WO2018123920A1 - Tricyclic compound having sulfinyl and pharmaceutical composition containing said compound - Google Patents

Abstract

Provided are: a compound that exhibits a broad antibacterial spectrum against various bacteria, including gram-negative bacteria; and a pharmaceutical composition that has antibacterial activity against carbapenem-resistant bacteria.

Description

Tricyclic compound having sulfinyl and pharmaceutical composition containing the same

The present invention relates to a novel tricyclic compound having antibacterial activity, an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and a pharmaceutical composition containing them.

Various β-lactam drugs have been developed so far, and β-lactam drugs have become clinically very important antibacterial drugs. However, an increasing number of bacterial strains have acquired resistance to β-lactam drugs by producing β-lactamase that degrades β-lactam drugs.
According to Ambler's molecular taxonomy, β-lactamases are broadly classified into four classes. 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 (such as OXA type). Of these, class A, C, and D types are broadly classified into serine-β-lactamases, while class B types are broadly classified into metallo-β-lactamases, which are known to hydrolyze β-lactam drugs by different mechanisms. ing.
In recent years, by the production of serine-β-lactamases including Klebsiella pneumoniae Carbapeenase (KPC) in addition to class A (ESBL) and class D with an extended substrate range, and further, class B metallo-β-lactamases, The existence of Gram-negative bacteria highly resistant to many β-lactam drugs including carbapenem and carbapenem has become a clinical problem. In particular, Enterobacteriaceae bacteria that produce KPC and metallo-β-lactamase are known to exhibit high resistance to carbapenem antibacterial agents, which are important for the treatment of Gram-negative bacterial infections.
A β-lactam drug exhibits an antibacterial action by inhibiting a bacterial cell wall synthase having transpeptidase activity, commonly called penicillin binding protein (hereinafter referred to as PBP) (Non-patent Document 1). On the other hand, as described above, β-lactamase produced by resistant bacteria efficiently recognizes and degrades β-lactam drugs, thereby inactivating the antibacterial activity of β-lactam drugs. From this, if it is possible to avoid recognition of β-lactamase and maintain inhibitory activity against PBP, it is considered that an effective β-lactam drug can be created even against resistant bacteria. However, their similarity to substrate recognition is very high, making it extremely difficult to distinguish structurally and preventing the creation of β-lactam drugs that are effective against resistant bacteria.
Cephem compounds that exhibit moderate activity against gram-negative bacteria, including metallo-β-lactamase-producing gram-negative bacteria are known (eg, Patent Document 1), but stronger antibacterial activity, especially various β-lactamase-producing gram The development of β-lactam drugs effective against negative bacteria is eagerly desired.
Patent Documents 2 and 3 report β-lactam compounds having a novel skeleton, but do not describe antibacterial activity against the above-mentioned carbapenem-resistant bacteria and the like that have become problematic in recent years. Moreover, from the described antibacterial activity, it cannot be imagined at all that the compound group having this skeleton has an antibacterial activity in carbapenem-resistant bacteria.

International Publication No. 2007/119511 European Patent Application Publication No. 0253337 European Patent Application Publication No. 0249909

The present invention provides a tricyclic compound containing a substituted or unsubstituted 5-oxotetrahydrofuran ring having a strong antibacterial spectrum and having sulfinyl against various bacteria including Gram-negative bacteria. Furthermore, a carbapenem-resistant bacterium comprising a tricyclic compound having a substituted or unsubstituted 5-oxotetrahydrofuran ring and having sulfinyl, an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof A pharmaceutical composition having antibacterial activity is provided. Preferably, a compound showing strong antibacterial activity against β-lactamase-producing gram-negative bacteria, or a pharmaceutical composition containing the compound is provided. More preferably, a compound showing strong antibacterial activity against a KPC-type carbapenemase-producing bacterium, a class B-type metallo-β-lactamase (MBL) -producing gram-negative bacterium, or a pharmaceutical composition containing the compound is provided. To do. More preferably, in addition to the β-lactamase, a compound exhibiting effective antibacterial activity against Gram-negative bacteria that produce substrate-specific extended β-lactamase (ESBL) and / or class C β-lactamase, or Pharmaceutical compositions containing the compounds are provided.

This invention solves the said subject by having the following structural characteristics at least, and provides the pharmaceutical composition which has an antibacterial action with respect to a carbapenem resistant microbe.
1) It has a tricyclic mother nucleus containing a 6-membered ring having sulfinyl.
2) It has a tricyclic mother nucleus containing a substituted or unsubstituted 5-oxotetrahydrofuran ring.
3) An amide substituent (a carbonylamino group having a substituent) is present on the lactam ring in the tricyclic mother nucleus.

(Item 1) Formula:

Or an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
(Item 2) Formula:

The compound according to item 1, which is any of the above, an ester thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
(Item 3) A pharmaceutical composition comprising the compound according to item 1 or 2, its ester or pharmaceutically acceptable salt, or a hydrate thereof.
(Item 4) The pharmaceutical composition according to item 3, which has an antibacterial action.
(Item 5) An antibacterial agent comprising the compound according to item 1 or 2, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
(Item 6) A cell wall synthesis inhibitor comprising the compound according to item 1 or 2, an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
(Item 7) A method for treating a disease associated with bacterial infection, which comprises administering the compound according to item 1 or 2, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof. Its prevention method.
(Item 8) The compound according to item 1 or 2, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof for treating or preventing a disease associated with bacterial infection.

(Item 9) A pharmaceutical composition for oral administration comprising the compound according to item 1 or 2, an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

(Item 10) Tablets, powders, granules, capsules, pills, films, suspensions, emulsions, elixirs, syrups, limonades, spirits, aromatic liquids, extracts, decoctions or tinctures Item 10. A pharmaceutical composition according to Item 9.

(Item 11) Sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troche tablets, sublingual tablets, buccal tablets, chewable tablets, orally disintegrating tablets, dry syrup, soft capsules, microcapsules or sustained-release capsules Item 11. A pharmaceutical composition according to Item 10, which is an agent.

(Item 12) A pharmaceutical composition for parenteral administration, comprising the compound according to item 1 or 2, an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

(Item 13) The pharmaceutical composition according to item 12, for transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop or intravaginal administration.

(Item 14) Injections, drops, eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings, gargles, enemas, ointments, plasters, jellys 14. A pharmaceutical composition according to item 12 or 13, which is a cream, a patch, a poultice, a powder for external use or a suppository.

(Item 15) A pharmaceutical composition for children or the elderly, comprising the compound according to item 1 or 2, an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

(Item 16) The compound according to item 1 or 2, its ester form or a pharmaceutically acceptable salt thereof, or a hydrate thereof, a β-lactamase inhibitor, an antibacterial agent having anti-gram positive bacterial activity and / or Or a pharmaceutical composition comprising a combination with an antibacterial agent having anti-anaerobic activity.

(Item 17) The compound according to item 1 or 2, its ester form or a pharmaceutically acceptable salt thereof, or a hydrate thereof, a β-lactamase inhibitor, an antibacterial agent having anti-gram positive bacterial activity and / or Or a pharmaceutical composition for combination therapy with an antibacterial agent having anti-anaerobic activity.

The compound of the present invention is useful as a pharmaceutical in that it has at least one of the following characteristics.
A) Exhibits a broad antibacterial spectrum against various gram-negative bacteria.
B) Exhibits a broad antibacterial spectrum against various gram-positive bacteria.
C) Strong antibacterial activity against β-lactamase-producing gram-negative bacteria.
D) Strong antibacterial activity against multidrug-resistant bacteria, particularly class B type metallo-β-lactamase-producing gram-negative bacteria.
E) Strong antibacterial activity against the substrate-specific extended β-lactamase (ESBL) -producing bacterium.
F) Strong antibacterial activity against gram-negative bacteria producing class C β-lactamase.
G) Strong antibacterial activity against carbapenem-resistant bacteria.
H) Strong antibacterial activity against Enterobacteriaceae bacteria resistant to over-the-counter drugs.
I) It exhibits strong antibacterial activity against carbapenem-resistant Enterobacteriaceae (CRE) producing carbapenemases such as Klebsiella pneumoniae Carbapenemase (KPC) and New Delhi metallo-beta-lactamase (NDM).
J) Does not show cross-resistance with existing cephem and / or carbapenem drugs.
K) Does not show side effects such as fever after administration in vivo.
L) The stability of the compound (for example, solution stability and light stability in various liquid properties) and / or solubility in water is high.
M) It has excellent pharmacokinetic characteristics such as high blood concentration, high oral absorption, high membrane permeability, long duration of effect, and high tissue migration.
N) The inhibitory action against CYP enzyme (for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
O) High metabolic stability.
P) Does not cause gastrointestinal disorders (eg, diarrhea, hemorrhagic enteritis, gastrointestinal ulcer, gastrointestinal bleeding, etc.).
Q) Does not cause nephrotoxicity, hepatotoxicity, cardiotoxicity (for example, QTc prolongation, etc.), convulsions or the like.

Hereinafter, embodiments of the present invention will be described with respect to the present invention. Throughout this specification, expressions in the singular (eg, “a”, “an”, “the” in the case of English, corresponding articles, adjectives, etc. in other languages, etc.) It should be understood to include the concept of shape. In addition, it is to be understood that terms used in the specification are used in the meaning normally used in the art unless otherwise specified. Thus, unless defined otherwise, all technical and chemical technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control. Hereinafter, specific definitions of terms specifically used in the present specification will be described.
The term “consisting of” means having only the configuration requirements.
The term “comprising” is not limited to the constituent elements and means that elements not described are not excluded.

The compounds of the present invention are not limited to specific isomers except for the bonds described in the wedge notation, and all possible isomers (eg keto-enol isomer, imine-enamine isomer, diastereoisomer) Isomers, optical isomers, rotational isomers, geometric isomers, etc.), racemates or mixtures thereof.
Among the compounds of the present invention, when a compound having an asymmetric atom (eg, carbon atom, sulfur atom) and a substituent on the asymmetric atom is indicated by a solid line, the configuration of the asymmetric atom cannot be specified. Is a single stereoisomer (R-form or S-form) or a mixture thereof.

For example, when the compound of the present invention is represented by the following formula (Ia):

Each isomer has the following structure:

(Where -W- is the formula:

Or

R ^4A is a hydrogen atom; R ^4B is a hydrogen atom or substituted or unsubstituted alkyl; R ¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted carbocycle A compound represented by the formula).
Here, the substituted or unsubstituted alkyl of R ^{4B and} the substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted carbocyclic group of R ¹⁰ are the same as those of the compound according to Item 1 or 2 Corresponding specific substituents shall be included.
The compound of the present invention preferably has, for example, the configuration represented by the following formula (Ia-1).

(Where -W- is the formula:

R ^4A is a hydrogen atom; R ^4B is a hydrogen atom or substituted or unsubstituted alkyl; R ¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted carbocycle Formula group)
Note that the notation in the following formula means the same steric configuration as in the above formula (Ia-1).

(Where -W- is the formula:

R ^4A is a hydrogen atom; R ^4B is a hydrogen atom or substituted or unsubstituted alkyl; R ¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted carbocycle Formula group)

For example, when the compound of the present invention is represented by the following formula (Ia), the substitution positions on the skeleton of the compound of the present invention are named as follows. In this specification, the A-position side chain and the B-position side chain represent groups bonded to the A-position and B-position of the following mother nucleus.

The ester form in the compound of the present invention is, for example, described in the case where the compound of the present invention is represented by the above formula (Ia). In that case, the ester form is included. Here, in the case where carboxy is present on the B-position side chain, the ester form is obtained when carboxy is substituted at the terminal of the substituent on the “substituted alkyl, substituted alkenyl or substituted carbocyclic group” of R ^10. And the ester of carboxy. These ester forms include esters that are easily metabolized in the body to form a carboxy state.

Protecting groups such as carboxy described above include Protective Groups in Organic Synthesis, T. et al. W. By Greene, John Wiley & Sons Inc. (1991) and the like, and any group that can be protected and / or deprotected can be used. For example, alkyl (eg, methyl, ethyl, t-butyl), alkylcarbonyloxymethyl (eg, pivaloyl), substituted Arylalkyl (eg: benzyl, benzhydryl, phenethyl, p-methoxybenzyl, p-nitrobenzyl), silyl group (eg: t-butyldimethylsilyl, diphenyl t-butylsilyl) and the like.

One or more hydrogen, carbon and / or other atoms of the compounds of the present invention may be replaced with hydrogen, carbon and / or isotopes of other atoms, 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 and ¹⁸ F, respectively. Hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur and fluorine are included. The compounds of the present invention also include compounds substituted with such isotopes. The compound substituted with the isotope is useful as a pharmaceutical and includes all radiolabeled compounds of the present invention. A “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.

The radioactive label of the compound of the present invention can be prepared by a method well known in the art. For example, a tritium-labeled compound of the compound of the present invention can be prepared by introducing tritium into a specific compound of the present invention, for example, by a catalytic dehalogenation reaction using tritium. This method involves reacting a compound in which the compound of the present invention is appropriately halogen-substituted with tritium gas in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). ¹⁴ C-labeled compounds can be prepared by using raw materials having ¹⁴ C carbon.

The salt of the compound of the present invention is a salt with an alkali metal, an alkaline earth metal, or the like when carboxy or phospho is present on the carboxy at the A position and / or B side chain. And those in which the amino group present in the B-position side chain forms a salt with an inorganic acid or organic acid.

Examples of the pharmaceutically acceptable salt of the compound of the present invention include, for example, the compound of the present invention, an alkali metal (for example, lithium, sodium, potassium, etc.), an alkaline earth metal (for example, calcium, barium, etc.), magnesium, and a transition metal. (Eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline, etc.) and salts with amino acids Or inorganic acids (eg, hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (eg, formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, Lactic acid, tartaric acid, oxalic acid, male Phosphate, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p- toluenesulfonic acid, methanesulfonic acid, and salts with ethanesulfonic acid, etc.). These salts can be formed by a commonly performed method.

The compound of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.) and / or a crystal polymorph, and the present invention includes such various solvates and crystals. Also includes polymorphs. The “solvate” may be coordinated with any number of solvent molecules (for example, water molecules) with respect to the compound of the present invention. When the compound of the present invention or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate. In addition, the crystalline polymorph may be formed by recrystallizing the compound of the present invention or a pharmaceutically acceptable salt thereof.

The compound of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs. A prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo. Prodrugs include compounds that are enzymatically oxidized, reduced, hydrolyzed and converted to the compounds of the present invention under physiological conditions in vivo, compounds that are hydrolyzed by gastric acid, etc. and converted to the compounds of the present invention, etc. Include. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.

When the compound of the present invention or a pharmaceutically acceptable salt thereof has a hydroxy group, for example, the compound having a hydroxy group and an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride, and a mixed anion. Examples thereof include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting with hydride or using a condensing agent. 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—, CH ₂ N (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 —, and p—CH ₃ PhSO ₃ — can be mentioned.

As described in the following general synthesis methods and examples, the compound of the present invention can be obtained by bonding side chain sites to the A-position and B-position of the skeleton of the following intermediate, respectively. Examples of the protecting group P include protecting groups described in the following general synthesis. Preferred examples include benzhydryl group, paramethoxybenzyl group, trityl group, 2,6-dimethoxybenzyl group, methoxymethyl group, benzyl group. Examples thereof include an oxymethyl group and a 2- (trimethylsilyl) ethoxymethyl group. Examples of the leaving group include halogen (Cl, Br, I, F), methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy and the like.

(Manufacturing method A)

(Wherein, -T- is ^-CR 4A ^{R 4B} - a and;
R ^4A is a hydrogen atom; R ^4B is a hydrogen atom or substituted or unsubstituted alkyl;
R ³ is a hydrogen atom;
P ¹ represents an amino-protecting group, and P ² and P ³ each independently represent a carboxy-protecting group. )
Process 1
Compound (IV) is obtained by subjecting compound (II) and compound (III) to addition reaction and intramolecular cyclization reaction. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, alcohols (eg methanol, Eta Lumpur, t-butanol, etc.), and water are exemplified. These solvents may be used alone or in combination of two or more.
Acetone and HMPA are preferred. The reaction temperature is usually about −100 to 100 ° C., preferably about −20 to 40 ° C., more preferably about 10 to 30 ° C. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.

Process 2
It subjected the compound protecting group P ³ of (IV) under acidic conditions deprotection reaction to obtain subsequently a compound by subjecting the intramolecular cyclization reaction under condensing agent present in the (V). Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, alcohols (eg methanol, Eta Lumpur, t-butanol, etc.), and water are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dichloromethane. Examples of the acid used for the deprotection reaction include organic acids and inorganic acids. For example, trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like can be mentioned. Trifluoroacetic acid is preferred. Examples of the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide, carbonyldiimidazole and the like. The reaction temperature is usually about −100 to 100 ° C., preferably about −20 to 40 ° C., more preferably about 0 to 20 ° C. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.

Process 3
Compound (VI) is obtained by subjecting amino protecting group P ¹ containing an acyl group of compound (V) to an alcoholysis reaction in the presence of a base or a deprotection reaction under acidic conditions. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, alcohols (eg methanol, Eta Lumpur, t-butanol, etc.), and water are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dichloromethane. The alcoholysis decomposition reaction can be activated by phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride or the like. Preferably, it is phosphorus pentachloride. Examples of the base include organic bases. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine, dimethylaniline and the like can be mentioned. Pyridine is preferred. Then add alcohol. As the alcohol, methanol, ethanol, propanol or the like can be used. Ethanol is preferable. Examples of the acid used in the deprotection reaction under acidic conditions include organic acids and inorganic acids. For example, trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like can be mentioned. The reaction temperature is usually about −100 to 100 ° C., preferably about −70 to 20 ° C., more preferably about −70 to −30 ° C. for the alcoholysis reaction. The deprotection reaction under acidic conditions is usually about −100 to 100 ° C., preferably about −20 to 40 ° C., more preferably about −20 to 20 ° C. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.

(Wherein R ¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted carbocyclic group; other symbols are as defined above)
Process 4
Compound (VIII) is obtained by subjecting compound (VI) to a condensation reaction with compound (VII) in the presence of a base. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, MeCN, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, alcohols (eg, methanol, ethanol Etc. t- butanol), and water are exemplified. These solvents may be used alone or in combination of two or more. Examples of the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, phosphorus oxychloride, methanesulfonyl chloride, dicyclohexylcarbodiimide, carbonyldiimidazole, and phenyl phosphate dichloride. Examples of the base include triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like. The reaction temperature is usually about −100 to 100 ° C., preferably about −80 to 20 ° C., more preferably about −20 to 20 ° C. The reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.

Process 5
Compound (IX) is obtained by oxidizing compound (VIII). Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, MeCN, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, alcohols (eg, methanol, ethanol Etc. t- butanol), and water are exemplified. These solvents may be used alone or in combination of two or more. Examples of the oxidizing agent include peracetic acid, m-chloroperbenzoic acid, hydrogen peroxide, sodium tungstate, and the like. The reaction temperature is usually about −100 to 100 ° C., preferably about −80 to 20 ° C., more preferably about −20 to 20 ° C. The reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.

Step 6
All protecting groups of compound (IX) are subjected to a deprotection reaction under acidic conditions to give compound (IC). As the acid, an organic acid or an inorganic acid can be used. Examples thereof include trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, aluminum chloride, titanium chloride and the like. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, MeCN, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, alcohols (eg, methanol, ethanol Etc. t- butanol), and water are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dichloromethane. The reaction temperature is usually about −100 to 100 ° C., preferably about −80 to 20 ° C., more preferably about −20 to 20 ° C. The reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.

The obtained compound (IC) can be further chemically modified to synthesize ester forms, or pharmaceutically acceptable salts or solvates thereof.

(Manufacturing method C)

(In the formula, each A is independently halogen; other symbols are as defined above)
Process 1
Compound (XIX) is obtained by oxidizing compound (XVIII). Examples of the oxidizing agent include selenium dioxide and oxon. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, alcohols (eg methanol, Eta Lumpur, t-butanol, etc.), and water are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dichloromethane. The reaction temperature is usually about −50 to 150 ° C., preferably about 20 to 120 ° C., more preferably about 60 to 100 ° C. The reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
Process 2
Compound (XXI) is obtained by alkylation reaction of compound (II) and compound (XIX) and subsequent cyclization reaction. Examples of the base include triethylamine, diisopropylethylamine, pyridine, morpholine, and lutidine. Triethylamine is preferable. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, alcohols (eg methanol, Eta Lumpur, t-butanol, etc.), and water are exemplified. These solvents may be used alone or in combination of two or more. Acetone and HMPA are preferred. The reaction temperature is usually about −100 to 100 ° C., preferably about −20 to 40 ° C., more preferably about 10 to 30 ° C. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
Process 3
Compound (XXII) is obtained by reacting compound (XXI) with α-haloacetic acid halide. Examples of the base used include triethylamine, diisopropylethylamine, pyridine, morpholine, and lutidine. Triethylamine is preferable. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dichloromethane. The reaction temperature is usually about −100 to 100 ° C., preferably about −20 to 40 ° C., more preferably about 0 to 20 ° C. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
Process 4
Compound (XXIII) is obtained by converting the halide of compound (XXII) into a phosphonium salt, followed by intramolecular cyclization in the presence of a base. For forming the phosphonium salt, triphenylphosphine, triethylphosphine, tributylphosphine and the like are used, and triphenylphosphine is preferable. Examples of the base include sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine, sodium methoxide, sodium ethoxide, and potassium tert-butoxide. Sodium bicarbonate is preferable. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, alcohols (eg methanol, Eta Lumpur, t-butanol, etc.), and water are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dimethylformamide. The reaction temperature is usually about −100 to 100 ° C., preferably about −20 to 40 ° C., more preferably about 10 to 30 ° C. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
Process 5
Compound (V ′) is obtained by reducing the double bond of compound (XXIII). The reduction is performed using catalytic hydrogenation or a reducing agent, and examples of the reducing agent include sodium borohydride, lithium borohydride, borohydride and the like. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, alcohols (eg methanol, Eta Lumpur, t-butanol, etc.), and water are exemplified. These solvents may be used alone or in combination of two or more. Preferred are methanol, isopropanol and the like. The reaction temperature is usually about −100 to 50 ° C., preferably about −60 to 0 ° C., more preferably about −50 to −20 ° C. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.

The compound of the present invention has a broad spectrum of antibacterial activity, and various diseases caused by pathogenic bacteria in various mammals including humans such as respiratory tract infections, urinary tract infections, respiratory infections, sepsis, nephritis, gallbladder It can be used for the prevention or treatment of inflammation, oral infection, endocarditis, pneumonia, osteomyelitis, otitis media, enteritis, empyema, wound infection, opportunistic infection and the like.

The compound of the present invention is a gram-negative bacterium, preferably a gram-negative bacterium of the family Enterobacteriaceae (E. coli, Klebsiella, Serratia, Enterobacter, Citrobacter, Morganella, Providencia, Proteus, etc.) (Hemophilus, Moraxella, etc.) and glucose non-fermenting Gram-negative bacteria (Pseudomonas other than Pseudomonas aeruginosa, Stenotrophomonas, Burkholderia, Acinetobacter, etc.). Stable to β-lactamases belonging to classes A, B, C and D produced by these gram-negative bacteria, and resistant to various β-lactam drugs such as ESBL-producing bacteria represented by TEM, SHV, KPC, etc. Has high antibacterial activity against gram-negative bacteria. In particular, it is extremely stable against metallo-β-lactamases belonging to class B including NDM type, IMP type, VIM type, L-1 type, etc., so various β-lactam drug resistant gram-negative bacteria including cephem and carbapenem It is also effective against Further preferable compounds have characteristics such as high blood concentration, long duration of effect, and / or remarkable tissue transferability as pharmacokinetics. Preferred compounds are safe in terms of side effects such as no fever and no nephrotoxicity. Further, preferred compounds have high water solubility and good pharmacokinetics, and are suitable as injections and oral drugs.

The compound of the present invention can be administered orally or parenterally. In the case of oral administration, the compound of the present invention is any of ordinary preparations, for example, solid preparations such as tablets, powders, granules and capsules, liquid preparations, oil suspensions, or liquid preparations such as syrups and elixirs. It can also be used as a dosage form. In the case of parenteral administration, the compound of the present invention can be used as an aqueous or oily suspension injection or nasal solution. In the preparation, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like can be arbitrarily used. The formulations of the present invention are prepared by combining (eg, 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 parenterally or orally as an injection, capsule, tablet or granule, but is preferably administered as an injection. The dose is usually about 0.1 to 100 mg / day, preferably about 0.5 to 50 mg / day per kg of the body weight of the patient or animal. Good. When used as an injection, the carrier is, for example, distilled water, physiological saline or the like, and a base for adjusting pH may be used. Carriers when used as capsules, granules, tablets are known excipients (eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (eg, starch, gum arabic, carboxymethyl cellulose) , Hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (eg, magnesium stearate, talc, etc.).

Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, and Test Examples, but the present invention is not limited thereto.

Moreover, the abbreviation used in this specification represents the following meaning.
Boc: tert-butoxycarbonyl BH or Bzh: benzohydryl DIAD: diisopropyl azodicarboxylate DMF: N, N-dimethylformamide DMA: N, N-dimethylacetamide DMAP: 4-dimethylaminopyridine EDC: 1- (3-dimethylaminopropyl ) -3-ethylcarbodiimide HMPA: hexamethylphosphoric triamide HOBt: 1-hydroxybenzotriazole mCPBA: m-chloroperbenzoic acid Me: methyl ODS: octadecylsilyl t-Bu: tert-butyl TBS: tert-butyldimethylsilyl TFA : Trifluoroacetic acid TBAF: Tetrabutylammonium fluoride Tr: Trityl PMB: Paramethoxybenzyl Ph: Phenyl

The NMR analysis obtained in the examples was performed at 400 MHz and measured using DMSO-d ₆ , CDCl _{3 and the} like.

The LCMS analysis obtained in the examples was measured under the following conditions.
Measurement condition A:
Column: ACQUITY UPLC® BEH C18 (1.7 μm id 2.1 × 50 mm) (Waters)
Flow rate: 0.8 mL / min PDA detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution gradient: After performing a linear gradient of 5% -100% solvent [B] in 3.5 minutes 100% solvent [B] was maintained for 0.5 min.
Measurement condition B:
Column: Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm)
(Shimadzu)
Flow rate: 1.6 mL / min PDA detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution. Gradient: Linear gradient of 10% -100% solvent [B] is performed for 3 minutes. 100% solvent [B] was maintained for 5 minutes.

The powder X-ray diffraction measurement (XRPD) of the crystalline solid obtained in the examples is performed under 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. It was. When measured under measurement condition 2, the peak where the 2-Theta (2θ) value appears in the vicinity of 38 ° is an aluminum peak.
(Measurement condition 1):
Bruker D-8 Discover
Measurement method: Reflection method Light source type: Cu tube Use wavelength: CuKα ray tube current: 40 mA
Tube voltage: 40 kV
Sample plate: Glass X-ray incident angles: 3 ° and 12 °
(Measurement condition 2):
MiniFlex600 made by Rigaku
Type of light source: Cu tube Use wavelength: CuKα tube current: 10 mA
Tube voltage: 30Kv
Sample plate: Al
Measuring range: 3 ° -40 °
Step width: 0.01 deg
Scan speed: 10 deg / min
Example 1

Synthesis of compound 1f

Step 1 Synthesis of Compound 1b A DMF (307 mL) solution of Compound 1a (43.8 g, 300 mmol) was heated to 60 ° C. To this was added dicyclohexylamine (59.6 mL, 300 mmol) and 1-bromo-3-methyl-2-butene (38.1 mL, 300 mmol). After stirring at 60 ° C. for 1 hour, the precipitated solid was removed by filtration. Water was added to the filtrate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and diphenyldiazomethane (64.1 g, 330 mmol) was added to a tetrahydrofuran (321 mL) solution of the obtained residue under ice cooling, followed by stirring at room temperature for 7 hours. After standing at room temperature for 2 days, the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 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 = 7.3 Hz), 5.38 (1H, t, J = 7.3 Hz), 6.86 (1H, s), 7.26-7.36 (10H, m).

Step 2 Synthesis of Compound 1c To a solution of Compound 1b (104 g, 273 mmol) in dichloromethane (520 mL) was added N, N, N ′, N′-tetramethyldiaminomethane (149 mL, 1093 mmol). Under ice-cooling, acetic anhydride (129 mL, 1367 mL) and acetic acid (109 mL, 1914 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (hexane-ethyl acetate) to obtain 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 To a solution of Compound 1c (10.0 g, 25.5 mmol) in acetone (100 mL), Compound 1d (6.02 g, 25.5 mmol) and hexamethylphosphoric triamide (15.5 mL, 89 mmol) were added. The mixture was further stirred at room temperature for 1 hour. Water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (hexane-ethyl acetate) to obtain 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 Under a nitrogen atmosphere, a solution of compound 1e (6.80 g, 10.8 mmol) in dichloromethane (34 mL) was cooled to −10 ° C. A solution of TFA (34 mL, 441 mmol) in dichloromethane (34 mL) was added dropwise thereto, and the mixture was stirred at −10 ° C. for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and a solution of the obtained residue in dichloromethane (50 mL) was cooled to 0 ° C. To this, EDC hydrochloride (4.15 g, 21.6 mmol) was added and stirred at room temperature for 1 hour. Water was added and extracted with dichloromethane. The organic layer was washed with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (hexane-ethyl acetate) to obtain 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).
Example 4

Synthesis of compound 5a

Step 1 Synthesis of Compound 5a Under a nitrogen atmosphere, 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. to give compound 1f ( A solution of 3.00 g, 6.75 mmol) in dichloromethane (15 ml) was added. After stirring for 1 hour under ice cooling, the mixture was cooled to −78 ° C. and ethanol (15 ml) was added. After stirring at −25 ° C. to −15 ° C. for 1 hour, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture. The organic layer was separated and dried over magnesium sulfate. After magnesium sulfate was filtered, tosyl acid monohydrate (5.14 g, 27.0 mmol) and ethyl acetate (50 ml) were added, and the mixture was concentrated under reduced pressure to distill off dichloromethane. The precipitated crystals were collected by filtration to obtain Compound 5a (1.64 g, yield 49%).
1H-NMR (DMSO-d6) 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 (1.0H, 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 (3.0 H, 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
(Example 7)

Synthesis of compound 39g

Step 1 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 added for 4 hours 30 hours at room temperature in a hydrogen atmosphere. Stir for minutes. The catalyst was removed by Celite filtration, 5% palladium carbon (15.1 g, 7.09 mmol) was added again, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. The catalyst was removed by Celite filtration, diphenyldiazomethane (15.1 g, 78.0 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was distilled off, ethyl acetate and diisopropyl ether were added, and the resulting solid was collected by filtration and dried to obtain compound 39f (27.5 g, yield 71%).
1H-NMR (CDCl3) 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 39g Phosphorus pentachloride (15.4 g, 73.7 mmol) was suspended in dichloromethane (200 mL) and cooled to 0 ° C. To this suspension were added pyridine (6.55 mL, 81.0 mmol) and compound 39f (20.0 g, 36.9 mmol), and the mixture was stirred at 0 ° C. for 30 minutes. The solution was cooled to −78 ° C., ethanol (200 mL) was added, the temperature was raised to −30 ° C., and the mixture was stirred for 2 hours. Purified water (33.2 mL, 1.84 mol) was added to this solution and stirred. The reaction solution was further diluted with purified water, 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 obtain 39 g of compound (14.1 g, yield 83%) as crystals.
1H-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 value: 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 (%)
(Example 34)

Synthesis of Compound I-074

Step 1 Synthesis of Compound 74b Compound 74a (31.5 g, 70.9 mmol) synthesized by the method described in Patent WO2016175223A was dissolved in tetrahydrofuran (320 mL), and 5% palladium carbon (15.1 g, 7.09 mmol) was added. The mixture was stirred at room temperature for 4 hours and 30 minutes in a hydrogen atmosphere. The catalyst was removed by Celite filtration, 5% palladium carbon (15.1 g, 7.09 mmol) was added again, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. The catalyst was removed by Celite filtration, diphenyldiazomethane (15.1 g, 78.0 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was distilled off, ethyl acetate and diisopropyl ether were added, and the resulting solid was collected by filtration and dried to obtain Compound 74b (27.5 g, yield 71%).
1H-NMR (CDCl3) 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. To this suspension were added pyridine (6.55 mL, 81.0 mmol) and compound 74b (20.0 g, 36.9 mmol), and the mixture was stirred at 0 ° C. for 30 minutes. The solution was cooled to −78 ° C., ethanol (200 mL) was added, the temperature was raised to −30 ° C., and the mixture was stirred for 2 hours. Purified water (33.2 mL, 1.84 mol) was added to this solution and stirred. The reaction solution was further diluted with purified water, 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 compound 74c (14.1 g, yield 83%) as crystals.
1H-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 value: 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 To a tetrahydrofuran solution of the compound 74d (1.3 g, 10.0 mmol), triphenylphosphine (2.62 g, 10.0 mmol) was added and cooled to 0 ° C. DIAD (1.94 mL, 10.0 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue was poured into methanol, and the resulting solid was collected by filtration. The obtained solid was washed with methanol and dried to obtain compound 74e (1.67 g, yield 61%) as a 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 Under a nitrogen atmosphere, a solution of compound 74e (1.68 g, 6.10 mmol) in dichloromethane (34 mL) was cooled to 0 ° C. To this was added methylhydrazine (0.340 mL, 6.41 mmol), and the mixture was stirred at 0 ° C. for 1 hour. The resulting insoluble material 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 the mixture was stirred at 0 ° C. for 1 hour. The filtrate was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product (2.54 g) containing 74 g of the compound.
MS (m + 1) = 400 Measurement Condition A 1.23 minutes Step 5 Synthesis of Compound 74h Compound 74c (461 mg, 1.00 mmol) was suspended in ethyl acetate (4.60 mL), and the compound obtained in Step 4 Crude product (439 mg) containing 74 g was added and cooled to −30 ° C. To this suspension were added phenyl dichlorophosphate (0.164 mL, 1.10 mmol) and N-methylmorpholine (0.44 mL, 4.00 mmol), and the mixture was stirred at −30 ° C. for 1 hour. Purified water was added to this solution, the solvent was distilled off, and the mixture was extracted with ethyl acetate. This organic layer was washed with purified water and then with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the resulting residue was subjected to silica gel chromatography to obtain compound 74h (740 mg, 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, measurement condition A
Step 6 Synthesis of Compound 74i The crude product (740 mg) containing Compound 74h was dissolved in dichloromethane (4.00 mL) and cooled to −40 ° C. To this solution was added metachloroperbenzoic acid (70%, 249 mg, 1.01 mmol) and stirred at −40 ° C. for 30 minutes. A sodium thiosulfate aqueous solution was added to the reaction solution, the solvent was distilled off, and the mixture was extracted with ethyl acetate. This organic layer was washed with purified water, saturated aqueous sodium hydrogen carbonate, and then saturated 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, measurement condition A
Step 7 A solution of 670 mg of the crude product containing Compound 74i in Compound I-074 in dichloromethane (3.7 mL) was cooled to −30 ° C., and then anisole (0.445 mL, 4.08 mmol) and 2 mol / L aluminum chloride / Nitromethane solution (2.04 mL, 4.08 mmol) was sequentially added, and the mixture was stirred at −30 ° C. for 30 minutes. Diisopropyl ether, ice, and acetonitrile were added to the reaction solution in this order and the mixture was stirred to completely dissolve insoluble matter, and then the aqueous layer was separated. The organic layer was extracted again with water, all the aqueous layers were combined, HP20-SS resin was added, and acetonitrile was distilled off under reduced pressure. The resulting mixture was purified by ODS column chromatography (water-acetonitrile). Fractions containing the desired compound were collected, concentrated under reduced pressure, and lyophilized to obtain Compound I-074 (240 mg, 53% yield) as a white powder.
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, measurement condition A
Elemental analysis: C20H21N5O10S2 (H2O) 2.8
Calculated 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 To a solution of glycerol (921 mg, 10 mmol) in tetrahydrofuran (9 mL) was added imidazole (1.70 g, 25 mmol), and then tert-butyldimethylsilyl chloride (3.17 g, 21 mmol) in tetrahydrofuran (3.17 g, 21 mmol). 18 mL) solution was added dropwise under ice cooling. 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 obtain compound 75b-1 (3.13 g, yield 98%) as a colorless oil.
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 Compound 75b-1 (3.13 g, 9.8 mmol) in tetrahydrofuran (31 mL) was added to N-hydroxyphthalimide (1.91 g, 11.7 mmol), triphenylphosphine (3.07 g, 11.7 mmol) was added, and a 1.9 mol / L DIAD / toluene solution was added dropwise under ice cooling. After stirring at room temperature for 1 hour, the mixture 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 obtain 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).
Steps 3 and 4 Synthesis of Compound 75f-1 To a solution of Compound 75c-1 (3.07 g, 6.6 mmol) in dichloromethane (30 mL) was added methylhydrazine (0.383 mL, 7.2 mmol) at −30 ° C. 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, the mixture was concentrated under reduced pressure, diluted hydrochloric acid was added to the residue, 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. 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 obtain compound 75f-1 (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).

Steps 5 and 6 Synthesis of Compound 75c To compound 75a (13.8 g, 104 mmol) was added trifluoroacetic anhydride (17.7 mL, 125 mmol) under ice cooling. The mixture was stirred for 3 hours under ice cooling and then concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated again under reduced pressure to obtain Compound 75b. The obtained compound 75b was directly used in the next reaction without purification.
To a solution of the total amount of Compound 75b in tetrahydrofuran (64 mL), p-methoxybenzyl alcohol (23.2 g, 168 mmol) and DMAP (1.37 g, 11.2 mmol) were added, and the mixture was heated to reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue, and the aqueous layer was separated. 2 mol / L hydrochloric acid was added to the separated aqueous layer until pH = 2, and the mixture was extracted 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 under reduced pressure to give a mixture of compound 75c and 75c-ii (21 g, yield 74%) as a colorless oil.
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 To a solution of a mixture of compound 75c and 75c-ii (21 g, 83 mmol) in dichloromethane (300 mL) was added triphenylphosphoranylideneacetonitrile (26.3 g, 87 mmol), 4-dimethylaminopyridine (1.02 g, 8.3 mmol) and EDC hydrochloride (17.5 g, 92 mmol) were added in order. After stirring at room temperature for 1.5 hours, the mixture was concentrated under reduced pressure, water was added to the residue, 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 obtain a mixture of compound 75d and 75d-ii (25.88 g, yield 58%) as a white foam.
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, 7.1 Hz), 3.22 (1H, dd, J = 16.0, 7.7 Hz), 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 compounds 75d and 75d-ii (25.9 g, 48 mmol) in dichloromethane (520 mL) was stirred at −78 ° C. for 1 hour while bubbling ozone gas. The system was replaced with nitrogen gas, dimethyl sulfide (10.7 mL, 145 mmol) was added, and the mixture was stirred at −78 ° C. for 5 minutes. Subsequently, 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. The temperature of the reaction mixture was raised to about 0 ° C., 5% aqueous sodium carbonate solution was added, and the mixture was stirred at room temperature for 5 minutes. Dichloromethane was distilled off under reduced pressure, followed by extraction with ethyl acetate, and 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 obtain a mixture of compound 75e and 75e-ii (6.11 g, yield 36%) as a white foam.
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 = 8.1 Hz), 7.26 (4H, br s).
Step 9, 10 Synthesis of Compound 75h To a solution of a mixture of Compound 75e and 75e-ii (6.11 g, 17.5 mmol) in dichloromethane (30 mL) was added N, N, N′N′-tetramethylmethanediamine under ice-cooling. (7.17 mL, 52.6 mmol) was added, and acetic anhydride (6.30 mL, 66.6 mmol) and acetic acid (5.32 mL, 93 mmol) were added dropwise in this order. After stirring overnight at room temperature, ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered to obtain an ethyl acetate solution of a mixture of compounds 75f and 75e-ii.
To an ethyl acetate solution of a mixture of the obtained compounds 75f and 75e-ii, 75 g (2.49 g, 10.5 mmol) of compound and hexamethylphosphoric triamide (9.16 mL, 52.6 mmol) were added. After stirring at room temperature overnight, water was added to the reaction mixture, 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 obtain Compound 75h (2.64 g, yield 42%) as a white foam.
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 and 12 Trifluoroacetic acid (10.2 mL, 133 mmol) was added dropwise at −20 ° C. to a dichloromethane (20 mL) solution of compound 75h (2.64 g, 4.42 mmol) of compound 75j. After stirring at −20 ° C. for 1 hour, the reaction mixture was added to an ice-cooled mixture of aqueous sodium bicarbonate and dichloromethane. Subsequently, dilute hydrochloric acid was added until pH = 2, followed by extraction 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 to obtain Compound 75i. The obtained compound 75i was used in the next reaction without purification.
To a solution of the total amount of the obtained compound 75i in dichloromethane (26 mL), EDC hydrochloride (933 mg, 4.87 mmol) was added under ice cooling. After stirring at room temperature for 1 hour, water was added to the reaction mixture, 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 resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 75j (1.94 g, yield 96%) as a white foam.
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 and 14 A solution of compound 75l in 75 g-1 (484 mg, 0.7 mmol) in dimethylacetamide (1.6 mL) was cooled to −20 ° C., and then triethylamine (0.019 mL, 0.14 mmol), methane chloride Sulfonyl (0.060 mL, 0.77 mmol) was added. Solution A was obtained by stirring at −20 ° C. for 30 minutes.
After cooling a suspension of phosphorus pentachloride (292 mg, 1.4 mmol) in dichloromethane (1.6 mL) to −78 ° C., pyridine (0.124 mL, 1.5 mmol) was added, followed by compound 75j (321 mg, 0. 7 mmol) in dichloromethane (1.6 mL) was added dropwise. After stirring at −10 ° C. for 1 hour, the reaction mixture was cooled to −78 ° C. and cooled ethanol (3.2 mL) was added. After stirring at −30 ° C. for 2 hours, the mixture was cooled to −50 ° C. and water (0.63 mL) was added. After stirring again at −30 ° C. for 30 minutes, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then filtered. Ethyl acetate was added to the filtrate, and dichloromethane and methanol were distilled off under reduced pressure to obtain an ethyl acetate solution of compound 75k.
To an ethyl acetate solution of the obtained compound 75k, pyridine (0.068 mL, 0.84 mmol) and the solution A obtained above were added under ice cooling. After stirring for 30 minutes under ice-cooling, diluted hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed in turn with water, aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 75l (318 mg, yield 50%) as a white foam.
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 To a solution of compound 75m in synthetic compound 75l (318 mg, 0.35 mmol) in dichloromethane (1.6 mL), 69% mCPBA (105 mg, 0.42 mmol) in dichloromethane (1.6 mL) was added dropwise at −40 ° C. . After stirring at −40 ° C. for 20 minutes, 15% aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed in turn with an aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 75m (274 mg, yield 85%) as a white foam.
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 Compound 75m (274 mg, 0.3 mmol) in dichloromethane (2.7 mL) to −40 ° C., anisole (0.32 mL, 3.0 mmol), 2 mol / L aluminum chloride / Nitromethane solution (1.5 mL, 3.0 mmol) was sequentially added, and the mixture was stirred at −30 ° C. for 30 minutes. Diisopropyl ether, ice water, and acetonitrile were added to the reaction solution and stirred to completely dissolve insoluble matters, and then the aqueous layer was separated. After the organic layer was extracted again with water, all aqueous layers were combined, HP20-SS resin was added, 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). Fractions containing the desired compound were collected and added to a 0.2 mol / L aqueous sodium hydroxide solution pH = 6, followed by a small amount of dry ice. The resulting solution was concentrated under reduced pressure and lyophilized to give I-075 (85 mg, 52% yield) as a white powder.
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, Retention time: 0.39 min, (Measurement condition A)
Elemental analysis: C18H20N5NaO10S2 (H2O) 3.7
Calculated values: 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, 65% yield) was prepared in the same manner as in Step 14 of Example 35 using Compound 75k (238 mg, 0.7 mmol) and Compound 76a (459 mg, 0.7 mmol). Got.
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 Compound 76c (392 mg, yield 87%) was obtained in the same manner as in 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, 47% yield) was obtained in the same manner as in Step 16 of Example 35 using Compound 76c (392 mg, 0.39 mmol).
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, retention time: 0.39 min, (measurement condition A)
Elemental analysis: C18H17N5Na2O11S2 (H2O) 6.2
Calculated value: 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, Synthesis of Compound 77c To a solution of Compound 75k (340 mg, 1.0 mmol) in dichloromethane (3.4 mL), Compound 77a (364 mg, 1.1 mmol), EDC hydrochloride (230 mg, 1.2 mmol) were cooled with ice. ) Was added. After stirring for 1 hour under ice-cooling, diluted hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed in turn with water, aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain Compound 77b as an orange foam. The obtained compound 77b was directly used in the next reaction without purification.
Compound 77c (401 mg, 60% yield) was obtained in the same manner as in Step 15 of Example 35 using the obtained total amount of compound 77b.
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 I-077 (127 mg, 41% yield) was obtained in the same manner as in 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, retention time: 0.48 min, (measurement condition A)
(Example 38)

Synthesis of Compound I-078

Step 1, Synthesis of Compound 78c Compound 78b was obtained in the same manner as in 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 directly used in the next reaction without purification.
Compound 78c (578 mg, 67% yield) was obtained in the same manner as in Step 15 of Example 35 using the total amount of compound 78b obtained.
_{^{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, 49% yield) was obtained in the same manner as in 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, retention time: 0.53 min, (measurement condition A)
(Example 39)

Synthesis of Compound I-079

Step 1, Synthesis of Compound 79c Compound 79b was obtained in the same manner as in 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 directly used in the next reaction without purification.
Compound 79c (695 mg, yield 80%) was obtained by the same method as in Step 15 of Example 35 using the obtained entire amount of Compound 79b.
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, 46% yield) was obtained in the same manner as in 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, retention time: 0.62 min, (measurement condition A)
Elemental analysis: C18H17N5Na1.8O10S2 (H2O) 3.2
Calculated values: 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 (%)
(Example 40)

Synthesis of Compound I-080

Step 1 Synthesis of Compound 80b To a solution of methylamine (33% ethanol solution, 1.43 mL, 11.51 mmol) in acetone (44 mL) was added N, N-dimethylaniline (1.46 mL, 11.51 mmol) under ice-cooling. In addition, Compound 80a (1 mL, 11.51 mmol) was added dropwise, and the resulting solution was stirred at room temperature for 1 hour, dried under reduced pressure, added with 10% aqueous citric acid solution, and extracted with ethyl acetate. The obtained organic layer was washed successively with an 8.4% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, the inorganic matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give compound 80b (409.5 mg, 23 .4%) was obtained as a crude product of a yellow oil.
MS (M + 1) = 151, RT = 0.41 min, measurement condition A

Step 2 Synthesis of Compound 80c To a solution of hydroxyphthalimide (440 mg, 2.69 mmol) in acetonitrile (3.3 mL), triethylamine (373 μL, 2.69 mmol) and compound 80b (409.5 mg, 2.69 mmol) were added under ice cooling. In addition, the resulting solution was stirred at room temperature for 4 hours, and then the inorganic substance was filtered and concentrated under reduced pressure. Add 10% aqueous potassium carbonate solution and extract with ethyl acetate. The obtained organic layer was washed successively with 10% aqueous potassium carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, inorganic substances were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 80c (160.5 mg, 25.4%) as a white solid.
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 In the same manner as in Step 4 of Example 34, Compound 80d and Compound 74f were used to obtain Compound 80d (235.9 mg, 96.1%) as a crude product of yellow oil.
MS (M + 1) = 359, RT = 1.02 min, measurement condition A

Step 4 Synthesis of Compound 80e In the same manner as in Step 5 of Example 34, Compound 80e (334.9 mg, 79.9%) was obtained as a white foam using Compound 80d and Compound 74c.
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 In the same manner as in Step 6 of Example 34, Compound 80f (332.2 mg, 97.2%) was obtained as a white foam crude product using Compound 80e.
MS (M + 1) = 781, RT = 2.19 min, measurement condition A

Step 6 Synthesis of Compound I-080 In the same manner as in Step 7 of Example 34, Compound I-080 (155.8 mg, 71.2%) was obtained as a white solid using Compound 80f.
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 min, measurement condition A
(Example 43)

Synthesis of Compound I-083

Step 1, Synthesis of Compound 83c Compound 83b was obtained in the same manner as in Step 37 of Example 37 using Compound 75k (340 mg, 1.0 mmol) and Compound 83a (379 mg, 1.1 mmol). The obtained compound 83b was directly used in the next reaction without purification.
Compound 83c (420 mg, yield 62%) was obtained in the same manner as in Step 15 of Example 35 using the total amount of compound 83b obtained.
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 Compound I-083 (159 mg, 48% yield) was obtained in the same manner as in 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, retention time: 0.43 min, (measurement condition A)
Elemental analysis: C17H17N6NaO9S2 (H2O) 3.5
Calculated values: 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, Synthesis of Compound 84c Compound 84b was obtained in the same manner 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 directly used in the next reaction without purification.
Compound 84c (672 mg, yield 77%) was obtained in the same manner as in Step 15 of Example 35 using the obtained total amount of compound 84b.
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, 54% yield) was obtained in the same manner as in 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, retention time: 0.65 min, (measurement condition A)
Elemental analysis: C19H17N5Na1.8O10S2 (H2O) 4.9
Calculated values: 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) and 2-phenylacrylic acid (7.11 g, 48.0 mmol). After stirring at 70 ° C. for 4 hours, the reaction solution was cooled to room temperature. To this was added calcium carbonate (7.19 g, 52.0 mmol). To this was added benzyl bromide (6.18 mL, 52 mmol) little by little and stirred for 1 hour at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dilute hydrochloric acid and saturated brine, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane / ethyl acetate) to give 85b (12.2 g, yield 50%).
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 Compound 85b (12.2 g, 19.9 mmol) obtained in Step 1 in dichloromethane (183 mL) was cooled to −78 ° C., and ozone was bubbled through for 30 minutes. After completion of the reaction, oxygen and nitrogen were bubbled in this order, dimethyl sulfide (4.40 mL, 59.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography (hexane / ethyl acetate) to obtain 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 To a solution of Compound 85c (6.4 g, 17.4 mmol) obtained in Step 2 in dichloromethane (64 mL), N, N, N ′, N′-tetramethyldiaminomethane (9.47 mL, 69.5 mmol) was added and cooled to 0 ° C., and acetic anhydride (11.5 mL, 122 mmol) was added slowly. Acetic acid (4.97 mL, 87 mmol) was added thereto, and the mixture was stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, dichloromethane was distilled off under reduced pressure, and water was added. The aqueous layer was extracted with ethyl acetate and washed with water, and then the organic layer was dried over anhydrous magnesium sulfate. 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) and HMPA (60) synthesized by the method described in document EP253337 in a solution of the crude product of Compound 85d obtained in Step 3 in ethyl acetate (66 mL) 2 mL, 346 mmol) and stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. After filtration, the residue obtained by evaporation under reduced pressure was subjected to silica gel chromatography (hexane / ethyl acetate) to obtain Compound 85f as a crude product (3.9 g) of a mixture of four isomers.
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 85 g of Compound To a solution of the crude product of Compound 85f obtained in Step 4 (3.9 g, corresponding to 6.2 mmol) in methanol (39 mL) was added 5% palladium carbon (1.3 g, 0.62 mmol). The mixture was stirred for 8 hours under a hydrogen atmosphere of 4 atm. After filtering insoluble matter, 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 filtering insoluble matter, 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 diluted hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off and the resulting dichloromethane (10 mL) was cooled to 0 ° C. To this, EDC hydrochloride (1.45 g, 7.58 mmol) was added and stirred at 0 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane / ethyl acetate) to obtain a crude product (700 mg) of a mixture of a plurality of isomers of compound 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. To this suspension was added a crude product (700 mg, corresponding to 1.38 mmol) containing pyridine (0.333 mL, 4.13 mmol) and 85 g of compound, and the mixture was stirred at 0 ° C. for 30 minutes. The solution was cooled to −78 ° C., ethanol (7 mL) was added, the temperature was raised to −30 ° C., and the mixture was stirred for 2 hours. Purified water (2.0 mL) was added to this solution and stirred for 30 minutes. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, 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 designated as Solution A.
A solution of compound 85h (663 mg, 1.65 mmol) in DMA (7 mL) is cooled to −20 and triethylamine (0.267 mL, 1.93 mmol) and methanesulfonyl chloride (0.139 mL, 1.79 mmol) are added and stirred for 1 hour. This was designated 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 mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, sodium bicarbonate and saturated brine, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane / ethyl acetate) to obtain a crude product (650 mg) of a mixture of a plurality of isomers of Compound 85i.
MS (m + 1) = 774, 2.82 minutes, measurement condition A

Step 7 Synthesis of Compound 85j Using compound 85i crude product (650 mg, corresponding to 0.84 mmol) obtained in Step 6 of Compound 85j, Compound 85i contains a plurality of isomers in the same manner as in Step 6 of Example 34. Obtained as a crude product (540 mg).
MS (m + 1) = 790, 2.54 minutes, measurement condition A
MS (m + 1) = 790, 2.65 minutes, measurement condition A

Step 8 Synthesis of Compound I-085 Using the crude product of Compound 85j obtained in Step 7 (540 mg, corresponding to 0.68 mmol), Compound I-085 (126 mg, 126 mg, Yield 32%) was obtained as a mixture of four isomers (ratio of about 0.6: 0.7: 1: 1.2).
MS (m + 1) = 578, 0.71 minutes, measurement condition A
MS (m + 1) = 578, 0.76 minutes, measurement condition A
MS (m + 1) = 578, 0.80 minutes, measurement condition A
¹ H-NMR (ratio of four 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 = 11.4 Hz), 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 (0.7H , 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 50)

Synthesis of Compound I-132

Step 1 Synthesis of Compound 132b To a solution of Compound 132a (3.55 g, 21.01 mmol, described in JP59909441B2 in the synthesis method) in acetonitrile (35.5 mL), triethylamine (18.2 mL, 131 mmol), trifluoromethanesulfonic acid under ice-cooling tert-Butyldimethylsilyl (20.26 mL, 88 mmol) was added. The resulting solution was stirred with ice cooling for 3.5 hours, water (7.1 mL) and acetic acid (6.16 mL, 108 mmol) were added, and the mixture was further stirred with ice cooling for 2 hours. Water was added to the resulting solution and extracted with dichloromethane. The organic layer was washed with 8.4% aqueous sodium hydrogen carbonate solution, 2N aqueous hydrochloric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. Inorganic substances were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate), and fractions containing the product were collected and concentrated under reduced pressure to give Compound 132b (10.88 g). Obtained as a yellow oil.
MS (M + 1) = 283, RT = 2.39 min, measurement condition A
Step 2 In the same manner as in Step 2 of the synthesis of Compound 132c Synthesis Intermediate 34A, purification was performed by silica gel column chromatography (hexane-ethyl acetate) using Compound 132b to obtain Compound 132c (4.59 g) as a white foam. It was.
MS (M + 1) = 282, RT = 2.11 min, measurement condition A
Step 3 Synthesis of Compound 132d To a solution of hydroxyphthalimide (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) is added and the resulting solution is stirred at 60 ° C. for 3 hours, then water is added and extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, the inorganic matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 132d (1.288 g, 18.7% (3 step yield from Compound 132a)) as a white solid.
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 Step 4 of Example 34, Compound 46A (1.19 g, 68.9%) was obtained as a white solid crude product using Compound 132d.
MS (M + 1) = 489, RT = 1.83 min, measurement condition A
Step 5 Synthesis of Compound 132g In the same manner as in Step 5 of Example 34, Compound 46A was used to obtain Compound 132g (1.2036 g, 66.2%) as a white foam.
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 In the same manner as in Step 6 of Example 34, Compound 132h (1.211 g, 99.7%) was obtained as a crude product of white foam using Compound 132g.
MS (M + 1) = 911, RT = 2.71 min, measurement condition A
Step 7 Synthesis of Compound I-132 In the same manner as in Step 7 of Example 34, compound I-132 (581.3 mg, 81.8%) was obtained as a white solid using compound 132h.
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 = 4.8 Hz), 5.91 (1H, d, J = 4.8 Hz), 7.24 (1H, s).
MS (M + 1) = 531.05, RT = 0.30 min, measurement condition A
Elemental analysis: C17H18N6O10S2 (H2O) 2.5
Calculated 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

Step 1 Synthesis of Compound 146b Compound 146a (10.91 g, 53.9 mmol), (triphenylphosphoranylidene) acetonitrile (19.51 g, 64.7 mmol) DMAP (0.66 g, 5.39 mmol) in dichloromethane (100 ml) EDC hydrochloride (12.41 g, 64.7 mmol) was added under a nitrogen atmosphere under ice cooling. After stirring at room temperature for 1 hour, water was added and extracted with dichloromethane. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered and concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the precipitated solid was collected by filtration to obtain Compound 146b (22.81 g, 87%).
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 = 7.5 Hz).
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 stirred while bubbling ozone gas until the raw material disappeared. The system was replaced with nitrogen gas, 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 stirred at −78 ° C. for 3 hours. The reaction mixture was heated to about −20 ° C., 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. Magnesium sulfate was filtered and concentrated under reduced pressure. Silica gel column chromatography eluting with hexane / ethyl acetate. 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 = 7.5 Hz).
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, and acetic anhydride (8.08 ml, 85 mmol) and acetic acid (6.84 ml, 120 mmol) were added dropwise in this order. 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 extracted with hexane. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered and then concentrated under reduced pressure to obtain Compound 146d (4.78 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), and compound 146e (5.20 g, 22.01 mmol) was added under nitrogen cooling under ice-cooling. Triethylamine (0.469 ml, 3.39 mmol) was added sequentially. After stirring for 2 hours under ice cooling, diluted hydrochloric acid 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. Magnesium sulfate was filtered and concentrated under reduced pressure. Silica gel column chromatography eluting with hexane / ethyl acetate. Fractions containing the desired compound were concentrated under reduced pressure to obtain compounds 146f-1 and 146f-2 as a mixture. (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 cooled to trifluoroacetic acid (20 ml, 260 mmol). ) Was added. The mixture was stirred for 4 hours under ice cooling and then concentrated under reduced pressure. Water was added to the residue and extracted with dichloromethane. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered and concentrated under reduced pressure. The total amount of the obtained residue was dissolved in dichloromethane (20 ml), and EDC hydrochloride (0.899 g, 4.69 mmol) was added under ice cooling. 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. Magnesium sulfate was filtered and concentrated under reduced pressure. Silica gel column chromatography eluting with hexane / ethyl acetate. Fractions containing the desired compound were concentrated under reduced pressure to obtain compounds 146g-1 and 146g-2 as a mixture. (1.39 g, 80%)
LC / MS (measurement condition A): RT: 2.08 min, [M + H] = 445
Step 6 Synthesis of Compounds 146h-1 and 146h-2 Compounds 146h-1 and 146h were synthesized in the same manner as in Step 5 of Example 45 using compounds 146g-1 and 146g-2 (0.70 g, 1.58 mmol). -2 was obtained as a mixture. (0.96g, 86%)
LC / MS (measurement condition A): RT: 2.57 min, [M + H] = 710
Step 7 Synthesis of Compounds 146i-1 and 146i-2 The compounds 146h-1 and 146h-2 (0.96 g, 1.35 mmol) were synthesized by the same method as in Step 6 of Example 34, and silica gel column chromatography was used. Purification gave compound 146i-1 (0.46 g, 47%) and compound 146i-2 (0.41 g, 42%), respectively.
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, 4.6 Hz), 2.78 (1H, dt, J = 11.8, 4.6 Hz), 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 = 7.5 Hz).
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), Pd (PPh ₃ ) ₄ ( 37 mg, 0.032 mmol) was added in order. After stirring for 1 hour under ice-cooling, diluted hydrochloric acid 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. Magnesium sulfate was filtered and then concentrated under reduced pressure to obtain Compound 146j (0.43 g, 99%). Compound 146j was used in the next reaction without purification.
LC / MS (measurement condition A): RT: 1.72 min, [M + H] = 686
Step 9 Synthesis of Compound I-146 Compound I-146 was obtained in the same manner as in 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 = 7.5 Hz).
LC / MS (measurement condition B): RT: 0.74 min, [M + H] = 530
C18H19N5O10S2 (H2O) 2.4
Calculated C: 37.75%, H: 4.19%, N: 12.23%, S: 11.20%
Measured value C: 37.58%, H: 4.12%, N: 12.46%, S: 11.15%
(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), Compound 148b (6.83 g, 18.16 mmol) was added, and the mixture was stirred at 60 ° C. overnight. . Ethyl acetate and water were sequentially added to the reaction solution, and the ethyl acetate layer was separated. The obtained ethyl acetate solution was washed in turn with water and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with hexane / ethyl acetate. The fractions containing the desired compound were collected and the solvent was distilled off under reduced pressure to give compound 148c. Yield 6.56 g (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 tert-butyldimethylchlorosilane (86 mg, 0.57 mmol) and imidazole (39 mg, 0.57 mmol) were added under ice cooling. Were sequentially added, followed by stirring at room temperature for 1 hour. Ethyl acetate and water were sequentially added to the reaction solution, and the ethyl acetate layer was separated. The obtained ethyl acetate solution was washed in turn with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 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 ozone gas was passed at −78 ° C. until the solution colored blue. Next, dimethyl sulfide (8.66 ml, 117 mmol) was added to the reaction solution, followed by stirring while gradually raising the temperature to room temperature. The reaction solution was evaporated under reduced pressure, the resulting residue was subjected to silica gel column chromatography, eluted with hexane / ethyl acetate, and the fractions containing the desired compound were collected, and the solvent was removed under reduced pressure. Was distilled off to obtain Compound 148e. Yield 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 (83 ml), bis (dimethylamino) methane (10.31 ml, 76 mmol) was added under ice cooling, and anhydrous A solution of acetic acid (8.93 ml, 94 mmol) in dichloromethane (15 ml) was added dropwise over 1 hour. A solution of acetic acid (7.56 ml, 132 mmol) in dichloromethane (10 ml) was further added dropwise to the reaction solution over 20 minutes, followed by stirring overnight at room temperature. Hexane was added to the reaction solution and concentrated under reduced pressure to remove dichloromethane. Water was added to the resulting solution to separate the hexane layer. The hexane layer was washed with water, sodium bicarbonate water and saturated brine in that order, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 148f. Yield 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), compound 148 g (5.40 g, 22.8 mmol) and then triethylamine (0.487 ml, 3.51 mmol) was added and stirred for 2 hours. Ethyl acetate and dilute hydrochloric acid were added to the reaction solution, and the ethyl acetate layer was separated. The obtained solution was washed with water and saturated brine in that order, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with hexane / ethyl acetate. Fractions containing the desired compound were collected, and the solvent was distilled off under reduced pressure to convert compound 148h into several isomers. Obtained as a mixture of bodies. 7.35 g (61%).
LC / MS (measurement condition A): RT: 3.19 min, [M + H] = 685
Step 6 Synthesis of Compound 148i The isomer mixture of Compound 148h (2.74 g, 4 mmol) obtained in Step 5 was dissolved in methanol (27 ml), and 10% -palladium carbon (2.13 g, 2 mmol) was added. The mixture was stirred overnight under a hydrogen atmosphere of 5 atm. The insoluble material was filtered through Celite, and toluene was added to the resulting solution, and then the solvent was distilled off under reduced pressure. The obtained residue was dissolved in dichloromethane (19 ml), and EDC hydrochloride was added under ice cooling, followed by stirring at room temperature for 1 hour. The reaction solution was evaporated under reduced pressure, ethyl acetate and water were added, and the ethyl acetate layer was separated. The obtained ethyl acetate layer was washed with water and saturated brine in that order and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with hexane / ethyl acetate. Fractions containing the desired compound were collected and the solvent was distilled off under reduced pressure to obtain Compound 148i. Yield 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), imidazole (39 mg, 0.58 mmol), and tert-butyldimethylchlorosilane (87 mg, 0) under ice cooling. .58 mmol) was added sequentially. The reaction solution was stirred at room temperature for 30 minutes, and then ethyl acetate and water were added to separate the ethyl acetate layer. The obtained ethyl acetate layer was washed with water and saturated brine in that order and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with hexane / ethyl acetate. The fractions containing the desired compound were collected and the solvent was distilled off under reduced pressure to obtain Compound 148j. Yield 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 148l Phosphorus pentachloride (72 mg, 0.35 mmol) was suspended in methylene chloride (1 ml), pyridine (31 mg, 0.38 mmol) was added under ice cooling, and the mixture was stirred for 15 minutes under ice cooling. did. Compound 148j (100 mg, 0.17 mmol) was added to the reaction mixture, and the mixture was stirred for 30 minutes under ice cooling, and then poured into methanol (3 ml) that had been ice-cooled in advance. The solution was stirred for 30 minutes under ice cooling, then diluted with dichloromethane and water, and the dichloromethane layer was separated. The obtained dichloromethane layer was washed with water and saturated brine in that order, and dried over magnesium sulfate to obtain an amino form of a dichloromethane solution.
Meanwhile, compound 148k (104 mg, 0.26 mmol) was dissolved in dimethylacetamide (1 ml), and triethylamine (46 μl, 0.33 mmol) and methanesulfonyl chloride (23 μl, 0.30 mmol) were sequentially added at −20 ° C. The mixture was stirred at 15 ° C. for 20 minutes. This solution was added to the above-mentioned amino compound in dichloromethane under ice-cooling and stirred at the same temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure, diluted hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The resulting solution was washed with water, aqueous sodium bicarbonate and saturated brine in that order, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane / ethyl acetate. Fractions containing the desired compound were collected and the solvent was distilled off under reduced pressure to obtain compound 148l. Yield 117 mg (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 148l (114 mg, 0.14 mmol) was dissolved in dichloromethane (1.1 ml) and m-chloroperbenzoic acid (36 mg, 0.14 mmol) in dichloromethane (0.6 ml) at −78 ° C. ) The solution was added. The reaction solution was stirred at −78 ° C. for 20 minutes, ethyl acetate and an aqueous sodium thiosulfate solution were added, and the mixture was concentrated under reduced pressure, and the ethyl acetate layer was separated. The obtained ethyl acetate layer was washed with sodium bicarbonate water and saturated brine in that order and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with hexane / ethyl acetate. Fractions containing the desired compound were collected and the solvent was distilled off under reduced pressure to obtain compound 148m. Yield 97 mg (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 (95 mg, 0.11 mmol) was dissolved in methylene chloride (1.9 ml), anisole (121 μl, 1.11 mmol) at −30 ° C., and then 2M / L-aluminum chloride. -Nitromethane solution (554 μl, 1.11 mmol) was added and stirred at -20 ° C for 30 minutes. Isopropyl ether, ice water, and acetonitrile were added to the reaction solution, and the aqueous layer was separated. After adding 3 ml of HP20SS resin to the obtained aqueous solution and concentrating under reduced pressure, it was chromatographed on a column connected in the order of HP20SS and ODS. Eluting with water / acetonitrile, the fractions containing the desired compound were collected, and the solvent was concentrated under reduced pressure, followed by lyophilization to obtain Compound I-148. Yield 26 mg (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 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 54)

The synthesis method of compounds 1B, 4A, 5A, 9A, 10A, 33A, 34A, 41A, 53A, and 59A, which are intermediates, is shown below.
(Synthesis of Compound 1B)

Step 1 Synthesis of Compound 87b
Using compound 87a (3.15 g, 14 mmol) synthesized by the method described in US20140086846, 87b was synthesized in the same manner as in Step 3 of Example 34. The obtained crude product was subjected to silica gel column chromatography (hexane-ethyl acetate) to obtain a crude product (2.1 g) containing compound 87b.
MS (m + 1) = 370, 1.96 minutes, measurement condition A
Step 2 Synthesis of Compound 1B Using the crude product (2.1 g, equivalent to 5.70 mmol) containing Compound 87b obtained in Step 1, the crude product of Compound 1B was prepared in the same manner as in Step 4 of Example 34. Was synthesized. The crude product of compound 1B (2.8 g) was used in the next reaction without purification.
MS (m + 1) = 494, 1.82 minutes, measurement condition A
(Synthesis of Compound 4A)

Step 1 Synthesis of Compound 89b The same method as in Step 3 of Example 34 using Compound 89a (5.2 g, 15.5 mmol) synthesized by the method described in Tetrahedron, 61 (7), 1827-1833; 2005 Gave a crude product of compound 89b. The crude product of compound 89b (8.7 g) was used in the next reaction without purification.
MS (m + 1) = 480, 3.68 minutes, measurement condition A
Step 2 Synthesis of Compound 4A A 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 compound 4A (8.7 g) was used in the next reaction without purification.
MS (m + 1) = 604, 3.49 minutes, measurement condition A
(Synthesis of Compound 5A)

Step 1 Synthesis of Compound 90b Compound 90b (6.9 g, yield 91%) was synthesized from compound 90a synthesized by the method described in Tetrahedron, 61 (7), 1827-1833; 2005.
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 Using the compound 90b obtained in Step 1 (7.2 g, corresponding to 15 mmol), a crude product of Compound 90c was synthesized in the same manner as in Step 3 of Example 34. The crude product of compound 90c (8.7 g) was used in the next reaction without purification.
MS (m + 1) = 480, 3.68 minutes, measurement condition A
Step 3 Synthesis of Compound 5A Using the compound 90c (10.1 g, equivalent to 21 mmol) obtained in Step 2, a crude product of Compound 5A was synthesized in the same manner as in Step 4 of Example 34. The crude product of compound 5A (11.2 g) was used in the next reaction without purification.
MS (m + 1) = 604, 3.49 minutes, measurement condition A

(Synthesis of Compound 9A)

Step 1 Synthesis of Compound 9A A crude product of Compound 9A was synthesized in the same manner as in Step 4 of Example 34 using Compound 95a (3.35 g, 10 mmol) synthesized by the method described in WO2012059041. The obtained crude product of compound 9A (4.1 g) was used in the next reaction without purification.
MS (M + 1) = 460, 2.68 minutes, measurement condition A
(Synthesis of Compound 10A)

Step 1 Synthesis of Compound 10A A crude product of Compound 10A was synthesized in the same manner as in Step 4 of Example 34 using Compound 96a (3.35 g, 10 mmol) synthesized by the method described in WO2011059041. The obtained crude product of compound 10A was used in the next reaction without purification.
MS (M + 1) = 460, RT = 2.68 minutes, measurement condition A
(Synthesis of Compound 33A)

Step 1 Synthesis of Compound 119b To a solution of D-threonine (15 g, 126 mmol) in water (222 mL) was added potassium bromide (45 g, 378 mmol), 9M aqueous sulfuric acid (56 mL, 504 mmol), and sodium nitrite at −20 ° C. (13.03 g, 189 mmol) are added little by little while paying attention to foaming. After the reagent was added, the resulting solution was stirred overnight at room temperature, then urea (22.69 g, 378 mmol) was added under ice cooling, the mixture was stirred for 5 minutes, saturated brine was added, and the mixture was extracted 7 times with ethyl acetate. . The obtained organic layer was dried over anhydrous magnesium sulfate, the inorganic substance was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain Compound 119b (20.8 g, 90.3%) as a crude product of 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 To a solution of Compound 119b (20.8 g, 114 mmol) in tetrahydrofuran (125 mL) is added dropwise a solution of diphenyldiazomethane (22.08 g, 114 mmol) in tetrahydrofuran (83 mL) over 1 hour under ice cooling. After adding the reagents, 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 obtain Compound 119c (32.57 g, 82.1%) as a yellow oil.
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 To a solution of hydroxyphthalimide (15.47 g, 112 mmol) in ethyl acetate (163 mL) and water (98 mL), potassium carbonate (15.47 g, 112 mmol), tetrabutylammonium bromide (3.01 g, 9. 33 mmol), compound 119c (32.57 g, 93 mmol) is added and the resulting solution is vigorously stirred overnight at room temperature, followed by addition of ice-cold water and extraction with ethyl acetate. The obtained organic layer was washed with a 10% aqueous potassium carbonate solution three times, water and saturated brine in that order, dried over anhydrous magnesium sulfate, the inorganic matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 119d (6.28 g, 15.6%) as a white solid.
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 Step 4 of Example 35, compound 33A (8.7 mg, 100%) was obtained as a white foam using compound 119d.
MS (M + 1) = 556, RT = 2.14 min, measurement condition A
(Synthesis of Compound 34A)

Step 1 Synthesis of Compound 120b In the same manner as in Step 1 of the synthesis of Compound 33A, Compound 120b was used to obtain Compound 120b (8.6 g, 67.5%) as a crude product of 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 To a solution of Compound 120b (8.6 g, 56.2 mmol) in 1,4-dioxane (86 mL) was added di-tert-butyl dicarbonate (17 mL, 73.1 mmol), ammonium carbonate (6.75 g). 70.3 mmol), pyridine (2.27 mL, 28.1 mmol) are added, and the resulting solution is stirred at room temperature for 5 days, then dried under reduced pressure, water is added, and the mixture is extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, the inorganic matter was removed by filtration, concentrated under reduced pressure, and diisopropyl ether was added to the obtained white solid to obtain a white suspension. The mixture was stirred at room temperature for 15 minutes, and the precipitated white solid was collected by filtration to obtain 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 Step 3 of the synthesis of Compound 33A, Compound 120d (436.4 mg, 11.2%) was obtained as a white solid using Compound 120c.
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 34A In the same manner as in Step 4 of Example 34, Compound 34A (437 mg, 65.4%) was obtained as a white solid crude product using Compound 120d.
MS (M + 1) = 359, RT = 1.01 min, measurement condition A
(Synthesis of Compound 41A)

Step 1 Synthesis of Compound 127b In the same manner as in Step 1 of the synthesis of Compound 38A, Compound 127b (998.9 mg, 38.0%) was obtained as a white solid using Compound 127a.
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 Step 4 of Example 34, Compound 41A (1.0695 g, 68.6%) was obtained as a white solid crude product using Compound 127b.
MS (M + 1) = 346, RT = 1.15 min, measurement condition A
(Synthesis of Compound 53A)

Step 1 Synthesis of Compound 142b As in Step 3 of Example 34, using Compound 142a (5.23 g, 15.5 mmol) obtained by the method described in Bioorganic & Medicinal Chemistry, 19 (7), 2114-2124; 2011 Thus, compound 142b (5.13 g, yield 69%) was obtained.
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 Using compound 142b (2.41 g, 5.00 mmol) of compound 53A, using the method of Step 4 of Example 34, ethyl acetate was added to the obtained crude product, and the resulting solid was collected by filtration. This gave compound 53A (1.11 g, 37% yield).
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 Intermediate 59A)

Step 1 Synthesis of Compound 153b
Journal of Organic Chemistry, 78 (14), 7281-7287; Compound 153a (7.91 g, 50.0 mmol) obtained by the method of 2013 was dissolved in acetone (80.0 mL) and purified water (20.0 mL), Potassium osmate (IV) dihydrate (0.184 g, 0.500 mol) and N-methylmorpholine N-oxide (11.7 g, 100 mmol) were added, and the mixture was stirred at room temperature for 1 hour. A sodium thiosulfate (37.2 g, 150 mmol) aqueous solution was added, and acetone was distilled off. The target product was extracted from the aqueous layer 6 times with a mixture of ethyl acetate and tetrahydrofuran, the collected organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, the solvent was evaporated under reduced pressure, and 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-anisaldehyde dimethyl acetal (7.95 g, 43.6 mmol) and 10-camphorsulfonic acid (0.507 g, 2.18 mmol) was added, and the mixture was heated to reflux for 2 hours and 30 minutes. The reaction solution was cooled to room temperature, and saturated aqueous sodium hydrogen carbonate was added. Dichloromethane was distilled off, and the target product was extracted from the aqueous layer with ethyl acetate. The collected organic layer was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain Compound 153c (4.48 g, yield: 66%) as an inseparable mixture.
MS (M + 1): 311.15; 1.95 min (measurement condition A)
Step 3 Synthesis of Compound 153d Compound 153c (4.48 g, 14.4 mmol) was dissolved in toluene (50.0 mL), phenoxydiphenylphosphine (8.03 g, 28.9 mmol) and N-hydroxyphthalimide (4.71 g, 28.9 mmol) was added, followed by dropwise addition of 40% diethyl azodicarboxylate in toluene (13.1 mL, 28.9 mmol). The mixture was stirred at room temperature for a whole day and night, the insoluble matter was removed, the solvent was distilled off, and the obtained residue was subjected to silica gel chromatography to obtain Compound 153d (4.68 g, yield 71%).
MS (M + 1): 456.16; 2.58 (measurement condition A)
Step 4 Using compound 153d (4.68 g, 10.3 mmol) of compound 59A, the reaction was carried out in the same manner as in Step 4 of Example 34, and the resulting residue was subjected to silica gel chromatography. Elution with% triethylamine ethyl acetate solution and methanol was performed, and the fraction containing the desired product was concentrated to obtain Compound 59A (2.82 g, yield 40%).
(Example 55)

Synthesis of Compound I-158

Step 1, Synthesis of Compound 158b Compound 75k (340 mg, 1.0 mmol) in ethyl acetate (5 mL) was cooled to −40 ° C., Compound 46A (537 mg, 1.1 mmol), phenyl dichlorophosphate (0.224 mL) 1.5 mmol) and N-methylmorpholine (0.220 mL, 2.0 mmol) were added slowly in order. After stirring at −40 ° C. for 1 hour, dilute aqueous hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed in turn with water, aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain Compound 158a as a yellow foam. The obtained compound 158a was directly used in the next reaction without purification.
Compound 158b (521 mg, 63% yield) was obtained by the same method as in Step 15 of Example 35 using the total amount of compound 158a obtained.
¹ H-NMR (CDCl ₃ ) δ: 0.04 (6H, s), 0.86 (9H, s), 1.23 (3H, d, J = 7.2 Hz), 1.54 (9H, s), 1.73 (3H, s), 1.78 (3H, s), 2.29 (1H, t, J = 13.8 Hz), 3.05 (1H, dd, J = 14.2, 7.0 Hz), 3.38-3.45 (1H, m), 3.70-3.73 (1H, m) , 3.76-3.79 (2H, m), 4.09 (2H, d, J = 3.9 Hz), 4.63 (1H, q, J = 4.9 Hz), 4.82-4.89 (3H, m), 5.37-5.41 (1H, m ), 6.04 (1H, dd, J = 9.7, 5.1 Hz), 7.31 (1H, s), 8.01 (1H, s), 8.75 (1H, s).
Step 3 Synthesis of Compound I-158 Compound I-158 (112 mg, 31% yield) was obtained in the same manner as in Step 16 of Example 35 using Compound 158b (521 mg, 0.63 mmol).
¹ H-NMR (D ₂ O) δ: 1.19 (3H, d, J = 7.3 Hz), 2.74 (1H, t, J = 12.9 Hz), 3.19-3.26 (1H, m), 3.54-3.65 (2H, m), 4.01-4.10 (2H, m), 4.88 (1H, t, J = 4.1 Hz), 5.00 (1H, d, J = 4.8 Hz), 5.91 (1H, d, J = 4.8 Hz), 7.13 ( 1H, s).
MS (m + 1) = 545, Retention time: 0.27 min, (Measurement condition A)
Elemental analysis: C18H19N6NaO10S2 (H2O) 3.8
Calculated values: C, 34.05; H, 4.22; N, 13.24; Na, 3.62; S, 10.10 (%)
Found: C, 34.10; H, 4.13; N, 13.18; Na, 3.79; S, 9.94 (%)

The following compounds were synthesized by the same method as above using the above intermediate.

The following compounds can be synthesized by the same method as described above.

Test example 1
In vitro antibacterial activity of the compound of the present invention was confirmed.
(Test method)
The minimum inhibitory concentration (MIC) was measured according to the method recommended by CLSI (Clinical and Laboratory Standards Institute), the inoculum was 5 × 10 ⁵ CFU / mL, and the test medium was cation-adjusted Mueller Hinton broth. It was carried out by a micro liquid dilution method.
The strains used are shown in the table below.

(result)
The test results are shown below. In the table, the unit of the numerical value of the 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.
(Test method)
The affinity of E. coli NIHJ JC-2 for PBP was assessed by a competitive assay using fluorescently labeled penicillin. The compound solution of the present invention was added to the E. coli NIHJ JC-2 membrane fraction, incubated at 30 ° C. for 10 minutes, fluorescently labeled penicillin was added to a final concentration of 15 μM, and further incubated at 30 ° C. for 30 minutes. The reaction was stopped by incubation at 30 ° C for 15 minutes after addition of 120 mg / mL-PCG / 10% -sarkosyl. After removing the outer membrane components by centrifugation at 8600C and 14600 rpm for 30 minutes, SDS buffer and 2-mercaptoethanol were added, and the protein was denatured by heating in a boiling water bath for 3 minutes. A part of the gel was applied to a 7.5% SDS-PAGE gel, electrophoresed at 290 V / 30 mA, and analyzed with LAS3000 (BIO-RAD).
(result)
It was suggested that the compound of the present invention exhibits PBP3 affinity.

Test Example 1-2
The in vivo antibacterial activity of the compounds of the present invention was evaluated.
(Test method)
Animals used were Jcl: ICR male mice, 5 weeks old. K. pneumoniae ATCC 13883 was used as an evaluation strain. Four and one day before infection, cyclophosphamide was administered intraperitoneally at doses of 150 mg / kg and 100 mg / kg to induce neutropenia. Under anesthesia, infection is induced by nasal inoculation of the infected bacterial solution at about 1 × 10 ⁶ CFU / mouse, and the compound of the present invention is 0.1, 0.3, 1 or Single or repeated subcutaneous administration at a dose of 3 mg / kg. After euthanasia treatment at 10 hours after infection, the lungs were collected and the number of viable bacteria in the lungs was measured by preparing lung homogenates.
(result)
The number of viable bacteria in the lung after administration of the compound of the present invention was significantly reduced as compared with the start of treatment.

From the above results, the compound of the present invention has a broad antibacterial spectrum, particularly shows a strong antibacterial spectrum against gram-negative bacteria, and / or produces multi-drug resistant bacteria, particularly class B type metallo-β-lactamases Strong antibacterial activity against gram negative bacteria and / or strong antibacterial activity against class A β-lactamase producing gram negative bacteria such as KPC. Furthermore, it also has strong antibacterial activity against class C β-lactamase-producing gram-negative bacteria. It is also effective against multidrug-resistant bacteria including carbapenem resistance, and has high stability against β-lactamase-producing gram-negative bacteria.

Test Example 2: CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively. The degree to which the amount of metabolite produced was inhibited by the compound of the present invention was evaluated.

The reaction conditions were as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 μmol / L (4 points) .

As a reaction solution in a 96-well plate, each of 5 types of substrate, human liver microsome, and the compound of the present invention are added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH, a coenzyme, is added as an indicator for metabolic reaction. Started. After reacting at 37 ° C. for 15 minutes, the reaction was stopped by adding a methanol / acetonitrile = 1/1 (V / V) solution. After centrifuging at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the centrifugation supernatant was quantified with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite) Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.

The residual activity (%) at each concentration of the compound of the present invention added to the solvent was calculated by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the concentration and inhibition rate were calculated. The IC ₅₀ was calculated by inverse estimation using a logistic model.

Test Example 3: Examination of BA test oral absorbability Experimental materials and methods (1) Animals used: Mice or SD rats were used.
(2) Breeding conditions: Mice or SD rats were allowed to freely take solid feed and sterilized tap water.
(3) Setting of dose and grouping: Oral administration and intravenous administration were administered at a predetermined dose. Groups were set up as follows. (Dose may vary for each compound)
Oral administration 1-30 mg / kg (n = 2-3)
Intravenous administration 0.5-10 mg / kg (n = 2-3)
(4) Preparation of administration solution: Oral administration was administered as a solution or suspension. Intravenous administration was solubilized.
(5) Administration method: Oral administration was forcibly administered into the stomach with an oral sonde. Intravenous administration was carried out from the tail vein using a syringe with an injection needle.
(6) Evaluation items: 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: The plasma concentration-time curve area (AUC) is calculated using the non-linear least squares program WinNonlin (Registered Trademark) for plasma compound concentration transition, and the oral administration group and intravenous administration The bioavailability (BA) of the compound of the present invention was calculated from the AUC of the group.

Test Example 4: Metabolic stability test A commercially available pooled human liver microsome and the compound of the present invention are reacted for a certain period of time, and the residual ratio is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. did.

In 0.2 mL buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL human liver microsomes in the presence of 1 mmol / L NADPH The reaction was carried out at 37 ° C. for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction solution was added to 100 μL of a methanol / acetonitrile = 1/1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifugal supernatant was quantified by LC / MS / MS, and the residual amount of the compound of the present invention after the reaction was calculated with the compound amount at 0 minute reaction as 100%. The hydrolysis reaction can be carried out in the absence of NADPH, the glucuronic acid conjugation reaction can be carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same operation can be carried out thereafter.

Test Example 5: CYP3A4 fluorescence MBI test The CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compounds of the present invention by metabolic reaction. 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by CYP3A4 enzyme (E. coli-expressed enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC). CYP3A4 inhibition was evaluated using 7-HFC production reaction as an index.

The reaction conditions are as follows: substrate, 5.6 μmol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 μmol / L (6 points) ).

The enzyme and the compound solution of the present invention are added to the 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition, and the substrate and K-Pi buffer are added to another 96-well plate. A part of the solution was transferred so as to be diluted by 1/10, and a reaction using NADPH as a coenzyme was started as an indicator (no pre-reaction). After reaction for a predetermined time, acetonitrile / 0.5 mol / L The reaction was stopped by adding Tris (trishydroxyaminomethane) = 4/1 (V / V). In addition, NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer. The reaction was started by shifting the part. After the reaction for a predetermined time, the reaction was stopped by adding acetonitrile / 0.5 mol / L Tris (trishydroxyaminomethane) = 4/1 (V / V). The fluorescence value of 7-HFC, which is a metabolite, was measured using a fluorescent plate reader on the plate on which each index reaction was performed. (Ex = 420nm, Em = 535nm)

A control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when each concentration of the compound of the present invention was added was calculated. Was used to calculate IC ₅₀ by inverse estimation using a logistic model. The case where the difference in IC ₅₀ values was 5 μmol / L or more was designated as (+), and the case where it was 3 μmol / L or less was designated as (−).

Test Example 6: Fluctuation Ames Test
The mutagenicity of the compounds of the present invention was evaluated.
Twenty microliters of Salmonella typhimurium TA98, TA100) cryopreserved was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For the TA98 strain, 9 mL of the bacterial solution was centrifuged (2000 × g, 10 minutes) to remove the culture solution. 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. MicroF containing 110 mL Exposure medium (Biotin: 8 μg / mL, Histidine: 0.2 μg / mL, Glucose: 8 mg / mL) suspended in 25 g / L, MgSO ₄ · 7H ₂ 0: 0.1 g / L) Buffer). The TA100 strain was added to 120 mL of Exposure medium with respect to the 3.16 mL bacterial solution to prepare a test bacterial solution. Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 μg / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 μg / mL 2-aminoanthracene DMSO solution for the strain and 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 μL of the test bacterial solution (498 μL of the test bacterial solution and S9 under metabolic activation conditions). (mixture of 90 μL of mix) was mixed and incubated at 37 ° C. for 90 minutes with shaking. 460 μL of the bacterial solution exposed to the compound of the present invention was added 2300 μL of Indicator medium (MicroF buffer solution containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL). 50 μL each, and dispensed into 48 wells / dose of the microplate, and statically cultured at 37 ° C. for 3 days. Since wells containing bacteria that have acquired growth ability by mutation of the amino acid (histidine) synthase gene change from purple to yellow due to pH change, the number of bacteria growth wells that changed to yellow in 48 wells per dose was counted. Evaluation was made in comparison with the negative control group. A negative mutagenicity is indicated as (−), and a positive mutagenicity is indicated as (+).

Test Example 7: hERG Test For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, using HEK293 cells expressing human ether-a-go-related gene (hERG) channel, it is important for ventricular repolarization process The action of the compounds of the present invention on the delayed rectifier K ⁺ current (I _Kr ), which plays an important role, was investigated.
Using a fully automatic patch clamp system (PatchXpress 7000A, Axon Instruments Inc.) and holding the cells at a membrane potential of −80 mV by whole cell patch clamp, a +40 mV depolarization stimulus was applied for 2 seconds, followed by a −50 mV repolarization. The I _Kr elicited when the stimulus was applied for 2 seconds was recorded. After the generated current is stabilized, an extracellular fluid (NaCl: 135 mmol / L, KCl: 5.4 mmol / L, NaH ₂ PO ₄ : 0.3 mmol / L, in which the compound of the present invention is dissolved at a target concentration, 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-piperazineethanesulfonic acid): 10 mmol / L, pH = 7.4) was applied to the cells for 10 minutes at room temperature. From the obtained I _Kr , the absolute value of the maximum tail current was measured based on the current value at the holding membrane potential using analysis software (DataXpress ver. 1, Molecular Devices Corporation). Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention was calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I _Kr was evaluated.

Test Example 8: Solubility test The solubility of the compound of the present invention was determined under the condition of addition of 1% DMSO. Prepare a 10 mmol / L compound solution in DMSO, add 6 μL of the compound solution of the present invention to pH 6.8 artificial intestinal fluid (0.2 mol / L potassium dihydrogen phosphate test solution 250 mL, add 0.2 mol / L NaOH test solution 118 mL, water) Was added to 594 μL. After allowing to stand at 25 ° C. for 16 hours, the mixed solution was subjected to suction filtration. The filtrate was diluted 2-fold with methanol / water = 1/1 (V / V), and the concentration in the filtrate was measured by HPLC or LC / MS / MS using the absolute calibration curve method.

Test Example 9: Powder Solubility Test An appropriate amount of the compound of the present invention is put in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, water is added to 7.0 mL of hydrochloric acid to 1000 mL), JP-2 solution (Add 500 mL of water to 500 mL of phosphate buffer solution at pH 6.8), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution is added to 1.08 g of TCA to make 100 mL) 200 μL each Added. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C. for 1 hour, the mixture is filtered, and 100 μL of methanol is added to 100 μL of each filtrate to perform 2-fold dilution. Change the dilution factor as necessary. Make sure there are no bubbles and deposits, seal and shake. The compound of the present invention is quantified using HPLC by the absolute calibration curve method.

Test Example 10: About 5 mg of visual solubility test compound is weighed into three microscopic test tubes, and each medium (water for injection, saline feed, 0.5% glucose solution) is added to a compound concentration of 20%. After stirring by vortex, visually check for dissolution. If so, the solubility in the medium is> 20%. Each medium (water for injection, raw food injection, glucose solution) is further added to these test solutions to prepare a test solution with a compound concentration of 10%. After stirring by vortexing, the presence or absence of dissolution is visually confirmed. If dissolved, the solubility in the medium should be 20% to 10%. Similarly, test to 5% concentration, 2.5% concentration, 1% concentration, and if not soluble at 1% concentration, the solubility in the medium should be <1%. Measure and record the pH with 1% test solution.

Test Example 11: pKa measurement (capillary electrophoresis method (capillary electrophoresis method, CE method) measurement method)
This method is a separation method using free migration of each sample component in a buffer solution containing an electrolyte using a capillary zone electrophoresis technique.
After injecting a compound solution into a fused silica capillary filled with a buffer adjusted to pH 2.5 to 11.5 and applying a high voltage (Inlet side +, Outlet side-) to the capillary, the compound is at the buffer pH. It moves at a speed that reflects the ionization state (+ charged compounds are fast, -charged compounds are slow). The difference between the migration time of this compound and the migration time of neutral molecule (DMSO) was plotted against pH, and pKa was calculated by fitting. The measurement conditions are shown below.
Equipment used: Beckman P / ACE system MDQ PDA
Electrophoresis: pH2.5 to 11.5 Buffer (containing 10vol% MeOH)
Sample solution: Blank DMSO 10 μL + Injection water 90 μL
Sample 10 mM DMSO stock solution 4 μL + DMSO 6 μL + Injection water 90 μL
(Method)
Capillary: Fused silica capillary (BECKMAN COULTER, inner diameter 50μm, overall length 30.2cm, effective length 20.0cm)
Applied voltage: 10 kV (331 V / cm)
Applied air pressure: 0.7 psi
Capillary temperature: 25 ° C
Electroosmotic flow marker: DMSO
Detection: UV multi-wavelength absorption detection (measurement wavelength: 215 nm, 238 nm)
Sample injection: pressurized method (0.5 psi, 5 sec)

The compound of the present invention has a broad antibacterial spectrum especially against gram-negative bacteria and is effective as an antibacterial agent having strong antibacterial activity against β-lactamase-producing gram-negative bacteria. In addition, since it has good pharmacokinetics and high water solubility, it is particularly effective as an injection or oral drug.

Claims (8)

1. formula:
   

   

   
   

   

   
   Or an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
   
2. formula:
   

   

   
   

   

   
   The compound according to claim 1, an ester form thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
   
3. A pharmaceutical composition comprising the compound according to claim 1 or 2, an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
   
4. The pharmaceutical composition according to claim 3, which has an antibacterial action.
   
5. The antibacterial agent containing the compound of Claim 1 or 2, its ester body, those pharmaceutically acceptable salts, or those hydrates.
   
6. A cell wall synthesis inhibitor comprising the compound according to claim 1 or 2, an ester thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
   
7. A method for treating or preventing a disease associated with bacterial infection, which comprises administering the compound according to claim 1 or 2, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof. .
   
8. The compound according to claim 1 or 2, an ester thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof for treating or preventing a disease associated with bacterial infection.