similar to that of Example 1, using 6-[(4 R )-4-(aminomethyl)-2-oxopyryrrolidin-1-yl]-2 H -pyridine[ 3,2- b ][1,4] -3( 4H )-one (Reference Example 11, 0.127 g, 0.51 mmol) was prepared.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.79 (bs, 2H), 2.61 (bs, 4H), 3.50 (m, 2H), 3.68 (m, 1H), 4.02 (m, 2H), 4.26 (m, 2H), 4.35 (m, 1H), 4.59 (s, 2H), 7.38 (d, J = 8.8 Hz, 1H), 7.80 (m, 2H), 7.99 (d, J = 8.0 Hz, 1H) , 8.28 (s, 1H), 8.38 (s, 1H).

MS: 474 (M+H) ⁺ .

[Reference Example 12] N-[4-(difluoromethoxy)phenyl]methanesulfonamide

4-Difluoromethoxyaniline (1.0 g, 6.29 mmol) was dissolved in tetrahydrofuran (10 ml). Pyridine (1.0 ml, 12.58 mmol) and methanesulfonium chloride (0.7 ml, 9.43 mmol) were added thereto at 0-5 ° C, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate. It was concentrated under reduced pressure. The crude product (1.5 g) was used directly in the next step.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 2.97 (s, 3H), 7.16 (d, J = 8.8Hz, 2H), 7.16 (t, J = 74.4Hz, 1H), 7.24 (d, J =9.2 Hz, 2H), 9.77 (s, 1H)

[Reference Example 13] N-[4-(difluoromethoxy)-2-nitrophenyl]methanesulfonamide

Dissolving N-[4-(difluoromethoxy)phenyl]methanesulfonamide in chloroform (15 ml) (Reference Example 7, 1.7 g, 7.17 mmol), Acetic anhydride (1.0 ml, 10.76 mmol) was added thereto at room temperature, after which the mixture was heated to 60 °C. To the same temperature, nitric acid (0.4 ml, 8.61 mmol) was added dropwise over a period of 3 minutes. Heating was continued for an additional 30 minutes, then the mixture was cooled to room temperature, poured into water and extracted with ethyl acetate (x3). The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product 1.7 g (84.16%) was used directly in the next step without purification.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 3.11 (s, 3H), 7.35 (t, J = 73.2Hz, 1H), 7.59 (dd, J = 8.8,2.8Hz, 1H), 7.66 (d , J = 8.8 Hz, 1H), 7.86 (d, J = 2.8 Hz, 1H), 9.83 (s, 1H).

MS (-ve mode): 281 (M-H).

[Reference Example 14] N- [4- (difluoromethoxy) -2-nitrophenyl] - N - (methyl sulfonic acyl) ethyl amine Gan

N-[4-(difluoromethoxy)-2-nitrophenyl]methanesulfonamide (1.1 g, 3.90 mmol) and potassium carbonate (0.65 g, 4.68 mmol) were placed on dry N. N-dimethylformamide (5 ml) was added to ethyl bromoacetate (0.6 mL, 4.68 mmol) at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and a brine solution, dried over anhydrous sodium sulfate and evaporated. %) of the target compound.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 1.20 (t, 7.2 Hz, 3H), 3.16 (s, 3 H), 4.16 (q, 7.2 Hz, 2H), 4.52 (bs, 2H), 7.44 (t, J = 72.8 Hz, 1H), 7.64 (dd, J = 8.8, 3.2 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 3.2 Hz, 1H).

MS: 369 (M+H) ⁺ .

[Reference Example 15] 7-(Difluoromethoxy)-4-(methylsulfonyl)-3,4-dihydroquine Porphyrin-2(1 H )-one

N- [4- (difluoromethoxy) -2-nitrophenyl] - N - (methyl sulfonic acyl) Gan acid ethyl ester (1.8 g, 4.89 mmol) was dissolved in dry methanol (20 ml In the middle, palladium on carbon (0.5 g, 30% w/w) was added. The reaction mixture was stirred under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered and washed with methanol. The filtrate and the washings were concentrated under reduced pressure to give a crude material, which was purified by silica gel column chromatography (ethyl acetate/hexane) to yield 1.0 g (64.10%) of the desired compound.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 2.98 (s, 3H), 4.25 (s, 2H), 6.81 (d, J = 2.8Hz, 1H), 6.87 (dd, J = 8.8,2.4Hz , 1H), 7.22 (t, J = 73.6 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 10.91 (s, 1H).

MS (-ve mode): 291 (M-H).

[Reference Example 16] 7-(difluoromethoxy)quine Porphyrin-2(1 H )-one

In two Dissolve 7-(difluoromethoxy)-4-(methylsulfonyl)-3,4-dihydroquine in alkane (10 mL) Porphyrin-2(1 H )-one (1.0 g, 3.43 mmol) was added cesium carbonate (0.65 g, 2.06 mmol) and stirred at 100 ° C overnight. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, and the solution was washed with water and brine, dried over anhydrous sodium sulfate and evaporated

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 7.06 (dd, J = 8.8,2.8Hz, 1H), 7.14 (d, J = 2.8Hz, 1H), 7.37 (t, J = 73.6Hz, 1H ), 7.79 (d, J = 8.8 Hz, 1H), 8.08 (s, 1H).

MS (-ve mode): 211 (M-H).

[Reference Example 17] 1-(3-Bromopropyl)-7-(difluoromethoxy)quine Porphyrin-2(1 H )-one

Dibromopropane (1.2 ml, 11.89 mmol) and potassium hydroxide (0.16 g, 2.83 mmol) were placed in anhydrous dimethyl hydrazine (10 mL). 7-(difluoromethoxy)quine was added in portions to the above reaction mixture at 10 °C. Porphyrin-2(1 H )-one (0.5 g, 2.36 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The crude product was purified using silica gel column chromatography (ethyl acetate /hexane) to yield 0.27 g (34.62%).

[Example 3] 6-[(4 R )-4-({3-[7-(difluoromethoxy)-2-oxoquinequin Morpholine -1 (2 H) - yl] propyl} amino) -2-oxo pyrrolidin-l-yl] -2 H - pyrido [3,2- b] [1,4] -3(4 H )-ketone

Dissolve 1-(3-bromopropyl)-7-(difluoromethoxy)quine in dry N,N-dimethylformamide (2.0 ml) Porphyrin-2(1 H )-one (Reference Example 17, 0.135 g, 0.405 mmol), 6-[(4 R )-4-amino-2-oxopyrrolidin-1-yl]-2 H -pyrido[3,2- b ][1,4] -3( 4H )-one (Reference Example 10, 0.1 g, 0.405 mmol), and diisopropylethylamine (0.13 mL, 0.81 mmol). The reaction mixture was stirred at 50 ° C for 16 hours. The reaction mixture was poured into EtOAc (EtOAc)EtOAc. The crude product was purified by preparative thin layer chromatography (methanol / dichloromethane) to yield 25 mg (12.32%) of desired compound.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.78 (m, 2H), 2.39 (m, 2H), 2.60 (bs, 2H), 2.79 (dd, J = 15.2,7.2Hz, 1H), 3.38 (bs, 1H), 3.74 (m, 1H), 4.01 (dd, J = 10.8, 6.4 Hz, 1H), 4.24 (t, J = 7.2 Hz, 2H), 4.60 (s, 2H), 7.20 (dd, J = 8.8, 2.4 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.46 (t, J = 73.6 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 8.18 (s, 1H), 11.17 (bs, 1H).

MS: 501 (M+H) ⁺ .

[Example 4] 6-{(4 R )-4-[({3-[7-(difluoromethoxy)-2-oxyquine -1( 2H )-yl]propyl}amino)methyl]-2-oxopyryrrolidin-1-yl}-2 H -pyrido[3,2- b ][1,4] -3 (4 H) - one is a manner analogous to Example 3, using 6 - [(4 R) -4- ( aminomethyl) -2-oxo pyrrolidin-l-yl] -2 H - pyrido [3,2- b ][1,4] -3( 4H )-one (Reference Example 11, 0.106 g, 0.405 mmol) was prepared.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.79 (m, 2H), 2.08 (s, 1H), 2.45 (m, 2H), 2.63 (bs, 5H), 3.67 (dd, J = 10.8, 6.4 Hz, 1H), 4.03 (m, 1H), 4.24 (bs, 2H), 4.60 (s, 2H), 7.21 (dd, J = 8.8, 2.4 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.47 (t, J = 73.6 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H) , 8.20 (s, 1H), 11.17 (bs, 1H).

MS: 515 (M+H) ⁺ .

[Reference Example 18] 1-(4-bromobutyl)-6,7-difluoroquine Porphyrin-2(1 H )-one

Place 6,7-difluoroquine in dry N,N-dimethylformamide (30 ml) Porphyrin-2(1 H )-one (5 g, 27.45 mmol) followed by lithium hydride (260 mg, 32.9 mmol) in portions at 0 °C. The mixture was stirred at 0 ° C for 1 hour, then 1,4-dibromobutane (4.9 mL, 41.4 mmol) was slowly added. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and water and extracted with ethyl acetate (x3). The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (ethyl acetate /hexane) to yield 3.5 g (40.2%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.71-1.78 (m, 2H), 1.87-1.95 (m, 2H), 3.57-3.60 (t, J = 6.6 Hz, 2H), 4.20 (t, J=7.6Hz, 2H), 7.87-7.99(m, 2H), 8.24(s, 1H).

[Example 5] 6-[(4 R )-4-{[4-(6,7-difluoro-2-oxoquinequin -1( 2H )-yl)butyl]amino}-2-oxopyryrrolidin-1-yl]-3,4-dihydro- 2H -pyrido[3,2- b ][1 , 4] 2-ketone

1-(4-Bromobutyl)-6,7-difluoroquine was placed in dry N,N-dimethylformamide (2.0 mL) Porphyrin-2(1 H )-one (Reference Example 18, 0.300 g, 0.946 mmol), 6-[(4 R )-4-amino-2-oxopyrrolidin-1-yl]-3, 4-dihydro-2 H -pyrido[3,2- b ][1,4] 2-ketone (Reference Example 10, 0.400 g, 1.6 mmol), and diisopropylethylamine (0.265 mL, 1.69 mmol). The reaction mixture was heated at 80 °C for 4 hours. The reaction mixture was cooled to room temperature, poured into water and extracted with EtOAc. The ethyl acetate extract was dried over anhydrous sodium sulfate under reduced pressure. The crude product was purified by flash chromatography (methanol / dichloromethane) to yield 100 mg (20%) of desired compound.

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.50 (m, 2H), 1.65 (m, 2H), 2.37 (m, 1H), 2.54 (m, 3H), 2.77 (dd, J = 7.2Hz , J = 16.8 Hz, 1H), 3.71 (bs, 1H), 3.98 (bs, 1H), 4.16 (t, J = 7.5 Hz, 2H), 4.59 (s, 2H), 7.37 (d, J = 8.8 Hz) , 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.88 (dd, J = 5.2 Hz, J = 7.6 Hz, 1H), 7.97 (dd, J = 2.0 Hz, J = 8.4 Hz, 1H) , 8.24 (s, 1H), 11.16 (bs, 1H).

MS: 485 (M+H) ⁺ .

[Reference Example 19] 4-{[Terbutyl(diphenyl)decyl]oxy}butan-1-ol

Sodium hydride (22.19 g, 0.554 mol) was added portionwise to a stirred solution of butane-1,4-diol (50 g, 0.554 mol) in tetrahydrofuran (500 mL) at 0 ° C under argon. And the reaction mixture was stirred at 0 ° C for 30 minutes. The temperature was maintained at 0 ° C, and tert-butyldibenzoylalkyl chloride (1726 ml, 0.665 mol) was added dropwise thereto over 30 minutes, and the mixture was stirred at 0 ° C for 1 hour. Water (200 ml) was added dropwise while maintaining the temperature at 0 ° C, followed by ethyl acetate (300 ml). The two layers were separated and the aqueous layer was extracted with ethyl acetate (x3). The organic layer was dried and concentrated to dryness. The crude product was purified by silica gel column chromatography (ethyl acetate /hexane) to yield 125 g (68.68%) of the desired compound.

^{1 H-NMR (400MHz, CDCl} 3) δ: 0.90 (s, 9H), 1.64 (m, 2H), 1.70 (m, 2H), 3.72 (m, 2H), 3.72 (m, 2H), 7.42 (m , 6H), 7.64 (dd, J = 1.2 Hz, J = 6.4 Hz, 4H).

[Reference Example 20] Tert-butyl (4-iodobutoxy) diphenyl decane

[Formula 44]

Imidazole (25.94 g, 381 mmol) and triphenylphosphine (149.77 g, 0.571 mmol) were added in portions to 4-[t-butyl(diphenyl)decylalkyl] at room temperature under argon atmosphere. The butane-1-ol (125 g, 0.381 mmol) was dissolved in a stirred solution of dry toluene (1250 ml) and the reaction mixture was stirred for about 10 minutes. Next, iodine (145 g, 0.571 mol) was added portionwise at 0 ° C, and the temperature was maintained at 0 ° C. After the addition, the reaction mixture was stirred at room temperature for 30 minutes and the reaction mixture was cooled to 0 ° C, then Saturated sodium thiosulfate solution (800 ml) was added. The reaction mixture was extracted with ethyl acetate (x2), and ethyl acetate extracts were dried and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate /hexane) to afford 80 g (47.

^{1 H-NMR (400MHz, CDCl} 3) δ: 0.90 (s, 9H), 1.64 (m, 2H), 1.96 (m, 2H), 3.18 (m, 2H), 3.67 (m, 2H), 7.42 (m , 6H), 7.64 (dd, J = 1.2 Hz, J = 6.4 Hz, 4H).

[Reference Example 21] 1-(4-{[T-butyl(diphenyl)indenyl]oxy}butyl)-7-methoxyquin Porphyrin-2(1 H )-one

Lithium hydride (0.148 g, 1.8 mol) was added to 7-methoxyquin at 0 ° C under argon. The porphyrin-2(1 H )-one (3 g, 1.7 mol) was dissolved in a stirred solution of dry N,N-dimethylformamide (30 mL). The reaction mixture was allowed to stir at room temperature for about 30 minutes. Tributyl(4-iodobutoxy)diphenyl decane dissolved in dry N,N-dimethylformamide (15 ml) was added portionwise at room temperature (Ref. Example 15, 8.95 g, 2.0 mol) and allowed to stir at room temperature overnight. The reaction mixture was cooled to 0 ° C, EtOAc (EtOAc) The mixture was filtered through celite to remove solid impurities and washed with ethyl acetate (50 mL). The two layers obtained were separated and the ethyl acetate layer was dried and concentrated to dryness. The crude product was purified by using a Combiflash (ethyl acetate/hexane) column to yield 2.5 g (30.19%) of desired compound.

^{1 H-NMR (400MHz, CDCl} 3) δ: 0.90 (s, 9H), 1.69 (m, 2H), 1.85 (m, 2H), 3.72 (m, 2H), 3.93 (s, 3H), 4.25 (m , 2H), 6.76 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 9.2 Hz, J = 2.4 Hz, 1H), 7.42 (m, 6H), 7.64 (dd, J = 1.2 Hz, J =6.4 Hz, 4H), 7.79 (d, J = 9.2 Hz, 1H), 8.13 (s, 1H).

MS: 487 (M+H) ⁺ .

[Reference Example 22] 1-(4-hydroxybutyl)-7-methoxyquin Porphyrin-2(1 H )-one

Tetra-n-butylammonium fluoride (1M, tetrahydrofuran solution; 10.28 ml, 10.2 mol) was added dropwise to 1-(4-{[t-butyl(diphenyl)decylalkyl] at 0 ° C under argon. Oxyethyl}butyl)-7-methoxyquin The porphyrin-2(1 H )-one (2.5 g, 1.1 mol) was dissolved in dry tetrahydrofuran (25 mL). The reaction mixture was stirred at room temperature for about 1 hour. The reaction mixture was cooled to 0 ° C, EtOAc (EtOAc) The two layers were separated and the ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated to dry. The crude product obtained was purified using Combiflash (ethyl acetate/hexane) to yield 1.2 g (94.48%) of desired compound.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.70 (m, 2H), 1.88 (m, 2H), 3.77 (m, 2H), 3.93 (s, 3H), 4.27 (m, 2H), 6.82 (d , J = 2.8 Hz, 1H), 6.93 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 8.13 (s, 1H).

MS: 285 (M+H) ⁺ .

[Reference Example 23] 4-(7-Methoxy-2-oxoquine Porphyrin-1(2 H )-yl)butanal

Dess Martin periodinane (0.683 g, 0.161 mol) was added in portions to 1-(4-hydroxybutyl)-7-methoxyquinoline at 0 ° C under argon. The porphyrin-2( 1H )-one (0.2 g, 0.080 mol) was dissolved in a stirred solution of dichloromethane (10 mL) and the reaction mixture was allowed to stand at room temperature for about 2 hours. The reaction mixture was cooled to 0.degree. C., and the pH was adjusted to 7 by the addition of saturated sodium hydrogen carbonate solution, followed by a saturated sodium thiosulfate solution (15 ml). The two layers were separated and the aqueous layer was extracted with dichloromethane. The dichloromethane layers were combined, dried over anhydrous sodium sulfate and concentrated to dry. The crude product obtained (0.2 g) was used directly in the next step.

[Reference Example 24] 1-(4-{[Terbutyl(diphenyl)decyl]oxy}butyl)-7-difluoromethoxyquin Porphyrin-2(1 H )-one

Lithium hydride (0.041 g, 0.51 mol) was added to 7-difluoromethoxyquin at 0 ° C under argon atmosphere. The porphyrin-2(1 H )-one (1 g, 0.47 mol) was dissolved in a stirred solution of dry N,N-dimethylformamide (10 mL) and then allowed to stir at room temperature about 30 minute. Tributyl(4-iodobutoxy)diphenyl decane dissolved in dry N,N-dimethylformamide (5 ml) was added dropwise at room temperature (Ref. Example 15, 2.5 g, 0.56 mol) and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was cooled to 0 ° C, EtOAc (EtOAc)EtOAc. The two layers were separated and the ethyl acetate layer was dried and concentrated to dry. The obtained crude product was purified using Combiflash (ethyl acetate/hexane) to yield 1.0 g (40.65%) of the desired compound.

^{1 H-NMR (400MHz, CDCl} 3) δ: 0.90 (s, 9H), 1.64 (m, 2H), 1.86 (m, 2H), 3.72 (m, 2H), 4.22 (m, 2H), 6.58 (t , J=72.8 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 7.10 (dd, J=8 Hz, J=2.4 Hz, 1H), 7.42 (m, 6H), 7.64 (dd, J= 2.4Hz, J=8Hz, 4H), 7.88 (d, J=8Hz, 1H), 8.24(s, 1H).

MS: 523 (M+H) ⁺ .

[Reference Example 25] 1-(4-Hydroxybutyl)-7-difluoromethoxyquin Porphyrin-2(1 H )-one

Tetra-n-butylammonium fluoride (1M, tetrahydrofuran solution; 7.6 ml, 0.766 mol) was added dropwise to 1-(4-{[t-butyl(diphenyl)decylalkyl] at 0 ° C under argon. Oxyethyl}butyl)-7-difluoromethoxyquin The porphyrin-2( 1H )-one (1.0 g, 0.383 mol) was dissolved in dry tetrahydrofuran (10 ml), and the mixture was stirred at room temperature for about 1 hour. The reaction mixture was cooled to 0 ° C, EtOAc (EtOAc) Separate the two layers. The ethyl acetate layer was dried and concentrated to dryness. The crude product obtained was purified using Combiflash (ethyl acetate / hexane) to yield 0.4 g (74.07%) of desired compound.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.69 (m, 2H), 1.85 (m, 2H), 3.77 (m, 2H), 4.27 (m, 2H), 6.58 (dd, J = 72.8Hz, 1H ), 7.13 (dd, J = 8.8 Hz, J = 2.4 Hz, 2H), 7.88 (d, J = 8.8 Hz, 1H), 8.25 (s, 1H).

[Reference Example 26] 4-(7-difluoromethoxy-2-oxoquine Porphyrin-1(2 H )-yl)butanal

[Formula 50]

Dess-Martin periodinane (0.895 g, 0.211 mol) was added in portions to 1-(4-hydroxybutyl)-7-difluoromethoxyquinoline at 0 ° C under argon atmosphere. The porphyrin-2( 1H )-one (0.3 g, 0.105 mol) was dissolved in a stirred solution of dichloromethane (10 mL) and the mixture was stirred at room temperature for about 2 hr. The reaction mixture was cooled to 0.degree. C. and saturated sodium bicarbonate solution was added until pH was neutral, then saturated sodium thiosulfate solution (10 ml). The two layers were separated and the aqueous layer was extracted with dichloromethane (x3), concentrated, dried and concentrated to yield crude product (0.3 g) which was used directly in the next step.

[Example 6] 6-[(4 R )-4-{[4-(7-methoxy-2-oxoquinequin Morpholine -1 (2 H) - yl) butyl] amino} -2-oxopyrrolidin-l-yl] -2 H - pyrido [3,2- b] [1,4] -3(4 H )-ketone

4-(7-methoxy-2-oxoquine Morpholine -1 (2 H) - yl) butyraldehyde (Reference Example 23,0.2 g, 0.08 mole) and 6 - [(4 R) -4- amino-2-oxo-side pyrrolidin-1-yl] - 2 H -pyrido[3,2- b ][1,4] -3( 4H )-one (Reference Example 10, 0.201 g, 0.08 mol) was dissolved in a mixture of tetrahydrofuran and methanol (1:1, 10 ml) and stirred under argon for about 30 minutes. The reaction mixture was cooled to 0.degree. C. and sodium triacetoxyborohydride (0.258 g, 1.8 moles) was then portioned and allowed to stand at room temperature for about 2 hours. The reaction mixture was cooled to 0.degree. C. and saturated sodium bicarbonate solution was added until pH was neutral and filtered through Celite. The diatomaceous earth was washed with water (5 ml), and then the organic layer was evaporated. The residue was extracted with MeOH (5%) (EtOAc) (EtOAc) The crude product thus obtained was purified using Combiflash (methanol / dichloromethane) to afford 0.135 g (34.79%) of the desired compound.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.67 (m, 2H), 1.85 (m, 2H), 2.54 (dd, J = 4,17.2Hz, 1H), 2.83 (m, 3H), 3.54 (m , 1H), 3.93 (s, 3H), 4.05 (m, 2H), 4.25 (m, 2H), 4.60 (s, 2H), 6.76 (d, J = 2.8 Hz, 1H), 6.90 (dd, J = 9.2 Hz, J = 2.4 Hz, 1H), 7.14 (d, 8.8 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 8.10 (s, 1H) ), 9.60 (bs, 1H).

MS: 479 (M+H) ⁺ and 477 (MH) ^- .

[Example 7] 6-[(4 R )-4-{[4-(7-Difluoromethoxy-2- oxoquine Morpholine -1 (2 H) - yl) butyl] amino} -2-pyrrolidin-l-yl] -2 H - pyrido [3,2- b] [1,4] -3( 4H )-one (0.08 g (21.97%)) was used in a similar manner to Example 6 using 4-(7-difluoromethoxy-2-oxoquine Morpholine -1 (2 H) - yl) butyraldehyde (Reference Example 26,0.2 g, 0.070 mole) and 6 - [(4 R) -4- amino-2-oxo-side pyrrolidin-1-yl] - 2 H -pyrido[3,2- b ][1,4] -3( 4H )-one (Reference Example 10, 0.175 g, 0.070 mol) was prepared.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.69 (m, 2H), 1.85 (m, 2H), 2.54 (dd, J = 4.4,17.2Hz, 1H), 2.83 (m, 3H), 3.54 (m , 1H), 3.93 (m, 1H), 4.05 (m, 1H), 4.25 (m, 2H), 4.60 (s, 2H), 6.63 (d, J = 72.8 Hz, 1H), 7.10 (dd, J = 7.6 Hz, 2H), 7.17 (d, 8.8 Hz, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 8.22 (s, 1H), 8.9 (bs , 1H).

MS: 515 (M+H) ⁺ .

The method for measuring the antibacterial activity of the compound of the present invention was carried out in accordance with a standard method prescribed by the Japanese Society of Chemotherapy, and the results were shown by MIC (μg/mL) (Table 1).

[Industrial Applicability]

The compound of the present invention, a salt thereof, or a hydrate thereof exhibits broad and strong antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, and it also has excellent safety. Therefore, the compound of the present invention, a salt thereof, or a hydrate thereof is expected to exhibit an excellent effect for treating and/or preventing an infectious disease.

Claims (11)

A compound represented by the following formula (1) or a salt thereof: Wherein R represents a hydrogen atom; m represents an integer of 1 or 2; n represents an integer of 0 or 1; and Ar ¹ represents a bicyclic heterocyclic group represented by the following formula: Wherein: A ^a represents nitrogen; A ^b and A ^c represent CH; R ¹ represents a methoxy group, a difluoromethoxy group, a halogen atom, or a cyano group; R ² represents a hydrogen atom or a halogen atom; and Ar ² represents a formula Representative bicyclic heterocyclic group: The compound or a salt thereof according to claim 1, wherein the sum of m and n is 1, 2 or 3. The compound or a salt thereof according to claim 1 or 2, wherein R ¹ represents a methoxy group. The compound or a salt thereof according to claim 1 or 2, wherein R ¹ represents a difluoromethoxy group. The compound or a salt thereof according to claim 1 or 2, wherein R ¹ represents a cyano group. The compound or a salt thereof according to claim 1 or 2, wherein R ¹ and R ^{2 each} represent a halogen atom. The compound or a salt thereof according to claim 6, wherein R ¹ and R ^{2 each} represent a fluorine atom. A compound according to claim 1 or a salt thereof, which is selected from the group consisting of 3-side oxy-4-(3-{[(3 R )-5-side oxy-1-(3-side) Oxy-3,4-dihydro-2 H -pyrido[3,2- b ][1,4] -6-yl)pyrrolidin-3-yl]amino}propyl)-3,4-dihydroquine Porphyrin-6-carbonitrile; 3-oxo-4-[3-({[(3 R )-5-sideoxy-1-(3- side oxy-3,4-dihydro-2 H -pyridyl) [3,2- b ][1,4] -6-yl)pyrrolidin-3-yl]methyl}amino)propyl]-3,4-dihydroquine Phenyl-6-carbonitrile; 6-[(4 R )-4-({3-[7-(difluoromethoxy)-2-oxoquine Morpholine -1 (2 H) - yl] propyl} amino) -2-oxo pyrrolidin-l-yl] -2 H - pyrido [3,2- b] [1,4] -3(4 H )-keto; 6-[(4 R )-4-[({3-[7-(difluoromethoxy)-2-oxyquine Morpholine -1 (2 H) - yl] propyl} amino) methyl] -2-oxo-pyrrolidin-l-yl] -2 H - pyrido [3,2- b] [1,4] -3(4 H )-keto; 6-[(4 R )-4-{[4-(6,7-difluoro-2-oxoquine -1( 2H )-yl)butyl]amino}-2-oxopyrrolidin-1-yl]-3,4-dihydro- 2H -pyrido[3,2- b ][1, 4] 2-ketone; 6-[(4 R )-4-{[4-(7-methoxy-2-oxoquine) Morpholine -1 (2 H) - yl) butyl] amino} -2-pyrrolidin-l-yl] -2 H - pyrido [3,2- b] [1,4] -3( 4H )-one; and 6-[(4 R )-4-{[4-(7-difluoromethoxy-2-oxoquine) Morpholine -1 (2 H) - yl) butyl] amino} -2-pyrrolidin-l-yl] -2 H - pyrido [3,2- b] [1,4] -3(4 H )-ketone. An agent comprising a compound according to any one of claims 1 to 8 or a salt thereof as an active ingredient agent thereof. A therapeutic agent for an infectious disease, which comprises, as an active ingredient thereof, a compound according to any one of claims 1 to 8 or a salt thereof. A method for treating an infectious disease, which comprises administering a compound according to any one of claims 1 to 8 or a salt thereof.