TW201833119A - Tricyclic compounds having sulfinyl or sulfonyl and pharmaceutical compositions containing them - Google Patents

Abstract

It is intended to provide a compound that exhibits a wide antibacterial spectrum against various bacteria including gram-negative bacteria, and a pharmaceutical composition having an antibacterial activity against carbapenem-resistant bacteria. A pharmaceutical composition comprises a compound represented by the formula (I), an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof. (In the formula, -W- is -S(=O)- or -S(=O)2-, -T- is -CR<SP>4A</SP>R<SP>4B</SP>- or -CR<SP>5A</SP>R<SP>5B</SP> -CR<SP>6A</SP>R<SP>6B</SP>-, R<SP>4A</SP>, R<SP>4B</SP>, R<SP>5A</SP>, R<SP>5B</SP>, R<SP>6A</SP> and R<SP>6B</SP> are each independently a hydrogen atom or the like, R1 is a substituted or unsubstituted heterocyclic group or the like, R<SP>2A</SP> and R<SP>2B</SP> are each independently a hydrogen atom or the like, or R<SP>2A</SP> and R<SP>2B</SP> together form a substituted or unsubstituted methylidene and the like, and R3 is a hydrogen atom or the like.).

Description

 Tricyclic compound having sulfinyl group or sulfonyl group and pharmaceutical composition containing the same  

The present invention relates to a novel tricyclic compound having an antibacterial action, an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt, or a hydrate thereof, and a pharmaceutical composition containing the same.

To date, a variety of β -endoamine drugs have been developed, and β -endoxime drugs are clinically very important antibacterial drugs. However, by generating the β - lactam drugs decomposition β - lactam enzyme obtain β - lactam resistant strains of drugs is increasing.

According to the molecular classification of Ambler, β-endoprolinase is roughly classified into four categories. That is, Class A (TEM type, SHV type, CTX-M type, KPC type, etc.), Class B (NDM type, IMP type, VIM type, L-1 type, etc.), Class C (AmpC type, ADC type, etc.) ), class D (OXA type, etc.). Among these, it is known that A, C, and D are serine-β-endoguanidase, and on the other hand, class B is roughly classified as metal-β-endoguanidase, which are respectively subjected to different mechanisms. Beta-naprostamine drug hydrolysis.

In recent years, in addition to the expanded type A (ESBL) and D types of the matrix region, the serine-β-endoprolase containing Klebsiella pneumoniae Carbapenemase (KPC), Contains the production of a B-type metal-β-endoaminase, whereby there is a highly resistant gram-free drug for a variety of β-endoamine drugs including cephem and carbapenem. The negative bacteria, the presence of such Gram-negative bacteria has become a clinical problem. In particular, it is known that enterobacteriaceae bacteria which produce KPC and metal-β-endoprostanase exhibit high resistance to carbapenem-based antibacterial drugs which are important in the treatment of Gram-negative bacterial infections.

The β-namidamide drug exhibits an antibacterial action by inhibiting cell wall synthesis enzyme (known as Penicillin Binding Protein (PBP) described below) of a bacteria having transpeptidase activity (Non-Patent Document 1). On the other hand, the β-endoprotonase produced by the drug-resistant bacteria as described above effectively recognizes and decomposes the β-endamine drug, thereby deactivating the β-endamine drug and losing the antibacterial activity. active. Therefore, if it is possible to avoid the recognition of β-endosaminolase and maintain the inhibitory activity against PBP, a β-endoamine drug which is also effective against drug-resistant bacteria can be created. However, the similarity of the matrix identification of the two is very high, and it is extremely difficult to distinguish the structure, and the creation of the β-endamine drug which is effective against the resistant bacteria is hindered.

Although a cephem compound exhibiting moderate activity to Gram-negative bacteria including Gram-negative bacteria producing metal-β-endosaminolase has been known (Example: Patent Document 1), it is still ardent It is hoped that a more effective antibacterial activity can be developed, especially for various Gram-negative bacteria producing β-endosaminolase.

In Patent Documents 2 and 3, a novel skeleton β-endoxime-based compound has been taught, but the antibacterial activity against the carbapenem-resistant bacteria and the like which have been a problem in recent years has not been described. Further, from the viewpoint of the antibacterial activity described, it is not conceivable that the compound group having the skeleton has an antibacterial activity against carbapenem-resistant bacteria.

 [Previous Technical Literature]    [Patent Literature]  

[Patent Document 1] International Publication No. 2007/119511

[Patent Document 2] European Patent Application Publication No. 0253337

[Patent Document 3] European Patent Application Publication No. 0249909

 [Non-patent literature]  

[Non-Patent Document 1] Chemical Reviews, 2005, Vol. 105, 395-424

The present invention provides a tricyclic compound comprising a substituted or unsubstituted 5-oxotetrahydrofuran ring or a 6-oxotetrahydropyran ring, and having a sulfinyl group or a sulfonyl group, the tricyclic compound It exhibits a strong antibacterial spectrum for a variety of bacteria including Gram-negative bacteria.

Further, a pharmaceutical composition comprising a tricyclic compound, an ester thereof or a pharmaceutically acceptable salt, or a hydrate of the same, which comprises a substituted or unsubstituted 5-oxo group is provided The tetrahydrofuran ring is either a substituted or unsubstituted 6-oxotetrahydropyran ring and has a sulfinyl group or a sulfonyl group, and the pharmaceutical composition has an antibacterial activity against a carbapenem-resistant bacterium. It is preferred to provide a compound or a pharmaceutical composition containing the compound which exhibits strong antibacterial activity against Gram-negative bacteria which produce β-endosaminolase. More preferably, a compound or a pharmaceutical composition containing the compound for producing a KPC type carbapenemase (Klebsiella pneumoniae carbapenemase) and a B type metal-β-endosminase (MBL) is provided. Negative bacteria show strong antibacterial activity. Still more preferably, a compound or a pharmaceutical composition containing the same for producing a matrix-specific expanded β-endoprostase (ESBL) and/or C type in addition to the above β-endoprostanase is provided. Gram-negative bacteria of β-endosaminolase also showed potent antibacterial activity.

The present invention provides a pharmaceutical composition which has at least the following structural features, thereby solving the above problems and having an antibacterial action against carbapenem-resistant bacteria.

1) A tricyclic parent core comprising a 6-membered ring having a sulfinylene group or a sulfonyl group.

2) A tricyclic parent core comprising a substituted or unsubstituted 5-oxotetrahydrofuran ring or a substituted or unsubstituted 6-oxotetrahydropyran ring.

3) A decylamine substituent (carbonylamine group having a substituent) on the indoleamine ring in the tricyclic nucleus.

(Item 1) A pharmaceutical composition comprising a compound represented by the formula (I), an ester thereof or a salt which is pharmaceutically acceptable, or a hydrate thereof. (wherein, -W- is -S(=O)- or -S(=O) ₂ -; -T- is -CR ^4A R ^4B - or -CR ^5A R ^5B -CR ^6A R ^6B -;R ^4A And R ^4B , R ^5A , R ^5B , R ^6A and R ^6B are each independently a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, a decyl group, a decyloxy group, a thiol group, a sulfo group, a diphosphoryl group, a cyano group, Nitro, ureido, indolyl, fluorenyl, substituted or unsubstituted amine, substituted or unsubstituted aminecarboxamidine, substituted or unsubstituted amine sulfonyl group, substituted or unsubstituted alkyl group, substituted Or an unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyloxy group, a substituted or unsubstituted alkynyloxy group, a substituted or unsubstituted alkanesulfonyl group Alkyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenyl Sulfosyl, Alken or unsubstituted alkynyl sulfinyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or not Substituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclicoxy group, substituted or unsubstituted non-aromatic heterocyclic oxy group, substituted or unsubstituted aromatic carboepoxy group, substituted or unsubstituted Aromatic heterocyclic oxy group, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group, substituted or unsubstituted aromatic carbo oxycarbonyl group, substituted Or an unsubstituted aromatic heterocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic carbocyclic thio group, a substituted or unsubstituted non-aromatic heterocyclic thio group, a substituted or unsubstituted aromatic carbocyclic thio group, Substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted non-aromatic carbosulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic carbon Cyclosulfinyl, substituted or unsubstituted aromatic heterocyclic sulfin a substituted, unsubstituted, non-aromatic carbosulfonyl group, a substituted or unsubstituted non-aromatic heterocyclic sulfonyl group, a substituted or unsubstituted aromatic carbocyclic sulfonyl group, or a substituted or unsubstituted An aromatic heterocyclic sulfonyl group; R ¹ is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group; R ^2A and R ^2B are a) R ^2A and R ^2B are each independently a hydrogen atom; , substituted or unsubstituted amino, sulfo, substituted or unsubstituted sulfonyl, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted amide, hydroxy, fluorenyl, or the substituted carbonyloxy group, or form b) R ^2A and R ^2B together a substituted or unsubstituted alkylene group, a substituted or unsubstituted hydroxyimino, or ^{= N-NR 13A R 13B;} R 13A and R ^{13B is} independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted amine carbenyl group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted group. heterocyclic group; R ³ is a hydrogen atom, -OCH ₃ or -NH-CH (= O); R 11 is carboxy or tetrazolyl; R ^7A and R ^7B are each independently hydrogen Sub or substituted or unsubstituted alkyl).

(Claim 2) The pharmaceutical composition according to Item 1, which is a compound containing R ¹ as a substituted or unsubstituted aromatic heterocyclic group, an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt, or the like In hydrates.

(A) The pharmaceutical composition according to the first aspect, which is a compound containing R ¹ as a group represented by the following formula, an ester thereof, or a salt which is pharmaceutically acceptable, or a hydrate thereof. (wherein X is CH, CCl, CF, or N).

The pharmaceutical composition according to any one of the items 1 to 3, wherein the R ^2A and the R ^2B together form a methylene group having the substituents shown below:

Or a compound of a substituted or unsubstituted hydroxyimino group shown below, an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt, or a hydrate thereof: (wherein R ¹⁰ is a hydrogen atom, a sulfo group, a substituted or unsubstituted alkoxysulfonyl group, a substituted or unsubstituted alkenyloxysulfonyl group, a substituted or unsubstituted alkynylsulfonyl group, a substitution Or an unsubstituted carbooxysulfonyl group, a substituted or unsubstituted heterocyclooxysulfonyl group, a diphosphoryl group, a substituted or unsubstituted amine carbenyl group, a substituted or unsubstituted amine sulfonyl group, Substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted oxycarbonyl, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocarbonylcarbonyl, substituted or unsubstituted heterocyclic oxycarbonyl, substituted Or an unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group).

The pharmaceutical composition according to any one of the items 1 to 3, which is a compound containing R ^2A and R ^2B together as a group represented by the following formula, or an ester thereof or the like The salt allowed, or the hydrates: (wherein R ⁸ and R ⁹ may each independently be a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or a non-substituted group. a substituted carbocyclic group, or a substituted or unsubstituted heterocyclic group, or R ⁸ and R ⁹ together form a substituted or unsubstituted methylene group, or R ⁸ and R ⁹ together with an adjacent atom form a substituted or unsubstituted a non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; Q is a single bond, a substituted or unsubstituted carbocyclic diyl group or a substituted or unsubstituted heterocyclic diyl group; m is 0 to 3 An integer; R ¹² is a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a carboxyl group, a hydroxyl group, a substituted or a non-substituted group. Substituted amine, sulfo, phosphonium, cyano, hydroxyiminomethyl, amine carbhydryl, substituted or unsubstituted monoalkylamine, fluorenyl, substituted or unsubstituted dialkylamine Mercapto, substituted or unsubstituted monoalkylamine sulfonyl, substituted or unsubstituted dialkylamine sulfonyl, substituted or Substituted alkanesulfonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkanesulfonyl imido, alkoxycarbonylamino, alkoxyamine, mercaptoamine Sulfhydryl, ureido, sulfhydryl, alkanesulfonylamino, sulfonyl, sulfonylamino, alkanesulfonylaminomethylamino, alkylamine sulfonylaminocarbyl, A substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted 4th-order ammonium group).

The pharmaceutical composition according to any one of the items 1 to 5, wherein the compound containing R ³ is a hydrogen atom, an ester thereof or a salt which is equivalent to a pharmaceutical agent, or the like Hydrate.

The pharmaceutical composition according to any one of the items 1 to 6 wherein -T- is -CR ^4A R ^4B -, and R ^4A and R ^4B are each independently a hydrogen atom or A compound which is a substituted or unsubstituted alkyl group, an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt or a hydrate thereof.

The pharmaceutical composition according to any one of the items 1 to 7 wherein the compound containing -W- is -S(=O)-, the ester thereof or the equivalent of pharmaceutically acceptable a salt or a hydrate thereof.

The pharmaceutical composition according to any one of the items 1 to 7 wherein -W- is a compound of the following formula, an ester thereof or a salt which is pharmaceutically acceptable or contains The hydrates:

The pharmaceutical composition according to any one of the items 1 to 7, wherein the compound, the ester thereof or the salt which is pharmaceutically acceptable or contains the hydrate , -W- is the following:

The pharmaceutical composition according to any one of the items 1 to 7 wherein the compound containing -W- is -S(=O) ₂ -, the ester thereof or the equivalent of the pharmaceutical composition A salt that is tolerated or contains such a hydrate.

(Item 12) as claimed in any one of the pharmaceutical composition according to items 1 to item 11, comprising based compound R ¹¹ is carboxyl, an ester thereof or the equivalent of a pharmaceutically tolerated salt, or contains such Hydrate.

The pharmaceutical composition according to any one of the items 1 to 12, wherein R ^7A and R ^7B are a compound having a hydrogen atom, an ester thereof or a salt which is pharmaceutically acceptable Or contain such hydrates.

The pharmaceutical composition according to the first aspect, which comprises a compound of the formula (I), an ester thereof, or a pharmaceutically acceptable salt or a hydrate thereof: [where, -W- is the following formula: R ^4A is a hydrogen atom; R ^4B is a hydrogen atom or a methyl group; and R ¹ is the following formula: (wherein, X is CH); R ^7A and R ^7B are a hydrogen atom; and R ^2A and R ^2B together form a hydroxyimino group or the following formula: (wherein R ⁸ and R ⁹ may each independently be a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, an alkyl group, or a hydroxyalkyl group, or R ⁸ and R ⁹ together with an adjacent carbon atom form a substituted or unsubstituted non-substituted group. An aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; m is an integer of 0 to 3, and R ¹² is a hydrogen atom, a carboxyl group, a sulfo group, an amine carbenyl group, a hydroxylamine formamyl group, an alkoxy group Aminomethyl hydrazino, or hydroxy); R ³ is a hydrogen atom; R ¹¹ is a carboxy group].

The pharmaceutical composition according to the item 1, wherein the compound represented by the formula (I) is the compound I-001, I-004, I-005, I-007, I-009, I-015. , I-023, I-024, I-026, I-027, I-047, I-048, I-049, I-052, I-053, I-059, I-060, and I-061 Either.

The pharmaceutical composition according to any one of the items 1 to 15, which is an antibacterial agent.

(Item 17) An antibacterial agent which comprises a compound represented by the formula (I), an ester thereof or a salt which is pharmaceutically acceptable, or a hydrate thereof. (wherein, -W- is -S(=O)- or -S(=O) ₂ -; -T- is -CR ^4A R ^4B - or -CR ^5A R ^5B -CR ^6A R ^6B -;R ^4A And R ^4B , R ^5A , R ^5B , R ^6A and R ^6B are each independently a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, a decyl group, a decyloxy group, a thiol group, a sulfo group, a diphosphoryl group, a cyano group, Nitro, ureido, indolyl, fluorenyl, substituted or unsubstituted amine, substituted or unsubstituted aminecarboxamidine, substituted or unsubstituted amine sulfonyl group, substituted or unsubstituted alkyl group, substituted Or an unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyloxy group, a substituted or unsubstituted alkynyloxy group, a substituted or unsubstituted alkanesulfonyl group Alkyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenyl Sulfosyl, Alken or unsubstituted alkynyl sulfinyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or not Substituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclicoxy group, substituted or unsubstituted non-aromatic heterocyclic oxy group, substituted or unsubstituted aromatic carboepoxy group, substituted or unsubstituted Aromatic heterocyclic oxy group, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group, substituted or unsubstituted aromatic carbo oxycarbonyl group, substituted Or an unsubstituted aromatic heterocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic carbocyclic thio group, a substituted or unsubstituted non-aromatic heterocyclic thio group, a substituted or unsubstituted aromatic carbocyclic thio group, Substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted non-aromatic carbosulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic carbon Cyclosulfinyl, substituted or unsubstituted aromatic heterocyclic sulfin a substituted, unsubstituted, non-aromatic carbosulfonyl group, a substituted or unsubstituted non-aromatic heterocyclic sulfonyl group, a substituted or unsubstituted aromatic carbocyclic sulfonyl group, or a substituted or unsubstituted An aromatic heterocyclic sulfonyl group; R ¹ is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group; R ^2A and R ^2B are a) R ^2A and R ^2B are each independently a hydrogen atom; , substituted or unsubstituted amino, sulfo, substituted or unsubstituted sulfonyl, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted amide, hydroxy, or substituted a carbonyloxy group, or b) R ^2A and R ^2B together form a substituted or unsubstituted methylene group, a substituted or unsubstituted hydroxyimino group, or =N-NR ^13A R ^13B ; R ^13A and R ^13B are each independently Is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted amine carbenyl group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic ring. group; R ³ is a hydrogen atom, -OCH ₃ or -NH-CH (= O); R 11 is carboxy or tetrazolyl; R ^7A and R ^7B are each independently a hydrogen atom or A substituted or unsubstituted alkyl).

(Item 18) A cell wall synthesis inhibitor comprising a compound represented by the following formula (I), an ester thereof or a pharmaceutically acceptable salt or a hydrate thereof: (wherein, -W- is -S(=O)- or -S(=O) ₂ -; -T- is -CR ^4A R ^4B - or -CR ^5A R ^5B -CR ^6A R ^6B -;R ^4A And R ^4B , R ^5A , R ^5B , R ^6A and R ^6B are each independently a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, a decyl group, a decyloxy group, a thiol group, a sulfo group, a diphosphoryl group, a cyano group, Nitro, ureido, indolyl, fluorenyl, substituted or unsubstituted amine, substituted or unsubstituted aminecarboxamidine, substituted or unsubstituted amine sulfonyl group, substituted or unsubstituted alkyl group, substituted Or an unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyloxy group, a substituted or unsubstituted alkynyloxy group, a substituted or unsubstituted alkanesulfonyl group Alkyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenyl Sulfosyl, Alken or unsubstituted alkynyl sulfinyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or not Substituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclicoxy group, substituted or unsubstituted non-aromatic heterocyclic oxy group, substituted or unsubstituted aromatic carboepoxy group, substituted or unsubstituted Aromatic heterocyclic oxy group, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group, substituted or unsubstituted aromatic carbo oxycarbonyl group, substituted Or an unsubstituted aromatic heterocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic carbocyclic thio group, a substituted or unsubstituted non-aromatic heterocyclic thio group, a substituted or unsubstituted aromatic carbocyclic thio group, Substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted non-aromatic carbosulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic carbon Cyclosulfinyl, substituted or unsubstituted aromatic heterocyclic sulfin a substituted, unsubstituted, non-aromatic carbosulfonyl group, a substituted or unsubstituted non-aromatic heterocyclic sulfonyl group, a substituted or unsubstituted aromatic carbocyclic sulfonyl group, or a substituted or unsubstituted An aromatic heterocyclic sulfonyl group; R ¹ is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group; R ^2A and R ^2B are a) R ^2A and R ^2B are each independently a hydrogen atom; , substituted or unsubstituted amino, sulfo, substituted or unsubstituted sulfonyl, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted amide, hydroxy, or substituted a carbonyl group, or b) R ^2A and R ^2B together form a substituted or unsubstituted alkylene group, a substituted or unsubstituted hydroxyimino, or ^{= N-NR 13A R 13B;} R 13A and R ^13B are each independently Is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted amine carbenyl group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic ring. group; R ³ is a hydrogen atom, -OCH ₃ or -NH-CH (= O); R 11 is carboxy or tetrazolyl; R ^7A and R ^7B are each independently a hydrogen atom It is a substituted or unsubstituted alkyl).

(Item 19) a compound, an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt, or a hydrate of the above, the above compounds are I-075, I-076, I-077, I-078, I-079 Any of I-080, I-082, I-083, I-084, I-087, I-093, I-110, I-121, I-132, and I-144.

(20th) A pharmaceutical composition comprising the compound according to item 19, an ester thereof or a salt which is pharmaceutically acceptable or a hydrate thereof.

(Item 21) The pharmaceutical composition according to Item 20, which has an antibacterial action.

(Item 1B) A pharmaceutical composition comprising a compound represented by the following formula, an ester thereof or a salt which is pharmaceutically acceptable, or a hydrate thereof. (wherein, -W- is -S(=O)- or -S(=O) ₂ -; -T- is -CR ^4A R ^4B - or -CR ^5A R ^5B -CR ^6A R ^6B -;R ^4A And R ^4B , R ^5A , R ^5B , R ^6A and R ^6B are each independently a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, a decyl group, a decyloxy group, a thiol group, a sulfo group, a diphosphoryl group, a cyano group, Nitro, ureido, indolyl, fluorenyl, substituted or unsubstituted amine, substituted or unsubstituted aminecarboxamidine, substituted or unsubstituted amine sulfonyl group, substituted or unsubstituted alkyl group, substituted Or an unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyloxy group, a substituted or unsubstituted alkynyloxy group, a substituted or unsubstituted alkanesulfonyl group Alkyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenyl Sulfosyl, Alken or unsubstituted alkynyl sulfinyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or not Substituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclicoxy group, substituted or unsubstituted non-aromatic heterocyclic oxy group, substituted or unsubstituted aromatic carboepoxy group, substituted or unsubstituted Aromatic heterocyclic oxy group, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group, substituted or unsubstituted aromatic carbo oxycarbonyl group, substituted Or an unsubstituted aromatic heterocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic carbocyclic thio group, a substituted or unsubstituted non-aromatic heterocyclic thio group, a substituted or unsubstituted aromatic carbocyclic thio group, Substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted non-aromatic carbosulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic carbon Cyclosulfinyl, substituted or unsubstituted aromatic heterocyclic sulfin a substituted, unsubstituted, non-aromatic carbosulfonyl group, a substituted or unsubstituted non-aromatic heterocyclic sulfonyl group, a substituted or unsubstituted aromatic carbocyclic sulfonyl group, or a substituted or unsubstituted An aromatic heterocyclic sulfonyl group; R 1 is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group; R ^2A and R ^2B are a) R ^2A and R ^2B are each independently a hydrogen atom; A substituted or unsubstituted amino group, a sulfo group, a substituted or unsubstituted amine sulfonyl group, a carboxyl group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted amine carbenyl group, a hydroxyl group, or a substituted carbonyl group An oxy group, or b) R ^2A and R ^2B together form a substituted or unsubstituted methylene group, or a substituted or unsubstituted hydroxyimine group; R ³ is a hydrogen atom, -OCH ₃ or -NH-CH ( = O); R ¹¹ is carboxy or tetrazolyl; R ^7A and R ^7B are each independently a hydrogen atom or a substituted or unsubstituted alkyl).

The pharmaceutical composition according to Item 1B, which is a compound containing R ¹ as a substituted or unsubstituted aromatic heterocyclic group, an ester thereof, or a salt which is equivalent to a pharmaceutically acceptable salt, or the like Hydrate.

The pharmaceutical composition according to Item 1B, which is a compound containing R ¹ as a group represented by the following formula, an ester thereof or a salt which is pharmaceutically acceptable, or a hydrate thereof, (wherein X is CH, CCl, CF, or N).

The pharmaceutical composition according to any one of the items 1 to 3, wherein the R ^2A and the R ^2B together form a methylene group having the substituents shown below: or

Or a compound of a substituted or unsubstituted hydroxyimino group shown below, an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt, or a hydrate thereof: (Wherein, R ¹⁰ is a hydrogen atom or a substituted or unsubstituted alkyl).

The pharmaceutical composition according to any one of the items 1 to 3, which is a compound containing R ^2A and R ^2B together as a group represented by the following formula, or an ester thereof or the like The salt allowed, or the hydrates: (wherein R ⁸ and R ⁹ may each independently be a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group, Or R ⁸ and R ⁹ together form a substituted or unsubstituted methylene group, or R ⁸ and R ⁹ together with an adjacent atom form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic hybrid Ring; Q is a single bond, a substituted or unsubstituted carbocyclic diyl group or a substituted or unsubstituted heterocyclic diyl group; m is an integer of 0 to 3; R ¹² is a hydrogen atom, a halogen, an alkyl group, a haloalkyl group , alkoxy, carboxy, hydroxy, amine, sulfo, diphosphoryl, boron, cyano, hydroxyiminomethyl, amine carbhydryl, alkoxycarbonylamine, alkoxyamine Sulfhydryl, hydroxylamine, mercapto, ureido, alkanesulfonylamino, sulfonyl, sulfonylamino, alkanesulfonylaminomethylamino, alkylamine sulfonylamine An fluorenyl, substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted 4th-order ammonium group).

The pharmaceutical composition according to any one of the items 1 to 5, wherein the compound containing R ³ is a hydrogen atom, an ester thereof, or a salt which is pharmaceutically acceptable, or the like Hydrate.

The pharmaceutical composition according to any one of the items 1 to ^4, wherein -T- is -CR ^4A R ^4B -, and R ^4A and R ^4B are each independently a hydrogen atom or A compound which is a substituted or unsubstituted alkyl group, an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt or a hydrate thereof.

The pharmaceutical composition according to any one of the items 1 to 4, wherein the compound containing -W- is -S(=O)-, the ester thereof or the equivalent of pharmaceutically acceptable a salt, or a hydrate of the same.

The pharmaceutical composition according to any one of the items 1 to 7 of the present invention, wherein -W- is a compound of the following formula, an ester thereof or a salt which is pharmaceutically acceptable or Etc. hydrate:

The pharmaceutical composition according to any one of the items 1 to 7 of the present invention, wherein -W- is a compound of the following formula, an ester thereof or a salt which is pharmaceutically acceptable or Etc. hydrate:

The pharmaceutical composition according to any one of the items 1 to 4, wherein the compound containing -W- is -S(=O) ₂ -, the ester thereof or the equivalent of the pharmaceutical product Permissible salts, or such hydrates.

The pharmaceutical composition according to any one of the items 1 to 4, wherein the compound having R ¹¹ is a carboxyl group, an ester thereof, or a salt which is equivalent to a pharmaceutically acceptable substance, or the like Hydrate.

The pharmaceutical composition according to any one of the items 1 to 4, wherein the R ^7A and R ^7B are a hydrogen atom, or the compound wherein R ^7A is an alkyl group and R ^7B is a hydrogen atom And the ester thereof or the salt which is pharmaceutically acceptable or the hydrate.

The pharmaceutical composition according to Item 1B, wherein the compound of the formula (I) is a compound of the following formula, an ester thereof, or a salt which is pharmaceutically acceptable, or a hydrate thereof: (where, -W- is the following formula: R ^4A is a hydrogen atom; R ^4B is a hydrogen atom or a methyl group; and R ¹ is the following formula: (wherein, X is CH); R ^7A is a hydrogen atom or an alkyl group; R ^7B is a hydrogen atom; and R ^2A and R ^2B together form a hydroxyimino group or the following formula: (wherein R ⁸ and R ⁹ may each independently be a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, an alkyl group, or a hydroxyalkyl group, or R ⁸ and R ⁹ together with an adjacent carbon atom form a substituted or unsubstituted non-substituted group. An aromatic carbocyclic ring or a substituted or non-substituted non-aromatic heterocyclic ring; m is an integer from 0 to 3, and R ¹² is a hydrogen atom, a carboxyl group, a sulfo group, an amine carbenyl group, a hydroxylamine formamyl group, an alkoxy group Aminomethylhydrazine or a hydroxy group; R ³ is a hydrogen atom; and R ¹¹ is a carboxyl group.

The pharmaceutical composition according to any one of the items 1 to 4, wherein the pharmaceutical composition has an antibacterial action.

(Item 1A) A pharmaceutical composition comprising a compound represented by the following formula, an ester thereof, or a pharmaceutically acceptable salt or a hydrate thereof (wherein, -W- is -S(=O)- or -S(=O) ₂ -; -T- is -CR ^4A R ^4B - or -CR ^5A R ^5B -CR ^6A R ^6B -;R ^{4A , R 4B, R 5A, R} 5B, R 6A and R ^6B are each independently a hydrogen atom, a halogen, hydroxy, carboxy, acyl, acyl group, mercapto group, sulfo group, phospho group, a cyano group, Nitro, ureido, indolyl, fluorenyl, substituted or unsubstituted amine, substituted or unsubstituted aminecarboxamidine, substituted or unsubstituted amine sulfonyl group, substituted or unsubstituted alkyl group, substituted Or an unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyloxy group, a substituted or unsubstituted alkynyloxy group, a substituted or unsubstituted alkanesulfonyl group Alkyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenyl Sulfosyl, Alken or unsubstituted alkynyl sulfinyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or not Substituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclicoxy group, substituted or unsubstituted non-aromatic heterocyclic oxy group, substituted or unsubstituted aromatic carboepoxy group, substituted or unsubstituted Aromatic heterocyclic oxy group, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group, substituted or unsubstituted aromatic carbo oxycarbonyl group, substituted Or an unsubstituted aromatic heterocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic carbocyclic thio group, a substituted or unsubstituted non-aromatic heterocyclic thio group, a substituted or unsubstituted aromatic carbocyclic thio group, Substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted non-aromatic carbosulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic carbon Cyclosulfinyl, substituted or unsubstituted aromatic heterocyclic sulfin a substituted, unsubstituted, non-aromatic carbosulfonyl group, a substituted or unsubstituted non-aromatic heterocyclic sulfonyl group, a substituted or unsubstituted aromatic carbocyclic sulfonyl group, or a substituted or unsubstituted An aromatic heterocyclic sulfonyl group; R ¹ is a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group; R ^2A and R ^2B are a) R ^2A and R ^2B are each independently a hydrogen atom; , substituted or unsubstituted amino, sulfo, substituted or unsubstituted sulfonyl, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted amide, hydroxy, or substituted A carbonyloxy group, or b) R ^2A and R ^2B together form a substituted or unsubstituted methylene group, or a substituted or unsubstituted hydroxyimine group; R ³ is a hydrogen atom, -OCH ₃ or -NH-CH (=O)).

(Ath 2A) The pharmaceutical composition according to Item 1A, which is a compound containing R1 as a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group, an ester thereof or the like It is equivalent to the salt allowed in the pharmaceutical industry, or the hydrate.

(Ath. 3A) The pharmaceutical composition according to Item 1A, which is a compound containing R ¹ as a group represented by the following formula, an ester thereof or a pharmaceutically acceptable salt or a hydrate thereof: or (wherein X is CH, CCl, CF, CBr or N).

The pharmaceutical composition according to any one of the items 1 to 3, wherein R ^2A and R ^2B together form a methylene group having the substituents shown below: or

Or a compound of a substituted or unsubstituted hydroxyimino group shown below, an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt, or a hydrate thereof: (wherein R ¹⁰ is a hydrogen atom, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted alkyl group).

(Item 5A) as Item 1A to 3A, item pharmaceutical composition according to any one, the system contains R ^2A and R ^2B together into a group of compounds of the formula shown, an ester thereof or a pharmaceutically equal to the The salt allowed, or the hydrates: (wherein R ⁸ and R ⁹ may each independently be a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group, Or R ⁸ and R ⁹ together form a substituted or unsubstituted methylene group, or R ⁸ and R ⁹ together with an adjacent atom form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic hybrid Ring; Q is a single bond, a substituted or unsubstituted carbocyclic diyl group or a substituted or unsubstituted heterocyclic diyl group; m is an integer from 0 to 3.

(Item 6A)

The pharmaceutical composition according to any one of the items 1 to 5, wherein the compound having R ³ is a hydrogen atom or -OCH ₃ , an ester thereof or a salt which is equivalent to a pharmaceutically acceptable substance, or the like Hydrate.

(Item 7A)

The pharmaceutical composition according to any one of the items 1 to 6 wherein the compound containing -T- is -CR ^4A R ^4B -, the ester thereof or the salt which is equivalent to the pharmaceutical, or the like Hydrate.

(Item 8A)

The pharmaceutical composition according to any one of the items 1 to 7 of the present invention, wherein the compound containing -W- is -S(=O)-, the ester thereof or the salt which is equivalent to the pharmaceutically acceptable substance, or the Etc. hydrate.

(Item 9A)

The pharmaceutical composition according to any one of the items 1 to 7 of the present invention, wherein -W- is a compound of the following formula, an ester thereof or a pharmaceutically acceptable salt or a hydrate thereof:

(Item 10A)

The pharmaceutical composition according to any one of the items 1 to 7 of the present invention, which contains -W- a compound of the following formula, an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt or a hydrate thereof :

(Item 11A)

The pharmaceutical composition according to any one of the items 1 to 7 of the present invention, wherein the compound containing -W- is -S(=O) ₂ -, the ester thereof or the salt which is pharmaceutically acceptable or These hydrates.

(Item 12A)

The pharmaceutical composition according to any one of items 1 to 11A has an antibacterial action.

(Item 13A)

A pharmaceutical composition which is a pharmaceutical composition for oral administration, which comprises the compound according to any one of items 1B to 14B and any one of items 1A to 11A, an ester thereof or the same. Permissible salts, or such hydrates.

(Item 14A) The pharmaceutical composition according to Item 13A, which is a tablet, a powder, a granule, a capsule, a pill, a film, a suspension, an emulsion, an elixir, a syrup, a lemonade (lemonades) , alcohol, aroma, extract, decoction or tincture.

(Item 15A)

The pharmaceutical composition according to Item 14A, which is a sugar-coated tablet, a film-coated tablet, an enteric coated tablet, a sustained-release tablet, a throat tablet, a sublingual tablet, a buccal tablet, a chewable tablet, an orally disintegrating tablet, or a granule for syrup ( Dry syrup), soft capsules, microcapsules or sustained release capsules.

(Item 16A)

A pharmaceutical composition comprising a pharmaceutical composition according to any one of items 1B to 14B and 1A to 11A, or an ester thereof, or a pharmaceutical composition thereof. Permissible salts, or such hydrates.

(Item 17A)

The pharmaceutical composition according to Item 16A is administered percutaneously, subcutaneously, intravenously, intraarterially, intramuscularly, intraperitoneally, transmucosally, by inhalation, nasally, by eye, by ear or intravaginally.

(Item 18A)

The pharmaceutical composition according to Item 16A or 17A, which is an injection, a drip, an eye drop, a nasal spray, an ear lotion, an aerosol, an inhalant, an emulsion, an injection, a coating agent, a mouthwash Agent, sputum, ointment, plaster, jelly, cream, patch, lozenge, topical powder or suppository.

(Item 19A)

A pharmaceutical composition comprising a compound according to any one of items 1B to 14B and any one of items 1 to 11A, an ester thereof or the same as a pharmaceutical composition for a child or an elderly person. Salts permitted herein, or such hydrates.

(Item 20A)

A pharmaceutical composition, which is a compound according to any one of items 1B to 14B and any one of items 1 to 11A, an ester thereof or a pharmaceutically acceptable salt or a hydrate thereof It is combined with a β-endosaminolase inhibitor, an antibacterial agent having activity against Gram-positive bacteria, and/or an antibacterial agent having activity against anaerobic bacteria.

(Item 21A)

A pharmaceutical composition for use in a compound according to any one of items 1B to 14B and any one of items 1 to 11A, an ester thereof, or a salt which is pharmaceutically acceptable, or the like Hydrate, a combination of a β-endosaminolase inhibitor, an antibacterial agent having activity against Gram-positive bacteria, and/or an antibacterial agent having activity against anaerobic bacteria.

The compound according to the present invention has at least one of the characteristics described below, and is useful as a pharmaceutical.

A) shows a strong antibacterial spectrum against various bacteria of Gram-negative bacteria.

B) shows a good antibacterial spectrum against various bacteria of Gram-positive bacteria.

C) shows strong antibacterial activity against Gram-negative bacteria producing β-endoprostanase.

D) Strong antibacterial activity against multi-drug resistant bacteria, especially against Gram-negative bacteria that produce B-type metal-β-endosaminolase.

E) shows strong antibacterial activity against bacteria which produce matrix-specific expanded β-endosaminolase (ESBL).

F) shows strong antibacterial activity against Gram-negative bacteria producing C-type β-endosaminolase.

G) shows strong antibacterial activity against carbapenem resistant bacteria.

H) Strong antibacterial activity against enterobacteriaceae bacteria resistant to commercial drugs in the market.

I) Carbapenems producing carbapenemase such as Klebsiella pneumoniae Carbapenemase (KPC) and New Delhi metallo-beta-lactamase (NDM) Drug-resistant enterobacteriaceae bacteria (CRE) show strong antibacterial activity.

J) Does not show cross-resistance to existing cephem drugs and/or carbapenem drugs.

K) After administration to a living body, side effects such as fever are not exhibited.

L) stability of the compound (for example, solution stability in various liquid properties, photostability, etc.) and/or high solubility in water.

M) has the advantages of high blood concentration, high oral absorption, high membrane penetration, long duration of action, or high tissue mobility.

N) The inhibitory effect on CYP enzymes (eg, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.

O) High metabolic stability.

P) does not cause digestive tract disorders (eg, diarrhea, hemorrhagic enteritis, peptic ulcer, gastrointestinal bleeding, etc.).

Q) Does not cause nephrotoxicity, hepatotoxicity, cardiotoxicity (eg, QTc prolongation, etc.), sputum, and the like.

Hereinafter, embodiments of the invention will be described with respect to the present invention. In the full text of this manual, the singular type of expression (for example, in English, the articles, adjectives, etc. corresponding to "a", "an", "the", etc.), unless otherwise specified, It should be understood that it also includes the concept of a plural form. Moreover, the terms used in the specification, unless otherwise specified, are to be understood as meanings that are used in the field. Therefore, all the terms of the technical terms and the technical terms used in the present specification have the same meaning as those generally understood by those of ordinary skill in the art to which the invention belongs. When there is something wrong, this manual (including definitions) takes precedence. The terms specifically used in the present specification are specifically defined below.

The term "made from" means that it has only constituent elements.

The term "including" means not limited to the constituent elements, and does not exclude undocumented elements.

"Substitutable by a substituent group A" means that the same or different substitutions selected from one or two or more substituents of the substituent group A may be substituted at any position.

"Substituted by Substituent Group B", "Substituted by Substituent Group C", "Substituted by Substituent Group D", "Substituted by Substituent Group E", "Substituted by Substituent Group F", "Substitutable for group G", "substitutable for substituent group H", "substitutable for substituent group I", "substitutable for substituent group J", and "substitutable for substituent group Z" All are the same as above.

Unless otherwise stated, the terms used in this specification are defined as follows, either alone or in combination with other terms.

"Halogen" means fluorine, chlorine, bromine or iodine. It is preferably fluorine or chlorine.

The "alkyl group" is a linear or branched hydrocarbon group having a carbon number of 1 to 15, preferably a carbon number of 1 to 10, more preferably a carbon number of 1 to 6, more preferably a carbon number of 1 to 4. . For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl , isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-decyl, n-decyl and the like.

Preferred examples of the "alkyl group" include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a second butyl group, a tert-butyl group, and a n-pentyl group. More preferred aspects include methyl, ethyl, n-propyl, isopropyl and t-butyl groups.

The "alkenyl group" has one or more double bonds at any position, and has a carbon number of 2 to 15, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and still more preferably carbon. A linear or branched hydrocarbon group of 2 to 4 is used. For example, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, isoprenyl, butadienyl, pentenyl, isopentenyl, pentane Alkenyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecene Base, pentadecyl and the like.

Preferred examples of the "alkenyl group" include a vinyl group, an allyl group, a propenyl group, an isopropenyl group, and a butenyl group.

The "alkynyl group" has one or two or more triple bonds at any position, and has a carbon number of 2 to 10, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and still more preferably carbon. A linear or branched hydrocarbon group of 2 to 4 is used. It is also possible to further have a double bond at any position. For example, it includes an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, a hexynyl group, a heptynyl group, an octynyl group, a decynyl group, a decynyl group, and the like.

Preferred examples of the "alkynyl group" include an ethynyl group, a propynyl group, a butynyl group, and a pentynyl group.

"Alkyl" means a nail base and a carbonyl group having a substituent.

The "carbonyl group having a substituent" may, for example, be a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted alkenylcarbonyl group, a substituted or unsubstituted alkynylcarbonyl group, a substituted or unsubstituted aromatic carbocyclic carbonyl group, a substituent or Non-substituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkoxy A substituted or unsubstituted alkenyloxy group, a substituted or unsubstituted alkynyloxy group, a substituted or unsubstituted carbo epoxy group, a substituted or unsubstituted heterocyclic oxy group, and the like.

"Alkylcarbonyl" means a group in which the above "alkyl group" is bonded to a carbonyl group. For example, a methylcarbonyl group, an ethylcarbonyl group, a propylcarbonyl group, an isopropylcarbonyl group, a tert-butylcarbonyl group, an isobutylcarbonyl group, a second butylcarbonyl group, a pentylcarbonyl group, an isopentylcarbonyl group, a hexylcarbonyl group, etc. may be mentioned. .

Preferred examples of the "alkylcarbonyl group" include a methylcarbonyl group, an ethylcarbonyl group and a n-propylcarbonyl group.

"Alkenylcarbonyl" means a group in which the above "alkenyl group" is bonded to a carbonyl group. For example, an ethyl carbonyl group, a propylene carbonyl group, etc. are mentioned.

"Alkynylcarbonyl" means a radical to which the above "alkynyl" is bonded to a carbonyl group. For example, an ethynylcarbonyl group, a propynylcarbonyl group, etc. are mentioned.

"Alkoxy" means a nail methoxy group and a substituted carbonyloxy group. The "carbonyloxy group having a substituent" means a group in which the above-mentioned "carbonyl group having a substituent" is bonded to an oxygen atom. For example, a substituted or unsubstituted alkylcarbonyloxy group, a substituted or unsubstituted alkenylcarbonyloxy group, a substituted or unsubstituted alkynylcarbonyloxy group, a substituted or unsubstituted aromatic carbocyclic carbonyloxy group, A substituted or unsubstituted non-aromatic carbocyclic carbonyloxy group, a substituted or unsubstituted aromatic heterocyclic carbonyloxy group, a substituted or unsubstituted non-aromatic heterocyclic carbonyloxy group, or the like.

The "alkylcarbonyloxy group" means a group in which the above "alkylcarbonyl group" is bonded to an oxygen atom. For example, methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, and butyloxycarbonyl Base. Preferred examples of the "alkylcarbonyloxy group" include a methylcarbonyloxy group and an ethylcarbonyloxy group.

The "alkenylcarbonyloxy group" means a group in which the above "alkenylcarbonyl group" is bonded to an oxygen atom. For example, a vinyl carbonyloxy group, a propylene carbonyloxy group, etc. are mentioned.

"Alkynylcarbonyloxy" means a group in which the above "alkynylcarbonyl group" is bonded to an oxygen atom. For example, an ethynylcarbonyloxy group, a propynylcarbonyloxy group, etc. are mentioned.

"Alkoxy" means a group in which the above "alkyl group" is bonded to an oxygen atom. For example, a methoxy group, an ethoxy group, a n-propyloxy group, an isopropyloxy group, an n-butyloxy group, a t-butyloxy group, an isobutyloxy group, a 2nd butyloxy group, Pentoyloxy, isopentyloxy, hexyloxy and the like.

Preferred examples of the "alkoxy group" include a methoxy group, an ethoxy group, a n-propyloxy group, an isopropyloxy group, a hexyloxy group and the like.

"Alkenyloxy" means a group in which the above "alkenyl group" is bonded to an oxygen atom. For example, a vinyl group, an allyloxy group, a 1-propenyloxy group, a 2-butenyloxy group, a 2-pentenyloxy group, a 2-hexenyloxy group, 2 a heptyloxy group, a 2-octenyloxy group or the like.

"Alkynyloxy" means a group in which the above "alkynyl group" is bonded to an oxygen atom. For example, an ethynyloxy group, a 1-propynyloxy group, a 2-propynyloxy group, a 2-butynyloxy group, a 2-pentynyloxy group, a 2-hexynyloxy group, 2 a heptynyloxy group, a 2-octynyloxy group or the like.

"Alkylsulfonyl" means a group in which the above "alkyl group" is bonded to a sulfonyl group. For example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, and second butylsulfonate can be mentioned. Base.

Preferred examples of the "alkylsulfonyl group" include a methylsulfonyl group, an ethylsulfonyl group and the like.

"Alkenylsulfonyl" means a group in which the above "alkenyl group" is bonded to a sulfonyl group. For example, a vinyl sulfonyl group, a propylene sulfonyl group, etc. are mentioned.

"Alkynylsulfonyl" means a group in which the above "alkynyl group" is bonded to a sulfonyl group. For example, an ethynylsulfonyl group, a propynylsulfonyl group or the like can be mentioned.

"Alkoxycarbonyl" means a group in which the above "alkoxy" is bonded to a carbonyl group. For example, a methyloxycarbonyl group, an ethyloxycarbonyl group, a propyloxycarbonyl group, an isopropyloxycarbonyl group, a tert-butyloxycarbonyl group, an isobutyloxycarbonyl group, a secondbutyloxy group A carbonyl group, a pentyloxycarbonyl group, an isopentyloxycarbonyl group, a hexyloxycarbonyl group or the like.

Preferred examples of the "alkoxycarbonyl group" include a methyloxycarbonyl group, an ethyloxycarbonyl group, and a propyloxycarbonyl group.

"Alkenyloxycarbonyl" means a group in which the above "alkenyloxy group" is bonded to a carbonyl group. For example, a vinyl (oxy) oxycarbonyl group, a propylene oxycarbonyl group, etc. are mentioned.

"Alkynyloxycarbonyl" means a group in which the above "alkynyloxy group" is bonded to a carbonyl group. For example, an ethynyloxycarbonyl group, a propynyloxycarbonyl group, etc. are mentioned.

The "alkylthio group" means a group in which the above "alkyl group" is replaced by a hydrogen atom bonded to a sulfur atom of a hydrogenthio group. For example, a methylthio group, an ethylthio group, a n-propylthio group, an isopropylthio group, etc. are mentioned. Preferred examples of the "alkylthio group" include a methylthio group, an ethylthio group, a n-propylthio group, an isopropylthio group, a hexylthio group and the like.

The "alkenylthio group" means a group in which the above "alkenyl group" is replaced by a hydrogen atom bonded to a sulfur atom of a sulfur group. For example, an ethylthio group, an acrylylthio group, etc. are mentioned.

The "alkynylthio group" means a group in which the above "alkynyl group" is replaced by a hydrogen atom bonded to a sulfur atom of a sulfur group. For example, an ethynylthio group, a propynylthio group or the like can be mentioned.

"Alkylsulfinyl" means a group in which the above "alkyl group" is bonded to a sulfinyl group. For example, a methylsulfinyl group, an ethylsulfinyl group, a n-propylsulfinyl group, an isopropylsulfinyl group, etc. are mentioned.

"Alkenylsulfinyl" means a group in which the above "alkenyl" is bonded to a sulfinyl group. For example, an ethyl sulfinyl group, a propenyl sulfinyl group, etc. are mentioned.

"Alkynylsulfinyl" means a group in which the above "alkynyl group" is bonded to a sulfinyl group. For example, an ethynyl sulfinyl group, a propynyl sulfinyl group, etc. are mentioned.

The "aromatic carbocyclic group" means a monocyclic ring or a cyclic aromatic hydrocarbon group of two or more rings. For example, a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, etc.

A preferred aspect of the "aromatic carbocyclic group" is phenyl.

The "non-aromatic carbocyclic group" means a monocyclic ring or a cyclic saturated hydrocarbon group of 2 or more rings or a cyclic non-aromatic unsaturated hydrocarbon group. The "non-aromatic carbocyclic group" having two or more rings also includes a monocyclic ring or a ring of two or more rings of a non-aromatic carbocyclic group condensed with the ring of the above "aromatic carbocyclic group". In addition, the bond key can come from either ring.

Further, the "non-aromatic carbocyclic group" also includes a crosslinking group as described below or a group forming a spiro ring.

The monocyclic non-aromatic carbocyclic group preferably has a carbon number of from 3 to 16, more preferably from 3 to 12 carbon atoms, still more preferably from 3 to 8 carbon atoms. For example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclodecyl group, a cyclodecyl group, a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, and a ring can be mentioned. Hexenyl, cycloheptenyl, cyclohexadienyl and the like.

Examples of the non-aromatic carbocyclic group having two or more rings include a dihydroindenyl group, a fluorenyl group, an ethylphthyl group, a tetrahydronaphthyl group, an anthracenyl group and the like.

"Aromatic carbocyclic ring" means a ring derived from the above "aromatic carbocyclic group". "Non-aromatic carbocyclic ring" means a ring derived from the above "non-aromatic carbocyclic group".

One of the "non-aromatic carbocyclic groups" may be a "cycloalkyl group". "Cycloalkyl" means a monocyclic or a cyclic saturated hydrocarbon group of 2 or more rings, and also includes a crosslinking group or a group forming a spiro ring. It is preferably from 3 to 16 carbon atoms, more preferably from 3 to 12 carbon atoms, and still more preferably from 3 to 8 carbon atoms. It is preferably a single ring. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl, bicyclooctane, decahydronaphthalene, norbornyl, adamantane Base, spirobicyclopentane, etc. Preferred examples of the "cycloalkyl group" include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

"Carbocyclyl" includes the above "aromatic carbocyclic group" and "non-aromatic carbocyclic group". "Carbocycle" means a ring derived from the above "carbocyclic group". "Carbocyclic diyl" means a divalent group derived from the above "carbocyclic group".

The "aromatic heterocyclic group" means a monocyclic ring or a ring-shaped or more aromatic ring group having one or two or more hetero atoms selected arbitrarily selected from O, S and N in the ring. The aromatic heterocyclic group having two or more rings also includes a monocyclic ring or an aromatic heterocyclic group having two or more rings and a ring of the above-mentioned "aromatic carbocyclic group".

The monocyclic aromatic heterocyclic group is preferably from 5 to 8 members, more preferably 5 members or 6 members. For example, in the case of a 5-membered monocyclic aromatic heterocyclic group, pyrrole group, imidazolyl group, pyrazolyl group, furyl group, thienyl group, and iso are mentioned. Azolyl, Azolyl, The oxazolyl group, the isothiazolyl group, the thiazolyl group, the thiadiazolyl group, etc., and the monocyclic aromatic heterocyclic group of 6 members may, for example, be a pyridyl group or a fluorene group. Base, pyrimidinyl, pyridyl Base, triazolyl, three Base, tetrazolyl, and the like.

Examples of the aromatic heterocyclic group of the 2-ring group include a mercapto group, an isodecyl group, a carbazolyl group, and an anthracene group. Base, quinolyl, isoquinolyl, Olinyl group, hydrazine Base, quinazolinyl, Pyridyl, quin Polinyl, fluorenyl, acridinyl, benzimidazolyl, benzene Azolyl, benzo Azolyl, benzene Diazolyl, phenylisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzotriazolyl, imidazopyridyl, triazole Pyridyl, imidazothiazolyl, pyridyl And base, Zizolopyridyl, thiazolopyridyl and the like.

Examples of the aromatic heterocyclic group having 3 or more rings include, for example, carbazolyl, acridinyl, xanthylene, and thiophene Base Thioyl, brown Base, dibenzofuranyl and the like.

The "non-aromatic heterocyclic group" means a monocyclic ring or a cyclic non-aromatic ring group of two or more rings, which has one or more or the same or different selected from O, S and N in the ring. Hetero atom. The non-aromatic heterocyclic group having two or more rings also includes a monocyclic or bicyclic or higher non-aromatic heterocyclic group and the above "aromatic carbocyclic group", "non-aromatic carbocyclic group", and/or "aromatic The ring of each of the heterocyclic groups is condensed. Further, the non-aromatic heterocyclic group having two or more rings also includes a condensation of the above-mentioned "non-aromatic carbocyclic group" with the ring of the above "aromatic heterocyclic group". In addition, the bond key can come from either ring.

Further, the "non-aromatic heterocyclic group" also includes a group which is crosslinked as described below or a group which forms a spiro ring.

The monocyclic non-aromatic heterocyclic group is preferably from 3 to 8 members, more preferably 5 members or 6 members. For example, a dioxolyl group, a thiiryl group, an oxifenyl group, an oxetanyl group, an oxathiolanyl group, an azetidinyl group, a thietyl group may be mentioned. , thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl, piperidinyl, piperidine Base, tetrahydropyridyl, tetrahydrofuranyl, tetrahydropyranyl, dihydrothiazole, tetrahydrothiazole, tetrahydroisothiazole, dihydrogen Base, hexahydrozine, tetrahydrodiazide, tetrahydroanthraquinone Base, hexahydropyrimidinyl, dioxolane, two Base, aziridine, dioxolinyl, oxetanyl, thiolanyl, thienyl, thio Alkyl, azepan-1-yl and the like.

Examples of the non-aromatic heterocyclic group having 2 or more rings include a porphyrin group and an isoindolyl group. Basis , octahydro-7H-pyrano[2,3-c]pyridin-7-yl, hexahydro-2H-pyrano[3,2-c]pyridine-6(5H)-yl, 7,8 - Dihydropyrido[4,3-d]pyrimidin-6(5H)-yl and the like.

The "aromatic heterocyclic ring" means a ring derived from the above "aromatic heterocyclic group". The "non-aromatic heterocyclic ring" means a ring derived from the above "non-aromatic heterocyclic group".

The "heterocyclic group" includes the above "aromatic heterocyclic group" and "non-aromatic heterocyclic group". "Heterocycle" means a ring derived from the above "heterocyclic group". The "heterocyclic diyl group" means a divalent group derived from the above "heterocyclic group".

"Aromatic Carboepoxy", "Aromatic Carbocyclic Carbonyl", "Aromatic Carboepoxycarbonyl", "Aromatic Carbocyclic Carbonyloxy", "Aromatic Carbocyclic Sulfuryl", "Aromatic Carbon" The "aromatic carbocyclic group" of the sulfinyl group and the "aromatic carbocyclic sulfonyl group" are also the same as the above "aromatic carbocyclic group".

The "aromatic carbocyclic group" means a group in which the above "aromatic carbocyclic ring" is bonded to an oxygen atom. For example, a phenyloxy group, a naphthyloxy group, etc. are mentioned.

The "aromatic carbocyclic carbonyl group" means a group in which the above "aromatic carbocyclic ring" is bonded to a carbonyl group. For example, a benzamidine group, a naphthylcarbonyl group, etc. are mentioned.

The "aromatic carbocyclic carbonyl group" means a group in which an "aromatic carbocyclic group" is bonded to a carbonyl group. For example, a phenyloxycarbonyl group, a naphthyloxycarbonyl group, etc. are mentioned.

The "aromatic carbocyclic carbonyloxy group" means a group in which an "aromatic carbocyclic carbonyl group" is bonded to an oxygen atom. For example, a phenylcarbonyloxy group, a naphthylcarbonyloxy group, etc. are mentioned.

The "aromatic carbocyclic thio group" means a group in which an "aromatic carbocyclic ring" is replaced by a hydrogen atom bonded to a sulfur atom of a sulfur group. For example, a phenylthio group, a naphthylthio group, etc. are mentioned.

"Aromatic carbocyclic sulfinyl" means a group in which an "aromatic carbocyclic ring" is bonded to a sulfinyl group. For example, a phenylsulfinylene group, a naphthylsulfinyl group, etc. are mentioned.

"Aromatic carbosulfonyl" means a group in which an "aromatic carbocyclic ring" is bonded to a sulfonyl group. For example, a phenylsulfonyl group, a naphthylsulfonyl group, etc. are mentioned.

"Non-aromatic carbocyclic oxy group", "non-aromatic carbocyclic carbonyl group", "non-aromatic carbocyclic carbonyl group", "non-aromatic carbocyclic carbonyl group", "non-aromatic carbocyclic thio group" The "non-aromatic carbocyclic sulfonyl group" and the "non-aromatic carbocyclic group" of the "non-aromatic carbocyclic sulfonyl group" are also the same as the above-mentioned "non-aromatic carbocyclic group".

The "non-aromatic carbocyclic group" means a group in which the above "non-aromatic carbocyclic ring" is bonded to an oxygen atom. For example, a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, a cyclooctyloxy group, a cyclopropenyloxy group, a cyclobutenyloxy group , cyclopentenyloxy, cyclohexenyloxy, cycloheptenyloxy, cyclohexadienyloxy, indanyloxy, tetrahydronaphthyloxy, decyloxy, Adamantyloxy and the like.

The "non-aromatic carbocyclic carbonyl group" means a group in which the above "non-aromatic carbocyclic ring" is bonded to a carbonyl group. For example, a cyclopropylcarbonyl group, a cyclohexylcarbonyl group, a cyclopropenylcarbonyl group, a dihydroindenylcarbonyl group, etc. are mentioned.

The "non-aromatic carbocyclic carbonyl group" means a group in which the above "non-aromatic carbocyclic group" is bonded to a carbonyl group. For example, a cyclopropyloxycarbonyl group, a cyclohexyloxycarbonyl group, a cyclohexenyloxycarbonyl group, etc. are mentioned.

The "non-aromatic carbocyclic carbonyloxy group" means a group in which the above "non-aromatic carbocyclic carbonyl group" is bonded to an oxygen atom. For example, a cyclopropylcarbonyloxy group, a cyclohexylcarbonyloxy group, a cyclohexenylcarbonyloxy group, etc. are mentioned.

The "non-aromatic carbocyclic thio group" means a group in which the above "non-aromatic carbocyclic ring" is replaced by a hydrogen atom bonded to a sulfur atom of a sulfur group. For example, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cycloheptylthio, cyclooctylthio, cyclopropenylthio, cyclobutenylsulfide , cyclopentenylthio, cyclohexenylthio, cycloheptenylthio, cyclohexadienylthio, indanylthio, tetrahydronaphthylthio, decylthio, Adamantylthio group and the like.

The "non-aromatic carbocyclic sulfinyl group" means a group in which the above "non-aromatic carbocyclic ring" is bonded to a sulfinyl group. For example, a cyclopropylsulfinyl group, a cyclobutylsulfinyl group, a cyclopentylsulfinyl group, a cyclohexylsulfinyl group, a cycloheptylsulfinyl group, a cyclohexenylsulfinium group can be mentioned. A group, a tetrahydronaphthylsulfinyl group, an adamantyl sulfinyl group or the like.

"Non-aromatic carbosulfonyl" means a group in which the above "non-aromatic carbocyclic ring" is bonded to a sulfonyl group. For example, a cyclopropylsulfonyl group, a cyclohexylsulfonyl group, a cyclohexenylsulfonyl group, etc. are mentioned.

"Aromatic heterocyclic oxy group", "aromatic heterocyclic carbonyl group", "aromatic heterocyclic oxycarbonyl group", "aromatic heterocyclic carbonyloxy group", "aromatic heterocyclic thio group", "aromatic hybrid" The "aromatic sulfonyl group" and the "aromatic heterocyclic ring" of the "aromatic heterocyclic sulfonyl group" are also the same as the above "aromatic heterocyclic group".

The "aromatic heterocyclic oxy group" means a group in which the above "aromatic heterocyclic ring" is bonded to an oxygen atom. For example, a pyridyloxy group, Zozoyloxy and the like.

The "aromatic heterocyclic carbonyl group" means a group in which the above "aromatic heterocyclic ring" is bonded to a carbonyl group. For example, a pyrrolylcarbonyl group, a pyrazolylcarbonyl group, a pyridylcarbonyl group, An oxalylcarbonyl group, a fluorenylcarbonyl group or the like.

The "aromatic heterocyclic oxycarbonyl group" means a group in which the above "aromatic heterocyclic oxy group" is bonded to a carbonyl group. For example, a pyridyloxycarbonyl group, An oxazoyloxycarbonyl group or the like.

The "aromatic heterocyclic carbonyloxy group" means a group in which the above "aromatic heterocyclic carbonyl group" is bonded to an oxygen atom. For example, a pyridylcarbonyloxy group, Azolylcarbonyloxy and the like.

The "aromatic heterocyclic thio group" means a group in which the above "aromatic heterocyclic ring" is substituted with a hydrogen atom bonded to a sulfur atom of a sulfur group. For example, a pyridylthio group, Azoylthio group and the like.

The "aromatic heterocyclic sulfinyl group" means a group in which the above "aromatic heterocyclic ring" is bonded to a sulfinyl group. For example, a pyridylsulfinyl group, Azolylsulfinyl and the like.

The "aromatic heterocyclic sulfonyl group" means a group in which the above "aromatic heterocyclic ring" is bonded to a sulfonyl group. For example, a pyridylsulfonyl group, Oxylsulfonyl and the like.

"Non-aromatic heterocyclic oxy group", "non-aromatic heterocyclic carbonyl group", "non-aromatic heterocyclic oxycarbonyl group", "non-aromatic heterocyclic carbonyloxy group", "non-aromatic heterocyclic thio group" The "non-aromatic heterocyclic sulfinyl group" and the "non-aromatic heterocyclic group" of the "non-aromatic heterocyclic sulfonyl group" are also the same as the above-mentioned "non-aromatic heterocyclic group".

The "non-aromatic heterocyclic oxy group" means a group in which the above "non-aromatic heterocyclic ring" is bonded to an oxygen atom. For example, a dioxolyloxy group, a thiiryloxy group, an oxicyclyloxy group, an oxetanyloxy group, an oxathiolanyloxy group, a nitrogen heterocycle Butanoxy, thiacyclohexyloxy, thiazolidinyloxy, pyrrolidinyloxy, pyrrolinyloxy, imidazolidinyloxy, imidazolinyloxy, pyrazolidinyloxy , pyrazolinyloxy, pyrrolidinyloxy, piperidine Alkoxy, morpholinyloxy, porphyrinoxy, Baseoxy and the like.

The "non-aromatic heterocyclic carbonyl group" means a group in which the above "non-aromatic heterocyclic ring" is bonded to a carbonyl group. For example, a dioxopentylcarbonyl group, an oxetanylcarbonyl group, a pyrazolinylcarbonyl group, a morpholinecarbonyl group, a morpholinylcarbonyl group, a porphyrinylcarbonyl group, etc. are mentioned.

The "non-aromatic heterocyclic oxycarbonyl group" means a group in which the above "non-aromatic heterocyclic oxy group" is bonded to a carbonyl group. For example, a piperidinyloxycarbonyl group, a tetrahydrofuranyloxycarbonyl group, etc. are mentioned.

The "non-aromatic heterocyclic carbonyloxy group" means a group in which the above "non-aromatic heterocyclic carbonyl group" is bonded to an oxygen atom. For example, a piperidinylcarbonyloxy group, a tetrahydrofuranylcarbonyloxy group, etc. are mentioned.

The "non-aromatic heterocyclic thio group" means a group in which the above-mentioned "non-aromatic heterocyclic ring" is substituted with a hydrogen atom bonded to a sulfur atom of a sulfur group. For example, a dioxolylthio group, a thiirylthio group, an oxacyclopropylthio group, an oxetanylthio group, an oxathiolanylthio group, a nitrogen heterocycle Butyrylthio, thiacyclohexylthio, thiazolidinylthio, pyrrolidinylthio, pyrrolinylthio, imidazolidinylthio, imidazolinylthio, pyrazolylthio Base, pyrazolinylthio, pyrrolidinylthio, piperid Thiothio group, morpholinylthio group, porphyrinylthio group, Base thiol and the like.

The "non-aromatic heterocyclic sulfinyl group" means a group in which the above "non-aromatic heterocyclic ring" is bonded to a sulfinyl group. For example, a piperidinylsulfinyl group, a tetrahydrofuranylsulfinyl group, etc. are mentioned.

The "non-aromatic heterocyclic sulfonyl group" means a group in which the above "non-aromatic heterocyclic ring" is bonded to a sulfonyl group. For example, a piperidinylsulfonyl group, a tetrahydrofuranylsulfonyl group, etc. are mentioned.

"Substituted or unsubstituted alkyl", "substituted or unsubstituted alkenyl", "substituted or unsubstituted alkynyl", "substituted or unsubstituted alkoxy", "substituted or unsubstituted alkenyloxy" "Substituted or unsubstituted alkynyloxy", "substituted or unsubstituted alkanesulfonyl", "substituted or unsubstituted alkenylsulfonyl", "substituted or unsubstituted alkynylsulfonyl" , "substituted or unsubstituted alkoxycarbonyl group", "substituted or unsubstituted alkoxycarbonyl group", "substituted or unsubstituted alkynyloxycarbonyl group", "substituted or unsubstituted alkoxysulfonyl group", "substituted" Or an unsubstituted alkenyloxysulfonyl group, a "substituted or unsubstituted alkynyloxysulfonyl group", a "substituted or unsubstituted alkylthio group", a "substituted or unsubstituted alkenylthio group", "Substituted or unsubstituted alkynylthio", "substituted or unsubstituted alkylsulfinyl", "substituted or unsubstituted alkenylsulfinyl", "substituted or unsubstituted alkynylsulfinyl" "Alkyl", "substituted or unsubstituted alkanesulfonyl imido", "substituted or unsubstituted alkylcarbonyl", "substituted Or unsubstituted alkenylcarbonyl", "substituted or unsubstituted alkynylcarbonyl", "substituted or unsubstituted alkylcarbonyloxy", "substituted or unsubstituted alkenylcarbonyloxy", "substituted or unsubstituted" The substituent of the substituted alkynylcarbonyloxy group and the "substituted or unsubstituted carboxyalkyl group" may be a group selected from the group of the substituents A described later. The carbon atom at any position may be bonded to one or two or more groups selected from the group A of substituents described later. The substituent group A may be further substituted with one or two or more substituents selected from the substituent group Z. When two or more substituents are present, they may be the same or different.

Substituent group A: halogen, hydroxy, carboxy, amine, imido, hydroxyamino, hydroxyiminomethyl, methionyl, methionyloxy, amine carbaryl, sulfonamide, sulphur Base, sulfinic acid group, sulfo group, thiomethyl sulfonyl group, thiocarboxyl group, dithiocarboxyl group, thiamine, cyano group, nitro group, nitroso group, azide group, fluorenyl group, ureido group, formazan group Base, mercapto, trialkylsulfonyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxycarbonyl, monoalkylamino, di Alkylamino, alkanesulfonyl, alkenylsulfonyl, alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfonylamino, dialkylsulfonylamine Base, alkylimine, alkenyleneimine, alkynylene, alkylcarbonylimido, alkenylcarbonylimine, alkynylcarbonylimido, alkoxyimino, olefin Aminimido, alkynyloxyimido, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxycarbonyl, alkoxycarbonyl, alkynyloxycarbonyl, alkylthio, alkenyl sulfide Base, alkynylthio, alkylsulfinyl, alkene A sulfinyl group, an alkynyl sulfinyl group, a monoalkylamine methyl sulfonyl group, a dialkylamine carbaryl group, a monoalkylamine sulfonyl group, a dialkylamine sulfonyl group, a 4- to ammonium group, Aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic a heterocyclic oxy group, an aromatic carbocyclic carbonyl group, a non-aromatic carbocyclic carbonyl group, an aromatic heterocyclic carbonyl group, a non-aromatic heterocyclic carbonyl group, an aromatic carbocyclic oxycarbonyl group, a non-aromatic carbocyclic carbonyl group, an aromatic a heterocyclic oxycarbonyl group, a non-aromatic heterocyclic oxycarbonyl group, an aromatic carbocycloalkoxy group, a non-aromatic carbocycloalkoxy group, an aromatic heterocycloalkoxy group, a non-aromatic heterocycloalkoxy group, Aromatic carbocycloalkoxycarbonyl, non-aromatic carbocyclic alkoxycarbonyl, aromatic heterocycloalkoxycarbonyl, non-aromatic heterocycloalkoxycarbonyl, aromatic carboalkylalkylamine, non-aromatic carbocycloalkyl Amine group, aromatic heterocyclic alkylamino group, non-aromatic heterocyclic alkylamino group, aromatic carbocyclic thio group, non-aromatic carbocyclic thio group, aromatic Group, non-aromatic heterocyclic group, non-aromatic carbocyclic acyl sulfo, sulfo carbocyclic aromatic acyl, heterocyclic aromatic sulfonic acyl, sulfo, and non-aromatic heterocyclic acyl.

"Substituted or unsubstituted monoalkylamine methyl fluorenyl", "substituted or unsubstituted dialkylamine carbhydryl", "substituted or unsubstituted monoalkylamine sulfonyl" and "substituted or unsubstituted" The substituent in the alkyl moiety of the dialkylamine sulfonyl group may, for example, be a group selected from the group of substituents A described later. The carbon atom at any position may be bonded to one or two or more groups selected from the group A of substituents described later. The substituent group A may be further substituted with one or two or more substituents selected from the substituent group Z. When two or more substituents are present, they may be the same or different.

"Substituted or unsubstituted aromatic carbocyclic group", "substituted or unsubstituted non-aromatic carbocyclic group", "substituted or unsubstituted aromatic heterocyclic group", "substituted or unsubstituted non-aromatic hybrid" "cyclic group", "substituted or unsubstituted aromatic carbocyclic oxy group", "substituted or unsubstituted non-aromatic carbocyclic oxy group", "substituted or unsubstituted aromatic heterocyclic oxy group", "substituted or Unsubstituted non-aromatic heterocyclic oxy", "substituted or unsubstituted aromatic carbocyclic carbonyl", "substituted or unsubstituted non-aromatic carbocyclic carbonyl", "substituted or unsubstituted aromatic heterocyclic carbonyl" "Substituted or unsubstituted non-aromatic heterocyclic carbonyl group", "substituted or unsubstituted aromatic carbocyclic oxycarbonyl group", "substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group", "substituted or "Unsubstituted aromatic heterocyclic oxycarbonyl", "substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl", "substituted or unsubstituted aromatic carbocyclic thio", "substituted or unsubstituted non-aromatic Group of carbocyclic thio groups", "substituted or unsubstituted aromatic heterocyclic sulphur "Substituted or unsubstituted non-aromatic heterocyclic thio", "substituted or unsubstituted aromatic carbocyclic sulfinyl", "substituted or unsubstituted non-aromatic carbocyclic sulfinyl" "Substituted or unsubstituted aromatic heterocyclic sulfinyl", "substituted or unsubstituted non-aromatic heterocyclic sulfinyl", "substituted or unsubstituted aromatic carbosulfonyl", " Substituted or unsubstituted non-aromatic carbosulfonyl, "substituted or unsubstituted aromatic heterocyclosulfonyl", "substituted or unsubstituted non-aromatic heterocyclic sulfonyl", "substituted or not Substituted carbocyclic group, "substituted or unsubstituted heterocyclic group", "substituted or unsubstituted carbocyclic ring", "substituted or unsubstituted heterocyclic ring", "substituted or unsubstituted non-aromatic carbocyclic ring" "Substituted or unsubstituted non-aromatic heterocyclic ring", "substituted or unsubstituted carbocyclic oxy group", "substituted or unsubstituted heterocyclic oxy group", "substituted or unsubstituted carbo oxycarbonyl group" , "substituted or unsubstituted heterocyclic oxycarbonyl", "substituted or unsubstituted carbocyclic sulfonyl", " Substituted or unsubstituted heterocyclooxysulfonyl", "substituted or unsubstituted carbocyclic diyl", "substituted or unsubstituted heterocyclic diradical", "substituted or unsubstituted aromatic carbocyclic oxycarbonyl" ", substituted or unsubstituted non-aromatic carbocyclic carbonyloxy group", "substituted or unsubstituted aromatic heterocyclic carbonyloxy group" and "substituted or unsubstituted non-aromatic heterocyclic carbonyloxy group" The substituents on the ring of "aromatic carbocyclic ring", "non-aromatic carbocyclic ring", "aromatic heterocyclic ring", "non-aromatic heterocyclic ring", "carbocyclic ring" and "heterocyclic ring" are exemplified by the following description. Base group B. The atom at any position on the ring may be bonded to one or two or more groups selected from the substituent group B described later. The substituent group B may be further substituted with one or two or more substituents selected from the substituent group Z. When two or more substituents are present, they may be the same or different.

Substituent group B: pendant oxy group, halogen, hydroxy group, carboxyl group, amine group, imino group, hydroxylamine group, hydroxyiminomethyl group, formamyl group, methyl decyloxy group, amine carbaryl group, amine sulfonate Sulfhydryl, thiol, sulfinate, sulfo, thiomethyl, thiol, dithiocarboxy, thiamine, cyano, cyanoalkyl, nitro, nitroso, azide Base, mercapto, ureido, formamidine, decyl, trialkylsulfonyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy , hydroxyalkoxy, alkoxyalkyl, alkoxyalkoxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, cyanoalkyl, alkoxyalkyl, alkoxyalkoxy alkoxy Base, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, monoalkylcarbonylamine , dialkylcarbonylamino, monoalkylsulfonylamino, dialkylsulfonylamino, alkylimine, alkenylimine, alkynylene, alkylcarbonylimido, alkene Carbocarbonylimine, alkynylcarbonylimine, alkoxy Imino, haloalkoxyimino, alkenyloxyimido, alkynyloxyimido, alkoxyalkoxyimine, methylene, alkylmethylene, alkoxycarbonyl Methyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxycarbonyl, alkoxycarbonyl, alkynyloxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkyl, alkylthio , alkenylthio, alkynylthio, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, monoalkylamine, dialkylamine, mercapto, monoalkane Amidoxime, dialkylamine sulfonyl, aromatic carbocyclic, non-aromatic carbocyclic, aromatic heterocyclic, non-aromatic heterocyclic, aromatic carboepoxy, non-aromatic Carboepoxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, aromatic carbocyclic ring Oxycarbonyl, non-aromatic carbo-oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, aromatic carbocycloalkyl, non-aromatic carbocycloalkyl, aromatic heterocycloalkane a base, a non-aromatic heterocycloalkyl group, an aromatic carbocycloalkenyl group, a non-aromatic carbocyclic group, an aromatic carboalkoxy group, a non-aromatic carbocyclic alkoxy group, an aromatic heterocycloalkoxy group, Non-aromatic heterocycloalkoxy, aromatic carboalkoxy alkoxy, aromatic carbosiloxane alkoxy, aromatic carbocycloalkoxycarbonyl, non-aromatic carbocyclic alkoxycarbonyl, aromatic Cycloalkoxycarbonyl, non-aromatic heterocycloalkoxycarbonyl, aromatic carbosiloxane, non-aromatic carbosiloxane, aromatic heterocyclic oxyalkyl, non-aromatic heterocyclic oxyalkyl Base, aromatic carbocyclic alkoxyalkyl group, non-aromatic carbocyclic alkoxyalkyl group, aromatic heterocycloalkoxyalkyl group, non-aromatic heterocycloalkoxyalkyl group, aromatic carboepoxy group Imino, non-aromatic carboxyoxyimino, alkoxy aromatic carbocycloalkoxy, aromatic carbocyclic sulfonyl, non-aromatic carbocyclic sulfonyl, aromatic heterocyclic amine Sulfonyl, non-aromatic heterocyclic amine sulfonyl, aromatic carboalkylalkylsulfonyl, aromatic carboalkylalkyl, non-aromatic carboalkylalkyl, aromatic Cycloalkylamino group, non-aromatic heterocyclic alkylamino group, aromatic carbocyclic thio group, non-aromatic carbocyclic thio group, aromatic heterocyclic thio group, non-aromatic heterocyclic thio group, non-aromatic carbon A cyclosulfonyl group, an aromatic carbocyclic sulfonyl group, an aromatic heterocyclic sulfonyl group, and a non-aromatic heterocyclic sulfonyl group.

Further, the "substituted or unsubstituted non-aromatic carbocyclic group" and the "substituted or unsubstituted non-aromatic heterocyclic group" may be substituted by a "sideoxy group". In this case, for example, a group in which two hydrogen atoms on a carbon atom are substituted with a pendant oxy group is used.

The above-mentioned "substituted or unsubstituted non-aromatic carbocyclic ring", "substituted or unsubstituted non-aromatic heterocyclic ring", "substituted or unsubstituted non-aromatic carbocyclic alkyl group", "substituted or unsubstituted aromatic ring" a heterocycloalkyl group, a "substituted or unsubstituted non-aromatic carbocyclic oxy group", a "substituted or unsubstituted non-aromatic heterocyclic oxy group", a "substituted or unsubstituted non-aromatic carbocyclic carbonyl group", "Substituted or unsubstituted non-aromatic heterocyclic carbonyl", "substituted or unsubstituted non-aromatic carbocyclic carbonyl", "substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl", "substituted or unsubstituted" Substituted non-aromatic carbocyclic carbonyloxy", "substituted or unsubstituted non-aromatic heterocyclic carbonyloxy", "substituted or unsubstituted non-aromatic carbocyclic thio", "substituted or unsubstituted non-substituted" Aromatic heterocyclic thio", "substituted or unsubstituted non-aromatic carbosulfinyl", "substituted or unsubstituted non-aromatic heterocyclic sulfinyl", "substituted or unsubstituted non-aromatic Group of carbocyclic sulfonyl groups, and "substituted or unsubstituted non-aromatic heterocyclic sulfonyl groups" The non-aromatic carbocyclic ring and the non-aromatic heterocyclic ring moiety may be substituted by a "sideoxy group" in the same manner as described above.

Examples of the substituent of the "substituted or unsubstituted amino group", the "substituted or unsubstituted amine carbenyl group", and the "substituted or unsubstituted amine sulfonyl group" include the substituent group C described later. When there are two substituents, they may be the same or different. The substituent group C may be further substituted with one or two or more substituents selected from the substituent group Z. When two or more substituents are present, they may be the same or different.

Substituent group C: hydroxyl group, carboxyl group, amine group, cyano group, trialkylsulfonyl group, alkyl group, alkenyl group, alkynyl group, alkoxy group, alkoxyalkyl group, alkylcarbonyl group, alkenylcarbonyl group, alkynyl group Carbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkoxy, olefin Alkyl, alkynyloxy, alkoxycarbonyl, alkoxycarbonyl, alkynyloxycarbonyl, aminomethylhydrazine, an amine sulfonyl group, a hydroxyimino group, an alkoxyimino group, a hydroxyalkoxyimino group, a carboxy alkane An oxyimino group, a 4-substituted ammonium group which may be substituted by an alkyl group, an aromatic carbocyclic group, a non-aromatic carbocyclic group, an aromatic heterocyclic group, a non-aromatic heterocyclic group, an aromatic carbon epoxy group, Non-aromatic carbocyclicoxy group, aromatic heterocyclic oxy group, non-aromatic heterocyclic oxy group, aromatic carbocyclic carbonyl group, non-aromatic carbocyclic carbonyl group, aromatic heterocyclic carbonyl group, non-aromatic heterocyclic carbonyl group, aromatic Group of carbocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, aromatic carbocycloalkyl, non-aromatic Carbocycloalkyl, aromatic heterocycloalkyl, non-aromatic heterocycloalkyl, aromatic carboalkoxy, non-aromatic carbocycloalkoxy, aromatic heterocycloalkoxy, non-aromatic heterocyclic Alkoxy group, aromatic carbocyclic alkoxycarbonyl group, non-aromatic carbocyclic alkoxycarbonyl group, aromatic heterocycloalkoxycarbonyl group, non-aromatic heterocycloalkoxycarbonyl group, aromatic carboalkoxyalkyl group, non-aromatic Carbocyclic alkoxyalkyl, aromatic heterocycloalkoxyalkyl, non-aromatic heterocycloalkoxyalkyl, non-aromatic carbosulfonyl, aromatic carbosulfonyl, aromatic Cyclosulfonyl, and non-aromatic heterocyclic sulfonyl.

Substituent group Z: pendant oxy group, halogen, hydroxy group, carboxyl group, amine group, imine group, hydroxylamine group, hydroxyiminomethyl group, formamyl group, methyl methoxy group, amine mercapto group, amine sulfonate Sulfhydryl, thiol, sulfinate, sulfo, thiomethyl, thiol, dithiocarboxy, thiamine, cyano, cyanoalkyl, nitro, nitroso, azide Base, mercapto, ureido, formamidine, decyl, trialkylsulfonyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy , hydroxyalkoxy, alkoxyalkyl, alkoxyalkoxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, cyanoalkyl, alkoxyalkyl, alkoxyalkoxy alkoxy Base, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkanesulfonyl, alkenylsulfonyl, alkynylsulfonyl, monoalkylcarbonylamine, Dialkylcarbonylamino, monoalkylsulfonylamino, dialkylsulfonylamino, alkylimino, alkenylimine, alkynylene, alkylcarbonylimido, alkenyl Carbonyl imino, alkynylcarbonylimine, alkoxy Amine, haloalkoxyimino, alkenyloxyimido, alkynyloxyimido, alkoxyalkoxyimine, methylene, alkylmethylene, alkoxycarbonyl Alkyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxycarbonyl, alkoxycarbonyl, alkynyloxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkyl, alkylthio, Alkenylthio, alkynylthio, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, monoalkylamine, dialkylamine, mercapto, monoalkyl Aminesulfonyl, dialkylamine sulfonyl, aromatic carbocyclic, non-aromatic carbocyclic, aromatic heterocyclic, non-aromatic heterocyclic, aromatic carboepoxy, non-aromatic carbon Epoxy group, aromatic heterocyclic oxy group, non-aromatic heterocyclic oxy group, aromatic carbocyclic carbonyl group, non-aromatic carbocyclic carbonyl group, aromatic heterocyclic carbonyl group, non-aromatic heterocyclic carbonyl group, aromatic carbon epoxy Carbonyl group, non-aromatic carbocyclic oxycarbonyl group, aromatic heterocyclic oxycarbonyl group, non-aromatic heterocyclic oxycarbonyl group, aromatic carbocyclic alkyl group, non-aromatic carbocyclic alkyl group, aromatic heterocycloalkyl group Non-aromatic heterocycloalkyl, aromatic carbocycloalkenyl, non-aromatic carbocycloalkenyl, aromatic carboalkoxy, non-aromatic carbocycloalkoxy, aromatic heterocycloalkoxy, non Aromatic heterocycloalkoxy, aromatic carboalkoxy alkoxy, aromatic carbosiloxane alkoxy, aromatic carbocycloalkoxycarbonyl, non-aromatic carbocyclic alkoxycarbonyl, aromatic heterocyclic Alkoxycarbonyl, non-aromatic heterocycloalkoxycarbonyl, aromatic carbosiloxane, non-aromatic carbosiloxane, aromatic heterocyclic oxyalkyl, non-aromatic heterocyclic oxyalkyl , an aromatic carboalkyloxyalkyl group, a non-aromatic carbocyclic alkoxyalkyl group, an aromatic heterocycloalkoxyalkyl group, a non-aromatic heterocycloalkoxyalkyl group, an aromatic carbocyclic alkyl group Amine, non-aromatic carbocyclic oxyalkylene group, alkoxy aromatic carbocycloalkoxy group, aromatic carbocyclic sulfonyl group, non-aromatic carbocyclic sulfonyl group, aromatic heterocyclic amine sulfonate Sulfhydryl, non-aromatic heterocyclic amine sulfonyl, aromatic carboalkylalkylsulfonyl, aromatic carboalkylalkyl, non-aromatic carboalkylalkyl, aromatic heterocycle Alkylamino group, non-aromatic heterocyclic alkylamino group, aromatic carbocyclic thio group, non-aromatic carbocyclic thio group, aromatic heterocyclic thio group, non-aromatic heterocyclic thio group, non-aromatic carbocyclic ring A sulfonyl group, an aromatic carbocyclic sulfonyl group, an aromatic heterocyclic sulfonyl group, and a non-aromatic heterocyclic sulfonyl group.

"Substituted or unsubstituted monoalkylamine methyl fluorenyl" and "substituted or unsubstituted dialkylamine carbhydryl" amine mercapto moiety, and "substituted or unsubstituted monoalkylamine sulfonyl" The substituent of the aminesulfonyl moiety of the "substituted or unsubstituted dialkylamine sulfonyl group" is exemplified by the substituent group C described later. When there are two substituents, they may be the same or different. The substituent group C may be further substituted with one or two or more substituents selected from the substituent group Z. When two or more substituents are present, they may be the same or different.

The substituent of the "substituted or unsubstituted methylene group" and the "substituted or unsubstituted hydroxyimino group" may, for example, be a carboxyl group, a sulfo group, a substituted or unsubstituted alkoxysulfonyl group, a substituted or unsubstituted group. Alkenyloxysulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted carbooxysulfonyl, substituted or unsubstituted heterocyclooxysulfonyl, diphosphoryl , substituted or unsubstituted amine mercapto, substituted or unsubstituted sulfonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted oxycarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or Unsubstituted carbocyclic carbonyl, substituted or unsubstituted heterocyclic oxycarbonyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbon a cyclic group, a substituted or unsubstituted heterocyclic group, and the like. When substituted with a plurality of substituents, the substituents may be the same or different.

"Haloalkyl" means a group in which one or more of the above "halogen" is bonded to the above "alkyl group". For example, monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2 2,2-Trifluoroethyl, 2,2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like.

Preferred examples of the "haloalkyl group" include a trifluoromethyl group and a trichloromethyl group.

"Haloalkoxy" means a group in which the above "haloalkyl group" is bonded to an oxygen atom. For example, a monofluoromethoxy group, a monofluoroethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a trifluoroethoxy group, a trichloroethoxy group, etc. are mentioned.

Preferred examples of the "haloalkoxy group" include a trifluoromethoxy group, a trichloromethoxy group and the like.

"Alkoxyalkyl" means a group in which the above "alkoxy" is bonded to the above "alkyl group". For example, a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group, etc. are mentioned.

The "alkoxy alkoxy group" means a group in which the above "alkoxy group" is bonded to the above "alkoxy group". For example, a methoxymethoxy group, a methoxyethoxy group, an ethoxymethoxy group, an ethoxyethoxy group, etc. are mentioned.

The "alkylimido group" means a group in which the above "alkyl group" is substituted with a hydrogen atom bonded to a nitrogen atom of an imine group. For example, a methylimine group, an ethyl imine group, a n-propyl imine group, an isopropylimino group, etc. are mentioned.

The "alkenyl imine group" means a group in which the above "alkenyl group" is substituted with a hydrogen atom bonded to a nitrogen atom of an imine group. For example, an ethyl imino group, a propenyl imine group, etc. are mentioned.

The "alkynylene group" means a group in which the above "alkynyl group" is replaced by a hydrogen atom bonded to a nitrogen atom of an imine group. For example, an ethynyleneimine group, a propynyl imino group, etc. are mentioned.

The "alkylcarbonylimino group" means a group in which the above "alkylcarbonyl group" is substituted with a hydrogen atom bonded to a nitrogen atom of an imine group. For example, a methylcarbonylimino group, an ethylcarbonylimino group, a n-propylcarbonylimino group, an isopropylcarbonylimino group, etc. are mentioned.

The "alkenylcarbonylimido group" means a group in which the above "alkenylcarbonyl group" is replaced by a hydrogen atom bonded to a nitrogen atom of an imine group. For example, an ethyl (carbonyl) carbonylimine group, a propylene carbonylimino group, etc. are mentioned.

The "alkynylcarbonylimino group" means a group in which the above "alkynylcarbonyl group" is substituted with a hydrogen atom bonded to a nitrogen atom of an imine group. For example, an ethynylcarbonylimino group, a propynylcarbonylimino group, etc. are mentioned.

The "alkoxyimino group" means a group in which the above "alkoxy group" is substituted with a hydrogen atom bonded to a nitrogen atom of an imine group. For example, a methyloxyimino group, an ethyloxyimino group, a n-propyloxy imine group, an isopropyloxy imine group, etc. are mentioned.

The "alkenyloxyimine group" means a group in which the above "alkenyloxy group" is substituted with a hydrogen atom bonded to a nitrogen atom of an imine group. For example, a vinyl oxyimino group, a propylene oxyimino group, etc. are mentioned.

The "alkynyloxyimine group" means a group in which the above "alkynyloxy group" is substituted with a hydrogen atom bonded to a nitrogen atom of an imine group. For example, an ethynyloxyimino group, a propynyloxyimino group, etc. are mentioned.

"Trialkylsulfonyl" means a group in which the above three "alkyl groups" are bonded to a ruthenium atom. The three alkyl groups may be the same or different. For example, a trimethyl fluorenyl group, a triethyl fluorenyl group, a tert-butyl dimethyl fluorenyl group, etc. are mentioned.

"Carbocycloalkyl", "aromatic carbocycloalkyl", "non-aromatic carbocycloalkyl", "heterocycloalkyl", "aromatic heterocycloalkyl", "non-aromatic heterocycloalkyl" "Carbocycloalkoxy", "aromatic carbocyclic alkoxy", "non-aromatic carbocyclic alkoxy", "heterocycloalkoxy", "aromatic heterocycloalkoxy", " Non-aromatic heterocycloalkoxy", "carbocycloalkoxycarbonyl", "aromatic carbocycloalkoxycarbonyl", "non-aromatic carbocyclic alkoxycarbonyl", "heterocycloalkoxycarbonyl", "aromatic "heterocyclic oxycarbonyl", "non-aromatic heterocyclic oxycarbonyl", "carbocycloalkoxyalkyl", "aromatic carboalkyloxyalkyl", "non-aromatic carbocyclic alkoxyalkyl" "," "heterocycloalkoxyalkyl", "aromatic heterocycloalkoxyalkyl", "non-aromatic heterocycloalkyloxyalkyl", "carbocycloalkylamino", "aromatic Carbocyclic alkylamine group, "non-aromatic carbocyclic alkylamine group", "heterocycloalkylamino group", "aromatic heterocyclic alkylamino group", "non-aromatic heterocyclic alkylamino group" And "carboxyalkyl The group is also part of the above-mentioned "alkyl" same.

The "aromatic carbocycloalkyl group" means an alkyl group substituted with one or two or more of the above "aromatic carbocyclic groups". Examples thereof include a benzyl group, a phenethyl group, a phenylpropyl group, a diphenylmethyl group, a trityl group, a naphthylmethyl group, and the groups shown below: Wait.

Preferred examples of the "aromatic carbocyclic alkyl group" include a benzyl group, a phenethyl group, a diphenylmethyl group and the like.

The "non-aromatic carbocycloalkyl group" means an alkyl group substituted with one or two or more of the above "non-aromatic carbocyclic groups". Further, the "non-aromatic carbocyclic alkyl group" also includes a "non-aromatic carbocyclic alkyl group" in which the alkyl moiety is substituted by the above "aromatic carbocyclic group". For example, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, and the base shown below are mentioned: Wait.

"Carbocycloalkyl" includes "aromatic carbocyclic alkyl" and "non-aromatic carbocycloalkyl". Preferred examples of the "carbocycloalkyl group" include a benzyl group, a phenethyl group, a diphenylmethyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, and the following The basis of the show: Wait.

The "aromatic heterocycloalkyl group" means an alkyl group substituted with one or two or more of the above "aromatic heterocyclic groups". Further, the "aromatic heterocycloalkyl group" also includes an "aromatic heterocycloalkyl group" in which an alkyl moiety is substituted with the above "aromatic carbocyclic group" and/or "non-aromatic carbocyclic group". For example, a pyridylmethyl group, a furylmethyl group, an imidazolylmethyl group, a decylmethyl group, a benzothienylmethyl group, Azylmethyl, different Azylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benzo Azylmethyl group, the group shown below Wait.

The "non-aromatic heterocycloalkyl group" means an alkyl group substituted with one or two or more of the above "non-aromatic heterocyclic groups". Further, the "non-aromatic heterocycloalkyl group" also includes a non-aromatic group in which the alkyl moiety is substituted by the above "aromatic carbocyclic group", "non-aromatic carbocyclic group" and/or "aromatic heterocyclic group". Heterocycloalkyl". For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, and piperidin Base methyl group, the base shown below: Wait.

The "heterocycloalkyl group" includes "aromatic heterocycloalkyl group" and "non-aromatic heterocycloalkyl group". Preferred examples of the "heterocycloalkyl group" include pyridylmethyl group, furylmethyl group, imidazolylmethyl group, mercaptomethyl group, benzothienylmethyl group, Azylmethyl, different Azylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benzo Azylmethyl, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperid Base methyl group, the base shown below: Wait.

The "aromatic carbocycloalkoxy group" means an alkoxy group substituted by one or two or more of the above "aromatic carbocyclic groups". For example, a benzyloxy group, a phenethyloxy group, a phenylpropyloxy group, a benzhydryloxy group, a trityloxy group, a naphthylmethyloxy group, and the base shown below are mentioned: Wait.

The "non-aromatic carbocyclic alkoxy group" means an alkoxy group substituted by one or two or more of the above "non-aromatic carbocyclic groups". Further, the "non-aromatic carbocyclic alkoxy group" also includes a "non-aromatic carbocyclic alkoxy group" in which the alkyl moiety is substituted with the above "aromatic carbocyclic group". For example, a cyclopropylmethyloxy group, a cyclobutylmethyloxy group, a cyclopentylmethyloxy group, a cyclohexylmethyloxy group, and the base shown below are mentioned: Wait.

The "aromatic heterocycloalkoxy group" means an alkoxy group substituted by one or two or more of the above "aromatic heterocyclic groups". Further, the "aromatic heterocycloalkoxy group" also includes an "aromatic heterocycloalkoxy group" in which the alkyl moiety is substituted with the above "aromatic carbocyclic group" and/or "non-aromatic carbocyclic group". For example, a pyridylmethyloxy group, a furylmethylmethyloxy group, an imidazolylmethyloxy group, a mercaptomethyloxy group, a benzothienylmethyloxy group, an isothiazolylmethyloxy group, Pyrazolylmethyloxy, isopyrazolylmethyloxy, pyrrolidinylmethyloxy, benzo Azylmethyloxy group, the group shown below: Wait.

The "non-aromatic heterocyclic alkoxy group" means an alkoxy group substituted by one or two or more of the above "non-aromatic heterocyclic groups". Further, the "non-aromatic heterocycloalkoxy group" also includes a non-aromatic moiety in which the alkyl moiety is substituted by the above "aromatic carbocyclic group", "non-aromatic carbocyclic group" and/or "aromatic heterocyclic group". Family heterocycloalkoxy". For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, and piperidin Methyloxy group, the group shown below: Wait.

The "aromatic carbocycloalkoxycarbonyl group" means an alkoxycarbonyl group substituted with one or two or more of the above "aromatic carbocyclic groups". For example, a benzyloxycarbonyl group, a phenethyloxycarbonyl group, a phenylpropyloxycarbonyl group, a benzhydryloxycarbonyl group, a trityloxycarbonyl group, a naphthylmethyloxycarbonyl group, The base shown below: Wait.

The "non-aromatic carbocycloalkoxycarbonyl group" means an alkoxycarbonyl group substituted with one or two or more of the above "non-aromatic carbocyclic groups". Further, the "non-aromatic carbocyclic alkoxycarbonyl group" also includes a "non-aromatic carbocyclic alkoxycarbonyl group" in which the alkyl moiety is substituted with the above "aromatic carbocyclic group". For example, a cyclopropylmethyloxycarbonyl group, a cyclobutylmethyloxycarbonyl group, a cyclopentylmethyloxycarbonyl group, a cyclohexylmethyloxycarbonyl group, and the following groups are mentioned: Wait.

The "aromatic heterocycloalkoxycarbonyl group" means an alkoxycarbonyl group substituted with one or two or more of the above "aromatic heterocyclic groups". Further, the "aromatic heterocycloalkoxycarbonyl group" also includes an "aromatic heterocycloalkoxycarbonyl group" in which an alkyl moiety is substituted with the above "aromatic carbocyclic group" and/or "non-aromatic carbocyclic group". For example, a pyridylmethyloxycarbonyl group, a furylmethyloxycarbonyl group, an imidazolylmethyloxycarbonyl group, a mercaptomethyloxycarbonyl group, a benzothienylmethyloxycarbonyl group, Azylmethyloxycarbonyl, different Azylmethyloxycarbonyl, thiazolylmethyloxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxy Carbonyl group, benzo Azolylmethyloxycarbonyl, the group shown below: Wait.

The "non-aromatic heterocycloalkoxycarbonyl group" means an alkoxycarbonyl group substituted with one or two or more of the above "non-aromatic heterocyclic groups". Further, the "non-aromatic heterocycloalkoxycarbonyl group" also includes a non-aromatic moiety in which the alkyl moiety is substituted by the above "aromatic carbocyclic group", "non-aromatic carbocyclic group" and/or "aromatic heterocyclic group". A heterocyclic alkoxycarbonyl group. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, and piperidin Methyloxy group, the group shown below: Wait.

The "aromatic carbocycloalkyloxyalkyl group" means an alkoxyalkyl group substituted by one or two or more of the above "aromatic carbocyclic groups". For example, benzyloxymethyl, phenethyloxymethyl, phenylpropyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthyl Alkoxymethyl group, the group shown below: Wait.

The "non-aromatic carbocyclic alkoxyalkyl group" means an alkoxyalkyl group substituted by one or two or more of the above "non-aromatic carbocyclic groups". Further, the "non-aromatic carboalkyloxyalkyl group" also includes a "non-aromatic carboalkyloxyalkyl group substituted by the above-mentioned "aromatic carbocyclic group" in the alkyl moiety to which the non-aromatic carbocyclic ring is bonded. "." For example, a cyclopropylmethyloxymethyl group, a cyclobutylmethyloxymethyl group, a cyclopentylmethyloxymethyl group, a cyclohexylmethyloxymethyl group, and the base shown below are mentioned: Wait.

The "aromatic heterocycloalkoxyalkyl group" means an alkoxyalkyl group substituted by one or two or more of the above "aromatic heterocyclic groups". Further, the "aromatic heterocycloalkoxyalkyl group" also includes an aromatic moiety in which the alkyl moiety bonded to the aromatic heterocyclic ring is substituted by the above "aromatic carbocyclic group" and/or "non-aromatic carbocyclic group". Family heterocycloalkoxyalkyl". For example, pyridylmethyloxymethyl, furylmethyloxymethyl, imidazolylmethyloxymethyl, decylmethyloxymethyl, benzothienylmethyloxymethyl base, Azylmethyloxymethyl, different Azylmethyloxymethyl, thiazolylmethyloxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrole Pyridylmethyloxymethyl, benzo Azylmethyloxymethyl, the group shown below: Wait.

The "non-aromatic heterocycloalkoxyalkyl group" means an alkoxyalkyl group substituted by one or two or more of the above "non-aromatic heterocyclic groups". Further, the "non-aromatic heterocycloalkyloxyalkyl group" also includes an alkyl moiety bonded to a non-aromatic heterocyclic ring via the above "aromatic carbocyclic group", "non-aromatic carbocyclic group" and/or ""Aromatic heterocyclic alkoxyalkyl group" substituted with an aromatic heterocyclic group. For example, tetrahydropyranylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, and piperidin Methyloxymethyl group, the group shown below: Wait.

The "carboxyalkyl group" means a group in which one or two or more carboxyl groups are replaced by a hydrogen atom bonded to a carbon atom of an "alkyl group". For example, carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 1-carboxypropyl, 2-carboxypropyl, 1,2-dicarboxyethyl, 2-carboxy-(1-methyl Ethyl, 2-carboxy-(1-carboxymethyl)ethyl and the like.

It is preferably an alkyl group substituted with 1 or 2 carboxyl groups.

The alkyl group preferably has a carbon number of from 1 to 8, more preferably from 1 to 6, still more preferably from 1 to 3.

The "monoalkylamino group" means a group in which the above "alkyl group" is substituted with one hydrogen atom bonded to the nitrogen atom of the amine group. For example, a methylamino group, an ethylamino group, an isopropylamino group, etc. are mentioned.

The "dialkylamino group" means a group in which two hydrogen atoms bonded to a nitrogen atom of an amine group are replaced by the above "alkyl group". The two "alkyl groups" may be the same or different. For example, a dimethylamino group, a methylethylamine group, a methyl isopropylamino group, a tert-butylmethylamino group, etc. are mentioned.

"Hydroxyimino" means an N-hydroxyimino group.

"Hydroxyiminomethyl" means an N-hydroxyiminomethyl group and represents a group represented by the following formula: (wherein, a bond bonded to a wavy line of a hydroxyl group means that the bond is a cis, a trans or a mixture thereof).

"Hydroxyiminoethyl" means an N-hydroxyiminoethyl group and represents a group represented by the following formula: (wherein, a bond bonded to a wavy line of a hydroxyl group means that the bond is a cis, a trans or a mixture thereof).

"Hydroxyiminopropyl" means an N-hydroxyiminopropyl group and represents a group represented by the following formula: (wherein, a bond bonded to a wavy line of a hydroxyl group means that the bond is a cis, a trans or a mixture thereof).

The "hydroxyalkyl group" means a group in which one or two or more hydroxyl groups are replaced by a hydrogen atom bonded to a carbon atom of an "alkyl group". For example, a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-hydroxypropyl group, a 1,2-hydroxyethyl group, a 2-hydroxy-(1-hydroxymethyl)ethyl group, or the like can be given.

It is preferably an alkyl group substituted with 1 or 2 hydroxyl groups.

The alkyl group preferably has a carbon number of from 1 to 8, more preferably from 1 to 6, still more preferably from 1 to 3.

The "alkoxy" moiety in the "alkoxycarbonylamino group" and "alkoxyaminocarbonyl group" is the same as the above "alkoxy group".

The "alkylsulfonyl" group in "alkylsulfonylamino" and "alkylsulfonylaminocarbonyl" is the same as the above "alkylsulfonyl".

The "alkylamino group" moiety in the "alkylaminosulfonylaminocarbonyl group" includes the above-mentioned "monoalkylamino group" and "dialkylamino group".

The "quaternary ammonium group" is a cyclic or acyclic, saturated or unsaturated monovalent group containing a 4-stage ammonium cation (N ⁺ ). In the case of acyclic, the bonding bond is bonded to a 4- to ammonium cation, and in the case of a ring, the bonding bond may also be bonded to an arbitrary ring comprising a quaternary ammonium cation. The group may have one or more hetero atoms selected from O, S and N in addition to the fourth-order ammonium cation. For example, a trimethylammonium group, a pyridyl group, a pyrimidinyl group, a pyrrolidinyl group, a piperidinyl group, etc. are mentioned.

It is preferably a cyclic saturated or unsaturated monovalent group containing a 4- to ammonium cation.

The substituent in the "substituted or unsubstituted four-stage ammonium group" may, for example, be one or two or more selected from the group of substituents B. The substituent may also be bonded to any atom containing a 4-stage ammonium cation. The substituent group B may be further substituted with one or two or more groups selected from the substituent group Z. When two or more substituents are present, they may be the same or different. Preferred is a group selected from the substituent group E.

Substituent group E: halogen, hydroxy, phosphonium, sulfo, carboxy, alkyl, haloalkyl, alkoxy, decyl, amine carbaryl, sulfonyl, alkylamine, fluorenyl, Alkylsulfonyl, alkoxycarbonyl, carbocyclyl, heterocyclyl, carbocycloalkyl, and heterocycloalkyl.

The substituent in the "substituted or unsubstituted hydroxyiminomethyl group" may be exemplified by the substituent group B. The substituent may also be bonded to an atom at any position. The substituent group B may be further substituted with one or two or more groups selected from the substituent group Z. When two or more substituents are present, they may be the same or different. Preferred is a group selected from the substituent group H.

Substituent group H: alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocycloalkyl, and heterocycloalkyl.

The "aminoalkyl group" means a group in which one or two or more amine groups are replaced by a hydrogen atom bonded to a carbon atom of the "alkyl group". For example, an aminomethyl group, an aminoethyl group, an aminopropyl group, a 1,2-diaminoethyl group, etc. are mentioned.

Preferred is an alkyl group substituted with one amine group. The alkyl group preferably has a carbon number of from 1 to 8, more preferably from 1 to 6, still more preferably from 1 to 3.

The "cyanoalkyl group" means a group in which one or two or more cyano groups are replaced by a hydrogen atom bonded to a carbon atom of an "alkyl group". For example, a cyanomethyl group, a cyanoethyl group, a cyanopropyl group, a 1,3-dicyanopropyl group, etc. are mentioned. Preferred is an alkyl group substituted with one cyano group. The alkyl group preferably has a carbon number of from 1 to 8, more preferably from 1 to 6, still more preferably from 1 to 3.

The "aminomethanealkyl group" means a group in which one or two or more amine carbenyl groups are replaced by a hydrogen atom bonded to a carbon atom of an "alkyl group". For example, an aminomethylmethyl group, an amine methyl decyl ethyl group, an amine methyl propyl propyl group, a 1,3-aminomethyl propyl propyl group, etc. are mentioned.

Preferred is an alkyl group substituted with one amine methyl fluorenyl group. The alkyl group preferably has a carbon number of from 1 to 8, more preferably from 1 to 6, still more preferably from 1 to 3.

The "sulfoalkyl group" means a group in which one or two or more sulfo groups are replaced by a hydrogen atom bonded to a carbon atom of the "alkyl group". For example, a sulfomethyl group, a sulfoethyl group, a sulfopropyl group, a 1,3-disulfopropyl group, etc. are mentioned.

Preferred is an alkyl group substituted with one sulfo group. The alkyl group preferably has a carbon number of from 1 to 8, more preferably from 1 to 6, still more preferably from 1 to 3.

The "hydroxyiminoalkyl group" means a group in which one hydroxyimino group is replaced by a hydrogen atom bonded to a carbon atom of the above "alkyl group". Examples thereof include a hydroxyiminomethyl group, a hydroxyiminoethyl group, a hydroxyiminopropyl group, a hydroxyiminobutyl group, a hydroxyiminopentyl group, and a hydroxyiminohexyl group.

The alkyl group preferably has a carbon number of from 1 to 8, more preferably from 1 to 6, still more preferably from 1 to 3.

Although R ¹ , R ^2A , R ^2B , R ³ , W, T, R ^4A , R ^4B , R ^5A , R ^5B , R ^6A , R ^6B among the compounds represented by formula (I) or (I') are shown. And examples of R ^7A , R ^7B , X , R ⁸ , R ⁹ , R ¹¹ , R ¹² , Q, m and R ¹⁰ or preferred embodiments, but the scope of the invention is not limited to the following. Preferred are the compounds of the possible combinations described below.

A preferred aspect of the ring of "substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group" of R ¹ is a 5 to 6 membered ring, and in a more preferred aspect, is substituted or An unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group. Preferred examples of the substituent include a halogen, a hydroxyl group, an amine group and the like. The substituent may be substituted with 1 to several at any position which may be substituted, and the number of the substituents is preferably 1 to 3, more preferably 1 or 2.

Preferable examples of R ¹ include a phenyl group, a hydroxyphenyl group, a dihydroxyphenyl group, a phenyl group substituted with any number of halogens, a phenyl group substituted with an arbitrary number of halogens and a hydroxyl group, an aminothiazolyl group, and optionally A number of halogen-substituted aminothiazoles, aminylthiadiazolyl, isothiazolyl, aminylisothiazolyl, aminoisothiazolyl substituted with any number of halogens, thienyl, furyl, benzothiazole, pyridine Base, aminopyridyl, pyrimidinyl, aminopyrimidinyl, anthracene a pyridyl group substituted with any number of halogens and amine groups, a pyrimidinyl group substituted with any number of halogens and amine groups, and the like. More preferred are phenyl, hydroxyphenyl, dihydroxyphenyl, chlorodihydroxyphenyl, aminothiazolyl, aminothiazolyl substituted with any number of halogens, aminothiadiazolyl, aminopyridyl , aminopyrimidinyl, aminoisothiazolyl and the like. More preferred are aminothiazolyl, aminochlorothiazolyl, aminofluorothiazolyl, aminobromothiazolyl or aminothiathiazolyl.

Preferred examples of R ¹ include the groups shown below.

or (where X is CH, CCl, CF, CBr or N)

More specific examples of R ¹ include the groups shown below.

(where X is CH, CCl, CF, CBr or N)

A more preferable example of X is CH, CF or N.

The most preferable examples of the carbocyclic group of R ¹ include the groups shown below.

Particularly preferred examples of the heterocyclic group of R ¹ include the groups shown below.

More preferable examples of the heterocyclic group of R ¹ include the groups shown below.

Particularly preferred examples of the heterocyclic group of R ¹ include the groups shown below.

In the case of R ^2A and R ^2B , a) R ^2A and R ^2B are each independently a hydrogen atom, a substituted or unsubstituted amino group, a sulfo group, a substituted or unsubstituted amine sulfonyl group, a carboxyl group, a substituted or unsubstituted group. For the alkoxycarbonyl group, the substituted or unsubstituted amine carbenyl group, the hydroxyl group, or the carbonyloxy group having a substituent, for example, in the preferred embodiment of the following formula: Can be cited as follows: or Substituted amine groups shown below: or (wherein R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are each independently a hydrogen atom, a hydroxyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or Non-substituted alkynyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted alkoxy group, substituted or unsubstituted alkenyloxy group, substituted or unsubstituted alkynyloxy group a substituted or unsubstituted carbooxy group, or a substituted or unsubstituted heterocyclic oxy); or a group shown below: or

The substituted aminoxime group shown below: or (wherein ring C represents a substituted or unsubstituted heterocyclic group); a substituted amine indenyl group shown below: or (wherein ring B represents a substituted or unsubstituted heterocyclic group); or a substituted oxy group shown below: or (Wherein, R ¹⁸ and R ¹⁹ each independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl, Substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted a carbooxy group, or a substituted or unsubstituted heterocyclic oxy group; a substituted carbonyloxy group shown below: or (wherein ring C represents a substituted or unsubstituted heterocyclic group) and the like.

Alternatively, when R ^2A and R ^2B together form a substituted or unsubstituted methylene group, a group represented by the following formula is preferred: (wherein R ²¹ is a substituted or unsubstituted alkyl group, and a wavy line between a carbon atom forming a double bond and R ²¹ represents a cis, a trans or a mixture thereof).

Preferred substituents of the substituted or unsubstituted alkyl group of R ²¹ are a halogen, a hydroxyl group, a carboxyl group, and more preferably a carboxyl group.

R ^{21 is} preferably a substituted or unsubstituted alkyl group having 1 to 3 carbon atoms.

Preferably, (wherein R ²¹ has the same meaning as described above)

formula: The preferred aspect is or (wherein, a wavy line between a carbon atom forming a double bond and a carboxyl group or an alkyl group means a mixture of cis, trans or the like), more preferably or (wherein, a wavy line between a carbon atom forming a double bond and a carboxyl group or an alkyl group means a mixture of cis, trans or the like), and more preferably or

Alternatively, R ^2A and R ^2B may be taken together to form a substituted or unsubstituted hydroxyimino group, preferably of the formula: (wherein R ¹⁰ is a hydrogen atom, a sulfo group, a substituted or unsubstituted alkoxysulfonyl group, a substituted or unsubstituted alkenyloxysulfonyl group, a substituted or unsubstituted alkynylsulfonyl group, a substitution or Unsubstituted carbooxysulfonyl, substituted or unsubstituted heterocyclooxysulfonyl, diphosphoryl, substituted or unsubstituted amide, substituted or unsubstituted sulfonyl, substituted Or an unsubstituted alkoxycarbonyl group, a substituted or unsubstituted oxycarbonyl group, a substituted or unsubstituted alkynyloxycarbonyl group, a substituted or unsubstituted carbocyclic oxycarbonyl group, a substituted or unsubstituted heterocyclic oxycarbonyl group, a substituted or An unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group, an imide group nitrogen atom and oxygen The wavy line between atoms represents the group shown by cis, trans or a mixture of such). More preferably, it is based on the following formula: (Wherein, R ¹⁰ is the same as the aforementioned sense).

When R ¹⁰ is a substituted or unsubstituted alkyl group, preferred examples of the substituent include a halogen, a hydroxyl group, a carboxyl group, a cyano group, a substituted or unsubstituted amino group, and a substituted or unsubstituted amine group. Sulfhydryl, sulfo, diphosphoryl, ureido, substituted or unsubstituted sulfonyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy , fluorenyl, decyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted oxycarbonyl, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic, substituted or unsubstituted Cyclo, substituted or unsubstituted heterocyclic oxy, substituted or unsubstituted carbooxy, substituted or unsubstituted carbocyclic carbonyl, substituted or unsubstituted heterocyclic carbonyl, substituted or unsubstituted carbooxy A carbonyl group, a substituted or unsubstituted heterocyclic oxycarbonyl group or the like, more preferably a halogen, a hydroxyl group, a carboxyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted amine carbenyl group, a substituted or unsubstituted alkoxy group. , substituted or unsubstituted hydroxyiminomethyl, and substituted or unsubstituted 4 Group of selected groups. The substituent may have one or two or more at any position which may be substituted, and when two or more substituents are present, they may be the same or different.

In the case of a more preferred substituent, it is a halogen, a hydroxyl group, a carboxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted amine carbenyl group, a sulfo group, a substituted or unsubstituted heterocyclic ring. A selected group of a substituted, unsubstituted or unsubstituted hydroxyiminomethyl group, a substituted or unsubstituted quaternary ammonium group.

In the case of a further preferred substituent, it is a halogen, a hydroxyl group, a carboxyl group, a cyano group, an amine group which may be substituted with a substituent group E, an amine methyl group which may be substituted with a substituent group E, a sulfo group, a heterocyclic group which may be substituted with a substituent group E, a hydroxyiminomethyl group which may be substituted with a substituent group H, or a 4-stage ammonium group which may be substituted with a substituent group E.

When R ¹⁰ is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group, in terms of a preferred substituent, it is a halogen, a hydroxyl group, a carboxyl group, a cyano group, a sulfo group, a substituent or Unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted amine indenyl, diphosphoryl, ureido, substituted or unsubstituted hydroxyiminomethyl, substituted or unsubstituted 4 Ammonium group and the like.

In the case of a more preferred substituent, it is a halogen, a hydroxyl group, a carboxyl group, an amine mercapto group, a sulfo group, a cyano group, a hydroxyalkyl group, a carboxyalkyl group, an amine mercaptoalkyl group, a sulfoalkyl group, a cyano group. Alkyl and the like.

In the case of a further preferred substituent, it is a hydroxyl group, a carboxyl group, a hydroxymethyl group, or a carboxymethyl group.

R ^{10 is} preferably a hydrogen atom, an alkyl group, a sulfo group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocycloalkyl group, a substituted or unsubstituted haloalkyl group, a substituted or a non-substituted group. Substituted aminoalkyl, substituted or unsubstituted cyanoalkyl, substituted or unsubstituted carboxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted phosphinoalkyl, substituted or non Substituted amine mercaptoalkyl, substituted or unsubstituted sulfoalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted hydroxyiminoalkyl, substituted or unsubstituted pyridyl. More preferably, it is a non-aromatic carbocyclic group which may be substituted by the substituent group F, an aromatic heterocycloalkyl group which may be substituted by the substituent group F, a haloalkyl group which may be substituted by the substituent group G, a substitutable group a G-substituted carboxyalkyl group, a cyanoalkyl group which may be substituted with a substituent group G, an aminoalkyl group which may be substituted with a substituent group E, an amine mercaptoalkyl group which may be substituted with a substituent group G, may be substituted a sulfoalkyl group substituted with a group G, a hydroxyalkyl group which may be substituted with a substituent group G, or a pyridyl group which may be substituted with a substituent group E.

Substituent group G: halogen, hydroxy, and carboxyl.

In a more preferred aspect of R ¹⁰ , an alkyl group which may be substituted with a substituent group E, an alkenyl group which may be substituted with a substituent group G, a heterocyclic group which may be substituted with a substituent group G, or may be used. Substituted group E substituted or unsubstituted aminoalkyl.

Preferable examples of the case where R ^2A and R ^2B together form a substituted or unsubstituted hydroxyimino group include the following groups.

(R ¹⁰ A is a hydrogen atom, a sulfo group, an alkyl group which may be substituted with the substituent group D, an alkenyl group which may be substituted with the substituent group D, an alkynyl group which may be substituted with the substituent group D, and a substituent group D a substituted heterocyclic group, or a carbocyclic group which may be substituted with a substituent group D, the wavy line between the nitrogen atom of the imine group and the oxygen atom means cis, trans or a mixture thereof)

Substituent group D: halogen, hydroxy group, carboxyl group, cyano group, amine group which may be substituted by substituent group C, amine mercapto group which may be substituted by substituent group C, sulfo group, phosphorus phosphide group, boron group, Aminesulfonyl, alkoxy, alkenyloxy, alkynyloxy, decyl, decyloxy, alkoxycarbonyl, alkoxycarbonyl, alkynyloxycarbonyl, substituted by a substituent group H, substituted by a substituent group C a hydroxyiminomethyl group, a heterocyclic group which may be substituted with a substituent group F, a carbocyclic group which may be substituted with a substituent group F, a heterocyclic oxy group, a carboepoxy group, a carbocyclic carbonyl group, a heterocyclic carbonyl group, An oxycarbonyl group, a heterocyclic oxycarbonyl group, and a quaternary ammonium group which may be substituted with a substituent group E.

Substituent group F: halogen, hydroxy, carboxy, pendant oxy, alkyl, and haloalkyl.

More preferred examples include the following.

(wherein R ¹⁰ A has the same meaning as described above)

Preferred examples of R ¹⁰ A is a hydrogen atom, the alkyl group may be substituted by I substituent group, the group may be substituted with I substituent group of alkenyl group, the substituent group may be a substituted non-aromatic carbocyclic group of F group, may be A non-aromatic heterocyclic group substituted with a substituent group F or an aromatic heterocyclic group which may be substituted with a substituent group F.

Substituent group I: halogen, a hydroxyl group, a carboxyl group, a cyano group, a sulfo group, a phosphonium group, an amine group which may be substituted with a substituent group C, an amine methyl group which may be substituted with a substituent group C, a sulfo group, An aminoxime group substituted with a substituent group C, a heterocyclic group which may be substituted with a substituent group F, and a 4-stage ammonium group which may be substituted with a substituent group E.

More preferred examples of R ¹⁰ A are a hydrogen atom, an alkyl group which may be substituted with a substituent group J, an alkenyl group which may be substituted with a substituent group G, a non-aromatic carbocyclic group which may be substituted with a substituent group G, or A non-aromatic heterocyclic group substituted with a substituent group G.

Substituent group J: hydroxyl group, carboxyl group, halogen, amine mercapto group, alkylamine mercapto group, diphosphoryl group, aminesulfonylamino group, amine mercaptoamine group.

Other preferred examples of the case where R ^2A and R ^2B together form a substituted or unsubstituted hydroxyimino group include the following groups.

(wherein R ⁸ and R ⁹ may each independently be a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted amine carbenyl group, a substituted or unsubstituted alkyl group, a substitution group. Or an unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group, or R ⁸ and R ⁹ together form a substituted or unsubstituted methylene group, or R ⁸ and R ⁹ together with an adjacent atom form a substitution or a non- a substituted carbocyclic group or a substituted or unsubstituted heterocyclic group; Q is a single bond, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group; m is an integer of 0 to 3) .

Better (wherein R ⁸ and R ⁹ may each independently be a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, an alkyl group, a hydroxyalkyl group, or a carboxyalkyl group, or R ⁸ and R ⁹ together with adjacent atoms may be substituted a carbocyclic group substituted with a group F or a heterocyclic group which may be substituted with a group of substituents F; m is 0 or 1).

In another preferred aspect when R ^2A and R ^2B together form a substituted or unsubstituted hydroxyimino group, the following groups are exemplified: (wherein R ⁸ and R ⁹ may each independently be a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group. , or R ⁸ and R ⁹ together form a substituted or unsubstituted methylene group, or R ⁸ and R ⁹ together with an adjacent atom form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic ring a heterocyclic ring; Q is a single bond, a substituted or unsubstituted carbocyclic diyl group, or a substituted or unsubstituted heterocyclic diyl group; m is an integer of 0 to 3; R ¹² is a hydrogen atom, a haloalkyl group, or Substituting the group selected by group D).

Better (wherein R ⁸ and R ⁹ may each independently be a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, an alkyl group, a hydroxyalkyl group, or a carboxyalkyl group, or R ⁸ and R ⁹ together with adjacent atoms may be substituted a carbocyclic group substituted with a group F or a heterocyclic group which may be substituted with a substituent group F; m is 0 or 1; R ¹² is a hydrogen atom, a haloalkyl group, a diphosphoryl group, a sulfo group, or a group of substituents D selected base).

R ^{12 is} preferably a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, a cyano group, a diphosphoryl group, a sulfo group, an amine group which may be substituted with a substituent group C, an amine carbenyl group which may be substituted with a substituent group C, or a sulfonate. a group, an aminesulfonyl group which may be substituted with a substituent group C, a hydroxyiminomethyl group which may be substituted with a substituent group H, a heterocyclic group which may be substituted with a substituent group F, or may be substituted with a substituent group E Grade 4 ammonium group.

More preferably, R ¹² is a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, a cyano group, an amine group, a sulfo group, a diphosphoryl group, an amine methyl group, an amine sulfonyl group, an alkylamine methyl group, an alkylamine sulfonium group. A hydroxyiminomethyl group, a trifluoromethyl group, an alkoxycarbonylamino group, an amine sulfonylamino group, a decylamino group, a hydroxyamine carbhydryl group, or an alkoxyamine fluorenyl group.

Q is preferably a single bond.

m is preferably an integer of 0 to 2, more preferably 0 or 1.

"R ⁸ and R ⁹ are each independently a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted amine carbenyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted one. When a carbocyclic group or a substituted or unsubstituted heterocyclic group is used, examples thereof include a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxyl group, a carboxyl group, a methyl group, an ethyl group, an isopropyl group, a t-butyl group, and a single group. Fluoromethyl, difluoromethyl, trifluoromethyl, carboxymethyl, carboxyethyl, amine-mercaptomethyl, amine-mercaptoethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, Ethoxymethyl, methoxyethyl, ethoxyethyl, methylthiomethyl, ethylthiomethyl, benzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-carboxybenzyl, 3,4-dihydroxyphenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, anthracene Base, pyrimidinyl, pyridyl Base, triazolyl, three Base, tetrazolyl, different Azolyl, Azolyl, Diazole, isothiazolyl, thiazolyl, thiadiazolyl, furyl, and thienyl.

Preferably, R ⁸ and R ⁹ are each independently a hydrogen atom, a fluorine atom, a methyl group, an ethyl group, an isopropyl group, a carboxymethyl group, a hydroxymethyl group, or a hydroxyethyl group.

Preferred is a combination of R ⁸ and R ⁹ (R ⁸ , R ⁹ ) (hydrogen atom, hydrogen atom), (hydrogen atom, fluorine atom), (fluorine atom, hydrogen atom), (hydrogen atom, methyl group). , (methyl, hydrogen atom), (methyl, methyl), (hydrogen atom, ethyl), (ethyl, hydrogen atom), (ethyl, ethyl), (hydrogen atom, isopropyl), (isopropyl group, hydrogen atom), (isopropyl group, isopropyl group), (hydrogen atom, carboxymethyl group), (carboxymethyl group, hydrogen atom), (hydrogen atom, hydroxymethyl group), (hydroxymethyl group) , a hydrogen atom), (a hydrogen atom, a hydroxyethyl group), or a (hydroxyethyl group, a hydrogen atom).

More preferably as a combination of the R ⁸ and R ^9, (R ^8, R ⁹⁾ system (hydrogen atom, hydrogen atom), (a hydrogen atom, a fluorine atom), (a fluorine atom, a hydrogen atom), (a hydrogen atom, a methyl group) , (methyl, hydrogen atom), (methyl, methyl), (hydrogen atom, ethyl), (ethyl, hydrogen atom), (hydrogen atom, isopropyl), (isopropyl, hydrogen atom) (hydrogen atom, hydroxymethyl), (hydroxymethyl, hydrogen atom), (hydrogen atom, hydroxyethyl), or (hydroxyethyl, hydrogen atom).

As another preferable combination of R ⁸ and R ⁹ , (R ⁸ , R ⁹ ) (hydrogen atom, hydrogen atom), (methyl group, hydrogen atom), (methyl group, methyl group), (ethyl group, hydrogen group) Atom), (isopropyl group, hydrogen atom), (hydroxymethyl group, hydrogen atom), or (hydroxyethyl group, hydrogen atom).

In the case of a better aspect, the following basis can be cited.

or (In the formula, each definition has the same meaning as the above.)

A better aspect is the basis shown below.

or

In the case where "R ⁸ and R ⁹ together form a substituted or unsubstituted methylene group", the following formula is exemplified: (wherein R ²² and R ²³ are each independently a hydrogen atom or a substituted or unsubstituted alkyl group).

Preferred examples of R ²² and R ²³ are each independently a hydrogen atom, a methyl group, a fluoromethyl group, a trifluoromethyl group, an ethyl group or the like, and more preferably a hydrogen atom.

"R ⁸ and R ⁹ together with an adjacent atom form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring", preferably a single ring of 3 to 6 members, more preferably It is a 3 or 4 member ring. Preferred examples thereof include cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, ethylene oxide, thiocyclopropane, nitrogen cyclopropene, sulfur cyclopropene, azetidine, and oxalate. Cyclobutane, thiocyclobutane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, tetrahydropyran, and the like. More preferred examples are cyclopropane or cyclobutane.

The substituent when R ⁸ and R ⁹ form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring together with an adjacent atom is 1 to 5 selected from the substituent group B. When the substituent is present in plural, it may be the same or different. More preferably, it is 1 to 3 groups selected from the substituent group F, and when there are a plurality of substituents, they may be the same or different.

Preferred embodiments of R ⁸ and R ⁹ are each independently a hydrogen atom, a fluorine atom, a methyl group, an ethyl group, an isopropyl group, a carboxyl group, a hydroxyl group, a carboxymethyl group, a hydroxymethyl group, or a hydroxyethyl group, or R. ⁸ and R ⁹ together with the adjacent atoms form a non-aromatic carbocyclic ring which may be substituted with a substituent group F.

More preferred aspects of R ⁸ and R ⁹ are independently a hydrogen atom, a fluorine atom, a methyl group, a hydroxyl group, a carboxyl group, a carboxymethyl group, a hydroxymethyl group, or a hydroxyethyl group, or R ⁸ and R ⁹ and a contiguous atom. Together, a cyclopropyl group which may be substituted with a substituent group F is formed.

When R ^2A and R ^2B together form =N-NR ^13A R ^13B , a group represented by the following formula is contained.

(wherein R ^13A and R ^13B are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted amine carbenyl group, a substituted or unsubstituted carbocyclic ring. Base, or substituted or unsubstituted heterocyclic group)

Preferable examples of R ^13A include an alkyl group which may be substituted with a substituent group G, an alkylcarbonyl group which may be substituted with a substituent group G, an amine carbenyl group and the like.

Preferable examples of R ^13B include a hydrogen atom, an alkyl group and the like.

R ³ is a hydrogen atom, OCH ₃ or NH-CH(=O), preferably a hydrogen atom.

R ¹¹ is a carboxyl group or a tetrazolyl group. When R ¹¹ is a tetrazolyl group, the following formula is preferred.

R ^{11 is} preferably a carboxyl group.

-W- is -S (= O) - or -S (= O) ₂ -. When -W- is -S(=O)-, it contains the following formula: , or a mixture of such, preferably the following: or,

-W- is preferably of the following formula: Or -S(=O) ₂ -.

-W is better for the following:

-T- is -CR ^4A R ^4B - or -CR ^5A R ^5B -CR ^6A R ^6B -. Preferable examples of R ^4A , R ^4B , R ^5A , R ^5B , R ^6A and R ^6B each independently represent a hydrogen atom, a halogen, a hydroxyl group, an amine group, a monoalkylamino group, a dialkylamino group or a carboxyl group. , carboxy, sulfonyl, monoalkylamine sulfonyl, dialkylamine sulfonyl, alkyl, haloalkyl, haloalkoxy, alkoxy, decyl, decyloxy, cyano, Methyl fluorenyl, fluorenyl, amine carbamoyloxy.

Preferred ^embodiments of R ^4A and R ^4B are each independently a hydrogen atom, a hydroxyl group, an alkyl group, an amine group, a carboxyl group, a methyl group, a methoxy group, a trifluoromethyl group, a trifluoromethoxy group, and a cyano group. more preferably R ^4A is a hydrogen atom, and R ^4B is hydrogen atom, an alkyl group or a hydroxyl group. In the preferred ^aspects of R ^5A , R ^5B , R ^6A and R ^6B , each independently is a hydrogen atom, a hydroxyl group, an amine group, a carboxyl group, a methyl group, a methoxy group, a trifluoromethyl group, or a trifluoromethyl group. Oxyl, cyano. In a more preferred aspect, R ^5A and R ^6A are each a hydrogen atom, and R ^5B and R ^6B are each independently a hydrogen atom or a hydroxyl group. More preferably, R ^5A , R ^5B , R ^6A and R ^6B are a hydrogen atom. -T- is preferably based -CR ^4A R ^4B -, more preferably _{-CH 2 -, - C (CH} 3) H -, - C (CH 3) 2 - or -C (OH) H-.

As other preferable aspects of -T-, the following formula can be cited.

(wherein R ^4A and R ^{4B have the} same meaning as described above)

R ^{4A is} preferably a hydrogen atom, and R ^{4B is} preferably a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a phenyl group, a hydroxymethyl group, a carboxymethyl group, an aminomethyl group, a fluoromethyl group, or a hydroxyl group. More preferably, R ^4A and R ^4B are a hydrogen atom, or R ^4A is a hydrogen atom and R ^4B is a methyl group.

R ^7A and 7B are each independently a hydrogen atom or a substituted or unsubstituted alkyl group. Preferred substituents for "substituted or unsubstituted alkyl" are those selected from the group consisting of halogen, hydroxy, cyano, alkoxy and haloalkoxy. More preferred substituents are halogen. When it is a "substituted or unsubstituted alkyl group", the alkyl group has a carbon number of from 1 to 8, preferably from 1 to 6, more preferably from 1 to 3, still more preferably 1.

Preferred ^embodiments of R ^7A and R ^7B are each independently a hydrogen atom or an alkyl group, and more preferably each independently a hydrogen atom or a methyl group. In a more preferred aspect, R ^7A and R ^7B are each a hydrogen atom, or either of R ^7A and R ^7B is a hydrogen atom, and the other is a methyl group. In a particularly preferred embodiment, R ^7A and R ^7B are each a hydrogen atom, or R ^7A is a methyl group, and R ^7B is a hydrogen atom.

As other preferable ^aspects of R ^7A and R ^7B , the following formula can be cited.

(wherein R ^7A and R ^{7B have the} same meaning as described above)

R ^7A and R ^7B particularly preferred aspect of the lines are both a hydrogen atom.

In the formula (I), preferred combinations of -W- and -T- are as follows.

i)-W- is the following formula: ,or And -T- is -CR ^4A R ^4B - or -CR ^5A R ^5B -CR ^6A R ^6B -.

Ii) -W- is -S(=O) ₂ and -T- is -CR ^4A R ^4B - or -CR ^5A R ^5B -CR ^6A R ^6B -.

In the formula (I), a more preferable combination of -W- and -T- is as follows.

i)-W- is the following: And -T- is -CH ₂ -.

The following formula:

In terms of the preferred aspect, it is of the following formula: or [Wherein, R ¹ is the following formula: or (wherein X is CH, CCl, CF, CBr or N); the other symbols have the same meanings as described above. R ^14A is a hydrogen atom, an amine group, an alkylamino group, or an alkyl group; the other symbols have the same meanings as described above. )

Among them, a more preferable aspect of R ¹ is the group shown below.

Preferred embodiments of the compounds of the present invention are exemplified below. The compounds shown in the following embodiments are all combinations of the specific examples.

(Embodiment 1)

-W- is the following: ,or -T- is -CR ^4A R ^4B - or -CR ^5A R ^5B -CR ^6A R ^6B -; R ^4A and R ^4B are each independently a hydrogen atom or a hydroxyl group; R ^5A , R ^5B , R ^6A and R ^6B are a hydrogen atom; R ¹ is of the formula: or (wherein each definition has the same meaning as described above); R ^2A and R ^2B together form a methylene group having the substituents shown below: or (wherein, a wavy line between a carbon atom forming a double bond and a carboxyl group or an alkyl group means a mixture of cis, trans or the like) or a formula: (wherein R ⁸ and R ⁹ may each independently be a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, an alkyl group, or a hydroxyalkyl group, or R ⁸ and R ⁹ together with an adjacent carbon atom form a substituted or unsubstituted non-substituted group. An aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; m is an integer from 0 to 3, and R ¹² is a hydrogen atom, a carboxyl group, a sulfo group, an amine carbenyl group, a hydroxylamine formamyl group, an alkoxy group acyl carbamoyl group, or a hydroxyl group); R ^7A is a hydrogen atom or an alkyl group; R ^7B is a hydrogen atom; R ¹¹ is carboxy; and R ³ is a hydrogen atom or OCH _3.

(Embodiment 2)

-W- is -S(=O) ₂ ; -T- is -CR ^4A R ^4B - or -CR ^5A R ^5B -CR ^6A R ^6B -; R ^4A and R ^4B are each independently a hydrogen atom or a hydroxyl group; R ^5A , R ^5B , R ^6A and R ^6B are a hydrogen atom; R ¹ is of the formula: or (wherein each definition has the same meaning as described above); R ^2A and R ^2B together form a methylene group having the substituents shown below: or (wherein, a wavy line between a carbon atom forming a double bond and a carboxyl group or an alkyl group means a mixture of cis, trans or the like), or the following formula: (wherein each definition has the same meaning as described above); and R ³ is a hydrogen atom or OCH ₃ .

(Embodiment 3)

Formula (I) is the following formula (I-1): (where W is the following formula: Or _{-S (= O) 2 -;} - T- is -CR ^4A R ^4B -; R ^4A and R ^4B are independently a hydrogen atom or a substituted or unsubstituted alkyl group; R ¹ is a substituted or unsubstituted An aromatic heterocyclic group; R ^2A and R ^2B together form a methylene group having a substituent shown below: or (wherein, a wavy line between a carbon atom forming a double bond and a carboxyl group or an alkyl group means a mixture of cis, trans or the like), or a substituted or unsubstituted hydroxyimino group shown below: Wherein R ¹⁰ is a hydrogen atom or a substituted or unsubstituted alkyl group; the wavy line between the nitrogen atom of the imine group and the oxygen atom represents a mixture of cis, trans or the like; and R ¹¹ is a carboxyl group. Or a tetrazolyl group; R ^7A is a hydrogen atom or a substituted or unsubstituted alkyl group; R ^7B is a hydrogen atom; and R ³ is a hydrogen atom).

(Embodiment 4)

Formula (I) is the following formula (I-1): (where W is the following formula:

Or _{-S (= O) 2 -;} - T- is -CR ^4A R ^4B -; R ^4A and R ^4B are independently a hydrogen atom or a substituted or unsubstituted alkyl group; R ¹ is represented by the following formula of base: (wherein X is CH, CCl, CF, or N); and R ^2A and R ^2B together form a methylene group having the substituents shown below: or Or a substituted or unsubstituted hydroxyimino group as shown below: Wherein R ¹⁰ is a hydrogen atom or a substituted or unsubstituted alkyl group; the wavy line between the nitrogen atom of the imine group and the oxygen atom represents a mixture of cis, trans or the like; and R ¹¹ is a carboxyl group. Or a tetrazolyl group; R ^7A is a hydrogen atom or a substituted or unsubstituted alkyl group; R ^7B is a hydrogen atom; and R ³ is a hydrogen atom).

(Embodiment 5)

Formula (I) is of the following formula (IA): (where W is the following formula: Or -S(=O) ₂ -; R ^4A is a hydrogen atom; R ^4B is a hydrogen atom or a methyl group; and R ¹ is a group represented by the following formula: (wherein X is CH, CCl, CF, or N); R ^7A is a hydrogen atom or an alkyl group; R ^7B is a hydrogen atom; and R ^2A and R ^2B together form an N-hydroxyimine group or the following formula: (wherein R ⁸ and R ⁹ may each independently be a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group. , or R ⁸ and R ⁹ together form a substituted or unsubstituted methylene group, or R ⁸ and R ⁹ together with an adjacent atom form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic ring a heterocyclic ring; Q is a single bond, a substituted or unsubstituted carbocyclic diyl group, or a substituted or unsubstituted heterocyclic diyl group; m is an integer of 0 to 3; R ¹² is a hydrogen atom, a haloalkyl group, or Substituent group D is selected; R ³ is a hydrogen atom; R ¹¹ is a carboxyl group).

(Embodiment 6)

Formula (I) is of the following formula: (where, -W- is the following formula: R ^4A is a hydrogen atom; R ^4B is a hydrogen atom or a methyl group; and R ¹ is the following formula: (wherein, X is CH); R ^7A is a hydrogen atom or an alkyl group; R ^7B is a hydrogen atom; and R ^2A and R ^2B together form an N-hydroxyimino group or the following formula: (wherein R ⁸ and R ⁹ may each independently be a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, an alkyl group, or a hydroxyalkyl group, or R ⁸ and R ⁹ together with an adjacent carbon atom form a substituted or unsubstituted non-substituted group. An aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; m is an integer from 0 to 3, and R ¹² is a hydrogen atom, a carboxyl group, a sulfo group, an amine carbenyl group, a hydroxylamine formamyl group, an alkoxy group a carbamide group or a hydroxy group; R ³ is a hydrogen atom; and R ¹¹ is a carboxyl group).

(Embodiment 7)

Formula (I) is of the following formula: [where, -W- is the following formula: R ^4A is a hydrogen atom; R ^4B is a hydrogen atom or a methyl group; and R ¹ is the following formula: (wherein, X is CH); R ^7A is a hydrogen atom or an alkyl group; R ^7B is a hydrogen atom; and R ^2A and R ^2B together form an N-hydroxyimino group or the following formula: (wherein R ⁸ and R ⁹ may each independently be a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, an alkyl group, or a hydroxyalkyl group, or R ⁸ and R ⁹ together with an adjacent carbon atom form a substituted or unsubstituted non-substituted group. An aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; m is an integer from 0 to 3, and R ¹² is a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, a cyano group, an amine group, a sulfo group, an amine formamidine Alkylsulfonyl, hydroxyiminomethyl, trifluoromethyl, alkoxycarbonylamino, aminesulfonylamino, decylamino, hydroxyaminemethanyl, or alkoxyamine Sulfhydryl); R ³ is a hydrogen atom; R ¹¹ is a carboxyl group].

The compound (I) of the present invention is not limited to a specific isomer, and includes all possible isomers (for example, a keto-enol isomer, an imine-enamine isomer, a non-image isomer, an optical Isomers, rotamers, geometric isomers, etc.), racemates or mixtures thereof.

When the compound (I) of the present invention is a compound having an asymmetric carbon and the substituent on the asymmetric carbon is described in a solid line, it means that the asymmetric carbon is configured as a single stereoisomer which is not specific. (R or S body), or a mixture of such.

For example, formula (I) The system contains: and Wait.

Preferably, it is a formula (I-1) (wherein each definition has the same meaning as the foregoing).

The following formula is represented by the same configuration as the above formula (I-1).

The nomenclature of the substitution position on the skeleton of the formula (I) is as follows. The α -side side chain and the β -side side chain system in the present specification represent a group bonded to the α -position and the β -position of the parent core described below.

The ester of the formula (I) or the formula (I') is preferably an ester body comprising a carboxyl group at the α -position and/or a carboxyl group at the β -position side chain. The ester of a carboxyl group on the side chain of the β -position may be exemplified by the terminal of R ¹ or R ^2A or R ^2B represented by the following formula, a substituted or unsubstituted amino group, a substituted or unsubstituted amine sulfonyl group, or a carboxyl group. a substituted or unsubstituted lower alkoxycarbonyl group, a substituted or unsubstituted amine carbenyl group, a carboxyl group having a substituent such as a carbonyloxy group, or the like having an ester structure, etc. [for example, when it is a carboxyl group (-COOH), it is shown to be An ester which represents a -COOR ^P1 structure together with R ^P1 which represents an ester residue of a carboxyl group or the like, and which contains a carboxyl group which is easily metabolized in the body: (In the formula, each symbol has the same meaning as the above.)

The protective group such as the above carboxyl group may be protected and/or deprotected by a method described in Protective Groups in Organic Synthesis, TW Greene, John Wiley & Sons Inc. (1991), and the like. For example, a lower alkyl group (for example, methyl group, ethyl group, or tert-butyl group), a lower alkylcarbonyloxymethyl group (for example, trimethylethenyl group), and a substituted aralkyl group (for example) may be mentioned. Examples: benzyl, diphenylmethyl, phenethyl, p-methoxybenzyl, p-nitrobenzyl, sulfhydryl (eg, tert-butyldimethylguanidino, diphenyl) Tertiary butyl fluorenyl) and the like.

More than one hydrogen, carbon and/or other atoms of the compound of formula (I) or formula (I') may be substituted with hydrogen, carbon and/or other atomic isotopes, respectively. Examples of such isotopes are ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I and ³⁶ Cl, respectively. It contains hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine. The compound of formula (I) or formula (I') also includes a compound substituted with the isotope. Compounds substituted with this isotope are also useful as pharmaceuticals, including all radioactive labels of compounds of formula (I) or formula (I'). Moreover, the present invention also encompasses a "radiolabeling method" for producing the "radioactive label", and a tool for research and/or diagnosis of metabolic drug dynamics research, binding assays.

The radiolabel of the compound of formula (I) or formula (I') can be prepared by methods known in the art. For example, the hydrazine-labeled compound represented by the formula (I) or the formula (I') can be introduced into the specific formula represented by the formula (I) or the formula (I') by, for example, a catalytic dehalogenation reaction using hydrazine. Modulated in the compound. This method comprises prepending a compound of formula (I) or formula (I') with a halogen-substituted precursor in the presence or absence of a suitable catalyst, such as Pd/C, in the presence or absence of a base. The substance reacts with helium gas. Suitable methods for modulating other hydrazine-labeled compounds can be found in the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). ^{The 14} C-labeled compound can be prepared by using a starting material having a ¹⁴ C carbon.

The salt of the compound represented by the formula (I) or the formula (I') includes a carboxyl group at the α -position and/or a carboxyl group at the β -position and/or a side-chain amine group at the β -position, forming a salt with an inorganic acid or an organic acid.

The pharmaceutically acceptable salt of the compound represented by the formula (I) or the formula (I') may, for example, be a compound represented by the formula (I) or the formula (I') and an alkali metal (for example, lithium, sodium, Potassium, etc.), alkaline earth metals (eg, calcium, barium, etc.), magnesium, migration metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, Ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, pyridinium, quinoline, etc.) and salts of amino acids, or with inorganic acids (eg, hydrochloric acid, sulfuric acid, Nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydrogen iodide, etc.), organic acids (eg, formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, anti-butyl a salt of enedic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, and the like. In particular, a salt with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid or methanesulfonic acid can be mentioned. These salts can be formed by a commonly employed method.

The compound represented by the formula (I) or the formula (I') or a pharmaceutically acceptable salt thereof is a case where a solvent (for example, a hydrate or the like) and/or a polymorph crystal is formed, and the present invention also encompasses Such various solvent and polymorphic crystals. The "solvent" may be a compound of the formula (I) or the formula (I') coordinated to any number of solvent molecules (e.g., water molecules, etc.). When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is placed in the atmosphere, it may absorb water and adhere to the adsorbed water to form a hydrate. Further, by recrystallizing the compound represented by the formula (I) or the formula (I') or a pharmaceutically acceptable salt thereof, it is possible to form the polymorph crystal.

The compound represented by the formula (I) or the formula (I') or a pharmaceutically acceptable salt thereof may be formed by forming a prodrug, and the present invention also encompasses such various prodrugs. A prodrug is a derivative of a compound of the invention having a chemically or metabolically degradable group, which is a compound of the compound of the invention which is pharmaceutically active in-vivo by decomposition of the vehicle or under physiological conditions. . The prodrug includes a compound which can be converted into a compound represented by the formula (I) or the formula (I') by oxidation, reduction, hydrolysis or the like of an enzyme under physiological conditions in a living body; can be converted into a compound by hydrolysis of gastric acid or the like. A compound of the compound represented by the formula (I) or the formula (I'). Methods and methods of making suitable precursor derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs have their own activity.

When the compound represented by the formula (I) or the formula (I') or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, a compound having a hydroxyl group and a suitable mercapto halide, a suitable acid anhydride, and the like can be exemplified. The sulfonyl chloride, a suitable sulfonyl anhydride, and a mixed acid anhydride are reacted, or a sulfoxy derivative or a sulfonoxy derivative produced by a reaction using a condensing agent is used as a precursor. For example, CH ₃ COO-, C ₂ H ₅ COO-, t-BuCOO-, C ₁₅ H ₃₁ COO-, PhCOO-, (m-NaOOCPh) COO-, NaOOCCH ₂ CH ₂ COO-, CH ₃ CH ( NH ₂ )COO-, CH2N(CH ₃ ) ₂ COO-, CH ₃ SO ₃ -, CH ₃ CH ₂ SO ₃ -, CF ₃ SO ₃ -, CH ₂ FSO ₃ -, CF ₃ CH ₂ SO ₃ -, p _{-CH 3 -O-PhSO 3 -,} PhSO 3 -, p-CH 3 PhSO 3 -.

As described in the following general synthesis methods and examples, the compound of the present invention represented by the formula (I) or the formula (I') can be bonded to the side chain by the α -position and the β -position of the skeleton of the following intermediate, respectively. Get it from the part. Examples of the protecting group P include the protecting groups described in the following general synthesis, and preferred examples thereof include a diphenylmethyl group, a p-methoxybenzyl group, a trityl group, and a 2,6-dimethoxy group. A benzyl group, a methoxymethyl group, a benzyloxymethyl group or a 2-(trimethylindenyl)ethoxymethyl group. Further, examples of the leaving group include halogen (Cl, Br, I, F), methanesulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group and the like.

 (Method A)  

(wherein, W, T, R ³ , R ^7A and R ^{7B have the} same meanings as defined above, -W ¹ is -H, -SH or -CH ₂ -SH, and P ₁ represents a protecting group of an amine group, P ₂ and P ₃ independently represents a protecting group of a carboxyl group.)

 step 1  

The compound (IV) is obtained by subjecting the compound (II) to the compound (III) by an addition reaction and an intramolecular cyclization reaction. Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. Preferred are acetone and HMPA. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -20 to 40 ° C, more preferably from about 10 to 30 ° C. Although the reaction time varies depending on the solvent and the reaction temperature, it is usually from 0.5 to 48 hours.

 Step 2  

The protecting group P _{3 of} the compound (IV) is subjected to a deprotection reaction under acidic conditions, followed by intramolecular cyclization in the presence of a condensing agent, whereby the compound (V) is obtained. Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. Preferred is dichloromethane. The acid used in the deprotection reaction may, for example, be an organic acid or an inorganic acid. For example, trifluoroacetic acid, toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, etc. are mentioned. Preferred is trifluoroacetic acid. The condensing agent may, for example, be 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexylcarbodiimide or carbonyldiimidazole. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -20 to 40 ° C, more preferably from about 0 to 20 ° C. Although the reaction time varies depending on the solvent and the reaction temperature, it is usually from 0.5 to 48 hours.

 Step 3  

The carboxy protecting group P ₁ containing a mercapto group of the compound (V) is subjected to an alcoholysis reaction in the presence of a base or a deprotection reaction under acidic conditions, whereby the compound (VI) is obtained. Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. Preferred is dichloromethane. The alcohol decomposition reaction can be activated by phosphorus pentachloride, phosphorus pentabromide, phosphonium chloride, sulfoxide, and the like. Preference is given to phosphorus pentachloride. The base may, for example, be an organic base or the like. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine, dimethylaniline, etc. are mentioned. Preferred is pyridine. The alcohol is then added. As the alcohol, methanol, ethanol, propanol or the like can be used. Preferred is ethanol. The acid used in the deprotection reaction under acidic conditions may, for example, be an organic acid or an inorganic acid. For example, trifluoroacetic acid, toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, etc. are mentioned. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -70 to 20 ° C, more preferably from about -70 to -30 ° C as the alcohol decomposition reaction. The deprotection reaction under acidic conditions is usually from about -100 to 100 ° C, preferably from about -20 to 40 ° C, more preferably from about -20 to 20 ° C. Although the reaction time varies depending on the solvent and the reaction temperature, it is usually from 0.5 to 48 hours.

(wherein, each symbol has the same meaning as described above)

 Step 4  

The compound (VIII) is obtained by subjecting the compound (VI) to a condensation reaction in the presence of a compound (VII) with a base. Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg MeCN, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. The condensing agent may, for example, be 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, phosphonium chloride, methanesulfonium chloride, dicyclohexylcarbodiimide. , carbonyl diimidazole, phenyl phosphate dichloride, and the like. The base may, for example, be triethylamine, pyridine, diisopropylethylamine, N-methylimidazole or N-methylmorpholine. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -80 to 20 ° C, more preferably from about -20 to 20 ° C. Although the reaction time varies depending on the reagent and solvent to be used, it is usually from 0.5 to 24 hours.

 Step 5  

Compound (IX) is obtained by oxidizing compound (VIII). Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg MeCN, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. Examples of the oxidizing agent include peracetic acid, m-chloroperoxybenzoic acid, hydrogen peroxide, and sodium tungstate. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -80 to 20 ° C, more preferably from about -20 to 20 ° C. Although the reaction time varies depending on the reagent and solvent to be used, it is usually from 0.5 to 24 hours.

 Step 6  

The entire protection of the compound (IX) is carried out under a acidic condition to carry out a deprotection reaction to obtain a compound (IC). As the acid, an organic acid or an inorganic acid can be used. For example, trifluoroacetic acid, toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, aluminum chloride, titanium chloride, etc. are mentioned. Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg MeCN, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. Preferred is dichloromethane. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -80 to 20 ° C, more preferably from about -20 to 20 ° C. Although the reaction time varies depending on the reagent and solvent to be used, it is usually from 0.5 to 24 hours.

Further, the obtained compound (IC) may be further chemically modified to synthesize an ester or a salt or a solvent which is pharmaceutically acceptable.

 (Method B)  

(wherein P ₃ represents a protecting group of a tetrazolyl group, and other symbols have the same meanings as defined above, and a protecting group of a tetrazolyl group can use, for example, the same protecting group as a protecting group of a carboxyl group)

 step 1  

Compound (XI) is obtained by deprotecting compound (V). The protecting group P _{2 of the} compound (V), although different depending on the protecting group, can usually be deprotected by acidic conditions or hydrogenation of a catalyst. As the acid, an organic acid or an inorganic acid can be used. For example, trifluoroacetic acid, toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, aluminum chloride, titanium chloride, etc. are mentioned. Preferred is aluminum chloride. Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg MeCN, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. Preferred is dichloromethane. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -80 to 20 ° C, more preferably from about -20 to 20 ° C. Although the reaction time varies depending on the reagent and solvent to be used, it is usually from 0.5 to 24 hours.

 Step 2  

The compound (XII) is obtained by converting the carboxylic acid of the compound (XI) to a guanamine group. Examples of the carboxylic acid activating reagent include sulfinium chloride, oxalic acid chloride, ethyl chlorocarbonate, di-tert-butyl dicarbonate, carbonyl diimidazole, and dicyclohexylcarbodiimide. Preferred is di-tert-butyl dicarbonate. Examples of the amide aminating agent include ammonia, ammonium chloride, ammonium formate, ammonium carbonate, and the like. Preferred is ammonium carbonate. The base may, for example, be pyridine, dimethylaminopyridine, mepyridine, triethylamine or diisopropylethylamine. Preferred is pyridine. Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. Preferably two alkyl. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -80 to 20 ° C, more preferably from about -20 to 20 ° C. Although the reaction time varies depending on the reagent and solvent to be used, it is usually from 0.5 to 24 hours.

 Step 3  

The guanamine group of the compound (XII) is converted into a cyano group using a dehydrating reagent in the presence of a base, whereby the compound (XIII) is obtained. Examples of the dehydrating agent include sulfinium chloride, grass chloroform, trifluoroacetic anhydride, acetic anhydride, phosphorus pentachloride, and phosphorus pentoxide. Trifluoroacetic anhydride is preferred. A base may also be present in the reaction. The base may, for example, be pyridine, pyridyl, triethylamine, dimethylpyridine or diisopropylethylamine. Preferred is pyridine. Examples of the reaction solvent are as follows: ethers (for example: anisole, two Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. Preferred is tetrahydrofuran. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -80 to 20 ° C, more preferably from about -20 to 20 ° C. Although the reaction time varies depending on the reagent and solvent to be used, it is usually from 0.5 to 24 hours.

 Step 4  

Then, the cyano group of the compound (XIII) is converted into a tetrazolyl group, whereby the compound (XIV) is obtained. When the cyano group is converted to a tetrazolyl group, it can be converted using trimethylsulfonium azide, sodium azide, hydrogen azide, or diphenylphosphoric acid azide. Preferred is trimethylsulfonyl azide. A tin reagent or the like may be added to the reaction catalyst. Examples of the tin reagent include dibutyltin oxide. Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. Preferably two alkyl. The reaction temperature is usually from about -50 to 150 ° C, preferably from about 20 to 120 ° C, more preferably from about 60 to 100 ° C. Although the reaction time varies depending on the reagent and solvent to be used, it is usually from 0.5 to 24 hours.

 Step 5  

The protective group is introduced into the tetrazolyl group of the compound (XIV), whereby the compound (X) is obtained. Examples of the protecting group include p-methoxybenzyl, diphenylmethyl, trimethyldecylethyl, benzyloxymethyl, methoxymethyl and the like. These protecting groups allow the corresponding alkyl halide to be reacted in the presence of a base or introduced using a diazo. The base may, for example, be pyridine, pyridyl, triethylamine, dimethylpyridine or diisopropylethylamine.

 Step 6  

The carboxy protecting group P ₁ containing a mercapto group of the compound (X) is subjected to an alcoholysis reaction in the presence of a base or a deprotection reaction under acidic conditions, whereby the compound (XV) is obtained. Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. Preferred is dichloromethane. The alcohol decomposition reaction can be activated by phosphorus pentachloride, phosphorus pentabromide, phosphonium chloride, sulfoxide, and the like. Preference is given to phosphorus pentachloride. The base may, for example, be an organic base or the like. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine, dimethylaniline, etc. are mentioned. Preferred is pyridine. The alcohol is then added. As the alcohol, methanol, ethanol, propanol or the like can be used. Preferred is ethanol. The acid used in the deprotection reaction under acidic conditions may, for example, be an organic acid or an inorganic acid. For example, trifluoroacetic acid, toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, etc. are mentioned. With respect to the reaction temperature, the alcohol decomposition reaction is usually carried out at about -100 to 100 ° C, preferably about -70 to 20 ° C, more preferably about -70 to -30 ° C. The deprotection reaction under acidic conditions is usually carried out at a temperature of from about -100 to 100 ° C, preferably from about -20 to 40 ° C, more preferably from about -20 to 20 ° C. Although the reaction time varies depending on the solvent and the reaction temperature, it is usually from 0.5 to 48 hours.

(wherein, each symbol has the same meaning as described above)

 Step 7  

The compound (XVI) is subjected to a condensation reaction in the presence of a compound (VII) with a base to thereby obtain a compound (XVI). Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg MeCN, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. The condensing agent may, for example, be 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, phosphonium chloride, methanesulfonium chloride, dicyclohexylcarbodiimide. , carbonyl diimidazole, phenyl phosphate dichloride, and the like. The base may, for example, be triethylamine, pyridine, diisopropylethylamine, N-methylimidazole or N-methylmorpholine. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -80 to 20 ° C, more preferably from about -20 to 20 ° C. Although the reaction time varies depending on the reagent and solvent to be used, it is usually from 0.5 to 24 hours.

 Step 8  

The compound (XVI) is oxidized, whereby the compound (XVIII) is obtained. Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg MeCN, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. Examples of the oxidizing agent include peracetic acid, m-chloroperoxybenzoic acid, hydrogen peroxide, and sodium tungstate. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -80 to 20 ° C, more preferably from about -20 to 20 ° C. Although the reaction time varies depending on the reagent and solvent to be used, it is usually from 0.5 to 24 hours.

 Step 9  

The entire protection of the compound (XVIII) is subjected to a deprotection reaction under acidic conditions to obtain a compound (IT). As the acid, an organic acid or an inorganic acid can be used. For example, trifluoroacetic acid, toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, aluminum chloride, titanium chloride, etc. are mentioned. Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg MeCN, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. Preferably, the reaction temperature of methylene chloride is usually from about -100 to 100 ° C, preferably from about -80 to 20 ° C, more preferably from about -20 to 20 ° C. Although the reaction time varies depending on the reagent and solvent to be used, it is usually from 0.5 to 24 hours.

 (Method C)  

(wherein, each symbol has the same meaning as described above)

 step 1  

The compound (XVIII) is oxidized, whereby the compound (XIX) is obtained. Examples of the oxidizing agent include selenium dioxide, oxonium, and the like. Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. Preferred is dichloromethane. The reaction temperature is usually from about -50 to 150 ° C, preferably from about 20 to 120 ° C, more preferably from about 60 to 100 ° C. Although the reaction time varies depending on the reagent and solvent to be used, it is usually from 0.5 to 24 hours.

 Step 2  

The compound (XXI) is obtained by an alkylation reaction of the compound (XX) with the compound (XIX) and subsequent cyclization. The base may, for example, be triethylamine, diisopropylethylamine, pyridine, morpholine or dimethylpyridine. Preferred is triethylamine. Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. Preferred are acetone and HMPA. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -20 to 40 ° C, more preferably from about 10 to 30 ° C. Although the reaction time varies depending on the solvent and the reaction temperature, it is usually from 0.5 to 48 hours.

 Step 3  

The compound (XXI) is reacted with an α-haloacetic acid halide, whereby the compound (XXII) is obtained. The base to be used may, for example, be triethylamine, diisopropylethylamine, pyridine, morpholine or dimethylpyridine. Preferred is triethylamine. Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, water, and the like. These solvents may be used singly or in combination of two or more. Preferred is dichloromethane. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -20 to 40 ° C, more preferably from about 0 to 20 ° C. Although the reaction time varies depending on the solvent and the reaction temperature, it is usually from 0.5 to 48 hours.

 Step 4  

The halide of the compound (XXII) is converted into a phosphonium salt, followed by intramolecular cyclization in the presence of a base, whereby the compound (XXIII) is obtained. The formation of the onium salt may, for example, be triphenylphosphine, triethylphosphine or tributylphosphine, and is preferably triphenylphosphine. The base may be exemplified by sodium carbonate, sodium hydrogencarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine, sodium methoxide, sodium ethoxide, and potassium third potassium hydride. . Preferred is sodium hydrogencarbonate. Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. Preferred is dimethylformamide. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -20 to 40 ° C, more preferably from about 10 to 30 ° C. Although the reaction time varies depending on the solvent and the reaction temperature, it is usually from 0.5 to 48 hours.

 Step 5  

The double bond of the compound (XXIII) is reduced, whereby the compound (XXIV) is obtained. The reduction is carried out using a catalyst hydrogenation or a reducing agent, and examples of the reducing agent include sodium borohydride, lithium borohydride, and boron hydride. Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. Methanol, isopropanol or the like is preferred. The reaction temperature is usually from about -100 to 50 ° C, preferably from about -60 to 0 ° C, more preferably from about -50 to -20 ° C. Although the reaction time varies depending on the solvent and the reaction temperature, it is usually from 0.5 to 48 hours.

 Step 6  

Carboxy-amino protecting group of the compound (XXIV) the carbonyl group of the acyl contains P ₁ deprotection reaction carried out in the presence of a base under alcoholysis reaction or decomposition of acidic conditions, whereby to obtain a compound (XXV). Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. Preferred is dichloromethane. The alcohol decomposition reaction can be activated by phosphorus pentachloride, phosphorus pentabromide, phosphonium chloride, sulfoxide, and the like. Preference is given to phosphorus pentachloride. The base may, for example, be an organic base or the like. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine, dimethylaniline, etc. are mentioned. Preferred is pyridine. The alcohol is then added. As the alcohol, methanol, ethanol, propanol or the like can be used. Preferred is ethanol. The acid used in the deprotection reaction under acidic conditions may, for example, be an organic acid or an inorganic acid. For example, trifluoroacetic acid, toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, etc. are mentioned. With respect to the reaction temperature, the alcohol decomposition reaction is usually carried out at about -100 to 100 ° C, preferably about -70 to 20 ° C, more preferably about -70 to -30 ° C. The deprotection reaction under acidic conditions is usually carried out at a temperature of from about -100 to 100 ° C, preferably from about -20 to 40 ° C, more preferably from about -20 to 20 ° C.

 Step 7  

The compound (XXV) is subjected to a condensation reaction with the compound (VII) in the presence of a base, whereby the compound (XXVI) is obtained. Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg MeCN, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, water, and the like. These solvents may be used singly or in combination of two or more. The condensing agent may, for example, be 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, phosphonium chloride, methanesulfonium chloride, dicyclohexylcarbodiimide. , carbonyl diimidazole, phenyl phosphate dichloride, and the like. The base may, for example, be triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine or dimethylaniline. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -80 to 20 ° C, more preferably from about -20 to 20 ° C. Although the reaction time varies depending on the reagent and solvent to be used, it is usually from 0.5 to 24 hours.

 Step 8  

The compound (XXVI) is oxidized, whereby the compound (XXVII) is obtained. Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg MeCN, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. Examples of the oxidizing agent include peracetic acid, m-chloroperoxybenzoic acid, hydrogen peroxide, and sodium tungstate. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -80 to 20 ° C, more preferably from about -20 to 20 ° C. Although the reaction time varies depending on the reagent and solvent to be used, it is usually from 0.5 to 24 hours.

 Step 9  

The entire protection of the compound (XXVII) is subjected to a deprotection reaction under acidic conditions to give a compound (IC'). As the acid, an organic acid or an inorganic acid can be used. For example, trifluoroacetic acid, toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, aluminum chloride, titanium chloride, etc. are mentioned. Examples of the reaction solvent are as follows: ethers (eg, anisole, two) Alkanes, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane , chloroform, carbon tetrachloride), hydrocarbons (eg n-hexane, benzene, toluene), guanamines (eg, formamide, N,N-dimethylformamide, N,N-dimethyl Acetamine, N-methylpyrrolidone, ketones (eg acetone, methyl ethyl ketone), nitriles (eg MeCN, propionitrile), nitros (eg nitromethane, nitro Ethane, nitrobenzene), dimethyl hydrazine, alcohols (for example, methanol, ethanol, tert-butanol, etc.), water, and the like. These solvents may be used singly or in combination of two or more. Preferred is dichloromethane. The reaction temperature is usually from about -100 to 100 ° C, preferably from about -80 to 20 ° C, more preferably from about -20 to 20 ° C. Although the reaction time varies depending on the reagent and solvent to be used, it is usually from 0.5 to 24 hours.

The compound of the present invention has antibacterial activity against a broad spectrum of antibacterial activity and can be used for preventing or treating various diseases caused by pathogenic bacteria of various mammals including humans, and can be used, for example, in respiratory tract infections, urinary tract infections, and breathing. Systemic infection, sepsis, nephritis, cholecystitis, oral infection, endocarditis, pneumonia, meningitis, otitis media, enteritis, empyema, traumatic infection, opportunistic infection, etc.

The compound of the present invention is especially a Gram-negative bacterium, preferably a Gram-negative bacterium against the bacteria of the intestine (Escherichia coli, Klebsiella, Saw bacillus, Enterobacter, Citrobacter, Morganella, Provedenia, Proteus, etc.), Gram-negative bacteria (Haemophilus, Moraxella, etc.) colonized in the respiratory system and non-fermentative Gram-negative bacteria (false except Pseudomonas aeruginosa) Monocytogenes, Stenotrophomonas, Burkholderia, Acinetobacter, etc.) show high antibacterial activity. For those gram-negative bacteria produced that fall A, B, C, and the Class D β - lactam enzyme stability, the bacteria produce for TEM type, SHV type, as the type ESBL by KPC representative for a variety of Gram-negative bacteria with β -endoxime drug resistance have high antibacterial activity. In particular, it is extremely stable for metals containing β -endo-amines such as NDM type, IMP type, VIM type, L-1 type, etc., and various β -endoxime drugs containing cephem and carbapenem. Drug-resistant Gram-negative bacteria are also effective. Further preferred compounds have a high concentration in the body, a high concentration in the blood, a long duration of effect, and/or significant tissue migration. Further, a preferred compound is safe in that it does not exhibit fever or side effects such as nephrotoxicity. Further, preferred compounds are high in water solubility and have good dynamics in the body, and are suitable as an injectable drug and an oral drug.

The compounds of the invention may be administered orally or parenterally. For oral administration, the compound of the present invention can be used in a usual preparation, for example, a solid preparation such as a tablet, a powder, a granule or a capsule, a liquid preparation, an oily suspension, or a syrup or an expectorant. Use in any dosage form. For parenteral administration, the compound of the present invention can be used as an aqueous or oily suspension injection, nasal spray. In the preparation, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers, and the like can be used arbitrarily. The formulations of the present invention can be made by combining (e.g., mixing) a therapeutically effective amount of a compound of the present invention with a pharmaceutically acceptable carrier or diluent.

The compound of the present invention can be administered as an injection, a capsule, a tablet, or a granule rather than orally or orally, and is preferably administered as an injection. The dose is usually from about 0.1 to 100 mg/day, preferably from about 0.5 to 50 mg/day, per 1 kg of the patient or animal, and may be administered in two to four divided doses as needed. The carrier used as an injection may be, for example, distilled water, physiological saline or the like, and a base or the like for adjusting the pH may be used. As a carrier for use in capsules, granules, and lozenges, it is a well-known excipient (for example, starch, lactose, white sugar, calcium carbonate, calcium phosphate, etc.), a binder (for example, starch, gum arabic, carboxymethyl group). Cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (for example, magnesium stearate, talc, etc.).

[Examples]

Hereinafter, the present invention will be described in more detail by way of examples, reference examples, test examples and formulation examples, but the invention is not limited thereto.

In addition, the abbreviation used in this specification shows the following meaning.

Boc: third butoxycarbonyl

BH or Bzh: diphenylmethyl

DIAD: diisopropyl azodicarboxylate

DMF: N,N-dimethylformamide

DMA: N,N-dimethylacetamide

EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

HOBt: 1-hydroxybenzotriazole

mCPBA: m-chloroperoxybenzoic acid

Me: methyl

ODS: octadecyl fluorenyl

t-Bu: third butyl

TFA: trifluoroacetic acid

TBAF: tetrabutylammonium fluoride

PMB: p-methoxybenzyl

Ph: phenyl

The NMR analysis obtained in the examples was carried out at 400 MHz, and measurement was carried out using DMSO-d ₆ , CDCl ₃ or the like.

The LCMS analysis obtained in the examples was measured under the following conditions.

Measurement condition A: Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d.2.1x50mm) (WaterS)

Flow rate: 0.8mL/min

PDA detection wavelength: 254nm

Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid

Gradient: After a linear gradient of 5%-100% solvent [B] for 3.5 minutes, 100% solvent [B] was maintained for 0.5 minutes.

Measurement condition B: Column: Shim-pack XR-ODS (2.2 μm, i.d. 50 x 3.0 mm) (Shimadzu)

Flow rate: 1.6mL/min

PDA detection wavelength: 254nm

Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid

Gradient: After a linear gradient of 10% to 100% solvent [B] for 3 minutes, 100% vehicle [B] was maintained for 5 minutes.

The powder X-ray diffraction measurement (XRPD) of the crystalline solid obtained in the examples was carried out under the conditions of the following measurement conditions 1 or 2 according to the powder X-ray diffraction measurement method described in the general test method of the Japanese Pharmacopoeia. Further, when the measurement was carried out under the measurement condition 2, the 2-Theta (2θ) value appeared as a peak of the peak of the aluminum near the peak of 38°.

(Measurement condition 1): D-8DiScover manufactured by Bruker

Determination method: reflection method

Light source type: Cu tubular bulb

Use wavelength: CuKα ray

Tube current: 40mA

Tube voltage: 40Kv

Sample board: glass

X-ray incident angle: 3° and 12°

(Measurement Condition 2): MiniFlex 600 manufactured by Rigaku Corporation

Light source type: Cu tubular bulb

Use wavelength: CuKα ray

Tube current: 10mA

Tube voltage: 30Kv

Sample board: aluminum (Al)

Measuring range: 3° to 40°

Step width: 0.01deg

Scanning speed: 10deg/min

 [Example 1]    Synthesis of Compound I-001 and Compound I-002  

 Step 1 Synthesis of Compound 1b  

A solution of compound 1a (43.8 g, 300 mmol) in DMF (307 mL) was warm. Dicyclohexylamine (59.6 mL, 300 mmol) and 1-bromo-3-methyl-2-butene (38.1 mL, 300 mmol) were added thereto. After stirring at 60 ° C for 1 hour, the precipitated solid was removed by filtration. Water was added to the filtrate, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. EtOAc (EtOAc m. After standing at room temperature for 2 days, the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compound 1b (104 g, yield 91%).

¹ H-NMR (CDCl ₃ ) δ: 1.73 (3H, s), 1.76 (3H, s), 2.79 (2H, t, J = 6.2 Hz), 3.18 (2H, t, J = 6.2 Hz), 4.74 ( 2H,d,J=7.3Hz), 5.38(1H,t,J=7.3Hz), 6.86(1H,s), 7.26-7.36(10H,m).

 Step 2 Synthesis of Compound 1c  

N,N,N',N'-tetramethyldiaminomethane (149 mL, 1093 mmol) was added to a solution of Compound 1b (104 g, 293 mmol) in dichloromethane. Acetic anhydride (129 mL, 1367 mL) and acetic acid (109 mL, 1914 mmol) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour, and then the solvent was evaporated under reduced pressure. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by column chromatography (hexane-ethyl acetate) to afford Compound 1c (79 g, 74%).

¹ H-NMR (CDCl ₃ ) δ: 1.74 (3H, s), 1.77 (3H, s), 3.48 (2H, s), 4.78 (2H, d, J = 7.4 Hz), 5.39 (1H, t, J =7.4 Hz), 6.25 (1H, s), 6.36 (1H, s), 6.86 (1H, s), 7.26-7.35 (10H, m).

 Step 3 Synthesis of Compound 1e  

Compound 1d (6.02 g, 25.5 mmol) and hexamethylphosphonium triamine (15.5 mL, 89 mmol) were added to a solution of Compound 1c (10.0 g, 25.5 mmol) in acetone (100 mL). Water was added and extraction was carried out with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane-ethyl acetate) to afford Compound 1e (2.1 g, yield 13.1%).

¹ H-NMR (CDCl ₃ ) δ: 1.65 (3H, s), 1.69 (3H, s), 2.34 (2H, t, J = 4.5 Hz), 2.69 (1H, dd, J = 13.6, 2.8 Hz), 2.81 (1H, br s), 2.91-2.98 (1H, m), 3.59 (1H, d, J = 16.1 Hz), 3.65 (1H, d, J = 16.1 Hz), 3.77 (1H, s), 4.67 ( 1H, dd, J = 12.0, 7.5 Hz), 4.88 (1H, dd, J = 12.0, 7.5 Hz), 5.08 (1H, d, J = 4.7 Hz), 5.33 (1H, t, J = 7.5 Hz), 5.51 (1H, dd, J = 9.5, 4.7 Hz), 6.09 (1H, d, J = 9.5 Hz), 6.86 (1H, s), 7.26-7.40 (17H, m).

 Step 4 Synthesis of Compound 1f  

A solution of compound 1e (6.80 g, 10.8 mmol) in dichloromethane (34 mL) was cooled to -10. A solution of TFA (34 mL, 441 mmol) in dichloromethane (34 mL) was then evaporated. Water was added to the reaction liquid, and extraction was performed with dichloromethane. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and a methylene chloride (50 mL) solution of the obtained residue was cooled to 0. Thereto, EDC hydrochloride (4.15 g, 21.6 mmol) was added and stirred at room temperature for 1 hour. Water was added and the mixture was extracted with dichloromethane. The organic layer was washed with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The obtained residue was purified by column chromatography (hexane-ethyl acetate) to afford Compound 1f (4.0 g, 83%).

¹ H-NMR (CDCl ₃ ) δ: 1.71 (3H, s), 1.77 (3H, s), 2.60-2.67 (2H, m), 2.75 (1H, dd, J = 18.1, 9.0 Hz), 2.94 (1H) , dd, J = 14.4, 4.3 Hz), 3.19-3.25 (1H, m), 4.73-4.83 (2H, m), 4.96-4.98 (1H, m), 5.36 (1H, t, J = 6.8 Hz), 5.53 (1H, dd, J = 8.7, 4.7 Hz), 6.16 (1H, d, J = 8.6 Hz), 7.26-7.39 (6H, m).

 Step 5 Synthesis of Compound 1h  

After the suspension of phosphorus pentachloride (1.25 g, 6.00 mmol) in dichloromethane (13.3 mL) was cooled to -40 ° C, pyridine (0.969 mL, 12.0 mmol) was added, followed by the compound 1f (1.33 g, 3.00 mmol) . After stirring for 1 hour under ice cooling, the reaction mixture was cooled to -78 ° C, and ethanol (13.3 mL) was added. After stirring at -30 ° C for 30 minutes, an aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and extracted with dichloromethane. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After the inorganic substance was removed by filtration, it was concentrated to about 10 ml under reduced pressure to obtain a dichloromethane solution (solution A). After a solution of 1 g (682 mg, 1.70 mmol) of DMA (4.9 mL) was cooled to -20 ° C, triethylamine (0.291 mL, 2.10 mmol), methanesulfonium chloride (0.148 mL, 1.90 mmol) was added. Solution B was obtained by stirring at -20 ° C for 1 hour.

To a half amount of the solution A (about 5 ml, corresponding to 1.50 mmol), 5 ml of dichloromethane was added, and under ice cooling, pyridine (0.121 mL, 1.50 mmol) and a solution B were added. After stirring for 1 hour under ice cooling, dilute aqueous hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated sodium bicarbonate, water and saturated brine, and dried over anhydrous magnesium sulfate. After filtering over magnesium sulfate, it was concentrated under reduced pressure and applied to a silica gel column chromatography, eluting with hexane/ethyl acetate. The fractions containing the desired compound were concentrated under reduced pressure to give compound 1h (0.44 g, yield 41%).

¹ H-NMR (CDCl ₃ ) δ: 8.74 (1H, d, J = 8.5 Hz), 8.07 (1H, s), 7.39 (1H, s), 5.66 (1H, dd, J = 8.5, 4.6 Hz), 5.39 (1H, t, J = 7.3 Hz), 5.08 (1H, d, J = 4.6 Hz), 4.86 - 4.71 (4H, m), 3.33 - 3.27 (1H, m), 3.10 (1H, dd, J = 14.6, 4.1 Hz), 2.83-2.73 (2H, m), 2.64 (1H, dd, J = 14.6, 8.5 Hz), 1.76 (3H, s), 1.72 (3H, s), 1.54 (9H, s), 1.47 (9H, s).

 Step 6 Synthesis of Compound 1i  

Compound 1h (0.75 g, 1.06 mmol) was dissolved in acetonitrile (4 ml) and EtOAc (4 ml). After cooling to -20 ° C, 37% peracetic acid solution (0.20 ml, 1.11 mmol) was added. After stirring for 1 hour under ice cooling, a 10% aqueous sodium sulfite solution and ethyl acetate were added and the mixture was separated, and the organic layer was washed with water, saturated sodium bicarbonate and saturated brine, and dried over magnesium sulfate. After filtering the magnesium sulfate, it was concentrated under reduced pressure, and applied to a silica gel column chromatography, eluting with hexane/ethyl acetate. The chromatographic fractions containing the desired compound were concentrated under reduced pressure to give Compound 1i (0.64 g, yield 84%) as a mixture of the mixture.

¹ H-NMR (CDCl ₃ ) δ: 9.18 (0.2H, d, J = 7.0 Hz), 8.41 (1.0H, d, J = 9.3 Hz), 8.12 (1.0H, s), 7.34 (0.8H, s ), 7.32 (0.2H, s), 5.97 (1.0H, dd, J = 9.2, 4.8 Hz), 5.39 (1.2H, t, J = 7.3 Hz), 5.23-5.20 (0.2H, m), 4.91 4.62 (6.0H, m), 3.81-3.72 (1.0H, m), 3.64 (0.2H, dd, J = 14.7, 3.6 Hz), 3.57-3.51 (0.2H, m), 3.42 (1.0H, dd, J = 14.5, 5.0 Hz), 3.20 (0.2H, dd, J = 14.7, 5.8 Hz), 2.96 (1.0H, dd, J = 17.8, 7.7 Hz), 2.86 (0.2H, dd, J = 18.5, 9.3 Hz), 2.47-2.38 (2.0H, m), 1.74 (7.2H, t, J = 10.0 Hz), 1.54 (10.8H, s), 1.48-1.45 (10.8H, m).

 Step 7 Synthesis of Compound I-001 and Compound I-002  

Compound 1i (0.64 g, 0.882 mmol) was dissolved in dichloromethane (10 ml), and after cooling to -40 ° C, then anisole (1.16 ml, 10.6 mmol) and 2 mol/L aluminum chloride/nitromethane were added sequentially. The solution (5.29 ml, 10.6 mmol) was stirred at -30 °C for 30 min. The reaction solution was dissolved in water, dissolved in 2 mol/L hydrochloric acid or acetonitrile, and washed with diisopropyl ether. HP20-SS resin was added to the aqueous layer and acetonitrile was distilled off under reduced pressure. The resulting mixture was subjected to HP20-SS column chromatography and dissolved in water/acetonitrile. After the chromatographic fraction containing the desired compound was concentrated under reduced pressure, the compound I-001 and the compound I-002 of white powder were obtained by lyophilization.

Yield: Compound I-001: 272.8 mg (yield 57%)

Compound I-002: 57.6 mg (yield 12%)

 Compound I-001  

¹ H-NMR (D ₂ O) δ: 7.22 (1H, s), 5.88 (1H, d, J = 4.8 Hz), 5.00 (1H, d, J = 4.8 Hz), 3.65-3.52 (2H, m) , 3.06 (1H, dd, J = 18.3, 7.7 Hz), 2.82 (1H, dd, J = 14.6, 12.7 Hz), 2.55 (1H, d, J = 18.3 Hz).

Elemental analysis: C16H15N5O10S2(H2O)2.3

Calculated values: C, 35.40; H, 3.64; N, 12.90; S, 11.81 (%)

Found: C, 35.39; H, 3.57; N, 13.11; S, 11.79 (%)

 Compound I-002  

¹ H-NMR (DMSO-D ₆ ) δ: 9.87 (1H, d, J = 7.9 Hz), 7.27 (2H, s), 6.85 (1H, s), 5.59 (1H, dd, J = 7.9, 4.6 Hz ), 4.90 (1H, d, J = 4.6 Hz), 4.58 (2H, s), 3.02-2.87 (2H, m).

Elemental analysis: C16H15N5O10S2(H2O)2.1

Calculated: C, 35.64; H, 3.59; N, 12.99; S, 11.89 (%)

Found: C, 35.72; H, 3.66; N, 13.18; S, 11.73 (%)

 [Embodiment 2]    Synthesis of Compound I-003  

 Step 1 Synthesis of Compound 2a  

Compound 1h (0.75 g, 1.06 mmol) was dissolved in dichloromethane (10 mL). After stirring for 1 hour under ice cooling, saturated baking soda water was added and liquid separation was carried out, and the organic layer was washed with water, saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. After filtering the magnesium sulfate, it was concentrated under reduced pressure, and applied to a silica gel column chromatography, eluting with hexane/ethyl acetate. The chromatographic fractions containing the desired compound were concentrated under reduced pressure to afford compound 2a (0.09 g, yield 12%).

¹ H-NMR (CDCl ₃ ) δ: 8.70 (1H, d, J = 9.5 Hz), 7.36 (1H, s), 6.07 (1H, dd, J = 9.5, 5.0 Hz), 5.38 (1H, t, J = 7.5 Hz), 4.95 (1H, d, J = 5.0 Hz), 4.88 (1H, dd, J = 11.9, 7.7 Hz), 4.81 (1H, t, J = 6.0 Hz), 4.75 (1H, d, J) = 16.8 Hz), 4.69 (1H, d, J = 16.8 Hz), 4.01-3.95 (1H, m), 3.32 (1H, dd, J = 15.1, 5.3 Hz), 3.00 (1H, dd, J = 15.1, 12.2 Hz), 2.89 (1H, dd, J = 18.0, 7.6 Hz), 2.43 (1H, d, J = 17.7 Hz), 1.78 (3H, s), 1.73 (3H, s), 1.54 (9H, s) , 1.46 (9H, s).

 Step 2 Synthesis of Compound I-003  

Compound I-003 was synthesized by the same method as Step 7 of Compound 1-001 using Compound 2a (0.09 g, 0.121 mmol).

Yield: 20.2 mg (yield 32%)

¹ H-NMR (DMSO-D ₆ ) δ: 9.50 (1H, d, J = 8.1 Hz), 7.18 (2H, s), 6.77 (1H, s), 5.83 (1H, dd, J = 8.1, 4.7 Hz ), 5.25 (1H, d, J = 4.7 Hz), 4.48 (2H, s), 2.92 (1H, d, J = 17.3 Hz), 2.35 (1H, d, J = 18.4 Hz).

MS(m+1)=518

 [Example 3]    Synthesis of Compound I-036  

 Step 1 Synthesis of Compound 36c  

Triphenylphosphine (8.80 g, 33.5 mmol) was added to a solution of compound 36a (5.0 g, 33.5 mmol) in tetrahydrofuran and cooled to 0 °C. DIAD (6.52 mL, 33.5 mmol) and diphenylmethyl hydroxyacetate were added thereto, and the mixture was stirred at 0 ° C for 1 hour. The reaction mixture was poured into a hexane-ethyl acetate mixture, and the resulting insoluble matter was filtered. The filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 10 g of crude product of compound 36b. To the DMA (60 mL) solution of this compound 36b, thiourea (15.3 g, 201 mmol) was added, and the mixture was stirred at 30 ° C for 24 hours. The insoluble material was filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 36c (1.5 g, 9.5%).

¹ H-NMR (CDCl ₃ ) δ: 4.78 (2H, d, J = 5.8 Hz), 4.94 (4H, br s), 5.26 (1H, dd, J = 10.4, 1.0 Hz), 5.36 (1H, dd, J=17.2, 1.3 Hz), 5.90-6.00 (1H, m), 6.96 (1H, s), 7.26-7.33 (10H, m).

 Step 2 Synthesis of Compound 36d  

Add morpholine (789 mg, 9.05 mmol) and Pd(PPh ₃ ) ₄ (105 mg, 0.091 mmol) in a solution of compound 36c (850 mg, 1.81 mmol) in tetrahydrofuran (13 mL) at room temperature. Stir under 1 hour. Water was added and extraction was carried out with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the compound 36d was quantitatively obtained by distillation under reduced pressure.

MS(m-1)=428.01

 Step 3 Synthesis of Compound 36g  

After a suspension of phosphorus pentachloride (0.754 g, 3.62 mmol) in dichloromethane (10 mL) was cooled to -40 ° C, pyridine (0.584 mL, 7.24 mmol) was added, followed by compound 36e (0.805 g, 1.81 mmol). After stirring for 1 hour under ice cooling, the reaction mixture was cooled to -78.degree. After stirring at -30 ° C for 2 hours, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and extracted with dichloromethane. After the organic layer was dried over anhydrous magnesium sulfate, the inorganic material was removed by filtration. Ethyl acetate was added to the filtrate, and dichloromethane and methanol were evaporated under reduced pressure to give ethyl acetate (yield A). HOBt (0.367 g, 2.72 mmol) was added to a solution of Compound 36d (777 mg, 1.81 mmol) in dichloromethane (10 mL), and the reaction solution was cooled to 0 °C. Thereto, EDC hydrochloride (0.416 g, 2.17 mmol) was added and stirred for 1 hour under ice cooling. The resulting insoluble matter was filtered, and the filtrate was added to the solution A under ice cooling, and stirred for 1 hour. Water was added thereto and extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, sodium hydrogencarbonate water and brine, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give crude product (1 g). This was dissolved in dichloromethane (10 mL), EtOAc (1. Thereto, a 2 mol/L aluminum chloride/nitromethane solution (1.48 mL, 13.6 mmol) was added, and the mixture was stirred at -30 ° C for 1 hour. Ice, diisopropyl ether, and acetonitrile were sequentially added to the reaction liquid, and the mixture was stirred to completely dissolve the insoluble matter, and then the aqueous layer was taken out. After the organic layer was again extracted with water, all the aqueous layers were combined, and acetonitrile was distilled off under reduced pressure by adding HP20-SS resin. The resulting mixture was purified by ODS column chromatography (water / acetonitrile). A chromatographic fraction containing the desired compound was collected, and after concentration under reduced pressure, 36 g (270 mg)

¹ H-NMR (D ₂ O) δ: 2.62 (1H, d, J = 18.2 Hz), 2.94 - 2.78 (2H, m), 3.15 - 3.06 (2H, m), 4.67 (2H, s), 5.26 ( 1H, d, J = 4.5 Hz), 5.61 (1H, d, J = 4.5 Hz).

Elemental analysis: C16H14FN5O9S2(H2O)4.2

Calculated values: C, 33.19; H, 3.90; F, 3.28; N, 12.09; S 11.07 (%)

Found: C, 33.14; H, 3.60; F, 3.25; N, 12.11; S, 11.05 (%)

 Step 4 Synthesis of Compound I-036  

Nitrogenation was carried out, and compound 36 g (16 mg, 0.034 mmol) was dissolved in a mixed solution of DMA (320 mL) and acetonitrile (230 mL). Thereto, 38% peracetic acid (0.020 mL) was added under ice cooling, and the mixture was stirred for 1 hour. An aqueous sodium hydrogensulfite solution was added to the reaction solution, and the mixture was stirred for 5 minutes, and then ice, diisopropyl ether, and acetonitrile were added in this order and stirred to completely dissolve the insoluble matter, and then the aqueous layer was taken out. After the organic layer was again extracted with water, all the aqueous layers were combined and HP20-SS resin was added, and acetonitrile was distilled off under reduced pressure. The resulting mixture was purified by HP20-SS resin column chromatography (water/acetonitrile). The chromatographic fractions containing the desired compound were collected, and after concentrating under reduced pressure, compound I-036 (3 mg) was obtained as white powder.

MS(m+1)=520

 [Example 4]    Synthesis of Compound I-005  

 Step 1 Synthesis of Compound 5a  

Phosphorus pentachloride (2.81 g, 13.5 mmol) and pyridine (1.20 ml, 14.9 mmol) were suspended in dichloromethane (15 ml) at -78 ° C, and compound 1f (3.00 g, 6.75 mmol) was added. Methyl chloride (15 ml) solution. After stirring for 1 hour under ice cooling, it was cooled to -78 ° C and ethanol (15 ml) was added. After stirring at -25 ° C to -15 ° C for 1 hour, saturated baking soda water was added to the reaction liquid. The organic layer was separated and dried over magnesium sulfate. After filtering magnesium sulfate, p-toluenesulfonic acid monohydrate (5.14 g, 27.0 mmol) and ethyl acetate (50 ml) were added, and the mixture was concentrated under reduced pressure, and dichloromethane was evaporated. The precipitated crystals were filtered off to give compound 5a (1.64 g, yield 49%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.64 (3.0H, br s), 7.47 (2.0H, d, J = 8.0 Hz), 7.11 (2.0H, d, J = 7.8 Hz), 5.37 (1.0) H, t, J = 7.0 Hz), 5.16 (1.0H, d, J = 4.6 Hz), 4.83 (1.0H, d, J = 4.6 Hz), 4.76 (1.0H, dd, J = 12.0, 7.3 Hz) , 4.66 (1.0H, dd, J = 12.3, 7.3 Hz), 3.00 (1.0H, dd, J = 18.2, 6.9 Hz), 2.87-2.77 (2.0H, m), 2.29 (3.0H, s), 1.74 (3.0H, s), 1.69 (3.0H, s).

XRPD (measurement condition 1): diffraction angle 2θ (°): 8.0, 11.1, 13.1, 17.1, 21.6, 22.9, 25.0, 25.5, 27.1

 Step 2, 3, 4 Synthesis of Compound I-005  

Compound 5b (578 mg, 1.1 mmol) synthesized by the method described in Bioorg. Med. Chem. 2007, 15, 6716-6732. was added to a suspension of compound 3a (499 mg, 1.0 mmol) in 10 mL of ethyl acetate. After phenyl chlorophosphate (232 mg, 1.1 mmol), N-methyl-fyfolin (405 mg, 4.0 mmol) was added at 0 ° C, and the mixture was stirred at 0 ° C for 1 hour, and then water was added and extracted with ethyl acetate. The organic layer was washed successively with 1 mol/L hydrochloric acid, 8.4% aqueous sodium hydrogencarbonate solution, water, and brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration, and concentrated under reduced pressure to give a crude product of compound 5c (965.1 mg) as a yellow foam.

Compound I-005 (184.4 mg, 35.7% yield (3 steps)) was obtained as white solid, m. m.

¹ H-NMR (D2O) δ: 1.58 (3H, d, J = 7.2 Hz), 2.56 (1H, d, J = 18.3 Hz), 2.83 (1H, dd, J = 14.6, 12.5 Hz), 3.07 (1H) , dd, J = 18.3, 7.8 Hz), 3.51-3.57 (1H, m), 3.61-3.69 (1H, m), 4.96 (1H, q, J = 7.1 Hz), 5.02 (1H, d, J = 4.8 Hz), 5.91 (1H, t, J = 7.0 Hz), 7.24 (1H, s).

MS (M+1) = 515, (measurement condition A)

Elemental analysis: C17H17N5O10S2(H2O)2.5

Calculated value C: 36.43% H: 3.96% N: 12.49% S: 11.44%

Found C: 36.28% H: 3.93% N: 12.63% S: 11.64%

 [Example 5]    Synthesis of Compound I-027  

 Step 1, 2, 3 Synthesis of Compound I-027  

The compound 27a (1181 mg, 1.8 mmol) and the compound 27b (490 mg, 1.5 mmol) which were synthesized by the method described in JP5909441B2 were used to obtain a colorless transparent oily compound 27c (617.2). Mg, 42.7% yield) of crude product.

The obtained compound 27c (617.2 mg, 0.64 mmol) was used to give the compound I-027 (144.7 mg, 42.5% yield (2 step)) as white solid.

¹ H-NMR (D2O) δ: 2.56 (1.0H, d, J = 18.2 Hz), 2.81-2.84 (1.2H, m), 3.00-3.09 (1.2H, m), 3.22 (0.2H, dd, J =12.0,6.0 Hz), 3.51-3.57 (1.2H, m), 3.65 (1.0H, dd, J=14.9, 5.1 Hz), 3.72 (0.2H, dd, J=7.1, 3.5 Hz), 4.04-4.08 (2.4H, m), 4.94 - 4.95 (1.2H, m), 5.02 (1.0H, d, J = 4.5 Hz), 5.13 (0.2H, d, J = 4.3 Hz), 5.71 (0.2H, d, J = 4.3 Hz), 5.91 (1.0H, d, J = 4.8 Hz), 6.80 (0.2H, s), 7.19 (0.2H, s), 7.23 (1.0H, s).

MS (M+1) = 531, (measurement condition A)

Elemental analysis: C17H17N5O11S2(H2O) ₂ .6

Calculated value C: 35.31% H: 3.87% N: 12.11% S: 11.09%

Found C: 35.46% H: 3.94% N: 12.09% S: 10.68%

 [Embodiment 6]    Synthesis of Compound I-037 and I-038  

 Step 1 Synthesis of Compound 37b  

Compound 37a (5.00 g, 31.9 mmol) was dissolved in tetrahydrofuran (50 ml), and a solution of diphenyldiazomethane (8.04 g, 41.4 mmol) in tetrahydrofuran (10 ml). After stirring at room temperature for one night, concentration was carried out under reduced pressure. It was applied to a ruthenium column chromatography and dissolved in hexane/ethyl acetate. The chromatographic fractions containing the desired compound were concentrated under reduced pressure to afford compound 37b ( 9.86 g, 96%).

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.31 (10H, m), 6.98 (1H, s), 6.66 (1H, d, J = 50.6 Hz).

 Step 2 Synthesis of Compound 37c  

The obtained compound 37b (2.00 g, 6.19 mmol) and N-hydroxyphthalimide (1.21 g, 7.43 mmol) were dissolved in dimethylformamide (20 ml), and diisopropylethylamine was added. (1.30 ml, 7.43 mmol). After stirring at room temperature for one night, water was added and extraction was carried out with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtering magnesium sulfate, it was concentrated under reduced pressure. Diisopropyl ether was added to the residue to precipitate a solid, and the precipitated solid was taken out by filtration to obtain compound 37c (2.28 g, 91%).

¹ H-NMR (CDCl ₃ ) δ: 7.87 (2H, dd, J = 5.6, 3.1 Hz), 7.80 (2H, dd, J = 5.5, 3.1 Hz), 7.43 - 7.28 (10H, m), 7.01 (1H) , s), 6.02 (1H, d, J = 57.2Hz).

 Step 3 Synthesis of Compound 37d  

The compound 37c (2.28 g, 5.62 mmol) was used to give the crude product of Compound 37d (3.45 g).

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.21 (10H, m), 7.14 (1H, s), 6.98 (1H, s), 6.18 (1H, d, J = 56.5 Hz), 1.53 (9H, s ).

 Step 4 Synthesis of Compound 37e  

Compound 37e (2.08 g, 55%) was obtained from the fluorine-based stereochemical non-image isomer 1:1 using the compound 37d (2.08 g, 4.95 mmol). mixture.

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.28 (10.0H, m), 6.99 (0.5H, s), 6.98 (0.5H, s), 6.32-6.17 (1.0H, m), 5.62-5.55 ( 1.0H, m), 5.37 (1.0H, t, J = 6.8 Hz), 4.90-4.73 (3.0H, m), 3.19 (1.0H, br s), 2.86-2.40 (4.0H, m), 1.75 ( 3.0H, s), 1.71 (3.0H, s), 1.55 (9.0H, s).

 Step 5 Synthesis of Compound 37f  

A mixture of compound 37f (0.91 g, 89%) was obtained by the same procedure as in the step 6 of Example 1 using Compound 37e (1.0 g, 1.19 mmol).

LC/MS (measurement condition A), retention time: 2.66, 2.71 minutes, [M+H]=854

 Step 6 Synthesis of Compound I-037 and I-038  

Compounds I-037 and I-038 were obtained by the same procedure as in Step 7 of Example 1, using Compound 37f (0.91 g, 1.07 mmol), using aluminum tetrachloride instead of aluminum trichloride.

Compound I-037: 79.3 mg (yield 12%)

¹ H-NMR (D2O) δ: 7.38 (1H, d, J = 3.4 Hz), 6.10 (1H, d, J = 57.2 Hz), 5.88 (1H, d, J = 4.8 Hz), 5.01 (1H, d , J = 4.8 Hz), 3.64 (1H, dd, J = 14.7, 5.2 Hz), 3.57-3.51 (1H, m), 3.06 (1H, dd, J = 18.3, 7.8 Hz), 2.82 (1H, dd, J=14.6, 12.6 Hz), 2.56 (1H, d, J = 18.2 Hz).

C16H14FN5O10S2(H2O)3.1

Calculated value C: 33.41%, H: 3.54%, F: 3.30%, N: 12.17%, S: 11.15%

Found C: 33.49%, H: 3.60%, F: 3.19%, N: 12.29%, S: 11.04%

Compound I-038: 41.5 mg (yield 6%)

^{1 H-NMR (D2O) δ} : 7.30 (1H, s), 6.08 (1H, d, J = 56.2Hz), 5.71 (1H, d, J = 4.4Hz), 5.11 (1H, d, J = 4.4Hz ), 3.71 (1H, dd, J = 13.2, 4.6 Hz), 3.62-3.55 (1H, m), 3.21 (1H, dd, J = 13.2, 11.0 Hz), 3.03 (1H, dd, J = 18.5, 8.3) Hz), 2.84 (1H, dd, J = 18.6, 3.1 Hz).

C16H14FN5O10S2(H2O)3.4

Calculated value C: 33.09%, H: 3.61%, F: 3.27%, N: 12.06%, S: 11.04%

Found C: 33.08%, H: 3.65%, F: 3.30%, N: 12.23%, S: 10.93%

 [Embodiment 7]    Synthesis of Compound I-039  

 Step 1 Synthesis of Compound 39b  

Compound 39a (4.89 g, 30.0 mmol) was dissolved in dimethylformamide (50.0 mL) and cooled to 0. Triethylamine (4.57 mL, 33.0 mmol) and 2-bromoacetonitrile (2.20 mL, 33.0 mmol) were added to this solution and stirred at room temperature. After completion of the reaction, the reaction solution was poured into purified water (150 mL), and the precipitated solid was filtered, washed with purified water, and then washed with hexane and air-dried to obtain compound 39b (5.32 g, yield 88%). ).

¹ H-NMR (CDCl ₃ ) δ: 7.93-7.88 (m, 2H), 7.85-7.80 (m, 2H), 4.96 (s, 2H).

 Step 2 Synthesis of Compound 39d  

Compound 39b (2.02 g, 10.0 mmol) was dissolved in dichloromethane (25.0 mL), cooled to -30 ° C, and methyl hydrazide (0.583 mL, 11.0 mmol) was added and stirred at room temperature for 30 minutes. The solid which precipitated was removed, and the reaction mixture was concentrated under reduced pressure. dichloromethane (25.0 mL) was added, and Compound 39c (2.72 g, 10.0 mmol) was added and stirred overnight at room temperature. The solvent was distilled off, and ethyl acetate, purified water and 2 mol/L hydrochloric acid water were added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with purified water, washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was concentrated under reduced pressure, and the precipitated solid was filtered and washed with ethyl acetate to afford compound 39d (1.88 g, yield: 58%).

¹ H-NMR (DMSO-D6) δ: 11.87 (br s, 1H), 7.55 (s, 1H), 5.11 (s, 2H), 1.48 (s, 9H).

 Step 3 Synthesis of Compound 39f  

Compound 39e (31.5 g, 70.9 mmol) was dissolved in tetrahydrofuran (320 mL), 5% palladium carbon (15.1 g, 7.09 mmol) was added, and the mixture was stirred at room temperature for 4 hours and 30 minutes under hydrogen atmosphere. The catalyst was removed by filtration through celite, and then 5% palladium carbon (15.1 g, 7.09 mmol) was added and stirred at room temperature for 1 hour under hydrogen atmosphere. The catalyst was removed by filtration through celite, and diphenyldiazomethane (15.1 g, 78.0 mmol) was added and stirred at room temperature for one hour. The solvent was distilled off, ethyl acetate and diisopropyl ether were added, and the resulting solid was filtered and dried, whereby compound 39f (27.5 g, yield 71%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.30 (m, 14H), 6.94 (s, 1H), 6.02 (d, J = 8.8 Hz, 1H), 5.55 (dd, J = 8.8, 4.7 Hz, 1H ), 4.99 (d, J = 4.7 Hz, 1H), 3.67 (d, J = 16.2 Hz, 1H), 3.61 (d, J = 16.2 Hz, 1H), 3.17 - 3.08 (m, 1H), 2.90 (dd) , J=14.6, 4.5 Hz, 1H), 2.62 (dd, J=14.6, 9.7 Hz, 1H), 2.54-2.50 (m, 2H).

 Step 4 Synthesis of Compound 39g  

Phosphorus pentachloride (15.4 g, 73.7 mmol) was suspended in dichloromethane (200 mL) and cooled to 0 °C. Pyridine (6.55 mL, 81.0 mmol) and Compound 6 (20.0 g, 36.9 mmol) were added to the suspension, and stirred at 0 ° C for 30 min. The solution was cooled to -78 ° C, ethanol (200 mL) was added and warmed to -30 ° C and stirred for 2 hr. Purified water (33.2 mL, 1.84 mol) was added to this solution and stirred. The reaction liquid was further diluted with purified water, and dichloromethane was distilled off, and the precipitated crystals were collected by filtration. The obtained crystals were washed with purified water and ethyl acetate and dried, to thereby afford crystals of compound 39 g (14.1 g, yield 83%).

¹ H-NMR (DMSO-D6) δ: 8.79 (br s, 2H), 7.47-7.27 (m, 10H), 6.91 (s, 1H), 5.18 (d, J = 4.6 Hz, 1H), 4.84 (d) , J = 4.6 Hz, 1H), 3.46-3.27 (m, 2H), 3.06 (dd, J = 18.3, 7.1 Hz, 1H), 2.89 (dd, J = 14.3, 6.0 Hz, 1H), 2.74 (dd, J=10.2, 20.0 Hz, 1H).

XRPD (measurement condition 2): diffraction angle 2θ (°): 4.2, 8.2, 10.0, 16.2, 17.7, 20.3, 21.4, 23.7, 23.9, 27.6, 28.4, 29.1, 29.5, 32.6

Elemental analysis C22H20N2O5SHCl(H2O)1.0

Calculated: C, 55.17; H, 4.84; N, 5.85; S, 6.69; Cl, 7.40 (%)

Found: C, 55.26; H, 4.87; N, 6.23; S, 6.68; Cl, 7.14 (%)

 Step 5 Synthesis of Compound 39h  

Compound 39 g (461 mg, 1.00 mmol) was suspended in ethyl acetate (5.00 mL). Compound 39d (392 mg, 1. To the suspension were added phenyl dichlorophosphate (0.193 mL, 1.30 mmol) and N-methyl-fyfolin (0.44 mL, 4.00 mmol), and the mixture was stirred at -40 ° C for 1 hour. Purified water was added to this solution, the solvent was distilled off, and extraction was performed with ethyl acetate. The organic layer was washed with purified water, washed with brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the obtained residue was applied to a silica gel column chromatography to afford compound 39h (758mg).

_{^{1 H-NMR (CDCl 3)}} δ: 8.70 (br s, 1H), 7.56-7.47 (m, 1H), 7.38-7.20 (m, 10H), 6.94 (s, 1H), 5.71 (dd, J = 8.5 , 4.6 Hz, 1H), 5.15 (d, J = 4.6 Hz, 1H), 4.92-4.82 (m, 2H), 3.24 - 3.17 (m, 1H), 3.10 - 3.04 (m, 1H), 2.76 - 2.67 ( m, 1H), 2.57-2.52 (m, 2H), 1.54 (s, 9H).

 Step 6 Synthesis of Compound 39i  

Compound 39h (366 mg, 0.50 mmol) was dissolved in dichloromethane (4.00 mL). To the solution was added m-chloroperoxybenzoic acid (138 mg, 0.550 mmol) and stirred at -40 °C for 30 min. An aqueous sodium thiosulfate solution was added to the reaction mixture, and the solvent was distilled off and extracted with ethyl acetate. The organic layer was washed with purified water, washed with brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography to yield Compound 39i (257 mg, yield 69%).

¹ H-NMR (CDCl ₃ ) δ: 8.54 (br s, 1H), 7.78 (d, J = 9.9 Hz, 1H), 7.37-7.28 (m, 11H), 7.01 (s, 1H), 6.03 (dd, J = 9.9, 4.9 Hz, 1H), 4.91-4.82 (m, 2H), 4.68 (d, J = 4.9 Hz, 1H), 3.74 - 3.67 (m, 1H), 3.46 (dd, J = 14.6, 5.0 Hz) , 1H), 2.63 (dd, J = 17.8, 7.8 Hz, 1H), 2.53-2.44 (m, 1H), 2.33 (d, J = 17.8 Hz, 1H), 1.60 (s, 9H).

 Step 7 Synthesis of Compound I-039  

Compound 39i (257 mg, 0.344 mmol) was dissolved in dichloromethane (3.0 mL) and cooled to -30 ° C, then, then, and then, and then, mL, 2.06 mmol), stirred at -30 ° C for 30 minutes. Purified water and diisopropyl ether were added to the reaction liquid. After adding acetonitrile to the reaction liquid to dissolve the precipitate, the aqueous layer was separated. The organic layer was extracted with purified water, and HP20SS was added to the combined aqueous layer and concentrated. The concentrated suspension was subjected to column chromatography coupled with HP20SS and ODS, and dissolved in water/acetonitrile to collect a chromatographic fraction containing the target substance, and the pH was set by using a 0.2 mol/L sodium hydroxide aqueous solution. As a seventh, a piece of dry ice was added, and concentrated under reduced pressure, and the obtained compound I-039 (yield: 121 mg, yield 70%) was obtained by lyophilizing the concentrate.

^{1 H-NMR (D2O) δ} : 7.18 (s, 1H), 5.87 (d, J = 4.5Hz, 1H), 5.05 (s, 2H), 5.01 (d, J = 4.8Hz, 1H), 3.64 (dd , J=14.7, 5.1 Hz, 1H), 3.58-3.52 (m, 1H), 3.08 (dd, J = 18.4, 7.8 Hz, 1H), 2.83 (dd, J = 12.1, 14.7 Hz, 1H), 2.57 ( d, J = 18.4 Hz, 1H).

MS (M+1): 483, holding time: 0.48 minutes (measurement condition A)

Elemental analysis C16H13N6NaO8S2(H2O)3.3

Calculated values: C, 34.08; H, 3.50; N, 14.90; Na, 4.08; S, 11.37 (%)

Found: C, 34.00; H, 3.45; N, 15.05; Na, 4.45; S, 11.21 (%)

 [Embodiment 8]    Synthesis of Compound I-040  

 Step 1 Synthesis of Compound 40b  

Compound 40a (3.27 g, 30.0 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0 ° C, triphenylphosphine (9.44 g, 36.0 mmol), N-hydroxyphthalimide (5.87 g, 36.0) Methyl) and DIAD (7.00 mL, 36.0 mmol) were stirred at room temperature for 1 hour. The solvent was distilled off and methanol was added, and the obtained solid was washed with methanol and dried, whereby Compound 40b (6.12 g, yield 80%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 8.66 (d, J = 6.0 Hz, 2H), 7.85-7.83 (m, 2H), 7.77-7.75 (m, 2H), 7.48 (d, J = 6.0 Hz, 2H) ), 5.25 (s, 2H).

 Step 2 Synthesis of Compound 40d  

Compound 40b (2.54 g, 10.0 mmol) was dissolved in dichloromethane (25.0 mL), cooled to -30 ° C, and methyl hydrazide (0.583 mL, 11.0 mmol) was added and stirred at room temperature for 30 minutes. The precipitated solid was removed, the reaction mixture was concentrated under reduced pressure, dichloromethane (25.0 mL) was added, and Compound 40c (2.72 g, 10.0 mmol) was added and stirred at room temperature overnight. The solvent was distilled off, and ethyl acetate, purified water and 2 mol/L hydrochloric acid water were added to the residue, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with purified water, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated, and the obtained solid was filtered and washed with ethyl acetate to afford compound 40d (1.84 g, yield 49%).

¹ H-NMR (DMSO-D ₆ ) δ: 11.77 (s, 1H), 8.56 (d, J = 6.3 Hz, 2H), 7.43 (s, 1H), 7.33 (d, J = 6.3 Hz, 2H), 5.26(s, 2H), 1.46(s, 9H).

 Step 3 Synthesis of Compound 40e  

Compound 40d (416 mg, 1.10 mmol) and compound 39 g (461 mg, 1.00 mmol) were suspended in dichloromethane (5.00 mL), cooled to 0 ° C, pyridine (0.178 mL, 2.20 mmol) and 1-(3-dimethyl) Aminopropyl)-3-ethylcarbodiimide hydrochloride (211 mg, 1.10 mmol) was stirred at 0 ° C for 1 hour. Purified water was added to this solution, the solvent was distilled off, and extraction was performed with ethyl acetate. The organic layer was washed with purified water, and then washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography to give Compound 40e (417 mg, yield 53%).

¹ H-NMR (CDCl ₃ ) δ: 8.52 - 8.42 (m, 3H), 7.56 (d, J = 7.8 Hz, 1H), 7.38 - 7.22 (m, 12H), 6.97 (s, 1H), 5.74 (dd , J=8.6, 4.7 Hz, 1H), 5.33-5.26 (m, 2H), 5.12 (d, J = 4.6 Hz, 1H), 3.12-3.06 (m, 1H), 2.91 (dd, J = 19.4, 6.7 Hz, 1H), 2.64-2.46 (m, 3H), 1.54 (s, 9H).

 Step 4 Synthesis of Compound 40f  

Compound 40f (156 mg, yield 76%) was synthesized in the same manner as in Step 6 of Example 7 using Compound 40e (200 mg, 0.25 mmol).

¹ H-NMR (CDCl ₃ ) δ: 8.63 (s, 1H), 8.57 (d, J = 5.9 Hz, 2H), 7.72 (d, J = 9.9 Hz, 1H), 7.37-7.29 (m, 13H), 7.01(s,1H),6.08(dd,J=9.9,4.9Hz,1H), 5.29(s,2H),4.64(d,J=4.9Hz,1H),3.72-3.65(m,1H),3.36 (dd, J = 14.5, 5.0 Hz, 1H), 2.62 (dd, J = 17.9, 7.8 Hz, 1H), 2.47-2.37 (m, 1H), 2.30 (d, J = 17.9 Hz, 1H), 1.54 ( s, 9H).

 Step 5 Synthesis of Compound I-040  

Compound 40f (156 mg, 0.195 mmol) was dissolved in dichloromethane (2.0 mL) and cooled to -30 ° C, and then, and then, and then mL, 1.17 mmol), stirred at -30 degrees for 30 minutes. Purified water and diisopropyl ether were added to the reaction liquid. After adding acetonitrile to the reaction liquid to dissolve the precipitate, the aqueous layer was separated. The organic layer was extracted with purified water, and HP20SS was added to the combined aqueous layer and concentrated. The concentrated suspension is subjected to column chromatography coupled with HP20SS and ODS, and dissolved in water/acetonitrile, and the chromatographic fraction containing the target substance is collected, concentrated under reduced pressure, and the concentrated liquid is freeze-dried. This gave I-040 of the compound powder. (yield 65.3 mg, yield 63%)

¹ H-NMR (DMSO-D6) δ: 9.35 (d, J = 7.3 Hz, 1H), 8.53 (d, J = 6.0 Hz, 2H), 7.40 (d, J = 5.9 Hz, 2H), 7.21. , 2H), 6.90 (s, 1H), 5.76 (dd, J = 7.3, 4.8 Hz, 1H), 5.20 (s, 2H), 4.97 (d, J = 4.8 Hz, 1H), 3.51-3.33 (m, 2H), 3.05 (dd, J = 18.2, 8.0 Hz, 1H), 2.87 (t, J = 13.5 Hz, 1H), 2.45 (d, J = 18.8 Hz, 1H).

MS (M+1): 535, holding time: 0.32 minutes (measurement condition A)

Elemental Analysis C20H18N6O8S2(H2O)4.3

Calculated values: C, 39.25; H, 4.38; N, 13.73; S, 10.48 (%)

Found: C, 39.15; H, 4.13; N, 13.94; S, 10.45 (%)

 [Embodiment 9]    Synthesis of Compound I-041  

 Step 1 Synthesis of Compound 41a  

Compound 40f (206 mg, 0.257 mmol) was dissolved in dimethylformamide (0.618 mL). Methyl iodide (0.080 mL, 1. Purified water was added to the reaction liquid, and extraction was performed with ethyl acetate. The organic layer was washed with purified water, then washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off to obtain a compound 41a. Compound 41a was used directly in the subsequent reaction without purification.

 Step 2 Synthesis of Compound I-041  

Compound I-041 (71.0 mg, yield 50%) was obtained in the same manner as in Step 5 of Example 8 using Compound 41a (0.257 mmol).

^{1 H-NMR (D2O) δ} : 8.77-8.71 (m, 2H), 8.05-8.00 (m, 2H), 7.13-7.08 (m, 1H), 5.95-5.90 (m, 1H), 5.57 (s, 2H ), 5.06-4.97 (m, 1H), 4.37 (s, 3H), 3.66-3.49 (m, 2H), 3.13 - 3.02 (m, 1H), 2.89-2.77 (m, 1H), 2.62-2.52 (m , 1H).

MS (M+1): 549, retention time: 0.29 minutes (measurement condition A)

Elemental analysis C21H20N6O8S2(H2O)4.5

Calculated: C, 40.06; H, 4.64; N, 13.35; S, 10.18 (%)

Found: C, 40.10; H, 4.65; N, 13.33; S, 10.10 (%)

 [Embodiment 10]    Synthesis of Compound I-042  

 Step 1 Synthesis of Compound 42b  

Compound 42a (2.29 g, 5.00 mmol) was dissolved in tetrahydrofuran (20.0 mL), cooled to 0 ° C, pyridine-3-methanol (655 mg, 6.00 mmol) and tributylphosphine (1.48 mL, 6.00 mmol) and 1'-(Azodicarbonyl)dipiperidine (1.51 g, 6.00 mmol) was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was applied to EtOAc ield.

¹ H-NMR (CDCl ₃ ) δ: 8.62 - 8.58 (m, 1H), 8.54 (dd, J = 4.9, 1.5 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.32 - 7.28 (m) , 15H), 6.96 (s, 1H), 6.51 (s, 1H), 5.31 (s, 2H), 4.35 (q, J = 7.0 Hz, 2H), 2.05 (s, 1H), 1.30 (t, J = 7.0Hz, 6H).

 Step 2 Synthesis of Compound 42c  

Compound 42b (886 mg, 1.62 mmol) was dissolved in tetrahydrofuran (4.00 mL) and methanol (4.00 mL), and a 1 mol/L aqueous sodium hydroxide solution (3.23 mL, 3.23 mmol) was added thereto, and the mixture was stirred at room temperature for 30 minutes, and then carried out for 30 minutes. Heat to reflux. The reaction solution was cooled to room temperature, and a 2 mol/L hydrochloric acid aqueous solution (1.62 mL, 3.23 mmol) was added thereto, and tetrahydrofuran and methanol were distilled off, and the precipitated solid was filtered off, washed with purified water and ethyl acetate, and dried. This gave compound 42c (660 mg, yield 79%).

¹ H-NMR (CDCl ₃ ) δ: 8.83 (s, 1H), 8.55-8.50 (m, 2H), 7.39 (dd, J = 7.7, 4.8 Hz, 1H), 7.34 - 7.19 (m, 16H), 6.85 (s, 1H), 5.15 (s, 2H).

 Step 3 Synthesis of Compound 42d  

Compound 42d was obtained in the same manner as in Step 3 of Example 8 using Compound 42c (531 mg, 1.27 mmol). (821 mg, yield 77%)

¹ H-NMR (CDCl ₃ ) δ: 8.60 (d, J = 2.0 Hz, 1H), 8.53-8.50 (m, 1H), 7.72 (dt, J = 7.8, 1.9 Hz, 1H), 7.35-7.28 (m) , 25H), 7.00 (s, 1H), 6.94 (s, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.73 (s, 1H), 5.61 (dd, J = 8.8, 4.8 Hz, 1H) , 5.32 (s, 2H), 5.02 (d, J = 4.8 Hz, 1H), 3.14 - 3.02 (m, 1H), 2.84 (dd, J = 14.4, 4.5 Hz, 1H), 2.58-2.45 (m, 3H) ).

 Step 4 Synthesis of Compound 42e  

Compound 42e (350 mg, yield 84%) was obtained in the same manner as in the step 6 of Example 7 using Compound 42d (410 mg, 0.442 mmol).

¹ H-NMR (CDCl ₃ ) δ: 8.65 (d, J = 1.6 Hz, 1H), 8.53 (dd, J = 4.8, 1.4 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.42 ( d, J = 10.2 Hz, 1H), 7.35-7.28 (m, 25H), 7.06 (s, 1H), 6.99 (s, 1H), 6.66 (s, 1H), 6.00 (dd, J = 10.2, 4.9 Hz , 1H), 5.33 (s, 2H), 4.51 (d, J = 4.9 Hz, 1H), 3.69-3.63 (m, 1H), 3.27 (dd, J = 14.4, 4.9 Hz, 1H), 2.60 (dd, J=17.9, 7.7 Hz, 1H), 2.37-2.24 (m, 2H).

 Step 5 Synthesis of Compound I-042  

Compound 42e (175 mg, 0.186 mmol) was dissolved in dichloromethane (1OmL), cooled to EtOAc, EtOAc (EtOAc (EtOAc) Stir for 1 hour. Purified water and diisopropyl ether were added to the reaction liquid. After adding acetonitrile to the reaction liquid to dissolve the precipitate, the aqueous layer was separated. The organic layer was extracted with purified water, and HP20SS was added to the combined aqueous layer and concentrated. The concentrated suspension is subjected to column chromatography coupled with HP20SS and ODS, and dissolved in water/acetonitrile, and the chromatographic fraction containing the target substance is collected, concentrated under reduced pressure, and the concentrate is freeze-dried. Powder compound I-042 (yield 65.3 mg, yield 63%).

¹ H-NMR (DMSO-D6) δ: 9.25 (d, J = 7.4 Hz, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.51 (dd, J = 4.6, 1.4 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.39 (dd, J = 7.7, 4.8 Hz, 1H), 7.21 (s, 2H), 6.88 (s, 1H), 5.73 (dd, J = 7.4, 4.9 Hz, 1H), 5.18 (s, 2H), 4.95 (d, J = 4.6 Hz, 1H), 3.48-3.45 (m, 1H), 3.43-3.32 (m, 1H), 3.04 (dd, J = 18.1, 7.9 Hz) , 1H), 2.85 (t, J = 13.4 Hz, 1H), 2.45 (d, J = 18.1 Hz, 1H).

MS (M+1): 536, holding time: 0.38 minutes (measurement condition A)

Elemental analysis C20H18N6O8S2(H2O)3.2

Calculated: C, 40.57; H, 4.15; N, 14.19; S, 10.83 (%)

Found: C, 40.58; H, 4.08; N, 14.16; S, 10.91 (%)

 [Example 11]    Synthesis of Compound I-043  

 step 1  

Using the pyridine-3-methanol, the compound 43a (245 mg, 0.306 mmol) was obtained in the same manner as in the procedure of the procedure of Example 8 to give the compound I-043.

¹ H-NMR (DMSO-D6) δ: 9.09-9.02 (m, 2H), 8.91 (d, J = 6.0 Hz, 1H), 8.54 (d, J = 8.0 Hz, 1H), 8.13 (dd, J = 7.9, 6.1 Hz, 1H), 7.23 (s, 2H), 6.94 (s, 1H), 5.59-5.53 (m, 1H), 5.37 (s, 2H), 4.78 (d, J = 4.8 Hz, 1H), 4.38 (s, 3H), 3.30-3.23 (m, 2H), 2.75-2.61 (m, 2H), 2.15 (d, J = 17.3 Hz, 1H).

MS (M+1): 548.97, retention time: 0.30 minutes (measurement condition A)

Elemental analysis C21H20N6O8S2(H2O)5.2

Calculated: C, 40.41; H, 4.59; N, 13.46; S, 10.27 (%)

Found: C, 40.33; H, 4.50; N, 13.68; S, 10.22 (%)

 [Embodiment 12]    Synthesis of Compound I-044  

 Step 1 Synthesis of Compound 44a  

(R)-isopropylidene glycerol (3.71 mL, 30.0 mmol) was dissolved in tetrahydrofuran (50.0 mL) and cooled to 0 °C. To this solution were added triphenylphosphine (8.66 g, 33.0 mmol), N-hydroxyphthalimide (5.38 g, 33.0 mmol) and 2.7 mol/L dimethyl azodicarboxylate/toluene solution. (12.22 mL, 33.0 mmol), stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure, and methanol was added and stirred. The obtained solid was collected by filtration, washed with methanol and dried, whereby Compound 44a (1.78 g, yield 21%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 7.86-7.83 (m, 2H), 7.78-7.75 (m, 2H), 4.53-4.47 (m, 1H), 4.36-4.29 (m, 1H), 4.20-4.12 ( m, 2H), 4.02-3.96 (m, 1H), 1.41 (s, 3H), 1.35 (s, 3H).

 Step 2 Synthesis of Compound 44b  

Using the compound 44a (1.77 g, 6.38 mmol), Compound 44b (1.16 g, yield 45%) was obtained in the same procedure as in Step 2 of Example 8.

¹ H-NMR (CDCl ₃ ) δ: 7.34 (s, 1H), 4.50-4.44 (m, 1H), 4.36-4.26 (m, 2H), 4.07 (dd, J = 6.7, 8.5 Hz, 1H), 3.84 (dd, J = 8.5, 5.8 Hz, 1H), 1.55 (s, 9H), 1.43 (s, 3H), 1.35 (s, 3H).

 Step 3 Synthesis of Compound 44c  

Compound 44c was obtained by the same method as Step 5 of Example 7 using Compound 44b (0.442 g, 1.10 mmol).

¹ H-NMR (CDCl ₃ ) δ: 7.54 (d, J = 7.8 Hz, 1H), 7.39-7.28 (m, 12H), 6.97 (s, 1H), 5.67 (dd, J = 8.3, 4.7 Hz, 1H) ), 5.13 (d, J = 4.7 Hz, 1H), 4.46-4.38 (m, 1H), 4.36-4.24 (m, 2H), 4.05 (dd, J = 6.4, 8.8 Hz, 1H), 3.80 (dd, J=5.4, 8.5 Hz, 1H), 3.20-3.15 (m, 1H), 3.08-3.01 (m, 1H), 2.69 (dd, J = 14.4, 9.8 Hz, 1H), 2.55 (d, J = 5.6 Hz) , 2H), 1.54 (s, 9H), 1.40 (s, 3H), 1.32 (s, 3H).

 Step 4 Synthesis of Compound 44d  

Compound 44d (729 mg, yield 88%) was obtained by the same procedure as in the step 6 of Example 7 using Compound 44c (1.00 mmol).

¹ H-NMR (CDCl ₃ ) δ: 8.45 (s, 1H), 7.72 (d, J = 9.8 Hz, 1H), 7.35-7.29 (m, 11H), 7.00 (s, 1H), 6.05 (dd, J) = 9.8, 4.9 Hz, 1H), 4.66 (d, J = 4.9 Hz, 1H), 4.47-4.41 (m, 1H), 4.38-4.32 (m, 1H), 4.26-4.19 (m, 1H), 4.15- 4.05 (m, 1H), 3.83 (dd, J = 8.5, 5.6 Hz, 1H), 3.75-3.68 (m, 1H), 3.41 (dd, J = 14.5, 5.0 Hz, 1H), 2.63 (dd, J = 17.9, 7.7 Hz, 1H), 2.53-2.44 (m, 1H), 2.33 (d, J = 17.2 Hz, 1H), 1.54 (s, 9H), 1.41 (s, 3H), 1.34 (s, 3H).

 Step 5 Synthesis of Compound I-044  

Compound I-044 (210 mg, yield: 78%) was obtained by the same procedure as in the step 7 of Example 7 using Compound 44d (412 mg, 0.500 mmol).

¹ H-NMR (D2O) δ: 7.05 (s, 1H), 5.89 (d, J = 4.8 Hz, 1H), 5.02 (d, J = 4.8 Hz, 1H), 4.34 (dd, J = 11.7, 4.1 Hz , 1H), 4.25 (dd, J = 11.7, 6.7 Hz, 1H), 4.13-4.05 (m, 1H), 3.74 - 3.69 (m, 1H), 3.68-3.60 (m, 2H), 3.58-3.52 (m , 1H), 3.07 (dd, J = 18.3, 7.8 Hz, 1H), 2.84 (dd, J = 12.5, 14.6 Hz, 1H), 2.57 (d, J = 18.3 Hz, 1H).

MS (M+1): 518, holding time: 0.36 minutes (measurement condition A)

Elemental analysis C17H18N5NaO10S2(H2O) ₂ (H2O)0.9

Calculated: C, 34.51; H, 4.05; N, 11.84; S, 10.84; Na, 3.89 (%)

Found: C, 34.57; H, 4.12; N, 11.91; S, 10.72; Na, 3.98 (%)

 [Example 13]    Synthesis of Compound I-045  

 Step 1 Synthesis of Compound 45a  

Potassium tert-butoxide (5.05 g, 45.0 mmol) was suspended in DMSO (80.0 mL), and a solution of N-Boc-hydroxylamine (5.47 g, 30.0 mmol) in DMSO was added and stirred at room temperature for 1 hour and 30 minutes. Ice-cold water was added to the reaction liquid, and the target was extracted from the aqueous layer with ethyl acetate. The collected organic layer was washed with purified water, then washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography to yield Compound 45a (9.20 g, yield: 100%).

¹ H-NMR (CDCl ₃ ) δ: 7.71 (br s, 1H), 4.27 (q, J = 6.3 Hz, 4H), 1.72 (s, 3H), 1.45 (dt, J = 25.7, 8.8 Hz, 9H) , 1.30 (t, J = 7.2 Hz, 6H).

 Step 2 Synthesis of Compound 45b  

Lithium aluminum hydride (0.759 g, 20.0 mmol) was added to tetrahydrofuran (30.0 mL) and cooled to 0 ° C. Compound 1 (3.05 g, 10.0 mmol) was added and stirred at 0 ° C for 1 hour and 30 minutes. Further, lithium aluminum hydride (0.190 g, 5.00 mmol) was added, and the mixture was stirred at 0 ° C for 30 minutes. Sodium sulfate decahydrate (10.0 g) was added in small portions in the reaction mixture. Further, anhydrous sodium sulfate was added to the reaction mixture, and the mixture was stirred at room temperature overnight. The solid was removed, and the filtrate was concentrated under reduced pressure, whereby compound 45b (1.00 g, yield 45%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 6.96 (br s, 1H), 3.70-3.61 (m, 4H), 3.52 (br s, 2H), 1.49 (s, 9H), 1.15 (s, 3H).

 Step 3 Synthesis of Compound 45c  

Compound 45b (1.00 g, 4.55 mmol) was dissolved in dichloromethane, and a 4 mol/L ethyl acetate solution (17.06 mL, 68.3 mmol) was added and stirred at room temperature for 45 minutes. The supernatant was removed and ethyl acetate was added again. The supernatant was again removed, and the resulting residue was dried under reduced pressure to give Compound 45c. The obtained compound 45c was used in the subsequent reaction without purification.

¹ H-NMR (D 2 O) δ: 3.82 (d, J = 12.5 Hz, 2H), 3.72 (d, J = 12.5 Hz, 2H), 1.35 (s, 3H).

 Step 4 Synthesis of Compound 45e  

Compound 45c (0.717 g, 4.55 mmol) was suspended in dichloromethane (10.0 mL), Compound 45d (0.991 g, 3.64 mmol), triethylamine (0.599 mL, 4.32 mmol) and methanol (23.0 mL) Stir for 1 hour and 30 minutes. Purified water was added to the reaction liquid, and the solvent was distilled off, and ethyl acetate, purified water, and 2 mol/L hydrochloric acid water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with purified water, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off to give Compound 45e (1.31 g, yield 77%). The obtained compound 45e was used in the subsequent reaction without purification.

¹ H-NMR (DMSO-D6) δ: 11.76 (s, 1H), 7.41 (s, 1H), 3.57-3.41 (m, 4H), 1.47 (s, 9H), 1.18 (s, 3H).

 Step 5 Synthesis of Compound 45f  

Compound 45f (918 mg, yield 78%) was obtained by the same procedure as in the step 3 of Example 8 using Compound 45e (732mg, 1.95mmol).

¹ H-NMR (CDCl ₃ ) δ: 8.90 (s, 1H), 8.44 (d, J = 8.7 Hz, 1H), 7.31 (tt, J = 9.7, 4.2 Hz, 11H), 6.96 (s, 1H), 5.66 (dd, J=8.7, 4.7 Hz, 1H), 5.10 (d, J=4.7 Hz, 1H), 3.79 (br s, 4H), 3.57 (br s, 1H), 3.41 (br s, 1H), 3.13-3.06 (m, 1H), 3.05-2.97 (m, 1H), 2.63 (dd, J=9.7, 14.4 Hz, 1H), 2.55-2.48 (m, 2H), 1.54 (s, 9H), 1.24 ( s, 3H).

 Step 6 Synthesis of Compound 45g  

Using the compound 56f (917 mg, 1.17 mmol), Compound 45 g (727 mg, yield 78%)

¹ H-NMR (CDCl ₃ ) δ: 8.79 (br s, 1H), 8.23 (d, J = 9.1 Hz, 1H), 7.37-7.29 (m, 11H), 7.00 (s, 1H), 5.94 (dd, J=9.1, 4.8 Hz, 1H), 4.73 (d, J=4.8 Hz, 1H), 3.85-3.60 (br m, 7H), 3.43 (dd, J=14.7, 4.8 Hz, 1H), 2.60-2.49 ( m, 2H), 2.29 (d, J = 17.4 Hz, 1H), 1.54 (s, 9H), 1.28 (s, 3H).

 Step 7 Synthesis of Compound I-045  

Compound I-045 (241 mg, yield: 87%) was obtained by the same procedure as in the step 7 of Example 7 using compound 45 g (399 mg, 0.500 mmol).

¹ H-NMR (D2O) δ: 7.03 (s, 1H), 5.91 (d, J = 4.8 Hz, 1H), 5.02 (d, J = 4.5 Hz, 1H), 3.86-3.73 (m, 4H), 3.65 (dd, J = 14.7, 5.2 Hz, 1H), 3.55 (ddd, J = 5.1, 7.8, 12.7 Hz, 1H), 3.07 (dd, J = 18.3, 7.8 Hz, 1H), 2.84 (dd, J = 14.6) , 12.5 Hz, 1H), 2.57 (d, J = 18.3 Hz, 1H), 1.34 (s, 3H).

MS (M+1): 518, holding time: 0.36 minutes (measurement condition A)

 [Embodiment 14]    Synthesis of Compound I-046  

 Step 1 Synthesis of Compound 46b  

A solution of compound 46a (2.67 g, 6.00 mmol) in dichloromethane (50 mL) was cooled to -30. Anisole (1.97 mL, 18.0 mmol) and a 2 mol/L aluminum chloride/nitromethane solution (9.00 mL, 18.0 mmol) were added thereto, and stirred at -30 ° C for 1 hour. Dilute hydrochloric acid was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was extracted with an aqueous solution of sodium hydrogencarbonate, and diluted hydrochloric acid was added to pH 2. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. Add 1,4-two to the residue obtained Alkane (22 mL), ammonium carbonate (0.72 g, 7.50 mmol), di-tert-butyl dicarbonate (1.81 mL, 7.80 mmol, pyridine (0.242 mL, 3.00 mmol), stirred at room temperature overnight. Water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, sodium hydrogen carbonate aqueous solution and brine, and the solvent was evaporated under reduced pressure. pyridine was added to the residue of tetrahydrofuran (23 mL). 1.45 mL, 18.0 mmol). After cooling the reaction mixture to -30 ° C, trifluoroacetic anhydride (1.27 mL, 9.00 mmol) was added and stirred at -30 ° C for 1 hour. The organic layer was washed with dilute hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. -ethyl acetate) to give Compound 46b (900 mg, 42%). MS (M+1) = 358.

 Step 2 Synthesis of Compound 46c  

1,4-two in compound 46b (900 mg) Trimethylsilyl azide (0.667 mL, 5.04 mmol) and dibutyltin oxide (62.8 mg, 0.25 mmol) were added to a solution of alkane (9.0 mL). The temperature of the reaction mixture was raised to 90 ° C and stirred for 1.5 hours. Diisopropyl ether was added to the reaction mixture, and extraction was carried out with an aqueous sodium hydrogencarbonate solution. Dilute hydrochloric acid was added to the aqueous layer, and the pH was adjusted to 2, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. A solution of the obtained residue in tetrahydrofuran (10 mL) was cooled to 0° C., and diphenyldiazomethane (0.587 g, 3.0 mmol) was added and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford crude product (1.2 g). MS (M+1) = 567, (measurement condition A)

 Step 3 Synthesis of Compound 46e  

After a suspension of phosphorus pentachloride (0.656 g, 3.15 mmol) in dichloromethane (23 mL) was cooled to -78 ° C, pyridine (0.288 <RTIgt; After stirring for 1 hour under ice cooling, the reaction mixture was cooled to -78 ° C, and ethanol (12 mL) was added. After stirring at -30 ° C for 1 hour, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and extracted with dichloromethane. After the organic layer was dried over anhydrous magnesium sulfate, the inorganic material was removed by filtration. Ethyl acetate was added to the filtrate, and dichloromethane was evaporated under reduced pressure to give ethyl acetate (yield A). A solution of compound 46d (885 mg, 2.21 mmol) in EtOAc (10 <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; The mixture was stirred at -10 ° C for 1 hour to obtain a dichloromethane solution of the compound 46d in methanesulfonate (solution B). The previous solution A was cooled to 0 ° C, and pyridine (0.254 mL, 3.15 mmol) and solution B were added thereto, and stirred at 0 ° C for 1 hour. Water was added to the reaction liquid, and extraction was performed with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, sodium hydrogencarbonate water and brine, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the crude product of product 46e (900 mg). [M+1]=832, (measurement condition A)

 Step 4 Synthesis of Compound I-046  

A DMA (6.6 mL)-acetonitrile (3.3 mL) solution containing a crude product (yield: 333 mg) of Compound 46e was cooled to 0 ° C, and aqueous acetic acid (36%, 0.148 mL, 0.80 mmol) was added. After stirring at 0 ° C for 1 hour, an aqueous solution of sodium hydrogensulfite was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, sodium hydrogencarbonate water and brine, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue in methylene chloride solution was cooled to -30 ° C, and then anisole (0.515 mL, 4.71 mmol) and 2 mol/L aluminum chloride/nitromethane solution (2.36 mL, 4.71 mmol) at -30 ° C Stir under 1 hour. Ice, diisopropyl ether, and acetonitrile were sequentially added to the reaction mixture, and the mixture was stirred. After the insoluble matter was completely dissolved, the aqueous layer was taken out. After the organic layer was again extracted with water, all the aqueous layers were combined, and HP20-SS resin was added thereto, and acetonitrile was distilled off under reduced pressure. The resulting mixture was purified by ODS column chromatography (water-acetonitrile). A chromatographic fraction containing the desired compound was collected, and after concentration under reduced pressure, a white powder of I-046 (60 mg) was obtained.

¹ H-NMR (D 2 O) δ: 2.65 (1H, d, J = 18.4 Hz), 2.91 (1H, dd, J = 18.4, 7.6 Hz), 3.07 (1H, dd, J = 14.5, 13.0 Hz), 3.76 (1H, dd, J = 14.5, 5.2 Hz), 3.85-3.91 (1H, m), 4.70 (2H, s), 5.22 (1H, d, J = 4.8 Hz), 5.89 (1H, d, J = 4.8) Hz), 7.12 (1H, s)

C16H15N9O8S2(H2O) 3.0 Calculated value C: 33.16%, H: 3.65%, N: 21.75%, S: 11.06%. Found C: 33.15%, H: 3.61%, N: 21.69%, S: 11.02%.

[M+1]=526, (measurement condition A)

 [Example 15]    Synthesis of Compound I-051  

 Step 1 Synthesis of Compound I-051  

Methylene chloride (6.0 mL) and mCPBA (70%, 370 mg) were added to the crude product ( 333 mg) of Compound 51a, and the mixture was stirred for 1 hour under ice cooling, and then aqueous sodium hydrogen extraction. The organic layer was washed with dilute hydrochloric acid, sodium hydrogencarbonate water and brine, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue in methylene chloride solution was cooled to -30 ° C, and then anilole (0.505 mL, 4.63 mmol) and 2 mol/L aluminum chloride/nitromethane solution (2.31 mL, 4.63 mmol) at -30 ° C Stir under 1 hour. Ice, diisopropyl ether and acetonitrile were added to the reaction liquid in this order, and the mixture was stirred. After the insoluble matter was completely dissolved, the aqueous layer was separated. After the organic layer was again extracted with water, all the aqueous layers were combined, and HP20-SS resin was added thereto, and acetonitrile was distilled off under reduced pressure. The resulting mixture was purified by ODS column chromatography (water-acetonitrile). A chromatographic fraction containing the desired compound was collected, and after concentration under reduced pressure, a white powder of &lt;RTIgt;

¹ H-NMR (D ₂ O) δ: 2.63 (1H, d, J = 18.2 Hz), 2.84 (1H, dd, J = 18.2, 7.7 Hz), 3.77 - 3.80 (2H, m), 4.19 - 4.25 ( 1H, m), 4.54 (2H, s), 5.57 (1H, d, J = 5.1 Hz), 5.94 (1H, d, J = 5.1 Hz), 7.03 (1H, s).

C16H15N9O9S2(H2O)2.7 Calculated C: 32.57%, H: 3.48%, N: 21.36%, S: 10.87%. Found C: 32.63%, H: 3.48%, N: 21.27%, S: 10.73%.

[M+1]=542, (measurement condition A)

 [Example 16]    Synthesis of Compound I-047  

 Step 1 Synthesis of Compound 47d  

To the compound 47a (1.26 g, 4.63 mmol) and the compound 47b (600 mg, 4.72 mmol), dichloromethane (3.6 mL) and methanol (5 mL) were added. After sodium hydrogencarbonate (397 mg, 4.72 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour, the reaction solution was concentrated. Compound 47c (1.38 g, 3 mmol) and ethyl acetate (13.8 mL) were added to the residue. After cooling to -20 ° C, phenyl dichlorophosphate (0.670 mL, 4.5 mmol) and N-methyl-fyfolin (1.98 mL, 18.0 mmol) were added and stirred for 30 minutes. After adding acetonitrile (10 m) thereto and stirring at room temperature for 30 minutes, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product (2.4 g). MS (M+1) = 788.02 (measurement condition A)

 Step 2 Synthesis of Compound I-047  

Methylene chloride (6.0 mL) was added to the crude product (1.2 g) containing Compound 47d, and cooled to -40 °C. mCPBA (70%, 370 mg) was added thereto, and the mixture was stirred at -40 ° C for 1 hour, and then an aqueous sodium hydrogensulfite solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, sodium hydrogen carbonate water and brine, and the organic layer was dried over anhydrous magnesium sulfate. The resulting residue in methylene chloride solution was cooled to -30 ° C, and anisole (1.64 mL, 15.0 mmol) and 2 mol/L aluminum chloride/nitromethane solution (7.50 mL, 15.0 mmol) were added at -30 ° C. Stir under 1 hour. Ice, diisopropyl ether, and acetonitrile were sequentially added to the reaction mixture, and the mixture was stirred. After the insoluble matter was completely dissolved, the aqueous layer was taken out. After the organic layer was again extracted with water, all the aqueous layers were combined, and HP20-SS resin was added thereto, and acetonitrile was distilled off under reduced pressure. The resulting mixture was purified by ODS column chromatography (water-acetonitrile). A chromatographic fraction containing the desired compound was collected, and after concentrated under reduced pressure, a white powder of I-047 (15 mg) was obtained.

¹ H-NMR (D ₂ O) δ: 2.56 (1H, d, J = 18.2 Hz), 2.84-2.77 (1H, m), 3.06 (1H, dd, J = 19.1, 7.5 Hz), 3.59 (2H, t, J = 19.1 Hz), 5.00 (1H, d, J = 4.5 Hz), 5.06 (2H, s), 5.89 (1H, d, J = 4.5 Hz), 7.13 (1H, s).

[M+1]=538, (measurement condition A)

 [Example 17]    Synthesis of Compound I-048  

 Step 1 Synthesis of Compound 48c  

To the compound 48a (2.65 g, 12.0 mmol) was added dichloromethane (26.5 mL). Toluene chloride (1.26 mL, 14.4 mmol) was added thereto. DMF (0.0093 mL, 0.12 mmol) was added and stirred at room temperature for 1 hour. One half of this dichloromethane solution was taken as solution A. To a solution of O-methylhydroxylamine hydrochloride (551 mg, 6.00 mmol), dichloromethane (1. 4 mL) and pyridine (1.06 mL, 13.2 mmol) were evaporated. Thereto, Solution A was added and stirred at 0 ° C for 1 hour. After adding diluted hydrochloric acid and methanol to the reaction mixture and stirring, the solid was taken out by filtration. Methylene chloride (6 mL), acetonitrile (10 mL) and methyl hydrazine (0.127 mL, 2.40 mmol) were added to 600 mg of the obtained solid. Stir at room temperature for 1 hour. The insoluble material was removed, and the resulting filtrate was cooled to 0 °C. Compound 48b (653 mg, 2.40 mmol) and methanol 5 mL were added thereto, and stirred at 0 ° C for 30 minutes. Dilute hydrochloric acid was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a crude product (860 mg). MS (M+1) = 376, (measurement condition A)

 Step 2 Synthesis of Compound I-048  

The compound I-048 (46 mg) was obtained by the same procedure as the procedure of Steps 1 to 2 of Example 16 using the crude product (374 mg) Compound Compound Compound Compound Compound Compound Compound Compound Compound

¹ H-NMR (D ₂ O) δ: 2.56 (1H, d, J = 18.4 Hz), 2.83 (1H, dd, J = 14.3, 13.0 Hz), 3.06 (1H, dd, J = 18.3, 7.7 Hz) , 3-5. (1H, d, J = 4.5 Hz), 5.87 (1H, d, J = 4.5 Hz), 7.24 (1H, s).

C17H18N6O10S2(H2O) 3.5 Calculated C: 34.40%, H: 4.25%, N: 14.16%, S: 10.80%. Found C: 34.35%, H4.21%, N: 14.28%, S: 10.73%.

MS (M+1) = 531, (measurement condition A)

 [Embodiment 18]    Synthesis of Compound I-049  

 Step 1 Synthesis of Compound 49c  

Compound 49a (1.35 g, 6 mmol), compound 49b (1.07 g, 3.93 mmol) and O-(4-methoxybenzyl)hydroxylamine (1.10 g, 7.2 mmol) were used as in Step 1 of Example 17. In the same manner, a crude product (1.9 g) containing Compound 49c was obtained. MS (M+1) = 481, (measurement condition B)

 Step 2 Synthesis of Compound I-049  

The compound I-049 (46 mg) was obtained by the same procedure as the the the

¹ H-NMR (D ₂ O) δ: 2.55 (1H, d, J = 18.4 Hz), 2.82 (1H, dd, J = 14.4, 12.9 Hz), 3.06 (1H, dd, J = 18.3, 7.7 Hz) , 3.51-3.57 (1H, m), 3.63 (1H, dd, J = 14.8, 5.2 Hz), 4.80 (3H, d, J = 4.3 Hz), 5.00 (1H, d, J = 4.8 Hz), 5.86 ( 1H, d, J = 4.8 Hz), 7.19 (1H, s).

C16H16N6O10S2(H2O)3.1 Calculated C: 33.58%, H: 3.91%, N: 14.68%, S: 11.20%. Found C: 33.71%, H4.05%, N: 14.67%, S: 10.98%.

MS (M+1) = 517, (measurement condition A)

 [Embodiment 19]    Synthesis of Compound I-050  

 Step 1 Synthesis of Compound I-050  

Using the compound 50a, the compound 1-050 (160 mg) was obtained by the same procedure as the steps 1 to 5 of Example 12.

¹ H-NMR (D ₂ O) δ: 2.55 (1H, d, J = 18.3 Hz), 2.82 (1H, dd, J = 14.4, 12.9 Hz), 3.06 (1H, dd, J = 18.3, 8.0 Hz) , 3.50-3.57 (1H, m), 3.60-3.72 (4H, m), 4.06-4.11 (1H, m), 4.30 (1H, dd, J=11.9, 5.9 Hz), 4.37 (1H, dd, J= 11.6, 5.8 Hz), 5.00 (1H, d, J = 4.8 Hz), 5.87 (1H, d, J = 4.8 Hz), 7.15 (1H, s).

C17H19N5O10S2(H2O) 2.1 Calculated value C: 36.77%, H: 4.21%, N: 12.61%, S: 11.55%. Found C: 36.94%, H: 4.32%, N: 12.56%, S: 11.30%.

[M+1]=518.01 (measurement condition A)

 [Example 20]    Synthesis of Compound I-015  

 Step 1 Synthesis of Compound I-015  

Using the compound 15a (538 mg, 1.00 mmol) and the compound 15b (836 mg, 1.68 mmol) synthesized according to the synthesis of the compound II-2 of WO2010050468, the free state of the compound I-015 was obtained in the same manner as in the step 2 of Example 17. Dissolved solution. 2 equal amounts of aqueous sodium hydroxide solution were added thereto. This was concentrated under reduced pressure, and lyophilized to give Compound I-015 (156 mg).

¹ H-NMR (D2O) δ: 1.26-1.42 (4H, m), 2.57 (1H, d, J = 18.4 Hz), 2.79-2.85 (1H, m), 3.07 (1H, dd, J = 18.4, 7.6 Hz), 3.66-3.52 (2H, m), 5.00 (1H, d, J = 4.8 Hz), 5.86 (1H, d, J = 4.8 Hz), 7.08 (1H, s).

[M+1]=528, (measurement condition A)

C18H15N5Na2O10S2(H2O)5.1 Calculated value: C: 32.59% H: 3.83% N: 10.56% Na: 6.93% S: 9.67%. Found: C: 32.49% H: 3.80% N: 10.74% Na: 7.08% S: 9.58%

 [Example 21]    Synthesis of Compound I-052  

 Step 1 Synthesis of Compound 52b  

To a solution of glycerol (921 mg, 10 mmol) in tetrahydrofuran (9 mL), EtOAc (EtOAc (EtOAc) Drip. After stirring overnight at room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compound 52b (3.13 g, yield 98%).

¹ H-NMR (CDCl ₃ ) δ: 0.07 (12H, s), 0.90 (18H, s), 2.45 (1H, d, J = 5.1 Hz), 3.63 (1H, s), 3.64 (4H, s).

 Step 2 Synthesis of Compound 52c  

After adding N-hydroxyphthalimide (1.91 g, 11.7 mmol) and triphenylphosphine (3.07 g, 11.7 mmol) to a solution of compound 52b (3.13 g, 9.8 mmol) in tetrahydrofuran (31 mL), A 1.9 mol/L DIAD/toluene solution was dropped under ice cooling. After stirring at room temperature for 1 hour, it was concentrated under reduced pressure, and methanol was added to the residue. The resulting solid was collected by filtration and dried under reduced pressure to give Compound 52c (3.07 g, yield 67%) as white solid.

¹ H-NMR (CDCl ₃ ) δ: 0.00 (6H, s), 0.02 (6H, s), 0.82 (18H, s), 3.94 (4H, ddd, J = 14.5, 9.5, 3.2 Hz), 4.33-4.38 (1H, m), 7.72 (2H, dd, J = 5.5, 3.1 Hz), 7.82 (2H, dd, J = 5.5, 3.1 Hz).

 Step 3, 4 Synthesis of Compound 52f  

Methyl hydrazine (0.383 mL, 7.2 mmol) was added at -30 ° C in a solution of compound 52c (3.07 g, 6.6 mmol) in dichloromethane. After stirring for 30 minutes under ice cooling, the resulting insoluble material was removed by filtration, and Compound 52e (1.79 g, 6.6 mmol) was added to the filtrate. After stirring at room temperature for 2 hours, it was concentrated under reduced pressure, and diluted hydrochloric acid was added to the residue, and ethyl acetate was evaporated. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. After the residue was dissolved in diisopropyl ether, triethylamine (1.1 mL, 7.9 mmol) was added. The solid which was formed was filtered, and dried under reduced pressure to give Compound 52f (1.79 g, yield 39%) as a white solid.

¹ H-NMR (DMSO-D ₆ ) δ: 0.04 (6H, s), 0.04 (6H, s), 0.86 (18H, s), 1.13 (9H, t, J = 6.5 Hz), 1.47 (9H, s ), 2.96 (6H, s), 3.70 (4H, d, J = 4.4 Hz), 3.96 (1H, t, J = 5.0 Hz), 7.10 (1H, s).

 Step 5 Synthesis of Compound 52h  

After adding 52 g of a compound (369 mg, 0.80 mmol) to a suspension of compound 52f (608 mg, 0.88 mmol) in ethyl acetate (7.4 mL), phenyldichlorophenyl phosphate (0.179 mL, 1.2 mmol), N- Kifulin (0.308 mL, 2.8 mmol) was dripped at -40 °C. After stirring at -40 ° C for 1 hour, dilute hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate).

¹ H-NMR (CDCl ₃ ) δ: 0.04 (6H, d, J = 2.0 Hz), 0.05 (6H, d, J = 1.9 Hz), 0.86 (9H, s), 0.87 (9H, s), 1.54 ( 9H, s), 2.54-2.61 (2H, m), 2.67 (1H, dd, J = 14.5, 9.7 Hz), 3.04 (1H, dd, J = 14.5, 4.5 Hz), 3.17 (1H, dq, J = 12.8, 3.8 Hz), 3.82-3.91 (4H, m), 4.42-4.48 (1H, m), 5.10 (1H, d, J = 4.7 Hz), 5.59 (1H, dd, J = 8.0, 4.7 Hz), 6.97 (1H, s), 7.30-7.38 (11H, m), 7.55 (1H, d, J = 8.0 Hz), 8.09 (1H, s).

 Step 6 Synthesis of Compound 52i  

A solution of 69% mCPBA (157 mg, 0.63 mmol) in dichloromethane (2.6 mL) was then evaporated at <RTI ID=0.0># </RTI> </RTI> <RTIgt; After stirring at -40 ° C for 40 minutes, a 15% aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with an aqueous sodium hydrogencarbonate solution and brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compound 52i (436 mg, yield: 82%).

¹ H-NMR (CDCl ₃ ) δ: 0.04 (6H, s), 0.05 (6H, s), 0.87 (9H, s), 0.88 (9H, s), 1.54 (9H, s), 2.32 (1H, d , J = 17.9 Hz), 2.45 (1H, t, J = 13.6 Hz), 2.64 (1H, dd, J = 17.9, 7.7 Hz), 3.41 (1H, dd, J = 14.4, 4.9 Hz), 3.70 - 3.90 (5H, m), 4.38-4.43 (1H, m), 4.61 (1H, d, J = 5.0 Hz), 6.07 (1H, dd, J = 10.0, 5.0 Hz), 7.00 (1H, s), 7.25- 7.38 (11H, m), 7.66 (1H, d, J = 10.0 Hz), 8.22 (1H, s).

 Step 7 Synthesis of Compound I-052  

After cooling a solution of compound 52i (436 mg, 0.43 mmol) in methylene chloride (4.4 mL) to -40 ° C, then, then, then, then, an The solution (2.15 mL, 4.3 mmol) was stirred at -30 ° C for 30 min. Diisopropyl ether, ice water, and acetonitrile were added to the reaction mixture, and the insoluble matter was completely dissolved, and then the aqueous layer was taken out. After the organic layer was again extracted with water, all the aqueous layers were combined, and HP20-SS resin was added thereto, and acetonitrile was distilled off under reduced pressure, and 2 mol/L hydrochloric acid (1.0 mL) was added. The resulting mixture was refined by ODS column chromatography (water-acetonitrile). A chromatographic fraction containing the desired compound was collected, and after adding a 0.2 mol/L sodium hydroxide aqueous solution to pH = 6, a small amount of dry ice was added. After the obtained solution was concentrated under reduced pressure, a white powder of I-052 (182 mg, yield 78%) was obtained.

¹ H-NMR (D ₂ O) δ: 2.57 (1H, d, J = 18.3 Hz), 2.84 (1H, dd, J = 14.8, 12.5 Hz), 3.07 (1H, dd, J = 18.3, 7.8 Hz) , 3.52-3.59 (1H, m), 3.65 (1H, dd, J = 14.8, 5.3 Hz), 3.86 (4H, t, J = 5.3 Hz), 4.41-4.46 (1H, m), 5.03 (1H, d , J = 4.6 Hz), 5.90 (1H, d, J = 4.9 Hz), 7.05 (1H, s).

MS (m + 1) = 518, retention time: 0.30 minutes, (measurement condition A)

Elemental analysis: C17H18N5NaO10S2(H2O)3.0

Calculated: C, 34.40; H, 4.08; N, 11.80; Na, 3.87; S, 10.80 (%)

Found: C, 34.50; H, 4.20; N, 11.92; Na, 3.84; S, 10.96 (%)

 [Example 22]    Synthesis of Compound I-053  

 Step 1, 2 Synthesis of Compound 53c  

Trifluoroacetic anhydride (17.7 mL, 125 mmol) was added to compound 53a (13.8 g, 104 mmol). After stirring for 3 hours under ice cooling, it was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated under reduced pressure to give Compound 53b. The obtained compound 53b was used in the subsequent reaction without purification.

p-Methoxybenzyl alcohol (23.2 g, 168 mmol), DMAP (1.37 g, 11.2 mmol) was added to a solution of the obtained compound 53b in tetrahydrofuran (64 mL). After the reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate and ethyl acetate were added to the residue, and the aqueous layer was taken. After adding 2 mol/L hydrochloric acid to the aqueous layer obtained until pH=2, extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a mixture of compound 53c and 53c-ii (21 g, yield 74%).

¹ H-NMR (DMSO-D ₆ ) δ: 1.09-1.12 (6H, m), 2.31-2.46 (2H, m), 2.53-2.63 (2H, m), 2.67-2.80 (2H, m), 3.75 ( 6H, s), 5.01 (4H, s), 6.92 (4H, d, J = 8.6 Hz), 7.29 (4H, d, J = 8.3 Hz).

 Step 3 Synthesis of Compound 53d  

Triphenylphosphoranylidene acetonitrile (26.3 g, 87 mmol), 4-dimethylamino group was added sequentially to a solution of a mixture of compound 53c and 53c-ii (21 g, 83 mmol) in dichloromethane (300 mL). Pyridine (1.02 g, 8.3 mmol), EDC hydrochloride (17.5 g, 92 mmol). After stirring at room temperature for 1 hour and a half, it was concentrated under reduced pressure, and water was added to the residue, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 53d and 53d- ii (25.88 g, yield 58%).

¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 6.8 Hz), 1.25 (3H, d, J = 7.1 Hz), 2.30 (1H, dd, J = 16.5, 4.7 Hz), 2.77- 2.85(2H,m), 3.02(1H,dd,J=13.9,7.1Hz), 3.22(1H,dd,J=16.0,7.7Hz),3.63-3.68(1H,m),3.78(6H,s) , 4.98-5.06 (4H, m), 6.84 (4H, d, J = 8.1 Hz), 7.27 (4H, d, J = 14.9 Hz), 7.49-7.61 (30H, m).

 Step 4 Synthesis of Compound 53e  

A mixture of the compound 53d and 53d-ii (25.9 g, 48 mmol) in dichloromethane (520 mL) was bubbled with ozone gas at -78 ° C while stirring for 1 hour. After replacing the inside of the system with nitrogen, dimethyl sulfide (10.7 mL, 145 mmol) was added, and the mixture was stirred at -78 ° C for 5 minutes. Next, 3-methyl-2-buten-1-ol (7.36 mL, 72.5 mmol) was added, and the mixture was stirred at -78 °C for 2 hours. After the reaction mixture was heated to about 0 ° C, a 5% aqueous sodium carbonate solution was added and stirred at room temperature for 5 minutes. After distilling off the dichloromethane under reduced pressure, the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compounds 53e and 53e-ii (6.11 g, yield 36%).

¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, d, J = 7.1 Hz), 1.23 (3H, d, J = 7.1 Hz), 1.74 (6H, s), 1.77 (6H, s), 2.49 ( 1H, dd, J = 16.9, 5.3 Hz), 2.82 - 2.91 (2H, m), 3.02 (1H, dd, J = 13.4, 7.1 Hz), 3.31 (1H, dd, J = 18.6, 7.7 Hz), 3.63 -3.70 (1H, m), 3.81 (6H, s), 4.73-4.76 (4H, m), 5.04 (4H, d, J = 8.8 Hz), 5.39 (2H, s), 6.88 (4H, d, J =8.1Hz), 7.26 (4H, br s).

 Step 5, 6 Synthesis of compound 53h  

N,N,N',N'-tetramethylmethanediamine (7.17 mL) was added to a mixture of compound 53e and 53e-ii (6.11 g, 17.5 mmol) in dichloromethane (30 mL) After 52.6 mmol), acetic anhydride (6.30 mL, 66.6 mmol) and acetic acid (5.32 mL, 93 mmol) were added dropwise. After stirring overnight at room temperature, ice water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the ethyl acetate solution of mixture of compound 53f and 53e-ii was obtained by filtration. In an ethyl acetate solution of a mixture of the obtained compound 53f and 53e-ii, compound 53 g (2.49 g, 10.5 mmol) and hexamethylphosphonium triamine (9.16 mL, 52.6 mmol) were added. After stirring at room temperature overnight, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound (yield: 42.

¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, d, J = 6.1 Hz), 1.70 (3H, s), 1.76 (3H, s), 2.50-2.54 (2H, m), 2.68 (1H, d , J = 14.7 Hz), 3.12 (1H, dd, J = 14.0, 11.5 Hz), 3.61 (2H, dd, J = 25.0, 15.9 Hz), 3.81 (3H, s), 4.04 (1H, s), 4.69 (1H, dd, J = 11.9, 7.6 Hz), 4.89 (1H, dd, J = 11.9, 7.6 Hz), 5.02 (2H, s), 5.07 (1H, d, J = 4.3 Hz), 5.37 (1H, t, J = 6.8 Hz), 5.46 (1H, dd, J = 9.1, 4.5 Hz), 6.09 (1H, d, J = 9.3 Hz), 6.88 (2H, d, J = 8.3 Hz), 7.24 - 7.39 ( 7H, m).

 Step 7, 8 Synthesis of Compound 53j  

Trifluoroacetic acid (10.2 mL, 133 mmol) was added dropwise at -20 ° C in EtOAc (20 mL). After stirring at -20 ° C for 1 hour, the reaction mixture was added to a mixture of ice-cooled aqueous sodium hydrogen carbonate and dichloromethane. Next, dilute hydrochloric acid was added until pH=2, and extraction was carried out with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the compound 53i was obtained by concentrating the filtrate under reduced pressure. The obtained compound 53i was used in the subsequent reaction without purification.

EDC hydrochloride (933 mg, 4.87 mmol) was added to a solution of EtOAc (EtOAc m. After stirring at room temperature for 1 hour, water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 53j (1.94 g, yield: 96%).

¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7.3 Hz), 1.71 (3H, s), 1.76 (3H, s), 2.53-2.88 (4H, m), 3.64 (2H, dd , J = 25.4, 16.0 Hz), 4.72-4.82 (2H, m), 4.99 (1H, d, J = 4.8 Hz), 5.36 (1H, t, J = 6.7 Hz), 5.63 (1H, dd, J = 8.8, 4.8 Hz), 6.06 (1H, d, J = 8.8 Hz), 7.27-7.39 (5H, m).

 Steps 9, 10 Synthesis of compound 53m  

After cooling a solution of compound 53 (963 mg, 2.4 mmol) in dimethylacetamide (4.6 mL) to -20 ° C, triethylamine (0.416 mL, 3.0 mmol), methanesulfonium chloride (0.218 mL, 2.8 mmol) ). The solution A was obtained by stirring at -20 ° C for 30 minutes.

After a suspension of phosphorus pentachloride (833 mg, 4.0 mmol) in dichloromethane (4.6 mL) was cooled to -78 ° C, pyridine (0.355 mL, 4.4 mmol) was added, followed by compound 53j (917 mg, 2.0 mmol) The methyl chloride (4.6 mL) solution was dropped. After stirring at -10 °C for 1 hour, the reaction mixture was cooled to -78 ° C and then cooled methanol (4.6 mL). After stirring at -30 ° C for 2 hours, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and filtered. Ethyl acetate was added to the filtrate, and dichloromethane and methanol were distilled off under reduced pressure to obtain a solution of compound 53k in ethyl acetate. Pyridine (0.194 mL, 2.4 mmol) and the solution A obtained above were added to the obtained ethyl acetate solution of compound 53k under ice cooling. After stirring under ice cooling for 30 minutes, dilute hydrochloric acid was added and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 53 m (1.33 g, yield: 92%).

¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, d, J = 7.1 Hz), 1.48 (9H, s), 1.54 (9H, s), 1.72 (3H, s), 1.76 (3H, s), 2.57-2.95 (4H, m), 3.70-3.85 (2H, m), 4.75 (2H, dd, J = 28.0, 16.7 Hz), 5.11 (1H, d, J = 4.7 Hz), 5.38 (1H, t, J = 7.3 Hz), 5.74 (1H, dd, J = 8.5, 4.7 Hz), 7.36 (1H, s), 8.07 (1H, s), 8.69 (1H, d, J = 8.5 Hz).

 Step 11 Synthesis of Compound 53n  

37% peracetic acid (0.258 mL, 1.44 mmol) was added dropwise at -20 ° C in a mixed solvent solution of compound 53 m (650 mg, 0.90 mmol) in acetonitrile (3 mL) and dimethylacetamide (3 mL). After stirring at -20 ° C for 1 hour, an aqueous solution of sodium hydrogensulfite was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed successively with water, aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 53n (397mg, yield: 60%).

¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, d, J = 7.3 Hz), 1.46 (9H, s), 1.58 (9H, s), 1.73 (3H, s), 1.77 (3H, s), 2.21-2.29(1H,m), 3.00-3.07(1H,m), 3.39(1H,dd,J=14.4,4.8Hz), 3.70-3.79(3H,m),4.59(1H,d,J=4.9 Hz), 4.72 (2H, dd, J = 26.7, 16.5 Hz), 5.39 (1H, t, J = 7.3 Hz), 5.95 (1H, dd, J = 9.4, 4.9 Hz), 7.34 (1H, s), 8.10 (1H, s), 8.41 (1H, d, J = 9.4 Hz).

 Step 12 Synthesis of Compound I-053  

Compound I-053 (139 mg, yield 46%) was obtained by the same procedure as in the step 7 of Example 21 using Compound 53n (397 mg, 0.54 mmol).

¹ H-NMR (D ₂ O) δ: 1.18 (3H, d, J = 7.1 Hz), 2.72 (1H, t, J = 15.2 Hz), 3.22 (1H, t, J = 7.1 Hz), 3.54-3.62 (2H, m), 4.59 (2H, s), 4.98 (1H, d, J = 4.8 Hz), 5.89 (1H, d, J = 4.8 Hz), 7.06 (1H, s).

MS (m + 1) = 516, holding time: 0.49 minutes, (measurement condition A)

Elemental analysis: C17H15N5Na2O10S2(H2O)3.8

Calculated: C, 32.52; H, 3.63; N, 11.15; Na, 7.32; S, 10.21 (%)

Found: C, 32.52; H, 3.57; N, 11.20; Na, 7.27; S, 10.15 (%)

 [Example 23]    Synthesis of Compound I-054  

 Step 1 Synthesis of Compound 54b  

A 4 mol/L hydrochloric acid/ethyl acetate solution was added to a solution of compound 54a (9.19 g, 30 mmol) in ethyl acetate (75 mL). After stirring at room temperature for 2 hours, the resulting solid was filtered and dried under reduced pressure to yield compound 54b (7.20 g, yield 99%) as white solid.

¹ H-NMR (DMSO-D ₆ ) δ: 3.18 (2H, s), 4.36 (2H, t, J = 5.3 Hz), 7.87-7.92 (4H, m), 8.20 (3H, s).

 Step 2 Synthesis of Compound 54c  

To a suspension of compound 54b (1. <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; After stirring for 1 hour under ice cooling, dilute hydrochloric acid was added and extracted with ethyl acetate. The organic layer was washed successively with water, aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the resulting solid was filtered and dried under reduced pressure to give Compound 54c (yield: 650 mg, yield: 55%).

¹ H-NMR (CDCl ₃ ) δ: 2.09 (3H, s), 3.57 (2H, dd, J = 9.8, 5.6 Hz), 4.27 (2H, t, J = 4.8 Hz), 6.82 (1H, s), 7.79 (2H, dd, J = 5.6, 3.1 Hz), 7.87 (2H, dd, J = 5.6, 3.1 Hz).

 Step 3 Synthesis of Compound 54e  

Compound 54e (877 mg, yield 71%) was obtained from Compound 54c (680 mg, 2.74 mmol).

¹ H-NMR (DMSO-D ₆ ) δ: 1.16 (9H, t, J = 7.3 Hz), 1.47 (9H, s), 1.79 (3H, s), 3.02 (6H, d, J = 5.6 Hz), 3.23 (2H, q, J = 5.8 Hz), 3.90 (2H, t, J = 5.8 Hz), 7.14 (1H, s), 8.38 (1H, s).

 Step 4 Synthesis of Compound I-054  

Using the compound 52g (369 mg, 0.80 mmol) and the compound 54e (417 mg, 0.88 mmol), Compound I-054 (156 mg)

¹ H-NMR (D ₂ O) δ: 2.00 (3H, s), 2.57 (1H, d, J = 18.3 Hz), 2.84 (1H, dd, J = 14.7, 12.5 Hz), 3.07 (1H, dd, J=18.3, 7.8 Hz), 3.53-3.59 (3H, m), 3.64 (1H, dd, J=14.7, 5.3 Hz), 4.28-4.37 (2H, m), 5.01 (1H, d, J=4.8Hz) ), 5.87 (1H, d, J = 4.8 Hz), 7.05 (1H, s).

MS (m + 1) = 529, retention time: 0.45 minutes, (measurement condition A)

 [Example 24]    Synthesis of Compound I-055  

 Step 1 Synthesis of Compound 55a  

To a suspension of compound 54b (1. <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; After stirring for 1 hour under ice cooling, dilute hydrochloric acid was added and extracted with ethyl acetate. The organic layer was washed successively with water, aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Isopropyl acetate was added to the residue, and the resulting solid was filtered off and dried under reduced pressure to give Compound 55a (1.15 g, yield 81%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 3.05 (3H, s), 3.43-3.47 (2H, m), 4.36 (2H, t, J = 4.8 Hz), 5.67 (1H, s), 7.79-7.82 (2H , m), 7.85-7.88 (2H, m).

 Step 2, 3 Synthesis of Compound 55c  

Using a compound 55a (1.15 g, 4.05 mmol), Compound 55 (yield: 740 mg, yield 38%) was obtained by the same procedure as Steps 3 and 4 of Example 21.

¹ H-NMR (DMSO-D ₆ ) δ: 1.16 (9H, t, J = 7.2 Hz), 1.47 (9H, s), 2.87 (3H, s), 3.03 (6H, s), 3.12 (2H, q , J = 5.6 Hz), 4.00 (2H, t, J = 5.6 Hz), 7.16 (1H, s), 7.54 (1H, t, J = 5.3 Hz).

 Step 3 Synthesis of Compound I-055  

Using the compound 52g (369 mg, 0.80 mmol) and the compound 55c (448 mg, 0.88 mmol), Compound I-055 (137 mg) was obtained by the same procedure as Steps 5 to 7 of Example 21.

¹ H-NMR (D ₂ O) δ: 2.57 (1H, d, J = 18.3 Hz), 2.83 (1H, dd, J = 14.7, 12.5 Hz), 3.04-3.11 (4H, m), 3.49-3.59 ( 3H,m), 3.64 (1H, dd, J=14.7, 5.2 Hz), 4.32-4.42 (2H, m), 5.02 (1H, d, J = 4.8 Hz), 5.88 (1H, d, J = 4.8 Hz) ), 7.06 (1H, s).

MS (m+1) = 565, holding time: 0.49 minutes, (measurement condition A)

 [Example 25]    Synthesis of Compound I-056  

 Step 1 Synthesis of Compound 56a  

To a suspension of compound 54b (2.43 g, 10 mmol) in dichloromethane (24 <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> trichloroacetone isocyanate (1.42 mL, 12 mmol), triethylamine (1.66 mL, 12 mmol). After stirring for 1 hour under ice cooling, dilute hydrochloric acid was added and extracted with ethyl acetate. The organic layer was washed successively with water, aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Isopropyl acetate was added to the residue, and the resulting solid was filtered off and dried under reduced pressure to give Compound 56a (2.74 g, yield 69%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 3.69 (2H, dd, J = 10.0, 5.6 Hz), 4.33 (2H, t, J = 4.9 Hz), 7.77-7.80 (2H, m), 7.85-7.89 (2H , m), 8.41 (1H, s), 8.73 (1H, s).

 Step 2, 3, 4 Synthesis of Compound 56d  

Methyl hydrazine (0.385 mL, 7.3 mmol) was added at -30 ° C in a solution of compound 56a (2.74 g, 6.9 mmol). After stirring for 30 minutes under ice cooling, the resulting insoluble material was removed by filtration, and Compound 52e (1.80 g, 6.6 mmol) was added to the filtrate. After stirring at room temperature for 2 hours, it was concentrated under reduced pressure, and diluted hydrochloric acid was added to the residue, and ethyl acetate was evaporated. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, whereby compound 56c was obtained as a yellow foam. The obtained compound 56c was used in the subsequent reaction without purification.

A 1 mol/L aqueous sodium hydroxide solution (16.5 mL, 16.5 mmol) was added to a solution of the total amount of the obtained compound 56c in methanol (34 mL). After stirring at room temperature for 3 hours, 2 mol/L hydrochloric acid (10 mL) was added and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. After the residue was dissolved in an ethyl acetate-methanol mixed solvent, triethylamine (1.1 mL, 7.9 mmol) was added. The resulting solid was taken up in vacuo and dried under reduced pressure to give compound 56d (yield: 43.

¹ H-NMR (DMSO-D ₆ ) δ: 1.14 (9H, t, J = 7.2 Hz), 1.47 (9H, s), 2.97 (6H, s), 3.16 (2H, d, J = 5.3 Hz), 3.88 (2H, t, J = 5.8 Hz), 5.44 (2H, s), 6.31 (1H, s), 7.11 (1H, s).

 Step 5 Synthesis of Compound 56e  

After a suspension of compound 56d (418 mg, 0.88 mmol) in dimethylacetamide (3.7 mL) was cooled to -20 ° C, triethylamine (0.022 mL, 0.16 mmol), methanesulfonium chloride (0.075 mL, 0.96) Mm). The solution B was obtained by stirring at -20 ° C for 30 minutes.

To a suspension of compound 52g (369 mg, 0.80 mmol),EtOAc (EtOAc) After stirring for 30 minutes under ice cooling, dilute hydrochloric acid was added and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compound 56e (529 mg, yield: 84%).

¹ H-NMR (CDCl ₃ ) δ: 1.52 (9H, s), 2.46-2.66 (4H, m), 3.10-3.23 (4H, m), 3.46 (1H, br s), 4.18 (1H, s), 4.86 (2H, s), 5.09 (1H, d, J = 4.6 Hz), 5.48 (1H, s), 5.63 (1H, dd, J = 8.2, 4.6 Hz), 6.93 (1H, s), 7.22-7.36 (11H, m), 8.65 (1H, s).

 Step 6 Synthesis of Compound I-056  

Using the compound 56e (529 mg, 0.68 mmol), Compound I-056 (167 mg) was obtained by the same procedure as Steps 6 and 7 of Example 21.

¹ H-NMR (D ₂ O) δ: 2.57 (1H, d, J = 18.3 Hz), 2.83 (1H, dd, J = 14.6, 12.5 Hz), 3.07 (1H, dd, J = 18.3, 7.7 Hz) , 3.47 (2H, t, J = 5.0 Hz), 3.53-3.59 (1H, m), 3.64 (1H, dd, J = 14.6, 5.2 Hz), 4.25 - 4.35 (2H, m), 5.02 (1H, d , J = 4.8 Hz), 5.88 (1H, d, J = 4.8 Hz), 7.05 (1H, s).

MS (m + 1) = 530, holding time: 0.40 minutes, (measurement condition A)

 [Example 26]    Synthesis of Compound I-057 and I-058  

 Step 1 Synthesis of Compound 57b  

After a solution of Meldrum's acid 57a (30.0 g, 208 mmol) in dichloromethane (300 mL) was chilled, pyridine (33.6 mL, 416 mmol) was added, followed by 2-bromopropyl bromide (24.0 mL) , 229 mmol). After stirring for 30 minutes under ice cooling, 1 mol/L hydrochloric acid was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered over magnesium sulfate and evaporated. The obtained brown oil was dissolved in tert-butyl alcohol (225 mL), and stirred at 80 ° C for 45 min. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 57b (41.5 g, 80%). This 57b obtained a mixture of ketone bodies: alcohols = 4.5:1.

Keto: ¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.77 (3H, d, J = 6.8 Hz), 3.54 (1H, d, J = 15.9 Hz), 3.77 (1H, d, J =15.9 Hz), 4.62 (1H, q, J = 6.8 Hz).

Enol: ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 1.83 (3H, d, J = 6.8 Hz), 4.43 (1H, q, J = 6.8 Hz), 5.16 (1H, s), 12.23 (1H, s).

 Step 2 Synthesis of Compound 57c  

In compound 57b (41.5 g, 165 mmol) Selenium (IV) oxide (40.4 g, 364 mmol) was added to the alkane (215 mL) solution, and stirred at 80 ° C for 1.5 hours. After cooling the reaction mixture to room temperature, the insoluble material was filtered over Celite, and washed with ethyl acetate. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 57c (21.3 g, 46%).

¹ H-NMR (CDCl ₃ ) δ: 1.52 (9H, s), 1.82 (3H, d, J = 6.8 Hz), 4.77 (1H, s), 4.86 (1H, q, J = 6.8 Hz), 4.99 ( 1H, s).

 Step 3 Synthesis of Compounds 57e and 57f  

The compound 57d (3.19 g, 13.5 mmol) and the compound 57c (3.82 g, 13.5 mmol) were dissolved in acetone (38 mL), and hexamethylphosphonium triamine (15.7 mL, 90.0 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. After the reaction mixture was ice-cooled, triethylamine (2.06 mL, 14.8 mmol) was added and stirred at 0 ° C for 30 min. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 57e (2.18 g, 38%) and 57f (483mg, 8.5%).

Compound 57e: ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, d, J = 6.3 Hz), 1.49 (9H, s), 3.74 (2H, s), 4.15 (1H, q, J = 6.3 Hz) , 4.42 (1H, s), 4.99-5.08 (2H, m), 5.99 (1H, d, J = 7.1 Hz), 7.31-7.43 (5H, m).

Compound 57f: ¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, d, J = 6.8 Hz), 1.47 (9H, s), 3.64 (1H, d, J = 16.2 Hz), 3.68 (1H, d, J = 16.2 Hz), 4.04 (1H, q, J = 6.8 Hz), 4.70 (1H, s), 5.48 (1H, dd, J = 8.6, 4.5 Hz), 5.52 (1H, d, J = 4.5 Hz) , 5.88 (1H, d, J = 8.6 Hz), 7.24 - 7.41 (5H, m).

 Step 4 Synthesis of Compound 57g  

After a solution of compound 57f (505.4 mg, 1.20 mmol) in dichloromethane (5 mL), EtOAc, EtOAc (EtOAc, EtOAc) After stirring for 1 hour under ice cooling, a saturated aqueous solution of ammonium chloride was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 57 g (386 g, 59%).

¹ H-NMR (CDCl ₃ ) δ: 1.34 (9H, s), 1.47 (3H, d, J = 7.1 Hz), 3.67 (1H, d, J = 16.4 Hz), 3.69 (1H, d, J = 16.4) Hz), 3.95 (2H, s), 4.18 (1H, q, J = 7.1 Hz), 5.52 (1H, d, J = 4.8 Hz), 5.68 (1H, dd, J = 8.8, 4.8 Hz), 5.90 ( 1H, d, J = 8.8 Hz), 7.25-7.42 (5H, m).

[M+Na]=563, hold time: 2.47 minutes, (measurement condition B)

 Step 5 Synthesis of Compound 57h  

Triphenylphosphine (224 mg, 0.856 mmol) was added to a solution of compound 57 g (386 mg, 0.713 mmol). After stirring at room temperature for 1 hour, 8.4% aqueous sodium hydrogencarbonate solution (1.78 mL, 1.78 mmol) was added. After stirring at room temperature for 20 minutes, water and ethyl acetate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered over magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 57h (375 mg, quant).

¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 1.50 (3H, d, J = 7.1 Hz), 3.65 (1H, d, J = 15.4 Hz), 3.66 (1H, d, J = 15.4) Hz), 4.58 (1H, q, J = 7.1 Hz), 5.04 (1H, d, J = 4.5 Hz), 5.68 (1H, dd, J = 8.8, 4.5 Hz), 6.17 (1H, s), 6.22 ( 1H, d, J = 8.8 Hz), 7.24 - 7.41 (5H, m).

[M+H]=445, holding time: 2.17 minutes, (measurement condition B)

 Step 6 Synthesis of Compound 57i  

A mixed solution of compound 57h (315 mg, 0.709 mmol) in 2-propanol (3 mL)-tetrahydrofuran (3 mL) was cooled to -50 ° C, sodium borohydride (37.5 mg, 0.992 mmol) was added, and the temperature was raised from -50 °C to -20 °C. After maintaining at -20 ° C to -10 ° C and stirring for 5.5 hours, a saturated aqueous solution of ammonium chloride was added, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 57i (84.2 mg, 27%).

¹ H-NMR (CDCl ₃ ) δ: 1.33 (3H, d, J = 6.8 Hz), 1.51 (9H, s), 2.52 (1H, d, J = 17.7 Hz), 2.60 (1H, dd, J = 11.1) , 7.6 Hz), 2.68 (1H, dd, J = 17.7, 7.6 Hz), 2.79 (1H, dq, J = 11.1, 6.8 Hz), 3.63 (1H, d, J = 16.4 Hz), 3.65 (1H, d , J = 16.4 Hz), 5.04 (1H, d, J = 4.8 Hz), 5.60 (1H, dd, J = 8.8, 4.8 Hz), 6.02 (1H, d, J = 8.8 Hz), 7.23 - 7.42 (5H , m).

[M+H]=447, hold time: 2.13 minutes, (measurement condition B)

 Step 7 Synthesis of Compound 57j  

To a suspension of phosphorus pentachloride (214 mg, 1.03 mmol) in dichloromethane (4 mL), EtOAc (. After the reaction mixture was cooled to -78 ° C, a solution of compound 57i (76.5 mg, 0.171 mmol) After stirring for 2.5 hours under ice cooling, the reaction mixture was cooled to -50 ° C and methanol (2 mL) was added. After stirring at -30 ° C for 1 hour, water (1.23 mL) was added. After stirring at -30 ° C for 30 minutes, an aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and then filtered over magnesium sulfate, and the filtrate was evaporated under reduced pressure to dichloromethane to yield about 5 mL.

 Step 8 Synthesis of Compound 57l  

A solution of compound 57k (103 mg, 0.257 mmol) in EtOAc (1.sub.5 mL) was cooled to -20 &lt;0&gt;C, triethylamine (0.045 <RTIgt; The mixture was stirred for 30 minutes to obtain a reaction mixture A. Pyridine (0.017 mL, 0.205 mmol) was added to a solution of 57j in m. After stirring at 0 ° C for 2 hours, water was added, and dichloromethane was distilled off under reduced pressure. Ethyl acetate and 2 mol/L hydrochloric acid were added, extracted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 57l (99.4mg, 82%).

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.50 (3H, d, J = 7.0 Hz), 1.54 (9H, s), 1.55 (9H, s), 2.53 (1H, d, J =17.9 Hz), 2.57 (1H, dd, J = 11.0, 7.8 Hz), 2.71 (1H, dd, J = 17.9, 7.8 Hz), 2.83 (1H, dq, J = 11.0, 7.0 Hz), 4.74 (1H) , d, J = 16.9 Hz), 4.77 (1H, d, J = 16.9 Hz), 5.17 (1H, d, J = 4.9 Hz), 5.73 (1H, dd, J = 8.3, 4.9 Hz), 7.37 (1H) , s), 8.10 (1H, brs), 8.60 (1H, d, J = 8.3 Hz).

[M+H]=712, hold time: 2.62 minutes, (measurement condition B)

 Step 9 Synthesis of Compound 57m  

Compound 57l (99.4 mg, 0.140 mmol) was dissolved in acetonitrile (2 mL) and EtOAc (2 mL). After cooling to -20 ° C, 37% peracetic acid (0.075mL, 0.419mmol) was added. After stirring at 0 ° C for 40 minutes, a 10% aqueous sodium hydrogensulfite solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 57m (98.9mg, 97%). The 57m system obtained a mixture of β-α:2.5:1 non-image isomers.

Β-i-quinone of compound 57m: [M+H]=728, retention time: 2.46 minutes, (measurement condition B)

Α-limide of compound 57m: [M+H]=728, retention time: 2.42 minutes, (measurement condition B)

 Step 10 Synthesis of Compound I-057 and I-058  

Add a solution of the compound 57 m (98.9 mg, 0.136 mmol) in dichloromethane (2 mL), EtOAc (EtOAc (EtOAc) Stir at -30 ° C to -23 ° C for 30 minutes. The reaction mixture was dissolved in ice water, 1 mol/L hydrochloric acid and acetonitrile, and then washed with diisopropyl ether. HP20-SS resin was added to the aqueous layer, and acetonitrile was distilled off under reduced pressure. The resulting mixture was purified by ODS column chromatography (water-acetonitrile). The chromatographic fraction containing the desired compound was mixed, and a 0.1 mol/L sodium hydroxide aqueous solution was slowly dropped under ice cooling using a pH meter, and then a small piece of dry ice was added. After the mixture was concentrated under reduced pressure, Compound I-057 (13.5 mg, 18%) and I-058 (3.0 mg, 3. Compound I-057 was obtained as a mixture of β:α=2.4:1 non-imagewise isomers.

Compound I-057: [M+H]=516, retention time: 0.81 min, (measurement condition B)

Compound ^{I-058: 1 H-NMR} δ (D 2 O): 1.53 (3H, d, J = 6.4Hz), 2.80 (1H, d, J = 18.6Hz), 3.01 (1H, dd, J = 18.6, 7.9 Hz), 3.21 (1H, dq, J = 12.2, 6.4 Hz), 3.29 (1H, dd, J = 12.2, 7.9 Hz), 4.59 (2H, s), 5.16 (1H, d, J = 4.3 Hz) , 5.79 (1H, d, J = 4.3 Hz), 7.07 (1H, s).

[M+H]=516, hold time: 0.77 minutes, (measurement condition B)

 [Example 27]    Synthesis of Compound I-059  

 Step 1 Synthesis of Compound 59b  

Compound 59a (2.69 g, 13.0 mmol) was used to give the compound (m.

¹ H-NMR (DMSO-d ₆ ) δ: 1.47 (9H, s), 3.62 (2H, t, J = 5.3 Hz), 4.11 (2H, t, J = 5.3 Hz), 4.70 (1H, brs), 7.40 (1H, s), 11.76 (1H, brs).

[M+H]=332, hold time: 1.16 minutes, (measurement condition B)

 Step 2, 3 Synthesis of Compound 59e  

Compound 59c (1.00 g, 2.25 mmol) was used to give the title compound m. After the solution was ice-cooled, compound 59b (745 mg, 2.25 mmol) and EDC hydrochloride (948 mg, 4. After stirring at 0 ° C for 2 hours, water was added, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compound 59e (922mg, 64%).

¹ H-NMR (CDCl ₃ ) δ: 1.54 (9H, s), 1.72 (3H, s), 1.76 (3H, s), 2.61-2.74 (2H, m), 2.78 (1H, dd, J = 17.9, 8.3 Hz), 2.94 (1H, brs), 3.08 (1H, m), 3.22 (1H, m), 3.87 (2H, brs), 4.37 (2H, brs), 4.80 (2H, m), 5.12 (1H, m), 5.30 (1H, m), 5.38 (1H, m), 5.68 (1H, m), 7.31 (1H, s).

[M+H]=640, hold time: 1.89 minutes, (measurement condition B)

 Step 4 Synthesis of Compound 59f  

Compound 59e (353.7 mg, 75%) was obtained in the same manner as in Step 6 of Example 1 using Compound 59e (461 mg, 0.721 mmol).

¹ H-NMR (CDCl ₃ ) δ: 1.54 (9H, s), 1.74 (3H, s), 1.77 (3H, s), 2.43 (1H, d, J = 17.8 Hz), 2.50 (1H, m), 2.97 (1H, m), 3.50 (1H, dd, J = 14.6, 4.9 Hz), 3.68-3.96 (3H, m), 4.34 - 4.50 (2H, m), 4.71 (1H, d, J = 4.8 Hz) , 4.76-4.93 (2H, m), 5.40 (1H, m), 6.04 (1H, dd, J = 9.9, 4.8 Hz), 7.35 (1H, s), 7.92 (1H, d, J = 9.9 Hz), 8.26 (1H, brs).

[M+H]=656.00 (1.83 minutes) (Shimadzu)

 Step 4 Synthesis of Compound I-059  

The compound I-059 (215 mg, 78%) was obtained.

¹ H-NMR (D ₂ O) δ: 2.57 (1H, d, J = 18.3 Hz), 2.83 (1H, dd, J = 14.7, 12.5 Hz), 3.07 (1H, dd, J = 18.3, 7.9 Hz) , 3.55 (1H, ddd, J = 12.5, 7.9, 5.1 Hz), 3.64 (1H, dd, J = 14.7, 5.1 Hz), 3.90 (2H, m), 4.34 (2H, m), 5.01 (1H, d , J = 4.7 Hz), 5.88 (1H, d, J = 4.7 Hz), 7.04 (1H, s).

[M+H]=488, holding time: 0.38 minutes, (measurement condition B)

C16H16N5O9S2Na1(H2O) 4.3 Calculated C: 32.74%, H: 4.23%, N: 11.93%, S: 10.93%, Na: 3.92%. Found C: 32.90%, H: 4.16%, N: 12.09%, S: 10.75%, Na: 3.92%.

 [Example 28]    Synthesis of Compound I-060  

 Step 1 Synthesis of Compound 60c  

Compound 60a (1.29 g, 5.86 mmol) was dissolved in chloroform (200 mL). After stirring at 0 ° C for 1.5 hours, the white solid was filtered and washed with dichloromethane. The filtrate was concentrated to about 20 mL, and the precipitated white solid was filtered and washed with dichloromethane to give a solution A. Compound 60b (1.60 g, 5.86 mmol) was dissolved in methanol (26 mL), and solution A was added under ice cooling. After stirring at 0 ° C for 3 hours, dichloromethane was added to the white solid obtained by the filtration of the solution A to prepare a suspension, and the suspension was ultrasonicated, and the residual white solid was removed. The filtrate was added to the reaction solution. Repeat this operation. After stirring, the solution was concentrated to give a white solid, which was obtained by filtration, to afford compound 60c (1.56 g, 77%).

¹ H-NMR (DMSO-d ₆ ) δ: 1.47 (9H, s), 4.50 (2H, s), 6.99 (1H, brs), 7.46 (1H, brs), 7.49 (1H, s), 11.82 (1H) , brs).

[M+H]=345, hold time: 1.13 minutes, (measurement condition B)

 Step 2 Synthesis of Compound 60e  

Using Compound 60c (600 mg, 1.74 mmol) and Compound 60d (1.00 g, 2.25 mmol), Compound 60e (718 mg, 49%).

¹ H-NMR (CDCl ₃ ) δ: 1.54 (9H, s), 1.69 (3H, s), 1.72 (3H, s), 2.63-2.75 (2H, m), 2.79 (1H, dd, J = 18.1, 8.3 Hz), 3.11 (1H, dd, J = 14.6, 4.4 Hz), 3.28 (1H, m), 4.65 (1H, d, J = 16.2 Hz), 4.74 - 4.83 (3H, m), 5.13 (1H, d, J = 4.6 Hz), 5.34 (1H, m), 5.65 (1H, dd, J = 8.0, 4.6 Hz), 6.47 (1H, brs), 6.61 (1H, brs), 7.21 (1H, s), 8.51 (1H, brs), 9.53 (1H, brs).

[M+H]=653, hold time: 1.84 minutes, (measurement condition B)

 Step 3 Synthesis of Compound 60f  

Compound 60e (239 mg, 6367 mmol) was used to give the compound (yield: 239 mg, 63%).

¹ H-NMR (CDCl ₃ ) δ: 1.54 (9H, s), 1.73 (3H, s), 1.77 (3H, s), 2.43 (1H, d, J = 18.1 Hz), 2.51 (1H, m), 2.96 (1H, m), 3.48 (1H, m), 3.70 (1H, m), 4.68 (2H, s), 4.72 (1H, m), 4.83 (2H, m), 5.39 (1H, m), 6.00 (1H, m), 6.69 (1H, brs), 6.97 (1H, brs), 7.29 (1H, s), 8.26 (1H, brs), 9.47 (1H, brs).

[M+H]=669.05 (1.77 minutes) (Shimadzu)

 Step 4 Synthesis of Compound I-060  

The compound 60f (239 mg, 0.357 mmol) was used to give the compound (m.

¹ H-NMR (D ₂ O) δ: 2.57 (1H, d, J = 18.3 Hz), 2.83 (1H, dd, J = 14.7, 12.4 Hz), 3.07 (1H, dd, J = 18.3, 7.8 Hz) , 3.55 (1H, ddd, J = 12.4, 7.8, 5.3 Hz), 3.63 (1H, dd, J = 14.7, 5.3 Hz), 4.73 (1H, d, J = 16.2 Hz), 4.76 (1H, d, J) =16.2 Hz), 5.02 (1H, d, J = 4.6 Hz), 5.88 (1H, d, J = 4.6 Hz), 7.13 (1H, s).

[M+H]=501, hold time: 0.38 minutes, (measurement condition B)

C16H15N6O9S2Na1(H2O)3.8 Calculated C: 32.52%, H: 3.86%, N: 14.22%, S: 10.85%, Na: 3.89%. Found C: 32.57%, H: 3.92%, N: 14.35%, S: 10.65%, Na: 3.94%.

 [Example 29]    Synthesis of Compound I-061  

 Step 1 Synthesis of Compound 61b  

Compound 61a (2.00 g, 6.87 mmol) was used to give the compound (yield: Compound: Compound:

¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 1.55 (9H, s), 2.68 (2H, t, J = 6.1 Hz), 4.52 (2H, t, J = 6.1 Hz), 7.38 ( 1H, s).

[M+H]=416, holding time: 1.89 minutes, (measurement condition B)

 Step 2 Synthesis of Compound 61d  

The compound 61b (1.03 g, 2.48 mmol) and the compound 61c (1.00 g, 2.25 mmol) were combined to give the compound 61d (1.45 g, 89%).

¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 1.54 (9H, s), 1.72 (3H, s), 1.76 (3H, s), 2.63-2.85 (5H, m), 3.13 (1H) , dd, J = 14.4, 4.3 Hz), 3.31 (1H, m), 4.52 (2H, m), 4.81 (2H, m), 5.08 (1H, d, J = 4.6 Hz), 5.38 (1H, m) , 5.62 (1H, dd, J = 8.3, 4.6 Hz), 7.32 (1H, s), 7.65 (1H, d, J = 8.3 Hz), 8.26 (1H, brs).

[M+H]=724, hold time: 2.33 minutes, (measurement condition B)

 Step 3 Synthesis of Compound 61e  

The compound 61d (725 mg, 1.00 mmol) was used to give the compound (yield: 261 mg, 37%).

¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 1.54 (9H, s), 1.73 (3H, s), 1.77 (3H, s), 2.43 (1H, d, J = 17.8 Hz), 2.47(1H,m), 2.72(2H,t,J=7.4Hz), 2.98(1H,dd,J=17.8,7.7Hz), 3.48(1H,dd,J=14.7,4.9Hz),3.76(1H , m), 4.51 (2H, m), 4.65 (1H, d, J = 4.9 Hz), 4.81 (1H, dd, J = 12.2, 7.4 Hz), 4.89 (1H, dd, J = 12.2, 7.4 Hz) , 5.40 (1H, m), 6.07 (1H, dd, J = 10.0, 4.9 Hz), 7.28 (1H, s), 7.64 (1H, d, J = 10.0 Hz), 8.28 (1H, brs).

 Step 4 Synthesis of Compound I-061  

Compound 61- (276 mg, 0.373 mmol) was used to give the compound I-061 (133 mg, 64%).

¹ H-NMR (D ₂ O) δ: 2.57 (1H, d, J = 18.3 Hz), 2.68 (2H, t, J = 6.4 Hz), 2.82 (1H, dd, J = 14.8, 12.3 Hz), 3.06 (1H, dd, J = 18.3, 7.8 Hz), 3.55 (1H, ddd, J = 12.3, 7.8, 5.3 Hz), 3.64 (1H, dd, J = 14.8, 5.3 Hz), 4.45 (2H, t, J) =6.4 Hz), 5.00 (1H, d, J = 4.8 Hz), 5.86 (1H, d, J = 4.8 Hz), 7.03 (1H, s).

[M+H]=516, holding time: 0.39 minutes, (measurement condition B)

C17H15.2N5O10S2Na1.8(H2O) 3.9 Calculated C: 32.65%, H: 3.71%, N: 11.20%, S: 10.25%, Na: 6.62%. Found C: 32.61%, H: 3.86%, N: 11.44%, S: 10.07%, Na: 6.52%.

 [Example 30]    Synthesis of Compound I-062 and I-063  

 Step 1 Synthesis of Compound 62b  

Compound 62a (5.0 g, 34.9 mmol) was dissolved in dichloromethane (50 ml), diphenyldichloromethane (8.14 g, 41.9 mmol) was added and stirred for 1 hour. After the reaction mixture was concentrated under reduced pressure, the mixture was applied to methylene chloride column chromatography and eluted with chloroform/ethyl acetate. The chromatographic fractions containing the desired compound were concentrated under reduced pressure to yield compound 62b (5.77 g, 53%).

¹ H-NMR (CDCl ₃ ) δ: 7.43 - 7.28 (10H, m), 6.74 (1H, s), 6.62 (1H, s), 3.92 (3H, s).

 Step 2 Synthesis of Compound 62c  

Compound 62b (5.77 g, 18.7 mmol) was dissolved in ethanol (30 ml) and tetrahydrofuran (30 ml), and sodium borohydride (1.41 g, 37.3 mmol) was added under ice cooling. After stirring for 1 hour under ice cooling, it was stirred at room temperature for 3 hours. Dilute hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtering magnesium sulfate, it was concentrated under reduced pressure to give a crude product of compound 62c (5.50 g).

¹ H-NMR (CDCl ₃ ) δ: 7.43 - 7.26 (10H, m), 6.69 (1H, s), 5.96 (1H, s), 4.61 (2H, s), 1.96 (1H, br s).

 Step 3 Synthesis of Compound 62d  

The whole amount of the obtained compound 62c was dissolved in tetrahydrofuran (50 mL), and N-hydroxyphthalimide (3.65 g), triphenylphosphine (5.87 g), azodicarboxylic acid II were added under ice cooling. 2-methoxyethyl ester (5.24 g). After stirring for 1 hour under ice cooling, the solvent was distilled off. The residue was purified by silica gel column chromatography (dissolved in chloroform/ethyl acetate), and the collected solution containing the chromatographic fraction of the target was concentrated, and the precipitated solid was filtered using methanol and dried. Compound 62d was synthesized. Yield: 6.27 g (79%) ¹ H-NMR (CDCl ₃ ) δ: 7.83-7.81 (2H, m), 7.76-7.74 (2H, m), 7.41-7.27 (10H, m), 6.67 (1H, s ), 6.28 (1H, s), 5.16 (2H, s).

 Step 4 Synthesis of Compound 62e  

Compound 62e was synthesized by the same method as Step 2 of Example 1 using Compound 62d (2.00 g, 4.69 mmol).

Yield: 1.89g (73%)

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (8H, m), 7.25-7.21 (3H, m), 6.64 (1H, s), 6.02 (1H, s), 5.05 (2H, s), 1.52 (9H, s).

 Step 5 Synthesis of Compound 62g  

The compound 62e (1.24 g, 2.25 mmol) and the compound 62f (1.00 g, 2.25 mmol) were used to obtain the compound 62g (1.67 g, 87%).

¹ H-NMR (CDCl ₃ ) δ: 1.54 (9H, s), 1.66 (3H, s), 1.70 (3H, s), 2.34 (1H, dd, J = 14.4, 9.1 Hz), 2.51 (1H, dd , J = 18.2, 3.3 Hz), 2.63 (1H, dd, J = 18.2, 8.3 Hz), 2.76 (1H, dd, J = 14.4, 4.3 Hz), 3.08 (1H, m), 4.75 (2H, m) , 5.03 (1H, d, J = 4.5 Hz), 5.20 (1H, d, J = 13.9 Hz), 5.27-5.35 (2H, m), 5.70 (1H, dd, J = 8.6, 4.5 Hz), 6.07 ( 1H, s), 6.65 (1H, s), 7.20 (1H, s), 7.24-7.47 (10H, m), 8.65 (1H, brs).

[M+H]=859, hold time: 2.92 minutes, (measurement condition B)

 Step 6 Synthesis of Compound 62h  

Using 62 g of the compound (860 mg, 1.00 mmol), the compound was obtained in the same manner as in the step 6 of Example 1, to obtain a mixture of a compound of 62h (782 mg, 89%) of the β-form and the ?

Β-limide of compound 62h: [M+H]=875, retention time: 2.87 minutes, (measurement condition B)

Α-limide of compound 62h: [M+H]=875, retention time: 2.81 minutes, (measurement condition B)

 Step 7 Synthesis of Compound I-062 and I-063  

Compound 62-(782 mg, 0.894 mmol) was used to give Compound I-062 (215 mg, 43%), I-063 (55.6 mg, 11%).

Compound I-062: ¹ H-NMR (D ₂ O) δ: 2.56 (1H, d, J = 18.3 Hz), 2.79 (1H, dd, J = 13.9, 11.8 Hz), 3.06 (1H, dd, J = 18.3, 7.4 Hz), 3.54 (1H, ddd, J = 11.8, 7.4, 5.4 Hz), 3.59 (1H, dd, J = 13.9, 5.4 Hz), 4.96 (1H, d, J = 4.8 Hz), 5.22 ( 1H, d, J = 14.2 Hz), 5.22 (1H, d, J = 14.2 Hz), 5.86 (1H, d, J = 4.8 Hz), 6.12 (1H, s), 7.08 (1H, s).

[M+H]=541, holding time: 0.92 minutes, (measurement condition B)

Compound I-063: ¹ H-NMR (D ₂ O) δ: 2.82 (1H, dd, J = 18.6, 2.9 Hz), 3.03 (1H, dd, J = 18.6, 8.3 Hz), 3.17 (1H, dd, J = 13.1, 11.0 Hz), 3.56 (1H, dddd, J = 11.0, 8.3, 4.8, 2.9 Hz), 3.65 (1H, dd, J = 13.1, 4.8 Hz), 5.08 (1H, d, J = 4.3 Hz) ), 5.22 (2H, s), 5.68 (1H, d, J = 4.3 Hz), 6.11 (1H, s), 7.06 (1H, s).

[M+H]=541, hold time: 0.60 minutes, (measurement condition B)

C18H14.7N6O10S2Na1.3 (H2O) 3.7 calculated C: 34.01%, H: 3.50%, N: 13.22%, S: 10.09%, Na: 4.70%. Found C: 33.96%, H: 3.59%, N: 13.31%, S: 10.21%, Na: 4.66%.

 [Example 31]    Synthesis of Compound I-064  

 Step 1 Synthesis of Compound 64b  

Dimethyl dicarbonate (2.63 g, 19.7 mmol) was added to a solution of ethanolamine 64a (1.19 mL, 19.7 mmol) in dichloromethane (12 mL). After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated under reduced pressure. After the residue was dissolved in tetrahydrofuran (20 mL) and ice-cooled, N-hydroxyphthalimide (3.85 g, 23.6 mmol) and triphenylphosphine (6.18 g, 23.6 mmol) were added, followed by azo Diisopropyl carboxylic acid (4.58 mL, 23.6 mmol). After stirring at room temperature for 23 hours, the reaction mixture was concentrated under reduced pressure. After dissolving the residue in methanol, the residue was concentrated under reduced pressure, and the obtained white solid was filtered off to afford compound 64b (1.34 g, 26%).

¹ H-NMR (CDCl ₃ ) δ: 3.50 (2H, m), 3.72 (3H, s), 4.27 (2H, t, J = 4.8 Hz), 5.91 (1H, brs), 7.78 (2H, m), 7.86 (2H, m).

[M+H]=265, holding time: 1.24 minutes, (measurement condition B)

 Step 2 Synthesis of Compound 64d  

A solution of 64b (1.34 g, 5.07 mmol) in dichloromethane (20 mL) After stirring at 0 ° C for 50 minutes, the insoluble matter was removed, and the mixture was evaporated under reduced pressure to dichloromethane (yield: 10 mL) to obtain a dichloromethane solution of hydroxylamine. A further prepared solution of 64c (1.38 g, 5.07 mmol) in methanol (20 mL) was ice-cooled. After stirring at 0 ° C for 1 hour, dichloromethane was distilled off under reduced pressure. Ethyl acetate and water were added, followed by addition of 2 mol/L hydrochloric acid, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered over magnesium sulfate, and concentrated under reduced pressure to give compound 64d (1.80 g, 91%).

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 3.25 (2H, m), 3.53 (3H, s), 4.08 (2H, t, J = 6.2 Hz), 7.15 (1H, m), 7.42 (1H, s), 11.81 (1H, s), 13.93 (1H, brs).

[M+H]=389, hold time: 1.35 minutes, (measurement condition B)

 Step 3 Synthesis of Compound 64f  

To a suspension of phosphorus pentachloride (937 mg, 4.50 mmol) in dichloromethane (10 mL), pyridine (0.400 mL, 4. After cooling the reaction mixture to -78 ° C, compound 64e (1.0 g, 2.25 mmol). After stirring for 40 minutes under ice cooling, the reaction mixture was cooled to -78 ° C, and ethanol (10 mL) was added. After stirring at -30 ° C for 35 minutes, water (2.25 mL) was added. After stirring at -30 ° C for 35 minutes, an aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. After filtered over magnesium sulfate, the filtrate was evaporated under reduced pressure to dichloromethane (dichloromethane) to obtain a dichloromethane solution (solution A). A solution of compound 64d (961 mg, 2.48 mmol) in EtOAc (EtOAc) (EtOAc: EtOAc. Stirring was carried out for 40 minutes to obtain a suspension (suspension B). Pyridine (0.218 mL, 2.70 mmol) was added to solution A under ice cooling, and then suspension B was dropped. After stirring at 0 ° C for 35 minutes, water was added, and dichloromethane was evaporated under reduced pressure. Ethyl acetate and 2 mol/L hydrochloric acid were added, and the mixture was extracted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 64f (1.14 g, 72%).

¹ H-NMR (CDCl ₃ ) δ: 1.54 (9H, s), 1.72 (3H, s), 1.76 (3H, s), 2.63-2.75 (2H, m), 2.80 (1H, dd, J = 18.1, 8.3 Hz), 3.13 (1H, dd, J = 14.6, 4.3 Hz), 3.31 (1H, m), 3.52 (2H, m), 3.56 (3H, s), 4.35 (2H, m), 4.81 (2H, m), 5.11 (1H, d, J = 4.6 Hz), 5.33 (1H, m), 5.38 (1H, m), 5.70 (1H, dd, J = 8.7, 4.6 Hz), 7.29 (1H, s), 7.81 (1H, d, J = 8.7 Hz), 8.25 (1H, brs).

[M+H]=697, hold time: 2.00 minutes, (measurement condition B)

 Step 4 Synthesis of Compound 64g  

Compound 64f (563 mg, 0.808 mmol) was dissolved in acetonitrile (2.8 mL) and DMA (2.8 mL). After cooling to -20 ° C, 37% peracetic acid (0.218 mL, 1.21 mmol) was added. After stirring at 0 ° C for 1.5 hours, a 10% sodium hydrogen sulfite solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane-ethyl acetate, ethyl acetate-methanol) to afford compound 64 g (320mg, 56%).

¹ H-NMR (CDCl ₃ ) δ: 1.54 (9H, s), 1.74 (3H, s), 1.78 (3H, s), 2.39-2.54 (2H, m), 2.99 (1H, dd, J = 17.7, 7.6 Hz), 3.43-3.57 (3H, m), 3.65 (3H, s), 3.78 (1H, m), 4.28-4.43 (2H, m), 4.69 (1H, d, J = 4.9 Hz), 4.82 ( 1H, dd, J = 12.2, 7.4 Hz), 4.89 (1H, dd, J = 12.2, 7.4 Hz), 5.40 (1H, m), 5.93 (1H, m), 6.07 (1H, dd, J = 9.8, 4.9 Hz), 7.31 (1H, s), 7.74 (1H, d, J = 9.8 Hz), 8.22 (1H, brs).

 Step 5 Synthesis of Compound I-064  

Add a solution of the compound (64 g, 0.448 mmol) in dichloromethane (6.5 mL), and then Stir at -30 ° C to -26 ° C for 1.5 hours. The reaction mixture was dissolved in ice water, 2 mol/L hydrochloric acid, acetonitrile, and then washed with diisopropyl ether. HP20-SS resin was added to the aqueous layer, and acetonitrile was distilled off under reduced pressure. The resulting mixture was purified by ODS column chromatography (water-acetonitrile). The chromatographic fraction containing the desired compound was mixed, and a 0.2 mol/L aqueous sodium hydroxide solution (1.3 mL) was slowly dropped under ice cooling, and a small piece of dry ice was added at a pH of 4.78, and the pH was 4.37. After the mixture was concentrated under reduced pressure, Compound I-064 (185 mg, 73%).

¹ H-NMR (D ₂ O) δ: 2.57 (1H, d, J = 18.3 Hz), 2.84 (1H, dd, J = 14.3, 12.3 Hz), 3.07 (1H, dd, J = 18.3, 7.5 Hz) , 3.49 (2H, m), 3.52-3.64 (2H, m), 3.65 (3H, s), 4.31 (2H, m), 5.01 (1H, d, J = 4.8 Hz), 5.88 (1H, d, J =4.8Hz), 7.04(1H, s).

[M+H]=545, holding time: 0.56 minutes, (measurement condition B)

C18H19N6O10S2Na1(H2O) 3.5 Calculated C: 34.34%, H: 4.16%, N: 13.35%, S: 10.19%, Na: 3.65%. Found C: 34.21%, H: 4.26%, N: 13.56%, S: 10.06%, Na: 3.50%.

 [Example 32]    Synthesis of Compound I-065  

 Step 1 Synthesis of Compound 65c  

Compound 65a (5.00 g, 28.7 mmol) was dissolved in MeOH (50 mL). After stirring for 1 hour under ice cooling, it was stirred at room temperature for one night. Concentration under reduced pressure gave a crude product of compound 65c. Compound 65c was used in the subsequent reaction without purification.

 Step 2 Synthesis of Compound 65d  

The obtained compound 65c (corresponding to 28.7 mmol) was dissolved in tetrahydrofuran (30 ml), and acetic acid (4.92 ml, 86 mmol) and 1 mol/L of TBAF tetrahydrofuran solution (86 ml, 86 mmol) was added. After stirring for 3 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. After filtering the magnesium sulfate, it was concentrated under reduced pressure, and applied to a silica gel column chromatography, eluting with hexane/ethyl acetate. The chromatographic fractions containing the desired compound were concentrated under reduced pressure to give a mixture of about 2:1 of the oxime isomers of compound 65d (4.36 g, 78%).

¹ H-NMR (CDCl ₃ ) δ: 7.55 (1H, t, J = 4.0 Hz), 7.29 (3H, t, J = 7.8 Hz), 6.89 (4H, d, J = 8.1 Hz), 5.04 (1H, s), 5.02 (2H, s), 4.41 (1H, d, J = 3.5 Hz), 4.26 (2H, d, J = 4.0 Hz), 3.81 (5H, s).

 Step 3 Synthesis of Compound 65e  

Compound 65d (4.36g, 22.33mmol), N-hydroxyphthalimide (4.37g, 26.8mmol), triphenylphosphine (7.03g, 26.8mmol) were dissolved in tetrahydrofuran (45ml), cooled in ice Bis(2-methoxyethyl) azodicarboxylate (6.28 g, 26.8 mmol) was added. After stirring for 1 hour under ice cooling, concentration was carried out under reduced pressure. Methanol was added to the residue, and the precipitated solid was taken out by filtration to obtain a 2:1 oxime isomer mixture of compound 65e (5.06 g, 67%).

¹ H-NMR (CDCl ₃ ) δ: 7.85-7.81 (3.0H, m), 7.77-7.75 (3.0H, m), 7.68 (1.0H, t, J = 6.2 Hz), 7.23-7.17 (3.0H, m), 6.84 (1.0H, d, J = 7.8 Hz), 6.76 (2.0H, d, J = 8.3 Hz), 5.03-5.01 (1.0H, m), 5.00 (1.0H, br s), 4.94 ( 2.0H, br s), 4.75 (2.0H, d, J = 6.3 Hz), 3.79 (1.5H, s), 3.77 (3.0H, s).

 Step 4 Synthesis of Compound 65f  

The compound 65e (1.00 g, 2.94 mmol) was synthesized in the same manner as in the step 2 of Example 1 to obtain a crude product of the compound 65f (1.20 g, 88%) of an isomer mixture of about 2:1. .

[M+H]=465, holding time: 1.98 minutes, (measurement condition A)

 Step 5 Synthesis of Compound 65h  

Compound 65f (1.04 g, 2.25 mmol) and compound 65 g (1.00 g, 2.25 mmol) were used in the same manner as in Steps 2 and 3 of Example 27 to obtain a compound of a ruthenium isomer mixture of about 1.2:1. A crude product of 65 h (1.60 g, 92%).

[M+H]=773, hold time: 2.67 minutes, (measurement condition B)

 Step 6 Synthesis of Compound 65i  

Compound 65h (860 mg, 1.11 mmol) was used to give the title compound m m m m m m m m

[M+H]=789, hold time: 2.60 minutes, 2.63 minutes, (measurement condition B)

 Step 7 Synthesis of Compound I-065  

Compound 65i (613 mg, 0.777 mmol) was used in the same manner as in Example 1 and Step 6 to obtain Compound I-065 (87.1 mg, 21%) as a 1.7:1 mixture of oxime.

Major: ¹ H-NMR (D2O) δ: 2.57 (1H, d, J = 18.3 Hz), 2.82 (1H, dd, J = 14.6, 12.4 Hz), 3.07 (1H, dd, J = 18.3, 7.8 Hz) , 3.55 (1H, ddd, J = 12.4, 7.8, 5.3 Hz), 3.62 (1H, dd, J = 14.6, 5.3 Hz), 4.84 (2H, d, J = 5.6 Hz), 5.00 (1H, d, J) = 4.8 Hz), 5.87 (1H, d, J = 4.8 Hz), 7.08 (1H, s), 7.71 (1H, t, J = 5.6 Hz).

Minor: ¹ H-NMR (D2O) δ: 2.57 (1H, d, J = 18.3 Hz), 2.82 (1H, dd, J = 14.6, 12.4 Hz), 3.07 (1H, dd, J = 18.3, 7.8 Hz) , 3.50-3.67 (2H, m), 5.01 (1H, d, J = 4.6 Hz), 5.07 (1H, dd, J = 16.4, 3.9 Hz), 5.09 (1H, dd, J = 16.4, 3.9 Hz), 5.88 (1H, d, J = 4.6 Hz), 7.09 (1H, s), 7.15 (1H, t, J = 3.9 Hz).

[M+H]=501, holding time: 0.57 minutes, (measurement condition B)

C16H15N6O9S2Na1(H2O) 3.3 Calculated C: 33.03%, H: 3.74%, N: 14.44%, S: 11.02%, Na: 3.95%. Found C: 32.99%, H: 3.74%, N: 14.68%, S: 10.79%, Na: 3.83%.

 [Example 33]    Synthesis of Compound I-066 and I-067  

 Step 1 Synthesis of Compound 66g  

After a solution of compound 57e (5.54 g, 13.2 mmol) eluted eluted eluted eluted eluted eluted eluted After stirring for 2 hours under ice cooling, a saturated aqueous solution of ammonium chloride was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered over magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 66 g (4.21 g, 59%).

¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, d, J = 6.7 Hz), 1.48 (9H, s), 3.73 (2H, s), 4.01 (1H, d, J = 13.6 Hz), 4.02 ( 1H, d, J = 13.6 Hz), 4.26 (1H, q, J = 6.7 Hz), 5.07-5.13 (2H, m), 6.03 (1H, m), 7.29-7.43 (5H, m).

 Step 2 Synthesis of Compound 66h  

Triphenylphosphine (2.45 g, 9.33 mmol) was added to a solution of compound 66 g (4.21 g, 7.78 mmol). After stirring at room temperature for 1.5 hours, 8.4% aqueous sodium hydrogencarbonate (20.0 mL, 20.0 mmol) was added. After stirring at room temperature for 20 minutes, water and ethyl acetate were added to the reaction mixture, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 66h (1.76 g, 51%).

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.65 (3H, d, J = 6.6 Hz), 3.65 (1H, d, J = 16.7 Hz), 3.66 (1H, d, J = 16.7) Hz), 4.13 (1H, m), 5.04 (1H, d, J = 4.3 Hz), 5.60 (1H, dd, J = 9.1, 4.3 Hz), 6.10 (1H, m), 6.19 (1H, d, J = 9.1 Hz), 7.24 - 7.42 (5H, m).

[M+Na]=467, hold time: 2.19 minutes, (measurement condition B)

 Step 3 Synthesis of Compound 66i  

A solution of compound 66h (360 mg, 0.810 mmol) in methanol (10.5 mL) was cooled to -50[deg.] C. and sodium borohydride (92.0 mg, 2.43 mmol). After stirring at -50 °C for 4.5 hours, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 66i (216 mg, 60%).

¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H, d, J = 6.9 Hz), 1.53 (9H, s), 2.60 (1H, dd, J = 18.6, 10.2 Hz), 3.12 (1H, dd, J =18.6, 8.5 Hz), 3.21 (1H, qd, J=6.9, 2.6 Hz), 3.34 (1H, ddd, J = 10.2, 8.5, 2.6 Hz), 3.69 (2H, s), 4.84 (1H, d, J = 4.4 Hz), 5.35 (1H, dd, J = 8.4, 4.4 Hz), 6.11 (1H, d, J = 8.4 Hz), 7.28-7.41 (5H, m).

[M+Na]=469, hold time: 2.13 minutes, (measurement condition B)

 Step 4 Synthesis of Compound 66j  

To a suspension of phosphorus pentachloride (218 mg, 1.05 mmol) in dichloromethane (2.5 mL), pyridine (0.093 mL, 1. After the reaction mixture was cooled to -78 ° C, a solution of compound 66i (234 mg, 0.524 mmol) After stirring for 30 minutes under ice cooling, the reaction mixture was cooled to -78[deg.] C. After stirring at -30 ° C for 45 minutes, water (0.944 mL) was added. After stirring at -30 ° C for 25 minutes, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and then filtered over magnesium sulfate.

 Step 5 Synthesis of Compound 66l  

A solution of compound 57k (210 mg, 0.524 mmol) in MeOH (1.sub.5mL) was cooled to -20 &lt;0&gt;C, triethylamine (0.102 mL, 0.734 mmol) and methanesulfonium chloride (0.053 mL, 0.681 mmol), -20 ° C The mixture was stirred for 30 minutes to obtain a reaction mixture A. Pyridine (0.051 mL, 0.629 mmol) was added to a dichloromethane solution of Compound 66j obtained in Step 4 under ice cooling, and then the reaction mixture A was dropped. After stirring at 0 ° C for 40 minutes, water was added, and dichloromethane was evaporated under reduced pressure. Ethyl acetate and 2 mol/L hydrochloric acid were added, extracted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 66l ( 334 mg, 90%).

¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, d, J = 6.8 Hz), 1.46 (9H, s), 1.54 (9H, s), 1.55 (9H, s), 2.64 (1H, dd, J =18.4, 10.1 Hz), 3.22 (1H, dd, J = 18.4, 8.3 Hz), 3.38 (1H, m), 3.56 (1H, m), 4.76 (1H, d, J = 16.9 Hz), 4.78 (1H) , d, J = 16.9 Hz), 4.97 (1H, d, J = 4.3 Hz), 5.52 (1H, dd, J = 8.1, 4.3 Hz), 7.44 (1H, s), 8.07 (1H, s), 8.69 (1H, d, J = 8.1 Hz).

[M+H]=712, hold time: 2.63 minutes, (measurement condition B)

 Step 6 Synthesis of Compound 66m  

Compound 66l (431 mg, 0.605 mmol) was dissolved in acetonitrile (2 mL) and DMA (2 mL). After cooling to -20 ° C, 37% peracetic acid (0.380 mL, 2.12 mmol) was added. After stirring at 0 ° C for 50 minutes, a 10% aqueous sodium hydrogensulfite solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 66m (283mg, 64%). Compound 66m affords a 4:1 mixture of non-image isomers of anthraquinone.

[M+H]=728, hold time: 2.45 minutes, (measurement condition B)

 Step 7 Synthesis of Compound I-066 and I-067  

Add a solution of the compound 66m (283 mg, 0.388 mmol) in dichloromethane (6 mL), EtOAc (3. Stir at -30 ° C to -23 ° C for 20 minutes. The reaction mixture was dissolved in ice water, 2 mol/L hydrochloric acid and acetonitrile, and then washed with diisopropyl ether. HP20-SS resin was added to the aqueous layer, and acetonitrile was distilled off under reduced pressure. The resulting mixture was purified by ODS column chromatography (water-acetonitrile). The chromatographic fraction containing the desired compound was mixed, and a 0.1 mol/L aqueous sodium hydroxide solution was slowly dropped under ice cooling, and then a small piece of dry ice was added. After the mixture was concentrated under reduced pressure, Compound I-066 (28.8 mg, 13%) and Compound I-067 (138 mg, 63%).

Compound I-066: ¹ H-NMR (D ₂ O) δ: 1.29 (3H, d, J = 7.6 Hz), 2.74 (1H, d, J = 18.4 Hz), 3.01 (1H, dd, J = 18.4, 8.3 Hz), 3.68 (1H, m), 3.82 (1H, m), 4.59 (2H, s), 5.17 (1H, d, J = 4.8 Hz), 5.95 (1H, d, J = 4.8 Hz), 7.07 (1H, s).

[M+H]=516, hold time: 0.82 minutes, (measurement condition B)

Compound I-067: ¹ H-NMR (D ₂ O) δ: 1.56 (3H, d, J = 7.3 Hz), 2.99 (1H, dd, J = 22.5, 13.9 Hz), 3.39-3.51 (2H, m) , 3.64 (1H, m), 4.59 (2H, s), 5.13 (1H, d, J = 4.8 Hz), 5.54 (1H, d, J = 4.8 Hz), 7.00 (1H, s).

[M+H]=516, holding time: 0.47 minutes, (measurement condition B)

C17H15.1N5O10S2Na1.9(H2O)3.8 Calculated C: 32.63%, H: 3.66%, N: 11.19%, S: 10.25%, Na: 6.98%. Found C: 32.65%, H: 3.78%, N: 11.39%, S: 10.05%, Na: 7.00%.

The following compounds were synthesized by the same method.

 [Example 34]    Synthesis of Compound I-074  

 Step 1 Synthesis of Compound 74b  

The compound 74a (31.5 g, 70.9 mmol) synthesized according to the method described in the international patent WO2016175223A was dissolved in tetrahydrofuran (320 mL), and 5% palladium carbon (15.1 g, 7.09 mmol) was added thereto, and stirred at room temperature under a hydrogen atmosphere. 30 minutes in an hour. The catalyst was removed by diatomaceous earth, and 5% palladium carbon (15.1 g, 7.09 mmol) was further added thereto, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The catalyst was removed by filtration through celite, and diphenyldiazomethane (15.1 g, 78.0 mmol) was added and stirred at room temperature for one hour. The solvent was distilled off, ethyl acetate and diisopropyl ether were added, and the resulting solid was filtered and dried to give compound 74b (27.5 g, yield 71%).

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.30 (m, 14H), 6.94 (s, 1H), 6.02 (d, J = 8.8 Hz, 1H), 5.55 (dd, J = 8.8, 4.7 Hz, 1H ), 4.99 (d, J = 4.7 Hz, 1H), 3.67 (d, J = 16.2 Hz, 1H), 3.61 (d, J = 16.2 Hz, 1H), 3.17 - 3.08 (m, 1H), 2.90 (dd) , J=14.6, 4.5 Hz, 1H), 2.62 (dd, J=14.6, 9.7 Hz, 1H), 2.54-2.50 (m, 2H).

 Step 2 Synthesis of Compound 74c  

Phosphorus pentachloride (15.4 g, 73.7 mmol) was suspended in dichloromethane (200 mL) and cooled to 0 °C. Pyridine (6.55 mL, 81.0 mmol) and Compound 74b (20.0 g, 36.9 mmol) were added to this suspension, and stirred at 0 ° C for 30 min. The solution was cooled to -78 ° C, ethanol (200 mL) was added and warmed to -30 ° C and stirred for 2 hr. Purified water (33.2 mL, 1.84 mol) was added to this solution and stirred. The reaction liquid was further diluted with purified water, and dichloromethane was distilled off, and the precipitated crystals were collected by filtration. The obtained crystals were washed with purified water and ethyl acetate and dried to give crystals of compound 74c (14.1 g, yield 83%).

¹ H-NMR (DMSO-D6) δ: 8.79 (br s, 2H), 7.47-7.27 (m, 10H), 6.91 (s, 1H), 5.18 (d, J = 4.6 Hz, 1H), 4.84 (d) , J = 4.6 Hz, 1H), 3.46-3.27 (m, 2H), 3.06 (dd, J = 18.3, 7.1 Hz, 1H), 2.89 (dd, J = 14.3, 6.0 Hz, 1H), 2.74 (dd, J=10.2, 20.0 Hz, 1H).

XRPD (measurement condition 2): diffraction angle 2θ (°): 4.2, 8.2, 10.0, 16.2, 17.7, 20.3, 21.4, 23.7, 23.9, 27.6, 28.4, 29.1, 29.5, 32.6

Elemental analysis C22H20N2O5SHCl(H2O)1.0

Calculated: C, 55.17; H, 4.84; N, 5.85; S, 6.69; Cl, 7.40 (%)

Found: C, 55.26; H, 4.87; N, 6.23; S, 6.68; Cl, 7.14 (%)

 Step 3 Synthesis of Compound 74e  

Triphenylphosphine (2.62 g, 10.0 mmol) was added to a solution of compound 74d (1.3 g, 10.0 mmol) in THF. DIAD (1.94 mL, 10.0 mmol) was added thereto, and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and methanol was poured into the obtained residue, and the resulting solid was filtered. The obtained solid was washed with methanol and dried to give compound 74e (1.67 g, yield 61%) of white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.71-1.78 (1H, m), 2.17-2.27 (1H, m), 3.20-3.25 (1H, m), 3.82-3.95 (2H, m), 4.06 (1H, Dd, J = 11.5, 3.6 Hz), 4.31 (1H, d, J = 11.5 Hz), 4.78 (1H, d, J = 3.4 Hz), 6.01 (1H, d, J = 4.9 Hz), 7.77-7.81 ( 2H, m), 7.85-7.88 (2H, m).

 Step 4 Synthesis of Compound 74g  

A solution of compound 74e (1.68 g, 6.10 mmol) in dichloromethane (34 mL) was cooled to EtOAc. Thereto, methyl hydrazine (0.340 mL, 6.41 mmol) was added, and the mixture was stirred at 0 ° C for 1 hour. The resulting insoluble matter was filtered. The filtrate was cooled to 0 °C. Compound 74f (1.58 g, 5.80 mmol) and methanol (10 mL) were added thereto, and stirred at 0 ° C for 1 hour. The filtrate was distilled off under reduced pressure, and water was added and extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude product (2.54 g).

MS (m + 1) = 400 measurement conditions A 1.23 minutes

 Step 5 Synthesis of Compound 74h  

The compound 74c (461 mg, 1.00 mmol) was suspended in ethyl acetate (4.60 mL), and the crude product (yield: 439 mg) of the compound obtained in the step 4 was added and cooled to -30 °C. To the suspension were added phenyl dichlorophosphate (0.164 mL, 1.10 mmol) and N-methyl-fyfolin (0.44 mL, 4.00 mmol), and stirred at -30 ° C for 1 hour. Purified water was added to this solution, the solvent was distilled off, and extraction was performed with ethyl acetate. The organic layer was washed with purified water, washed with brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography to afford compound 74h (740mg, yield 92%).

¹ H-NMR (CDCl ₃ ) δ: 1.54 (9H, s), 1.78-1.84 (1H, m), 2.18-2.29 (1H, m), 2.54-2.56 (2H, m), 2.69 (1H, dd, J=14.6, 9.5 Hz), 3.02-3.18 (4H, m), 3.84-3.95 (2H, m), 4.01 (1H, dd, J=11.2, 3.0 Hz), 4.22 (1H, d, J = 10.8 Hz) ), 4.62 (1H, d, J = 2.9 Hz), 5.12 (1H, d, J = 4.8 Hz), 5.70 (1H, dd, J = 8.7, 4.8 Hz), 5.87 (1H, d, J = 4.8 Hz) ), 6.99 (1H, s), 7.29-7.36 (10H, m), 8.09 (1H, s).

MS (m+1) = 806, 2.4 minutes, assay condition A

 Step 6 Synthesis of 74i  

The crude product (740 mg) containing Compound 74h was dissolved in dichloromethane (4.00 mL) and cooled to -40. To the solution was added m-chloroperoxybenzoic acid (70%, 249 mg, 1.01 mmol), and stirred at -40 ° C for 30 min. An aqueous sodium thiosulfate solution was added to the reaction mixture, and the solvent was distilled off and extracted with ethyl acetate. The organic layer was washed with purified water and saturated aqueous sodium hydrogen carbonate, and then washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off to obtain a residue (670 mg) containing Compound 74i.

MS (m + 1) = 822, 2.34 minutes, assay condition A

 Step 7 Synthesis of Compound I-074  

After cooling a solution containing 670 mg of the crude product of compound 74i in dichloromethane (3.7 mL) to -30 ° C, then, then, then, then, then, then, then, then, then, then, then, then, then, then, then The solution (2.04 mL, 4.08 mmol) was stirred at -30 ° C for 30 min. Diisopropyl ether, ice, and acetonitrile were sequentially added to the reaction mixture, and the mixture was stirred to completely dissolve the insoluble matter, and then the aqueous layer was taken out. After the organic layer was again extracted with water, all the aqueous layers were combined and HP20-SS resin was added, and acetonitrile was distilled off under reduced pressure. The resulting mixture was purified by ODS column chromatography (water-acetonitrile). The chromatographic fractions containing the desired compound were collected, and concentrated under reduced pressure to give a white powdery compound I-074 (240 mg, yield 53%).

¹ H-NMR (D ₂ O) δ: 1.96 (1H, br s), 2.26-2.34 (1H, m), 2.56 (1H, d, J = 18.2 Hz), 2.78-2.86 (1H, m), 3.06 (1H, dd, J = 18.2, 7.5 Hz), 3.24 (1H, br s), 3.52-3.66 (2H, m), 3.88-3.96 (2H, m), 4.11-4.22 (2H, m), 4.94 5.00 (2H, m), 5.88-5.93 (2H, m), 7.18 (1H, s).

MS (m+1) = 556, 0.53 minutes, assay condition A

Elemental analysis: C20H21N5O10S2(H2O) ₂ .8

Calculated value C: 39.64%, H: 4.42%, N: 11.56%, S: 10.58%.

Found C: 39.47%, H: 4.50%, N: 11.85%, S: 10.50%.

 [Example 35]    Synthesis of Compound I-075  

 Step 1 Synthesis of Compound 75b-1  

After adding imidazole (1.70 g, 25 mmol) to a solution of glycerol (921 mg, 10 mmol) in tetrahydrofuran (9 mL), a solution of &lt;RTI ID=0.0&gt; Drop it down. After stirring overnight at room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 75b-1 (3.13 g, yield 98%).

¹ H-NMR (CDCl ₃ ) δ: 0.07 (12H, s), 0.90 (18H, s), 2.45 (1H, d, J = 5.1 Hz), 3.63 (1H, s), 3.64 (4H, s).

 Step 2 Synthesis of Compound 75c-1  

After adding N-hydroxyphthalimide (1.91 g, 11.7 mmol) and triphenylphosphine (3.07 g, 11.7 mmol) to a solution of compound 75b-1 (3.13 g, 9.8 mmol) in tetrahydrofuran (31 mL) A 1.9 mol/L DIAD/toluene solution was dropped under ice cooling. After stirring at room temperature for 1 hour, it was concentrated under reduced pressure, and methanol was added to the residue. The resulting solid was taken up in vacuo and dried under reduced pressure to give compound 75c-1 (3.07 g, yield 67%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 0.00 (6H, s), 0.02 (6H, s), 0.82 (18H, s), 3.94 (4H, ddd, J = 14.5, 9.5, 3.2 Hz), 4.33-4.38 (1H, m), 7.72 (2H, dd, J = 5.5, 3.1 Hz), 7.82 (2H, dd, J = 5.5, 3.1 Hz).

 Step 3, 4 Synthesis of Compound 75f-1  

Methyl hydrazine (0.383 mL, 7.2 mmol) was added at -30 ° C in a solution of compound 75c-1 (3.07 g, 6.6 mmol) in dichloromethane. After stirring for 30 minutes under ice cooling, the resulting insoluble material was removed by filtration, and compound 75e-1 (1.79 g, 6.6 mmol) was added to the filtrate. After stirring at room temperature for 2 hours, it was concentrated under reduced pressure, and diluted hydrochloric acid was added to the residue, and ethyl acetate was used for extraction. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. After the residue was dissolved in diisopropyl ether, triethylamine (1.1 mL, 7.9 mmol) was added. The resulting solid was collected by filtration and dried under reduced pressure to give compound 75f-1 (1.79 g, yield 39%) as white solid.

¹ H-NMR (DMSO-D ₆ ) δ: 0.04 (6H, s), 0.04 (6H, s), 0.86 (18H, s), 1.13 (9H, t, J = 6.5 Hz), 1.47 (9H, s ), 2.96 (6H, s), 3.70 (4H, d, J = 4.4 Hz), 3.96 (1H, t, J = 5.0 Hz), 7.10 (1H, s).

 Step 5, 6 Synthesis of Compound 75c  

Trifluoroacetic anhydride (17.7 mL, 125 mmol) was added to compound 75a (13.8 g, 104 mmol). After stirring for 3 hours under ice cooling, it was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was again concentrated under reduced pressure to give Compound 75b. The obtained compound 75b was used in the subsequent reaction without purification.

p-Methoxybenzyl alcohol (23.2 g, 168 mmol) and DMAP (1.37 g, 11.2 mmol) were added to a solution of the total amount of the obtained compound 75b in tetrahydrofuran (64 mL). After the reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate and ethyl acetate were added to the residue, and the aqueous layer was taken. After adding 2 mol/L hydrochloric acid to the water layer which was taken out to pH=2, extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give a mixture of compound 75c and 75c-ii (21 g, yield 74%).

¹ H-NMR (DMSO-D ₆ ) δ: 1.09-1.12 (6H, m), 2.31-2.46 (2H, m), 2.53-2.63 (2H, m), 2.67-2.80 (2H, m), 3.75 ( 6H, s), 5.01 (4H, s), 6.92 (4H, d, J = 8.6 Hz), 7.29 (4H, d, J = 8.3 Hz).

 Step 7 Synthesis of Compound 75d  

Triphenylphosphine acetonitrile (26.3 g, 87 mmol) and 4-dimethylaminopyridine (1.02 g) were added sequentially to a solution of a mixture of compound 75c and 75c-ii (21 g, 83 mmol) in dichloromethane (300 mL). 8.3 mmol), EDC hydrochloride (17.5 g, 92 mmol). After stirring at room temperature for 1 hour and a half, it was concentrated under reduced pressure, and water was added to the residue, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 75d and 75d- ii (25.88 g, yield 58%).

¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 6.8 Hz), 1.25 (3H, d, J = 7.1 Hz), 2.30 (1H, dd, J = 16.5, 4.7 Hz), 2.77- 2.85(2H,m), 3.02(1H,dd,J=13.9,7.1Hz), 3.22(1H,dd,J=16.0,7.7Hz),3.63-3.68(1H,m),3.78(6H,s) , 4.98-5.06 (4H, m), 6.84 (4H, d, J = 8.1 Hz), 7.27 (4H, d, J = 14.9 Hz), 7.49-7.61 (30H, m).

 Step 8 Synthesis of Compound 75e  

A solution of a mixture of compound 75d and 75d-ii (25.9 g, 48 mmol) in methylene chloride (520 mL) was stirred at -78 ° C while stirring for one hour. After replacing the inside of the system with nitrogen, dimethyl sulfide (10.7 mL, 145 mmol) was added, and the mixture was stirred at -78 ° C for 5 minutes. Next, 3-methyl-2-buten-1-ol (7.36 mL, 72.5 mmol) was added, and the mixture was stirred at -78 °C for 2 hours. After the reaction mixture was heated to about 0 ° C, a 5% aqueous sodium carbonate solution was added and stirred at room temperature for 5 minutes. After distilling off the dichloromethane under reduced pressure, the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compounds 75e and 75e-ii (6.11 g, yield 36%).

¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, d, J = 7.1 Hz), 1.23 (3H, d, J = 7.1 Hz), 1.74 (6H, s), 1.77 (6H, s), 2.49 ( 1H, dd, J = 16.9, 5.3 Hz), 2.82 - 2.91 (2H, m), 3.02 (1H, dd, J = 13.4, 7.1 Hz), 3.31 (1H, dd, J = 18.6, 7.7 Hz), 3.63 -3.70 (1H, m), 3.81 (6H, s), 4.73-4.76 (4H, m), 5.04 (4H, d, J = 8.8 Hz), 5.39 (2H, s), 6.88 (4H, d, J =8.1Hz), 7.26 (4H, br s).

 Steps 9, 10 Synthesis of Compound 75h  

N,N,N',N'-tetramethylmethanediamine (7.17 mL) was added to a mixture of compound 75e and 75e-ii (6.11 g, 17.5 mmol) in dichloromethane (30 mL). After 52.6 mmol), acetic anhydride (6.30 mL, 66.6 mmol) and acetic acid (5.32 mL, 93 mmol) were added dropwise. After stirring overnight at room temperature, ice water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the ethyl acetate solution of mixture of compound 75f and 75e-ii was obtained by filtration.

In an ethyl acetate solution of a mixture of the obtained compound 75f and 75e-ii, a compound 75 g (2.49 g, 10.5 mmol) and hexamethylphosphonium triamine (9.16 mL, 52.6 mmol) were added. After stirring at room temperature overnight, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate).

¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, d, J = 6.1 Hz), 1.70 (3H, s), 1.76 (3H, s), 2.50-2.54 (2H, m), 2.68 (1H, d , J = 14.7 Hz), 3.12 (1H, dd, J = 14.0, 11.5 Hz), 3.61 (2H, dd, J = 25.0, 15.9 Hz), 3.81 (3H, s), 4.04 (1H, s), 4.69 (1H, dd, J = 11.9, 7.6 Hz), 4.89 (1H, dd, J = 11.9, 7.6 Hz), 5.02 (2H, s), 5.07 (1H, d, J = 4.3 Hz), 5.37 (1H, t, J = 6.8 Hz), 5.46 (1H, dd, J = 9.1, 4.5 Hz), 6.09 (1H, d, J = 9.3 Hz), 6.88 (2H, d, J = 8.3 Hz), 7.24 - 7.39 ( 7H, m).

 Steps 11, 12 Synthesis of Compound 75j  

Trifluoroacetic acid (10.2 mL, 133 mmol) was added dropwise at -20 ° C in EtOAc (EtOAc). After stirring at -20 ° C for 1 hour, the reaction mixture was added to a mixture of ice-cooled aqueous sodium hydrogencarbonate and dichloromethane. Next, dilute hydrochloric acid was added until pH = 2, and extraction was carried out with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, whereby Compound 75i was obtained. The obtained compound 75i was used in the subsequent reaction without purification.

EDC hydrochloride (933 mg, 4.87 mmol) was added under ice cooling under aq. After stirring at room temperature for 1 hour, water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 75j (1.94 g, yield: 96%).

¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7.3 Hz), 1.71 (3H, s), 1.76 (3H, s), 2.53-2.88 (4H, m), 3.64 (2H, dd , J = 25.4, 16.0 Hz), 4.72-4.82 (2H, m), 4.99 (1H, d, J = 4.8 Hz), 5.36 (1H, t, J = 6.7 Hz), 5.63 (1H, dd, J = 8.8, 4.8 Hz), 6.06 (1H, d, J = 8.8 Hz), 7.27-7.39 (5H, m).

 Steps 13, 14 Synthesis of Compound 75l  

After cooling a solution of compound 75f-1 (484 mg, 0.7 mmol) in dimethylacetamide (1.6 mL) to -20 ° C, triethylamine (0.019 mL, 0.14 mmol), methanesulfonium chloride (0.060 mL, 0.77 mmol). The solution A was obtained by stirring at -20 ° C for 30 minutes.

After a suspension of phosphorus pentachloride (292 mg, 1.4 mmol) in dichloromethane (1.6 mL) was cooled to -78 ° C, pyridine (0.124 mL, 1.5 mmol) was added, followed by compound 75j (321 mg, 0.7 mmol) The methyl chloride (1.6 mL) solution was dropped. After stirring at -10 ° C for 1 hour, the reaction mixture was cooled to -78 ° C, and then cooled ethanol (3.2 mL). After stirring at -30 ° C for 2 hours, it was cooled to -50 ° C, and water (0.63 mL) was added. After stirring again at -30 ° C for 30 minutes, an aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and filtered. Ethyl acetate was added to the filtrate, and dichloromethane and methanol were distilled off under reduced pressure, whereby ethyl acetate solution of compound 75k was obtained.

Pyridine (0.068 mL, 0.84 mmol) and the solution A obtained above were added to an ethyl acetate solution of the obtained compound 75k under ice cooling. After stirring for 30 minutes under ice cooling, dilute hydrochloric acid was added and extracted with ethyl acetate. The organic layer was washed successively with water, aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate).

¹ H-NMR (CDCl ₃ ) δ: 0.04 (3H, s), 0.05 (3H, s), 0.05 (3H, s), 0.06 (3H, s), 0.87 (9H, s), 0.88 (9H, s ), 1.24 (3H, d, J = 7.2 Hz), 1.54 (9H, s), 1.72 (3H, s), 1.77 (3H, s), 2.62 (1H, dd, J = 14.4, 12.5 Hz), 2.84 - 2.94 (2H, m), 3.05-3.11 (1H, m), 3.81-3.89 (4H, m), 4.43-4.48 (1H, m), 4.75-4.86 (2H, m), 5.10 (1H, d, J = 4.8 Hz), 5.39 (1H, t, J = 7.5 Hz), 5.70 (1H, dd, J = 8.3, 4.8 Hz), 7.29 (1H, s), 7.62 (1H, d, J = 8.3 Hz) , 8.12 (1H, s).

 Step 15 Synthesis of Compound 75m  

A solution of 69% mCPBA (105 mg, 0.42 mmol) in dichloromethane (1.6 mL) was then evaporated. After stirring at -40 ° C for 20 minutes, a 15% aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with an aqueous sodium hydrogencarbonate solution and brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate).

¹ H-NMR (CDCl ₃ ) δ: 0.04 (3H, s), 0.04 (3H, s), 0.05 (6H, s), 0.87 (9H, s), 0.88 (9H, s), 1.23 (3H, d , J = 7.4 Hz), 1.54 (9H, s), 1.73 (3H, s), 1.77 (3H, s), 3.02-3.10 (1H, m), 3.39 (1H, dd, J = 14.4, 4.7 Hz) , 3.77-3.79 (2H, m), 3.81-3.90 (4H, m), 4.37-4.43 (1H, m), 4.58 (1H, d, J = 5.0 Hz), 4.78-4.91 (2H, m), 5.38 -5.42 (1H, m), 6.06 (1H, dd, J = 10.0, 5.0 Hz), 7.25 (1H, s), 7.65 (1H, d, J = 10.0 Hz), 8.24 (1H, s).

 Step 16 Synthesis of Compound I-075  

After cooling a solution of the compound 75m (274mg, 0.3mmol) in dichloromethane (2.7mL) to -40°C, then an anisole (0.32mL, 3.0mmol), 2mol/L of aluminum chloride/nitromethane was added sequentially. The solution (1.5 mL, 3.0 mmol) was stirred at -30 ° C for 30 min. Diisopropyl ether, ice water, and acetonitrile were added to the reaction liquid and stirred, and the insoluble matter was completely dissolved, and then the aqueous layer was taken out. After the organic layer was again extracted with water, all the aqueous layers were combined and HP20-SS resin was added thereto, and acetonitrile was distilled off under reduced pressure, and 2 mol/L hydrochloric acid (1.0 mL) was added. The resulting mixture was purified by ODS column chromatography (water-acetonitrile). A chromatographic fraction containing the desired compound was collected, and after adding a 0.2 mol/L aqueous sodium hydroxide solution to pH = 6, a small amount of dry ice was added. After the obtained solution was concentrated under reduced pressure, a white powder of 1--075 (yield: 52%).

¹ H-NMR (D ₂ O) δ: 1.19 (3H, d, J = 7.2 Hz), 2.69-2.78 (1H, m), 3.19-3.26 (1H, m), 3.54-3.64 (2H, m), 3.86 (4H, t, J = 5.1 Hz), 4.41-4.47 (1H, m), 4.99 (1H, d, J = 4.6 Hz), 5.89 (1H, d, J = 4.6 Hz), 7.05 (1H, s ).

MS (m + 1) = 532, holding time: 0.39 minutes, (measurement condition A)

Elemental analysis: C18H20N5NaO10S2(H2O)3.7

Calculated: C, 34.86; H, 4.45; N, 11.29; Na, 3.71; S, 10.34 (%)

Found: C, 34.81; H, 4.41; N, 11.46; Na, 3.65; S, 10.18 (%)

 [Example 36]    Synthesis of Compound I-076  

 Step 1 Synthesis of Compound 76b  

Compound 76b (446 mg, yield: 65%) was obtained by the same procedure as in the step 14 of Example 35, using compound 75k (238 mg, 0.7 mmol).

¹ H-NMR (CDCl ₃ ) δ: 0.01 (3H, s), 0.02 (3H, s), 0.83 (9H, s), 1.25 (3H, d, J = 7.0 Hz), 1.53 (9H, s), 1.70 (3H, s), 1.75 (2H, s), 2.53 (1H, dd, J = 14.6, 11.3 Hz), 2.81-2.89 (2H, m), 3.05-3.11 (1H, m), 3.75 (1H, s), 4.10-4.19 (3H, m), 4.67-4.82 (2H, m), 5.06 (1H, d, J = 4.8 Hz), 5.13 (1H, dd, J = 6.0, 3.5 Hz), 5.37 (1H) , t, J = 7.5 Hz), 5.57 (1H, dd, J = 7.3, 4.8 Hz), 6.96 (1H, s), 7.28-7.31 (11H, m), 8.10 (1H, s), 8.19 (1H, d, J = 7.3 Hz).

 Step 2 Synthesis of Compound 76c  

The compound 76c (392 mg, yield: 87%) was obtained by the same procedure from the procedure of the step 15 of Example 35 using Compound 76b (446 mg, 0.46 mmol).

¹ H-NMR (CDCl ₃ ) δ: 0.01 (3H, s), 0.02 (3H, s), 0.82 (9H, s), 1.21. (3H, d, J = 7.3 Hz), 1.54 (9H, s), 1.71 (3H, s), 1.75 (3H, s), 3.05 (1H, t, J = 7.2 Hz), 3.29 (1H, dd, J = 14.4, 4.8 Hz), 3.75-3.78 (3H, m), 4.13 -4.21 (3H, m), 4.47 (1H, d, J = 5.0 Hz), 4.76-4.88 (2H, m), 5.04 (1H, t, J = 5.1 Hz), 5.39 (1H, s), 5.97 ( 1H, dd, J=9.4, 5.0 Hz), 6.97 (1H, s), 7.21 (1H, s), 7.28-7.36 (10H, m), 7.90 (1H, d, J = 9.4 Hz), 8.18 (1H) , s).

 Step 3 Synthesis of Compound I-076  

Compound I-076 (110 mg, yield: 47%) was obtained by the same procedure from the procedure of Step 16 of Example 35 using Compound 76c (392mg, 0.39mmol).

¹ H-NMR (D ₂ O) δ: 1.19 (3H, d, J = 7.2 Hz), 2.70-2.77 (1H, m), 3.18-3.26 (1H, m), 3.55-3.65 (2H, m), 3.94-4.03 (2H, m), 4.74 (1H, dd, J = 6.5, 3.5 Hz), 5.00 (1H, d, J = 4.8 Hz), 5.90 (1H, d, J = 4.8 Hz), 7.06 (1H) , s).

MS (m+1) = 546, holding time: 0.39 minutes, (measurement condition A)

Elemental analysis: C18H17N5Na2O11S2(H2O)6.2

Calculated: C, 30.83; H, 4.23; N, 9.99; Na, 6.56; S, 9.14 (%)

Found: C, 30.95; H, 4.45; N, 9.99; Na, 6.52; S, 9.05 (%)

 [Example 37]    Synthesis of Compound I-077  

 Step 1, 2 Synthesis of Compound 77c  

Compound 6a (364 mg, 1.1 mmol) and EDC hydrochloride (230 mg, 1.2 mmol) were added to a solution of compound 75k (340 mg, 1.0 mmol). After stirring for 1 hour under ice cooling, dilute aqueous hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give Compound 77b as an orange foam. The obtained compound 6b was used in the subsequent reaction without purification.

Using the same amount of the obtained compound 77b, Compound 77c (401 mg, yield 60%) was obtained by the same procedure as in the step 15 of Example 1.

¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, d, J = 7.3 Hz), 1.54 (9H, s), 1.73 (3H, s), 1.77 (3H, s), 3.01-3.08 (1H, m ), 3.48 (1H, dd, J = 14.5, 4.7 Hz), 3.75-3.94 (5H, m), 4.36-4.47 (2H, m), 4.69 (1H, d, J = 4.8 Hz), 4.78-4.91 ( 2H, m), 3.70-3.94 (1H, m), 6.02 (1H, dd, J = 9.6, 4.8 Hz), 7.34 (1H, s), 7.91 (1H, d, J = 9.5 Hz), 8.29 (1H) , s).

 Step 3 Synthesis of Compound I-077  

Compound 1-006 (127 mg, yield: 41%) was obtained by the same procedure from the procedure of step 16 of Example 35 using Compound 77c (401 mg, 0.60 mmol).

¹ H-NMR (D ₂ O) δ: 1.19 (3H, d, J = 7.1 Hz), 2.73 (1H, t, J = 13.0 Hz), 3.19-3.26 (1H, m), 3.54-3.63 (2H, m), 3.90 (2H, t, J = 4.3 Hz), 4.35 (2H, t, J = 4.0 Hz), 4.98 (1H, d, J = 4.8 Hz), 5.88 (1H, d, J = 4.5 Hz) , 7.04 (1H, s).

MS (m + 1) = 502, holding time: 0.48 minutes, (measurement condition A)

 [Example 38]    Synthesis of Compound I-078  

 Steps 1, 2 Synthesis of Compound 78c  

Compound 78b was obtained by the same method as Step 14 of Example 35, using Compound 75k (340 mg, 1.0 mmol) and Compound 78a (631 mg, 1.2 mmol). The obtained compound 78b was used in the subsequent reaction without purification.

Using the same amount of the obtained compound 78b, Compound 78c (578 mg, yield: 67%) was obtained by the same procedure as Step 15 of Example 35.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7.3 Hz), 1.54 (9H, s), 1.63 (3H, d, J = 7.0 Hz), 1.71 (3H, s), 1.75 ( 3H, s), 3.01-3.08 (1H, m), 3.31 (1H, dd, J = 14.4, 4.7 Hz), 3.76-3.78 (2H, m), 4.42 (1H, d, J = 5.0 Hz), 4.76 -4.89 (2H, m), 5.05-5.09 (1H, m), 5.38 (1H, t, J = 7.3 Hz), 6.05 (1H, dd, J = 9.9, 5.0 Hz), 6.94 (1H, s), 7.22 (1H, s), 7.28-7.35 (10H, m), 7.78 (1H, d, J = 9.9 Hz), 8.14 (1H, s).

 Step 3 Synthesis of Compound I-078  

Compound I-078 (188 mg, yield 49%) was obtained by the same procedure as in the step 16 of Example 35 using Compound 78c (578 mg, 0.67 mmol).

¹ H-NMR (D ₂ O) δ: 1.18 (3H, d, J = 7.2 Hz), 1.48 (3H, d, J = 7.0 Hz), 2.68-2.76 (1H, m), 3.18-3.25 (1H, m), 3.54-3.62 (2H, m), 4.68 (1H, q, J = 7.0 Hz), 4.99 (1H, d, J = 4.9 Hz), 5.91 (1H, d, J = 4.9 Hz), 7.04 ( 1H, s).

MS (m + 1) = 530, holding time: 0.53 minutes, (measurement condition A)

 [Example 39]    Synthesis of Compound I-079  

 Step 1, 2 Synthesis of Compound 79c  

Compound 79b was obtained by the same method as Step 14 of Example 35, using Compound 75k (340 mg, 1.0 mmol) and Compound 79a (631 mg, 1.2 mmol). The obtained compound 79b was used in the subsequent reaction without purification.

Using the same amount of the obtained compound 79b, Compound 79c (695 mg, yield: 80%) was obtained by the same procedure as Step 15 of Example 35.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7.2 Hz), 1.54 (9H, s), 1.62 (3H, d, J = 7.3 Hz), 1.72 (3H, s), 1.75 ( 3H, s), 3.01-3.09 (1H, m), 3.30 (1H, dd, J = 14.5, 4.8 Hz), 3.74 - 3.77 (2H, m), 4.54 (1H, d, J = 5.0 Hz), 4.79 -4.90 (2H, m), 5.04 (1H, q, J = 7.0 Hz), 5.39 (1H, t, J = 7.4 Hz), 6.03 (1H, dd, J = 10.0, 5.0 Hz), 6.94 (1H, s), 7.16 (1H, s), 7.27-7.32 (10H, m), 7.89 (1H, d, J = 10.0 Hz), 8.18 (1H, s).

 Step 3 Synthesis of Compound I-079  

Compound I-079 (214 mg, yield 46%) was obtained by the same procedure as in the step 16 of Example 35 using Compound 79c (695 mg, 0.80 mmol).

¹ H-NMR (D ₂ O) δ: 1.18 (3H, d, J = 7.3 Hz), 1.47 (3H, d, J = 7.0 Hz), 2.68-2.76 (1H, m), 3.18-3.25 (1H, m), 3.54-3.62 (2H, m), 4.63 (1H, q, J = 7.0 Hz), 4.98 (1H, d, J = 4.8 Hz), 5.88 (1H, d, J = 4.8 Hz), 7.05 ( 1H, s).

MS (m + 1) = 530, holding time: 0.62 minutes, (measurement condition A)

Elemental analysis: C18H17N5Na1.8O10S2(H2O)3.2

Calculated: C, 34.51; H, 3.76; N, 11.18; Na, 6.61; S, 10.23 (%)

Found: C, 34.50; H, 3.80; N, 11.42; Na, 6.66; S, 10.00 (%)

 [Embodiment 40]    Synthesis of Compound I-080  

 Step 1 Synthesis of Compound 80b  

N-N-dimethylaniline (1.46 mL, 11.51 mmol) was added to a solution of methylamine (33% in ethanol, 1.43 mL, 11.51 mmol) in acetone (44 mL). After dropping the obtained solution at room temperature for 1 hour, it was dried under reduced pressure, and a 10% aqueous citric acid solution was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with 8.4% aqueous sodium hydrogencarbonate solution and brine, and dried over anhydrous magnesium sulfate, and the organic substance was removed by filtration, and concentrated under reduced pressure to give compound 80b (409.5 mg, 23.4%) A crude product in the form of a yellow oil.

MS (M+1) = 151, RT = 0.41 minutes, assay condition A

 Step 2 Synthesis of Compound 80c  

In a solution of hydroxyphthalic acid imine (440 mg, 2.69 mmol) in acetonitrile (3.3 mL), triethylamine (373 μL, 2.69 mmol), compound 80b (409.5 mg, 2.69 mmol) After the resulting solution was stirred at room temperature for 4 hours, the inorganic material was filtered and concentrated under reduced pressure. A 10% aqueous potassium carbonate solution was added, and extracted with ethyl acetate. The obtained organic layer was washed with a 10% aqueous potassium carbonate solution, water, and brine, and dried over anhydrous magnesium sulfate, and the organic substance was removed by filtration and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 80c (160.5mg, 25.4%).

¹ H-NMR (CDCl ₃ ) δ: 2.93 (3H, d, J = 4.9 Hz), 4.72 (2H, s), 7.74-7.77 (1H, m), 7.80-7.83 (2H, m), 7.84-7.90 (2H,m).

 Step 3 Synthesis of Compound 80d  

The compound 80c and the compound 74f were used to give the crude product of the compound 80d (235.9 mg, 96.1%) as a yellow oil.

MS (M+1)=359, RT=1.02 min, assay condition A

 Step 4 Synthesis of Compound 80e  

The compound 80d and the compound 74c were used in the same manner as in the step 5 of Example 34 to obtain Compound 80e (334.9 mg, 79.9%) as a white foam.

¹ H-NMR (CDCl ₃ ) δ: 1.51 (9H, s), 2.47-2.70 (3H, m), 2.73 (3H, d, J = 4.8 Hz), 3.12-3.24 (2H, m), 4.63 (1H) , d, J = 15.9 Hz), 4.95 (1H, d, J = 15.9 Hz), 5.17 (1H, d, J = 4.5 Hz), 5.69 (1H, dd, J = 8.0, 4.6 Hz), 6.64 - 6.65 (1H, br m), 6.91 (1H, s), 7.03 (1H, s), 7.09-7.17 (3H, m), 7.26-7.35 (7H, m), 8.65 (1H, s), 9.23 (1H, s).

 Step 5 Synthesis of Compound 80f  

The compound 80e was used in the same manner as in the step 6 of Example 34 to obtain a white foamy crude product of compound 80f (332.2 mg, 97.2%).

MS (M+1) = 781, RT = 2.19 minutes, assay condition A

 Step 6 Synthesis of Compound I-080  

This was carried out in the same manner as in the step 7 of Example 34, using Compound 80f to afford Compound I-080 (155.8mg, 71.2%) as a white solid.

¹ H-NMR (D ₂ O) δ: 2.56 (1H, d, J = 18.3 Hz), 2.80 (3H, s), 2.83 (1H, d, J = 13.9 Hz), 3.06 (1H, dd, J = 18.3, 7.7 Hz), 3.51-3.57 (1H, m), 3.62 (1H, dd, J = 14.6, 5.3 Hz), 4.72-4.74 (2H, m), 5.00 (1H, d, J = 4.6 Hz), 5.87 (1H, d, J = 4.6 Hz), 7.12 (1H, s).

MS (M+1) = 515.06, RT = 0.41 minutes, assay condition A

 [Example 41]    Synthesis of Compound I-081  

 Step 1 Synthesis of Compound 81c  

Compound 81a (852 mg, 3.64 mmol) obtained by a known method ( FR 2 475 555 A1) was dissolved in dichloromethane (8 mL), and methyl hydrazine (0.202 mL, 3.82 mmol) was added under ice cooling and stirred at 0 ° C 40 minute. The white solid was washed with dichloromethane and filtered, and the filtrate was concentrated under reduced pressure to about 4 mL to obtain a dichloromethane solution of hydroxylamine. 5b (990 mg, 3.64 mmol), methanol (4 mL), and dichloromethane (4 mL) were added to the separately prepared flask, and after ice-cooling, the hydroxylamine dichloromethane solution was dropped. After stirring at 0 ° C for 2.5 hours, the reaction solution was concentrated under reduced pressure. The obtained white solid was washed with dichloromethane and filtered to give Compound 81c (915mg, 70%).

¹ H-NMR (DMSO-d ₆ ) δ: 1.47 (9H, s), 2.72 (6H, s), 3.12 (2H, m), 4.29 (2H, m), 7.34 (1H, s), 11.68 (1H) , brs).

[M+H]=359.10 (1.13 minutes) (measurement condition B)

 Step 2 Synthesis of Compound 81e  

A suspension of compound 81c (326 mg, 0.910 mmol) Water and an aqueous solution of sodium hydrogencarbonate were added, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After filtering the magnesium sulfate, the residue was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate, ethyl acetate-methanol) to afford compound 81e (382mg, 55%).

[M+H]=765.20 (2.53 minutes) (measurement condition B)

 Step 3 Synthesis of Compound 81f  

Compound 81e (617 mg, 0.806 mmol) was dissolved in dichloromethane (6 mL), cooled to -78 ° C, then trifluoroacetic acid (0.068 mL, 0.887 mmol) was added, followed by m-chloroperoxybenzoic acid (310 mg, 1.23 mmol) of dichloromethane (5 mL) was added dropwise. After stirring at -78 ° C for 1.5 hours, an aqueous sodium thiosulfate solution was added and the mixture was extracted with ethyl acetate. After washing twice with an aqueous sodium hydrogencarbonate solution, it was dried over anhydrous magnesium sulfate. After the magnesium sulfate was filtered, and the residue was evaporated, mjjjjjjjjjj

[M+H]=781.20 (2.41 minutes) (measurement condition B)

 Step 4 Synthesis of Compound I-081  

Compound 81f (134 mg, 0.171 mmol) was used to give Compound I-081 (52.5 mg, 60%).

¹ H-NMR (D ₂ O) δ: 2.57 (1H, d, J = 18.3 Hz), 2.85 (1H, dd, J = 14.8, 12.4 Hz), 2.97 (6H, s), 3.08 (1H, dd, J = 18.3, 7.9 Hz), 3.56 (1H, ddd, J = 12.4, 7.9, 5.3 Hz), 3.59 (2H, m), 3.66 (1H, dd, J = 14.8, 5.3 Hz), 4.59 (2H, m ), 5.02 (1H, d, J = 4.8 Hz), 5.88 (1H, d, J = 4.8 Hz), 7.10 (1H, s).

[M+H]=515.00 (0.39 minutes) (measurement condition B)

C18H22N6O8S2(H ₂ O) 4.4 Calculated C: 36.41%, H: 5.23%, N: 14.15%, S: 10.80%. Found C: 36.36%, H: 5.06%, N: 14.51%, S: 10.46%.

 [Example 42]    Synthesis of Compound I-082  

 Step 1 Synthesis of Compound 82b  

Compound 82a (650 mg, 2.10 mmol) obtained by a known method (WO 2013051597 A1) was dissolved in water (6.5 ml), potassium cyanate (340 mg, 4.20 mmol) was added, and the mixture was stirred at 60 ° C for 2 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure. The obtained residue was dissolved in methanol, and then concentrated under reduced pressure to obtain a crude product of compound 82b.

 Step 2 Synthesis of Compound 82d  

The compound 82b (454 mg, 2.10 mmol) and 82c (967 mg, 2.10 mmol) were used to give the compound (yield: 565 mg, 43%).

[M+H]=623.10 (1.84 minutes) (measurement condition B)

 Step 3 Synthesis of Compound 82e  

The compound 82d (293 mg, 0.470 mmol) was used to give the crude product of Compound 82e.

[M+H]=623.10 (1.84 minutes) (measurement condition B)

 Step 4 Synthesis of Compound I-082  

Compound 82e (300 mg, 0.470 mmol) was used in the same manner as step 7 of Example 34 to give a mixture of compound I-082 (124 mg, 56%) as a non-image mixture (about 1:1).

¹ H-NMR (D ₂ O) δ: 2.54 (0.5H, d, J = 18.3 Hz), 2.55 (0.5H, d, J = 18.3 Hz), 2.75-2.86 (1H, m), 3.01-3.10 ( 1H, m), 3.45-3.56 (1H, m), 3.60 (0.5H, dd, J = 14.6, 5.3 Hz), 3.64 (0.5H, dd, J = 14.6, 5.3 Hz), 4.91 (0.5H, d , J = 4.8 Hz), 4.93 (0.5H, d, J = 4.8 Hz), 5.38 (0.5H, s), 5.39 (0.5H, s), 5.77 (0.5H, d, J = 4.8 Hz), 5.78 (0.5H, d, J = 4.8 Hz), 6.78 (0.5H, s), 6.83 (0.5H, s).

[M+H]=473.00 (0.24 minutes) (measurement condition B)

C15H16N6O8S2(H ₂ O) 2.9 calculated C: 34.34%, H: 4.19%, N: 16.02%, S: 12.22%. Found C: 34.08%, H: 4.18%, N: 16.27%, S: 11.93%.

 [Example 43]    Synthesis of Compound I-083  

 Steps 1, 2 Synthesis of Compound 83c  

Using the compound 75k (340 mg, 1.0 mmol) and the compound 83a (379 mg, 1.1 mmol), Compound 83b was obtained by the same procedure as Step 1 of Example 37. The obtained compound 83b was used in the subsequent reaction without purification. Using the same amount of the obtained compound 83b, Compound 83c (420 mg, yield: 62%) was obtained by the same procedure as in the step 15 of Example 35.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7.3 Hz), 1.54 (9H, s), 1.72 (3H, s), 1.76 (3H, s), 2.98-3.05 (1H, m ), 3.42-3.46 (1H, m), 3.66-3.72 (1H, m), 3.76-3.79 (1H, m), 4.66 (2H, br s), 4.70 (1H, d, J = 4.6 Hz), 4.78 -4.88 (2H, m), 5.38 (1H, t, J = 7.3 Hz), 5.97 (1H, s), 7.28 (1H, s), 8.38 (1H, s).

 Step 3 Synthesis of Compound I-083  

The compound I-083 (159 mg, yield 48%) was obtained by the same procedure from the procedure of Step 16 of Example 35 using Compound 83c (420 mg, 0.62 mmol).

¹ H-NMR (D ₂ O) δ: 1.19 (3H, d, J = 7.2 Hz), 2.69-2.77 (1H, m), 3.19-3.26 (1H, m), 3.54-3.62 (2H, m), 4.75 (2H, d, J = 6.1 Hz), 4.98 (1H, d, J = 4.8 Hz), 5.87 (1H, d, J = 4.8 Hz), 7.13 (1H, s).

MS (m + 1) = 515, holding time: 0.43 minutes, (measurement condition A)

Elemental analysis: C17H17N6NaO9S2(H2O)3.5

Calculated: C, 34.06; H, 4.04; N, 14.02; Na, 3.83; S, 10.70 (%)

Found: C, 34.16; H, 4.11; N, 14.01; Na, 3.78; S, 10.54 (%)

 [Example 44]    Synthesis of Compound I-084  

 Step 1, 2 Synthesis of Compound 84c  

Compound 84b was obtained by the same procedure as in Step 14 of Example 35, using Compound 75k (340 mg, 1.0 mmol) and Compound 84a (631 mg, 1.2 mmol). The obtained compound 84b was used in the subsequent reaction without purification.

Using the same amount of the obtained compound 84b, Compound 84c (672 mg, yield: 77%) was obtained by the same procedure as Step 15 of Example 35.

¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, d, J = 7.2 Hz), 1.54 (9H, s), 1.72 (3H, s), 1.76 (3H, s), 3.02-3.09 (1H, m ), 3.36 (1H, dd, J = 14.4, 4.7 Hz), 3.75-3.78 (2H, m), 4.56 (1H, d, J = 5.0 Hz), 4.79 - 4.90 (2H, m), 5.39 (1H, t, J = 7.3 Hz), 6.03 (1H, dd, J = 9.9, 5.0 Hz), 6.92 (1H, s), 7.23 - 7.33 (11H, m), 7.75 (1H, d, J = 9.9 Hz), 8.19 (1H, s).

 Step 3 Synthesis of Compound I-084  

Compound I-084 (242 mg, yield 54%) was obtained by the same procedure as step 16 of Example 35 using Compound 84c (672 mg, 0.77 mmol).

¹ H-NMR (D ₂ O) δ: 1.18 (3H, d, J = 7.2 Hz), 1.26-1.43 (4H, m), 2.68-2.76 (1H, m), 3.18-3.25 (1H, m), 3.54-3.62 (2H, m), 4.97 (1H, d, J = 4.8 Hz), 5.86 (1H, d, J = 4.8 Hz), 7.08 (1H, s).

MS (m+1) = 542, holding time: 0.65 minutes, (measurement condition A)

Elemental analysis: C19H17N5Na1.8O10S2(H2O)4.9

Calculated: C, 34.10; H, 4.04; N, 10.47; Na, 6.18; S, 9.58 (%)

Found: C, 34.05; H, 4.11; N, 10.67; Na, 6.16; S, 9.41 (%)

 [Example 45]    Synthesis of Compound I-085  

 Step 1 Synthesis of Compound 85b  

DMF (30 mL) was added to compound 85a (15.1 g, 40 mmol) After stirring at 70 ° C for 4 hours, the reaction solution was cooled to room temperature. Thereto, calcium carbonate (7.19 g, 52.0 mmol) was added. Benzyl bromide (6.18 mL, 52 mmol) was added in small portions, and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. After washing with water, dilute hydrochloric acid and saturated brine, the mixture was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), whereby 85b (12.2 g, yield 50%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 0.92 (9H, s), 2.26 (1H, ddd, J = 14.2, 14.0, 7.8 Hz), 2.75 (1H, ddd, J = 14.2, 14.0, 7.4 Hz), 4.53 (1H, dd, J = 7.8, 7.5 Hz), 4.90 (1H, d, J = 12.8 Hz), 5.05 (1H, d, J = 12.8 Hz), 7.11 - 7.51 (20H, m).

 Step 2 Synthesis of Compound 85c  

A solution of the compound 85b (12.2 g, 19.9 mmol) obtained from step 1 in dichloromethane (183 mL) was cooled to -78. After completion of the reaction, the mixture was ventilated with oxygen and nitrogen, and then dimethyl sulfide (4.40 mL, 59.5 mmol) was added and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the obtained residue was purified to silica gel column chromatography (hexane/ethyl acetate) to afford compound 85c (6.4 g, yield 88%).

¹ H-NMR (CDCl ₃ ) δ: 1.53 (9H, s), 3.14 (1H, dd, J = 19.2, 4.3 Hz), 3.73 (1H, dd, J = 19.2, 10.1 Hz), 4.16 (1H, dd , J = 10.1, 4.3 Hz), 5.07 (1H, d, J = 12.6 Hz), 5.16 (1H, d, J = 12.6 Hz), 7.32-7.20 (10H, m).

 Step 3 Synthesis of Compound 85d  

In a solution of the compound 85c (6.4 g, 17.4 mmol) from m. m. m. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m After cooling to 0 ° C, acetic anhydride (11.5 mL, 122 mmol) was slowly added. Acetic acid (4.97 mL, 87 mmol) was added thereto, and stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and dichloromethane was distilled off under reduced pressure, and then water was added. The aqueous layer was extracted with ethyl acetate and washed with water. After filtration, the solvent was distilled off under reduced pressure to obtain a crude product of compound 85d.

¹ H-NMR (CDCl ₃ ) δ: 1.56 (9H, s), 4.92 (1H, s), 5.12 (1H, d, J = 12.4 Hz), 5.19 (1H, d, J = 12.4 Hz), 5.97 ( 1H, s), 6.35 (1H, s), 7.35-7.22 (10H, m).

 Step 4 Synthesis of Compound 85f  

Compound 85e (4.09 g, 17.3 mmol) synthesized by the method described in the document EP253337, and HMPA (60.2 mL, 346 mmol) were added to a solution of the crude product of the compound 85d obtained in Step 3 in ethyl acetate (66 mL). Stir at room temperature overnight. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, aqueous sodium hydrogencarbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, the residue obtained by distillation under reduced pressure was applied to a silica gel column chromatography (hexane/ethyl acetate) to obtain a crude product (3.9 g) of a mixture of four compounds of compound 85f.

MS (m + 1) = 617, measurement condition A, 2.39 minutes

MS (m + 1) = 617, measurement condition A, 2.42 minutes

MS (m + 1) = 617, measurement condition A, 2.52 minutes

MS (m+1) = 617, measurement condition A, 2.62 minutes

 Step 5 Synthesis of Compound 85g  

5% palladium on carbon (1.3 g, 0.62 mmol) was added to a solution of the crude product of Compound 85f (3.9 g, 6.2 mmol. . After the insoluble material was filtered, 5% palladium carbon (8.1 g, 3.8 mmol) was added to the filtrate, and the mixture was stirred overnight under a hydrogen atmosphere of 4 atm. After the insoluble matter was filtered, the solvent was distilled off under reduced pressure. After adding water to the residue and extracting with ethyl acetate, the organic layer was washed with diluted hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. After filtration, dichloromethane (10 mL) obtained by distilling off the solvent was cooled to 0 °C. Thereto, EDC hydrochloride (1.45 g, 7.58 mmol) was added and stirred at 0 ° C overnight. After adding water to the reaction mixture and extracting with ethyl acetate, the organic layer was washed with dilute hydrochloric acid, aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain a crude product (700 mg) of a mixture of a mixture of a mixture of a compound of 85 g.

MS (m + 1) = 509, 2.28 minutes, measurement condition A

MS (m + 1) = 509, 2.41 minutes, measurement condition A

 Step 6 Synthesis of Compound 85i  

Phosphorus pentachloride (573 g, 2.75 mmol) was suspended in dichloromethane (7.0 mL) and cooled to 0 °C. Pyridine (0.333 mL, 4.13 mmol) and a crude product (700 mg, corresponding to 1.38 mmol) containing 85 g of compound were added to the suspension, and the mixture was stirred at 0 ° C for 30 minutes. The solution was cooled to -78 ° C, ethanol (7 mL) was added and warmed to -30 ° C and stirred for 2 hr. Purified water (2.0 mL) was added to this solution and stirred for 30 minutes. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was concentrated to about 10 mL, and this was taken as solution A.

A solution of compound EtOAc (EtOAc EtOAc (EtOAc) (EtOAc) This is taken as solution B.

Solution A was cooled to 0 ° C, pyridine (0.333 mL, 4.13 mmol) and solution B were added and stirred for 1 hour. Water was added to the reaction liquid, and extraction was performed with ethyl acetate. The organic layer was washed with diluted hydrochloric acid, sodium hydrogencarbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain a crude product (650 mg) of a mixture of a plurality of compounds of compound 85i.

MS (m + 1) = 774, 2.82 minutes, assay condition A

 Step 7 Synthesis of Compound 85j  

A crude product (540 mg) containing a plurality of isomers of the compound 85i was obtained by the same procedure as in the step 6 of Example 34, using the crude product of the compound 85i obtained in the step 6 (650 mg, corresponding to 0.84 mmol). .

MS (m + 1) = 790, 2.54 minutes, assay condition A

MS (m+1) = 790, 2.65 minutes, assay condition A

 Step 8 Synthesis of Compound I-085  

Using the crude product of the compound 85j obtained in the step 7 (540 mg, which corresponds to 0.68 mmol), the compound of the compound I-085 (126 mg, yield 32%) was obtained in the same manner as in the step 7 of Example 34. A mixture of structures (a ratio of about 0.6:0.7:1:1.2).

MS (m+1) = 578, 0.71 min, assay condition A

MS (m+1) = 578, 0.76 min, assay condition A

MS (m+1) = 578, 0.80 min, assay condition A

¹ H-NMR (ratio of 4 isomers = about 0.6:0.7:1:1.2, D ₂ O) δ: 3.01-3.09 (1.4H, m), 3.22-3.48 (2.8H, m), 3.54- 3.66 (2.8H, m), 3.70-3.80 (2.8H, m), 3.97-3.87 (0.7H, m), 4.19 (0.6H, s), 4.46 (1.2H, d, J = 11.4Hz), 4.81 -4.84 (7H, m), 4.90 (0.7H, d, J = 10.7 Hz), 5.07 (0.6H, d, J = 4.8 Hz), 5.24 (1.2H, d, J = 4.3 Hz), 5.32 (0.7) H, d, J = 4.8 Hz), 5.44 (1.0H, d, J = 12.2 Hz), 5.46 (1.0H, d, J = 4.6 Hz), 5.57 (1.2H, d, J = 4.3 Hz), 5.62 (0.7H, d, J = 4.8 Hz), 5.89 (0.6H, d, J = 4.8 Hz), 6.06 (1.0H, d, J = 4.6 Hz), 7.16-7.24 (3.5H, m), 7.26- 7.53 (17.5H, m).

 [Example 46]    Synthesis of Compound I-093  

 Step 1 Synthesis of Compound 93c  

Add a solution of the compound 93a (0.57 g, 5.00 mmol) in MeOH (27 mL) EtOAc. 3 hours. Ethyl acetate was added to the residue obtained by distilling off the reaction mixture under reduced pressure, and extracted with dilute hydrochloric acid. The aqueous layer was washed with ethyl acetate and then evaporated under reduced pressure. A solution of 1.1 g of the obtained residue in acetonitrile (22 mL) was cooled to -20. To the reaction solution were added phenyl dichlorophosphate (0.891 mL, 6.00 mmol) and N-methylfeverin (1.65 mL, 15.0 mmol), and the mixture was stirred at room temperature for 1 hour. Dilute hydrochloric acid was added to this solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off to synthesize a crude product of the compound 93c. The crude product (2 g) of the compound 93c was used in the subsequent reaction without purification.

MS (m+1) = 774, 2.78 minutes, assay condition A

 Step 2 Synthesis of Compound I-093  

Using the crude product of Compound 93c obtained in Step 1 (2 g, 2.6 mmol), Compound I-093 (250 mg) was obtained by the same procedure as Steps 6 and 7 of Example 34.

¹ H-NMR (D 2 O) δ: 2.59 (1H, d, J = 18.4 Hz), 2.84 (1H, t, J = 13.6 Hz), 3.10 (1H, dd, J = 18.4, 7.8 Hz), 3.49-3.58 (1H, m), 3.66 (1H, dd, J = 14.8, 5.0 Hz), 5.03 (1H, d, J = 4.6 Hz), 5.90 (1H, d, J = 4.6 Hz), 7.46 (1H, s) .

MS (m+1) = 524, 0.26 minutes, measurement condition A

 [Example 47]    Synthesis of Compound I-137  

 Step 1 Synthesis of Compound 137b  

The compound 137a (265 mg, 0.346 mmol) was dissolved in dichloromethane (3 mL), and then cooled to -78 ° C, then dichloromethane (5 mL) of m-chloroperoxybenzoic acid (190 mg, 0.762 mmol) was dissolved. After stirring at -78 ° C for 1 hour, an aqueous sodium thiosulfate solution was added and the mixture was extracted with ethyl acetate. After washing twice with an aqueous sodium hydrogencarbonate solution, it was dried over anhydrous magnesium sulfate. After filtering magnesium sulfate, it was concentrated under reduced pressure to give Compound 137b (227 mg, 82%).

[M+H]=797.20 (2.45 minutes), measurement condition B

 Step 2 Synthesis of Compound I-137  

The compound 137b (227 mg, 0.284 mmol) was used to give the compound (m.

¹ H-NMR (D ₂ O) δ: 2.56 (1H, d, J = 18.2 Hz), 2.83 (1H, dd, J = 14.8, 12.4 Hz), 3.06 (1H, dd, J = 18.2, 7.8 Hz) , 3.38 (3H, s), 3.39 (3H, s), 3.54 (1H, ddd, J = 12.4, 7.8, 5.3 Hz), 3.64 (1H, dd, J = 14.8, 5.3 Hz), 3.90 (2H, m ), 4.73 (2H, m), 5.00 (1H, d, J = 4.8 Hz), 5.86 (1H, d, J = 4.8 Hz), 7.08 (1H, s).

[M+H]=531.05 (1.01 min), measurement condition B

C18H22N6O9S2(H ₂ O) 3.4 Calculated C: 36.53%, H: 4.91%, N: 14.20%, S: 10.84%. Found C: 36.53%, H: 4.89%, N: 14.49%, S: 10.54%.

 [Example 48]    Synthesis of Compound I-138  

 Step 1 Synthesis of Compound 138b  

Compound 138a (134 mg, 0.171 mmol) was dissolved in EtOAc (3 mL). After stirring at room temperature for 3 hours, it was concentrated under reduced pressure to obtain a crude product of compound 138b.

[M+]=795.25 (2.37 minutes), measurement condition B

 Step 2 Synthesis of Compound 7  

Compound 138b (174 mg, 0.189 mmol) was used to give the title compound (m.

¹ H-NMR (D ₂ O) δ: 2.57 (1H, d, J = 18.3 Hz), 2.84 (1H, dd, J = 14.8, 12.5 Hz), 3.07 (1H, dd, J = 18.3, 7.8 Hz) , 3.21 (9H, s), 3.55 (1H, ddd, J = 12.5, 7.8, 5.1 Hz), 3.65 (1H, dd, J = 14.8, 5.1 Hz), 3.81 (2H, m), 4.72 (2H, m) ), 5.01 (1H, d, J = 4.8 Hz), 5.87 (1H, d, J = 4.8 Hz), 7.10 (1H, s).

[M+H]=529.00 (0.35 minutes), measurement condition B

 [Example 49]    Synthesis of Compound I-139  

 Step 1 Synthesis of Compound 139c  

The compound 139a (467 mg, 1.25 mmol) and the compound 139b (576 mg, 1.25 mmol) synthesized by the method described in EP92830A2 were synthesized in the same manner as the synthesis of the compound 5e (step 2) to obtain the compound 139c (436 mg, 45%).

[M+H]=780.15 (2.77 minutes), measurement condition B

 Step 2 Synthesis of Compound 139d  

The compound 139c (436 mg, 0.560 mmol) was used to give the crude product of Compound 139d (456 mg).

[M+H]=796.15 (2.69 minutes), measurement condition B

 Step 3 Synthesis of Compound I-139  

A solution of compound 139d (446 mg, 0.560 mmol) in dichloromethane (9 mL) was cooled to -30 &lt;0&gt;C, &lt;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot; , 4.48 mmol), warmed from -30 ° C to 0 ° C and stirred for 2.5 hours. The reaction mixture was dissolved in ice water, 2 mol/L hydrochloric acid, acetonitrile, and then washed with diisopropyl ether. HP20-SS resin was added to the aqueous layer, and acetonitrile was distilled off under reduced pressure. The resulting mixture was purified by ODS column chromatography (water-acetonitrile). The chromatographic fractions containing the desired compound were mixed, and the mixture was concentrated under reduced pressure, and then lyophilized to afford Compound I-139 (160 mg, 67%).

¹ H-NMR (D ₂ O) δ: 2.53 (0.5H, d, J = 18.2 Hz), 2.55 (0.5H, d, J = 18.2 Hz), 2.69-2.89 (1H, m), 2.98-3.12 ( 1H, m), 3.40-3.70 (2H, m), 4.89 (0.5H, d, J = 4.8 Hz), 4.94 (0.5H, d, J = 4.8 Hz), 5.18 (1H, s), 5.19 (1H) , s), 5.70 (0.5H, d, J = 4.8 Hz), 5.84 (0.5H, d, J = 4.8 Hz), 6.90 (0.5H, s), 6.98 (0.5H, s).

[M+H]=430.00 (0.27 min), measurement condition B

C14H15N5O7S2(H ₂ O) 3.5 Calculated C: 34.14%, H: 4.50%, N: 14.22%, S: 13.02%. Found C: 34.14%, H: 4.39%, N: 14.33%, S: 12.84%.

 [Example 50]    Synthesis of Compound I-132  

 Step 1 Synthesis of Compound 132b  

To a solution of the compound 132a (3.55 g, 21.01 mmol, mp. Methyl decyl ester (20.26 mL, 88 mmol). After the resulting solution was stirred with ice-cooled for 3.5 hr, water (1. 7 mL) and acetic acid (6.16 mL, Water was added to the resulting solution, and extraction was carried out with dichloromethane. The organic layer was washed with a 8.4% aqueous sodium hydrogencarbonate solution, a 2N aqueous hydrochloric acid solution and brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate), and the fractions containing the product were collected and concentrated under reduced pressure. Compound 132b (10.88 g) as a yellow oil.

MS (M+1) = 283, RT = 2.39 min, assay condition A

 Step 2 Synthesis of Compound 132c  

In the same manner as in the step 2 of the synthesis of the intermediate 34A, the compound 132b was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the compound 132c (4.59 g) as a white foam.

MS (M+1)=282, RT=2.11 min, assay condition A

 Step 3 Synthesis of Compound 132d  

To a solution of hydroxyphthalic acid imine (2.87 g, 17.58 mmol) in N,N-dimethylformamide (41 mL), potassium carbonate (2.43 g, 17.58 mmol), Compound 132c (4.136 g, 14.65 mmol), the resulting solution was stirred at 60 ° C for 3 hours, then water was added and extracted with ethyl acetate. The obtained organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the inorganic substance was removed by filtration, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 132d (1.288 g, 18.7% (y.

¹ H-NMR (CDCl ₃ ) δ: 0.07 (6H, s), 0.88 (9H, s), 4.20 (1H, dd, J = 11.8, 3.8 Hz), 4.31 (1H, dd, J = 11.8, 2.3 Hz ), 4.73 (1H, dd, J = 3.7, 2.3 Hz), 5.62 (1H, br s), 7.70 (1H, br s), 7.78-7.81 (2H, m), 7.84-7.87 (2H, m).

 Step 4 Synthesis of Compound 46A  

In the same manner as in the step 4 of Example 34, Compound 132d was used to obtain a crude product of Compound 36A (1.19 g, 68.9%) as a white solid.

MS (M+1) = 489, RT = 1.83 min, assay condition A

 Step 5 Synthesis of Compound 132g  

In the same manner as in the step 5 of Example 34, Compound 46A was used to obtain 132 g (1.2036 g, 66.2%) of a white foamy compound.

¹ H-NMR (CDCl ₃ ) δ: 0.05 (3H, s), 0.05 (3H, s), 0.86 (9H, s), 1.54 (9H, s), 2.50-2.66 (3H, m), 3.06 (1H) , dd, J = 14.6, 4.2 Hz), 3.14 - 3.18 (1H, m), 4.02 (2H, d, J = 5.1 Hz), 4.84 (1H, t, J = 5.0 Hz), 5.08 (1H, d, J = 4.8 Hz), 5.63 (1H, dd, J = 8.3, 4.7 Hz), 6.10 (1H, br s), 6.56 (1H, br s), 6.95 (1H, s), 7.29-7.35 (10H, m ), 8.50-8.52 (1H, br m), 8.86 (1H, br s).

 Step 6 Synthesis of Compound 132h  

The compound 132g was used in the same manner as in the step 6 of Example 34 to obtain a crude product as a white foamy compound 132h (1.211 g, 99.7%).

MS (M+1) = 911, RT = 2.71 minutes, assay condition A

 Step 7 Synthesis of Compound I-132  

The compound 13h was used in the same manner as in the step 7 of Example 34 to give Compound I-132 (581.3mg, 81.8%) as a white solid.

¹ H-NMR (D ₂ O) δ: 2.56 (1H, d, J = 18.2 Hz), 2.83 (1H, dd, J = 14.7, 12.7 Hz), 3.06 (1H, dd, J = 18.3, 7.8 Hz) , 3.51-3.57 (1H, m), 3.65 (1H, dd, J = 14.8, 5.3 Hz), 4.01-4.09 (2H, m), 4.91 (1H, dd, J = 5.0, 3.5 Hz), 5.03 (1H) ,d,J=4.8Hz),

5.91 (1H, d, J = 4.8 Hz), 7.24 (1H, s).

MS (M+1) = 531.05, RT = 0.30 minutes, assay condition A

Elemental analysis: C17H18N6O10S2(H2O)2.5

Calculated value C: 35.48%, H: 4.03%, N: 14.60%, S: 11.14%.

Found C: 35.42%, H: 4.17%, N: 14.84%, S: 10.89%.

 [Example 51]    Synthesis of Compound I-146 and I-147  

 Step 1 Synthesis of Compound 146b  

Compound 146a (10.91 g, 53.9 mmol), (triphenylphosphine) acetonitrile (19.51 g, 64.7 mmol) DMAP (0.66 g, 5.39 mmol) was dissolved in dichloromethane (100 ml), under ice cooling under nitrogen EDC hydrochloride (12.41 g, 64.7 mmol) was added. After stirring at room temperature for 1 hour, water was added and the mixture was extracted with dichloromethane. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtering magnesium sulfate, it was concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the precipitated solid was filtered, whereby compound 146b (22.81 g, 87%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 7.63-7.46 (15H, m), 3.17 (1H, dd, J = 15.6, 8.7 Hz), 2.76-2.71 (2H, m), 1.65-1.60 (2H, m) , 1.40 (9H, s), 0.93 (3H, t, J = 7.5Hz).

 Step 2 Synthesis of Compound 146c  

Compound 146b (12.00 g, 24.71 mmol) was dissolved in dichloromethane (240 ml), cooled to -78 ° C, and the ozone gas was bubbled while stirring until the starting material disappeared. After replacing the inside of the system with nitrogen, dimethyl sulfide (5.48 ml, 74.1 mmol) was added, and the mixture was stirred at -78 ° C for 5 minutes. Then, allyl alcohol (2.52 ml, 37.1 mmol) was added, and the mixture was stirred at -78 °C for 3 hours. After the reaction mixture was heated to about -20 ° C, a 5% aqueous sodium carbonate solution was added and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtering magnesium sulfate, it was concentrated under reduced pressure. It was applied to a ruthenium column chromatography and dissolved in hexane/ethyl acetate. The chromatographic fractions containing the desired compound were concentrated under reduced pressure to give compound 146c (4.62 g, 69%).

¹ H-NMR (CDCl ₃ ) δ: 5.98-5.94 (1H, m), 5.41 (1H, dd, J = 17.2, 1.2 Hz), 5.32 (1H, dd, J = 10.4, 1.2 Hz), 4.75 (2H) , d, J = 6.0 Hz), 3.24 (1H, dd, J = 18.3, 9.5 Hz), 2.87-2.75 (2H, m), 1.69-1.58 (2H, m), 1.44 (9H, s), 0.94 ( 3H, t, J = 7.5Hz).

 Step 3 Synthesis of Compound 146d  

Compound 146c (4.62 g, 17.09 mmol) was dissolved in dichloromethane (20 ml), and N,N,N',N'-tetramethylmethanediamine (9.31 ml, 68.4 mmol) was added under nitrogen. After that, acetic anhydride (8.08 ml, 85 mmol) and acetic acid (6.84 ml, 120 mmol) were added dropwise. After stirring at room temperature for 10 hours, hexane was added, and dichloromethane was distilled off under reduced pressure. Water was added to the residue, and extraction was performed with hexane. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and brine, and dried over anhydrous magnesium sulfate. After filtering magnesium sulfate, it was concentrated under reduced pressure to give Compound 146d (4.7 g, 99%).

¹ H-NMR (CDCl ₃ ) δ: 6.33 (1H, s), 6.28 (1H, s), 6.03-5.93 (1H, m), 5.42 (1H, dd, J = 17.1, 1.2 Hz), 5.33 (1H) , dd, J = 10.4, 1.2 Hz), 4.80 (2H, t, J = 2.9 Hz), 3.44 (1H, t, J = 7.4 Hz), 1.93-1.86 (1H, m), 1.68-1.58 (1H, m), 1.42 (9H, s), 0.93 (3H, t, J = 7.4 Hz).

 Step 4 Synthesis of Compounds 146f-1 and 146f-2  

Compound 146d (4.78 g, 16.93 mmol) was dissolved in DMF (50 ml). Compound 146e (5.20 g, 22.01 mmol) and triethylamine (0.469ml, 3.39mmol). After stirring for 2 hours under ice cooling, dilute hydrochloric acid was added and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtering magnesium sulfate, it was concentrated under reduced pressure. It was applied to a ruthenium column chromatography and dissolved in hexane/ethyl acetate. The chromatographic fraction containing the desired compound was concentrated under reduced pressure to give a mixture of compound 146f-1 and 146f-2. (2.04g, 23%)

LC/MS (measurement condition A): RT: 2.47 min, [M+H] = 519

 Step 5 Synthesis of Compounds 146g-1 and 146g-2  

Compounds 146f-1 and 146f-2 (2.03 g, 3.91 mmol) were dissolved in dichloromethane (2 ml), cooled to -20 ° C, and trifluoroacetic acid (20 ml, 260 mmol). After stirring for 4 hours under ice cooling, concentration was carried out under reduced pressure. Water was added to the residue and the mixture was extracted with dichloromethane. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtering magnesium sulfate, it was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (20 ml), and then evaporated to ethyl acetate (0.899 g, 4.69 mmol). After stirring at room temperature for 30 minutes, dilute hydrochloric acid was added and the mixture was extracted with dichloromethane. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtering magnesium sulfate, it was concentrated under reduced pressure. It was applied to a ruthenium column chromatography and dissolved in hexane/ethyl acetate. The chromatographic fraction containing the desired compound was concentrated under reduced pressure to give a mixture of compound 146 g-1 and 146 g. (1.39g, 80%)

LC/MS (measurement condition A): RT: 2.08 min, [M+H] = 445

 Step 6 Synthesis of Compounds 146h-1 and 146h-2  

Using a compound 146g-1 and 146g-2 (0.70g, 1.58mmol), the compound was obtained in the same manner as in Step 5 of Example 45 to obtain a mixture of Compound 146h-1 and 146h-2. (0.96g, 86%)

LC/MS (measurement condition A): RT: 2.57 minutes, [M+H]=710

 Step 7 Synthesis of Compounds 146i-1 and 146i-2  

The compound 146h-1 and 146h-2 (0.96g, 1.35mmol) were synthesized by the same method as the step 6 of Example 34, and purified by silica gel column chromatography to obtain Compound 146i-1 (0.46 g, respectively). 47%) and compound 146i-2 (0.41 g, 42%).

Compound 146i-1

¹ H-NMR (CDCl ₃ ) δ: 8.41 (1H, d, J = 9.3 Hz), 8.14 (1H, br s), 7.34 (1H, s), 6.03-5.93 (2H, m), 5.41 (1H, Dd, J = 17.1, 1.1 Hz), 5.32 (1H, dd, J = 10.4, 1.1 Hz), 4.87 (1H, dd, J = 12.9, 6.1 Hz), 4.81 (1H, dd, J = 12.9, 6.1 Hz) ), 4.75 (1H, d, J = 16.6 Hz), 4.69 (1H, d, J = 16.6 Hz), 4.62 (1H, d, J = 4.8 Hz), 3.78-3.72 (1H, m), 3.37 (1H) ,dd,J=14.4,4.6Hz), 2.78(1H,dt,J=11.8,4.6Hz),2.32-2.25(1H,m),1.96-1.86(1H,m),1.54(9H,s), 1.48-1.40 (10H, m), 1.07 (3H, t, J = 7.5Hz).

Compound 146i-2

¹ H-NMR (CDCl ₃ ) δ: 8.40 (1H, d, J = 9.0 Hz), 8.14 (1H, br s), 7.35 (1H, s), 6.01-5.92 (2H, m), 5.42 (1H, Dd, J = 17.2, 1.1 Hz), 5.31 (1H, dd, J = 10.3, 1.1 Hz), 4.92-4.63 (5H, m), 3.56 (1H, dd, J = 12.6, 5.5 Hz), 3.44 (1H) , dd, J = 14.5, 5.5 Hz), 2.47-2.34 (2H, m), 1.78-1.71 (1H, m), 1.54 (9H, s), 1.48-1.42 (10H, m), 1.05 (3H, t , J = 7.3 Hz).

 Step 8 Synthesis of Compound 146j  

Compound 146i-1 (0.46 g, 0.634 mmol) was dissolved in tetrahydrofuran (5 ml), and aniline (69 μl, 0.761 mmol) and Pd(PPh ₃ ) ₄ (37 mg, 0.032 mmol) were sequentially added under nitrogen under ice cooling. . After stirring for 1 hour under ice cooling, dilute hydrochloric acid was added and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtering magnesium sulfate, it was concentrated under reduced pressure to give compound 146j (0.43 g, 99%). Compound 146j was used in the subsequent reaction without purification.

LC/MS (measurement condition A): RT: 1.72 min, [M+H] = 686

 Step 9 Synthesis of Compound I-146  

Compound 1-146 was obtained by the same procedure as Step 7 of Example 34 using Compound 146j (0.43 g, 0.627 mmol).

Compound I-146: 238.2 mg (yield 66%)

¹ H-NMR (D ₂ O) δ: 7.23 (1H, s), 5.88 (1H, d, J = 4.8 Hz), 4.98 (1H, d, J = 4.8 Hz), 3.62-3.56 (2H, m) , 3.01-2.96 (1H, m), 2.73 (1H, dd, J = 15.5, 14.1 Hz), 1.86-1.79 (1H, m), 1.49-1.41 (1H, m), 0.99 (3H, t, J = 7.5Hz).

LC/MS (measurement condition B): RT: 0.74 min, [M+H]=530

C18H19N5O10S2(H2O)2.4

Calculated value C: 37.75%, H: 4.19%, N: 12.23%, S: 11.20%

Found C: 37.58%, H: 4.12%, N: 12.46%, S: 11.15%

 Step 10 Synthesis of Compound 147a  

Using a compound 146i-2 (0.41 g, 0.565 mmol), Compound 147a (0.39 g). Compound 147a was used in the subsequent reaction without purification.

LC/MS (measurement condition A): RT: 1.68 min, [M+H] = 686

 Step 11 Synthesis of Compound I-147  

Using the compound 147a (0.39 g, 0.565 mmol), Compound 1-147 was obtained by the same procedure as Step 7 of Example 34.

Compound 1-147: 188.8 mg (yield 54%)

¹ H-NMR (D ₂ O) δ: 7.12 (1H, s), 5.87 (1H, d, J = 4.8 Hz), 4.99 (1H, d, J = 4.8 Hz), 4.65 (2H, s), 3.65 (1H, dd, J = 15.0, 5.6 Hz), 3.43 (1H, dd, J = 12.5, 5.6 Hz), 2.80 (1H, dd, J = 15.0, 12.5 Hz), 2.57 (1H, dd, J = 9.3) , 7.3 Hz), 1.76-1.69 (1H, m), 1.62-1.54 (1H, m), 1.01 (3H, t, J = 7.3 Hz).

LC/MS (measurement condition B): RT: 0.60 min, [M+H]=530

C18H19N5O10S2(H2O)3.7

Calculated value C: 36.27%, H: 4.46%, N: 11.75%, S: 10.76%

Found C: 36.26%, H: 4.24%, N: 11.90%, S: 10.58%

 [Example 52]    Synthesis of Compound I-148  

 Step 1 Synthesis of Compound 148c  

Compound 148a (3.49 g, 18.2 mmol) was dissolved in DMF (7 ml), and Compound 148b (6.83 g, 18.16 mmol) was added, and the mixture was stirred at 60 ° C overnight, and ethyl acetate and water were sequentially added to the reaction mixture. The ethyl acetate layer was taken out. The obtained ethyl acetate solution was washed successively with water and saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to chromatography on a silica gel column, eluted with hexane/ethyl acetate, and a chromatographic fraction containing the desired compound was collected, and the solvent was distilled off under reduced pressure, whereby compound 148c was obtained. The yield is 6.56g (64%).

¹ H-NMR (CDCl ₃ ) δ: 0.94 (9H, s), 1.86-1.90 (1H, m), 1.97-1.99 (1H, m), 2.86-2.95 (1H, m), 3.93-4.01 (2H, m), 4.94 (2H, s), 5.46-5.49 (1H, m), 7.19-7.70 (20H, m).

 Step 2 Synthesis of Compound 148d  

Compound 148c (325 mg, 0.57 mmol) was dissolved in DMF (2 ml), and then butyl dimethyl dimethyl chloro decane (86 mg, 0.57 mmol), imidazole (39 mg, 0.57 mmol) Stir for 1 hour. Ethyl acetate and water were added to the reaction mixture in this order, and the ethyl acetate layer was taken. The obtained ethyl acetate solution was washed successively with water and a saturated aqueous sodium chloride solution and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain compound 148d. Yield 381 mg (98%).

¹ H-NMR (CDCl ₃ ) δ: 0.10 (6H, s), 0.79 (9H, s), 1.43-1.45 (2H, m), 1.61 (9H, s), 2.84-2.85 (1H, m), 3.67 -3.68 (2H, m), 4.93-4.95 (2H, m), 7.30-7.70 (20H, m).

 Step 3 Synthesis of Compound 148e  

Compound 148d (29.63 g, 39 mmol) was dissolved in dichloromethane (444 ml), and then, toluene gas was passed at -78 ° C until the solution was colored blue. Next, dimethyl sulfide (8.66 ml, 117 mmol) was added to the reaction liquid, and the mixture was gradually stirred while warming to room temperature. The reaction solution was subjected to distillation under reduced pressure, and the obtained residue was subjected to chromatography on a silica gel column, eluted with hexane/ethyl acetate, and the fractions containing the desired compound were collected and evaporated under reduced pressure. The solvent was distilled off, whereby Compound 148e was obtained. The yield was 10.83 g (64%).

¹ H-NMR (CDCl ₃ ) δ: -0.09 (6H, t, J = 4.0 Hz), 0.75 (9H, d, J = 2.8 Hz), 1.44 (9H, s), 2.92 (1H, dd, J = 18.8, 5.3 Hz), 3.05 (1H, ddd, J = 11.7, 6.7, 3.8 Hz), 3.25 (1H, dd, J = 18.8, 8.0 Hz), 3.71 (1H, dd, J = 9.9, 4.6 Hz), 3.79 (1H, dd, J = 9.9, 5.8 Hz), 5.03 (2H, s), 7.22-7.25 (5H, m).

 Step 4 Synthesis of Compound 148f  

Compound 148e (8.25 g, 18.9 mmol) was dissolved in dichloromethane (3 mL), EtOAc (EtOAc, m. The dichloromethane (15 ml) solution was dripped for 1 hour. Further, a solution of acetic acid (7.56 ml, 132 mmol) in dichloromethane (10 ml) was added dropwise to the reaction mixture for 20 minutes, and then stirred at room temperature overnight. Hexane was added to the reaction mixture, and the mixture was concentrated under reduced pressure to remove dichloromethane. Water was added to the obtained solution, and the hexane layer was taken out. The hexane layer was washed successively with water, sodium bicarbonate and saturated brine, and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain compound 148f. The yield was 7.9 g (93%).

¹ H-NMR (CDCl ₃ ) δ: -0.09 (6H, s), 0.74 (10H, s), 1.46 (9H, s), 3.75-3.85 (3H, m), 5.02, 5.05 (2H, ABq, J =12.4 Hz), 6.21 (1H, s), 6.36 (1H, s), 7.20-7.27 (5H, m).

 Step 5 Synthesis of Compound 148h  

Compound 148f (7.88 g, 17.56 mmol) was dissolved in DMF (79 ml), 148 g (5.40 g, 22.8 mmol) of compound, and then triethylamine (0.487 ml, 3.51 mmol) was added, and the mixture was stirred for 2 hours. Ethyl acetate and dilute hydrochloric acid were added to the reaction mixture, and the ethyl acetate layer was taken out. The obtained solution was washed successively with water and saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography on a silica gel column, eluted with hexane/ethyl acetate, and a chromatographic fraction containing the desired compound was collected, and the solvent was distilled off under reduced pressure to obtain a compound of compound 148h. A mixture of isomers was 7.35 g (61%).

LC/MS (measurement condition A): RT: 3.19 minutes, [M+H]=685

 Step 6 Synthesis of Compound 148i  

The mixture of the 148h (2.74g, 4mmol) of the compound obtained in the step 5 was dissolved in methanol (27ml), 10%-palladium carbon (2.13g, 2mmol) was added, and then stirred overnight under a hydrogen atmosphere of 5 atm. . The insoluble matter was filtered through celite, and toluene was added to the obtained solution, and then the solvent was distilled off under reduced pressure. The obtained residue was dissolved in dichloromethane (19 ml), and the mixture was evaporated. The reaction solution was distilled off under reduced pressure, and ethyl acetate and water were added, and ethyl acetate layer was taken out. The obtained ethyl acetate layer was washed successively with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to chromatography on a silica gel column, eluted with hexane/ethyl acetate, and the fractions containing the desired compound were collected, and the solvent was distilled off under reduced pressure, whereby compound 148i was obtained. The yield was 136 g (7%).

¹ H-NMR (CDCl ₃ ) δ: 1.51 (9H, s), 1.56 (9H, s), 2.13 (1H, dd, J = 6.8, 5.1 Hz), 2.75 (1H, dd, J = 14.5, 12.1 Hz) ), 2.92-2.98 (2H, m), 3.10-3.16 (1H, m), 3.63, 3.67 (2H, ABq, J = 16.4 Hz), 3.85-4.02 (2H, m), 4.99 (1H, d, J = 4.9 Hz), 5.60 (1H, dd, J = 9.0, 4.8 Hz), 6.04 (1H, d, J = 9.2 Hz), 7.30-7.36 (9H, m).

 Step 7 Synthesis of Compound 148j  

Compound 148i (134 mg, 0.29 mmol) was dissolved in DMF (1.3 mL). After the reaction mixture was stirred at room temperature for 30 minutes, ethyl acetate and water were added, and ethyl acetate layer was taken. The obtained ethyl acetate layer was washed successively with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to column chromatography on silica gel, eluted with hexane/ethyl acetate, and the fractions containing the desired compound were collected, and the solvent was distilled off under reduced pressure, whereby compound 148j was obtained. The yield was 153 mg (92%).

¹ H-NMR (CDCl ₃ ) δ: 0.09 (6H, s), 0.88 (9H, s), 1.51 (9H, s), 1.56 (9H, s), 2.72 (1H, dd, J = 14.0, 12.0 Hz ), 2.95-3.06 (3H, m), 3.63, 3.67 (2H, ABq, J = 16.2 Hz), 3.81 (1H, t, J = 10.2 Hz), 4.00 (1H, dd, J = 11.1, 4.8 Hz) , 4.98 (1H, d, J = 4.5 Hz), 5.58 (1H, dd, J = 8.8, 4.8 Hz), 6.05 (1H, d, J = 8.3 Hz), 7.32-7.40 (5H, m).

 Step 8 Synthesis of Compound 1481  

Phosphorus pentachloride (72 mg, 0.35 mmol) was suspended in dichloromethane (1 ml), pyridine (31 mg, 0.38 mmol). Compound 148j (100 mg, 0.17 mmol) was added to the reaction mixture, and the mixture was stirred for 30 min. The solution was stirred for 30 minutes under ice cooling, diluted with dichloromethane and water, and then dichloromethane was taken. The obtained dichloromethane layer was washed with water and a saturated aqueous sodium chloride solution and dried over magnesium sulfate to obtain a dichloromethane solution of the amine form.

On the other hand, Compound 148k (104 mg, 0.26 mmol) was dissolved in dimethylacetamide (1 ml), and triethylamine (46 μl, 0.33 mmol) and methanesulfonium chloride (23 μl, 0.30) were sequentially added at -20 °C. Methyl), stirred at -15 ° C for 20 minutes. This solution was added to the above-mentioned amine form of dichloromethane solution under ice cooling, and stirred at the same temperature for 15 minutes. The reaction solution was concentrated under reduced pressure and diluted aqueous hydrochloric acid, and ethyl acetate was evaporated. The obtained solution was washed successively with water, baking soda water, and saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to chromatography on a silica gel column, eluted with hexane/ethyl acetate, and the fractions containing the desired compound were collected, and the solvent was distilled off under reduced pressure, whereby compound 1481 was obtained. Yield 117mg (80%)

¹ H-NMR (CDCl ₃ ) δ: 0.08 (6H, s), 0.88 (9H, s), 1.51-1.61 (27H, m), 2.77 (1H, dd, J = 15.4, 12.6 Hz), 2.99-3.06 (3H, m), 3.82 (1H, t, J = 10.5 Hz), 4.03 (1H, dd, J = 11.0, 4.9 Hz), 4.68-4.77 (3H, m), 5.10 (1H, d, J = 4.8 Hz), 5.72 (1H, dd, J = 8.5, 4.9 Hz), 7.37 (1H, s), 8.10 (1H, br s), 8.65 (1H, d, J = 8.3 Hz).

 Step 9 Synthesis of Compound 148m  

Compound 1481 (114 mg, 0.14 mmol) was dissolved in dichloromethane (1.sub.1 mL), and m. m. After the reaction mixture was stirred at -78 ° C for 20 minutes, ethyl acetate and aqueous sodium thiosulfate were added and concentrated under reduced pressure. The obtained ethyl acetate layer was washed successively with sodium bicarbonate and saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to chromatography on a silica gel column, eluted with hexane/ethyl acetate, and the fractions containing the desired compound were collected, and the solvent was distilled off under reduced pressure, whereby compound 148m was obtained. Yield 97mg (84%)

¹ H-NMR (CDCl ₃ ) δ: 0.09 (6H, s), 0.87-0.90 (9H, m), 1.38-1.60 (27H, m), 2.46 (1H, dd, J = 14.2, 13.1 Hz), 3.09 (1H, td, J = 7.7, 4.3 Hz), 3.56 (1H, dd, J = 14.6, 4.8 Hz), 3.72-3.79 (1H, m), 3.86 (1H, dd, J = 11.5, 8.2 Hz), 3.96-4.02 (1H, m), 4.56 (1H, d, J = 4.9 Hz), 4.72, 4.73 (2H, ABq, J = 11.0 Hz), 5.94 (1H, dd, J = 9.3, 5.0 Hz), 7.35 (1H, s), 8.33 (1H, d, J = 9.4 Hz).

 Step 10 Synthesis of Compound I-148  

Compound 148m (95mg, 0.11mmol) was dissolved in dichloromethane (1.9ml), and then added to the -30 ° C anisole (121μl, 1.11mmol), followed by 2M / L of aluminum chloride-nitromethane solution (554μl) , 1.11 mmol), stirred at -20 ° C for 30 minutes. Isopropyl ether, ice water and acetonitrile were added to the reaction liquid, and the aqueous layer was taken out. 3 ml of HP20SS resin was added to the obtained aqueous solution, and the mixture was concentrated under reduced pressure, and then subjected to column chromatography in which HP20SS and ODS were sequentially linked. The mixture was eluted with water/acetonitrile, and a chromatographic fraction containing the desired compound was collected. The solvent was concentrated under reduced pressure and then lyophilized to obtain Compound 1-148. Yield 26mg (38%)

¹ H-NMR (D ₂ O) δ: 2.90 (1H, t, J = 13.1 Hz), 3.34 (1H, d, J = 4.8 Hz), 3.67 (2H, dt, J = 18.2, 7.2 Hz), 3.84 (1H, dd, J = 12.0, 7.8 Hz), 3.97 (1H, dd, J = 12.0, 5.0 Hz), 5.00 (1H, d, J = 4.8 Hz), 5.88 (1H, d, J = 4.8 Hz) , 7.23 (1H, s).

LC/MS (measurement condition A): RT: 0.36 min, [M+H] = 532

Elemental analysis: C17H17N5O11S2(H2O)3.4

Calculated value C: 34.35%, H: 4.05%, N: 11.82%, S: 10.82%.

Found C: 34.23%, H: 3.89%, N: 11.93%, S: 11.16%.

 [Example 53]    Synthesis of Compound I-154  

 Step 1 Synthesis of Compound 154c  

Compound 154a (500 mg, 1.82 mmol) and 154b (700 mg, 1.52 mmol) synthesized by a known method (Jpn. Kokai Tokkyo Koho (1987), JP 62195385 A 19870828.), and step 2 of Example 41 were used. The same procedure was carried out to obtain Compound 154c (395 mg, 38%).

[M+H]=681.20,681.10 (2.38, 2.41 minutes), (measurement condition B)

 Step 2 Synthesis of Compound 154d  

The compound 154c (195 mg, 0.287 mmol) was used to give compound 154d (130 mg, 65%).

[M+H]=697.15,697.15 (2.28, 2.33 minutes), (measurement condition B)

 Step 3 Synthesis of Compound I-154  

Synthesis of Compound 154d (130 mg, 0.186 mmol

¹ H-NMR (D ₂ O) δ: 2.55 (0.6H, d, J = 18.3 Hz), 2.55 (0.4H, d, J = 18.3 Hz), 2.78-2.88 (1H, m), 3.06 (0.6H) , dd, J = 18.3, 7.8 Hz), 3.07 (0.4H, dd, J = 18.3, 7.8 Hz), 3.48-3.58 (1H, m), 3.60-3.70 (1H, m), 4.95 (0.6H, d , J = 4.9 Hz), 4.96 (0.4H, d, J = 4.9 Hz), 5.24 (0.4H, s), 5.25 (0.6H, s), 5.78 (0.4H, d, J = 4.9 Hz), 5.80 (0.6H, d, J = 4.9 Hz), 6.80 (0.4H, s), 6.83 (0.6H, s).

[M+H]=430.90 (0.25 minutes), (measurement condition B)

 [Example 54]  

The synthesis of the compounds 1A to 61A of the intermediate is shown below.

 (Synthesis of Compound 1A)  

 Step 1 Synthesis of Compound 86b  

86b was synthesized in the same manner as in the step 3 of Example 34 using Compound 86a (2.2 g, 15.0 mmol). The obtained crude product was subjected to silica gel column chromatography (hexane-ethyl acetate) to give a crude product (1.38 g) containing Compound 86b.

MS (m + 1) = 292, 1.09 minutes, measurement condition A

 Step 2 Synthesis of Compound 1A  

The crude product containing Compound 1A (MS (m+1) = 416, 1.08 min, was determined by the same method as the step 4 of Example 34, using the crude product (1.38 g). Condition A). The crude product (1.89 g) containing Compound 1A was used for the subsequent reaction without purification.

 (Synthesis of Compound 2A)  

 Step 1 Synthesis of Compound 87b  

87b was synthesized in the same manner as in the step 3 of Example 34, using the compound 87a (3.15 g, 14 mmol) which was synthesized by the method of US20140086846. The obtained crude product was subjected to silica gel column chromatography (hexane-ethyl acetate) to give a crude product (2.1 g) containing Compound 87b.

MS (m+1) = 370, 1.96 minutes, assay condition A

 Step 2 Synthesis of Compound 1B  

The crude product of Compound 1B was synthesized in the same manner as in Step 4 of Example 34, using a crude product (2.1 g, 5.70 mmol) containing Compound 87b obtained in Step 1. The crude product of Compound 1B (2.8 g) was used in the subsequent reaction without purification.

MS (m + 1) = 494, 1.82 minutes, assay condition A

 (Synthesis of Compound 3A)  

 Step 1 Synthesis of Compound 3A  

The compound 88a (1.71 g, 5.88 mmol) synthesized by the method described in Journal of Medicinal Chemistry, 33(1), 187-96; 1990 was used to synthesize the crude compound 3A in the same manner as in the step 4 of Example 34. Product. The crude product of Compound 3A (840 mg) was used in the subsequent reaction without purification.

MS (m+1) = 416, 1.44 minutes, assay condition A

 (Synthesis of Compound 4A)  

 Step 1 Synthesis of Compound 89b  

Using the compound 89a (5.2 g, 15.5 mmol) synthesized by the method described in Tetrahedron, 61 (7), 1827-1833; 2005, the crude compound 89b was obtained in the same manner as in the step 3 of Example 34. Product. The crude product of Compound 89b (8.7 g) was used in the subsequent reaction without purification.

MS (m+1) = 480, 3.68 minutes, measurement condition A

 Step 2 Synthesis of Compound 4A  

The crude product of Compound 4A was synthesized in the same manner as in Step 4 of Example 34, using Compound 89b (7.2 g, corresponding to 15 mmol) obtained in Step 1. The crude product of 4A (8.7 g) was used in the subsequent reaction without purification.

MS (m+1) = 604, 3.49 minutes, assay condition A

 (Synthesis of Compound 5A)  

 Step 1 Synthesis of Compound 90b  

Compound 90b (6.9 g, yield 91%) was synthesized using the compound 90a synthesized by the method described in Tetrahedron, 61 (7), 1827-1833;

¹ H-NMR (CDCl ₃ ) δ: 0.07 (12H, s), 0.90 (18H, s), 1.61-1.74 (2H, m), 3.02 (1H, d, J = 3.0 Hz), 3.51 (1H, dd , J = 10.0, 6.5 Hz), 3.59 (1H, dd, J = 10.0, 4.9 Hz), 3.87 - 3.76 (3H, m).

 Step 2 Synthesis of Compound 90c  

The crude product of the compound 90c was synthesized in the same manner as in the step 3 of Example 34, using the compound 90b (7.2 g, corresponding to 15 mmol) obtained in the step 1. The crude product of Compound 90c (8.7 g) was used in the subsequent reaction without purification.

MS (m+1) = 480, 3.68 minutes, measurement condition A

 Step 3 Synthesis of Compound 5A  

The crude product of Compound 5A was synthesized in the same manner as in Step 4 of Example 34, using Compound 90c (10.1 g, corresponding to 21 mmol) obtained in Step 2. The crude product of Compound 5A (11.2 g) was used in the subsequent reaction without purification.

MS (m+1) = 604, 3.49 minutes, assay condition A

 (Synthesis of Compound 6A)  

 Step 1 Synthesis of Compound 91b  

N-hydroxyphthalimide (1.91 g, 11.7 mmol), triphenylphosphine, was added to a solution of the compound 91a (3.13 g, 9.8 mmol) in tetrahydrofuran (31 mL), which was obtained by the method of WO2014136086. After (3.07 g, 11.7 mmol), a 1.9 mol/L DIAD/toluene solution was dropped under ice cooling. After stirring at room temperature for 1 hour, it was concentrated under reduced pressure, and methanol was added to the residue. The resulting solid was collected by filtration and dried under reduced pressure to give Compound 91b (3.0 g, yield: 67%) as white solid.

¹ H-NMR (CDCl ₃ ) δ: 0.00 (6H, s), 0.02 (6H, s), 0.82 (18H, s), 3.94 (4H, ddd, J = 14.5, 9.5, 3.2 Hz), 4.33-4.38 (1H, m), 7.72 (2H, dd, J = 5.5, 3.1 Hz), 7.82 (2H, dd, J = 5.5, 3.1 Hz).

 Step 2 Synthesis of Compound 6A  

Compound 91b (7.2 g, equivalent to 15 mmol) obtained in Step 2 and Compound 91c synthesized by the method described in Bioorganic & Medicinal ChemiStry, 15 (21), 6716-6732; 2007, were used in the same manner as in Example 34. 4 The crude product of Compound 6A was synthesized in the same manner. The crude product of Compound 6A (1.2 g) was used in the subsequent reaction without purification.

MS (m+1) = 591, 3.27 minutes, assay condition A

 (Synthesis of Compound 7A)  

 Step 1 Synthesis of Compound 92b  

Ethyl acetate (664 mL), water (664 mL), potassium carbonate (110 g, 793 mmol), and tetrabutylammonium bromide (21.3 g, 66.1 mmol) were added to N-hydroxyphthalimide (129 g, 793 mmol). And ethyl acetate (443 mL) of the compound 92a (221 g, 661 mmol) synthesized by the method described in Bioorg. Med. Chem. 2007, 5, 6716-6732., and stirred at room temperature overnight. After adding ice water to the reaction mixture, extraction was carried out with ethyl acetate. The organic layer was washed with a 10% aqueous potassium carbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford compound 92b (53.6 g, yield 19%).

¹ H-NMR (CDCl ₃ ) δ: 3.60-3.64 (1H, m), 3.97-4.03 (1H, m), 4.84-4.86 (1H, m), 7.02 (1H, s), 7.26-7.39 (10H, m), 7.80-7.76 (2H, m), 7.87-7.83 (2H, m).

 Step 2 Synthesis of Compound 7A  

The crude product of Compound 7A was synthesized in the same manner as in Step 4 of Example 34, using Compound 92b (1.05 g, 2.52 mmol) obtained in Step 1 and Compound 91c. The crude product of Compound 7A (950 mg) was used in the subsequent reaction without purification.

MS (m-1) = 543, 2.25 minutes, measurement condition B

 (Synthesis of Compound 8A)  

 Step 1 Synthesis of Compound 94a  

Hydroxyphthalic acid imine (4.89 g, 30.0 mmol) was dissolved in dimethylformamide (50.0 mL) and cooled to 0. Triethylamine (4.57 mL, 33.0 mmol) and 2-bromoacetonitrile (2.20 mL, 33.0 mmol) were added to this mixture and stirred at room temperature. After completion of the reaction, the reaction liquid was poured into purified water (150 mL), and the precipitated solid was collected by filtration, and the individual was washed with purified water, then washed with hexane, and air-dried to obtain compound 94a (5.32 g, yield). Rate 88%).

¹ H-NMR (CDCl ₃ ) δ: 7.93-7.88 (m, 2H), 7.85-7.80 (m, 2H), 4.96 (s, 2H).

 Step 2 Synthesis of Compound 8A  

Compound 94a (2.02 g, 10.0 mmol) was dissolved in dichloromethane (25.0 mL), and then cooled to -30 deg., and methyl hydrazine (0.583 mL, 11.0 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The precipitated solid was removed by filtration, and the mixture was evaporated, evaporated, mjjjjjjjjjjjjjjjj The solvent was distilled off, and ethyl acetate, purified water and 2 mol/L hydrochloric acid water were added to the obtained residue, and the object was extracted from the aqueous layer using ethyl acetate. The obtained organic layer was washed with purified water, washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was evaporated. The obtained solid was collected by filtration and washed with ethyl acetate to give Compound 8A (1.88 g, yield: 58%).

¹ H-NMR (DMSO-D ₆ ) δ: 11.87 (br s, 1H), 7.55 (s, 1H), 5.11 (s, 2H), 1.48 (s, 9H).

 (Synthesis of Compound 9A)  

 Step 1 Synthesis of Compound 9A  

The crude product of the compound 9A was synthesized in the same manner as in the step 4 of Example 34, using the compound 95a (3.35 g, 10 mmol) synthesized by the method of WO2012059041. The crude product (4.1 g) of the obtained compound 9A was used in the subsequent reaction without purification.

MS (M+1) = 460, 2.68 minutes, assay condition A

 (Synthesis of Compound 10A)  

 Step 1 Synthesis of Compound 10A  

The crude product of the compound 10A was synthesized in the same manner as in the step 4 of Example 34 using the compound 96a (3.35 g, 10 mmol) synthesized by the method described in WO2012059041. The crude product of the obtained compound 10A was used in the subsequent reaction without purification.

MS (M+1)=460, RT=2.68 min, assay condition A

 (Synthesis of Compound 11A)  

 Step 1 Synthesis of Compound 11A  

The crude product of the compound 11A was synthesized in the same manner as in the step 4 of Example 34, using the compound 97a (518 mg, 2.2 mmol) synthesized by the method of WO2014204263. The crude product (1.1 g) of the obtained compound 11A was used in the subsequent reaction without purification.

MS (M+1)=360, RT=1.34 minutes, measurement condition A

 (Synthesis of Compound 12A)  

 Step 1 Synthesis of Compound 98b  

A solution of the compound 98a (1.9 g, 17.9 mmol) in tetrahydrofuran (9.5 mL), which was obtained by the method of WO2012075456, was cooled to 0 °C. A solution of imidazole (1.34 g, 19.7 mmol) and tert-butyldimethylchloromethane (2.97 g, 19.7 mmol) in tetrahydrofuran (9.5 mL) was added. After the reaction solution was stirred at room temperature for 1 hour, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. Triphenylphosphine (4.7 g, 17.9 mmol) and N-hydroxyphthalimide (2.92 g, 17.9 mmol) were added to a solution of the obtained residue in tetrahydrofuran (19.8 mL), and cooled to 0 °C. DIAD (3.62 g, 17.9 mmol) was added thereto, and stirred at room temperature for 1 hour. The solvent was distilled off from the reaction liquid under reduced pressure, and toluene was added to the residue. The cured product was removed by filtration, and the filtrate was evaporated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (hexane-ethyl acetate) to afford compound 98b (5.4 g, yield 82%).

¹ H-NMR (CDCl ₃ ) δ: -0.01-0.01 (2H, m), 0.02 (3H, s), 0.03 (3H, s), 0.76 (9H, s), 3.37 (3H, s), 3. 3.74 (1H, m), 3.90-3.99 (2H, m), 7.75-7.72 (2H, m), 7.84-7.82 (2H, m).

MS (m+1) = 366, RT = 2.79 minutes, assay condition A

 Step 2 Synthesis of Compound 12A  

Using the compound 98b (5.4 g, 14.8 mmol) obtained in Step 1, the crude product of Compound 12A was obtained in the same manner as in Step 4 of Example 34. The obtained crude product was subjected to silica gel column chromatography (hexane-ethyl acetate) to obtain a mixture of two geometric isomers of compound 12A (5.5 g). Main isomer: MS (m + 1) = 490, RT = 2.58 min, assay condition A minor isomer: MS (m + 1) = 490, RT = 2.92 minutes, assay condition A

 (Synthesis of Compound 13A)  

 Step 1 Synthesis of Compound 99c  

Triphenylphosphine (2.62 g, 10 mmol) was added to a solution of compound 99a (2.23 g, 10.0 mmol) in tetrahydrofuran described in Bioorganic & Medicinal ChemiStry (2007), 15(21), 6716-6732 and described in Organic Letters 99, 18 (18), 4534-4537; Compound 99b (1.76 g, 10 mmol) synthesized by the method of 2016, cooled to 0 °C. DIAD (1.94 g mL, 10.0 mmol) was added thereto, and stirred at 0 ° C for 1 hour. The reaction mixture was distilled off under reduced pressure, and the obtained residue was poured toluene, and the resulting insoluble matter was filtered. The filtrate was evaporated under reduced pressure, and the obtained residue was purified by column chromatography (hexane-ethyl acetate) to afford crude product of product 99c (2.64 g).

MS (m + 1) = 382, RT = 3.09 minutes, measurement condition A

 Step 2 Synthesis of Compound 99d  

To a solution of the crude product of Compound 99c obtained in Step 1 in 2.64 g of DMA (26 mL), thiourea (3.16 g, 41.5 mmol) was added, and the mixture was stirred at 30 ° C for 3 hours. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. Tetrahydrofuran (50 mL) was added to the residue, and the mixture was cooled to 0° C., and the mixture was stirred, and the mixture was stirred at 0° C. for 30 minutes. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, a sodium hydrogen carbonate aqueous solution and brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of product 99d (2.7 g).

MS (m + 1) = 404, RT = 2.81 minutes, assay condition A

 Step 3 Synthesis of Compound 13A  

A solution of 2.7 g (corresponding to 6.69 mmol) of the crude product of the compound 99d obtained in the step 2 in tetrahydrofuran (27 mL) was added, and tetrakis(triphenylphosphine)palladium(0) (387 mg, 0. (035 mmol) and sulphurin were added. (2.91 mL, 33.5 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with diluted hydrochloric acid and brine and dried over anhydrous magnesium sulfate. Then, the crude product (2.8 g) of Compound 13A was obtained by distillation under reduced pressure.

MS (m + 1) = 364, RT = 2.02 minutes, assay condition A

 (Synthesis of Compound 14A)  

 Step 1 Synthesis of Compound 100b  

Using the compound 100a (2.8 g, 26.4 mmol) synthesized by the method described in Tetrahedron: Asymmetry, 26 (21-22), 1261-1267; 2015, 100b was synthesized in the same manner as in the step 1 of the synthesis of the compound 12A. (7.6 g, yield 79%).

¹ H-NMR (CDCl ₃ ) δ: -0.01-0.01 (2H, m), 0.02 (3H, s), 0.03 (3H, s), 0.76 (9H, s), 3.37 (3H, s), 3. 3.74 (1H, m), 3.90-3.99 (2H, m), 7.75-7.72 (2H, m), 7.84-7.82 (2H, m).

MS (m+1) = 366, RT = 2.79 minutes, assay condition A

 Step 2 Synthesis of Compound 14A  

Using the crude product of Compound 100b obtained in Step 1 (5.4 g, corresponding to 14.8 mmol), Compound 14A was synthesized in the same manner as in Step 4 of Example 34. The obtained crude product was subjected to silica gel column chromatography (hexane-ethyl acetate) to obtain a mixture of two geometric isomers of compound 14A (7.9 g).

Main isomer: MS (m+1) = 490, RT = 2.59 minutes, assay condition A

Secondary isomer: MS (m + 1) = 490, RT = 2.92 minutes, assay condition A

 (Synthesis of Compound 15A)  

 Step 1 Synthesis of Compound 101a  

Using the compound 99a (2.23 g, 10.0 mmol) and the compound 91a (3.53 g, 11.0 mmol), the compound 101a was synthesized in the same manner as in the step 1 of the synthesis of the compound 14A. The obtained compound 101a (5.3 g) was used in the next step without purification.

MS (m+1) = 526, RT = 3.76 minutes, assay condition A

 Step 2 Synthesis of Compound 15A  

The crude product containing the compound 15A was obtained in the same manner as in the steps 2 and 3 of the synthesis of the compound 14A using the compound 101a (5.3 g) obtained in the step 1. The crude product of the compound 15A was used in the subsequent reaction without purification.

MS (m + 1) = 508, RT = 3.30 minutes, determination condition B

 (Synthesis of Compound 16A)  

 Step 1 Synthesis of Compound 102b  

A crude product (2.8 g) of Compound 102b was obtained from Compound 99a (2.23 g, 10 mmol) and Compound 102a (1.54 g, 10.5 mmol).

MS (m-1) = 350, RT = 2.52 minutes, assay condition A

 Step 2 Synthesis of Compound 102c  

The crude product (1.7 g) of the compound 102c was obtained by the same procedure as in the step 2 of the synthesis of the compound 13A.

MS (m + 1) = 374, RT = 2.20 minutes, measurement condition A

 Step 3 Synthesis of Compound 18d  

A crude product (1.9 g) of the compound 16A was obtained by the crude product (yield: 4.5 mmol) of the compound 102c (1.7 g) obtained in the step 2 in the same manner as in the step of the synthesis of the compound 13A.

MS (m + 1) = 334, RT = 1.40 minutes, assay condition B

 (Synthesis of Compound 17A)  

 Step 1 Synthesis of Compound 103b  

The crude product (5 g) of Compound 103b was obtained from Compound 99a (2.23 g, 10 mmol) and Compound 103a (2.69 g, 10.5 mmol) in the same manner as in Step 1 for the synthesis of Compound 13A.

MS (m-1) = 460, RT = 2.47 minutes, assay condition A

 Step 2 Synthesis of Compound 103c  

The crude product (2.8 g) of the compound 103c was obtained by the same procedure as in the step 2 of the synthesis of the compound 13A.

MS (m-1) = 484, 2.56 minutes, assay condition A

 Step 3 Synthesis of Compound 17A  

The crude product (1.3 g) of the compound 17A was obtained by the crude product (yield: 5.8 mmol) of the compound 103c (2.8 g) obtained in the step 2 in the same manner as in the step 3 of the synthesis of the compound 13A.

MS (m+1) = 444, 2.00 minutes, assay condition B

 (Synthesis of Compound 18A)  

 Step 1 Synthesis of Compound 104b  

Using Compound 104a (511 mg, 5.0 mmol), Compound 104b (979 mg, yield: 79%)

¹ H-NMR (CDCl ₃ ) δ: 1.86-1.95 (2H, m), 2.00-2.07 (2H, m), 3.46-3.52 (2H, m), 4.03-4.11 (2H, m), 4.42-4.48 ( 1H, m), 7.74-7.78 (2H, m), 7.83-7.87 (2H, m).

 Step 2, 3 Synthesis of Compound 18A  

Using Compound 104b (979 mg, 4.0 mmol), Compound 18A (1.08 g, yield 61%) was obtained by the same procedure as Steps 3 and 4 of Example 35.

¹ H-NMR (DMSO-D ₆ ) δ: 1.14 (9H, t, J = 7.2 Hz), 1.47 (9H, s), 1.48-1.55 (2H, m), 1.83-1.88 (2H, m), 2.97 (6H, s), 3.36-3.42 (2H, m), 3.78-3.83 (2H, m), 4.12-4.17 (1H, m), 7.08 (1H, s).

 (Synthesis of Compound 19A)  

 Step 1 Synthesis of Compound 105b  

Compound 105b (449 mg, yield 36%) was obtained by the same procedure as in the step 2 of Example 35 using Compound 105a (521 mg, 5.0 mmol). ¹ H-NMR (CDCl ₃ ) δ: 4.09-4.23 (5H, m), 4.88 (2H, dd, J = 12.8, 6.1 Hz), 7.76-7.80 (2H, m), 7.85-7.89 (2H, m) .

 Step 2, 3 Synthesis of Compound 19A  

Using a compound 105b (706 mg, 2.8 mmol), Compound 19A (962 mg, yield: 75%) was obtained by the same procedure as Steps 3 and 4 of Example 35.

¹ H-NMR (DMSO-D ₆ ) δ: 1.16 (9H, t, J = 7.3 Hz), 1.47 (9H, s), 2.99 (6H, d, J = 6.5 Hz), 3.76 (2H, dd, J) =11.5, 5.0 Hz), 3.93-3.97 (1H, m), 4.01 (2H, dd, J = 11.5, 3.3 Hz), 4.71 (1H, d, J = 6.0 Hz), 4.77 (1H, d, J = 6.0Hz), 7.12 (1H, s).

 (Synthesis of Compound 20A)  

 Step 1 Synthesis of Compound 106b  

Compound 106b (1.17 g, yield 100%) was obtained by the same procedure as in the step 2 of Example 35 using Compound 106a (441 mg, 5.0 mmol).

¹ H-NMR (CDCl ₃ ) δ: 2.04-2.13 (1H, m), 2.30-2.36 (1H, m), 3.89-3.94 (2H, m), 4.13-4.18 (2H, m), 5.04-5.07 ( 1H, m), 7.75-7.80 (2H, m), 7.84-7.89 (2H, m).

 Step 2, 3 Synthesis of Compound 20A  

Compound 20A (1.14 g, yield 67%) was obtained by the same procedure from the procedure of Steps 3 and 4 of Example 35 using Compound 106b (1.17 g, 5.0 mmol).

¹ H-NMR (CDCl ₃ ) δ: 1.55 (9H, s), 2.13-2.29 (2H, m), 3.80-3.87 (2H, m), 4.05 (1H, q, J = 7.9 Hz), 4.13 (1H) , d, J = 10.8 Hz), 5.07 (1H, d, J = 4.1 Hz), 7.30 (1H, s).

 (Synthesis of Compound 21A)  

 Step 1 Synthesis of Compound 107b  

Imidazole (1.28 g, 18.7 mmol) and tert-butyldimethylmethyl chlorochloride (2.57 g, 17 mmol) were added sequentially to a solution of compound 107a (1.5 g, 17 mmol) in DMF (15 mL). After stirring at room temperature for 1 hour and a half, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compound 107b (2.16 g, yield 63%).

¹ H-NMR (CDCl ₃ ) δ: 0.09 (6H, s), 0.91 (9H, s), 1.93 (1H, t, J = 6.0 Hz), 4.18 (2H, d, J = 5.9 Hz), 4.25 ( 2H, s), 5.08-5.10 (2H, m).

 Step 2 Synthesis of Compound 107c  

Using a compound 107b (2.16 g, 10.7 mmol), Compound 107c (2.82 g, yield 76%).

¹ H-NMR (CDCl ₃ ) δ: 0.12 (6H, s), 0.93 (9H, s), 4.44 (2H, s), 4.70 (2H, s), 5.19 (1H, s), 5.34-5.35 (1H , m), 7.72-7.76 (2H, m), 7.80-7.84 (2H, m).

 Step 3, 4 Synthesis of Compound 21A  

Using a compound 107c (2.82 g, 8.1 mmol), Compound 21A (2.78 g, yield: 63%) was obtained by the same procedure as Steps 3 and 4 of Example 35.

¹ H-NMR (DMSO-D ₆ ) δ: 0.04 (6H, s), 0.88 (9H, s), 1.15 (9H, t, J = 7.2 Hz), 1.47 (9H, s), 2.99 (6H, d , J = 6.3 Hz), 4.13 (2H, s), 4.46 (2H, s), 5.09 (2H, d, J = 4.4 Hz), 7.08 (1H, s).

 (Synthesis of Compound 22A)  

 Step 1 Synthesis of Compound 22A  

The crude product of Compound 22A was obtained by the same procedure as Step 4 of Example 35 using Compound 108a (901 mg, 10 mmol). The obtained compound 22A was used in the subsequent reaction without purification.

 (Synthesis of Compound 23A)  

 Steps 1, 2 Synthesis of Compound 23A  

To a solution of compound 109a (2.0 g, 15.4 mmol) in MeOH (10 mL) EtOAc. After stirring at room temperature for 7 hours, methanol (40 mL) and sodium cyanoborohydride (1.93 g, 30.7 mmol) were added, and then 2 mol/L hydrochloric acid was added until pH=4. After stirring at room temperature for 1 hour, a 1 mol/L sodium hydroxide aqueous solution was added, and the mixture was concentrated under reduced pressure. Methanol was added to the obtained residue, and the insoluble matter was removed by filtration, whereby a methanol solution of the compound 109b was obtained. A crude product of the compound 23A was obtained by the same method as that of the step 4 of Example 35, using the solvent of the obtained compound 109b. The obtained compound 23A was subjected to column chromatography on a silica gel column, and the obtained crude product was directly used in the subsequent reaction.

 (Synthesis of Compound 24A)  

 Step 1 Synthesis of Compound 110b  

A 4 mol/L hydrochloric acid/ethyl acetate solution was added to a solution of compound 110a (9.19 g, 30 mmol) in ethyl acetate (75 mL). After stirring at room temperature for 2 hours, the resulting solid was filtered and dried under reduced pressure to give compound 110b (7.20 g, yield 99%) as white solid.

¹ H-NMR (DMSO-D ₆ ) δ: 3.18 (2H, s), 4.36 (2H, t, J = 5.3 Hz), 7.87-7.92 (4H, m), 8.20 (3H, s).

 Step 2 Synthesis of Compound 110c  

To a solution of the third butyl alcohol (1.61 mL, 16.9 mmol) in toluene (34 mL), chlorosulfonate (1.47 mL, 16.9 mmol). After stirring for 30 minutes under ice cooling, pyridine (3.41 mL, 42.3 mmol) was dropped under ice cooling. After further stirring under ice cooling for 1 hour, compound 14b (1.71 g, 7.1 mmol) and triethylamine (1.47 mL, 10.6 mmol) were added under ice cooling. After further stirring under ice cooling for 2 hours, dilute hydrochloric acid and tetrahydrofuran were added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compound 110c (1.20 g, yield 44%).

¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 3.50 (2H, dd, J = 10.0, 5.4 Hz), 4.36 (2H, t, J = 4.8 Hz), 6.29 (1H, t, J = 5.8 Hz), 7.21 (1H, s), 7.77-7.81 (2H, m), 7.84-7.89 (2H, m).

 Step 3 Synthesis of Compound 24A  

The crude product of Compound 24A was obtained by the same method as Steps 3 and 4 of Example 35 using Compound 110c (1.20 g, 3.1 mmol). The obtained compound 24A was used in the subsequent reaction without purification.

 (Synthesis of Compound 25A)  

 Step 1 Synthesis of Compound 25A  

The compound 111b (537 mg, 3.67 mmol) was dissolved in dichloromethane (5 ml) and methanol (5 ml), and Compound 111a (1.00 g, 3.67 mmol) was added under ice cooling. After stirring at room temperature for 30 minutes, concentration was carried out under reduced pressure. Diisopropyl ether was added to the residue, and the precipitated solid was filtered, whereby compound 25A (864.2 mg, 59%) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 7.09 (1H, s), 4.14 (2H, s), 1.48 (9H, s), 1.42 (9H, s).

 (Synthesis of Compound 26A)  

 Step 1 Synthesis of Compound 26A  

Using Compound 112b (900 mg, 3.31 mmol) and Compound 112a (580 mg, 3.62 mmol), Compound 26A (1.28 g, 93%) was obtained by the same procedure as Step 1 of Compound 25A.

¹ H-NMR (DMSO-D ₆ ) δ: 11.50 (1H, s), 7.05 (1H, s), 4.09 (2H, s), 2.77 (3H, s), 1.48 (9H, s), 1.40 (9H) , s).

 (Synthesis of Compound 27A)  

 Step 1 Synthesis of Compound 27A  

Using Compound 113b (1.00 g, 3.67 mmol), Compound 113a (451 mg, 4.04 mmol), triethylamine (0.56 ml, 4.04 mmol), Compound 27A (926.3 g) , 77%).

¹ H-NMR (DMSO-D ₆ ) δ: 11.75 (1H, br s), 11.23 (1H, br s), 7.70 (1H, s), 6.90 (2H, br s), 1.48 (9H, s).

 (Synthesis of Compound 28A)  

 Step 1 Synthesis of Compound 114c  

Compound 114a (1.087 ml, 7.93 mmol) and compound 114b (1.36 g, 8.32 mmol) were suspended in dichloromethane (10 mL) and 1,4-diazabicyclo[2.2.2] octane (0.18 g, 1.59) Methyl), stirred overnight at room temperature. The reaction solution was concentrated and applied to a sep. column chromatography, eluting with hexane / ethyl acetate. The chromatographic fractions containing the desired compound were concentrated under reduced pressure to give compound 114c (1.64 g, 72%).

¹ H-NMR (CDCl ₃ ) δ: 7.92 (2H, dd, J = 5.5, 3.1 Hz), 7.83 (2H, dd, J = 5.5, 3.1 Hz), 7.63 (1H, d, J = 12.2 Hz), 5.48 (1H, d, J = 12.2 Hz), 1.46 (9H, s).

 Step 2 Synthesis of Compound 28A  

Compound 28A (0.95 g) was synthesized in the same manner as in Step 4 of Example 34, using Compound 114c (0.58 g, 2.00 mmol) and Compound 114d (0.57 g, 2.10 mmol).

¹ H-NMR (CDCl ₃ ) δ: 7.86 (1H, d, J = 12.2 Hz), 7.41 (1H, s), 5.58 (1H, d, J = 12.2 Hz), 1.54 (9H, s), 1.46 ( 9H, s).

 (Synthesis of Compound 29A)  

 Step 1 Synthesis of Compound 115c  

Compound 115a (10.0 g, 32.2 mmol) was suspended in DMF (100 mL). After stirring at 60 ° C overnight, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtering magnesium sulfate, it was concentrated under reduced pressure. It was applied to a ruthenium column chromatography and dissolved in hexane/ethyl acetate. The chromatographic fractions containing the desired compound were concentrated under reduced pressure to afford compound 115c (6.70 g, 63%).

¹ H-NMR (CDCl ₃ ) δ: 10.13 (1H, br s), 8.85 (1H, br s), 7.21 (1H, s), 6.05-5.96 (1H, m), 5.45 (1H, dq, J = 17.2, 1.3 Hz), 5.32 (1H, dd, J = 10.5, 1.3 Hz), 4.87 (2H, dt, J = 5.8, 1.3 Hz), 1.55 (9H, s).

 Step 2 Synthesis of Compound 115e  

Compound 115c (2.89 g, 8.84 mmol) and compound 115d (2.00 g, 8.84 mmol) were dissolved in dichloromethane (30 ml), and 1,4-diazabicyclo[2.2.2] octane (0.099 g, 0.88 mmol), stirred at room temperature for 3 hours. The reaction solution was concentrated and applied to a sep. column chromatography, eluting with hexane / ethyl acetate. The chromatographic fractions containing the desired compound were concentrated under reduced pressure to give compound 115e (4.79 g, 98%).

¹ H-NMR (CDCl ₃ ) δ: 8.01 (1H, br s), 7.30 (1H, s), 6.14 (1H, s), 6.06-5.96 (1H, m), 5.45 (1H, dd, J = 17.3 , 1.3 Hz), 5.30 (1H, dd, J = 10.5, 1.3 Hz), 4.90 (2H, dt, J = 5.7, 1.3 Hz), 1.54 (9H, s), 1.49 (9H, s), 1.44 (9H) , s).

 Step 3 Synthesis of Compound 29A  

Compound 115e (4.79 g, 8.65 mmol) and aniline (0.95 ml, 10.38 mmol) were dissolved in tetrahydrofuran (50 ml), and Pd(PPh ₃ ) ₄ (1.00 g, 0.87 mmol) was added under ice cooling under ice. After stirring at room temperature for one hour, hydrochloric acid was added, and extraction was performed with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave Compound 29A (5.08 g).

[M+H]=514, RT=2.35 minutes, measurement condition A

 (Synthesis of Compound 30A)  

 Step 1 Synthesis of Compound 30A  

Compound 116a (5.14 g, 25.07 mmol, a synthesis method described in WO2009097578A1) was dissolved in dichloromethane (80 ml) and methanol (42 ml), and Compound 116b (6.55 g, 24.07 mmol) was added under ice cooling. After stirring overnight under ice cooling, the mixture was concentrated under reduced pressure. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration, and concentrated under reduced pressure to give a white foamy crude product of Compound 30A (8.688 g).

MS (M+1) = 346, RT = 1.09 minutes, measurement condition A

 (Synthesis of Compound 31A)  

 Step 1 Synthesis of Compound 31A  

In the same manner as in the first step of the synthesis of the compound 30A, the compound 117a (described in the synthesis method of Antiviral ChemiStry & Chemotherapy, 1994 (5) 1, 21-33) was used to obtain a white compound of the compound 31A (3.757 g, 90.3%). A foamy crude product.

MS (M+1) = 496, RT = 2.65 min, assay condition A

 (Synthesis of Compound 32A)  

 Step 1 Synthesis of Compound 32A  

In the same manner as in the step 1 of the synthesis of the compound 30A, the compound 118a (the synthesis method described in WO2009097578A1) was used to obtain a crude product in the form of a white foam of the compound 32A (1.236 g, 82.4%).

MS (M+1) = 388, RT = 1.00 min, assay condition A

 (Synthesis of Compound 33A)  

 Step 1 Synthesis of Compound 119b  

Add potassium bromide (45 g, 378 mmol), 9 M aqueous sulfuric acid (56 mL, 504 mmol) to a solution of D-threonine (15 g, 126 mmol) in water (222 mL). Sodium (13.03 g, 189 mmol) was put in little by little. After the preparation of the reagent, the obtained solution was stirred at room temperature overnight, and then urea (22.69 g, 378 mmol) was added under ice cooling, and the mixture was stirred for 5 minutes, and brine was added thereto, and the mixture was extracted 7 times with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the inorganic substance was removed by filtration, and concentrated under reduced pressure to obtain a crude product of compound 119b (20.8 g, 90.3%) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, d, J = 6.1 Hz), 4.14 - 4.18 (1H, m), 4.29 (1H, d, J = 4.4 Hz).

 Step 2 Synthesis of Compound 119c  

A solution of diphenyldiazomethane (22.08 g, 114 mmol) in tetrahydrofuran (83 mL) was added dropwise to a solution of EtOAc (EtOAc, EtOAc) After the reagent was charged, the resulting solution was stirred at room temperature overnight, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compound 119c (32.57 g, 82.1%).

¹ H-NMR (CDCl ₃ ) δ: 1.23-1.28 (3H, m), 2.79 (1H, d, J = 4.0 Hz), 4.12-4.15 (1H, m), 4.33 (1H, d, J = 4.9 Hz ), 6.91 (1H, s), 7.29-7.38 (10H, m).

 Step 3 Synthesis of Compound 119d  

Potassium carbonate (15.47 g, 112 mmol) and tetrabutylammonium bromide (3.01 g) were added to a solution of hydroxyphthalic acid imide (15.47 g, 112 mmol) in ethyl acetate (163 mL) and water (98 mL). 9.33 mmol), Compound 119c (32.57 g, 93 mmol), and the obtained mixture was stirred vigorously at room temperature overnight. The obtained organic layer was washed three times with 10% aqueous potassium carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and the organic substance was removed by filtration and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compound 119d (6.28 g, 15.

¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, d, J = 6.7 Hz), 3.46 (1H, br s), 4.28 (1H, br s), 4.76 (1H, d, J = 3.5 Hz), 7.02 (1H, s), 7.20-7.46 (10H, m), 7.75-7.77 (2H, m), 7.80-7.84 (2H, m).

 Step 4 Synthesis of Compound 33A  

In the same manner as in the step 4 of Example 35, Compound 119d was used to afford Compound 33A (8.7 mg, 100%).

MS (M+1) = 556, RT = 2.14 minutes, assay condition A

 (Synthesis of Compound 34A)  

 Step 1 Synthesis of Compound 120b  

In the same manner as in the step 1 of the synthesis of the compound 33A, the compound 120a was used to obtain a crude product of the compound 120b (8.6 g, 67.5%) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.85 (3H, d, J = 7.0 Hz), 4.41 (1H, q, J = 6.9 Hz).

 Step 2 Synthesis of Compound 120c  

1,4-two in compound 120b (8.6 g, 56.2 mmol) To a solution of alkane (86 mL), di-tert-butyl dicarbonate (17 mL, 73.1 mmol), ammonium carbonate (6.75 g, 70.3 mmol), pyridine (2.27 mL, 28.1 mmol) were added, and the resulting solution was stirred at room temperature. After 5 days, it was dried under reduced pressure, and water was added and extracted with ethyl acetate. The obtained organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the inorganic substance was removed by filtration, and concentrated under reduced pressure, and diisopropyl ether was added to the obtained white solid. The suspension was stirred at room temperature for 15 minutes, and the precipitated white solid was filtered, to afford Compound 120c (2.53 g, 29.7%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.89 (3H, d, J = 7.0 Hz), 4.41 (1H, q, J = 7.1 Hz), 5.88 (1H, br s), 6.32 (1H, br s).

 Step 3 Synthesis of Compound 120d  

In the same manner as in the step 3 of the synthesis of Compound 33A, Compound 120c was used to obtain Compound 120d (436.4 mg, 11.2%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.72 (3H, d, J = 7.0 Hz), 4.77 (1H, q, J = 7.0 Hz), 5.52 (1H, br s), 7.69 (1H, br s), 7.79-7.81(2H,m), 7.86-7.88(2H,m).

 Step 4 Synthesis of Compound 34  

The crude product of Compound 34A (437 mg, 65.4%) as a white solid was obtained using the compound 120d in the same manner as in the step 4 of Example 34.

MS (M+1)=359, RT=1.01 min, assay condition A

 (Synthesis of Compound 35A)  

 Step 1 Synthesis of Compound 35A  

In the same manner as in the step 1 of the synthesis of the compound 30A, the compound 121a (the synthesis method described in WO2013180197A1) was used to obtain a crude product of a white solid of the compound 35A (1.109 g, 83.5%).

MS (M+1) = 443, RT = 1.67 min, assay condition A

 (Synthesis of Compound 36A)  

 Step 1 Synthesis of Compound 122b  

The compound 122a was used in the same manner as in the step 1 of Example 40 to obtain a crude product of the compound 122b (556.8 mg, 29.1%) as a yellow oil.

MS (M+1) = 165, RT = 0.59 minutes, assay condition A

 Step 2 Synthesis of Compound 122c  

The compound 122b was used in the same manner as in the step 2 of Example 40 to obtain a crude product of Compound 122c (423.5 mg, 50.9%) as a yellow oil.

MS (M+1)=249, RT=1.05 min, assay condition A

 Step 3 Synthesis of Compound 36A  

The compound was obtained in the same manner as in the step 4 of Example 34 to give Compound 36A (504.3 mg, 79.4%) as a white solid.

MS (M+1) = 373, RT = 1.19 min, assay condition A

 (Synthesis of Compound 37A)  

 Step 1 Synthesis of Compound 123b  

The compound 123a was used in the same manner as in the step 1 of Example 40 to obtain a crude product of compound 123b (1.66 g, 60.5%) as a yellow oil.

MS (M+1)=238, RT=1.19 min, assay condition A

 Step 2 Synthesis of Compound 123c  

The same procedure as in the step 2 of Example 40 was carried out, and Compound 123b was used to obtain a crude product of Compound 123c (1.06 g, 47.5%) as a white solid.

MS (M+1)=321, RT=1.64 min, assay condition A

 Step 3 Synthesis of Compound 37A  

The compound 123c was used in the same manner as in the step 4 of Example 34 to obtain a white foamy crude product of Compound 37A (1.4681 g, 99.8%).

MS (M+1) = 445, RT = 1.42 minutes, assay condition A

 (Synthesis of Compound 38A)  

 Step 1 Synthesis of Compound 124b  

Compound 124a (9.01 mL, 123 mmol), triphenylphosphine (3.54 g, 13.49 mmol) was added to a solution of hydroxy phthalimin (2 g, 12.26 mmol) in dichloromethane (20 mL) Diisopropyl azodicarboxylate (2.66 mL, 13.49 mmol) was added dropwise. The resulting solution was allowed to stand in the refrigerator overnight, concentrated under reduced pressure, and water was added and extracted with ethyl acetate. The obtained organic layer was washed with water three times and saturated brine, dried over anhydrous magnesium sulfate, and the organic substance was removed by filtration, and reduced, and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate). The chromatographic fractions containing the product were collected, concentrated under reduced pressure, diisopropyl ether was added, and the precipitated crystals were filtered. After washing, Compound 124b (1.2026 g, 44.3%) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, d, J = 6.5 Hz), 3.57 (1H, dd, J = 13.4, 5.3 Hz), 3.74 (1H, dd, J = 13.3, 2.3 Hz), 4.32-4.38 (1H, m), 7.77-7.80 (2H, m), 7.86-7.87 (2H, m).

 Step 2 Synthesis of Compound 38A  

This was carried out in the same manner as in the step 4 of Example 34, using Compound 124b to obtain a crude product of Compound 38A (1.1516 g, 61.3%) as a white solid.

MS (M+1)=346, RT=1.13 min, assay condition A

 (Synthesis of Compound 39A)  

 Step 1 Synthesis of Compound 125b  

In a solution of compound 125a (820 mg, 3.96 mmol) in tetrahydrofuran (8.2 mL), EtOAc (EtOAc (EtOAc) Phosphine (1557 mg, 5.94 mmol) was added dropwise to diisopropyl azodicarboxylate (1.15 mL, 5.94 mmol). The obtained solution was allowed to stand in the refrigerator overnight, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to collect fractions containing the product. Concentration by pressure gave Compound 125b (957.7 mg, 57.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.52 (9H, s), 4.04 (2H, t, J = 5.8 Hz), 4.40 (2H, t, J = 6.2 Hz), 7.74 7.76(2H,m), 7.82-7.85(2H,m).

 Step 2 Synthesis of Compound 39A  

The compound 125b was used in the same manner as in the step 4 of Example 34 to obtain a crude product of the compound 39A (1.2268 g, 99.0%) as a yellow foam.

MS (M+1) = 547, RT = 2.32 min, assay condition A

 (Synthesis of Compound 40A)  

 Step 1 Synthesis of Compound 126b  

Trifluoroacetic acid (2.31 mL, 30 mmol) was added dropwise to a solution of the compound 126a (1026 mg, 5 mmol, mp. After the resulting solution was stirred at room temperature for 3.5 hours, it was concentrated under reduced pressure, and diisopropyl ether was added to the obtained colorless transparent oil. Compound 126b (533.7 mg, 48. ) a white solid.

¹ H-NMR (DMSO-D ₆ ) δ: 1.21 (6H, s), 3.49 (2H, s).

 Step 2 Synthesis of Compound 40A  

Compound 126b (533.7 mg, 2.435 mmol) was dissolved in methanol (5.3 ml), triethylamine (338 μL, 2.435 mmol) was added, and the mixture was stirred at room temperature for 5 minutes, and then compound 2 (663 mg, 2.435 mmol) was added under ice cooling. . After stirring overnight under ice cooling, the mixture was concentrated under reduced pressure. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration, and concentrated under reduced pressure to give a crude product of compound 40A (8.688 g) as a yellow foam.

MS (M+1)=360, RT=1.34 minutes, measurement condition A

 (Synthesis of Compound 41A)  

 Step 1 Synthesis of Compound 127b  

In the same manner as in the step 1 of the synthesis of Compound 38A, Compound 127a was used to obtain Compound 127b (998.9mg, 38.0%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, d, J = 6.5 Hz), 3.56-3.58 (2H, m), 3.72-3.74 (1H, m), 4.32-4.38 (1H, m), 7.79 -7.81(2H,m), 7.85-7.87(2H,m).

 Step 2 Synthesis of Compound 41A  

In the same manner as in the step 4 of Example 34, Compound 127b was used to obtain a crude product of Compound 41A (1.0695 g, 68.6%) as a white solid.

MS (M+1)=346, RT=1.15 min, assay condition A

 (Synthesis of Compound 42A)  

 Step 1 Synthesis of Compound 128c  

Compound 128a (6.86 g, 24.81 mmol) was dissolved in tetrahydrofuran (70 ml), and then, under ice cooling, compound 128b (5.26 g, 32.3 mmol), triphenylphosphine (12.79 g, 54.6 mmol), bis (2) -Methoxyethyl)azodicarboxylate (12.79 g, 54.6 mmol). After stirring for 1 hour under ice cooling, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and brine, and dried over anhydrous magnesium sulfate. After filtering magnesium sulfate, it was concentrated under reduced pressure. It was applied to a ruthenium column chromatography and dissolved in hexane/ethyl acetate. The chromatographic fractions containing the desired compound were concentrated under reduced pressure to give compound 128c (5.78 g, 55%).

[M+H]=422, RT=3.06 minutes, measurement condition A

 Step 2 Synthesis of Compound 42A  

Using a compound 128c (5.78 g, 13.71 mmol) and Compound 128d (3.73 g, 13.71 mmol), Compound 42A (7.79 g).

[M+H]=546, RT=2.81 min, assay condition A

 (Synthesis of Compound 43A)  

 Step 1 Synthesis of Compound 43A  

The compound 129a (described in the synthesis method described in WO2016001390) was used in the same manner as in the step 4 of Example 34 to obtain a crude product of a white solid of Compound 43A (4.98 g, 91.1%).

MS (M+1)=394, RT=1.04 min, assay condition A

 (Synthesis of Compound 44A)  

 Step 1 Synthesis of Compound 129b  

m-CPBA (69 wt%, 3.16 g, 12.64 mmol) in methylene chloride (30 mL), EtOAc (30 g, EtOAc (EtOAc) The solution dripped. The resulting solution was stirred at -78 ° C for 15 minutes, and the reaction mixture was poured into a mixture of ice-cold 15% aqueous sodium thiosulfate (30 mL) and 8% aqueous sodium hydrogencarbonate (30 mL), and stirred at room temperature for 30 min. Extracted with dichloromethane. The organic layer was washed with 8% aqueous sodium hydrogen carbonate solution and water and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure to give Compound 129b (3.1431 g, 98.2%) as a white foam.

MS (M+1) = 254, RT = 0.94 min, assay condition A

 Step 2 Synthesis of Compound 44A  

In the same manner as in the step 4 of Example 34, Compound 129b was used to obtain a crude product of Compound 44A (1.4237 g, 95.5%) as a white solid.

MS (M+1) = 378, RT = 0.99 min, assay condition A

 (Synthesis of Compound 45A)  

 Step 1 Synthesis of Compound 131b  

O-(2,4,6-trimethylsulfonyl)hydroxylamine (2.04 g, 9.48 mmol) was added to a solution of compound 131a (2 g, 7.9 mmol) in dichloromethane (100 mL). .Org. Chem., 1974, 39 (16), synthesis of pp 2458-2459). The obtained white suspension was stirred at room temperature overnight, and concentrated under reduced pressure to give a white solid. An aqueous solution of 8.4% sodium hydrogencarbonate was added to the obtained white solid, and extracted with ethyl acetate. The organic layer was washed with a 8.4% aqueous sodium hydrogencarbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure to give Compound 131b (881 mg, 41.

MS (M+1)=269, RT=0.86 min, assay condition A

 Step 2 Synthesis of Compound 45A  

The compound was applied in the same manner as in the step 4 of Example 34, and Compound 41b was used to obtain a crude product of Compound 45A (324.2 mg, 25.2%) as a white solid.

MS (M+1) = 393, RT = 0.97 min, assay condition A

 (Synthesis of Compound 47A)  

 Step 1 Synthesis of Compound 133b  

4-Bromocrotonic acid 133a (2.00 g, 12.1 mmol) was dissolved in tetrahydrofuran (20 mL), and diphenyldiazomethane (2.36 g, 12.1 mmol) was added. After stirring at room temperature for 16 hours, the reaction liquid was concentrated under reduced pressure to give a crude product of compound 133b (4.29 g).

¹ H-NMR (CDCl ₃ ) δ: 4.02 (2H, d, J = 7.3 Hz), 6.16 (1H, d, J = 15.3 Hz), 6.95 (1H, s), 7.09 (1H, dt, J = 15.3) , 7.3 Hz), 7.25-7.37 (10H, m).

 Step 2 Synthesis of Compound 133c  

Potassium carbonate (1.64 g, 11.9 mmol) was added to a solution of N-hydroxyphthalimide (1.93 g, 11.9 mmol) in DMF (20 mL). A solution of 133b (3.27 g, 9.87 mmol) in DMF (20 mL). Water was added to the reaction mixture, extracted with ethyl acetate, and the oil layer was washed with water. The solvent was distilled off under reduced pressure to give a solid, which was washed with diisopropyl ether and filtered to afford compound 133c (3.09 g, 81%, 2 s).

¹ H-NMR (CDCl ₃ ) δ: 4.88 (2H, dd, J = 5.6, 1.6 Hz), 6.29 (1H, dt, J = 15.9, 1.6 Hz), 6.94 (1H, s), 7.17 (1H, dt , J = 15.9, 5.6 Hz), 7.25-7.38 (10H, m), 7.73 - 7.79 (2H, m), 7.82 - 7.88 (2H, m).

[M+Na]=436 (2.67 minutes) measurement condition B

 Step 3 Synthesis of Compound 47A  

Compound 133c (2.00 g, 4.84 mmol) was dissolved in dichloromethane (20 mL), EtOAc (EtOAc) The white solid was washed with dichloromethane and filtered, and the filtrate was concentrated under reduced pressure to about 10 mL to obtain a dichloromethane solution of hydroxylamine. 133d (1.32g, 4.84mmol), methanol (10mL), and dichloromethane (10mL) were added to the separately prepared flask, and after cooling with ice, a hydroxylamine solution was added dropwise. After stirring at 0 ° C for 50 minutes, the reaction solution was concentrated under reduced pressure. Ethyl acetate, water, and 2 mol/L hydrochloric acid were added, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered over magnesium sulfate, and concentrated under reduced pressure to give a crude product of Compound 47A (2.80 g).

¹ H-NMR (CDCl ₃ ) δ: 1.52 (9H, s), 4.87 (2H, m), 6.18 (1H, m), 6.93 (1H, s), 7.07 (1H, dt, J = 15.8, 4.3 Hz ), 7.23-7.36 (11H, m).

[M+H]=538 (2.47 minutes) measurement condition B

 (Synthesis of Compound 48A)  

 Step 1 Synthesis of Compound 48A  

Compound 134a (1.49 g, 6.74 mmol) and 134b (1.83 g, 6.74 mmol) obtained by a known method (Farmaco, Edizione Scientifica (1974), 29(9), 710-19) were used to react with the compound. Step 3 of the synthesis of 47A was carried out in the same manner as in the synthesis. The obtained residue was solidified using ethyl acetate and diisopropyl ether, and the solid was filtered and washed with diisopropyl ether to give Compound 48A (1.72 g, 74%).

¹ H-NMR (CDCl ₃ ) δ: 1.55 (9H, s), 3.41 (3H, s), 3.72 (2H, m), 4.43 (2H, m), 7.37 (1H, s).

[M+H]=346 (1.35 minutes), measurement condition B

 (Synthesis of Compound 49A)  

 Step 1 Synthesis of Compound 135b  

A suspension of 3-hydroxy-γ-butyrolactone 135a (500 mg, 4.95 mmol) in tetrahydrofuran (20 mL) was ice-cooled, and N-hydroxyphthalimide (968 mg, 5.93 mmol) and triphenylphosphine (1.56) were added. g, 5.93 mmol), diisopropyl azodicarboxylate (1.23 mL, 5.93 mmol). After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure. The obtained residue was solidified using isopropyl alcohol, and the solid was filtered and washed with isopropyl alcohol, whereby Compound 135b (1.03 g, 85%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 2.44-2.60 (2H, m), 3.40 (1H, m), 3.72 (1H, m), 4.84 (1H, dd, J = 7.0, 4.0 Hz), 5.75 (1H) , brs), 7.71-7.77 (2H, m), 7.81-7.87 (2H, m).

[M+H]=247 (1.14 minutes), measurement condition B

 Step 2 Synthesis of Compound 49A  

The compound 135b (1.13 g, 4.57 mmol) and 135c (1.25 g, 4.57 mmol) were used to give the crude product of Compound 49A (1.96 g).

¹ H-NMR (CDCl ₃ ) δ: 1.54 (9H, s), 2.39-2.62 (2H, m), 3.27-3.46 (2H, m), 5.06 (1H, t, J = 8.4 Hz), 7.32 (1H) , s), 7.60 (1H, brs).

[M+H]=371 (1.19 minutes), measurement condition B

 (Synthesis of Compound 50A)  

 Step 1 Synthesis of Compound 50A  

The compound 136a (950 mg, 2.12 mmol) and 136b (577 mg, 2.12 mmol) synthesized by the method described in WO2015190587A1 were synthesized in the same manner as in the step 3 of the synthesis of the compound 47A to obtain the compound 50A (1.38). g) The crude product.

¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 1.51 (9H, s), 1.55 (9H, s), 4.07 (2H, m), 4.40 (2H, m), 7.33 (1H, s ).

[M+H]=573 (2.22 minutes), measurement condition B

 (Synthesis of Compound 51A)  

 Step 1 Synthesis of Compound 140b  

Compound 140a (2.78 g, 13.4 mmol) synthesized by a known method was dissolved in dichloromethane (28 mL), and the Dess-Martin reagent (5.69 g, 13.4 mmol) was added under ice cooling. After stirring at room temperature for 50 minutes, it was ice-cooled and an aqueous sodium thiosulfate solution was added, and extraction was performed with ethyl acetate. It was dried over anhydrous magnesium sulfate, filtered over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 140b (1.53 g, 56%).

¹ H-NMR (CDCl ₃ ) δ: 4.70 (2H, d, J = 1.6 Hz), 7.78-7.81 (2H, m), 7.86-7.90 (2H, m), 10.06 (1H, t, J = 1.6 Hz) ).

[M+H]=206 (0.93 minutes), measurement condition B

 Step 2 Synthesis of Compound 140c  

The compound 140b (1.53 g, 7.46 mmol) was dissolved in tetrahydrofuran (15 mL), and a 0.5 mol/L acetylene magnesium chloride tetrahydrofuran solution (19.8 mL, 9.92 mmol) was added dropwise under ice cooling. After stirring at 0 ° C for 1 hour, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate, filtered over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 140c (334mg, 19%).

¹ H-NMR (CDCl ₃ ) δ: 2.42 (1H, d, J = 2.3 Hz), 4.11 (1H, d, J = 5.4 Hz), 4.28 (1H, dd, J = 11.9, 7.8 Hz), 4.33 ( 1H, dd, J = 11.9, 3.0 Hz), 4.67 (1H, dddd, J = 7.8, 5.4, 3.0, 2.3 Hz), 7.77-7.83 (2H, m), 7.85-7.91 (2H, m).

[M+H]=232 (1.33 minutes), measurement condition B

 Step 3 Synthesis of Compound 51A  

The compound 140c (334 mg, 1.45 mmol) and 140d (393 mg, 1.45 mmol) were used in the same manner as in the step 3 of the synthesis of Compound 47A to give a crude product of Compound 51A.

¹ H-NMR (CDCl ₃ ) δ: 1.55 (9H, s), 2.44 (1H, brs), 4.23 (1H, dd, J = 12.2, 8.8 Hz), 4.38 (1H, dd, J = 12.2, 2.4 Hz ), 4.80 (1H, m), 7.29 (1H, s).

[M+H]=356 (1.41 min), measurement condition B

 (Synthesis of Compound 52A)  

 Step 1 Synthesis of Compound 141b  

Using the compound 141a (5.11 g, 15.2 mmol) obtained by the method described in Bioorganic & Medicinal Chemistry, 19(7), 2114-2124; 2011, the compound 141b was obtained in the same manner as in the step 3 of Example 34. (4.93 g, yield 67%).

¹ H-NMR (CDCl ₃ ) δ: 7.86-7.80 (m, 2H), 7.78-7.73 (m, 2H), 7.40 (d, J = 7.4 Hz, 6H), 7.28-7.17 (m, 9H), 4.87 -4.63 (m, 2H), 4.50-4.40 (m, 1H), 3.61 (dd, J = 10.9, 5.1 Hz, 1H), 3.56-3.48 (m, 1H).

 Step 2 Synthesis of Compound 52A  

The compound 141b (2.41 g, 5.00 mmol) was used, and ethyl acetate was added to the crude product obtained in the same manner as in the step 4 of Example 34, and the obtained solid was collected by filtration, whereby Compound 52A (0.741 g, Yield 25%).

¹ H-NMR (CDCl ₃ ) δ: 7.40 (d, J = 7.8 Hz, 6H), 7.27-7.16 (m, 10H), 4.66-4.62 (m, 2H), 4.55-4.51 (m, 1H), 3.40 -3.35 (m, 2H), 1.51 (s, 9H).

 (Synthesis of Compound 53A)  

 Step 1 Synthesis of Compound 142b  

Using the compound 142a (5.23 g, 15.5 mmol) obtained by the method described in Bioorganic & Medicinal Chemistry, 19(7), 2114-2124; 2011, the compound 142b was obtained in the same manner as in the step 3 of Example 34. (5.13 g, yield 69%).

¹ H-NMR (CDCl ₃ ) δ: 7.85-7.80 (m, 2H), 7.77-7.74 (m, 2H), 7.41 (d, J = 11.7 Hz, 6H), 7.35-7.18 (m, 9H), 4.87 -4.63 (m, 2H), 4.50-4.42 (m, 1H), 3.61 (dd, J = 10.8, 5.1 Hz, 1H), 3.56-3.47 (m, 1H).

 Step 2 Synthesis of Compound 53A  

The compound 142b (2.41 g, 5.00 mmol) was used, and ethyl acetate was added to the obtained crude product by the method of the step 4 of Example 34, and the obtained solid was filtered and taken out, whereby Compound 53A (1.11 g) was obtained. The rate is 37%).

¹ H-NMR (CDCl ₃ ) δ: 7.41 (d, J = 7.0 Hz, 6H), 7.28-7.17 (m, 10H), 4.73-4.62 (m, 2H), 4.61-4.54 (m, 1H), 3.45 -3.33 (m, 2H), 1.52 (s, 9H).

 (Synthesis of Compound 54A)  

 Step 1 Synthesis of Compound 143b  

(R)-3-Aminopropane-1,2-diol (2.60 g, 28.5 mmol) was suspended in tetrahydrofuran (30.0 mL), dibutyl dicarbonate (6.96 mL, 30.0 mmol) was added and stirred overnight . The reaction solution was concentrated, and the obtained residue was dissolved in dimethyl carbamide (55.0 mL), cooled to 0 s, and then, then,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 29.9 mmol) and stirred at room temperature for 3 hours and 30 minutes. Purified water was added to the solution, and the target was extracted from the aqueous layer with ethyl acetate. The organic layer was washed with purified water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography to obtain Compound 143b (3.56 g, yield 41%).

¹ H-NMR (CDCl ₃ ) δ: 4.95 (br s, 1H), 3.77-3.70 (m, 1H), 3.64 (dd, J = 10.2, 4.5 Hz, 1H), 3.53 (dd, J = 10.2, 6.1 Hz, 1H), 3.40-3.29 (m, 1H), 3.16-3.07 (m, 1H), 2.81 (d, J = 3.1 Hz, 1H), 1.44 (s, 9H), 0.90 (s, 9H), 0.06 (d, J = 7.5 Hz, 6H).

 Step 2 Synthesis of Compound 143c  

Using the compound 143b (3.55 g, 11.6 mmol), Compound 143c (5.14 g, yield 98%).

¹ H-NMR (CDCl ₃ ) δ: 7.85-7.80 (m, 2H), 7.78-7.75 (m, 2H), 5.70 (br s, 1H), 4.26 (br s, 1H), 4.00-3.92 (m, 2H), 3.56-3.44 (m, 2H), 1.46 (s, 9H), 0.82 (s, 9H), 0.03 (s, 6H).

 Step 3 Synthesis of Compound 54A  

The crude product of Compound 54A was obtained in the same manner as in Step 4 of Example 34 using Compound 143c (5.14 g, 11.4 mmol). The obtained crude product was used in the subsequent reaction without purification.

 (Synthesis of Compound 55A)  

 Step 1 Synthesis of Compound 55A  

Triethylamine (3.41 mL, 24.63 mmol), formic acid acetic anhydride (21.69 g, 246 mmol) was added to a solution of compound 149a (7.63 g, 24.. The mixture was stirred for 5 minutes, and a 1 mol/L aqueous hydrochloric acid solution was added and extracted with ethyl acetate. The obtained organic layer was washed twice with water and brine, dried over anhydrous magnesium sulfate, and the organics were removed by filtration and concentrated under reduced pressure. The yellow oil of the obtained crude product was refrigerated overnight, and toluene was added to the obtained adhesive white solid, and concentrated under reduced pressure. Diisopropyl ether was added, and the precipitated crystals were filtered off. Washing was carried out to obtain Compound 55A (5.9239 g, 79.8%) as a white solid.

¹ H-NMR (DMSO-D ₆ ) δ: 1.47 (9H, s), 5.42 (1H, d, J = 8.1 Hz), 7.07 (1H, s), 8.06 (1H, s), 8.68 (1H, d , J = 7.8 Hz), 11.54 (1H, s).

 (Synthesis of Intermediate 56A)  

 Step 1 Synthesis of Compound 56A  

O-(benzotriazol-1-yl)-N,N was added at room temperature in a solution of acetamic acid (431 mg, 4.84 mmol) in N,N-dimethylformamide (5 mL). N',N'-tetramethylhexafluorophosphate (1.592 g, 4.2 mmol) was stirred at room temperature for 30 minutes, and the resulting solution was used as the A solution. In a solution of compound 150a (1 g, 3.23 mmol) in N,N-dimethylformamide (10 mL), triethylamine (0.985 mL, 7.1 mmol), A solution was added under ice cooling, and the obtained solution was After stirring at room temperature for 4 hours, a 1N aqueous solution of hydrochloric acid was added and ethyl acetate was evaporated. The obtained organic layer was washed twice with water and brine, and dried over anhydrous sodium sulfate, and the organic substance was removed by filtration, and concentrated under reduced pressure to obtain compound 56A (462.3 mg, 41.6%). The crude product of the yellow solid.

MS (M+1)=345, RT=1.27 min, assay condition A

 (Synthesis of Intermediate 57A)  

 Step 1 Synthesis of Compound 57A  

To a solution of the compound 151a (350.8 mg, 0.515 mmol) in tetrahydrofuran (7.0 mL), tert-butyl sulfamoylcarbamate (121 mg, 0.618 mmol), triphenyl Phosphine (176 mg, 0.67 mmol) was added dropwise to diisopropyl azodicarboxylate (150 μL, 0.773 mmol). The resulting solution was allowed to stand at room temperature overnight. In the resulting solution, tert-butyl sulfonylaminocarbamate (121 mg, 0.618 mmol), triphenylphosphine (176 mg, 0.67 mmol), diisopropyl azodicarboxylate was added under ice cooling. (150 μL, 0.773 mmol) was dropped. The resulting solution was stirred at room temperature for 3 hours, then sulfonylaminocarbamic acid tert-butyl ester (363 mg, 1.854 mmol), triphenylphosphine (528 mg, 2.01 mmol), azo Diisopropyl carboxylic acid (450 μL, 2.319 mmol) was added dropwise. The obtained solution was stirred at room temperature for 1 hour, concentrated under reduced pressure, and the obtained white suspension was filtered, and the obtained yellow mother liquid was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate), and the fractions containing the product were collected and concentrated under reduced pressure to give compound 57A (311.1 mg, 70.3%) as a yellow oil. The crude product.

MS (M+1) = 859, RT = 2.57 minutes, assay condition A

 (Synthesis of Intermediate 58A)  

 Step 1 Synthesis of Compound 58A  

A solution of compound 152b (1.05 g, 6 mmol) in EtOAc (EtOAc) (EtOAc) Stir at 0 ° C for 30 minutes. Triethylamine (0.837 mL, 6.30 mmol) and racemic compound 152a (1.64 g, 6.00 mmol) were added and stirred at room temperature for 1 hour. Dilute hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain a crude product of compound 58A (330 mg).

MS (m+1) = 475, 2.34 minutes, assay condition A

 (Synthesis of Intermediate 59A)  

 Step 1 Synthesis of Compound 153b  

Compound 153a (7.91 g, 50.0 mmol) obtained by the method of Journal of Organic Chemistry, 78 (14), 7281-7287; 2013 was dissolved in acetone (80.0 mL) and purified water (20.0 mL), and citric acid was added. Potassium (IV) dihydrate (0.184 g, 0.500 mol) and N-methylofofolin N-oxide (11.7 g, 100 mmol) were stirred at room temperature for 1 hour. An aqueous solution of sodium thiosulfate (37.2 g, 150 mmol) was added, and acetone was distilled off. The target substance was extracted from the aqueous layer 6 times by a mixture of ethyl acetate and tetrahydrofuran, and the collected organic layer was dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a compound. 153b (7.5 g, 39.1 mmol).

¹ H-NMR (DMSO-D ₆ ) δ: 4.64 (s, 1H), 4.60 (dd, J = 6.7, 5.4 Hz, 2H), 3.50 (dd, J = 6.7, 11.0 Hz, 2H), 3.39 (dd , J = 5.4, 11.0 Hz, 2H), 1.40 (s, 9H).

 Step 2 Synthesis of Compound 153c  

Compound 153b (4.18 g, 21.8 mmol) was suspended in dichloromethane, p-methoxybenzaldehyde dimethyl acetal (7.95 g, 43.6 mmol) and 10-camphorsulfonic acid (0.507 g, 2.18 mmol) were added for 2 hours. Heat to reflux for 30 minutes. The reaction solution was cooled to room temperature, and saturated baking soda water was added. Dichloromethane was distilled off, and the target was extracted from aqueous layer with ethyl acetate. The collected organic layer was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, and filtered to remove the desiccant, and the solvent was evaporated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography to obtain an insoluble mixture of compound 153c (4.48 g, yield 66%).

MS (M+1): 311.15; 1.95 minutes (measurement condition A)

 Step 3 Synthesis of Compound 153d  

Compound 153c (4.48 g, 14.4 mmol) was dissolved in toluene (50.0 mL), and phenoxydiphenylphosphine (8.03 g, 28.9 mmol) and N-hydroxyphthalimide (4.71 g, 28.9 mmol) were added. Then, a 40% toluene solution of diethyl azodicarboxylate (13.1 mL, 28.9 mmol) was added dropwise. After stirring overnight at room temperature, the undesired material was removed, the solvent was distilled off, and the obtained residue was subjected to column chromatography to give compound 153d (4.68 g, yield 71%).

MS (M+1): 456.16; 2.58 (measurement condition A)

 Step 4 Synthesis of Compound 59A  

The compound 153d (4.68 g, 10.3 mmol) was used in the same manner as in the method of Step 4 of Example 34, and the obtained residue was applied to a silica gel column chromatography to give 5% triethylamine. The ester solution and methanol were dissolved, and the chromatographic fraction containing the target was concentrated to give Compound 59A (2.82 g, yield 40%).

 (Synthesis of Intermediate 60A)  

 Step 1 Synthesis of Compound 60A  

A solution of compound 155a (200 mg, 0.294 mmol) in THF (2 mL) was cooled to -30 &lt After stirring at -30 ° C for 1 hour, sodium hydrogencarbonate (123 mg, 1.47 mmol) and water (0.1 mL) were added and stirred at room temperature for 25 min. It was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compound 60A (129 mg, 61%).

[M+H]=724.15 (2.37 minutes), measurement condition B

 (Synthesis of Intermediate 61A)  

 Step 1 Synthesis of Compound 61A  

After a compound 156a (620 mg, 2.0 mmol) was added to a solution of Compound 156b (494 mg, 3.0 mmol) in dichloromethane (6 mL), triethylamine (1.11 mL, 4.0 mmol) . After stirring for 1 hour under ice cooling, dilute hydrochloric acid was added and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (yield of 5% triethylamine/ethyl acetate-methanol) to afford compound 61A (221 mg, yield: 28%) as an orange foam.

¹ H-NMR (CDCl ₃ ) δ: 1.52 (9H, s), 1.52 (9H, s), 5.32 (1H, d, J = 6.5 Hz), 6.89 (1H, s), 8.41 (1H, s).

Using the above intermediate, the following compound was synthesized by the same method as above.

The following compounds were synthesized by the same method as above.

 Test example 1  

The in vitro (In Vitro) antibacterial activity of the compounds of the invention was confirmed.

 (experiment method)  

The Minimum Inhibitory Concentration (MIC) was determined according to the method recommended by CLSI (Clinical and Laboratory Standards Institute), and the inoculum volume was 1×10 ⁵ CFU/mL. The medium was run using a cation-adjusted Mueller Hinton broth by micro-dilution.

The strains used are shown in the table below.

 (result)  

The test results are shown below. In the table, the numerical unit of inhibitory activity is μg/mL.

 Test Example 1-1  

The PBP (Penicillin Binding Protein) inhibitory activity of the compound of the present invention was confirmed.

 (experiment method)  

The affinity of PBP of E. coli NIHJ JC-2 was evaluated by fluorescence labeling of penicillin by a competition assay. The compound I-001 solution was added to the E. coli NIHJ JC-2 membrane chromatography fraction, and the mixture was incubated at 35 ° C for 10 minutes to add the final concentration of the fluorescently labeled penicillin to 15 mM, and further cultured at 35 ° C. minute. The reaction was stopped by ice cooling with an equal amount of 20% (w/v) sodium sarcosyl sarcosyl and 240 mg/mL penicillin G. After centrifugation at 8600 °C and 14600 rpm for 30 minutes to remove the outer membrane component, SDS buffer and 2-hydrazine ethanol were added, and the mixture was heated in a boiling water bath for 3 minutes to release the protein. A part of this was applied to a 7.5% SDS-PAGE gel, electrophoresed at 280 V/30 mA, and analyzed by LAS3000 (BIO-RAD).

 (result)  

The IC50 of Compound I-001 to PBP3 was 0.52 μg/mL, suggesting an affinity for PBP3.

 Test Example 1-2  

The in vivo antibacterial activity of the compounds of the invention is assessed.

 (experiment method)  

Five week old Jcl: ICR male mice were used in the animal line. The strain was evaluated using K. pneumonia SR-1. Cyclophosphamide was administered to the peritoneal cavity at a dose of 150 mg/kg and 100 mg/kg on the 4th and 1st day of infection, causing neutropenia. Under anesthesia, the infected bacterial solution was inoculated nasally at about 5×10 ⁵ CFU/mouse, thereby causing infection, and after 2, 5, and 8 hours of infection, the compound I-001 was treated at 3 mg/kg or 10 mg/kg. The dosage is administered intravenously. After euthanasia treatment at the time of infection for 10 hours, the lungs were taken to prepare lung homogenates, thereby measuring the number of bacteria in the lungs.

 (result)  

Compound I-001 showed good sterilization effect on K.pneumOniae SR-1, and the number of intrapulmonary bacteria after treatment decreased by 1.58 log10 CFU at the beginning of treatment.

 (experiment method)  

Animals used 5 week old Jcl: ICR male mice. The strain was evaluated using K. pneumoniae ATCC 13883. Cyclophosphamide was administered to the peritoneal cavity at a dose of 150 mg/kg and 100 mg/kg on the 4th and 1st day of infection, causing neutropenia. Under anesthesia, the infected bacterial solution was inoculated nasally at about 1×10 ⁶ CFU/mouSe to cause infection. After 2, 5, and 8 hours of infection, the compound I-027 was 0.1, 0.3, 1 or 3 mg/ The dose of kg is administered intravenously or repeatedly intravenously. After euthanasia treatment at the time of infection for 10 hours, the lungs were taken to prepare lung homogenates, thereby measuring the number of bacteria in the lungs.

 (result)  

The number of endophytic bacteria in the lungs from the start of treatment with compound I-027 was reduced by 0.8 to 1.9 log10 CFU.

From the above results, it is known that the compound represented by the formula (I) has a broad spectrum of antibacterial spectrum, particularly a strong antibacterial spectrum for Gram-negative bacteria, and/or for multi-drug resistant bacteria, particularly for the production of type B. The Gram-negative bacteria of the metal-β-endosmease exhibits strong antibacterial activity, and/or exhibits strong antibacterial activity against Gram-negative bacteria that produce β-endosaminolase of type A such as KPC. Further, it has strong antibacterial activity against Gram-negative bacteria which produce the C-type β-endosaminolase. Further, it has been shown to be effective against multi-drug resistant bacteria including carbapenem resistance, and also has high stability against Gram-negative bacteria producing β-endoprostase.

 Test Example 2: CYP inhibition test  

Using commercially available pooled human liver microsomes as a typical stromal metabolic responder for human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4), 7-ethoxy resorufin O-deethylation (CYP1A2) of (7-ethoxyresorufin), methyl-hydroxylation of tolbutamide (CYP2C9), 4'-hydroxylation of Mephenytoin (CYP2C19), dextromethorone O-demethylation (CYP2D6) of phenol (Dextromethorphan) and hydroxylation (CYP3A4) of terfenadine (CYP3A4) were used as indicators to evaluate the extent to which individual metabolite production was inhibited by the compounds of the present invention.

The reaction conditions are as follows: matrix, 0.5 μmol/L ethoxylated resorufin (CYP1A2), 100 μmol/L tolbutamide (CYP2C9), 50 μmol/L S-mefentoin (CYP2C19), 5 μmol /L of dextromethorol (CYP2D6), 1 μmol/L of tefenacidine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C; enzyme, pooling human liver microsomes 0.2 mg protein / mL; compounds of the invention Concentrations, 1, 5, 10, 20 μmol/L (4 types).

In a 96-well plate, five kinds of each matrix, human liver microsomes, and a compound of the present invention were added in the above composition in a 50 mmol/L Hepes buffer solution as a reaction solution, and NADPH belonging to a supplemental enzyme was added to start the reaction. Metabolic response of the indicator. After reacting at 37 ° C for 15 minutes, the reaction was stopped by adding a methanol / acetonitrile = 1 / 1 (V / V) solution. After centrifugation at 3000 rpm for 15 minutes, the resorufin (CYP1A2 metabolite) in the centrifugation supernatant was quantified by a fluorescent multi-label counter to give toluene butyrate hydroxylate (CYP2C9 metabolite), mefenexine. British 4' hydroxylate (CYP2C19 metabolite), dextrorphan (CYP2D6 metabolite), and tefinadine (CYP3A4 metabolite) were quantified by LC/MS/MS.

In the reaction system, only DMSO in which the solvent of the compound of the present invention was dissolved was added as a control group (100%), and the residual activity (%) of the compound of the present invention at various concentrations in the solvent was calculated, and the use concentration and the inhibition rate were determined. The IC50 is calculated by the inverse of the logistic model.

 Test Example 3: BA test  

Oral absorption of experimental materials review and methods

(1) Animal use: A mouse or a SD rat is used.

(2) Breeding conditions: The mice or SD rats were allowed to freely ingest solid feed and sterilized tap water.

(3) Administration amount, group setting: The predetermined administration amount is administered by oral administration or intravenous administration. Set the group as described below. (The amount of each compound is changed)

Oral administration 1 to 30 mg/kg (n=2 to 3)

Intravenous administration of 0.5 to 10 mg/kg (n=2 to 3)

(4) Preparation of the administration solution: Oral administration is carried out by solution or suspension. The intravenous administration is solubilized and administered.

(5) Method of administration: Oral administration is forcibly administered into the stomach by a oral syringe (sonde). Intravenous administration is administered from the tail vein by means of a syringe with an injection needle.

(6) Evaluation item: Blood was collected over time, and the concentration of the compound of the present invention in plasma was measured using LC/MS/MS.

(7) Statistical analysis: For the concentration of the compound of the present invention in plasma, the area under the concentration-time curve in plasma (AUC) was calculated using the non-linear least squares method WinNonlin (registered trademark), and the group was administered orally. The AUC of the intravenously administered group calculates the bioavailability (BA) of the compounds of the invention.

 Test Example 4: Metabolic stability test  

The commercially available pooled human liver microsomes were reacted with the compound of the present invention for a certain period of time, and the residual rate was calculated by comparison of the reaction sample and the unreacted sample, and the degree of metabolism of the compound of the present invention in the liver was evaluated.

In 0.2 mL buffer (50 mmol/L TriS-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride) containing human liver microsomes 0.5 mg protein/mL, in the presence of 1 mmol/L NADPH The reaction was carried out at 37 ° C for 0 minutes or 30 minutes (oxidation reaction). After the reaction, 50 μL of the reaction solution was added to 100 μL of a methanol/acetonitrile=1/1 (v/v) solution, and after mixing, the mixture was centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifugation supernatant was quantified by LC/MS/MS, and the amount of the compound at the time of the reaction was taken as 100%, and the residual amount of the compound of the present invention after the reaction was calculated. Further, the hydrolysis reaction was carried out in the absence of NADPH, and the glucuronic acid binding reaction was carried out in the presence of NADPH replaced with 5 mmol/L of UDP-glucuronic acid, after which the same operation was carried out.

 Test Example 5: CYP3A4 Fluorescent MBI Test  

The CYP3A4 fluorescent MBI assay is a metabolic assay to investigate the inhibition of CYP3A4 inhibition by the compounds of the invention. 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by CYP3A4 enzyme (Escherichia coli enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC). The 7-HFC production reaction was used as an indicator to evaluate CYP3A4 inhibition.

The reaction conditions are as follows: substrate, 5.6 μmol/L 7-BFC; pre-reaction time, 0 minutes or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C (room temperature); CYP3A4 content (coliform expression enzyme), 62.5 pmol/mL in the pre-reaction and 6.25 pmol/mL in the reaction (at the 10-fold dilution); the concentration of the compound of the present invention was 0.625, 1.25, 2.5, 5, 10, 20 μmol/L (6 species).

In a 96-well plate, in a K-Pi buffer (pH 7.4) as a pre-reaction solution, an enzyme, a solution of the compound of the present invention is added to the above-mentioned pre-reaction composition in another 96-well plate to make the matrix and K-Pi buffer was diluted to 1/10 to remove part of it, and NADPH supplemented with enzyme was added to start the reaction as an indicator (no pre-reaction). After the reaction for a predetermined time, by adding acetonitrile / 0.5 mol / L TriS (Trishydroxyaminomethane) = 4/1 (V/V) stops the reaction. Moreover, NADPH is added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction). After the pre-reaction for a predetermined time, the substrate is removed in a manner to dilute the matrix and the K-Pi buffer to 1/10. Part of it begins to react as an indicator. After the reaction for a predetermined period of time, the reaction was stopped by adding acetonitrile / 0.5 mol / L TriS (trihydroxyaminomethane) = 4 / 1 (V / V). The plate value of each index reaction was measured by a fluorescent plate reader to measure the fluorescence value of the 7-HFC of the metabolite. (Ex=420nm, Em=535nm)

In the reaction system, only DMSO in which the solvent of the compound of the present invention was dissolved was added as a control group (100%), and the residual activity (%) at the concentration of each compound in the solvent was calculated, and the concentration and inhibition rate were used. The IC50 is calculated by reversing the logic model. When the difference in IC50 value is 5 μmol/L or more, it is (+), and when it is 3 μmol/L or less, it is (-).

 Test Example 6: Fluctuation Ames Test  

The variability of the compounds of the invention is assessed.

20 μL of the cryopreserved Salmonella typhimurium strain (Salmonella typhimurium TA98 strain, TA100 strain) was inoculated to 10 mL of a liquid nutrient medium (2.5% Oxoid nutrient broth No. 2), and cultured at 37 ° C for 10 hours before shaking. In the TA98 strain, 9 mL of the bacterial solution was centrifuged (2000 × g, 10 minutes) to remove the culture solution. In 9 mL of Micro F buffer (K ₂ HPO ₄ : 3.5 g / L, KH ₂ PO ₄ : 1 g / L, (NH ₄ ) ₂ SO ₄ : 1 g / L, trisodium citrate dihydrate: 0.25 g / L, MgSO ₄ ‧7H ₂ 0: 0.1g / L) suspension of bacteria, adding 110mL of Exposure medium (containing biotin: 8μg / mL, histidine: 0.2μg / mL, glucose: 8mg / mL of Micro F buffer liquid). In the TA100 strain, 3.16 mL of the bacterial solution was added to 120 mL of the Exposure medium to prepare a test bacterial solution. The DMSO solution of the compound of the present invention (diluted from the highest dose of 50 mg/mL in a 2 to 3 times ratio), as a negative control group, was DMSO; as a positive control group, under the condition of non-metabolic activation, against the TA98 strain. It is a 50 μg/mL 4-nitroquinoline-1-oxide DMSO solution, which is 0.25 μg/mL of 2-(2-furyl)-3-(5-nitro-2-furanyl) for TA100 strain. A acrylamide DMSO solution; under metabolic activation conditions, a solution of 40 μg/mL of 2-aminoguanidine DMSO for TA98 strain and a solution of 20 μg/mL of 2-aminoguanidine DMSO for TA100 strain, 12 μL of each solution Each was mixed with 588 μL of the test bacterial solution (mixture of 498 μL of the test bacterial solution and 90 μL of S9mix under metabolic activation conditions), and cultured at 37 ° C for 90 minutes with shaking. 460 μL of the bacterial solution exposed to the compound of the present invention and an indicator medium (containing biotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL, bromocresol purple: 37.5 μg/mL) The mixture was mixed with 2300 μL of MicroF buffer, and dispensed in 50 μL of each well (microplate 48 wells/amount), and cultured at 37 ° C for 3 days. A well containing a bacterium having a proliferative ability by a mutation in an amino acid (histidine acid) synthetase gene, which changes color from purple to yellow due to a change in pH, so that it is colored into a yellow bacterium per 48 pores. Proliferation wells were counted and compared to the negative control group for evaluation. Those with negative variability are shown as (-), and those with positive variability are shown as (+).

 Test Example 7; hERG test  

For the purpose of assessing the risk of QT interval prolongation of the electrocardiogram of the present invention, HEK293 cells expressing human ether-a-go-go related gene (hERG) channels were used to review the compounds of the present invention as important roles in ventricular repolarization. The effect of delaying rectification of K ⁺ current (IKr).

Depolarization stimulation of +40 mV was recorded using a fully automated patch clamp system (PatchXpress 7000A, Axon Instruments Inc.) by maintaining the cells at a membrane potential of -80 mV by the whole-cell patch clamp method. The IKr induced by the repolarization stimulation of -50 mV for 2 seconds was given for 2 seconds. After the generated current was stabilized, the extracellular solution of the compound of the present invention was dissolved at a concentration of interest at room temperature (NaCl: 135 mmol/L, KCl: 5.4 mmol/L, NaH ₂ PO ₄ : 0.3 mmol/L, CaCl _{2 ).} ‧2H ₂ O: 1.8 mmol/L, MgCl ₂ ‧6H ₂ O: 1 mmol/L, glucose: 10 mmol/L, HEPES (4-(2-hydroxyethyl)-1-per The ethanesulfonic acid): 10 mmol/L, pH = 7.4) was applied to the cells for 10 minutes. The absolute value of the maximum tail current was measured from the obtained IKr using the analytical software (DataXpress ver. 1, Molecular Devices Corporation) with the current value in the film potential as a reference. Further, the inhibition rate of the maximum tail current before administration of the compound of the present invention was calculated, and the effect of the compound of the present invention on IKr was evaluated in comparison with the vehicle administration group (0.1% dimethyl sulfoxide solution).

 Test Example 8: Solubility test  

The solubility of the compounds of the invention was determined under conditions of 1% DMSO addition. The compound of the present invention was prepared by preparing a compound solution of 10 mmol/L in DMSO and adding 594 μL of pH 6.8 artificial intestinal juice (120 mL of a 0.2 mol/L NaOH test solution and 1000 mL to 0.2 mL of a 0.2 mol/L potassium dihydrogen phosphate test solution). 6 μL of solution. After standing at 25 ° C for 16 hours, the mixture was suction filtered. The filtrate was diluted 2-fold with methanol/water = 1/1 (v/v) and the concentration in the filtrate was determined by absolute calibration curve method using HPLC or LC/MS/MS.

 Test Example 9: Powder Solubility Test  

An appropriate amount of the compound of the present invention was placed in a suitable container, and 200 μL of JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid added to 1000 mL) and JP-2 solution (at pH 6) were added to each container. To 500 mL of the phosphate buffer solution of .8, 500 mL of water was added, and 20 mmol/L of sodium taurocholate (TCA)/JP-2 solution (JP-2 solution was added to TCA 1.08 g to obtain 100 mL). When all the amounts are dissolved after the addition of the test liquid, the compound of the present invention is appropriately added. After sealing, the mixture was shaken at 37 ° C for 1 hour, filtered, and 100 μL of methanol was added to 100 μL of each filtrate to carry out 2-fold dilution. The dilution ratio is changed as needed. After confirming that there are no bubbles and precipitates, they are sealed and oscillated. The compounds of the invention were quantified by HPLC using an absolute calibration curve method.

 Test Example 10: Visual Solubility Test  

About 5 mg of the compound was weighed and placed in three microtest tubes, and each medium (water for injection, physiological saline, 0.5% glucose solution) was added so that the concentration of the compound became 20%. After stirring with a vortex, it was visually confirmed whether or not there was dissolution. If dissolved, the solubility of the medium is set to >20%. Further, each medium (water for injection, physiological saline, and glucose solution) was added to the test liquid to prepare a test solution having a compound concentration of 10%, and the mixture was stirred by a vortex mixer, and visually confirmed to be dissolved. If dissolved, the solubility of the medium is set to 20% to 10%. The test of 5% concentration, 2.5% concentration, and 1% concentration was carried out in the same manner, and when the concentration was not dissolved at 1%, the solubility of the medium was set to <1%. The pH of the test solution at a concentration of 1% was measured and recorded.

 Test Example 11: pKa measurement [Method for measuring capillary electrophoresis (CE method)]  

A method of separating the sample components in the buffer containing the electrolyte by free-flowing using a capillary electrophoresis technique.

After injecting the compound solution into a fused silica capillary filled with a buffer prepared to have a pH of 2.5 to 11.5, after applying a high voltage [Inlet side +, Outlet side -] to the capillary, The compound moves at a rate that reflects the ionization state in the pH of the buffer (the positively charged compound is fast and the negatively charged compound is slow). The difference between the movement time of this compound and the movement time of the neutral molecule (DMSO) was plotted against the pH, and the pKa was calculated by an approximate solution. The measurement conditions are as follows.

Equipment: Beckman P/ACE System MDQ PDA

Electrophoresis solution: pH 2.5 to 11.5 buffer (containing 10 vol% MeOH)

Sample solution: calibrated DMSO 10 μL + water for injection 90 μL mixed sample 10 mM DMSO stock 4 uL + DMSO 6 μL + water for injection 90 μL

 (method)  

Capillary: fused silica capillary (BECKMAN COULTER, inner diameter 50μm, full length 30.2cm, effective length 20.0cm)

Additional voltage: 10kV (331V/cm)

Additional air pressure: 0.7 psi

Capillary temperature: 25 ° C

Electroosmotic flow label: DMSO

Detection: Multi-wavelength absorption detection in the ultraviolet region (measurement wavelength; 215 nm, 238 nm)

Sample injection: pressurization (0.5 psi, 5 seconds)

 Formulation example  

The formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention.

 Formulation Example 1: Lozenge  

The compound of the present invention, lactose and calcium stearate are mixed, pulverized and granulated, and then dried to prepare granules of an appropriate size. Next, calcium stearate is added and compression-molded to form a tablet.

 Formulation Example 2: Capsule  

The compound of the present invention, lactose and calcium stearate are uniformly mixed to prepare a powder or a fine powder. The powder is filled in a capsule container to form a capsule.

 Formulation Example 3: granules  

The compound of the present invention, lactose, and calcium stearate are uniformly mixed, and after compression molding, pulverization, granulation, and screening are carried out to prepare granules having an appropriate size.

 Formulation Example 4: Oral disintegration ingot  

The compound of the present invention and crystalline cellulose are mixed, granulated, and then tableted to form an orally disintegrating ingot.

 Formulation Example 5: dry syrup  

The compound of the present invention and lactose are mixed, pulverized, sized, and sieved to prepare a dry syrup of an appropriate size.

 Formulation Example 6: Injection  

The compound of the present invention and a phosphate buffer are mixed to prepare an injection.

 Formulation Example 7: Dropping agent  

The compound of the present invention and a phosphate buffer were mixed to prepare a drip.

 Formulation Example 8: Inhalation  

The compound of the present invention and lactose are mixed and finely pulverized to prepare an inhalant.

 Formulation Example 9: Ointment  

The compound of the present invention and petrolatum were mixed to prepare an ointment.

 Formulation Example 10: Adhesive  

A base such as a compound of the present invention and an adhesive paste is mixed to prepare a patch.

 [Industrial availability]  

The compound of the present invention has a broad spectrum of antibacterial spectrum especially for Gram-negative bacteria, and has high stability against Gram-negative bacteria producing β-endoprostanase, and is an effective antibacterial agent. Furthermore, the body dynamics are also good, and the water solubility is also high, so it is particularly effective as an injectable drug or an oral drug system.

Claims (21)

A pharmaceutical composition comprising a compound represented by the formula (I), an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt, or a hydrate thereof; Wherein -W- is -S(=O)- or -S(=O) ₂ -; -T- is -CR ^4A R ^4B - or -CR ^5A R ^5B -CR ^6A R ^6B -; R ^4A , R ^4B , R ^5A , R ^5B , R ^6A and R ^6B are each independently a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, a decyl group, a decyloxy group, a thiol group, a sulfo group, a diphosphoryl group, a cyano group, a nitrate Alkyl, ureido, indolyl, fluorenyl, substituted or unsubstituted amino, substituted or unsubstituted aminemethyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted alkyl, substituted or Unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfonyl Alkenyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenyl Sulfosin , substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or Non-substituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclicoxy group, substituted or unsubstituted non-aromatic heterocyclic oxy group, substituted or unsubstituted aromatic carboepoxy group, substituted or non-substituted a substituted aromatic heterocyclic oxy group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group, a substituted or unsubstituted aromatic carbocyclic oxycarbonyl group, Substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted aromatic carbocyclic thio , substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted non-aromatic carbosulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic Carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic Sulfhydryl, substituted or unsubstituted non-aromatic carbosulfonyl, substituted or unsubstituted non-aromatic heterocyclosulfonyl, substituted or unsubstituted aromatic carbosulfonyl, or substituted or unsubstituted An aromatic heterocyclic sulfonyl group; R ¹ is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group; R ^2A and R ^2B are: a) R ^2A and R ^2B are each independently a hydrogen atom; , substituted or unsubstituted amino, sulfo, substituted or unsubstituted sulfonyl, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminyl, hydroxy, decyl, or a carbonyloxy group having a substituent; or, b) R ^2A and R ^2B together form a substituted or unsubstituted methylene group, a substituted or unsubstituted hydroxyimino group, or =N-NR ^13A R ^13B ; R ^13A and R ^{13B is} independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted amine carbenyl group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted group. a heterocyclic group; R ³ is a hydrogen atom, -OCH ₃ or -NH-CH(=O); R ¹¹ is a carboxyl group or a tetrazolyl group; R ^7A and R ^7B are each independently The site is a hydrogen atom or a substituted or unsubstituted alkyl group. The pharmaceutical composition according to claim 1, wherein the compound containing R ¹ is a substituted or unsubstituted aromatic heterocyclic group, an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt, or the like Hydrate. The pharmaceutical composition according to claim 1, wherein the compound having R ¹ is a group represented by the following formula, an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt or a hydrate thereof; Wherein X is CH, CCl, CF, or N. The pharmaceutical composition according to any one of claims 1 to 3, wherein R ^2A and R ^2B together form a methylene group having a substituent shown below: or Or a substituted or unsubstituted hydroxyimino group-containing compound, an ester thereof, or a pharmaceutically acceptable salt, or a hydrate thereof; Wherein R ¹⁰ is a hydrogen atom, a sulfo group, a substituted or unsubstituted alkoxysulfonyl group, a substituted or unsubstituted alkenyloxysulfonyl group, a substituted or unsubstituted alkynylsulfonyl group, a substituted or Unsubstituted carboxycyclooxysulfonyl, substituted or unsubstituted heterocyclooxysulfonyl, diphosphoryl, substituted or unsubstituted aminecardenyl, substituted or unsubstituted amine sulfonyl, substituted Or an unsubstituted alkoxycarbonyl group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted alkynyloxycarbonyl group, a substituted or unsubstituted carbocyclic oxycarbonyl group, a substituted or unsubstituted heterocyclic oxycarbonyl group, a substituted or An unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group. The pharmaceutical composition according to any one of claims 1 to 3, which is a compound containing R ^2A and R ^2B together as a group represented by the following formula, or an ester thereof, or equivalent to a pharmaceutical one a salt, or a hydrate of the same; Wherein R ⁸ and R ⁹ are each independently a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted group. a carbocyclic group, or a substituted or unsubstituted heterocyclic group; or R ⁸ and R ⁹ together form a substituted or unsubstituted methylene group, or R ⁸ and R ⁹ together with an adjacent atom form a substituted or unsubstituted a non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; Q is a single bond, a substituted or unsubstituted carbocyclic diyl group or a substituted or unsubstituted heterocyclic diyl group; m is 0 to 3 An integer: R ¹² is a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a carboxyl group, a hydroxyl group, a substituted or a non-substituted group. Substituted amine, sulfo, diphosphoryl, cyano, hydroxyiminomethyl, aminecarboxamidine, substituted or unsubstituted monoalkylamine, mercapto, substituted or unsubstituted dialkylamine Mercapto, substituted or unsubstituted monoalkylamine sulfonyl, substituted or unsubstituted dialkylamine sulfonyl, Alken or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkanesulfonyl imido, alkoxycarbonylamino, alkoxyamine, mercapto, Hydroxyamine, mercapto, ureido, sulfhydryl, alkanesulfonylamino, amine sulfonyl, amine sulfonylamino, alkanesulfonylamine, mercaptoamine, alkylamine sulfonylamine A fluorenyl, substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted quaternary ammonium group. The pharmaceutical composition according to any one of claims 1 to 5, which is a compound containing R ³ as a hydrogen atom, an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt, or a hydrate thereof . The pharmaceutical composition according to any one of claims 1 to 6, which contains -T- is -CR ^4A R ^4B -, and R ^4A and R ^4B are each independently a hydrogen atom or a substituted or unsubstituted The alkyl compound, the ester thereof, or the equivalent of a pharmaceutically acceptable salt, or a hydrate thereof.  The pharmaceutical composition according to any one of claims 1 to 7, which is a compound containing -W- is -S(=O)-, an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt, Or such hydrates.   The pharmaceutical composition according to any one of claims 1 to 7, which contains -W- as a compound represented by the following formula, an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt, or the like Hydrate; The pharmaceutical composition according to any one of claims 1 to 7, which contains -W- as a compound represented by the following formula, an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt, or the like Hydrate; The pharmaceutical composition according to any one of claims 1 to 7, which contains -W- is a compound of -S(=O) ₂ -, an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt. Or such hydrates. The pharmaceutical composition according to any one of claims 1 to 11, which is a compound containing R ¹¹ as a carboxyl group, an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt or a hydrate thereof. The pharmaceutical composition according to any one of claims 1 to 12, which is a compound containing R ^7A and R ^{7B which are} simultaneously a hydrogen atom, an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt, or Wait for hydrates. The pharmaceutical composition according to claim 1, wherein the compound of the formula (I) is a compound represented by the following formula, an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt or a hydrate thereof; Where -W- is the one shown below: R ^4A is a hydrogen atom; R ^4B is a hydrogen atom or a methyl group; and R ¹ is represented by the following formula: Wherein X is CH; R ^7A and R ^7B are a hydrogen atom; and R ^2A and R ^2B together form a hydroxyimino group or the formula: Wherein R ⁸ and R ⁹ are each independently a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, an alkyl group, or a hydroxyalkyl group, or R ⁸ and R ⁹ may form a substituted or unsubstituted non-substituted carbon atom; An aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; m is an integer of 0 to 3, and R ¹² is a hydrogen atom, a carboxyl group, a sulfo group, an amine carbenyl group, a hydroxylamine formamyl group, an alkoxy group An amidoxime group or a hydroxyl group; R ³ is a hydrogen atom; and R ¹¹ is a carboxyl group.  The pharmaceutical composition according to claim 1, wherein the compound represented by the formula (I) is the compound I-001, I-004, I-005, I-007, I-009, I-015, Any of I-023, I-024, I-026, I-027, I-047, I-048, I-049, I-052, I-053, I-059, I-060, and I-061 One.    The pharmaceutical composition according to any one of claims 1 to 15, which is an antibacterial agent.   An antibacterial agent comprising a compound represented by the following formula (I), an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt or a hydrate thereof; Wherein -W- is -S(=O)- or -S(=O) ₂ -; -T- is -CR ^4A R ^4B - or -CR ^5A R ^5B -CR ^6A R ^6B -;R ^4A , R ^4B , R ^5A , R ^5B , R ^6A and R ^6B are each independently a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, a decyl group, a decyloxy group, a thiol group, a sulfo group, a diphosphoryl group, a cyano group, a nitrate Alkyl, ureido, indolyl, fluorenyl, substituted or unsubstituted amino, substituted or unsubstituted aminemethyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted alkyl, substituted or Unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkanesulfonyl , substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxycarbonyl, Substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenyl Sulfonyl Substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic, substituted or unsubstituted non-aromatic heterocyclic, substituted or unsubstituted aromatic carbocyclic, substituted or non-substituted Substituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclicoxy group, substituted or unsubstituted non-aromatic heterocyclic oxy group, substituted or unsubstituted aromatic carboepoxy group, substituted or unsubstituted Aromatic heterocyclic oxy group, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group, substituted or unsubstituted aromatic carbo oxycarbonyl group, substituted Or an unsubstituted aromatic heterocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic carbocyclic thio group, a substituted or unsubstituted non-aromatic heterocyclic thio group, a substituted or unsubstituted aromatic carbocyclic thio group, Substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted non-aromatic carbosulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic carbon Sulfosulfonyl, substituted or unsubstituted aromatic heterocyclic sulfin Mercapto, substituted or unsubstituted non-aromatic carbosulfonyl, substituted or unsubstituted non-aromatic heterocyclosulfonyl, substituted or unsubstituted aromatic carbosulfonyl, or substituted or unsubstituted An aromatic heterocyclic sulfonyl group; R ¹ is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group; R ^2A and R ^2B are: a) R ^2A and R ^2B are each independently a hydrogen atom; , substituted or unsubstituted amino, sulfo, substituted or unsubstituted sulfonyl, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminyl, hydroxy, or substituted a carbonyloxy group, or b) R ^2A and R ^2B together form a substituted or unsubstituted methylene group, a substituted or unsubstituted hydroxyimino group, or =N-NR ^13A R ^13B ; R ^13A and R ^13B respectively Independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted amine carbenyl group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic ring. group; R ³ is a hydrogen atom, -OCH ₃ or -NH-CH (= O); R 11 is carboxy or tetrazolyl; R ^7A and R ^7B are each independently Is a hydrogen atom or a substituted or unsubstituted alkyl of. A cell wall synthesis inhibitor comprising a compound represented by the following formula (I), an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt, or a hydrate thereof; Wherein -W- is -S(=O)- or -S(=O) ₂ -; -T- is -CR ^4A R ^4B - or -CR ^5A R ^5B -CR ^6A R ^6B -; R ^4A , R ^4B , R ^5A , R ^5B , R ^6A and R ^6B are each independently a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, a decyl group, a decyloxy group, a thiol group, a sulfo group, a diphosphoryl group, a cyano group, a nitrate Alkyl, ureido, indolyl, fluorenyl, substituted or unsubstituted amino, substituted or unsubstituted aminemethyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted alkyl, substituted or Unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkanesulfonyl , substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxycarbonyl, Substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenyl Sulfonyl Substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic, substituted or unsubstituted non-aromatic heterocyclic, substituted or unsubstituted aromatic carbocyclic, substituted or non-substituted Substituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclicoxy group, substituted or unsubstituted non-aromatic heterocyclic oxy group, substituted or unsubstituted aromatic carboepoxy group, substituted or unsubstituted Aromatic heterocyclic oxy group, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group, substituted or unsubstituted aromatic carbo oxycarbonyl group, substituted Or an unsubstituted aromatic heterocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic carbocyclic thio group, a substituted or unsubstituted non-aromatic heterocyclic thio group, a substituted or unsubstituted aromatic carbocyclic thio group, Substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted non-aromatic carbosulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic carbon Sulfosulfonyl, substituted or unsubstituted aromatic heterocyclic sulfin Mercapto, substituted or unsubstituted non-aromatic carbosulfonyl, substituted or unsubstituted non-aromatic heterocyclosulfonyl, substituted or unsubstituted aromatic carbosulfonyl, or substituted or unsubstituted An aromatic heterocyclic sulfonyl group; R ¹ is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group; R ^2A and R ^2B are: a) R ^2A and R ^2B are each independently a hydrogen atom; A substituted or unsubstituted amino group, a sulfo group, a substituted or unsubstituted amine sulfonyl group, a carboxyl group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted amine carbenyl group, a hydroxyl group, or a substituent a carbonyloxy group, or b) R ^2A and R ^2B together form a substituted or unsubstituted methylene group, a substituted or unsubstituted hydroxyimino group, or =N-NR ^13A R ^13B ; R ^13A and R ^13B are each independently Is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted amine carbenyl group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group. R ³ is a hydrogen atom, -OCH ₃ or -NH-CH(=O); R ¹¹ is a carboxyl group or a tetrazolyl group; R ^7A and R ^7B are each independently The hydrogen atom is either a substituted or unsubstituted alkyl group.  A compound, an ester thereof or a salt which is equivalent to a pharmaceutically acceptable salt, or a hydrate thereof, which is I-075, I-076, I-077, I-078, I-079, I-080 Any of I-082, I-083, I-084, I-087, I-093, I-110, I-121, I-132, and I-144.    A pharmaceutical composition comprising a compound described in claim 19, an ester thereof or a salt which is equivalent to a pharmaceutical agent or a hydrate thereof.    The pharmaceutical composition as described in claim 20 of the patent application has an antibacterial effect.