TW201906616A - Amide derivative - Google Patents

Abstract

The purpose of the invention is to find a novel compound having an excellent [beta]-lactamase inhibitory action, and to provide a useful prophylactic or therapeutic agent for bacterial infectious diseases, as a sole agent or in combination with a [beta]-lactam medicine. Disclosed is a compound represented by formula (1a) or (1b), or a pharmaceutically acceptable salt thereof. (In formulas (1a) and (1b), X represents an oxygen atom, a sulfur atom, or -NRa1-; Z represents a hydroxyl group, a C1-6 alkoxy group that may optionally be substituted, or -NRa2Rb1; Ra1, Ra2, and Rb1 are as defined in the Description; L represents a C1-6 alkylene group that may optionally be substituted; Y represents C(=O)NRd1Rd2 wherein Rd1 and Rd2 together form a 4 to 20-membered nitrogen-containing non-aryl hetero ring that may optionally be substituted and that includes, in the ring, the nitrogen atom constituting the amide bond of said Y; and R1, R2, R3, and R4 are as defined in the Description.).

Description

Indoleamine derivative

The present invention relates to a guanamine derivative useful as a medicine, or a pharmaceutically acceptable salt thereof. More specifically, it relates to a pharmaceutical composition containing a novel indoleamine derivative, or a pharmaceutically acceptable salt thereof. The present invention relates to a therapeutic agent containing the guanamine derivative or a pharmaceutically acceptable salt thereof.

Since the discovery of penicillin, antibacterial agents have always occupied an important position in the treatment of infectious diseases.

Among them, β-endoamine-based drugs (for example, penicillin-based antibacterial agents, cephalosporin-based antibacterial agents, and carbapenem-based antibacterial agents) are used for the treatment of bacterial infections in terms of strong bactericidal power and high safety. The most versatile agent. However, with the increase in the use of β-endoamine-based drugs, the emergence and spread of pathogenic bacteria that have developed resistance to β-endamine drugs have become a worldwide problem. Examples of the drug resistance mechanism of such pathogens include the production of β-endoprostanase, the structural change of the target molecule of the β-indoleamine-based drug, the decrease in the permeability of the drug into the cells, and the discharge of the drug. Hyperactivity, and the like, in particular, the production of β-endoprolinase which decomposes and deactivates the β-endoxime-based agent most affects the effectiveness of maintaining the β-endoxime-based agent. Various bacteria have continuously evolved β-endoprolinase against the potency of various β-endamine drugs. The β-endoaminase is classified into four classes, namely, Ambler class A, B, C, and D based on the amino acid sequences. Class A, C, and D enzymes are called serine-β-endoamines because they have a serine residue at the active site of the enzyme. In addition, Class B enzymes do not have silk at the active center of the enzyme. The amine acid residue has zinc (Zn ²⁺ ) as a metal ion, so it is called metal-β-endoguanase (zinc-β-endoguanase).

In order to solve the problem of drug resistance caused by the production of β-endoprostanase, it has been confirmed that it is effective to use a β-endoprostanase inhibitor and a β-endoxime-based agent, which are known to be commercially available. Clavulanic acid, sulbactam, and tazobactam of β-endoprostanase inhibitors mainly inhibit KPC (Klebsiella pneumoniae Carbapenemase, Klebsiella pneumoniae carbapenem) Class A β-endoaminase outside the enzyme, Avibactam inhibits Class A, Class C, including KPC, and β-type of Class D, including OXA-48 Amidase (Non-Patent Document 1). However, such existing β-endoprostanase inhibitors may not be effective and broadly inhibit all β-endoprostanase produced by various bacteria, for example, for Class B type metal-β-endoguanase display effect. In addition, in recent years, β-endoamine, which is called ESBLs (Extended Spectrum β-Lactamases), is more decomposed than the former (β-endoamine-based drug). The enzyme is isolated and has become a problem in new European and American countries as a new drug-resistant bacteria, especially a Causative bacteria in hospitals. In addition, in Japan, the emergence of metal-β-endoprostanase-producing bacteria, Communication has gradually become a problem. In view of such a situation, it is extremely important to treat β-endoprostanase-producing bacteria including ESBLs or metal-β-endoprostanase in the prevention of nosocomial infections. Furthermore, the evolution of pathogenic bacteria is rapid, and the possibility of new β-endoprostase-resistant bacteria is extremely high. Therefore, as a solution to these problems or preparations for the subject, the industry has demanded the development of a novel β-endosaminolase inhibitor, the structure of the novel β-endosaminolase inhibitor and the existing β-inner Since the glutaminase inhibitor is different, a wider range of β-endoprostanase inhibition or metal-β-endoguanamine inhibition is expected.

Recently, boric acid derivatives having a β-endosungase inhibitory action have been reported in Patent Documents 1 to 9 and the like. In the patent documents, the indoleamine derivative contained in the present invention, that is, a boric acid compound group having a unique cyclic amine or other side chain having a guanamine structure containing a nitrogen-containing non-aryl heterocyclic ring at a specific position, is not disclosed. Structure. [Prior Technical Literature] [Patent Literature]

[Patent Document 1] WO2014/107535 [Patent Document 2] WO2014/107536 [Patent Document 3] WO2015/179308 [Patent Document 4] WO2016/003929 [Patent Document 5] WO2016/149393 [Patent Document 6] WO2014/089365 [Patent [7] WO2014/110442 [Patent Document 8] WO2014/151958 [Patent Document 9] WO2015/191907 [Non-Patent Document]

[Non-Patent Document 1] Buynak. JD. Expert Opinion on Therapeutic Patents, 2013, 23 (11), 1469-1481.

[The problem that the invention wants to solve]

The problem to be solved by the present invention is to find a novel compound having an excellent β-endoprostanase inhibitory action, which is useful for bacterial infection by a combination with a β-namidamide-based agent or in a single dose. A preventive or therapeutic agent. Specifically, there is provided a method for treating sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia by use together with a β-endamine drug. , lung abscess, empyema, secondary infection of chronic respiratory diseases, pharyngitis, tonsillitis, osteophyte, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic vessels / A useful preventive or therapeutic agent for diseases such as secondary infections such as lymphadenitis, trauma/scald, and surgical wounds, urinary tract infections, genital infections, ocular infections, or odontogenic infections. [Technical means to solve the problem]

The inventors of the present invention conducted intensive studies and found that the compound represented by the following formula (1a), (1b), or (2), or a pharmaceutically acceptable salt thereof (hereinafter, also referred to as The "compound of the present invention") solves the above problems and completes the present invention. That is, the present invention is as follows.

[Item 1] A compound or a pharmaceutically acceptable salt thereof, which is represented by the formula (1a) or (1b): [In the formulae (1a) and (1b), X represents an oxygen atom, a sulfur atom, or -NR ^A1 -, Z represents a hydroxyl group, a substituted C _1-6 Alkoxy, or -NR ^A2 R ^B1 , R ^A1 , R ^A2 , R ^B1 The same or different, each independently represents 1) a hydrogen atom, 2) C _1-6 Alkyl, 3) C _3-10 Alicyclic base, 4) C _6-10 Aryl, 5) 5- or 6-membered heteroaryl, 6) 4- to 10-membered non-aryl heterocycle, 7) C _1-6 Alkylcarbonyl, 8) C _3-10 Alicyclic carbonyl, 9) C _6-10 Arylcarbonyl, 10) 5- or 6-membered heteroarylcarbonyl, 11) C _1-6 Alkylsulfonyl, 12) C _3-10 Alicyclic sulfonyl, 13) C _6-10 Arylsulfonyl, 14) 5 or 6 membered heteroarylsulfonyl, or 15) -OR ^C1 (wherein each of the above 2) to 14) may be substituted), here, R ^A2 And R ^B1 It is also possible to form a nitrogen-containing non-aryl heterocyclic ring of 4 to 10 members which can be substituted, R ^C1 Indicates 1) hydrogen atom 2) C _1-6 Alkyl 3) C _3-10 Alicyclic base 4) C _6-10 Any one of aryl 5) 5 or 6 member heteroaryl, or 6) 4 to 10 member non-aryl heterocyclic ring (wherein each of the above 2) to 6) may be substituted, L represents a replaceable C _1-6 Alkyl, Y represents C(=O)NR ^D1 R ^D2 , here, R ^D1 With R ^D2 Further, the nitrogen-containing non-aryl heterocyclic ring having 4 to 20 members which may be substituted in the ring and containing a nitrogen atom constituting the above-described Y-amine bond of the Y may be formed. ¹ , R ² , R ³ The same or different, each independently represents 1) a hydrogen atom, 2) a halogen atom, 3) a 5-membered heteroaryl group, 4) C _1-6 Alkoxy, 5) C _1-6 Alkylthio, or 6) -NR ^A3 R ^B2 Any of the substituents (wherein each of the above 3) to 5) may be substituted), R ⁴ Indicates 1) -COR ⁵ , 2) -SO ₂ -L ^a -R ⁵ (in the above 1) and 2), R ⁵ Means -NR ^A4 R ^B3 , -NR ^A4 -L ^b -B(OR ^E1 ) ₂ , -OR ^E1 Or can be replaced by C _1-6 Alkyl, L ^a Represents a single bond, or -NR ^A5 -), 3) -NR ^A6 R ^B4 , 4) -B(OR ^E1 ) ₂ , 5) -PO(OR ^E1 ) (OR ^E2 And 6) a heterocyclic group of 5 members which may be substituted, 7) a non-aryl heterocyclic ring of 5 members which may be substituted, or 8) a carboxylic acid equivalent (wherein 2), 4), 5) And the formula 6) comprises a carboxylic acid equivalent, and 7) may optionally comprise any of the above, R ^A3 , R ^A4 , R ^A5 , R ^A6 , R ^B2 , R ^B3 , R ^B4 Each independently the same or different, with the above R ^A1 , R ^A2 , R ^B1 The meaning is the same, here, in R ^A3 With R ^B2 , R ^A4 With R ^B3 Or R ^A6 With R ^B4 When the combination is bonded to the same nitrogen atom, these may also form a nitrogen-containing non-aryl heterocyclic ring of 4 to 10 members which may be substituted, R ^E1 Indicates 1) hydrogen atom, 2) C _1-6 Alkyl, 3) C _3-10 Alicyclic base, 4) C _6-10 Any one of an aryl group, 5) a 5- or 6-membered heteroaryl group, or 6) a 4 to 10 membered non-aryl heterocyclic ring (wherein each of the above 2) to 6) may be substituted) , where, in R ^E1 When the oxygen atom is bonded to the boron atom, two R ^E1 By C _2-4 The alkyl form forms a 5- to 7-membered non-aryl heterocyclic ring together with a boron atom and two oxygen atoms (the alkyl moiety of the non-aryl heterocyclic ring may be substituted), R ^E2 Represents a hydrogen atom, a C that can be substituted _1-6 Alkyl, or substituted C _3-10 Alicyclic base, L ^b Indicates a replaceable C _1-3 Alkyl]. [Claim 2] The compound according to Item 1, or a pharmaceutically acceptable salt thereof, wherein L is C _1-6 An alkyl group (the group may be selected from a halogen atom, a hydroxyl group, a cyano group, C _1-6 Alkyl, C _1-6 Alkoxy, -NR ^F1 R ^F2 1 to 3 substituents in place), R ^F1 , R ^F2 The same or different, each independently being a hydrogen atom, or C _1-6 alkyl. [Claim 3] The compound according to Item 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is C _1-3 Alkyl group (this group can pass 1-3 C _1-3 Alkyl substitution). The compound according to any one of items 1 to 3, wherein the L is a methylene group (-CH), or a pharmaceutically acceptable salt thereof ₂ -). The compound according to any one of items 1 to 4, wherein the Y is C(=O)NR, or a pharmaceutically acceptable salt thereof ^D1 R ^D2 , here, R ^D1 With R ^D2 It is also possible to form a nitrogen-containing non-aryl heterocyclic ring of 4 to 20 members which is formed by containing a nitrogen atom constituting the above-described Y in the amine bond in the ring, (the 4-20 member nitrogen-containing non-aryl heterocyclic ring) It can be selected from 1) halogen atom, 2) hydroxyl group, 3) carboxyl group, 4) cyano group, 5) -NR ^G1 R ^G2 , 6) -CR ^G3 (=NR ^H1 ), 7) -C(=NR ^H2 )NR ^G4 R ^G5 , 8) -C(=O)NR ^G6 R ^G7 , 9) -C(=O)NR ^G26 OR ^G27 , 10) -C(=O)NR ^G8 -SO ₂ -R ^G9 , 11) -SO ² -NR ^G10 R ^G11 , 12) -NR ^G12 -CR ^G13 (=NR ^H3 ), 13) -NR ^G14 -C(=NR ^H4 )NR ^G15 R ^G16 , 14) -NR ^G17 -C(=O)NR ^G18 R ^G19 , 15) -NR ^G20 -C(=O)R ^G21 , 16) -NR ^G22 -C(=O)OR ^G23 , 17) -NR ^G24 -SO ₂ -R ^G25 , 18) C _1-6 Alkyl, or 19) C _1-6 Alkoxy group (the C _1-6 Alkyl, C _1-6 The alkoxy group may be selected from the group consisting of 1) a halogen atom, 2) a hydroxyl group, 3) a carboxyl group, 4) a cyano group, 5) C _1-6 Alkoxy, 6) -NR ^I1 R ^I2 , 7) -CR ^I3 (=NR ^J1 ), 8) -C(=NR ^J2 )NR ^I4 R ^I5 , 9) -C(=O)NR ^I6 R ^I7 , 10) -C(=O)NR ^I8 -SO ₂ -R ^I9 , 11) -SO ₂ -NR ^I10 R ^I11 , 12) -NR ^I12 -CR ^I13 (=NR ^J3 ), 13) -NR ^I14 -C(=NR ^J4 )NR ^I15 R ^I16 , 14) -NR ^I17 -C(=O)NR ^I18 R ^I19 , 15) -NR ^I20 -C(=O)R ^I21 , 16) -NR ^I22 -C(=O)OR ^I23 , or 17) -NR ^I24 -SO ₂ -R ^I25 One to three substituents in the substitution of 1 to 3 substituents are substituted), here, R ^G1 , R ^G2 , R ^G3 , R ^G4 , R ^G5 , R ^G6 , R ^G7 , R ^G8 , R ^G9 , R ^G10 , R ^G11 , R ^G12 , R ^G13 , R ^G14 , R ^G15 , R ^G16 , R ^G17 , R ^G18 , R ^G19 , R ^G20 , R ^G21 , R ^G22 , R ^G23 , R ^G24 , R ^G25 , R ^G26 , R ^G27 , R ^I1 , R ^I2 , R ^I3 , R ^I4 , R ^I5 , R ^I6 , R ^I7 , R ^I8 , R ^I9 , R ^I10 , R ^I11 , R ^I12 , R ^I13 , R ^I14 , R ^I15 , R ^I16 , R ^I17 , R ^I18 , R ^I19 , R ^I20 , R ^I21 , R ^I22 , R ^I23 , R ^I24 , R ^I25 The same or different, each independently represents a hydrogen atom or can pass through -NR ^I26 R ^I27 Replace C _1-6 Alkyl, R ^I26 , R ^I27 Same or different, each independently represents a hydrogen atom or C _1-6 Alkyl, at R ^G1 With R ^G2 , R ^G4 With R ^G5 , R ^G6 With R ^G7 , R ^G10 With R ^G11 , R ^G15 With R ^G16 , R ^G18 With R ^G19 , R ^I1 With R ^I2 , R ^I4 With R ^I5 , R ^I6 With R ^I7 , R ^I10 With R ^I11 , R ^I15 With R ^I16 Or R ^I18 With R ^I19 When the combination is bonded to the same nitrogen atom, these may also form a nitrogen-containing non-aryl heterocyclic ring of 4 to 10 members which may be substituted, R ^H1 , R ^H2 , R ^H3 , R ^H4 , R ^J1 , R ^J2 , R ^J3 , R ^J4 The same or different, each independently is a hydrogen atom, a hydroxyl group, C _1-6 Alkyl, C _1-6 Alkoxy. The compound according to any one of items 1 to 5, wherein the Y is represented by any one of the following formulas (3A) or (3B): 2] Equation (3A); (3B): [In the formula (3A), m is an integer of 0, 1, 2 or 3, L ¹ Is a carbon atom, an oxygen atom, a carbonyl group (-C(=O)-) or -NR ^Y5 -, L ² And L ³ The same or different, each independently a carbon atom, or a carbonyl group (-C(=O)-), R ^Y1 , R ^Y2 , R ^Y3 Bonding at a position on the carbon atom in the nitrogen-containing ring that is capable of chemical substitution to satisfy a sufficient number of valences of all of the carbon atoms forming the ring (ie, R) ^Y1 , R ^Y2 , R ^Y3 There may be a plurality of), respectively, the same or different, each independently being 1) a hydrogen atom 2) a hydroxyl group, 3) -NR ^G1 R ^G2 , 4) -CR ^G3 (=NR ^H1 ) 5) -C(=NR ^H2 )NR ^G4 R ^G5 , 6) -NR ^G12 -CR ^G13 (=NR ^H3 ), 7) -NR ^G14 -C(=NR ^H4 )NR ^G15 R ^G16 , 8) -NR ^G20 -C(=O)R ^G21 , 9) -NR ^G24 -SO ₂ -R ^G25 , 10) -C(=O)NR ^G6 R ^G7 , 11) C _1-3 Alkyl, or 12) C _1-3 Alkoxy group (the C _1-3 Alkyl, C _1-3 The alkoxy group may be selected from a hydroxyl group, C _1-3 Alkoxy, -NR ^I1 R ^I2 Any of the substituents in the formula), (here, R ^G1 , R ^G2 , R ^G3 , R ^G4 , R ^G5 , R ^G6 , R ^G7 , R ^G12 , R ^G13 , R ^G14 , R ^G15 , R ^G16 , R ^G20 , R ^G21 , R ^G24 , R ^G25 , R ^I1 , R ^I2 The same or different, each independently represents a hydrogen atom or can pass through -NR ^I26 R ^I27 Replace C _1-3 Alkyl, R ^I26 , R ^I27 Same or different, each independently represents a hydrogen atom or C _1-6 Alkyl, R ^H1 , R ^H2 , R ^H3 And R ^H4 The same or different, each independently is a hydrogen atom, a hydroxyl group, C _1-3 Alkyl, C _1-3 Alkoxy), R ^Y1 And R ^Y2 Also bonded carbon atoms and R ^Y1 And R ^Y2 Each of them forms together with C _3-7 Alicyclic group or 4- to 7-membered non-aryl heterocyclic ring (C _3-7 An alicyclic group or a 4- to 7-membered non-aryl heterocyclic ring may be selected from a hydroxyl group, -NR ^I28 R ^I29 , C _1-3 Alkyl, C _1-3 Alkoxy group (the C _1-3 Alkyl, C _1-3 The alkoxy group may be selected from a hydroxyl group, C _1-3 Alkoxy, -NR ^I30 R ^I31 a substituent or a crosslinked structure in which a substituent in the substituent is substituted), R ^I28 , R ^I29 , R ^I30 , R ^I31 Same or different, each independently represents a hydrogen atom or C _1-3 Alkyl, R ^Y5 1) hydrogen atom 2) -CR ^G28 (=NR ^H5 ), 3) -C(=NR ^H6 )NR ^G29 R ^G30 , or 4) C _1-3 Alkyl, (the C _1-3 The alkyl group may be selected from a hydroxyl group, C _1-3 Alkoxy, -NR ^I32 R ^I33 Any of the substituents in place) (here, R ^G28 , R ^G29 , R ^G30 , R ^I32 , R ^I33 Same or different, each independently represents a hydrogen atom or C _1-3 Alkyl, R ^H5 And R ^H6 The same or different, each independently is a hydrogen atom, a hydroxyl group, C _1-3 Alkyl, C _1-3 Alkoxy), in the formula (3B), n is an integer of 1 or 2, L ⁴ Oxygen atom, sulfur atom, -SO ₂ -or-NR ^Y6 -, R ^Y4 Bonding at a position on the carbon atom in the nitrogen-containing ring that is capable of chemical substitution to satisfy a sufficient number of valences of all of the carbon atoms forming the ring (ie, R) ^Y4 There may be a plurality of separate), and the same or different, each independently being the above R ^Y1 , R ^Y2 , R ^Y3 In any of the definitions 1) to 12), R ^Y6 And R above ^Y5 The definition is the same)]. The compound according to any one of items 1 to 6 or a pharmaceutically acceptable salt thereof, wherein Y is represented by the following formulas (3C), (3D), (3E), (3F), Any of (3G) or (3H) means: [Chemical 3] Formula (3C); (3D); (3E); (3F); (3G); (3H): [In the formula (3C), R ^Y5 1) hydrogen atom 2) hydroxyl group, 3) -NR ^G1 R ^G2 , 4) -C(=NR ^H2 )NR ^G4 R ^G5 , 5) -NR ^G12 -CR ^G13 (=NR ^H3 ), 6) -NR ^G14 -C(=NR ^H4 )NR ^G15 R ^G16 , 7) -NR ^G20 -C(=O)R ^G21 , 8) -NR ^G24 -SO ₂ -R ^G25 , 9) -C(=O)NR ^G6 R ^G7 , 10) C _1-3 Alkyl, or 11) C _1-3 Alkoxy group (the C _1-3 Alkyl, C _1-3 The alkoxy group may be selected from a hydroxyl group, C _1-3 Alkoxy, -NR ^I1 R ^I2 Any of the substituents substituted in the), and R ^Y5 It may be substituted at any position chemically possible on a carbon atom in the nitrogen-containing ring of formula (3C) (here, R ^G1 , R ^G2 , R ^G4 , R ^G5 , R ^G6 , R ^G7 , R ^G12 , R ^G13 , R ^G14 , R ^G15 , R ^G16 , R ^G20 , R ^G21 , R ^G24 , R ^G25 , R ^I1 , R ^I2 The same or different, each independently represents a hydrogen atom or can pass through -NR ^I26 R ^I27 Replace C _1-3 Alkyl, R ^I26 , R ^I27 Same or different, each independently represents a hydrogen atom or C _1-6 Alkyl, R ^H2 , R ^H3 And R ^H4 Are all hydrogen atoms), p is an integer of 0, 1, or 2, q is an integer of 1 or 2, in formula (3D), L ⁵ Oxygen atom or -NR ^Y10 -, (here, R ^Y10 1) hydrogen atom 2) -CR ^G3 (=NR ^H1 ), 3) -C(=NR ^H2 )NR ^G4 R ^G5 , or 4) C _1-3 Alkyl, (the C _1-3 The alkyl group may be selected from a hydroxyl group, C _1-3 Alkoxy, -NR ^I1 R ^I2 Any of the substituents in place) (here, R ^G3 , R ^G4 , R ^G5 , R ^I1 , R ^I2 Same or different, each independently represents a hydrogen atom or C _1-3 Alkyl, R ^H1 And R ^H2 Are all hydrogen atoms), R ^Y6 Is a hydrogen atom, or C _1-3 Alkyl, (the C _1-3 Alkyl group can pass -NR ^I1 R ^I2 Replace), and R ^Y6 Any position chemically possible on a carbon atom in the nitrogen-containing ring of formula (3D) may be substituted, r is an integer of 1 or 2, in formula (3E), R ^Y7 Is 1) hydrogen atom, 2) hydroxyl group, 3) -NR ^G1 R ^G2 , or 4) C _1-3 Alkoxy group (the C _1-3 Alkoxy can be via -NR ^I1 R ^I2 Replace any of them, and R ^Y7 It can be substituted at any position chemically possible on a carbon atom in the nitrogen-containing ring of formula (3E) (here, R ^G1 , R ^G2 , R ^I1 , R ^I2 Same or different, each independently represents a hydrogen atom or C _1-3 Alkyl), in formula (3F), L ⁶ , L ⁷ , L ⁸ May be all methylene (-CH ₂ -), or any one can be -NR ^Y11 - the remaining two are methylene (-CH ₂ -) (here, R ^Y11 1) hydrogen atom 2) -CR ^G3 (=NR ^H1 ), or 3) C _1-3 Alkyl group (the C _1-3 Alkyl group can pass -NR ^I1 R ^I2 Replace any of them (here, R ^G3 , R ^I1 , R ^I2 Represents a hydrogen atom or C _1-3 Alkyl, R ^H1 Is a hydrogen atom), R ^Y8 For 1) -NR ^G1 R ^G2 , or 2) -NR ^G14 -C(=NR ^H4 )NR ^G15 R ^G16 Any of them, and R ^Y8 Any position chemically possible on a carbon atom in the nitrogen-containing ring of formula (3F) may be substituted (here, R ^G1 , R ^G2 , R ^G14 , R ^G15 , R ^G16 Same or different, each independently represents a hydrogen atom or C _1-3 Alkyl, R ^H4 Is a hydrogen atom), s is an integer of 0 or 1, in the formula (3G), L ⁹ Methylene (-CH) ₂ -) or carbonyl (-C(=O)-), L ¹⁰ Is an oxygen atom or -NH-, or L ⁹ Is an oxygen atom or -NH-, L ¹⁰ Methylene (-CH) ₂ -) or carbonyl (-C(=O)-), R ^Y9 Is a hydrogen atom, C _1-3 Alkyl group (the C _1-3 Alkyl group can pass -NR ^G1 R ^G2 Replace) or -NR ^G1 R ^G2 (here, R ^G1 , R ^G2 Same or different, each independently represents a hydrogen atom or C _1-3 Alkyl), in formula (3H), L ¹¹ Methylene (-CH) ₂ -), carbonyl (-C(=O)-), oxygen atom or -NH-]. [Claim 8] The compound according to Item 7, or a pharmaceutically acceptable salt thereof, wherein Y is represented by the formula (3C), and p is 0 and q is 1. [Claim 9] The compound according to Item 8, or a pharmaceutically acceptable salt thereof, wherein R ^Y5 For MeO-, NH ₂ -, hydrogen atom, HO-, NH ₂ -CH ₂ -, or H ₂ NCH ₂ CH ₂ NHC(=O)-. [10] The compound according to Item 8, or a pharmaceutically acceptable salt thereof, wherein R ^Y5 For MeO-. [Item 11] The compound of Item 8, or a pharmaceutically acceptable salt thereof, wherein R ^Y5 For NH ₂ -. [Claim 12] The compound according to Item 8, or a pharmaceutically acceptable salt thereof, wherein R ^Y5 It is a hydrogen atom. [Item 13] The compound according to Item 8, or a pharmaceutically acceptable salt thereof, wherein R ^Y5 For HO-. [Item 14] The compound according to Item 8, or a pharmaceutically acceptable salt thereof, wherein R ^Y5 For NH ₂ -CH ₂ -. [Claim 15] The compound according to Item 8, or a pharmaceutically acceptable salt thereof, wherein R ^Y5 H ₂ NCH ₂ CH ₂ NHC(=O)-. The compound according to any one of items 1 to 15, wherein the X is an oxygen atom or -NR, or a pharmaceutically acceptable salt thereof ^A1 -. The compound according to any one of items 1 to 15, wherein the X is an oxygen atom or a sulfur atom, or a pharmaceutically acceptable salt thereof. The compound according to any one of items 1 to 17, wherein the X is an oxygen atom, or a pharmaceutically acceptable salt thereof. The compound according to any one of items 1 to 18, wherein Z is a hydroxyl group, C, or a pharmaceutically acceptable salt thereof _1-6 Alkoxy or -NR ^A2 R ^B1 . The compound according to any one of items 1 to 19, wherein Z is a hydroxyl group or C, or a pharmaceutically acceptable salt thereof _1-6 Alkoxy. The compound according to any one of items 1 to 20, wherein Z is a hydroxyl group, or a pharmaceutically acceptable salt thereof. The compound of any one of items 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² The same or different, each independently being a hydrogen atom, a halogen atom, and a C which may be substituted by 1 to 5 halogen atoms _1-6 alkyl. The compound according to any one of items 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² All are hydrogen atoms. The compound according to any one of items 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R ³ It is a hydrogen atom, a halogen atom, a triazolyl group, a methoxy group, an ethoxy group or a methylthio group. The compound according to any one of items 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R ³ It is a hydrogen atom, a triazolyl group, a methoxy group or a methylthio group. The compound according to any one of items 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R ⁴ The following formulas (4A), (4B), (4C), (4D), (4E), (4F), (4G), (4H), (4I), (4J), (4K), (4L) Any one of (4M), (4N), (4O), (4P), (4Q) or (4R) means: (4A); (4B); (4C); (4D) (4E); (4F); (4G); (4H); (4I); (4J); (4K); (4L); (4M); (4N); (4O); (4P); (4Q); (4R): [In the formula (4Q) and (4R), R ^j Is a hydrogen atom, C _1-6 Alkyl, C _3-10 Alicyclic base (the C _1-6 Alkyl or C _3-10 An alicyclic group may be substituted by 1 to 5 halogen atoms), R ^k Is a hydrogen atom, C _1-6 Alkyl, C _1-6 Alkoxy group (the C _1-6 Alkyl, C _1-6 Alkoxy groups may be substituted by 1 to 5 halogen atoms), C _3-10 An alicyclic group, a phenyl group, a phenoxy group, a pyridyl group, a pyridyloxy group (the C _3-10 An alicyclic group, a phenyl group, a phenoxy group, a pyridyl group, a pyridyloxy group may be selected from 1 to 5 selected from a halogen atom, C _1-6 Alkyl, C _1-6 Substituted in the group consisting of alkoxy groups)]. [Claim 27] The compound of Item 26 or a pharmaceutically acceptable salt thereof, wherein R of Item 26 ⁴ Is the formula (4A) (ie, a carboxyl group). [Claim 28] The compound according to Item 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of (3R)-3-{[2-(3-aminopyrrolidin-1- ))-2-oxoethyl]thio}-2-hydroxy-7-methoxy-3,4-dihydro-2H-1,2-benzoxoxaborox-8-carboxylic acid [Chemical 5] (3R)-4,4-Dihydroxy-3-{[2-(3-Aminopyrrolidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5- Oxa-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chemical 6] , (3R)-2-hydroxy-7-methoxy-3-{[2-o-oxy-2-(pyrrolidin-1-yl)ethyl]thio}-3,4-dihydro-2H -1,2-benzoxoxaborox-8-carboxylic acid [Chemical 7] (3R)-4,4-Dihydroxy-3-{[2-Sideoxy-2-(pyrrolidin-1-yl)ethyl]thio}-8-methoxy-5-oxa- 4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chemical 8] , (3R)-2-hydroxy-3-{[2-o-oxy-2-(pyrrolidin-1-yl)ethyl]thio}-3,4-dihydro-2H-1,2-benzene Oxa-heteroborocyclo-8-carboxylic acid [Chemical 9] , (3R)-4,4-dihydroxy-3-{[2-trioxy-2-(pyrrolidin-1-yl)ethyl]thio}-5-oxa-4-boran anion heterobicyclic [4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chemical 10] , (3R)-2-hydroxy-7-methoxy-3-{[1-o-oxy-1-(pyrrolidin-1-yl)propan-2-yl]thio}-3,4-di Hydrogen-2H-1,2-benzoxoxaborylcyclo-8-carboxylic acid [Chemical 11] (3R)-4,4-Dihydroxy-3-{[1-o-oxy-1-(pyrrolidin-1-yl)propan-2-yl]thio}-8-methoxy-5- Oxa-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chemical 12] , (3R)-2-hydroxy-7-methoxy-3-{[2-(4-methylpiperazin-1-yl)-2-yloxyethyl]thio}-3,4-di Hydrogen-2H-1,2-benzoxaazepinehex-8-carboxylic acid [Chemical 13] (3R)-4,4-Dihydroxy-3-{[2-(4-methylpiperazin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5- Oxa-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chemical 14] , (3R)-2-hydroxy-7-methoxy-3-{[2-(3-methoxyazetidin-1-yl)-2-yloxyethyl]thio}-3,4 -Dihydro-2H-1,2-benzoxaazepinehex-8-carboxylic acid [Chemical 15] (3R)-4,4-Dihydroxy-3-{[2-(3-methoxyazetidin-1-yl)-2-yloxyethyl]thio}-8-methoxy- 5-oxa-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chemical 16] (3R)-3-{[2-(3-Aminoazetidin-1-yl)-2-oxoethyl]thio}-2-hydroxy-7-methoxy-3,4- Dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid [Chem. 17] (3R)-4,4-Dihydroxy-3-{[2-(3-Aminoazetidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5 -oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chemical 18] , (3R)-2-hydroxy-7-methoxy-3-{[2-o-oxy-2-(piperazin-1-yl)ethyl]thio}-3,4-dihydro-2H -1,2-benzoxoxaborox-8-carboxylic acid [Chemical 19] , (3R)-4,4-dihydroxy-3-{[2-o-oxy-2-(piperazin-1-yl)ethyl]thio}-8-methoxy-5-oxa- 4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chemical 20] (3R)-3-{[2-(4-Aminopiperidin-1-yl)-2-oxoethyl]thio}-2-hydroxy-7-methoxy-3,4-di Hydrogen-2H-1,2-benzoxaazepinene-8-carboxylic acid [Chem. 21] (3R)-4,4-Dihydroxy-3-{[2-(4-Aminopiperidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5- Oxa-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [22] , (3R)-3-{[2-(azetidin-1-yl)-2-oxoethyl]thio}-2-hydroxy-7-methoxy-3,4-dihydro-2H -1,2-benzoxaazepinehex-8-carboxylic acid [Chemical 23] , (3R)-4,4-dihydroxy-3-{[2-(azetidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5-oxa- 4-boron anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid [Chemical 24] (3R)-2-Hydroxy-7-methoxy-3-{[2-(3-methoxypyrrolidin-1-yl)-2-oxoethyl]thio}-3,4- Dihydro-2H-1,2-benzoxaazepinehex-8-carboxylic acid [Chemical 25] (3R)-4,4-Dihydroxy-3-{[2-(3-methoxypyrrolidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5 -oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chem. 26] , (3R)-3-({2-[2-(dimethylaminocarbamimido)pyrrolidin-1-yl]-2-yloxyethyl}thio)-2-hydroxy-7-methoxy Base-3,4-dihydro-2H-1,2-benzoxaazepinehex-8-carboxylic acid [Chem. 27] , (3R)-4,4-dihydroxy-3-({2-[2-(dimethylaminecarbamimido)pyrrolidin-1-yl]-2-oxoethyl}thio)-8 -Methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [28] , (3R)-2-hydroxy-7-methoxy-3-({2-[2-(methoxymethyl)pyrrolidin-1-yl]-2-oxoethyl}thio)- 3,4-dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid [Chemical 29] , (3R)-4,4-dihydroxy-3-({2-[2-(methoxymethyl)pyrrolidin-1-yl]-2-oxoethyl}thio)-8-A Oxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid [Chem. 30] (3R)-2-Hydroxy-7-methoxy-3-{[2-(porphyrin-4-yl)-2-oxoethyl]thio}-3,4-dihydro-2H- 1,2-benzoxaaborylcyclo-8-carboxylic acid [31] (3R)-4,4-Dihydroxy-3-{[2-(porphyrin-4-yl)-2-oxoethyl]thio}-8-methoxy-5-oxa-4 Boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [32] , (3R)-2-hydroxy-3-{[2-(3-hydroxyazetidin-1-yl)-2-yloxyethyl]thio}-7-methoxy-3,4-di Hydrogen-2H-1,2-benzoxoxaborylcyclo-8-carboxylic acid [Chem. 33] (3R)-4,4-Dihydroxy-3-{[2-(3-hydroxyazetidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5- Oxa-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chem. 34] (3R)-2-Hydroxy-3-({2-[2-(hydroxymethyl)pyrrolidin-1-yl]-2-yloxyethyl}thio)-7-methoxy-3, 4-dihydro-2H-1,2-benzoxoxaborylcyclo-8-carboxylic acid [Chem. 35] (3R)-4,4-Dihydroxy-3-({2-[2-(hydroxymethyl)pyrrolidin-1-yl]-2-oxoethyl}thio)-8-methoxy -5-oxa-4-boron anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid [Chem. 36] (3R)-2-Hydroxy-3-{[2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]thio}-7-methoxy-3,4-dihydro -2H-1,2-benzoxoxaboryl-8-carboxylic acid [Chem. 37] (3R)-4,4-Dihydroxy-3-{[2-(4-hydroxypiperidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5-oxygen Hetero-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chem. 38] (3R)-3-{[2-(3-Aminopyrrolidin-1-yl)-2-oxoethyl]thio}-2-hydroxy-7-(methylthio)-3, 4-Dihydro-2H-1,2-benzoxoxaborylcyclo-8-carboxylic acid [Chem. 39] (3R)-4,4-Dihydroxy-3-{[2-(3-Aminopyrrolidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5- Oxa-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [40] , (3R)-2-hydroxy-3-((2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)thio)-7-methoxy-3,4-dihydro -2H-1,2-benzoxoxaborox-8-carboxylic acid [Chemical 41] (3R)-4,4-Dihydroxy-3-[2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl]thio-8-methoxy-5-oxa- 4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [42] ,((3R)-((2-((3S)-Aminopyrrolidin-1-yl)-2-yloxyethyl)thio)-2-hydroxy-7-methoxy-3,4- Dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid [Chemical 43] (4R)-4-[2-[(3S)-3-Aminopyrrolidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy- 2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [44] ,((3R)-((2-((3R)-Aminopyrrolidin-1-yl)-2-yloxyethyl)thio)-2-hydroxy-7-methoxy-3,4- Dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid [45] (4R)-4-[2-[(3R)-3-Aminopyrrolidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy- 2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 46] (3R)-2-Hydroxy-7-methoxy-3-((2-(3-(methylamino)pyrrolidin-1-yl)-2-yloxyethyl)thio)-3 ,4-dihydro-2H-1,2-benzoxoxaborox-8-carboxylic acid [Chem. 47] , (4R)-3,3-dihydroxy-9-methoxy-4-[2-[3-(methylamino)pyrrolidin-1-yl]-2-oxoethyl]thio- 2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 48] (3R)-3-({2-[2-(Aminomethyl)pyrrolidin-1-yl]-2-oxoethyl}thio)-2-hydroxy-7-methoxy-3 ,4-dihydro-2H-1,2-benzoxoxaborox-8-carboxylic acid [Chem. 49] (4R)-4-[2-[2-(Aminomethyl)pyrrolidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy- 2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 50] ,(3R)-3-((2-(3-(Aminomethyl))pyrrolidin-1-yl)-2-yloxyethyl)thio)-2-hydroxy-7-methoxy-3 , 4-dihydro-2H-1,2-benzoxaazepinehex-8-carboxylic acid (higher polar non-image isomer (1)) [Chem. 51] , (4R)-4-[2-[3-(Aminomethyl)pyrrolidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy- 2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid (higher polar non-image isomer (1)) 52] ,(3R)-3-((2-(3-(Aminomethyl))pyrrolidin-1-yl)-2-yloxyethyl)thio)-2-hydroxy-7-methoxy-3 , 4-dihydro-2H-1,2-benzoxaazepinehex-8-carboxylic acid (lower polar non-image isomer (2)) [Chem. 53] , (4R)-4-[2-[3-(Aminomethyl)pyrrolidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy- 2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid (lower polar non-image isomer (2)) 54] (3R)-((2-(3-(Aminomethyl)azetidin-1-yl)-2-yloxyethyl)thio)-2-hydroxy-7-methoxy-3, 4-Dihydro-2H-1,2-benzoxoxaborylcyclo-8-carboxylic acid [Chem. 55] , (4R)-4-[2-[3-(Aminomethyl)azetidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy -2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 56] (3R)-3-[2-(4-Ethylimidopiperazin-1-yl)-2-oxoethyl]thio-2-hydroxy-7-methoxy-3,4- Dihydro-1,2-benzoxaazepinene-8-carboxylic acid [57] (4R)-4-[2-(4-Ethylimidopiperazin-1-yl)-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2 -oxa-3-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 58] (3R)-3-{[2-(3-Amino-4-methylpyrrolidin-1-yl)-2-yloxyethyl]thio}-2-hydroxy-7-methoxy- 3,4-dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid [Chem. 59] (4R)-4-[2-(3-Amino-4-methylpyrrolidin-1-yl)-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy -2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [60] (3R)-3-((2-(3-Aminopiperidin-1-yl)-2-oxoethyl)thio)-2-hydroxy-7-methoxy-3,4-di Hydrogen-2H-1,2-benzoxaazepinene-8-carboxylic acid (higher polar non-image isomer (1)) [Chem. 61] (4R)-4-[2-(3-Aminopiperidin-1-yl)-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2-oxo -3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid (higher polar non-image isomer (1)) [Chem. 62] (3R)-3-((2-(3-Aminopiperidin-1-yl)-2-oxoethyl)thio)-2-hydroxy-7-methoxy-3,4-di Hydrogen-2H-1,2-benzoxaazepinehex-8-carboxylic acid (lower polar non-image isomer (2)) [Chem. 63] (4R)-4-[2-(3-Aminopiperidin-1-yl)-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2-oxo -3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid (lower polar non-image isomer (2)) [Chem. 64] (3R)-3-((2-(2-(Aminomethyl)piperidin-1-yl)-2-yloxyethyl)thio)-2-hydroxy-7-methoxy-3 ,4-dihydro-2H-1,2-benzoxoxaboranyl-8-carboxylic acid [Chem. 65] (4R)-4-[2-[2-(Aminomethyl)piperidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy- 2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 66] (3R)-3-((2-(3-(2-Aminoethyl)amino)pyrrolidin-1-yl)-2-oxoethyl)thio)-2-hydroxy-7 -Methoxy-3,4-dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid (higher polar non-image isomer (1)) [Chem. 67] (4R)-4-[2-[3-(2-Aminoethylamino)pyrrolidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9- Methoxy-2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid (higher polar non-image isomer (1 )) [Chem. 68] (3R)-3-((2-(3-(2-Aminoethyl)amino)pyrrolidin-1-yl)-2-oxoethyl)thio)-2-hydroxy-7 -Methoxy-3,4-dihydro-2H-1,2-benzoxaazepinehex-8-carboxylic acid (lower polar non-image isomer (2)) [Chem. 69] (4R)-4-[2-[3-(2-Aminoethylamino)pyrrolidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9- Methoxy-2-oxa-3-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid (lower polar non-image isomer (2 )) [化70] (3R)-3-{[2-(3-Aminopyrrolidin-1-yl)-2-oxoethyl]thio}-6-chloro-2-hydroxy-7-methoxy-3 ,4-dihydro-2H-1,2-benzoxoxaborox-8-carboxylic acid [71] (4R)-4-[2-(3-Aminopyrrolidin-1-yl)-2-oxoethyl]thio-8-chloro-3,3-dihydroxy-9-methoxy- 2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 72] (3R)-((2-(4-(Aminomethyl)piperidin-1-yl)-2-yloxyethyl)thio)-2-hydroxy-7-methoxy-3,4 -dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid [Chem. 73] (4R)-4-[2-[4-(Aminomethyl)piperidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy- 2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [74] , (3R)-3-[(2-1,7-diazaspiro[4.4]decane-7-yl-2-yloxyethyl)thio]-2-hydroxy-7-methoxy- 3,4-Dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid (higher polar non-image isomer (1)) [Chem. 75] , (4R)-4-[2-(1,7-diazaspiro[4.4]decane-7-yl)-2-oxoethyl]thio-3,3-dihydroxy-9- Oxy-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid (higher polar non-image isomer (1) ) [Chem. 76] , (3R)-3-[(2-1,7-diazaspiro[4.4]decane-7-yl-2-yloxyethyl)thio]-2-hydroxy-7-methoxy- 3,4-Dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid (lower polar non-image isomer (2)) [Chem. 77] , (4R)-4-[2-(1,7-diazaspiro[4.4]decane-7-yl)-2-oxoethyl]thio-3,3-dihydroxy-9- Oxy-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid (lower polar non-image isomer (2) ) [化78] , (3R)-3-[(2-2,8-diazaspiro[4.5]decane-2-yl-2-yloxyethyl)thio]-2-hydroxy-7-methoxy- 3,4-Dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid [Chem. 79] , (4R)-4-[2-(2,8-diazaspiro[4.5]decane-2-yl)-2-oxoethyl]thio-3,3-dihydroxy-9- Oxy-2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [80] , (3R)-3-[2-(3-acetamimidyryryl-1-yl)-2-oxoethyl]thio-2-hydroxy-7-methoxy-3,4-dihydro -2H-1,2-benzoxaazepinehex-8-carboxylic acid [81] (4R)-4-[2-(3-Acetylpyrrolidin-1-yl)-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2-oxo Hetero-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 82] , (3R)-3-[(2-2,6-diazaspiro[3.4]octane-6-yl-2-yloxyethyl)thio]-2-hydroxy-7-methoxy- 3,4-dihydro-2H-1,2-benzoxaazepinehexa-8-carboxylic acid [Chem. 83] , (4R)-4-[2-(2,6-diazaspiro[3.4]octane-6-yl)-2-oxoethyl]thio-3,3-dihydroxy-9- Oxy-2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 84] , (3R)-2-hydroxy-7-methoxy-3-[(2-octahydropyrrolo[3,4-c]pyrrol-2-yl-2-yloxyethyl)thio]-3 ,4-dihydro-2H-1,2-benzoxoxaborox-8-carboxylic acid [Chem. 85] , (4R)-4-[(2-octahydropyrrolo[3,4-c]pyrrol-2-yl-2-oxoethyl)thio]-3,3-dihydroxy-9-methoxy Alkyl-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 86] (3R)-3-[2-(3-Aminopyrrolidin-1-yl)-2-oxoethyl]thio-2-hydroxy-7-(triazol-1-yl)-3, 4-Dihydro-1,2-benzoxaazepinene-8-carboxylic acid [Chem. 87] (4R)-4-[2-(3-Aminopyrrolidin-1-yl)-2-oxoethyl]thio-3,3-dihydroxy-9-(triazol-1-yl) -2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 88] , (3R)-2-hydroxy-7-methoxy-3-[2-o-oxy-2-(2-o-oxy-1,3-1,3-oxazolidin-3-yl)ethyl]thio -3,4-dihydro-2H-1,2-benzoxoxaborox-8-carboxylic acid [Chemical 89] , (4R)-3,3-dihydroxy-9-methoxy-4-[2-o-oxy-2-(2-o-oxy-1,3-oxazolidin-3-yl)ethyl Thio-2-oxo-3-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [90] , (3R)-3-[(2-2,7-diazaspiro[4.4]decane-2-yl-2-yloxyethyl)thio]-2-hydroxy-7-methoxy- 3,4-Dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid [Chem. 91] , (4R)-4-[2-(2,7-diazaspiro[4.4]decane-2-yl)-2-oxoethyl]thio-3,3-dihydroxy-9- Oxy-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 92] , (3R)-3-[2-(2,9-diazaspiro[4.5]decane-2-yl)-2-yloxyethyl]thio-2-hydroxy-7-methoxy- 3,4-Dihydro-1,2-benzoxaazepinehex-8-carboxylic acid [Chem. 93] , (3R)-3-[2-(2,9-diazaspiro[4.5]decane-2-yl)-2-yloxyethyl]thio-4,4-dihydroxy-8- Oxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chem. 94] , (3R)-3-[2-(1,7-diazaspiro[3.4]octane-7-yl)-2-oxoethylethyl]thio-2-hydroxy-7-methoxy- 3,4-Dihydro-1,2-benzoxaazepinehex-8-carboxylic acid [Chem. 95] , (3R)-3-[2-(1,7-diazaspiro[3.4]octane-7-yl)-2-oxoethyl]thio-4,4-dihydroxy-8- Oxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chem. 96] , (3R)-2-hydroxy-7-methoxy-3-[2-o-oxy-2-(2-oxo-imidazolidine-1-yl)ethyl]thio-3,4-di Hydrogen-1,2-benzoxaazepinene-8-carboxylic acid [Chemical 97] (3R)-4,4-Dihydroxy-8-methoxy-3-[2-o-oxy-2-(2-oxoisidazolidine-1-yl)ethyl]thio-5- Oxa-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chem. 98] (3R)-2-Hydroxy-7-methoxy-3-[2-o-oxy-2-(3-o-oxypyrazolidin-1-yl)ethyl]thio-3,4- Dihydro-1,2-benzoxaazepinene-8-carboxylic acid [Chem. 99] (3R)-4,4-Dihydroxy-8-methoxy-3-[2-o-oxy-2-(3-o-oxypyrazolidin-1-yl)ethyl]thio-5 -oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid [100] , (3R)-3-[2-[3-(2-Aminoethylaminemethylmercapto)azetidin-1-yl]-2-oxoethyl]thio-2-hydroxy-7- Methoxy-3,4-dihydro-1,2-benzoxaaborylcyclo-8-carboxylic acid [Chem. 101] , (3R)-3-[2-[3-(2-Aminoethylamine-carbamoyl)azetidin-1-yl]-2-oxoethyl]thio-4,4-dihydroxy -8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chem. 102] (3R)-3-[2-[5-(Aminomethyl)-2-oxo-1,3-1,3-oxazolidin-3-yl]-2-oxoethyl]thio-2 -hydroxy-7-methoxy-3,4-dihydro-1,2-benzoxaazepinehex-8-carboxylic acid [Chem. 103] (3R)-3-[2-[5-(Aminomethyl)-2-oxo-1,3-1,3-oxazolidin-3-yl]-2-oxoethyl]thio-4 ,4-dihydroxy-8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chem. 104] (3R)-3-[2-(4-Amino-3-oxooxypyrazin-1-yl)-2-oxoethylethyl]thio-2-hydroxy-7-methoxy- 3,4-dihydro-1,2-benzoxaazepinehex-8-carboxylic acid [Chem. 105] , (3R)-3-[2-(4-Amino-3-epoxypyrazolidin-1-yl)-2-oxoethyl]thio-4,4-dihydroxy-8- Oxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chem. 106] (3R)-3-[3-(3-Aminopyrrolidin-1-yl)-3-oxopropyl propyl]thio-2-hydroxy-7-methoxy-3,4-dihydro -1,2-benzoxaazepinene-8-carboxylic acid [107] (3R)-3-[3-(3-Aminopyrrolidin-1-yl)-3-oxopropyl propyl]thio-4,4-dihydroxy-8-methoxy-5-oxygen Hetero-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [化108] (3R)-3-[4-(3-Aminopyrrolidin-1-yl)-4-oxobutyl]thio-2-hydroxy-7-methoxy-3,4-dihydro- 1,2-benzoxoxaboryl-8-carboxylic acid [Chem. 109] Or (3R)-3-[4-(3-Aminopyrrolidin-1-yl)-4-oxobutylbutyl]thio-4,4-dihydroxy-8-methoxy-5-oxygen Hetero-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [110] . [Claim 29] The compound according to Item 28, wherein the compound is represented by the following compound name or structure: (3R)-4,4-dihydroxy-3-{[2- (3-Aminopyrrolidin-1-yl)-2-oxoethylethyl]thio}-8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1( 6), 7,9-triene-7-carboxylic acid [111] . [Claim 30] The compound according to Item 28 or 29, which is represented by the following compound name or structure: (3R)-4,4-dihydroxy-3-{[2-(3-aminopyrrolidine- 1-yl)-2-oxoethylethyl]thio}-8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-three Alkene-7-carboxylic acid disodium salt [112] . [Claim 31] The compound according to Item 28, wherein the compound is represented by the following compound name or structure: (3R)-4,4-dihydroxy-3-{[2- (3-methoxyazetidin-1-yl)-2-oxoethyl]thio}-8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸- 1(6),7,9-triene-7-carboxylic acid [Chemical 16] . [Claim 32] The compound according to Item 28 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following compound name or structure: (3R)-4,4-dihydroxy-3-{[2- (3-Aminoazetidin-1-yl)-2-oxoethylethyl]thio}-8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1 (6) 7,7-triene-7-carboxylic acid [Chemical 18] . [Claim 33] The compound according to Item 28, wherein the compound is represented by the following compound name or structure: (3R)-4,4-dihydroxy-3-{[2- (Azetidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid [Chemical 24] . [Claim 34] The compound according to Item 28, wherein the compound is represented by the following compound name or structure: (3R)-4,4-dihydroxy-3-{[2- (3-hydroxyazetidin-1-yl)-2-oxoethylethyl]thio}-8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1 ( 6), 7,9-triene-7-carboxylic acid [34] . [Claim 35] The compound according to Item 28 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following compound name or structure: (4R)-4-[2-[3-(aminomethyl) Azetidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2-oxa-3-boran anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-10-carboxylic acid disodium salt [Chemical 112A] . [Claim 36] The compound according to Item 28, wherein the compound is represented by the following compound name or structure: (3R)-3-[2-[3-(2-amino group) Ethylamine carbaryl)azetidin-1-yl]-2-oxoethyl]thio-2-hydroxy-7-methoxy-3,4-dihydro-1,2-benzooxo Heteroboranyl-8-carboxylic acid [Chem. 101] . [Claim 37] A medicine according to any one of items 1 to 36, or a pharmaceutically acceptable salt thereof. [Claim 38] The medicine according to Item 37, which is a therapeutic or prophylactic agent for bacterial infection. [Claim 39] A β-endoprostanase inhibitor comprising the compound according to any one of items 1 to 36 or a pharmaceutically acceptable salt thereof as an active ingredient. [Claim 40] A pharmaceutical composition comprising the compound according to any one of items 1 to 36, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [Claim 41] The pharmaceutical composition according to Item 40, which further contains an additional drug. [Claim 42] The composition according to Item 41, wherein the additional agent is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent or an anti-allergic agent. [Claim 43] The composition according to Item 41 or Item 42, wherein the additional agent is a β-namidamide-based drug. The composition according to any one of items 41 to 43 wherein the β-endamine compound which is an additional agent is preferably selected from the group consisting of amoxicillin and ampicillin (Bian Bixilin ( Pivampicillin), Hetacillin, Bacampicillin, Metamacicillin, Talampicillin, Epicurin, Carbenicillin (Carbenicillin) Carindacillin)), Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam (Pivmecillinam) )), Sulbenicillin, benzylpenicillin (G), clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin, Pina Penamecillin, phenoxymethylpenicillin (V), Propicillin, benzathine, phenoxymethylpenicillin, Pheriticillin, Cloxacillin (Dicloxacillin) Flucloxacillin, Oxacillin, Methicillin, Nafcillin, Faropenem, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Tomopenem, Razupenem, Cefazolin Cefazolin), Cephacetrile, Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cephaloridine, Cefalotin, Cephalosporin Cefapirin, Cefatrizine, Cefazedone, Cefazaflur, Cephradine, Cefroxadine, Ceftezole, Cefracloft Cefaclor), Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone Cefuroxime (Cefuroxime), cephalosporin Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole, Loracarbef, Cefixime, Ceftazidime, Ceftriaxone ), Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Cefodizime , cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefsulodin, cefteram, cephalosporin Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpod Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, Ceftiofur , Cefquinome, head Cefovecin, Aztreonam, Tigemonam, Carumonam, RWJ-442831, RWJ-333441, or RWJ-333442. [Claim 45] The composition according to Item 43 or Item 44, wherein the β-namidoxime-based agent is selected from the group consisting of Ceftazidime, Biapenem, Doripenem, and Ertape Ertapenem, Imipenem, Meropenem, or Panipenem. [Claim 46] The composition according to Item 43 or Item 44, wherein the β-namidoxime-based agent is selected from the group consisting of Aztreonam, Tigemonam, BAL30072, SYN2416 or Carumon South ( Carumonam). [Claim 47] The pharmaceutical composition according to Item 40, which is administered together with an additional agent. [Claim 48] The composition according to Item 47, wherein the additional agent is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent or an anti-allergic agent. [Claim 49] The composition according to Item 47 or Item 48, wherein the additional agent is a β-endamine drug. The composition according to any one of items 47 to 49, wherein the β-endamine compound which is an additional agent is preferably selected from the group consisting of amoxicillin and ampicillin (Bian Bixilin ( Pivampicillin), Hetacillin, Bacampicillin, Metamacicillin, Talampicillin, Epicurin, Carbenicillin (Carbenicillin) Carindacillin)), Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam (Pivmecillinam) )), Sulbenicillin, benzylpenicillin (G), clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin, Pina Penamecillin, phenoxymethylpenicillin (V), Propicillin, benzathine, phenoxymethylpenicillin, Pheriticillin, Cloxacillin (Dicloxacillin) Flucloxacillin, Oxacillin, Methicillin, Nafcillin, Faropenem, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Tomopenem, Razupenem, Cefazolin Cefazolin), Cephacetrile, Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cephaloridine, Cefalotin, Cephalosporin Cefapirin, Cefatrizine, Cefazedone, Cefazaflur, Cephradine, Cefroxadine, Ceftezole, Cefracloft Cefaclor), Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone Cefuroxime (Cefuroxime), cephalosporin Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole, Loracarbef, Cefixime, Ceftazidime, Ceftriaxone ), Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Cefodizime , cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefsulodin, cefteram, cephalosporin Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpod Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, Ceftiofur , Cefquinome, head Cefovecin, Aztreonam, Tigemonam, Carumonam, RWJ-442831, RWJ-333441, or RWJ-333442. [Claim 51] The composition according to Item 49 or Item 50, wherein the β-namidamide-based agent is selected from the group consisting of Ceftazidime, Biapenem, Doripenem, and Ertape. Ertapenem, Imipenem, Meropenem, or Panipenem. [Claim 52] The composition according to Item 49 or Item 50, wherein the β-endoxime-based agent is selected from the group consisting of Aztreonam, Tigemonam, BAL30072, SYN2416 or Carumon South ( Carumonam). [Item 53] A compound of the following formula (2) or a pharmaceutically acceptable salt thereof, [Chem. 113] (In the formula (2), Q represents a hydroxyl group, a thiol group, or -NHR ^A1 , Z, L, Y, R ¹ , R ² , R ³ , R ⁴ , R ^A1 It is the same as the definition described in Item 1, and the formula (1a) has the same meaning as the item 1). [Claim 54] The compound according to Item 53 or a pharmaceutically acceptable salt thereof, wherein L is the same as defined in any one of Items 2 to 4. [Claim 55] The compound according to any one of items 5 to 54 or a pharmaceutically acceptable salt thereof, wherein Y is the same as defined in any one of items 5 to 7. The compound according to any one of items 53 to 55, wherein the Q is a hydroxyl group or a thiol group, or a pharmaceutically acceptable salt thereof. The compound according to any one of items 53 to 56, wherein the Q is a hydroxyl group, or a pharmaceutically acceptable salt thereof. The compound according to any one of items 53 to 57, wherein the Z system is the same as defined in any one of items 19 to 21. The compound according to any one of items 53 to 58 or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² It is the same as the definition described in Item 22 or Item 23. The compound according to any one of items 53 to 59, or a pharmaceutically acceptable salt thereof, wherein R ³ It is the same as the definition described in Item 24 or Item 25. The compound according to any one of items 53 to 60, or a pharmaceutically acceptable salt thereof, wherein R ⁴ It is the same as the definition described in Item 26 or Item 27. [Claim 62] The compound according to Item 53 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 3-[(2R)-{[2-(3-aminopyrrolidin-1) -yl)-2-oxoethyl]thio}-2-(dihydroxyboryl)ethyl]-2-hydroxy-6-methoxybenzoic acid [Form 114] , 2-hydroxy-3-[(2R)-2-(hydroxyboranyl)-2-{[2-o-oxy-2-(pyrrolidin-1-yl)ethyl]thio}ethyl] -6-methoxybenzoic acid [化115] , 3-[(2R)-2-(Dihydroxyboryl)-2-{[2-o-oxy-2-(pyrrolidin-1-yl)ethyl]thio}ethyl]-2 -hydroxybenzoic acid [Chem. 116] , 3-[(2R)-2-(Dihydroxyboryl)-2-{[1-o-oxy-1-(pyrrolidin-1-yl)propan-2-yl]thio}ethyl ]-2-hydroxy-6-methoxybenzoic acid [Chemical 117] , 3-[(2R)-2-(Dihydroxyboryl)-2-{[2-(4-methylpiperazin-1-yl)-2-oxoethyl]thio}ethyl ]-2-hydroxy-6-methoxybenzoic acid [化118] , 3-[(2R)-2-(Dihydroxyboryl)-2-{[2-(3-methoxyazetidin-1-yl)-2-yloxyethyl]thio] Ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 119] , 3-[(2R)-2-{[2-(3-Aminoazetidin-1-yl)-2-yloxyethyl]thio}-2-(dihydroxyboryl)B 2-hydroxy-6-methoxybenzoic acid [120] , 3-[(2R)-2-(Dihydroxyboryl)-2-{[2-Sideoxy-2-(piperazin-1-yl)ethyl]thio}ethyl]-2 -hydroxy-6-methoxybenzoic acid [Chem. 121] , 3-[(2R)-2-{[2-(4-Aminopiperidin-1-yl)-2-yloxyethyl]thio}-2-(dihydroxyboryl)ethyl ]-2-hydroxy-6-methoxybenzoic acid [化122] , 3-[(2R)-2-{[2-(azetidin-1-yl)-2-yloxyethyl]thio}-2-(dihydroxyboryl)ethyl]-2 -hydroxy-6-methoxybenzoic acid [123] , 3-[(2R)-2-(Dihydroxyboryl)-2-{[2-(3-methoxypyrrolidin-1-yl)-2-yloxyethyl]thio}B 2-hydroxy-6-methoxybenzoic acid , 3-[(2R)-2-(Dihydroxyboryl)-2-({2-[2-(dimethylaminocarbamoyl)pyrrolidin-1-yl]-2-oxoxy B (yl)thio)ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 125] , 3-[(2R)-2-(Dihydroxyboryl)-2-({2-[2-(methoxymethyl)pyrrolidin-1-yl]-2-yloxyethyl} Thio)ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 126] , 3-[(2R)-2-(Dihydroxyboryl)-2-{[2-(porphyrin-4-yl)-2-yloxyethyl]thio}ethyl]-2- Hydroxy-6-methoxybenzoic acid [化127] , 3-[(2R)-2-(Dihydroxyboryl)-2-{[2-(3-hydroxyazetidin-1-yl)-2-yloxyethyl]thio}ethyl ]-2-hydroxy-6-methoxybenzoic acid [化128] , 3-[(2R)-2-(Dihydroxyboryl)-2-({2-[2-(hydroxymethyl)pyrrolidin-1-yl]-2-oxoethyl}thio) Ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 129] , 3-[(2R)-2-(Dihydroxyboryl)-2-{[2-(4-hydroxypiperidin-1-yl)-2-yloxyethyl]thio}ethyl] -2-hydroxy-6-methoxybenzoic acid [Chem. 130] , 3-[(2R)-2-{[2-(3-Aminopyrrolidin-1-yl)-2-oxoethyl]thio}-2-(dihydroxyboryl)ethyl ]-2-hydroxy-6-(methylthio)benzoic acid [Chem. 131] , 3-[(2R)-2-Dihydroxyboryl-2-{[2-(3-hydroxypyrrolidin-1-yl)-2-yloxyethyl]thio}ethyl]-2-hydroxyl -6-methoxybenzoic acid [化132] , 3-[(2R)-2-({2-[(3S)-3-Aminopyrrolidin-1-yl]-2-yloxyethyl}thio)-2-dihydroxyborylethyl ]-2-hydroxy-6-methoxybenzoic acid [化133] , 3-[(2R)-2-({2-[(3R)-3-Aminopyrrolidin-1-yl]-2-yloxyethyl}thio)-2-dihydroxyborylethyl ]-2-hydroxy-6-methoxybenzoic acid [Chem. 134] , 3-[(2R)-2-dihydroxyboryl-2-({2-[3-(methylamino)pyrrolidin-1-yl]-2-oxoethyl}thio)ethyl ]-2-hydroxy-6-methoxybenzoic acid [Chemical 135] , 3-[(2R)-2-({2-[2-(Aminomethyl)pyrrolidin-1-yl]-2-yloxyethyl}thio)-2-dihydroxyborylethyl ]-2-hydroxy-6-methoxybenzoic acid [Chemical 136] , 3-[(2R)-2-({2-[3-(Aminomethyl)pyrrolidin-1-yl]-2-yloxyethyl}thio)-2-dihydroxyborylethyl ]-2-hydroxy-6-methoxybenzoic acid (open ring corresponding to the more polar non-image isomer (1)) [Chem. 137] , 3-[(2R)-2-({2-[3-(Aminomethyl)pyrrolidin-1-yl]-2-yloxyethyl}thio)-2-dihydroxyborylethyl ]-2-hydroxy-6-methoxybenzoic acid (open ring corresponding to the less polar non-image isomer (2)) [Chem. 138] , 3-[(2R)-2-({2-[3-(Aminomethyl)azetidin-1-yl]-2-yloxyethyl}thio)-2-dihydroxyboryl 2-hydroxy-6-methoxybenzoic acid , 3-[(2R)-2-Dihydroxyboryl-2-{[2-(4-ethaneimidopiperazin-1-yl)-2-yloxyethyl]thio}ethyl] -2-hydroxy-6-methoxybenzoic acid [Chem. 140] , 3-[(2R)-2-{[2-(3-Amino-4-methylpyrrolidin-1-yl)-2-yloxyethyl]thio}-2-dihydroxyboryl 2-hydroxy-6-methoxybenzoic acid [Chemical 141] , 3-[(2R)-2-{[2-(3-Aminopiperidin-1-yl)-2-yloxyethyl]thio}-2-dihydroxyborylethyl]-2- Hydroxy-6-methoxybenzoic acid (open ring corresponding to the more polar non-image isomer (1)) [Chem. 142] , 3-[(2R)-2-{[2-(3-Aminopiperidin-1-yl)-2-yloxyethyl]thio}-2-dihydroxyborylethyl]-2- Hydroxy-6-methoxybenzoic acid (open ring corresponding to the less polar non-image isomer (2)) [Chem. 143] , 3-[(2R)-2-{[2-[2-(Aminomethyl)piperidin-1-yl]-2-yloxyethyl]thio}-2-dihydroxyborylethyl ]-2-hydroxy-6-methoxybenzoic acid [化144] , 3-{(2R)-2-[(2-{3-[(2-Aminoethyl)amino]pyrrolidin-1-yl}-2-yloxyethyl)thio]-2- Dihydroxyborylethyl}-2-hydroxy-6-methoxybenzoic acid (open ring corresponding to the more polar non-image isomer (1)) [Chem. 145] , 3-{(2R)-2-[(2-{3-[(2-Aminoethyl)amino]pyrrolidin-1-yl}-2-yloxyethyl)thio]-2- Dihydroxyborylethyl}-2-hydroxy-6-methoxybenzoic acid (open ring corresponding to the less polar non-image isomer (2)) [Chem. 146] , 3-[(2R)-2-{[2-(3-Aminopyrrolidin-1-yl)-2-yloxyethyl]thio}-2-dihydroxyborylethyl]-5- Chloro-2-hydroxy-6-methoxybenzoic acid [Chemical 147] , 3-[(2R)-2-({2-[4-(Aminomethyl)piperidin-1-yl]-2-yloxyethyl}thio)-2-dihydroxyborylethyl ]-2-hydroxy-6-methoxybenzoic acid [化148] , 3-[(2R)-2-Dihydroxyboryl-2-{[2-(1,7-diazaspiro[4.4]decane-7-yl)-2-oxoethyl]thio }Ethyl]-2-hydroxy-6-methoxybenzoic acid (open ring corresponding to the more polar non-image isomer (1)) [Chem. 149] , 3-[(2R)-2-Dihydroxyboryl-2-{[2-(1,7-diazaspiro[4.4]decane-7-yl)-2-oxoethyl]thio }Ethyl]-2-hydroxy-6-methoxybenzoic acid (open ring corresponding to the less polar non-image isomer (2)) [Chem. 150] , 3-[(2R)-2-Dihydroxyboryl-2-{[2-(2,8-diazaspiro[4.5]decan-2-yl)-2-yloxyethyl]thio }ethyl]-2-hydroxy-6-methoxybenzoic acid [化151] , 3-[(2R)-2-{[2-(3-acetamilidyrrolidin-1-yl)-2-yloxyethyl]thio}-2-dihydroxyborylethyl]-2 -hydroxy-6-methoxybenzoic acid [Chem. 152] , 3-[(2R)-2-dihydroxyboryl-2-{[2-(2,6-diazaspiro[3.4]octane-6-yl)-2-oxoethyl]thio }Ethyl]-2-hydroxy-6-methoxybenzoic acid [Chem. 153] , 3-[(2R)-2-dihydroxyboryl-2-{[2-(hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-2-yloxyethyl] Thioethyl}ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 154] , 3-[(2R)-2-{[2-(3-Aminopyrrolidin-1-yl)-2-yloxyethyl]thio}-2-dihydroxyborylethyl]-2- Hydroxy-6-(1H-1,2,3-triazol-1-yl)benzoic acid [Chem. 155] , 3-[(2R)-2-dihydroxyboryl-2-{[2-o-oxy-2-(2-o-oxy-1,3-1,3-oxazolidin-3-yl)ethyl]sulfide Ethyl}-2-hydroxy-6-methoxybenzoic acid [Chemical 156] , 3-[(2R)-2-Dihydroxyboryl-2-{[2-(2,7-diazaspiro[4.4]decan-2-yl)-2-yloxyethyl]thio }Ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 157] , 3-[(2R)-2-Dihydroxyboryl-2-{[2-(2,9-diazaspiro[4.5]decane-2-yl)-2-yloxyethyl]thio }Ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 158] , 3-[(2R)-2-dihydroxyboryl-2-{[2-(1,7-diazaspiro[3.4]octane-6-yl)-2-oxoethyl]thio }Ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 159] , 3-[(2R)-2-Dihydroxyboryl-2-{[2-Sideoxy-2-(2-Sideoxyimidazolidin-1-yl)ethyl]thio}ethyl]- 2-hydroxy-6-methoxybenzoic acid [化160] , 3-[(2R)-2-dihydroxyboryl-2-{[2-o-oxy-2-(3-o-oxypyrazolidin-1-yl)ethyl]thio}ethyl] -2-hydroxy-6-methoxybenzoic acid [Chem. 161] , 3-{(2R)-2-[(2-{3-[(2-Aminoethyl)aminemethanyl]azetidin-1-yl}-2-yloxyethyl)thio] -2-Dihydroxyborylethyl}-2-hydroxy-6-methoxybenzoic acid [Chem. 162] , 3-[(2R)-2-({2-[5-(Aminomethyl)-2-oxo-1,3-1,3-oxazolidine-3-yl]-2-yloxyethyl} Thio)-2-dihydroxyborylethyl]-2-hydroxy-6-methoxybenzoic acid [Chem. 163] , 3-[(2R)-2-{[2-(4-Amino-3-oxooxypyrazin-1-yl)-2-yloxyethyl]thio}-2-dihydroxyboron Ethylethyl]-2-hydroxy-6-methoxybenzoic acid , 3-[(2R)-2-{[3-(3-Aminopyrrolidin-1-yl)-3-yloxypropyl]thio}-2-dihydroxyborylethyl]-2 -hydroxy-6-methoxybenzoic acid [Chem. 165] Or 3-[(2R)-2-{[4-(3-Aminopyrrolidin-1-yl)-4-yloxybutyl]thio}-2-dihydroxyborylethyl]-2 -hydroxy-6-methoxybenzoic acid [Chemical 166] . [Claim 63] The compound according to Item 53 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 3-[(2R)-{[2-(3-Aminopyrrolidin-1) -yl)-2-oxoethyl]thio}-2-(dihydroxyboryl)ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 167] . The compound according to Item 53, wherein the compound is selected from the group consisting of 3-[(2R)-2-(dihydroxyboryl)-2- {[2-(3-Methoxyazetidin-1-yl)-2-oxoethyl]thio}ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 119] . [Claim 65] The compound according to Item 53 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 3-[(2R)-2-{[2-(3-Amino) Pyridin-1-yl)-2-oxoethyl]thio}-2-(dihydroxyboryl)ethyl]-2-hydroxy-6-methoxybenzoic acid [120] . [Claim 66] The compound according to Item 53 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 3-[(2R)-2-{[2-(azetidine-1- ))-2-oxoethyl]thio}-2-(dihydroxyboryl)ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 123] . The compound according to Item 53, wherein the compound is selected from the group consisting of 3-[(2R)-2-(dihydroxyboryl)-2- {[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]thio}ethyl]-2-hydroxy-6-methoxybenzoic acid [化128] . [Claim 68] The compound according to Item 53 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 3-[(2R)-2-({2-[3-(Amino A) Azetidin-1-yl]-2-oxoethyl}thio)-2-dihydroxyborylethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 139] . [Claim 69] The compound according to Item 53 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of 3-{(2R)-2-[(2-{3-[(2-amino) Ethyl)amine-methylmercapto]azetidin-1-yl}-2-oxoethyl)thio]-2-dihydroxyborylethyl}-2-hydroxy-6-methoxybenzoic acid [ 162] . [Claim 70] A pharmaceutical composition comprising the compound of the formula (1a) or (1b) according to any one of items 1 to 36, which may further comprise any one of items 53 to 69. A compound of the formula (2) is described. [Claim 71] A pharmaceutical composition comprising the compound of the formula (2) according to any one of items 53 to 69, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [Claim 72] The pharmaceutical composition according to Item 70 or Item 71, which is used together with an additional agent. [Claim 73] The composition according to Item 72, wherein the additional agent is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent or an anti-allergic agent. [Claim 74] The composition according to Item 72 or Item 73, wherein the additional agent is a β-endamine drug. The composition according to any one of items 72 to 74, wherein the β-endamine compound which is an additional agent is preferably selected from the group consisting of amoxicillin and ampicillin. Pivampicillin, Hetacillin, Bacampicillin, Metamacicillin, Talampicillin, Epicurin, Carbenicillin (card) Carindacillin, Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam Pivmecillinam, Sulbenicillin, benzylpenicillin (G), clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin , Penamecillin, phenoxymethylpenicillin (V), Propicillin, benzathine, phenoxymethylpenicillin, Pheriticillin, Cloxacillin (diclocillin) Dic Loxacillin), Flucloxacillin, Oxacillin, Methicillin, Nafcillin, Faropenem, Biapenem, Donipene Doripenem), Ertapenem, Imipenem, Meropenem, Panipenem, Tomopenem, Razupenem, Cephalosporin Cefazolin, Cephacetrile, Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cephaloridine, Cefalotin ), cefapirin, Cefatrizine, Cefazedone, Cefazaflur, Cephradine, Cefroxadine, Ceftezole, Cephalosporin Cefaclor, Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cephalops (Cefbuperazone), Cefuroxicin (Cefuroxi Me), Cefozonam, Cefoxitin, Cefotetan, Cefmetazole, Loracarbef, Cefixime, Ceftazidime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Cephalosporin Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Ceftelem (Cefteram), Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Ceftomylin (Cefter) Cefozopran), Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, Cephalosporium Ceftiofur, cefquinol (Cefq) Uinome), Cefovecin, Aztreonam, Tigemonam, Carumonam, RWJ-442831, RWJ-333441, or RWJ-333442. The composition according to Item 74 or Item 75, wherein the β-namidamide-based agent is selected from the group consisting of Ceftazidime, Biapenem, Doripenem, and Ertape. Ertapenem, Imipenem, Meropenem, or Panipenem. The composition according to Item 74 or Item 75, wherein the β-endoxime-based agent is selected from the group consisting of Aztreonam, Tigemonam, BAL30072, SYN2416 or Carumon South ( Carumonam). [Claim 78] A therapeutic agent for a bacterial infection, which comprises the compound according to any one of items 1 to 36, and the pharmaceutically acceptable salt thereof. [Claim 79] The therapeutic agent according to Item 78, wherein the bacterial infection is a bacterial infection associated with a bacteria which may have β-endoprostanase. [Claim 80] The therapeutic agent according to Item 75 or Item 79, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, paranasal inflammation, pneumonia , lung abscess, empyema, secondary infection of chronic respirator lesions, pharyngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic vessels Secondary infections such as lymphadenitis, trauma/scald, and surgical wounds, urinary tract infections, genital infections, ocular infections, or odontogenic infections. [Claim 81] The use of a compound according to any one of items 1 to 36, or a pharmaceutically acceptable salt thereof, for the manufacture of a therapeutic agent for bacterial infection. [Item 82] The use of Item 81, wherein the bacterial infection is a bacterial infection associated with a bacterium having a β-endosaminolase. [Item 83] The use of Item 81 or Item 82, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, paranasalitis, pneumonia, Lung abscess, empyema, secondary infection of chronic respirator lesions, pharyngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic vessel / Secondary infections such as lymphadenitis, trauma/scald, and surgical wounds, urinary tract infections, genital infections, ocular infections, or odontogenic infections. The use according to any one of items 81 to 83, wherein the therapeutic agent further comprises an additional agent. [Claim 85] The application according to Item 64, wherein the additional agent is an additional agent described in any one of Item 42 to Item 46. The use according to any one of items 81 to 83, wherein the therapeutic agent is administered together with an additional agent. The use of the additional agent according to any one of items 48 to 52, wherein the additional agent is the use of the additive. [Claim 88] A method for treating a bacterial infection, characterized in that a therapeutically effective amount of the compound according to any one of items 1 to 36 and item 53 to item 69 is administered to a patient in need of treatment or Its pharmaceutically acceptable salt. [Claim 89] The method according to Item 88, wherein the bacterial infection is a bacterial infection associated with a bacteria which may have β-endoprostanase. [90] The method according to Item 88 or Item 89, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, paranasalitis, pneumonia, Lung abscess, empyema, secondary infection of chronic respirator lesions, pharyngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic vessel / Secondary infections such as lymphadenitis, trauma/scald, and surgical wounds, urinary tract infections, genital infections, ocular infections, or odontogenic infections. [Claim 91] The method according to any one of items 88 to 90, wherein the method is administered together with an additional agent. [Claim 92] The method according to Item 91, wherein the additional agent is the additional agent described in any one of Item 42 to Item 46. [Claim 93] The compound according to any one of items 1 to 36, wherein the compound or a pharmaceutically acceptable salt thereof is used for the treatment of a bacterial infection. [Claim 94] The compound according to the item 93, wherein the bacterial infection is a bacterial infection associated with a bacterium having a β-endoprostanase, or a pharmaceutically acceptable salt thereof. The compound according to the item 93 or 94, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, or a pharmaceutically acceptable salt thereof. , otitis media, paranasal vaginitis, pneumonia, lung abscess, empyema, secondary infection of chronic respiratory disease, pharyngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess Secondary infections of deep skin infections, lymphatic/lymphitis, trauma/scald, and surgical wounds, urinary tract infections, genital infections, ocular infections, or odontogenic infections. [Claim 96] A medicinal compound according to any one of items 1 to 36, or a pharmaceutically acceptable salt thereof, and a septicemia, febrile neutrophil Reduction, bacterial meningitis, bacterial endocarditis, otitis media, paranasal rhinitis, pneumonia, lung abscess, empyema, secondary infection of chronic respiratory disease, pharyngitis, tonsillitis, osteomyelitis, arthritis, Secondary infections such as peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic/lymphitis, trauma/scald, and surgical wounds, urinary tract infections, genital infections, ocular infections At least one or more of the therapeutic agents for the odontogenic infection are combined. [Claim 97] A pharmaceutical composition comprising a β-namidamide-based pharmaceutical agent, wherein the pharmaceutical composition is as described in any one of Item 1 to Item 36 and Item 53 to Item 69 The compound or a pharmaceutically acceptable salt thereof is administered together. [Claim 98] The composition according to Item 97, wherein the β-endamine compound is selected from the group consisting of amoxicillin, ampicillin (Pivampicillin, Hetacillin, Bacampicillin). , Metamacicillin, Talampicillin, Epicurin, Carbennicillin (Carindacillin), Ticarcillin, Temocillin (Ticamcillin) Temocillin), Azlocillin, Piperacillin, Mezlocillin, Mecillinam (Pivmecillinam), Sulbenicillin, Benzethin (G) , Clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin, Penamecillin, Phenoxymethylpenicillin (V), Propicillin, benzathine, phenoxymethylpenicillin, Pheriticillin, cloxacillin (Dicloxacillin, Flucloxacillin), Oxacill (Oxacill) In), Methicillin, Nafcillin, Faropenem, Biapenem, Doripenem, Ertapenem, Imipenem Imipenem, Meropenem, Panipenem, Tomopenem, Razupenem, Cefazolin, Cephacetrile, Cephalosporin Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cephaloridine, Cefalotin, Cefapirin, Cefatrizine ), Cefazedone, Cefazaflur, Cephradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cephalosporin Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Ceftizoxime (Cefuzonam), Cexixitin, head Cefotetan, Cefmetazole, Loracarbef, Cefixime, Ceftazidime, Ceftriaxone, Cefcapene, Cephalosporin Cefdaloxime), Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Cefodizime, Cefoperazone, Cefotaxime ), Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome, Cefquinome, Cephalosporin Ceftobiprole, Ceftaroline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, Ceftiofur, Cefquinome, Cefovecin ), Aztreonam, for Monan (Tigemonam), carumonam (Carumonam), RWJ-442831, RWJ-333441, RWJ-333442, or in at least one of. The composition according to Item 97 or 98, wherein the β-endoperamine-based agent is selected from the group consisting of Ceftazidime, Biapenem, Doripenem, and Usta Ertapenem, Imipenem, Meropenem, or Panipenem. [Claim 100] The composition according to Item 97 or 98, wherein the β-indoleamine-based agent is selected from the group consisting of Aztreonam, Tigemonam, BAL30072, SYN2416 or Carumonan (Carumonam). [Claim 101] The composition according to any one of items 97 to 100, which is for use in the treatment of a bacterial infection. [Claim 102] The composition according to Item 101, wherein the bacterial infection is a bacterial infection associated with a bacteria which may have β-endoprostanase. [Claim 103] The composition according to Item 101 or Item 102, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, paranasal rhinitis, pneumonia , lung abscess, empyema, secondary infection of chronic respirator lesions, pharyngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic vessels Secondary infections such as lymphadenitis, trauma/scald, and surgical wounds, urinary tract infections, genital infections, ocular infections, or odontogenic infections. [Item 104] A manufacturing method (1b): [In the formula (1b), X, Z, L, Y, R ¹ , R ² , R ³ And R ⁴ A method of a compound as defined in Item 1 which is included in formula (1a): [Chem. 169] [In the formula (1a), X, Z, L, Y, R ¹ , R ² , R ³ And R ⁴ The step of adding a base to the compound represented by the formula (1b). [Claim 105] The method according to Item 104, wherein the base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate, potassium butoxide, methanol a group consisting of sodium, sodium ethoxide, sodium amide, and lithium diisopropyl guanamine. The method according to Item 104 or Item 105, wherein Z is a hydroxyl group, and the base is selected from the group consisting of lithium hydroxide, sodium hydroxide, and potassium hydroxide.

In the present invention, one or more of the above features are intended to be provided in addition to the combinations indicated. Further embodiments and advantages of the present invention will be understood by those skilled in the art upon reading the following detailed description. [Effects of the Invention]

The compound of the present invention has an excellent inhibitory effect on the serine acid-β-endoguanamine having a serine residue at the active center of the enzyme. Further, with respect to the more excellent aspect of the compound of the present invention, it is expected that a wide range of β-endosaminolase inhibitory effects on a plurality of β-endoprostanases or a metal having zinc (Zn ²⁺ ) at an enzyme active center -β-endoaminase inhibition. Therefore, the compound of the present invention can be used as a bacterial infection associated with a bacteria which may have β-endosaminolase, in particular, sepsis, febrile hooliganism by a single dose or in combination with a β-endamine compound. Scrotal reduction, bacterial meningitis, bacterial endocarditis, otitis media, paranasal vaginitis, pneumonia, lung abscess, empyema, secondary infection of chronic respirator lesions, pharyngitis, tonsillitis, osteomyelitis, joints Secondary infections such as inflammation, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic/lymphitis, trauma/scald, and surgical wounds, urinary tract infection, genital infection, eye A therapeutic and/or prophylactic agent for an infectious disease or a odontogenic infection is useful.

Hereinafter, the present invention will be described in further detail. Throughout the specification, the expressions of the singular forms are to be understood as including the concept of plural forms, unless otherwise specified. Therefore, the singular terms (for example, in the case of English, "a", "an", "the", etc.) are understood to include the concept of plural forms as long as they are not specifically mentioned. Further, the terms used in the present specification are to be understood as being used in the meaning commonly used in the art unless otherwise specified. Therefore, all the specific terms and scientific and technical terms used in the specification have the same meaning as those generally understood by those skilled in the art to which the invention belongs, unless otherwise defined. This specification (including definitions) takes precedence in contradictory situations.

In the present specification, the number of the substituents in the group defined by "substitutable" or "substituted" is not particularly limited as long as it can be substituted. Further, unless otherwise specified, the description of each group also corresponds to the case where the group is a part of a substituent or a substituent.

The term "base" means a 1-valent base. Further, in the description of the substituents and the like described below, the term "base" is also omitted.

The number of the substituents in the case of the definition of "substitutable" or "substituted" is not particularly limited as long as it can be substituted, and is one or plural. Further, unless otherwise specified, the description of each substituent is also true in the case where the substituent is a part or a substituent of another substituent.

The substituent which may be "substituted" is selected from the group consisting of the following substituent groups α, and may be substituted with the same or different substituents of 1 to 5. The type of the substituent is not particularly limited. When the atom to which the substituent is bonded is an oxygen atom, a nitrogen atom or a sulfur atom, the atom to be bonded in the substituent described below is not limited to the carbon atom. The substituent group α can be exemplified by: 1) a halogen atom 2) a hydroxyl group 3) a carboxyl group 4) a cyano group 5) a C _1-6 alkyl group 6) a C _2-6 alkenyl group 7) a C _2-6 alkynyl group 8) C _{1- 6} alkoxy 9) C _1-6 alkylthio 10) C _1-6 alkylcarbonyl 11) C _1-6 alkylsulfonyl (wherein 5) to 11) each substituent may be selected from substituted Substituted by the same or different 1 to 5 substituents in the group β) 12) C _3-10 alicyclic group 13) C _3-10 alicyclic oxy group 14) C _6-10 aryloxy group 15) 5 or 6 members of heteroaryloxy 16) 4 to 10 members of non-arylheteroaryloxy 17) C _3-10 alicyclic thiol 18) C _6-10 arylthio 19) 5 members or 6 members of heteroarylthio 20) 4 to 10 members of non-arylheterocyclic thiol 21) C _6-10 aryl 22) 5 or 6 members of heteroaryl 23) 4 to 10 members of non-aromatic Heterocycle 24) C _3-10 alicyclic carbonyl 25) C _6-10 arylcarbonyl 26) 5- or 6-membered heteroarylcarbonyl 27) 4 to 10 membered non-arylheterocyclic carbonyl 28) C _3-10 alicyclic sulfonyl 29) C _6-10 aryl sulfonyl 30) 5- or 6-membered heteroarylsulfonyl 31) 4- to 10-membered non-arylheterosulfonyl ( Wherein each of 12) to 31) may be substituted with 1 to 5 substituent groups β or 1) C _1-6 alkyl group) 32) -NR ^10a R ^11a 33) -SO ₂ -NR ^10b R ^11b 34 -NR ^10c -C(=O)R ^11c 35) -NR ^10d -C(=O)OR ^11d 36) -NR ^12a -C(=O)NR ^10e R ^11e 37) -NR ^10f -C(=S R ^11f 38) -NR ^10g -C(=S)OR ^11g , 39) -NR ^12b -C(=S)NR ^10h R ^11h 40) -NR ¹⁰ⁱ -SO ₂ -R ¹¹ⁱ 41) -NR ^12c -SO ₂ -NR ^10j R ^11j 42) -C(=O)OR ^10k 43) -C(=O)NR ^10l R ^11k 44) -C(=O)NR ^10m OR ^11l 45) -C(=O)NR ^12d -NR ¹⁰ⁿ R ^11m 46) -C(=S)OR ^10o 47) -C(=S)NR ^10p R ¹¹ⁿ 48) -C(=S)NR ^10q OR ^11o 49) -C(=S)NR ^12e - NR ^10r R ^11p 50) -C(=NR ^13a )R ^10s 51) -C(=NR ^13b )CHO 52) -C(=NR ^13c )NR ^10t R ^11q 53) -C(=NR ^13d )NR ^12f - NR ^10u R ^11r 54) -NR ^17c -C(=NR ^13k )R ^17d 55) -NR ^12g -C(=NR ^13e )-NR ^10v R ^11s 56) -NR ¹⁴ -C(=NR ^13f )-NR ^12h -NR ^10w R ^11t 57) -OC(=O)R ^10x 58) -OC(=O)OR ^10y 59) -OC(=O)NR ^10z1 R ^11u 60) -NR ¹²ⁱ -NR ^10z2 R ^11v 61) - NR ^10z3 OR ^11w , a substituent group β contains 1) a halogen atom, 2) a hydroxyl group, 3) a carboxyl group, 4) a cyano group, 5) a C _3-10 alicyclic group, 6) a C _1-6 alkoxy group, 7) C _3-10 alicyclic oxy, 8) C _1-6 alkylthio, 9) 5 or 6 membered heteroarylthio, 10) C _6-10 aryl, 11) 5 member or 6 members of heteroaryl, 12) 4 to 10 members of non-aryl heterocycle, 13) C _1-6 alkylcarbonyl, 14) C _3-10 alicyclic carbonyl, 15) C _6-10 arylcarbonyl, 16) 5 or 6 Heteroarylcarbonyl, 17) 4 to 10 membered non-arylheterocyclic carbonyl, 18) -NR ^15a R ^16a , 19) -SO ₂ -NR ^15b R ^16b , 20) -NR ^15c -C(=O R ^16c 21) -NR ^17a -C(=O)NR ^15d R ^16d , 22) -C(=O)NR ^15e R ^16e , 23) -C(=NR ^13g )R ^15f , 24) -C(= NR ^13h )NR ^15g R ^16f 25) -NR ^16g -C(=NR ¹³ⁱ )R ^15h 26) -NR ^17b -C(=NR ^13j )-NR ¹⁵ⁱ R ^16h (wherein the substituent group β, 5) to Each of the substituents of 19) may be substituted with one to five substituents selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a carboxyl group, and -NR ^18a R ^18b , R ^13a , R ^13b , R ^13c , R ^13d , R ^13e , R ^13f , R ^13g , R ^13h , R ¹³ⁱ , R ^13j , R ^{13k are the} same or different and each independently represents a hydrogen atom, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group. , R ^10a , R ^10b , R ^10c , R ^10d , R ^10e , R ^10f , R ^10g , R ^10h , R ¹⁰ⁱ , R ^10j , R ^10k , R ^10l , R ^10m , R ¹⁰ⁿ , R ^10o , R ^10p , R ^10q , R ^10r , R ^10s , R ^10t , R ^10u , R ^10v , R ^10w , R ^10x , R ^10y , R ^10z1 , R ^10z2 , R ^10z3 , R ^11a , R ^11b , R ^11c , R ^11d , R ^11e , R ^11f , R ^11g , R ^11h , R ¹¹ⁱ , R ^11j And R ^11k , R ^11l , R ^11m , R ¹¹ⁿ , R ^11o , R ^11p , R ^11q , R ^11r , ^11s , R ^11t , R ^11u , R ^11v , R ^11w , R ^12a , R ^12b , R ^12c , R ^12d And R ^12e , R ^12f , R ^12g , R ^12h , R ¹²ⁱ , R ¹⁴ , R ^15a , R ^15b , R ^15c , R ^15d , R ^15e , R ^15f , R ^15g , R ^15h , R ¹⁵ⁱ , R ^16a , R ^16b , R ^16c , R ^16d , R ^16e , R ^16f , R ^16g , R ^16h , R ^17a , R ^17b , R ^17c , R ^{17d are the} same or different and each independently represent a hydrogen atom or a C _1-6 alkyl group (the group) It may be substituted by the same or different one to three substituents selected from the group consisting of a hydroxyl group, a cyano group, a C _1-6 alkoxy group, and -NR ^18a R ^18b , and R ^18a and R ^{18b are the} same or different and each independently is hydrogen. Atom or C _1-6 alkyl.

The substituent which may be substituted may preferably be the following substituent. The substituent group α is preferably exemplified by: 1) a halogen atom 2) a hydroxyl group 3) a carboxyl group 4) a cyano group 5) a C _1-6 alkyl group 6) a C _1-6 alkoxy group 7) a C _1-6 alkylthio group 8) each of the C _1-6 alkylcarbonyl groups (wherein 5) to 8) may be substituted by the same or different substituents of 1 to 5 selected from the substituent group β) 9) C _3-10 lipid Ring group 10) C _3-10 alicyclic oxy 11) C _6-10 aryloxy 12) 5- or 6-membered heteroaryloxy 13) 4 to 10 member non-aryl heteroepoxy Base 14) C _3-10 alicyclic thiol 15) C _6-10 arylthio 16) 5- or 6-membered heteroarylthio 17) 4 to 10 membered non-arylheterocyclic thiol 18) C _6-10 aryl 19) 5- or 6-membered heteroaryl 20) 4 to 10 membered non-aryl heterocyclic ring 21) C _3-10 alicyclic carbonyl 22) C _6-10 arylcarbonyl 23) 5 or 6 member heteroarylcarbonyl groups 24) 4 to 10 members of the non-arylheterocyclic carbonyl group (wherein 9) to 24) each of the substituents may be 1 to 5 substituent groups β or 1) above _1-6 alkyl substituted) 25) -NR ^10a R ^11a 26) -SO ₂ -NR ^10b R ^11b 27) -NR ^10c -C(=O)R ^11c 28) -NR ^12a -C(=O)NR ^10d R ^11d 29) -NR ^10e -SO ₂ -R ^11e 30) -NR ^12b -SO ₂ -NR ^10f R ^11f 31) -C(=O)NR ^10g R ^11g 32) -C(=NR ^13a )R ^10h 33 ) -C(=NR ^13b )NR ¹⁰ⁱ R ^11h 34) -NR ^11f -C(=NR ^13c )R ^10g 35) -NR ^12c -C(=NR ^13d )-NR ^10j R ¹¹ⁱ , The substituent group β preferably contains 1) a halogen atom 2) a hydroxyl group 3) Cyano 4) C _3-10 alicyclic group 5) C _1-6 alkoxy 6) C _1-6 alkylthio 7) 5 or 6 members of heteroarylthio 8) 5 members or 6-membered heteroaryl 9) 4- to 10-membered non-aryl heterocyclic ring 10) C _1-6 alkylcarbonyl 11) C _3-10 alicyclic carbonyl 12) C _6-10 arylcarbonyl 13) 5 members Or a 6-membered heteroarylcarbonyl group 14) 4- to 10-membered non-arylheterocyclic carbonyl group 15) -NR ^15a R ^16a 16) -NR ^15b -C(=O)R ^16b 17) -NR ^17a -C(= O) NR ^15c R ^16c 18) -C(=O)NR ^15d R ^16d 19) -C(=NR ^13e )R ^15e 20) -C(=NR ^13f )NR ^15f R ^16e 21) -NR ^16f -C( =NR ^13g )R ^15g 22) -NR ^17b -C(=NR ^13h )-NR ^15h R ^16g (wherein, in the substituent group β, 4) to 14) each substituent may be selected from a halogen atom, a hydroxyl group, a group of cyano groups, carboxyl groups, substituted with 1 to 5 substituents in the group consisting of -NR ^18a R ^18b , R ^13a , R ^13b , R ^13c , R ^13d , R ^13e , R ^13f , R ^13g , R ^13h The same or different, each independently being a hydrogen atom, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, R ^10a , R ^10b , R ^10c , R ^{1 0d} , R ^10e , R ^10f , R ^10g , R ^10h , R ¹⁰ⁱ , R ^10j , R ^11a , R ^11b , R ^11c , R ^11d , R ^11e , R ^11f , R ^11g , R ^11h , R ¹¹ⁱ , R ^12a , R ^12b , R ^12c , R ^15a , R ^15b , R ^15c , R ^15d , R ^15e , R ^15f , R ^15g , R ^15h , R ^16a , R ^16b , R ^16c , R ^16d , R ^16e , R ^16f , R ^16g And R ^17a and R ^{17b are the} same or different and each independently is a hydrogen atom or a C _1-6 alkyl group (the group may be the same selected from the group consisting of a hydroxyl group, a cyano group, a C _1-6 alkoxy group, and -NR ^18a R ^18b ). Or different from 1 to 3 substituents), R ^18a and R ^{18b are the} same or different and each independently represents a hydrogen atom or a C _1-6 alkyl group.

Further, the substituent which may be substituted may further preferably be a substituent as described below. The substituent group α is further preferably exemplified by: 1) a halogen atom 2) a hydroxy group 3) a cyano group 4) a C _1-6 alkyl group 5) a C _1-6 alkoxy group 6) a C _1-6 alkylthio group 7) Each of the C _1-6 alkylcarbonyl groups (wherein 4) to 7) may be substituted by the same or different one to five substituents selected from the substituent group β) 8) 5 or 6 members Aryloxy 9) 4 to 10 membered non-arylheterocyclicoxy group 10) 5- or 6-membered heteroarylthio group 11) 4 to 10 membered non-arylheterocyclic thio group 12) C _{6- 10} aryl 13) 5 or 6 member heteroaryl 14) 4 to 10 member of the non-aryl heterocyclic ring (wherein 4) to 14) each substituent may be through 1 to 5 substituent groups β or 1) C _1-6 alkyl substituted) 15) -NR ^10a R ^11a 16) -NR ^11b -C(=O)R ^10b 17) -NR ^12a -C(=O)NR ^10c R ^11c 18) -C( =O)NR ^10d R ^11d 19) -C(=NR ^13a )R ^10e 20) -C(=NR ^13b )NR ^10f R ^11e 21) -NR ^11f -C(=NR ^13c )R ^10g 22) -NR ^12b -C(=NR ^13d )-NR ^10h R ^11g , the substituent group β is further preferably 1) a halogen atom, 2) a hydroxyl group, 3) a cyano group, 4) -NR ^15a R ^16a , 5) -NR ^15b -C (=O)R ^16b , 6) -NR ^17a -C(=O)NR ^15c R ^16c , 7) -C(=O)NR ^15d R ^16d , 8) -C(=NR ^13e )R ^15e , 9) -C(=NR ^13f )NR ^15f R ^16e 10) -NR ^16f -C(=NR ^13g )R ^15g , 11) -NR ^17b -C(=NR ^13h )-NR ^15h R ^16g , R ^13a , R ^13b , R ^13c , R ^13d , R ^13e , R ^13f , R ^13g and R ^{13h are the} same or different and each independently represents a hydrogen atom, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, R ^10a , R ^10b , R ^10c , R ^10d , R ^10e , R ^10f , R ^10g , R ^10h , R ^11a , R ^11b , R ^11c , R ^11d , R ^11e , R ^11f , R ^11g , R ^12a , R ^12b , R ^15a , R ^15b , R ^15c , R ^15d , R ^15e , R ^15f , R ^15g , R ^15h , R ^16a , R ^16b , R ^16c , R ^16d , R ^16e , R ^16f , R ^16g , R ^17a , R ^{17b are the} same or different and each independently represents a hydrogen atom or a C _1-6 alkane a group (the group may be substituted by the same or different one to three substituents selected from the group consisting of a hydroxyl group, a cyano group, a C _1-6 alkoxy group, and -NR ^18a R ^18b ), and R ^18a and R ^{18b are the} same or different, Each is independently a hydrogen atom or a C _1-6 alkyl group.

The term "C _1-6 " means that the number of carbon atoms is 1 to 6. The same is true for other figures. For example, the term "C _1-4 " means that the number of carbon atoms is _1-4 .

"Hetero atom" means an oxygen atom, a nitrogen atom, a sulfur atom or the like.

The "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. It is preferably a fluorine atom or a chlorine atom. Further, it is preferably a fluorine atom.

The "C _1-6 alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. The "C _1-6 alkyl group" is preferably a "C _1-4 alkyl group", more preferably a "C _1-3 alkyl group", and still more preferably a "C _1-2 alkyl group". Specific examples of the "C _1-6 alkyl group" are not limited thereto, and examples thereof include a methyl group, an ethyl group, a propyl group, a butyl group, an isopropyl group, an isobutyl group, and a third butyl group. Dibutyl, isopentyl, neopentyl, third amyl, 1,2-dimethylpropyl, and the like.

The "C _2-6 alkenyl group" means a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and having one or more carbon-carbon double bonds. The "C _2-6 alkenyl group" is preferably a "C _2-4 alkenyl group". Specific examples of the "C _2-6 alkenyl group" are not limited thereto, and examples thereof include a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, and a 2-butenyl group. -butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl and the like.

The "C _2-6 alkynyl group" means a linear or branched unsaturated aliphatic hydrocarbon group having one or two or more triple bonds. The "C _2-6 alkynyl group" is preferably a "C _2-4 alkynyl group". Specifically, it is not limited to these, and examples thereof include an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 1-methyl-2-propynyl group, and a 3-butyl group. Alkynyl, 1-pentynyl, 1-hexynyl and the like.

" _C3-10 alicyclic group" means a monocyclic or bicyclic non-aromatic hydrocarbon ring having 3 to 10 carbon atoms, and also includes a part having an unsaturated bond and a part having a crosslink. The structure, a part of the snail, and one or two carbonyl structures. The "alicyclic group" includes a cycloalkyl group, a cycloalkenyl group, and a cycloalkynyl group. The "C _3-10 alicyclic group" is preferably a "C _3-8 alicyclic group", more preferably a "C _3-6 alicyclic group", and further preferably a "C _4-6 ester". "Ring type", especially "C ₅ or C ₆ alicyclic base". Specific examples of the "C _3-10 alicyclic group" are not limited thereto, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and a ring. Propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexadienyl, cyclopentadienyl, cyclooctadienyl and the like.

In addition, the specific example of the "C _3-10 alicyclic group" which has a crosslinked structure is not limited to these, and examples thereof include those described below. [化170]

The "C _3-7 alicyclic group" means a substituent in which the "C _3-7 alicyclic group" is a monovalent group in the above "C _3-10 alicyclic group".

The "C _6-10 aryl group" means a monocyclic or bicyclic aromatic hydrocarbon ring having 6 to 10 carbon atoms, and specific examples thereof include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group. Wait. As the aryl group, a C _6-10 aryl group is usually exemplified, and a C ₆ or C ₁₀ aryl group is preferred.

"5 or 6 members of heteroaryl" means a monocyclic ring containing 5 to 6 atoms of the same or different 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. Aromatic heterocycle.

"5 or 6 members of the nitrogen-containing heteroaryl group" means containing, in addition to one nitrogen atom, the same or different 0 to 3 impurities selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. A monocyclic aromatic heterocyclic ring of 5 to 6 atoms of an atom.

Specific examples of the "6-membered heteroaryl group" are not limited thereto, and examples thereof include pyridine, hydrazine, pyrimidine, and pyridinium.

Specific examples of the "heteroaryl group of five members" are not limited thereto, and examples thereof include thiophene, pyrrole, thiazole, isothiazole, pyrazole, imidazole, furan, oxazole, isoxazole, and oxadiazole. , thiadiazole, triazole, tetrazole, etc., preferably triazole, tetrazole or thiadiazole.

The "heteroaryl group of 5 members or 6 members" means that the above "heteroaryl group of 5 members" or "heteroaryl group of 6 members" becomes a substituent of a monovalent group.

The "non-aryl heterocyclic ring of 4 to 20 members" means a single one containing 4 to 20 atoms containing the same or different one or two hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. A cyclic or bicyclic non-aromatic heterocyclic ring, including a portion having an unsaturated bond, a portion having a crosslinked structure, and a portion being subjected to a snail. The non-aryl heterocyclic ring may also form a condensed ring with an aryl or heteroaryl group. For example, the case of condensing with a C _6-10 aryl group or a 5- or 6-membered heteroaryl group is also included in the hetero ring. Further, in order to constitute the non-aryl heterocyclic ring, one or two carbonyl groups, a thiocarbonyl group, a sulfinyl group or a sulfonyl group may be contained, and for example, an indoleamine or a thioendamine may be contained in the non-aryl heterocyclic ring. a cyclic group such as a lactone, a thiolactone, a cyclic quinone imine, a cyclic urethane, or a cyclic thiocarbamate. Here, the oxygen atom of the carbonyl group, the sulfinyl group and the sulfonyl group and the sulfur atom of the thiocarbonyl group are not included in the number of 4 to 20 members (the size of the ring) and the number of the hetero atoms constituting the ring. Specific examples of the "non-aryl heterocyclic ring of 4 to 20 members" are not limited thereto, and examples thereof include azetidine, pyrrolidine, piperidine, piperidine, porphyrin, homopiperidine, and oxygen. Cyclobutane, tetrahydrofuran, tetrahydropyran or the like or a structure shown below. [化171] In addition, the specific example of the "non-aryl heterocyclic ring of 4 to 20 members" which has a cross-linking and a snail structure is not limited to these, and examples thereof include those shown below. [化172]

The "nitrogen-containing non-aryl heterocyclic ring of 4 to 20 members" means the same or different 0 or 1 selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom in addition to one nitrogen atom. A monocyclic or bicyclic non-aromatic heterocyclic ring of 4 to 20 atoms of a hetero atom, including a part having an unsaturated bond, a part having a crosslinked structure, and a part of a snail.

The "non-aryl heterocyclic ring of 4 to 10 members" means a substituent of "a non-aryl heterocyclic ring of 4 to 10 members" which is a monovalent group.

Specific examples of the "four-membered non-aryl heterocyclic ring" are not limited thereto, and examples thereof include azetidine, oxetane, and thietane. In addition, the specific example of the "four-membered non-aryl heterocyclic ring" having an unsaturated bond is not limited to these, and examples thereof include those shown below. [化173] Specific examples of the "non-aryl heterocyclic ring of five members" are not limited thereto, and examples thereof include pyrrolidine, pyrrolidone, oxazolidinone, tetrahydrofuran, and tetrahydrothiophene. In addition, the specific example of the "non-aryl heterocyclic ring of five members" having an unsaturated bond is not limited thereto, and examples thereof include those described below. [174] In addition, the specific example of the "non-aryl heterocyclic ring of five members" having a crosslinked structure is not limited thereto, and examples thereof include those described below. [化175] In addition, the specific example of the "non-aryl heterocyclic ring of five members" including a carbonyl group or a thiocarbonyl group is not limited thereto, and examples thereof include those described below. [化176]

Specific examples of the "non-aryl heterocyclic ring of 6 members" are not limited thereto, and examples thereof include piperidine, piperidine, porphyrin, tetrahydropyran, and tetrahydrothiopyran. In addition, the specific example of the "6-member non-aryl heterocyclic ring" which has an unsaturated bond is not limited to these, and the structure shown below is mentioned, for example. [化177] In addition, the specific example of the "non-aryl heterocyclic ring of six members" having a crosslinked structure is not limited thereto, and examples thereof include those described below. [化178]

"C _1-6 alkoxy" means "C _1-6 alkyl group", the C _1-6 alkyl portion of the above-described system and the same meaning as C _1-6 alkyl. The "C _1-6 alkoxy group" is preferably a "C _1-4 alkoxy group", more preferably a "C _1-3 alkoxy group", and further preferably a "C _1-2 alkoxy group". . Specific examples of the "C _1-6 alkoxy group" are not limited thereto, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, an isopropoxy group, and an isobutoxy group. And a third butoxy group, a second butoxy group, an isopentyloxy group, a neopentyloxy group, a third pentyloxy group, a 1,2-dimethylpropoxy group or the like.

The "C _3-6 alicyclic oxy group" means a (C _3-6 alicyclic group)-O- group, and the C _3-6 alicyclic moiety has the same meaning as the C _3-6 alicyclic group. The "C _3-6 alicyclic oxy group" is preferably a "C _3-5 alicyclic oxy group". Specific examples of the "C _3-6 alicyclic oxy group" are not limited thereto, and examples thereof include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, and a cyclohexyloxy group.

"C _6-10 aryloxy" C _6-10 aryl part of the same system with the above-described C _6-10 aryl group meaning. The "C _6-10 aryloxy group" is preferably a "C ₆ or C ₁₀ aryloxy group". Specific examples of the "C _6-10 aryloxy group" are not limited thereto, and examples thereof include a phenoxy group, a 1-naphthyloxy group, and a 2-naphthyloxy group.

The heteroaryl portion of the "5 or 6 member heteroaryloxy group" of 5 or 6 members has the same meaning as the "5 member heteroaryl group" or "6 member heteroaryl group". Specific examples of the "heteroaryloxy group of 5 members or 6 members" are not limited thereto, and examples thereof include a pyrazolyloxy group, a triazolyloxy group, a thiazolyloxy group, a thiadiazoleoxy group, and a pyridine. Oxyl, decyloxy and the like.

The non-aryl heterocyclic moiety of 4 to 10 members of the "4 to 10 member non-arylheterocyclic oxy group" has the same meaning as the above-mentioned "4 to 10 member non-aryl heterocyclic ring". The "non-arylheterocyclic oxy group of 4 to 10 members" is preferably a "non-arylheterocyclic oxy group of 4 to 6 members". Specific examples of the "4- to 10-membered non-arylheterocyclic oxy group" are not limited thereto, and examples thereof include tetrahydrofuranyloxy group, tetrahydropyranyloxy group, azacyclobutoxy group, and pyrrolidine. Oxyl, piperidinyloxy and the like.

"C _1-6 alkylthio group" of the C _1-6 alkyl portion of the above-described system and the same meaning as C _1-6 alkyl. The "C _1-6 alkylthio group" is preferably a "C _1-4 alkylthio group", more preferably a "C _1-3 alkylthio group". Specific examples of the "C _1-6 alkylthio group" are not limited thereto, and examples thereof include a methylthio group, an ethylthio group, a propylthio group, a butylthio group, an isopropylthio group, and an isobutylthio group. And a third butylthio group, a second butylthio group, an isopentylthio group, a neopentylthio group, a third amylthio group, a 1,2-dimethylpropylthio group or the like.

"C _3-10 alicyclic group" means a (C _3-10 alicyclic group) -S- group, the C _3-10 alicyclic portion of the above-described system and the C _3-10 alicyclic group have the same meaning . The "C _3-10 alicyclic thio group" is preferably a "C _3-6 alicyclic thio group". Specific examples of the "C _3-6 alicyclic thio group" are not limited thereto, and examples thereof include a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group, and a cyclohexylthio group.

"C _6-10 arylthio group" of the C _6-10 aryl moiety based same meaning as the above-described C _6-10 aryl group. The "C _6-10 arylthio group" is preferably a "C ₆ or C ₁₀ arylthio group". Specific examples of the "C _6-10 aryloxy group" are not limited thereto, and examples thereof include a phenylthio group, a 1-naphthylthio group, and a 2-naphthylthio group.

The heteroaryl group of 5 or 6 members of "5 or 6 members of heteroarylthio" has the same meaning as the above-mentioned "5-membered heteroaryl group" or "6-membered heteroaryl group". Specific examples of the "heteroarylthio group of 5 members or 6 members" are not limited thereto, and examples thereof include pyrazolylthio group, triazolethio group, thiazolylthio group, thiadiazolethio group, and pyridine sulfur. Base, thiol and the like.

The non-aryl heterocyclic moiety of 4 to 10 members of the "4- to 10-membered non-arylheterocyclic thio group" has the same meaning as the above-mentioned "4 to 10 member non-aryl heterocyclic ring". The "non-arylheterocyclic thio group of 4 to 10 members" is preferably a "non-arylheterocyclic thio group of 4 to 6 members". Specific examples of the "4 to 10 member non-arylheterocyclic thio group" are not limited thereto, and examples thereof include a tetrahydropyranylthio group and a piperidinylthio group.

The "C _1-6 alkylcarbonyl group" means a carbonyl group substituted by the above "C _1-6 alkyl group". The "C _1-6 alkylcarbonyl group" is preferably a "C _1-4 alkylcarbonyl group". Specific examples of the "C _1-6 alkylcarbonyl group" are not limited thereto, and examples thereof include an ethyl group, a propyl group, and a butyl group.

The "C _3-10 alicyclic carbonyl group" means a carbonyl group substituted by the above "C _3-10 alicyclic group". The "C _3-10 alicyclic carbonyl group" is preferably a "C _3-6 alicyclic carbonyl group". Specific examples of the "C _3-10 alicyclic carbonyl group" are not limited thereto, and examples thereof include a cyclopropylcarbonyl group and a cyclopentylcarbonyl group.

The "C _6-10 arylcarbonyl group" means a carbonyl group substituted by the above "C _6-10 aryl group". As the "C _6-10 arylcarbonyl group", a "C ₆ or C ₁₀ arylcarbonyl group" is preferred. Specific examples of the "C _6-10 arylcarbonyl group" are not limited thereto, and examples thereof include a benzamidine group, a 1-naphthalenecarbonyl group, and a 2-naphthalenecarbonyl group.

The "heteroarylcarbonyl group of 5 members or 6 members" means a carbonyl group substituted by the above "5 or 6 member heteroaryl groups". Specific examples of the "heteroarylcarbonyl group of 5 members or 6 members" are not limited thereto, and examples thereof include a pyrazolecarbonyl group, a triazolecarbonyl group, a thiazolecarbonyl group, a thiadiazolecarbonyl group, a pyridinecarbonyl group, and a fluorene carbonyl group. Wait.

The "4- to 10-membered non-arylheterocyclic carbonyl group" means a carbonyl group substituted by the above-mentioned "4 to 10 member non-aryl heterocyclic ring". The "non-arylheterocyclic carbonyl group of 4 to 10 members" is preferably a "4- to 6-membered non-arylheterocyclic carbonyl group". Specific examples of the "4- to 10-membered non-arylheterocyclic carbonyl group" are not limited thereto, and examples thereof include azetidinylcarbonyl group, pyrrolidinylcarbonyl group, piperidinylcarbonyl group, and porphyrincarbonyl group.

The "C _1-6 alkylsulfonyl group" means a sulfonyl group substituted by the above "C _1-6 alkyl group". The "C _1-6 alkylsulfonyl group" is preferably a "C _1-4 alkylsulfonyl group". Specific examples of the "C _1-6 alkylsulfonyl group" are not limited thereto, and examples thereof include a methylsulfonyl group, a propyl sulfonyl group, and a butyl sulfonyl group.

The "C _3-10 alicyclic sulfonyl group" means a sulfonyl group substituted by the above "C _3-10 alicyclic group". The "C _3-10 alicyclic sulfonyl group" is preferably a "C _3-6 alicyclic sulfonyl group". Specific examples of the "C _3-10 alicyclic sulfonyl group" are not limited thereto, and examples thereof include a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group, and a ring. Hexyl sulfonyl group and the like.

The "C _6-10 arylsulfonyl group" means a sulfonyl group substituted by the above "C _6-10 aryl group". The "C _6-10 arylsulfonyl group" is preferably a "C ₆ or C ₁₀ arylsulfonyl group". Specific examples of the "C _6-10 arylsulfonyl group" are not limited thereto, and examples thereof include a phenylsulfonyl group, a 1-naphthylsulfonyl group, and a 2-naphthylsulfonyl group.

The term "heteroarylsulfonyl group of 5 or 6 members" means a sulfonyl group substituted by the above "5 or 6 members of heteroaryl group". Specific examples of the "heteroarylsulfonyl group of 5 members or 6 members" include a pyridylsulfonyl group and the like.

The "C _1-6 alkylene group" means a substituent in which a saturated hydrocarbon group having 1 to 6 carbon atoms is a divalent group.

The "C _1-3 alkylene group" means a substituent in which a saturated hydrocarbon group having 1 to 3 carbon atoms is a divalent group.

"Carboxylic acid equivalent" means a bioisostere of a carboxylic acid, and other partial structures (functional groups) which exert biologically the same effects in a pharmaceutical molecule are referred to as biosimilars (in the present invention, As a concept of biological traits, it also includes precursor drug structures). The carboxylic acid equivalent is not limited thereto, and examples thereof include -SO ₃ H, -SO ₂ NHR ^19a , -B(OR ^e1 ) ₂ , -PO(OR ^e1 )(OR ^e2 ), - CONHR ^19a , -CONHSO ₂ R ^19a , -CONR ^19a CN, -CONHNHSO ₂ R ^19a and the following formulas (6A), (6B), (6C), (6D), (6E), (6F), (6G) , (6H), (6I), (6J), (6K), (6L), (6M), (6N), (6O), (6P), (6Q), (6R), (6S), ( Substituents represented by 6T), (6U), (6V) and (6W) (the group may be substituted by the same or different 1 to 3 R ^19b ), etc., [Chem. 179] [In the formulae (6V) and (6W), R ^j is a hydrogen atom, a C _1-6 alkyl group, or a C _3-10 alicyclic group (the C _1-6 alkyl group or the C _3-10 alicyclic group may be used. Substituted by 1 to 5 halogen atoms), R ^k is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group (the C _1-6 alkyl group, the C _1-6 alkoxy group may be 1 to 1) 5 halogen atoms substituted), C _3-10 alicyclic group, phenyl group, phenoxy group, pyridyl group, pyridyloxy group (the C _3-10 alicyclic group, phenyl group, phenoxy group, pyridyl group, The pyridyloxy group may be substituted by 1 to 5 substituents selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and a C _1-6 alkoxy group.], R ^19a and R ^{19b are the} same or different, and each Independently represents a hydrogen atom, a hydroxyl group, a C _1-6 alkyl group, a C _6-10 aryl group, a heteroaryl group of 5 or 6 members, a non-aryl heterocyclic ring of 4 to 10 members, and R ^e1 represents 1) a hydrogen atom, 2) C _1-6 alkyl, 3) C _3-10 alicyclic, 4) C _6-10 aryl, 5) 5 or 6 member heteroaryl, or 6) 4 to 10 member Any one of the arylheterocycles (wherein each of the above 2) to 6) may be substituted, wherein, in the case where R ^e1 is bonded to the boron atom via an oxygen atom, two R may be used. ^{E1 is} in the form of C _2-4 alkyl and boron And the two oxygen atoms together form a non-aryl heterocyclic ring of 5 to 7 members (the alkyl moiety of the non-aryl heterocyclic ring may be substituted), and R ^e2 represents a hydrogen atom, a C _1-6 alkyl group which may be substituted Or a C _3-10 alicyclic group which may be substituted. Preferably, R ^j is a hydrogen atom or a C _1-6 alkyl group, and R ^k is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _3-10 alicyclic group or a C ₃ group _; Any of the _-10 alicyclic oxy groups. Alternatively, it is preferred herein that R ^19a and R ^{19b are the} same or different and each independently represents a hydrogen atom, a hydroxyl group, or a C _1-6 alkyl group. Further, it is preferred herein that R ^e1 and R ^{e2 are the} same or different and each independently represents a hydrogen atom, a C _1-6 alkyl group, or a C _3-10 alicyclic group.

Preferred aspects of the compound of the present invention can be specifically exemplified in the form of the following compounds. a compound represented by the following formula or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² and R ^{3 are the} same or different and each independently is a substituent selected from a hydrogen atom, P1, P2 or P3. R ^Y is a substituent selected from Y1 to Y139.

[化180] R ³ : [Chem. 181] R ^Y : [化182] [化183]

More preferred aspects of the compounds of the invention may be exemplified by the compounds described below. a compound represented by the following formula or a pharmaceutically acceptable salt thereof, wherein R ³ is a substituent selected from a hydrogen atom or the above P1, P2 or P3, and R ^Y is selected from the above Y1 to Y139. Substituent. [化184]

Further preferred aspects of the compound of the present invention can be exemplified by the compound of the following Table (1) or a pharmaceutically acceptable salt thereof.

[Table 1-1] [Table 1-2] [Table 1-3]

Hereinafter, the compound of the present invention will be further described. In the compound of the present invention, stereoisomers such as tautomers and geometric isomers and optical isomers may be present depending on the kind of the substituent, but the present invention also encompasses these. That is, in the case where one or more asymmetric carbon atoms are present in the compound of the present invention, there are non-image or isomeric or optical isomers, but such non-image or a mixture of optical isomers or Individually isolated is also included in the compounds of the invention.

Further, the compound of the present invention may exist in a structure represented by the following formula (2) by an equilibrium state or the like due to environmental conditions such as temperature and humidity, or physical properties such as a solid, a liquid, or a solution. The compounds also include such. [Chem. 185] (In the formula (2), Q represents a hydroxyl group, a thiol group, -NHR ^a1 , and Z, L, Y, R ¹ , R ² , R ³ , R ⁴ and R ^a1 are the same as defined in the item 1. (1a) is the same as defined in item 1.) Further, for example, the structure of the compound of the present embodiment is based on the use of proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR), liquid chromatography mass spectrometry (LCMS), etc., and the industry believes that the most appropriate presumption, but only for each specific The structure estimation in the measurement environment, in particular, the structure of the above formula (1a), the structure of the formula (1b), and the structure of the formula (2) have various environmental conditions such as inherent properties of each compound, temperature, humidity, or solid, The possibility of mutual conversion of liquids, or physical factors such as solutions.

Further, various hydrates, solvates and polymorphs are also included in the compounds of the present invention.

Further, the compound of the present invention may also be substituted with an isotope element (for example, D, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ³⁵ S, ¹⁸ F, ¹²⁵ I, etc.). Compounds such as the compounds are also included in the compounds of the invention.

In the present invention, the term "pharmaceutically acceptable salt" means an acid addition salt and a base addition salt which are allowed to be used in pharmaceutically. The "pharmaceutically acceptable salt" is not limited thereto, and examples thereof include acetate, propionate, butyrate, formate, trifluoroacetate, maleate, and fumaric acid. Salt, tartrate, citrate, stearate, succinate, ethyl succinate, malonate, lactobionate, gluconate, glucoheptonate, benzoate, methane Acid salt, benzenesulfonic acid, tosylate, lauryl sulfate, malate, ascorbate, mandelate, gluconate, hydroxynaphthoate, pamoate, Cinnamate, adipate, cysteamine, N-acetin cysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinic acid, Acid addition salts such as oxalate, picrate, thiocyanate, undecanoate, acrylic acid polymer salt, carboxyvinyl polymer; inorganic base addition such as lithium salt, sodium salt, potassium salt, calcium salt a salt; an organic base addition salt such as porphyrin or piperidine; an addition salt with an amino acid such as aspartic acid or glutamic acid; and the like.

The compound of the present invention can be administered into a formulation, a pharmaceutical or a pharmaceutical composition directly or by using an appropriate preparation by oral administration or parenteral administration. Specific examples of the dosage forms are not limited thereto, and examples thereof include a tablet, a capsule, a powder, a granule, a liquid, a suspension, an injection, a patch, a dressing, and the like. Further, these preparations can be produced by a known method using an additive which is usually used as a pharmaceutical additive.

As such additives, excipients, disintegrators, binders, plasticizers, lubricants, coating agents, solubilizers, solubilizers, tackifiers, dispersants, stabilizers, sweeteners may be used as needed. , spices, etc. Specific examples of such additives are not limited thereto, and examples thereof include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, corn starch, partially gelatinized starch, and carboxymethylcellulose calcium. Cross-linked sodium carboxymethylcellulose, hydroxypropylcellulose, hypromellose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, and the like.

The dose of the compound of the present invention is appropriately selected depending on the animal to be administered, the route of administration, the disease, the age, body weight and symptoms of the patient. For example, in the case of oral administration, for adults, the lower limit per day is 0.01 mg (preferably 100 mg), and the upper limit is 10000 mg (preferably 6000 mg), which can be once per day. The method is administered in a manner or in a fractional order.

The compound of the present invention is a compound having an inhibitory activity against a serine acid-β-endoguanamine having a serine residue at an active center. Therefore, it can be used as a prophylactic or therapeutic agent for bacterial infections by being used in combination with an antibacterial agent. Specific examples of such bacterial infections include sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, paranasal inflammation, pneumonia, lung abscess, empyema, and chronic Secondary infection of ventilator lesions, pharyngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic/lymphitis, trauma/scald Secondary infections such as surgical wounds, urinary tract infections, genital infections, ocular infections, or odontogenic infections.

The compound of the present invention may be combined with at least one selected from the group consisting of an antibacterial agent, an antifungal drug, an antiviral drug, an antiinflammatory drug, and an antiallergic drug in order to treat one or more bacterial infections described in the present specification. use. Preferably, an antibacterial agent is mentioned, and a β-endoamine-based agent is further preferable, and specific examples thereof include amoxicillin and ampicillin (Pivampicillin, Hetacillin, and Becksilin). (Bacampicillin), Metaracicillin, Talampicillin, Epicurin, Carbenicillin (Carindacillin), Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam (Pivmecillinam), Sulbenicillin, Benzethin (G), Clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin, Penamecillin, Phenoxymethylpenicillin (V) ), Propicillin, benzathine phenoxymethylpenicillin, Pheriticillin, Cloxacillin (Dicloxacillin, Flucloxacillin), Europe Oxacillin, Methicillin, Nafcillin, Faropenem, Biapenem, Doripenem, Ertapenem, Asia Imipenem, Meropenem, Panipenem, Tomopenem, Razupenem, Cefazolin, Cephacetrile, Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cephaloridine, Cefalotin, Cefapirin, Ceftriaxone (Cefatrizine), Cefazedone, Cefazaflur, Cephradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole , Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cephalosporin Cefozonam, Cefoxitin (Cefo) Xitin), cefotetan, Cefmetazole, Loracarbef, Cefixime, Ceftazidime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Cefodizime, Cefoperazone, Cephalosporin Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten, Cefotaxime (Ceftiolene), Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome, Cefquinome ( Cefquinome), Ceftobiprole, Ceftaroline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, Ceftiofur, Cefquinome, Cephalosporin Cefovecin, Aztamine (Azt) Reonam), Tigemonam, Carumonam, RWJ-442831, RWJ-333441, or RWJ-333442. The administration time of the compound of the present invention and the therapeutic agents is not limited, and the administration may be carried out simultaneously with the administration target, or may be administered at intervals. Further, a combination of the compound of the present invention and the therapeutic agents can also be prepared. The dose of the therapeutic agents can be appropriately selected based on the amount used clinically. Further, the ratio of the compound of the present invention to the therapeutic agents can be appropriately selected depending on the administration target, the administration route, the target disease, the symptoms, the combination, and the like.

In another aspect of the present invention, when a pharmaceutical composition comprising an antibacterial agent such as a β-endoxime-based agent is used, the compound of the present invention can be administered simultaneously or at different times. Such a pharmaceutical composition comprising a beta-endoxime agent is also within the scope of the invention and can be used for the treatment or prevention of sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, Secondary nasal cavity inflammation, pneumonia, lung abscess, empyema, secondary infection of chronic respirator lesions, pharyngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin Bacterial infections such as infections, lymphatic/lymphulitis, trauma/scald, and surgical wounds such as secondary infections, urinary tract infections, genital infections, ocular infections, or odontogenic infections.

Such a pharmaceutical, preparation, or pharmaceutical composition can be prepared together or separately by using a compound of the present invention and/or an additional pharmaceutical agent (for example, an antibacterial agent such as a β-neutamine compound) by any technique known in the art. The compound or the various agents are prepared by mixing with any suitable components, and can be prepared into a suitable preparation, such as a tablet, a capsule, a powder, a granule, a liquid, or a suspension, by using any technique known in the art. Formulation by injection, injection, patch, and dressing. When the compound of the present invention and/or an additional agent (for example, an antibacterial agent such as a β-namidamide-based drug) is prepared in the form of various pharmaceutical agents, it may be provided in the form of a kit of two kinds of drugs, or may be provided. One component may be provided in the form of a single agent, or an additional component may be provided together (in the case of the compound of the present invention, an additional agent (for example, an antibacterial agent such as a β-endamine drug) may be added to the additional agent ( For example, in the case of an antibacterial agent such as a β-endoamine-based drug, a compound of the present invention) can be administered at the same time or in combination at different times (attached documents, etc.).

In the case where the compound of the present invention is used as an active ingredient of medicine, it is not intended to be used only for humans, but also for other animals other than humans (cat, dog, cow, chicken, fish, etc.).

Hereinafter, the method for producing the compound of the present invention will be described by way of example, but the present invention is of course not limited thereto.

The compound of the present invention is not limited to these, and can be produced, for example, by the production method described below. These manufacturing methods can be suitably modified based on the knowledge of those skilled in the art of organic synthesis. In the following production method, the compound used as a raw material may be used as long as it does not interfere with the reaction.

In the following production method, even if it is not specifically stated that the protecting group is used, when any of the functions other than the reaction point is changed depending on the reaction conditions, or when the treatment after the reaction is performed inappropriately, The target compound can be obtained by protecting the reaction site from the reaction site or after performing a series of reactions after the reaction or after a series of reactions. As the protecting group used in these processes, the literature (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, inc., New York (1999)) can be used. The usual protection base is described. Further, the introduction and removal of the protective group can be carried out by a method commonly used in organic synthetic chemistry (for example, the method described in the above literature) or according to the methods.

The starting materials and intermediates in the following production methods can be obtained by commercially available products, or can be obtained by a method described in a publicly known document or by a known compound according to a known method. Further, these starting materials and intermediates may be used as long as they do not interfere with the reaction.

The intermediates and target compounds in the following production methods can also be converted to other compounds contained in the present invention by appropriately converting the functional groups. The conversion of the functional groups at this time can be carried out by a method commonly used in organic synthetic chemistry (for example, R.C. Larock, "Comprehensive Organic Transformations", 2 ^nd Ed., John Wiley and Sons, inc., New York (1999). The method described, etc.) or according to the methods described.

The inactive solvent in the following production method means a raw material, a reagent, a base, an acid, a catalyst, a ligand, etc. which are not used in the reaction (hereinafter, also referred to as "the raw material used in the reaction" The solvent of the reaction. Further, even when the solvent used in the respective steps is reacted with the raw material or the like used in the reaction, the solvent can be used as an inactive solvent as long as the desired reaction proceeds and the target compound can be obtained.

A method for producing a compound of formula (1a) of the compound of the following formula (1-4) can be represented, for example, be produced by the following production method.

[Chem. 186] (wherein X, L, Y, R ¹ , R ² , R ³ , R ^{4 are} as defined in the item 1, Z ¹ is a hydroxyl group or a C _1-6 alkoxy group, H is a hydrogen atom, and LG is a leaving group. (For example, a halogen atom such as chlorine, bromine or iodine, a lower alkylsulfonyloxy group such as a methylsulfonyloxy group or a trihalomethylsulfonyloxy group such as a trifluoromethanesulfonyloxy group; And an arylsulfonyloxy group such as a benzenesulfonyloxy group or a p-toluenesulfonyloxy group, and PG ¹ and PG ² represent a C _1-6 alkyl group which may be substituted, or a protective group of a boronic acid (for example, The structure represented by the following formula, etc.) is mentioned.

[化187] PG ³ represents a hydrogen atom or a protecting group of a hydroxyl group (for example, a third butoxycarbonyl group, an ethyl fluorenyl group, a methoxymethyl group, a p-methoxybenzyl group, a tert-butyldimethylalkyl group, and a third group) a methyl decyl group or the like, a protecting group for a thiol group (for example, an acetaminomethyl group or a trityl group), or a protecting group for an amine group (for example, an ethoxycarbonyl group, a third butoxy group) Carbocarbonyl, ethyl hydrazino, benzhydryl, trifluoroethenyl, benzyloxycarbonyl, 3- or 4-chlorobenzyloxycarbonyl, triphenylmethyl, methylsulfonyl, p-toluenesulfonyl , trimethyldecyl, benzyloxycarbonyl, 3- or 4-chlorobenzyloxycarbonyl, benzylsulfonyl, benzyl, 4-nitrobenzyl, 4-methoxybenzyl, methyl, Ethyl, etc.).

The compound (1-1) as a starting material can be used by a commercially available person or by a known method (for example, WO2014/107536, WO2016/003929, etc.).

Further, the compound (1-2) can be used as a commercially available product or according to a publicly known document (Bioorg. Med. Chem. Lett. 26, 1589, 2016, Organic Letters, 14 (5), 1194, 2012, Tetrahedron). The methods described in Letters, 28 (45), 5563, 1987, EP126013, US474512, WO2000/022153, etc., or synthesized by known compounds according to known methods. The compound (1-2) may be used as long as it does not interfere with the reaction, and a functional group may be used as needed.

Step 1-1: Compound (1-3) can be produced by reacting compound (1-1) with an inactive solvent in the presence of a base and under normal pressure or under pressure with compound (1-2). . Specific examples of the inactive solvent include a halogen-based solvent such as dichloromethane or dichloroethane; an ether solvent such as THF (Tetrahydrofuran) or DME (Dimethyl ether); and N, N. An aprotic solvent such as dimethylformamide (DMF), N-methylpyrrolidone (NMP) or dimethyl hydrazine (DMSO). Examples of the base include triethylamine, diisopropylethylamine, potassium carbonate, and sodium hydride. The base can be used in an amount of 0.001 to 100 equivalents, preferably 1 to 50 equivalents, based on the compound (1-2). The reaction temperature is selected from the range of about -10 ° C to about 100 ° C.

Step 2: The reaction can be carried out from the corresponding compound (1-3) according to a known method (for example, WO2014/151958, WO2015/191907, WO2016/003929, etc.). It is preferable to manufacture by the manufacturing method (1-2-1) or the manufacturing method (1-2-2) shown below.

Production Method (1-2-1): The compound (1-4) can be produced by reacting the compound (1-3) with a boric acid in an inert solvent under acidic conditions as a starting material. Examples of the boric acid include phenylboric acid and 2-methylpropylboronic acid. The equivalent of boric acid can be used in the range of 0.001 to 100 equivalents, preferably 1 to 3 equivalents, based on the compound (1-3). Examples of the acid include hydrochloric acid, trifluoroacetic acid, and the like. The acid equivalent can be used in the range of 0.001 to 100 equivalents, preferably 1 to 10 equivalents, based on the compound (1-3). Specific examples of the inactive solvent include a halogenated hydrocarbon solvent such as dichloromethane or dichloroethane, a hydrocarbon solvent such as hexane or heptane, an ether solvent such as THF or DME, or acetonitrile or propionitrile. The nitrile solvent and water may be used singly or in the form of a mixed solvent. Further, the acid shown above can also be used as a solvent as it is. As the solvent, a mixed solvent of hexane/acetonitrile is preferably used. The reaction temperature is selected from the range of about -10 ° C to about 100 ° C.

Production Method (1-2-2): The compound (1-4) can be produced by reacting the compound (1-3) with triethyl decane in a trifluoroacetic acid solvent using the compound (1-3) as a starting material. The equivalent of triethyldecane can be used in the range of 0.001 to 100 equivalents, preferably 1 to 50 equivalents, based on the compound (1-3). The reaction temperature is selected from the range of about -10 ° C to about 70 ° C.

Production Method 1A The compound of the formula (1a) can be produced from the corresponding raw materials which can be purchased or prepared in the same manner as the production method of the above compound (1-7). [化188] (wherein X, Z, L, Y, R ¹ , R ² , R ³ , and R ⁴ are as defined in Item 1)

Production Method 1B The compound of the formula (1a) (trisubstituted boron compound) may be a compound of the formula (1b) by reacting it with a nucleophilic Z anion (Z ^- ) depending on the nature of the compound (tetrasubstituted boron) Compound) conversion. The compound (1b) is usually present in the form of a metal salt represented by the following formula. [化189] Wherein X, Z, L, Y, R ¹ , R ² , R ³ , R ^{4 are} as defined in item 1, Z ^- is a Z anion, for example, a hydroxide ion (denoted as HO ^- or ^- OH) , C _1-6 alkoxide (the C _1-6 alkoxide is represented by R ^u O ^- , R ^u is the above C _1-6 alkyl group), guanamine anion ( ^- NR ^a2 R ^b1 ), etc., M ⁺ is a monovalent metal cation, for example, an alkali metal ion such as sodium ion (Na ⁺ ), lithium ion (Li ⁺ ), potassium ion (K ⁺ ), and M ²⁺ is a divalent metal cation such as magnesium ion ( Mg ²⁺ ), alkaline ions such as calcium ions (Ca ²⁺ )

More specifically, the compound of the formula (1b) can be produced by adding a base as described below to the compound of the formula (1a). M ⁺ Z ^- or M ²⁺ (Z ^- ) ₂ as an ion pair can be used to add a base in the form of MZ or M(Z) ₂ to cause the reaction to produce (1b) as the base, for example When Z is a hydroxyl group, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide or the like may be mentioned, preferably lithium hydroxide, sodium hydroxide or potassium hydroxide, more preferably It is sodium hydroxide. Further, as the base, for example, when Z is a C _1-6 alkoxy group (R ^u O), a metal alkoxide such as potassium t-butoxide, sodium methoxide or sodium ethoxide may be mentioned. Further, as the base, for example, when Z is -NR ^a2 R ^b1 , a metal guanamine such as an amine sodium or a diisopropyl guanamine lithium may be mentioned.

Alternatively, M ⁺ Z ^- may be produced by adding other bases in the reaction system in which ZH or ZH is present.

For example, when ZH is water (H ₂ O), hydrogen hydroxide ions and sodium ions are respectively produced in the system by adding sodium hydride or sodium carbonate to the water, or hydrogen is added by adding potassium hydride or potassium carbonate to the water. Oxygen ions and potassium ions are produced separately in the system.

Further, for example, when ZH is a C _1-6 alcohol (the C _1-6 alcohol is represented by R ^u OH and the ^Ru is a C _1-6 alkyl group), sodium hydride is added to the ^Ru OH And the hydroxide ion and the sodium ion are respectively produced in the system, or by adding potassium hydride to R ^u OH, and C _1-6 alkoxide and potassium ion are respectively produced in the system.

Further, for example, when ZH is an amine (HNR ^a2 R ^b1 (the R ^a2 , R ^b1 is as defined in Item 1)), an amine is added by adding sodium hydride to the reaction system containing the HNR ^a2 R ^b1 The sodium hydride (NaNR ^a2 R ^b1 ) is produced separately in the system, and potassium hydride is added to the reaction system containing HNR ^a2 R ^b1 and, if necessary, an inactive solvent (for example, THF, toluene, etc.). Potassium decylamine (KNR ^a2 R ^b1 ) is produced separately in the system.

For example, in the compound of the formula (1a), the compound of the following formula (1a') wherein Z is a hydroxyl group, for example, the reaction of obtaining the compound according to the step 1-2 in the above production method 1 is carried out using an aqueous sodium hydroxide solution. Treatment, whereby the sodium salt compound of the formula (1b') can be obtained depending on the nature of the compound. [190] (wherein X, L, Y, R ¹ , R ² , R ³ , and R ⁴ are as defined in Item 1)

For example, in the compound of the formula (1a), the compound of the following formula (1a'') wherein Z is a hydroxyl group and R ⁴ is a carboxyl group, for example, after the reaction of obtaining the compound according to the step 1-2 in the above production method 1, Treatment with an aqueous solution of sodium hydroxide allows the disodium salt compound of the formula (1b'') to be obtained depending on the nature of the compound. [化191] (wherein X, L, Y, R ¹ , R ² , and R ³ are as defined in Item 1)

The intermediate and the target compound in the above production method can be purified by a method commonly used in organic synthetic chemistry (for example, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc.) ) and perform single purification. Further, each intermediate may be supplied to the next reaction without special purification.

The optically active substance of the compound of the present invention can be produced by optically dividing the optically active starting material or intermediate or by subjecting the intermediate or the final product to a racemic form. The method of optical division is not limited to these, and examples thereof include a separation method using an optically active column, and a separation method such as a stepwise crystallization method. The non-image isomer of the compound of the present invention is not limited thereto, and can be produced, for example, by a separation method such as column chromatography or fractional crystallization.

The pharmaceutically acceptable salt of the compound represented by the formula (1) is not limited thereto, and for example, it can be obtained by a solvent such as water, methanol, ethanol, 2-propanol, ethyl acetate or acetone. The compound represented by the method is produced by mixing with a pharmaceutically acceptable acid or base.

In this manual, "or / or" is used when "at least one or more" of the items listed in the article can be used. "or / or" is the same. In the case where it is clearly described in the specification as "in the range of two values", the range also includes two values themselves.

The scientific literature, patents, patent applications and the like cited in the present specification are hereby incorporated by reference in their entirety in their entireties in the extent the the the the the

The present invention has been described above in order to facilitate understanding of the present invention. The invention is described below with reference to the accompanying drawings, which are intended to be illustrative only and not intended to limit the invention. Therefore, the scope of the present invention is not limited to the embodiments described in the specification, and is not limited to the embodiments, and is only limited by the scope of the application. [Examples]

The present invention will be specifically described below by way of Reference Examples, Examples and Test Examples, but the present invention is of course not limited thereto. When necessary, the treatment of the animal used in the following examples is carried out in accordance with the standards stipulated by the animal care law, etc., when necessary. For the reagents, specifically, the products described in the examples are used, but they may be used instead of other manufacturers.

The identification of the compound was carried out by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR), liquid chromatography mass spectrometry (LCMS) or the like. Further, the nuclear magnetic resonance spectrum uses tetramethyl decane as an internal standard.

The column chromatography method and the reverse phase column chromatography method in the reference examples and the examples used a rubber tube column manufactured by Shanshan Co., Ltd. and an ODS-A tube column manufactured by YMC. Further, TLC (silicone plate) was purified by thin layer chromatography (TLC) using Silica gel 60F254 (Merck), and TLC (NH Silicone plate) was a TLC plate NH (FujiSilysia).

The various materials described in the Reference Examples and the Examples were obtained by the following machines. NMR spectrum: [ ¹ H-NMR] 400 MHz: JEOL JNM-AL Series AL400, or Bruker AVANCE III 400 MHz, or JEOL JNM-ECS Series ECS400 LC-MS Atlas: Waters ACQUITYTM UltraPerformance LC, or Agilent 1200 Series Agilent 6110 Quadrupole LC/MS

The compound names described in the Reference Examples and the Examples are named using ACD/Name (ACD/Labs 12.0, Advanced Chemistry Development Inc.), or a reference name based on a conventional name such as a known document, and are not necessarily limited to the IUPAC nomenclature. These compound names can be singularly converted to IUPAC names by the manufacturer.

The measurement conditions (hereinafter, also referred to as measurement methods) of the high-speed liquid chromatography mass spectrometer (LCMS) are as follows, and the value of the observed mass spectrometry [MS (m/z)] is [M+1] ⁺ Indicates that the hold time is expressed in Rt (minutes, min). Further, among the measured values, the measurement conditions used for the measurement were denoted by A to C. For example, when it is expressed as "LCMS: [M+H] ⁺ /Rt=620/1.32 ^A ", it is measured under the measurement condition A.

Determination condition A column: ACQUITY UPLC BEH C18 1.7 μm 2.1×30 mm column (solvent) Solvent: solution A: 0.05% HCOOH/H ₂ O, solution B: CH ₃ CN Gradient conditions: 0.0-1.3 minutes; A/ B=99/1～5/95 (linear gradient) 1.3-1.5 minutes; A/B=99/1 Flow rate: 0.80 mL/min UV: 220 nm, 254 nm Column temperature: 40 °C

Determination condition B column: XBridge C18 3.5 μm 50 × 4.6 mm column (solvent) Solvent: solution A: 10 mmol / L NH ₄ HCO ₃ aqueous solution, B solution: CH ₃ CN Gradient conditions: 0.0-1.4 minutes; A / B=95/5～5/95 (linear gradient) 1.4-3.0 minutes; A/B=5/95 Flow rate: 1.80 mL/min Column temperature: 50°C

Determination conditions C column: XBridge C18 3.5 μm 50 × 4.6 mm column (column) Solvent: Liquid A: 10 mmol / L NH ₄ HCO ₃ aqueous solution, B liquid: CH ₃ CN Gradient conditions: 0.0-0.2 minutes; A / B=95/5 0.2-1.7 minutes; A/B=95/5 to 95/5 (linear gradient) 1.7-3.0 minutes; A/B=95/5 Flow rate: 1.80 mL/min Tube temperature :50°C

In the reference examples, examples, and test examples, in order to simplify the description, the abbreviations shown in the above and the abbreviations shown below are used. s: single peak d: doublet t: triplet q: quadruple peak m: multiple peak br: wide peak dd: double doublet J: coupling constant Hz: Hertz δ: chemical shift Min: minute Trt: trityl TFA: trifluoromethane DMF: dimethylformamide THF: tetrahydrofuran DME: 1,2-dimethoxyethane DMAP: 4-dimethylaminopyridine Me: A MeCN: acetonitrile Boc: third butoxycarbonyl tBu or ^t Bu or t-Bu: third butyl Bn: benzyl TMS: trimethyl decyl HATU: 1-[bis(dimethylamino) y Methyl]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate N: equivalent concentration MEPM: meropenem MIC: minimum inhibitory concentration

Reference Example 1: 1-(pyrrolidin-1-yl)-2-thioethyl ketone

[化192]

Reference Example 1-(i): 1-(pyrrolidin-1-yl)-2-(tritylthio)acetone

[Chem. 193] Potassium carbonate (1.92 g, 13.9 mmol) and triphenylbenzene were added to a solution of 2-chloro-1-(pyrrolidin-1-yl)ethanone (1.23 g, 8.33 mmol) in DMF (13 mL). Methyl mercaptan (1.92 g, 6.94 mmol) and stirred for 20 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: chloroform/methanol = 99/1 to 95/5) to give the title compound (2.56 g).

¹ H-NMR (CDCl ₃ ) δ : 7.45 - 7.37 (5H, m), 7.28 - 7.12 (10H, m), 3.37 - 3.27 (2H, m), 3.04 - 2.95 (2H, m), 2.85 (2H, s), 1.82 - 1.65 (4H, m). Reference Example 1: 1-(pyrrolidin-1-yl)-2-thioethyl ketone

[Chem. 194] The compound of Reference Example 1-(i) (2.65 g, 6.11 mmol) was dissolved in dichloromethane (33 mL) and triethyl decane (1.5 mL, 9.45 mmol) and TFA (25 mL) The reaction solution was stirred for 3 hours. The reaction mixture was evaporated under reduced pressure, and ethyl acetate and aq. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol = 99/1 to 95/5) to give the title compound (1.71 g).

¹ H-NMR (CDCl ₃ ) δ : 3.61 - 3.40 (4H, m), 3.29 (2H, s), 2.11 - 1.81 (4H, m).

Reference Example 2: [1-(thioethenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

[Chem. 195]

Reference Example 2-(i): (tritylthio)acetic acid

[Chem. 196] Triphenylethanol (1.3 g, 4.99 mmol) and TFA (0.5 mL) were added to a solution of thioacetic acid (0.35 mL, 4.99 mmol) in dichloromethane (5 mL). The reaction liquid was distilled off under reduced pressure, and the obtained residue was recrystallized from dichloromethane / petroleum ether = 1 / 1 mixture (5 mL). The obtained crystals were filtered, washed with ice-cooled diethyl ether and dried to give the title compound (800 mg).

¹ H-NMR (CDCl ₃ ) δ: 7.45 - 7.22 (15H, m), 3.04 (2H, s).

Reference Example 2-(ii): {1-[(tritylthio)ethinyl]pyrrolidin-3-yl}carbamic acid tert-butyl ester

[Chem. 197] The compound of Reference Example 2-(i) (2.0 g, 5.98 mmol) and carbonyldiimidazole (1.01 g, 6.27 mmol) were dissolved in dichloromethane (30 mL) and stirred at room temperature for 45 min. Pyrrolidin-3-ylaminocarbamic acid tert-butyl ester (1.16 g, 6.27 mmol) was added to the reaction mixture, and stirred at room temperature for 3 hr. The reaction liquid was distilled off under reduced pressure, and the obtained residue was purified by hexane column chromatography (eluent: petroleum ether / ethyl acetate = 70/30 to 50/50) to obtain the title compound ( 2.8 g).

¹ H-NMR (CDCl ₃ ) δ : 7.48 - 7.43 (6H, m), 7.35 - 7.28 (6H, m), 7.26 - 7.19 (3H, m), 4.59 - 4.45 (1H, m), 4.19 - 4.06 ( 1H, m), 3.63 - 3.39 (2H, m), 3.33 - 3.22 (1H, m), 3.16 - 3.06 (1H, m), 2.95 - 2.83 (2H, m), 2.15 - 1.97 (1H, m), 1.87 - 1.65 (1H, m), 1.45 (9H, s), 1.44 (9H, s).

Reference Example 2: [1-(thioethenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

[Chem. 198] Triethyl decane (0.3 mL) was added to a solution of the compound (500 mg. Then, TFA (1 mL) was added, and the mixture was stirred at 15 ° C for 20 hours. Triethylamine (2.2 mL) was added to the reaction mixture at the same temperature to adjust the pH to 9, and the obtained solution was directly used for the next reaction.

Reference Examples 3 to 17 Reaction, post-treatment, and purification were carried out in the same manner as in the method described in Reference Example 2 to obtain the compound shown in Table (2).

[Table 2]

Reference Example 18: 2-[(Tertibutoxycarbonyl)oxy]-3-{(2R)-2-{[2-trioxy-2-(pyrrolidin-1-yl)ethyl]sulfide }}-2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylene-1,3,2-benzodioxaborolan Alkyl-2-yl]ethyl}benzoic acid tert-butyl ester

[Chem. 199]

Reference Example 18-(i): 3-(bromomethyl)-2-[(t-butoxycarbonyl)oxy]benzoic acid tert-butyl ester [Chem. 200] Commercially available tert-butyl 2-[(t-butoxycarbonyl)oxy]-3-methylbenzoate (14.76 g, 47.9 mmol) and N-bromosuccinimide at room temperature ( To a solution of 9.37 g, 52.7 mmol) of carbon tetrachloride (120 mL) was added dropwise benzamidine peroxide (1.16 g, 4.79 mmol), and stirred at 80 °C. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (13.58 g).

¹ H-NMR (CDCl ₃ ) δ: 7.86 (1H, dd, J = 7.8, 1.8 Hz), 7.53 (1H, dd, J = 7.8, 1.8 Hz), 7.27 - 7.19 (1H, m), 4.48 (1H , s), 1.55 (18H, s).

Reference Example 18-(ii): 2-[(Tertibutoxycarbonyl)oxy]-3-{[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4 , 6-methylene-1,3,2-benzodioxoborolan-2-yl]methyl}benzoic acid tert-butyl ester [Chem. 201] Reference compound 18-(i) (3.35 g, 8.65 mmol), bis[(+)-nonanediol] diboron (2.82 g, 7.86 mmol), [1,1'- under a nitrogen atmosphere. A solution of bis(diphenylphosphino)ferrocene]dichloropalladium(II) (288 mg, 0.393 mmol) and potassium acetate (2.32 g, 23.59 mmol) in DME (39 mL) was heated under reflux for 8 hours. After cooling the reaction mixture to room temperature, it was diluted with a mixed solution of n-hexane and ethyl acetate (1/1) (50 mL), and the insoluble matter was filtered off, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (yield: n-hexane / ethyl acetate = 90/10) to give the title compound (2.90 g).

¹ H-NMR (CDCl ₃ ) δ: 7.68 (1H, dd, J = 7.8, 1.8 Hz), 7.41 - 7.36 (1H, m), 7.15 - 7.09 (1H, m), 4.23 (1H, dd, J = 8.9, 2.1 Hz), 2.30 - 2.12 (2H, m), 2.26 (2H, s), 2.02 - 1.97 (1H, m), 1.89 - 1.76 (2H, m), 1.53 (18H, s), 1.36 (3H , s), 1.25 (3H, s), 1.16 (1H, d, J = 11.0 Hz), 0.79 (3H, s).

Reference Example 18-(iii): 2-[(Tertibutoxycarbonyl)oxy]-3-{(2S)-2-chloro-2-[(3aS,4S,6S,7aR)-3a,5 ,3-trimethylhexahydro-4,6-methylene-1,3,2-benzodioxolanecyclopentan-2-yl]ethyl}benzoic acid tert-butyl ester [Chem. 202] A solution of 2.7 mol/L n-butyllithium/n-hexane (0.808 mL, 2.16 mmol) was added dropwise to a solution of dichloromethane (0.23 mL) in THF (8 mL) over 30 min. A solution of the compound of Example 18-(ii) (700 mg, 1.44 mmol) in THF (2 mL) was applied dropwise. 0.5 mol/L zinc chloride/THF solution (4.03 mL, 2.12 mmol) was added to the reaction solution at the same temperature. The reaction solution was warmed to room temperature and stirred for 18 hours. After completion of the reaction, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 90/10 to 85/15) to give the title compound (568 mg). .

¹ H-NMR (CDCl ₃ ) δ: 7.79 (1H, dd, J = 7.8, 1.8 Hz), 7.48 - 7.44 (1H, m), 7.20 - 7.14 (1H, m), 4.34 (1H, dd, J = 8.7, 1.8 Hz), 3.68 - 3.61 (1H, m), 3.26 - 3.17 (1H, m), 3.08 - 2.99 (1H, m), 2.36 - 2.24 (1H, m), 2.22 - 2.13 (1H, m) , 2.07 - 2.02 (1H, m), 1.92 - 1.81 (2H, m), 1.54 (9H, s), 1.53 (9H, s), 1.35 (3H, s), 1.26 (3H, s), 1.08 (1H , d, J = 11.0 Hz), 0.81 (3H, s).

Reference Example 18: 2-[(Tertibutoxycarbonyl)oxy]-3-{(2R)-2-{[2-trioxy-2-(pyrrolidin-1-yl)ethyl]sulfide }}-2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylene-1,3,2-benzodioxaborolan Alkyl-2-yl]ethyl}benzoic acid tert-butyl ester

[化203] Triethylamine was added dropwise to a solution of the compound of Reference Example 18-(iii) (0.11 g, 0.206 mmol) and the compound of Example 1 (0.045 g, 0.308 mmol) in dichloromethane (1.4 mL) 0.057 mL, 0.411 mmol), and the reaction was stirred at room temperature for 21 h. Ethyl acetate was added to the reaction mixture, and the precipitated insoluble matter was filtered off. The filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol = 99/1 to 95/5) to give the title compound (90 mg).

¹ H-NMR (CDCl ₃ ) δ : 7.74 (1H, dd, J = 7.9, 1.8 Hz), 7.49 (1H, dd, J = 7.6, 1.5 Hz), 7.14 (1H, t, J = 7.6 Hz), 4.30 - 4.21 (1H, m), 3.51 - 3.37 (5H, m), 3.33 (2H, s), 3.08 - 2.87 (2H, m), 2.65 - 2.56 (1H, m), 2.34 - 2.21 (1H, m ), 2.15 - 2.05 (1H, m), 2.04 - 1.96 (1H, m), 1.93 - 1.76 (5H, m), 1.53 (9H, s), 1.52 (9H, s), 1.34 (3H, s), 1.24 (3H, s), 1.01 (1H, d, J = 11.0 Hz), 0.79 (3H, s).

Reference Example 19: (3aS, 4S, 6S, 7aR)-2-(bromomethyl)-3a,5,5-trimethylhexahydro-4,6-methylene-1,3,2-benzo Dioxaborolane [Chem. 204] Add (1S,2S,5S)-2,6,6-trimethylbicyclo[3.1.1] to a solution of diisopropyl (bromomethyl)borate (6.21 g, 11.2 mmol) in THF (25 mL) A solution of heptane-2,3-diol (4.76 g, 27.9 mmol) in THF (15 mL). Water (50 mL) was added to the reaction mixture, and extracted with ethyl acetate (60 mL×3×). The organic layer was washed with saturated brine (50 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give the title compound (4.46 g).

¹ H NMR (CDCl ₃ ) δ ; 4.39 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 2.66 (s, 3H), 2.33 - 2.42 (m, 2H), 2.07 - 2.13 (m, 1H), 1.88 - 1.97 (m, 2H), 1.44 (s, 3H), 1.31 (s, 3H), 1.22 (d, J = 11.2 Hz, 1 H), 0.86 (s, 3H).

Reference Example 20: 3-{(2R)-2-[(2-{3-[(Tertibutoxycarbonyl)amino]pyrrolidin-1-yl}-2-oxoethyl)thio] -2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylene-1,3,2-benzodioxolane- 2-butyl]ethyl}-2-[(t-butoxycarbonyl)oxy]-6-methoxybenzoic acid tert-butyl ester [Chem. 205] Reference Example 20-(i): 3-bromo-2-hydroxy-6-methoxybenzoic acid [Chem. 206] Bromine (1.35 mL, 24.7 mmol) was added dropwise to a solution of 2,6-dimethoxybenzoic acid (4.5 g, 24.7 mmol) in dichloromethane (90 mL). The reaction solution was warmed to room temperature and stirred for 30 hours. The reaction liquid was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0/100 to 80/20) to obtain the title compound ( 3.06 g).

¹ H NMR (CDCl ₃ ) δ ; 12.95 (1H, s), 11.36 (1H, br s), 7.69 (1H, d, J = 8.8 Hz), 6.47 (1H, d, J = 8.8 Hz), 4.10 (3H , s).

Reference Example 20-(ii): 3-Butyl-2-[(t-butoxycarbonyl)oxy]-6-methoxybenzoic acid tert-butyl ester [Chem. 207] To a solution of the compound of Example 20-(i) (12.8 g, 42.2 mmol) in dichloromethane (60 mL), di-t-butyl-di-dicarbonate (7.34 g, 33.7 mmol) and DMAP (1.53 g, 12.6) (mmol), the reaction was stirred at room temperature for 3 hours. The reaction solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0/100 to 15/85). 16.2 g).

¹ H NMR (CDCl ₃ ) δ ; 7.53 (1H, d, J = 7.2 Hz), 6.73 (1H, d, J = 7.2 Hz), 3.85 (3H, s), 1.59 (9H, s), 1.57 (9H, s).

Reference Example 20-(iii): 2-[(Tertibutoxycarbonyl)oxy]-6-methoxy-3-{[(3aS,4S,6S,7aR)-3a,5,5-III Methylhexahydro-4,6-methylene-1,3,2-benzodioxoborolan-2-yl]methyl}benzoic acid tert-butyl ester [Chem. 208] The suspension of pre-activated zinc powder (40 g, 612 mmol), the compound of Reference Example 19 (10 g, 36.6 mmol) in THF (100 mL) was slowly added dropwise 1.5 mol/L under nitrogen atmosphere. Diisobutylaluminum hydride / toluene solution (4.9 mL, 7.35 mmol). A solution of the compound of Example 19 (56 g, 205 mmol) in THF (200 mL) was applied dropwise. Heating was carried out while maintaining the reaction liquid at 45 ° C or higher, and THF (100 mL) was slowly added thereto, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was slowly added dropwise to the compound of Example 20-(ii) (40 g, 99 mmol) and bis(tri-tert-butylphosphine)palladium(0) (1.83 g, 3.59 mmol) of THF (600) In a solution of mL), stir at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography (ethyl acetate / n-hexane) to give the title compound (43.5 g).

¹ H-NMR (CDCl ₃ ) δ : 7.28 - 7.20 (1H, m), 6.73 (1H, d, J = 8.8 Hz), 4.26 (1H, dd, J = 8.9, 2.1 Hz), 3.79 (3H, s ), 2.36 - 2.09 (2H, m), 2.13 (s, 2H), 2.04 - 1.98 (1H, m), 1.91 - 1.82 (2H, m), 1.63 - 1.49 (1H, m), 1.56 (s, 9H ), 1.53 (s, 9H), 1.38 (s, 3H), 0.824 (6H, s).

Reference Example 20-(iv): 2-[(Tertibutoxycarbonyl)oxy]-3-{(2S)-2-chloro-2-[(3aS,4S,6S,7aR)-3a,5 ,5-trimethylhexahydro-4,6-methylene-1,3,2-benzodioxaborolan-2-yl]ethyl}-6-methoxybenzoic acid Butyl ester A 2.5 mol/L n-butyllithium/hexane solution was added dropwise to a solution of dichloromethane (0.35 mL, 5.79 mmol) in THF (10 mL) under argon and at -85 °C to -100 °C. 1 mL, 2.31 mmol), stirred at -100 °C for 30 minutes. A solution of the compound of Example 20-(iii) (1 g, 1.93 mmol) in THF (4 mL) was applied dropwise. Then, a 1 mol/L zinc chloride/THF solution (1.93 mL, 1.93 mmol) was added dropwise over 10 minutes, and the reaction mixture was warmed to room temperature and stirred for 22 hours. A saturated aqueous solution of ammonium chloride (20 mL) was added to the mixture, and the mixture was applied to ethyl acetate (25 mL×3×). The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate) to give the title compound (820 mg).

¹ H-NMR (CDCl ₃ ) δ : 7.33 (1H, d, J = 8.8 Hz), 6.76 (1H, d, J = 8.8 Hz), 4.40 - 4.35 (1H, m), 3.83 (3H, s), 3.68 (1H, t, J = 7.6 Hz), 3.18 - 3.09 (1H, m), 2.98 - 2.88 (1H, m), 2.40 - 2.16 (1H, m), 2.11 - 2.03 (1H, m), 1.97 - 1.83 (2H, m), 1.58 (9H, s), 1.54 (9H, s), 1.39 (3H, s), 1.30 (3H, s), 1.12 (1H, d, J = 11.2 Hz), 0.85 (3H , s).

Reference Example 20: 3-{(2R)-2-[(2-{3-[(Tertibutoxycarbonyl)amino]pyrrolidin-1-yl}-2-oxoethyl)thio] -2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylene-1,3,2-benzodioxolane- 3-butyl]ethyl}-2-[(t-butoxycarbonyl)oxy]-6-methoxybenzoic acid tert-butyl ester [Chem. 210] A solution of the compound of Example 20-(iv) (240 mg, 0.424 mmol) in dichloromethane (10 mL) The reaction liquid was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 80/20 to 20/80) to obtain the title compound ( 170 mg).

¹ H-NMR (CDCl ₃ ) δ : 7.37 - 7.29 (1H, m), 6.80 - 6.72 (1H, m), 5.09 - 4.64 (1H, m), 4.36 - 4.17 (2H, m), 3.82 (3H, s), 3.74 - 3.42 (3H, m), 3.35 - 3.16 (3H, m), 2.83 - 2.70 (1H, m), 2.65 - 2.51 (1H, m), 2.37 - 2.25 (1H, m), 2.21 - 1.99 (4H, m), 1.92 - 1.80 (2H, m), 1.57 (9H, s), 1.54 (9H, s), 1.45 (9H, s), 1.38 (3H, s), 1.28 (3H, s) , 1.13 - 0.97 (1H, m), 0.83 (s, 3H).

LCMS: [M+H] ⁺ /Rt=789.5/2.13 ^C

Reference Examples 21 to 35 The reaction, post-treatment, and purification were carried out in the same manner as in the method described in Reference Example 20 to obtain the compound shown in Table (3).

[Table 3-1] [Table 3-2] [Table 3-3]

Reference Example 36: 3-{(2R)-2-[(2-{3-[(Tertoxycarbonyl)amino]pyrrolidin-1-yl}-2-oxoethyl)thio] -2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylene-1,3,2-benzodioxolane- 2-butyl]ethyl}-2-[(t-butoxycarbonyl)oxy]-6-(methylthio)benzoic acid tert-butyl ester [Chem. 211]

Reference Example 36-(i): T-butyl 2-bromo-5-fluorophenyl carbonate [Chem. 212] DMAP (0.277 g, 2.26 mmol) was added to a mixture of 2-bromo-5-fluorophenol (5.0 mL, 45.3 mmol) and di-tert-butyl dicarbonate (12.62 mL, 54.3 mmol) at room temperature. Stir for 4 hours. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (yield: ethyl acetate/hexane) to give the title compound (12.5 g).

¹ H-NMR (CDCl ₃ ) δ: 7.53 (1H, dd, J = 8.9, 5.8 Hz), 6.98 (1H, dd, J = 8.9, 2.7 Hz), 6.87 (1H, td, J = 8.2, 3.1 Hz ), 1.55 (9H, s).

Reference Example 36-(ii): 3-Butyl-2-[(t-butoxycarbonyl)oxy]-6-fluorobenzoic acid tert-butyl ester [Chem. 213] LDA (34 mL, 68.0 mmol) was added dropwise to a solution of the compound (12.14 g, 41.7 mmol) in THF (85 mL). After the dropwise addition, the reaction solution was warmed to room temperature and stirred for 2 hours. 1 mol/L hydrochloric acid (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was dissolved in dichloromethane (112 mL), and di-t-butyl dicarbonate (12.55 mL, 54.1 mmol) and DMAP (0.52 g, 4.26) were added at room temperature. Mmmol) and stirred for 20 hours. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound (12.6 g).

¹ H-NMR (CDCl ₃ ) δ : 7.58 (1H, dd, J = 9.2, 5.5 Hz), 6.92 (1H, t, J = 8.9 Hz), 1.55 (9H, s), 1.54 (9H, s).

Reference Example 36-(iii): 3-bromo-2-[(t-butoxycarbonyl)oxy]-6-(methylthio)benzoic acid tert-butyl ester [Chem. 214] A solution of the compound of Example 36-(ii) (3.0 g, 7.67 mmol) and sodium methylthiolate (1.08 g, 15.34 mmol) in DMF (20 mL) was stirred at room temperature for 5.5 hr. The reaction mixture was evaporated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give the title compound (0.86 g).

¹ H-NMR (CDCl ₃ ) δ : 7.52 (1H, d, J = 8.5 Hz), 7.03 (1H, d, J = 8.5 Hz), 2.44 (3H, s), 1.58 (9H, s), 1.54 ( 9H, s).

Reference Example 36-(iv): 2-[(Tertibutoxycarbonyl)oxy]-6-(methylthio)-3-{[(3aS,4S,6S,7aR)-3a,5, 3-trimethylhexahydro-4,6-methylene-1,3,2-benzodioxoborolan-2-yl]methyl}benzoic acid tert-butyl ester [Chemical 215] Using the compound of Reference Example 36-(iii) (1.31 g, 3.13 mmol) as a starting material, the title compound was obtained by the same method as the method described in Reference Example 20-(iii). (1.6 g).

¹ H-NMR (CDCl ₃ ) δ : 7.28 - 7.20 (1H, m), 7.10 (1H, d, J = 7.9 Hz), 4.29 - 4.21 (1H, m), 2.41 (3H, s), 2.32 - 2.11 (2H, m), 2.16 (2H, s), 2.04 - 1.97 (2H, m), 1.92 - 1.77 (2H, m), 1.57 (9H, s), 1.51 (9H, s), 1.36 (3H, s ), 1.26 (3H, s), 0.80 (3H, s).

Reference Example 36-(v): 2-[(Tertibutoxycarbonyl)oxy]-3-{(2S)-2-chloro-2-[(3aS,4S,6S,7aR)-3a,5 ,5-trimethylhexahydro-4,6-methylene-1,3,2-benzodioxaborolan-2-yl]ethyl}-6-(methylthio)benzene T-butyl formate [Chemical 216] Using the compound of Reference Example 36-(iv) (1.56 g) as a starting material, the title compound (1.36 g) was obtained by the same procedure as the method described in Reference Example 20-(iv). ).

¹ H-NMR (CDCl ₃ ) δ : 7.32 (1H, d, J = 8.5 Hz), 7.10 (1H, d, J = 7.9 Hz), 4.39 - 4.30 (1H, m), 3.70 - 3.62 (1H, m ), 3.19 - 3.08 (1H, m), 2.99 - 2.88 (1H, m), 2.43 (3H, s), 2.38 - 2.26 (1H, m), 2.24 - 2.13 (2H, m), 2.08 - 1.98 (1H , m), 1.94 - 1.81 (1H, m), 1.58 (9H, s), 1.52 (9H, s), 1.36 (3H, s), 1.27 (3H, s), 1.09 (1H, d, J =11.0) Hz), 0.82 (3H, s).

Reference Example 36: 3-{(2R)-2-[(2-{3-[(Tertoxycarbonyl)amino]pyrrolidin-1-yl}-2-oxoethyl)thio] -2-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylene-1,3,2-benzodioxolane- 3-butyl]ethyl}-2-[(t-butoxycarbonyl)oxy]-6-(methylthio)benzoic acid tert-butyl ester [Chem. 217] Using the compound of Example 36-(v) (100 mg) as a starting material, the title compound (83 mg) was obtained.

LCMS: [M+H] ⁺ /Rt=805/1.245 min ^A

Reference Examples 37 to 64 The compounds shown in Table (3A) were obtained by a reaction, a post-treatment, and purification in the same manner as in the method of Reference Example 2.

[Table 3A-1] [Table 3A-2] [Table 3A-3] [Table 3A-4] [Table 3A-5]

Reference Examples 65 to 93 The compounds shown in Table (3B) were obtained by the same procedures as those in Reference Example 20, followed by the reaction, the workup, and the purification.

[Table 3B-1] [Table 3B-2] [Table 3B-3] [Table 3B-4] [Table 3B-5] [Table 3B-6] [Table 3B-7] [Table 3B-8] [Table 3B-9] [Table 3B-10] [Table 3B-11] [Table 3B-12]

Reference Example 93: 3-((2R)-2-((2-(3-((t-butoxycarbonyl))amino)-4-methylpyrrolidin-1-yl)-2-oxoxy Thio)-2-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylenebenzo-1,3,2-dioxa Boracyclopentan-2-yl)ethyl)-2-((t-butoxycarbonyl)oxy)-6-methoxybenzoic acid tert-butyl ester [Chem. 218]

Reference Example 93-(i): 3-((R)-2-((2-(Benzyloxy)-2-oxoethyl)thio)-2-((3aS,4S,6S,7aR) -3a,5,5-trimethylhexahydro-4,6-methylenebenzo-1,3,2-dioxaborolan-2-yl)ethyl)-2-(( Third butanyloxycarbonyl)oxy)-6-methoxybenzoic acid [Chem. 219] Add a solution of the compound of Example 20-(iv) (0.102 g, 0.181 mmol) and benzyl benzyl acetate (0.049 g, 0.271 mmol) in dichloromethane (0.90 mL). The reaction solution was stirred at room temperature for 16 hours. The reaction liquid was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0/100 to 80/20) to obtain the title compound ( 0.096 g).

¹ H-NMR (CDCl ₃ ) δ : 7.28 - 7.24 (5H, m), 7.19 (1H, d, J = 8.5 Hz), 6.62 (1H, d, J = 8.5 Hz), 5.08 (2H, s), 4.15 - 4.14 (1H, m), 3.72 (3H, s), 3.35 - 3.30 (2H, m), 2.82 - 2.73 (2H, m), 2.56 - 2.54 (1H, m), 2.19 - 2.17 (1H, m ), 2.03 - 2.01 (1H, m), 1.93 (1H, t, J = 5.5 Hz), 1.75 - 1.71 (2H, m), 1.49 (9H, s), 1.45 (9H, s), 1.26 (3H, s), 1.18 (3H, s), 0.88 (1H, d, J = 11.0 Hz), 0.73 (3H, s).

Reference Example 93-(ii): 2-(((R)-2-(3-(T-Butoxycarbonyl))-2-((t-butoxycarbonyl)oxy)-4-methoxy Phenyl)-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylenebenzo-1,3,2-dioxaboron Cyclopentan-2-yl)ethyl)thio)acetic acid [Chem. 220] 10% palladium on carbon (0.12 g) was added to a solution of the compound (96 mg, 0.135 mmol) in methanol (1.61 mL), and the mixture was stirred for 3 hours at room temperature under hydrogen atmosphere. . A few drops of 2N aqueous sodium hydroxide solution were added to the reaction mixture, and palladium carbon was removed by filtration through celite. A few drops of 1 N aqueous hydrochloric acid solution was added to the filtrate to make the solution acidic, and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and filtered, and the filtrate was evaporated under reduced pressure to give the title compound (0.058 g). The crude product was used in the next reaction without purification.

Reference Example 93: 3-((2R)-2-((2-(3-((t-butoxycarbonyl))amino)-4-methylpyrrolidin-1-yl)-2-oxoxy Thio)-2-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylenebenzo-1,3,2-dioxa Boracyclopentan-2-yl)ethyl)-2-((t-butoxycarbonyl)oxy)-6-methoxybenzoic acid tert-butyl ester [Chem. 221] The compound of Reference Example 93-(ii) (0.10 g, 0.161 mmol) and N-(4-methylpyrrolidin-3-yl)carbamic acid tert-butyl ester (0.048 g, 0.242 mmol) HATU (0.092 g, 0.242 mmol) was added to a solution of triethylamine (0.045 mL, 0.322 mmol) in DMF (1.61 mL). The reaction solution was stirred for 30 hours. The reaction liquid was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0/100 to 80/20) to obtain the title compound ( 0.055 g).

¹ H-NMR (CDCl3) δ : 7.33 - 7.31 (1H, m), 6.79 - 6.77 (1H, m), 5.45 - 5.38 (1H, m), 4.30 - 4.27 (1H, m), 3.82 (3H, s ), 3.72 - 3.68 (2H, m), 3.62 - 3.57 (2H, m), 3.42 - 3.40 (1H, m), 3.34 - 3.21 (2H, m), 3.18 - 3.03 (2H, m), 2.97 - 2.92 (1H, m), 2.81 - 2.77 (1H, m), 2.60 - 2.59 (1H, m), 2.34 - 2.32 (1H, m), 2.16 - 2.15 (1H, m), 2.02 - 2.01 (1H, m) , 1.87 - 1.83 (2H, m), 1.56 (9H, s), 1.53 (9H, s), 1.45 (9H, s), 1.36 (3H, s), 1.27 (3H, s), 1.02 - 0.99 (3H , m), 0.82 (3H, s).

Reference Example 94: 3-((2R)-2-((2-(3-((t-butoxycarbonyl)amino)pyrrolidin-1-yl)-2-oxoethyl)thio) -2-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylenebenzo-1,3,2-dioxaborolane 2-butyl)ethyl)-2-((t-butoxycarbonyl)oxy)-6-(1H-1,2,3-triazol-1-yl)benzoic acid tert-butyl ester 212A]

Reference Example 94-(i): 5-Butyl 2-methylphenyl carbonate (Chemical 213A) Add di-tert-butyl dicarbonate (15.7 g, 71.9 mmol) and DMAP (0.368 g, 3.01) to a solution of 5-bromo-2-methylphenol (11.2 g, 59.9 mmol) in dichloromethane (120 mL). (mmol), the reaction was stirred at room temperature for 6 hours. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (yield: petroleum ether / ethyl acetate) to give the title compound (15.7 g).

¹ H-NMR (CDCl ₃ ) δ : 7.26 - 7.24 (2H, m), 7.07 (1H, d, J = 7.9 Hz), 2.15 (3H, s), 1.53 (9H, s).

Reference Example 94-(ii): 3-Butyl 2-bromo-2-hydroxy-3-methylbenzoate [Chemical 214A] A 2N solution of lithium diisopropylamide (32.1 mL, 64.2 mmol) was added to a solution of the compound (15.4 g, 53.5 mmol) in THF (155 mL). After the reaction mixture was stirred at -78 ° C for 1 hour, the mixture was warmed to room temperature and stirred for 1 hour. A 1 N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, and the filtrate was distilled off under reduced pressure, and the obtained residue was purified by a gel column chromatography (eluent: petroleum ether / ethyl acetate). The title compound (13.7 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 11.20 (1H, s), 7.04-7.02 (2H, m), 2.17 (3H, s), 1.63 (9H, s).

Reference Example 94-(iii): 6-azido-2-hydroxy-3-methylbenzoic acid tert-butyl ester [Chemical 215A] Add sodium azide (1.35 g, 20.8 mmol), N, N'- to a mixed solution of the compound of Example 94-(ii) (2.82 g, 9.82 mmol) in ethanol (11.7 mL) / water (5 mL) Dimethylethylenediamine (0.138 g, 1.57 mmol), copper (I) iodide (0.187 g, 0.982 mmol) and sodium ascorbate (0.103 g, 0.520 mmol). The reaction solution was stirred at 80 ° C for 3 hours under a nitrogen atmosphere. After cooling to room temperature, a 0.2 N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, and the filtrate was distilled off under reduced pressure, and the obtained residue was purified by a gel column chromatography (eluent: petroleum ether / ethyl acetate). The title compound (2.09 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ : 11.52 (1H, s), 7.15 (1H, d, J = 8.5 Hz), 6.54 (1H, d, J = 8.5 Hz), 2.15 (3H, d, J = 6.7 Hz), 1.56 (9H, d, J = 1.8 Hz).

Reference Example 94-(iv): 6-azido-2-((t-butoxycarbonyl)oxy)-3-methylbenzoic acid tert-butyl ester [Chem. 216A] To a solution of the compound of Example 94-(iii) (4.30 g, 17.3 mmol) in dichloromethane (40 mL), di-t-butyl succinate (3.76 g, 17.3 mmol) and DMAP (0.316 g, 2.59) (mmol), the reaction was stirred at room temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate) to give the title compound (5.46 g).

¹ H-NMR (CDCl ₃ ) δ: 7.22 (1H, d, J = 8.5 Hz), 6.96 (1H, d, J = 8.5 Hz), 2.17 (3H, s), 1.56 (9H, s), 1.52 ( 9H, s).

Reference Example 94-(v): 6-azido-3-(bromomethyl)-2-((t-butoxycarbonyl)oxy)benzoic acid tert-butyl ester [Chem. 217A] N-bromosuccinimide (2.57 g, 14.5 mmol) and benzamidine peroxide were added to a solution of the compound of Example 94-(iv) (5.05 g, 14.5 mmol) in carbon tetrachloride (50 mL). 0.467 g, 1.45 mmol), the reaction solution was stirred under reflux with heating for 8 hr. After cooling to room temperature, it was filtered, and the filtrate was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate) to give the title compound ( 4.52 g).

¹ H-NMR (CDCl ₃ ) δ: 7.41 (1H, d, J = 8.5 Hz), 7.00 (1H, d, J = 8.5 Hz), 4.33 (2H, s), 1.51 (9H, s), 1.48 ( 9H, s).

Reference Example 94-(vi): 6-azido-2-((t-butoxycarbonyl)oxy)-3-(((3aS,4S,6S)-3a,5,5-trimethyl) Hexabutyl hexahydro-4,6-methylenebenzo-1,3,2-dioxaborolan-2-yl)methyl)benzoate [Chemical 218A] Add bis[(+) decane in a mixed solution of the compound of Example 94-(v) (4.35 g, 10.2 mmol) in dioxane (45 mL) / dimethyl hydrazine (9 mL) under a nitrogen atmosphere. Diol]diborane (7.27 g, 20.3 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (1.66 g, 2.03 mmol) and potassium acetate (2.99 g, 30.5) (mmol), the reaction solution was stirred under heating and reflux for 4 hours. After cooling to room temperature, the reaction liquid was distilled off under reduced pressure, and water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was distilled off under reduced pressure, and the obtained residue was purified by a silica gel column chromatography (eluent: petroleum ether / ethyl acetate). This gave the title compound (1.00 g).

¹ H-NMR (CDCl ₃ ) δ : 7.31 (1H, d, J = 8.5 Hz), 6.96 (1H, d, J = 8.5 Hz), 4.25 - 4.23 (1H, m), 2.30 - 2.22 (1H, m ), 2.19 - 2.14 (2H, m), 2.00 (1H, t, J = 5.8 Hz), 1.90 - 1.85 (3H, m), 1.55 (9H, s), 1.51 (9H, s), 1.36 (3H, s), 1.26 (3H, s), 1.16 (1H, d, J = 11.0 Hz), 0.80 (3H, s).

Reference Example 94-(vii): 6-azido-2-((t-butoxycarbonyl)oxy)-3-((S)-2-chloro-2-((3aS, 4S, 6S, 7aR)-3a,5,5-trimethylhexahydro-4,6-methylenebenzo-1,3,2-dioxaborolan-2-yl)ethyl)benzoic acid Tributyl ester [Chemical 219A] 1.55 mol/L n-butyllithium solution (2.05) was added dropwise to a solution of dichloromethane (0.34 mL, 5.29 mmol) in THF (2 mL) at -90 °C - -100 °C over 50 min. mL, 3.17 mmol), stirred at -100 °C for 50 minutes. A solution of the compound of Example 94-(vi) (0.93 g, 1.76 mmol) in THF (2 mL) was applied dropwise. After stirring at -90 ° C to -100 ° C for 30 minutes, the reaction solution was warmed to room temperature and stirred for 3 hours. A saturated aqueous solution of ammonium chloride (20 mL) was added to the mixture, and the mixture was applied to ethyl acetate (25 mL×3×). The organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate) to give the title compound (0.73 g).

¹ H-NMR (CDCl ₃ ) δ : 7.39 (1H, d, J = 8.5 Hz), 6.99 (1H, d, J = 8.5 Hz), 4.35 - 4.33 (1H, m), 3.65 (1H, t, J = 7.6 Hz), 3.14 (1H, dd, J = 14.6, 6.7 Hz), 2.95 (1H, dd, J = 14.6, 8.5 Hz), 2.35 - 2.30 (1H, m), 2.21 - 2.15 (1H, m) , 2.07 - 2.03 (1H, m), 1.91 - 1.84 (2H, m), 1.57 (9H, s), 1.52 (9H, d, J = 3.7 Hz), 1.37 (3H, s), 1.28 (3H, s ), 1.10 (1H, d, J = 11.0 Hz), 0.83 (3H, s).

Reference Example 94-(viii): 6-azido-3-((2R)-2-((2-(3-((t-butoxycarbonyl))amino)pyrrolidin-1-yl)-) 2-sided oxyethyl)thio)-2-((3aS,4S,6S)-3a,5,5-trimethylhexahydro-4,6-methylenebenzo-1,3,2- Dioxaborolan-2-yl)ethyl)-2-((t-butoxycarbonyl)oxy)benzoic acid tert-butyl ester [Chem. 220A] The title compound (0.105 g) was obtained from the title compound (0.105 g).

¹ H-NMR (CDCl ₃ ) δ : 7.38 - 7.35 (1H, m), 6.96 - 6.93 (1H, m), 4.71 - 4.52 (1H, m), 4.23 - 4.19 (1H, m), 4.19 - 4.12 ( 1H, m), 3.63 - 3.59 (1H, m), 3.52 - 3.37 (2H, m), 3.27 - 3.15 (3H, m), 2.92 - 2.85 (1H, m), 2.79 - 2.73 (1H, m), 2.58 - 2.52 (1H, m), 2.25 - 2.21 (1H, m), 2.14 - 2.09 (2H, m), 1.97 - 1.94 (1H, m), 1.82 - 1.75 (2H, m), 1.50 (9H, s ), 1.46 (9H, s), 1.38 (9H, s), 1.31 (3H, s), 1.21 (3H, s), 1.00 - 0.98 (1H, m), 0.75 (3H, s).

Reference Example 94-(ix): 3-((2R)-2-((2-(3-((t-butoxycarbonyl))amino)pyrrolidin-1-yl)-2-oxoxyethyl )thio)-2-((3aS,4S,6S)-3a,5,5-trimethylhexahydro-4,6-methylenebenzo-1,3,2-dioxaborane Pentane-2-yl)ethyl)-2-((t-butoxycarbonyl)oxy)-6-(4-(trimethyldecyl)-1H-1,2,3-triazole- 1-butyl)benzoic acid tert-butyl ester [Chemical 221A] Add copper (I) iodide (125 mg, 0.655 mmol) and trimethyl to a solution of the compound of Example 94-(viii) (105 mg, 0.131 mmol) in dioxane (2 mL). The alkyl acetylene (0.182 mL, 1.31 mmol) was stirred at 80 ° C for 60 hours. After cooling to room temperature, the reaction liquid was filtered, and the filtrate was distilled off under reduced pressure, and the obtained residue was purified by a silica gel column chromatography (eluent: petroleum ether / ethyl acetate). The title compound (62.6 mg).

LCMS: [M+H] ⁺ =899.1/1.46 min ^A

Reference Example 94: 3-((2R)-2-((2-(3-((t-butoxycarbonyl)amino)pyrrolidin-1-yl)-2-oxoethyl)thio) -2-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylenebenzo-1,3,2-dioxaborolane 2-butyl)ethyl)-2-((t-butoxycarbonyl)oxy)-6-(1H-1,2,3-triazol-1-yl)benzoic acid tert-butyl ester 222] 1 mol/L of tributylammonium fluoride (0.27 mL, 0.27 mmol) was added to a solution of the compound of Example 94-(ix) (60.9 mg, 0.068 mmol) in THF (1 mL). Stir under 8 hours. A saturated aqueous solution of ammonium chloride (3 mL) was added to the mixture and the mixture was applied to diethyl ether (5 mL×3×). The organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate) to give the title compound (38.5 mg).

¹ H-NMR (CDCl ₃ ) δ : 7.51 - 7.49 (1H, m), 7.45 - 7.43 (1H, m), 7.25 - 7.21 (1H, m), 6.96 (1H, d, J = 7.9Hz), 4.50 - 4.34 (1H, m), 3.96 - 3.94 (1H, m), 3.86 - 3.84 (1H, m), 3.36 - 3.28 (1H, m), 3.24 - 3.02 (2H, m), 2.97 - 2.87 (3H, m), 2.73 - 2.70 (1H, m), 2.61 - 2.53 (1H, m), 2.34 - 2.30 (1H, m), 1.97 - 1.94 (1H, m), 1.79 - 1.74 (2H, m), 1.51 - 1.43 (3H, m), 1.19 (9H, s), 1.07 (9H, s), 1.02 (3H, s), 0.99 (9H, s), 0.91 (3H, s), 0.75 - 0.67 (1H, m) , 0.46 (3H, s).

Reference Example 95: 3-((2R)-2-((2-(3-((t-butoxycarbonyl)amino)pyrrolidin-1-yl)-2-oxoethyl)thio) -2-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylenebenzo-1,3,2-dioxaborolane 2-butyl)ethyl)-2-((t-butoxycarbonyl)oxy)-5-chloro-6-methoxybenzoic acid tert-butyl ester [Chem. 223]

Reference Example 95-(i): 3-bromo-5-chloro-2-hydroxy-6-methoxybenzoic acid [Chem. 224] To a solution of the compound of Example 20-(ii) (4.0 g, 9.92 mmol) in chloroform (60 mL) was added sulfonium chloride (4.02 mL, 49.6 mmol), and the reaction mixture was stirred at 50 ° C for 12 hours. After cooling to room temperature, pyridin-2-amine (0.1 g, 1.06 mmol) was added to the reaction mixture, and the mixture was stirred for 1 hr. ).

¹ H-NMR (CDCl ₃ ) δ: 12.52 (1H, s), 7.79 (1H, s), 4.11 (3H, s).

Reference Example 95-(ii): 3-bromo-2-((t-butoxycarbonyl)oxy)-5-chloro-6-methoxybenzoic acid tert-butyl ester [Chem. 225] Add a di-tert-butyl dicarbonate (6.64 g, 30.4 mmol) to a mixed solution of the compound of Example 95-(i) (2.14 g, 7.60 mmol) in tert-butanol (25 mL) / THF (25 mL) ), DMAP (0.093 g, 0.76 mmol) and potassium carbonate (2.63 g, 19.1 mmol), and the mixture was stirred under heating under reflux for 48 hours. After cooling to room temperature, the reaction liquid was filtered, and a 0.2N aqueous hydrochloric acid solution was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was distilled off under reduced pressure, and the obtained residue was purified by a silica gel column chromatography (eluent: petroleum ether / ethyl acetate). This gave the title compound (3.20 g).

¹ H-NMR (CDCl ₃ ) δ: 7.61 (1H, s), 3.90 (3H, s), 1.56 (9H, s), 1.53 (9H, s).

Reference Example 95-(iii): 2-((Tertidinoxycarbonyl)oxy)-5-chloro-6-methoxy-3-(((3aS,4S,6S,7aR)-3a,5 ,3-trimethylhexahydro-4,6-methylenebenzo-1,3,2-dioxaborolan-2-yl)methyl)benzoic acid tert-butyl ester ] Using the compound of Reference Example 95-(ii) (3.2 g) as a starting material, the title compound (2.81 g) was obtained by the same method as the method described in Reference Example 20-(iii). ).

¹ H-NMR (CDCl ₃ ) δ : 6.98 (1H, s), 3.99 (1H, dd, J = 8.6, 1.8 Hz), 3.61 (3H, s), 2.04 - 2.00 (1H, m), 1.94 - 1.91 (1H, m), 1.86 (2H, s), 1.75 (1H, t, J = 4.9 Hz), 1.63 - 1.54 (2H, m), 1.29 (9H, s), 1.24 (9H, s), 1.11 ( 3H, s), 1.00 (3H, s), 0.91 (1H, d, J = 11.0 Hz), 0.54 (3H, s).

Reference Example 95-(iv): 2-((Tertibutoxycarbonyl)oxy)-5-chloro-3-((S)-2-chloro-2-((3aS,4S,6S,7aR) -3a,5,5-trimethylhexahydro-4,6-methylenebenzo-1,3,2-dioxaborolan-2-yl)ethyl)-6-methoxy Tert-butyl benzoate [Chemical 227] Using the compound of Reference Example 95-(iii) (1.46 g) as a starting material, the title compound (1.35 g) was obtained by the same method as the method described in Reference Example 20-(iv). ).

¹ H-NMR (CDCl ₃ ) δ: 7.39 (1H, s), 4.36 - 4.35 (1H, m), 3.89 (3H, s), 3.62 (1H, t, J = 7.6 Hz), 3.09 (1H, dd , J = 14.4, 7.6 Hz), 2.92 (1H, dd, J = 14.4, 8.3 Hz), 2.34 - 2.29 (1H, m), 2.22 - 2.18 (1H, m), 2.05 (1H, t, J = 5.2 Hz), 1.90 - 1.83 (2H, m), 1.56 (9H, s), 1.51 (9H, s), 1.37 (3H, s), 1.27 (3H, s), 1.04 (1H, d, J = 11.0 Hz ), 0.82 (3H, s).

Reference Example 95: 3-((2R)-2-((2-(3-((t-butoxycarbonyl)amino)pyrrolidin-1-yl)-2-oxoethyl)thio) -2-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methylenebenzo-1,3,2-dioxaborolane 2-butyl)ethyl)-2-((t-butoxycarbonyl)oxy)-5-chloro-6-methoxybenzoic acid tert-butyl ester [Chem. 227A] The title compound (0.24 g) was obtained from the title compound (0.24 g).

¹ H-NMR (CDCl ₃ ) δ : 7.41 - 7.40 (1H, m), 4.76 - 4.74 (1H, br m), 4.29 - 4.27 (1H, m), 4.23 - 4.20 (1H, m), 3.87 (3H , s), 3.68 - 3.65 (1H, m), 3.53 - 3.46 (2H, m), 3.34 - 3.24 (3H, m), 2.92 - 2.80 (2H, m), 2.59 - 2.54 (1H, m), 2.30 - 2.27 (1H, m), 2.18 - 2.06 (1H, m), 2.00 - 1.99 (2H, m), 1.84 - 1.80 (2H, m), 1.55 (9H, s), 1.50 (9H, s), 1.42 (9H, s), 1.36 (3H, s), 1.24 (3H, s), 0.95 (1H, t, J = 5.5 Hz), 0.79 (3H, s).

Example 1: (3R)-4,4-Dihydroxy-3-{[2-(3-Aminopyrrolidin-1-yl)-2-oxoethyl]thio}-8-methoxy -5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid disodium salt [Chem. 228] TFA (2 mL) and triethyl decane (0.3 mL) were added to the compound of Example 20 (140 mg, 0.177 mmol), and stirred at 45 ° C for 1.2 hours. The reaction liquid was distilled off under reduced pressure, and the pH was adjusted to 10 by adding a 1 mol/L aqueous sodium hydroxide solution and a saturated aqueous sodium hydrogencarbonate solution to the obtained residue at 0 °C. The mixed suspension was filtered, and the filtrate was purified by reverse phase column chromatography (eluent: acetonitrile/water) to give the title compound (41 mg).

¹ H-NMR (D ₂ O) δ : 6.86 (d, 1H, J = 8.0 Hz), 6.32 (d, 1H, J = 8.0 Hz), 3.97 - 3.56 (6H, m), 3.53 - 3.41 (2H, m), 3.09 - 3.32 (2H, m), 3.00 - 2.88 (1H, m), 2.74 - 2.61 (1H, m) 2.38 - 2.14 (1H, m), 2.13 - 1.86 (2H, m).

Example 2: (3R)-2-hydroxy-7-methoxy-3-{[2-o-oxy-2-(pyrrolidin-1-yl)ethyl]thio}-3,4-di Hydrogen-2H-1,2-benzoxoxaboryl-8-carboxylic acid [Chemical 229] Phenylboronic acid (9.1 mg, 0.074 mmol), 5 mol/L hydrochloric acid (0.163 mL, 0.816 mmol), and hexane were added to a solution of the compound of Example 21 (50 mg, 0.074 mmol) in acetonitrile (0.7 mL). 0.7 mL) and stirred at room temperature for 8 hours. After standing and separating the two layers, the upper layer of hexane was removed, and the acetonitrile layer was distilled off under reduced pressure using reverse phase column chromatography (eluent: water/acetonitrile = 1/99 to 95/5). The residue obtained was purified to give the title compound (7.3 mg).

¹ H-NMR (CD ₃ OD) δ: 7.00 (1H, d, J = 8.5 Hz), 6.42 (1H, d, J = 8.5 Hz), 3.78 (3H, s), 3.73 - 3.65 (4H, m) , 3.34 (2H, s), 3.02 - 2.93 (1H, m), 2.67 - 2.58 (1H, m), 2.43 - 2.37 (1H, m), 2.12 - 1.96 (4H, m). LCMS:[M+H] ⁺ /Rt=366/0.647 min ^A

Examples 3 to 17 The corresponding reference compounds 18 and 22 to 35 were used as starting materials, and the reaction, post-treatment, and purification were carried out in the same manner as in the methods described in Example 1 and Example 2 to obtain a table ( 4) The compound shown.

[Table 4-1] [Table 4-2]

The names of the compounds of Examples 3 to 17 are shown below. (3R)-2-hydroxy-3-{[2-o-oxy-2-(pyrrolidin-1-yl)ethyl]thio}-3,4-dihydro-2H-1,2-benzo Oxaborylcyclo-8-carboxylic acid (Example 3) (3R)-4,4-dihydroxy-3-{[1-o-oxy-1-(pyrrolidin-1-yl)propane-2 -yl]thio}-8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid disodium salt (Example 4) (3R)-4,4-Dihydroxy-3-{[2-(4-methylpiperazin-1-yl)-2-oxoethyl]thio}-8-methoxy 5-Ooxa-4-boroanion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid disodium salt (Example 5) (3R)-4, 4-Dihydroxy-3-{[2-(3-methoxyazetidin-1-yl)-2-oxoethyl]thio}-8-methoxy-5-oxa-4- Boron anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid disodium salt (Example 6) (3R)-4,4-dihydroxy-3-{[ 2-(3-Aminoazetidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid disodium salt (Example 7) (3R)-2-hydroxy-7-methoxy-3-{[2-sideoxy-2 -(piperazin-1-yl)ethyl]thio}-3,4-dihydro-2H-1,2-benzoxoxaborox-8-carboxylic acid (Example 8) (3R) -3-{[2-(4-Aminopiperidin-1-yl) -2-oxoethylethyl]thio}-2-hydroxy-7-methoxy-3,4-dihydro-2H-1,2-benzoxoxaborox-8-carboxylic acid ( Example 9) (3R)-4,4-Dihydroxy-3-{[2-(azetidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5- Oxa-4-boron anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid disodium salt (Example 10) (3R)-4,4-dihydroxyl -3-{[2-(3-methoxypyrrolidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5-oxa-4-boran anion heterobicyclo[ 4.4.0] 癸-1(6), 7,9-triene-7-carboxylic acid disodium salt (Example 11) (3R)-4,4-dihydroxy-3-({2-[2- (Dimethylamine-mercapto)pyrrolidin-1-yl]-2-oxoethyl}thio)-8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid disodium salt (Example 12) (3R)-4,4-dihydroxy-3-({2-[2-(methoxy) Methyl)pyrrolidin-1-yl]-2-oxoethyl}thio)-8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6) , 7,9-triene-7-carboxylic acid disodium salt (Example 13) (3R)-4,4-dihydroxy-3-{[2-(porphyrin-4-yl)-2-side oxygen Ethyl]thio}-8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid disodium salt (Example 1 4) (3R)-4,4-Dihydroxy-3-{[2-(3-hydroxyazetidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5 -oxa-4-boroanion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid disodium salt (Example 15) (3R)-4,4-di Hydroxy-3-({2-[2-(hydroxymethyl)pyrrolidin-1-yl]-2-oxoethyl}thio)-8-methoxy-5-oxa-4-boron anion Heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid disodium salt (Example 16) (3R)-4,4-dihydroxy-3-{[2- (4-Hydroxypiperidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1 (6 , 7,9-triene-7-carboxylic acid disodium salt (Example 17)

Example 18: (3R)-3-{[2-(3-Aminopyrrolidin-1-yl)-2-oxoethyl]thio}-2-hydroxy-7-(methylthio) -3,4-dihydro-2H-1,2-benzoxoxaboryl-8-carboxylic acid hydrochloride [Chem. 230] Add phenylboronic acid (9.3 mg, 0.077 mmol) and 5 mol/L hydrochloric acid (0.547 mL, 2.73) to a mixture of Reference Example 36 (88 mg, 0.109 mmol), acetonitrile (1.09 mL) and hexane (1.09 mL). Methyl), stirred at room temperature overnight. After standing and separating the layers, the hexane layer of the upper layer was removed, and the acetonitrile layer was distilled off under reduced pressure, and the obtained residue was washed with acetonitrile/methanol (1/1). The precipitated crystals were collected by filtration, washed with a mixture of acetonitrile/methanol (2/1), and dried to give the title compound (24.5 mg).

¹ H-NMR (CD ₃ OD) δ : 7.13 - 7.06 (1H, m), 6.82 (1H, d, J = 7.9 Hz), 4.15 - 4.01 (2H, m), 3.96 - 3.72 (3H, m), 3.51 - 3.26 (3H, m), 3.35 (3H, s), 3.10 - 3.00 (1H, m), 2.77 - 2.66 (1H, m), 2.58 - 2.43 (2H, m). LCMS:[M+H] ⁺ / Rt=397.2/0.527 min ^A

Example 19: (3R)-4,4-Dihydroxy-3-{[2-(3-Aminopyrrolidin-1-yl)-2-oxoethyl]thio}-8-methoxy Manufacture of 5-5-oxa-4-boron anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid disodium salt (manufacturing tetrasubstituted boron from trisubstituted boron compound) Method of compound) [Chem. 231] (3R)-3-{[2-(3-Aminopyrrolidin-1-yl)-2-oxoethyl]thio}-2-hydroxy-7-methoxy-3,4-di A 2 mol/L aqueous sodium hydroxide solution was added to a solution of hydrogen-2H-1,2-benzoxaazepine-8-carboxylic acid in acetonitrile, and the mixture was stirred at room temperature overnight. The title compound (the compound of Example 1) was obtained by purifying the reaction liquid by reverse phase column chromatography (eluent: acetonitrile / water).

Examples 20 to 54 The corresponding reference examples of the compounds 65 to 95 were used as starting materials, and the reaction, post-treatment, and purification were carried out in the same manner as in the methods described in Example 1 and Example 2, and Table (5) was obtained. The compound shown.

[Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9]

"*" indicates the presence of an asymmetric carbon atom. Examples 25 and 26, Examples 30 and 31, Examples 33 and 34, and Examples 37 and 38 are each a non-image isomer. "*(1)" indicates that in the following examples, the retention time (Rt) in the reverse phase column HPLC of LCMS is smaller, that is, the non-image isomer (1) which is more polar; "*(2) Similarly, in the following examples, the retention time (Rt) is larger in the LCMS and reverse phase column HPLC under the same conditions, that is, the non-image isomer (2) having a lower polarity. Furthermore, in the present specification, the sodium carboxylate group (-CO ₂ Na) may also be [Chem. 232]. The formal representations have the same meaning.

Examples 25 and 26: (4R)-4-[2-[3-(Aminomethyl)pyrrolidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9 -Methoxy-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-10-carboxylic acid disodium salt [Chem. 233] TFA (2.5 mL) and triethyl decane (0.6 mL) were added to the compound of Example 70 (180 mg, 0.244 mmol), and stirred at 45 ° C for 1.2 hours. The reaction liquid was distilled off under reduced pressure, and the pH was adjusted to 10 by adding a 1 mol/L aqueous sodium hydroxide solution and a saturated aqueous sodium hydrogencarbonate solution to the obtained residue at 0 °C. The mixed suspension was filtered, and the filtrate was purified by reverse phase column chromatography (eluent: acetonitrile/water) to obtain two non-image isomers of the title compound as white solids. High non-image isomer (1) (19.1 mg) and less polar non-image isomer (2) (11.2 mg).

Higher polarity non-image isomers (1) LCMS: [M+H] ⁺ /Rt=395.2/0.57 min ^{C 1} H NMR (400 MHz, D ₂ O) : δ 1.38 - 1.72 (m, 1H), 1.82 - 2.20 (m, 2H), 2.21 - 2.53 (m, 2H), 2.55 - 2.94 (m, 4H), 3.01 - 3.34 (m, 3H), 3.35 - 3.80 (m, 5H), 6.28 - 6.55 (m, 1H ), 6.77 - 7.37 (m, 1H). Non-image isomer of lower polarity (2) LCMS: [M+H] ⁺ /Rt=395.2/0.62 min ^{C 1} H NMR (400 MHz, D ₂ O) : δ 1.38 - 1.72 (m, 1 H), 1.82 - 2.20 (m, 2H), 2.18 - 3.36 (m, 9H), 3.39 - 3.80 (m, 5H), 6.28 - 6.55 (m, 1H), 6.77 - 7.37 ( m, 1H).

Examples 30 and 31: ((4R)-4-[2-(3-Aminopiperidin-1-yl)-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy Benzyl-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-10-carboxylic acid disodium salt [Chem. 234] TFA (2.5 mL) and triethyl decane (0.6 mL) were added to the compound of Example 73 (200 mg, 0.249 mmol), and stirred at 45 ° C for 1.2 hr. The reaction liquid was distilled off under reduced pressure, and the pH was adjusted to 10 by adding a 1 mol/L aqueous sodium hydroxide solution and a saturated aqueous sodium hydrogencarbonate solution to the obtained residue at 0 °C. The mixed suspension was filtered, and the filtrate was purified by reverse phase column chromatography (eluent: acetonitrile/water) to obtain two non-image isomers of the title compound as white solids. High non-image isomer (1) (21.6 mg) and less polar non-image isomer (2) (29.1 mg).

Higher polar non-image isomers (1) LCMS: [M+H] ⁺ /Rt=395.1/0.75 min ^{C 1} H NMR (400 MHz, CD ₃ OD): δ 1.42 - 1.89 (m, 3H), 1.96 - 2.12 (m, 1H), 2.23 - 2.36 (m, 1H), 2.76 - 3.23 (m, 4H), 3.22 - 3.51 (m, 2H), 3.57 - 4.25 (m, 6H), 6.31 - 6.46 (m, 1H ), 6.91 - 7.30 (m, 1H). Non-image isomer of lower polarity (2) LCMS: [M-OH] ⁺ /Rt=377.2/0.78 min ^{C 1} H NMR (400 MHz, CD3OD): δ 1.43 - 2.15 (m, 4H), 2.21 - 2.39 (m, 1H), 2.69 - 3.28 (m, 5H), 3.34 - 3.56 (m, 2H), 3.60 - 4.43 (m, 5H), 6.31 - 6.46 (m , 1H), 6.91 - 7.29 (m, 1H).

Examples 33 and 34: (4R)-4-[2-[3-(2-Aminoethylamino)pyrrolidin-1-yl]-2-oxoethyl]thio-3,3- Dihydroxy-9-methoxy-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-10-carboxylic acid disodium salt [Chem. 235] TFA (3 mL) and triethyl decane (0.6 mL) were added to the compound of Example 75 (250 mg, 0.268 mmol) and stirred at 45 ° C for 1.2 hr. The reaction liquid was distilled off under reduced pressure, and the pH was adjusted to 10 by adding a 1 mol/L aqueous sodium hydroxide solution and a saturated aqueous sodium hydrogencarbonate solution to the obtained residue at 0 °C. The mixed suspension was filtered, and the filtrate was purified by reverse phase column chromatography (eluent: acetonitrile/water) to obtain two non-image isomers of the title compound as white solids. High non-image isomer (1) (31.8 mg) and less polar non-image isomer (2) (31.5 mg).

Higher polar non-image isomers (1) LCMS: [M+H] ⁺ /Rt=424.3/0.80 min ^{C 1} H NMR (400 MHz, D2O): δ 1.61 - 2.24 (m, 3H), 2.60 - 2.77 ( m, 1H), 2.89 - 3.81 (m, 15H), 6.29 - 6.55 (m, 1H), 6.83 - 7.36 (m, 1H). Non-image isomer of lower polarity (2) LCMS: [M+H] ⁺ /Rt=424.2/0.84 min ^{C 1} H NMR (400 MHz, D2O): δ 1.59 - 2.33 (m, 3H), 2.60 - 2.78 (m, 1H), 2.83 - 3.82 (m, 15H), 6.29 - 6.55 ( m, 1H), 6.83 - 7.36 (m, 1H).

Examples 37 and 38: (4R)-4-[2-[3-(2-Aminoethylamino)pyrrolidin-1-yl]-2-oxoethyl]thio-3,3- Dihydroxy-9-methoxy-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-10-carboxylic acid disodium salt [Chem. 236] TFA (2.5 mL) and triethyl decane (0.8 mL) were added to the compound of Example 77 (220 mg, 0.265 mmol), and stirred at 45 ° C for 1.2 hr. The reaction liquid was distilled off under reduced pressure, and the pH was adjusted to 10 by adding a 1 mol/L aqueous sodium hydroxide solution and a saturated aqueous sodium hydrogencarbonate solution to the obtained residue at 0 °C. The mixed suspension was filtered, and the filtrate was purified by reverse phase column chromatography (eluent: acetonitrile/water) to obtain two non-image isomers of the title compound as white solids. High non-image isomer (1) (19.7 mg) and less polar non-image isomer (2) (23.3 mg).

Higher polar non-image isomers (1) LCMS: [M+H] ⁺ /Rt=421.3/0.76 min ^{C 1} H NMR (400 MHz, D2O): δ 1.74 - 2.34 (m, 7H), 2.58 - 2.77 ( m, 1H), 2.83 - 3.03 (m, 1H), 3.04 - 3.91 (m, 11H), 6.23 - 6.54 (m, 1H), 6.83 - 7.33 (m, 1H). Non-image isomers of lower polarity (2) LCMS: [M-OH] ^{+ /} Rt = 421.3 / 0.79 min ^{C 1} H NMR (400 MHz, D2O): δ 1.86 - 2.30 (m, 7H), 2.59 - 2.73 (m, 1H), 2.87 - 2.99 (m, 1H), 3.11 - 3.88 (m, 11H), 6.15 - 6.52 (m, 1H), 6.73 - 7.39 (m, 1H).

The names of the compounds of Examples 20 to 54 are shown below. (3R)-4,4-dihydroxy-3-[2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl]thio-8-methoxy-5-oxa-4 Boron anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid disodium salt (Example 20) (4R)-4-[2-[(3S)- 3-Aminopyrrolidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2-oxa-3-boroanion heterobicyclo[4.4.0癸-1(6), 7,9-triene-10-carboxylic acid disodium salt (Example 21) (4R)-4-[2-[(3R)-3-Aminopyrrolidine-1- 2-yloxyethyl]thio-3,3-dihydroxy-9-methoxy-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1(6),7 , 9-triene-10-carboxylic acid disodium salt (Example 22) (4R)-3,3-dihydroxy-9-methoxy-4-[2-[3-(methylamino)pyrrole Pyridin-1-yl]-2-oxoethyl]thio-2-oxo-3-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylate Acid disodium salt (Example 23) (4R)-4-[2-[2-(Aminomethyl)pyrrolidin-1-yl]-2-oxoethyl]thio-3,3-di Hydroxy-9-methoxy-2-oxa-3-boroanion heterobicyclo[4.4.0]indole-1(6), 7,9-triene-10-carboxylic acid disodium salt (Example 24) (4R)-4-[2-[3-(Aminomethyl)pyrrolidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2 - Oxygen -3-boron anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-10-carboxylic acid disodium salt (Example 25) (4R)-4-[2-[3- (Aminomethyl)pyrrolidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2-oxa-3-boroanion heterobicyclo[4.4 .0] 癸-1(6), 7,9-triene-10-carboxylic acid disodium salt (Example 26) (4R)-4-[2-[3-(Aminomethyl)azetidine -1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1 (6 , 7,9-Triene-10-carboxylic acid disodium salt (Example 27) (3R)-3-[2-(4-ethaneimidopiperazin-1-yl)-2-side oxygen Ethyl]thio-2-hydroxy-7-methoxy-3,4-dihydro-1,2-benzoxaazepinecyclo-8-carboxylic acid (Example 28) (4R)-4 -[2-(3-Amino-4-methylpyrrolidin-1-yl)-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2-oxa- 3-boran anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-10-carboxylic acid disodium salt (Example 29) (4R)-4-[2-(3-amine Isopiperidin-1-yl)-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2-oxa-3-boran anion heterobicyclo[4.4.0]癸- 1(6), 7,9-triene-10-carboxylic acid disodium salt (Example 30) (4R)-4-[2-(3-Aminopiperidin-1-yl)-2-sideoxy Ethyl Thio-3,3-dihydroxy-9-methoxy-2-oxa-3-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylate Acid disodium salt (Example 31) (4R)-4-[2-[2-(Aminomethyl)piperidin-1-yl]-2-oxoethyl]thio-3,3-di Hydroxy-9-methoxy-2-oxa-3-boroanion heterobicyclo[4.4.0]indole-1(6), 7,9-triene-10-carboxylic acid disodium salt (Example 32) (4R)-4-[2-[3-(2-Aminoethylamino)pyrrolidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9- Oxy-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-10-carboxylic acid disodium salt (Example 33) (4R)-4 -[2-[3-(2-Aminoethylamino)pyrrolidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2- Oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-10-carboxylic acid disodium salt (Example 34) (4R)-4-[2-( 3-aminopyrrolidin-1-yl)-2-oxoethyl]thio-8-chloro-3,3-dihydroxy-9-methoxy-2-oxa-3-boroanion heterobicyclic [4.4.0] 癸-1(6), 7,9-triene-10-carboxylic acid disodium salt (Example 35) (4R)-4-[2-[4-(Aminomethyl)piperidin Pyridin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2-oxa-3-boroanion heterobicyclo[4.4.0]癸- 1(6), 7,9-triene-10-carboxylic acid disodium salt (Example 36) (4R)-4-[2-(1,7-diazaspiro[4.4]decane-7- ))-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1(6),7 , 9-triene-10-carboxylic acid disodium salt (Example 37) (4R)-4-[2-(1,7-diazaspiro[4.4]decane-7-yl)-2-side Oxyethyl]thio-3,3-dihydroxy-9-methoxy-2-oxa-3-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene- 10-carboxylic acid disodium salt (Example 38) (4R)-4-[2-(2,8-diazaspiro[4.5]decan-2-yl)-2-oxoethyl]thio -3,3-dihydroxy-9-methoxy-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-10-carboxylic acid disodium Salt (Example 39) (4R)-4-[2-(3-Ethylpyrrolidin-1-yl)-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy Benzyl-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-10-carboxylic acid disodium salt (Example 40) (4R)-4- [2-(2,6-diazaspiro[3.4]octane-6-yl)-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2-oxa -3-boron anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-10-carboxylic acid disodium salt (Example 41) (4R)-4-[(2-octahydrogen) Pyrrolo[3,4-c] R-2-yl-2-yloxyethyl)thio]-3,3-dihydroxy-9-methoxy-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1 ( 6) 7,9-Triene-10-carboxylic acid disodium salt (Example 42) (3R)-3-[2-(3-Aminopyrrolidin-1-yl)-2-oxoethyl Thio-2-hydroxy-7-(triazol-1-yl)-3,4-dihydro-1,2-benzoxaazepinecyclo-8-carboxylic acid hydrochloride (Example 43) (3R)-2-hydroxy-7-methoxy-3-[2-o-oxy-2-(2-o-oxy-1,3-1,3-oxazolidin-3-yl)ethyl]thio -3,4-dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid (Example 44) (4R)-4-[2-(2,7-diazaspiro) [4.4] decane-2-yl)-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-10-carboxylic acid disodium salt (Example 45) (3R)-3-[2-(2,9-diazaspiro[4.5]decane- 2-yl)-2-oxoethyl]thio-2-hydroxy-7-methoxy-3,4-dihydro-1,2-benzoxaazepinecyclo-8-carboxylic acid ( Example 46) (3R)-3-[2-(1,7-diazaspiro[3.4]octane-7-yl)-2-oxoethyl]thio-2-hydroxy-7- Oxy-3,4-dihydro-1,2-benzoxaazepinene-8-carboxylic acid (Example 47) (3R)-2-hydroxy-7-methoxy-3-[2 - side oxy-2-(2- side Imidazolidin-1-yl)ethyl]thio-3,4-dihydro-1,2-benzoxaazepinene-8-carboxylic acid (Example 48) (3R)-2-hydroxyl -7-methoxy-3-[2-o-oxy-2-(3-o-oxypyrazol-1-yl)ethyl]thio-3,4-dihydro-1,2-benzene And oxaboroxine-8-carboxylic acid (Example 49) (3R)-3-[2-[3-(2-Aminoethylaminemethylmercapto)azetidin-1-yl]- 2-sided oxyethyl]thio-2-hydroxy-7-methoxy-3,4-dihydro-1,2-benzoxaazepinecyclo-8-carboxylic acid (Example 50) ( 3R)-3-[2-[5-(Aminomethyl)-2-oxo-1,3-1,3-oxazolidin-3-yl]-2-oxoethyl]thio-2-hydroxyl -7-methoxy-3,4-dihydro-1,2-benzoxaazepinecyclo-8-carboxylic acid (Example 51) (3R)-3-[2-(4-Amino) -3-Sideoxypyrazolidin-1-yl)-2-oxoethylethyl]thio-2-hydroxy-7-methoxy-3,4-dihydro-1,2-benzoxazepine Boracyclohexane-8-carboxylic acid (Example 52) (3R)-3-[3-(3-Aminopyrrolidin-1-yl)-3-oxopropyl]thio-2-hydroxyl -7-Methoxy-3,4-dihydro-1,2-benzoxaazepinecyclo-8-carboxylic acid (Example 53) (3R)-3-[4-(3-Amino) Pyrrolidin-1-yl)-4-oxobutyl]thio-2-hydroxy-7-methoxy-3,4-dihydro-1,2-benzoxaazepine-8- Carboxylic acid Example 54)

The pharmacological test methods and the results of the representative compounds of the present invention are shown below, and the present invention is not limited to the test examples.

Test Example 1: MEPM generating bacteria The minimum inhibitory concentration of (MIC) for β- lactam Evaluation To evaluate the enzyme β- lactam enzyme inhibitory activity of the test compound, and the evaluation of the test organism to produce the enzyme β- Amides The combined effect of the compound and the β-namidamide-based agent. When the meropenem (MEPM) was used as the β-endoxime-based antibacterial agent and the test compound was added at a fixed concentration (4 μg/mL) by a micro-liquid dilution method (comparative ratio: 2) The minimum inhibitory concentration (MIC) of MEPM for β-endoprostanase producing bacteria. When the test compound is used in combination, the MIC of the MEPM is less than 1/32, and the MIC of the MEPM is 1/32 to 1/16, and the MIC of the MEPM is 1/8 to 1/4. When it is set to C, the MIC of the MEPM is 1/2 or more, and it is set to D and is shown below. (Furthermore, "-" means untested) [Table 6-1] [Table 6-2] [Table 6-3]

Test Example 2: MEPM generation of bacteria The minimum inhibitory concentration (MIC) for evaluation in Test Example 1 β- lactam enzyme in the same manner, for example, E. coli ATCC BAA-2469 (NDM-1 ), Klebsiella pneumoniae ATCC BAA-2470 (NDM-1), Klebsiella pneumoniae NCTC 13439 (VIM-1), Klebsiella pneumoniae NCTC 13440 (VIM-1), and Escherichia coli NCTC 13476 (IMP), etc., can be evaluated The metal-β-endoaminase inhibitory activity of the test compound.

As described above, the present invention has been exemplified by the preferred embodiments of the present invention, but with respect to the present invention, it is understood that the scope of the invention should be construed only by the scope of the claims. The present application claims priority to Japanese Patent Application No. 2017-132614 (filed on Jul. 6, 2017), the content of which is incorporated herein by reference. The patents, patent applications, and documents cited in the present specification are to be understood as being the same as the description of the present specification. [Industrial availability]

The compound of the present invention exhibits a strong inhibitory effect on β-endoprostanase, and as sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, paranasal inflammation, Pneumonia, lung abscess, empyema, secondary infection of chronic respirator lesions, pharyngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymph A therapeutic agent and/or a prophylactic agent for secondary infections such as tube/lymphitis, trauma/scald, and surgical wounds, urinary tract infections, genital infections, ocular infections, or odontogenic infections.

Claims (106)

A compound or a pharmaceutically acceptable salt thereof, which is represented by the formula (1a) or (1b), wherein the formula (1a) or (1b): [In the formulae (1a) and (1b), X represents an oxygen atom, a sulfur atom, or -NR ^a1 -, Z represents a hydroxyl group, a substituted C _1-6 alkoxy group, or -NR ^a2 R ^b1 , R ^a1 R ^a2 and R ^{b1 are the} same or different and each independently represents 1) a hydrogen atom, 2) a C _1-6 alkyl group, 3) a C _3-10 alicyclic group, 4) a C _6-10 aryl group, 5) 5 members. Or 6-membered heteroaryl, 6) 4 to 10 membered non-aryl heterocyclic ring, 7) C _1-6 alkylcarbonyl group, 8) C _3-10 alicyclic carbonyl group, 9) C _6-10 aryl group Carbonyl, 10) 5- or 6-membered heteroarylcarbonyl, 11) C _1-6 alkylsulfonyl, 12) C _3-10 alicyclic sulfonyl, 13) C _6-10 arylsulfonate a 14, 6 or 6 membered heteroarylsulfonyl group, or 15) -OR ^c1 , (wherein each of the above 2) to 14) may be substituted), where R ^a2 and R ^b1 It is also possible to form a nitrogen-containing non-aryl heterocyclic ring which may be substituted by 4 to 10 members, and R ^c1 represents 1) a hydrogen atom 2) a C _1-6 alkyl group 3) a C _3-10 alicyclic group 4) Any one of C _6-10 aryl 5) 5 or 6 member heteroaryl, or 6) 4 to 10 member non-aryl heterocyclic ring (wherein 2) to 6) Substituted), L represents a C _1-6 alkyl group which may be substituted, and Y represents C(=O)NR ^D1 R ^d2 , where R ^d1 and R ^d2 may also be formed by a nitrogen-containing non-aryl heterocyclic group of 4 to 20 members which may be substituted by a nitrogen atom constituting the above-mentioned Y amide bond in the ring. Rings, R ¹ , R ² , and R ^{3 are the} same or different and each independently represents 1) a hydrogen atom, 2) a halogen atom, 3) a 5-membered heteroaryl group, 4) a C _1-6 alkoxy group, 5) C ₁ Any of _-6 alkylthio, or 6) -NR ^a3 R ^b2 (wherein each of the above 3) to 5) may be substituted, and R ⁴ represents 1) -COR ⁵ , 2) -SO ₂ -L ^a -R ⁵ (In the above formulas 1) and 2), R ⁵ represents -NR ^a4 R ^b3 , -NR ^a4 -L ^b -B(OR ^e1 ) ₂ , -OR ^e1 , or may be substituted C _1-6 alkyl, L ^a represents a single bond, or -NR ^a5 -), 3) -NR ^a6 R ^b4 , 4) -B(OR ^e1 ) ₂ , 5) -PO(OR ^e1 )(OR ^e2 ) And 6) a heterocyclic group of 5 members which may be substituted, 7) a non-aryl heterocyclic ring of 5 members which may be substituted, or 8) a carboxylic acid equivalent (wherein 2), 4), 5) and 6) the formula contains a carboxylic acid equivalent, 7) may repetitively comprise any of the above, and R ^a3 , R ^a4 , R ^a5 , R ^a6 , R ^b2 , R ^b3 , R ^b4 are each independently identical Or different, with the meaning of R ^a1 , R ^a2 , R ^{b1 above} Similarly, here, when R ^a3 and R ^b2 , R ^a4 and R ^b3 or a combination of R ^a6 and R ^b4 are bonded to the same nitrogen atom, these may also form a substituted 4 to 10 member. a nitrogen-containing non-aryl heterocyclic ring, R ^e1 represents 1) a hydrogen atom, 2) a C _1-6 alkyl group, 3) a C _3-10 alicyclic group, 4) a C _6-10 aryl group, 5) 5 members or Any of 6 heteroaryl, or 6) 4 to 10 membered non-aryl heterocyclic rings (wherein each of the above 2) to 6) may be substituted, wherein R ^{e1 is} via oxygen In the case where an atom is bonded to a boron atom, two R ^e1 may form a non-aryl heterocyclic ring of 5 to 7 members together with a boron atom and two oxygen atoms in the form of a C _2-4 alkyl group. The alkyl moiety of the aryl heterocycle may be substituted), R ^e2 represents a hydrogen atom, a substituted C _1-6 alkyl group, or a substituted C _3-10 alicyclic group, and L ^b represents a substitutable group. C _1-3 alkyl]. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is a C _1-6 alkylene group (the group may be selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a C _1-6 alkyl group, a C ₁ group) _-6 alkoxy, -NR ^f1 R ^f2 in the 1 to 3 substituents), R ^f1, R ^f2 identical or different, are each independently a hydrogen atom, or C _1-6 alkyl. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is a C _1-3 alkylene group (the group may be substituted with 1 to 3 C _1-3 alkyl groups). The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein L is methylene (-CH ₂ -). The compound according to any one of claims 1 to 4, wherein Y is C(=O)NR ^d1 R ^d2 , wherein R ^d1 and R ^d2 may also be formed together by the compound or a pharmaceutically acceptable salt thereof. a nitrogen-containing non-aryl heterocyclic ring having 4 to 20 members which is a nitrogen atom constituting the above-described Y-th sense amine bond, and the nitrogen-containing non-aryl heterocyclic ring of 4 to 20 members may be selected from 1 halogen. Atom, 2) hydroxy, 3) carboxy, 4) cyano, 5) -NR ^g1 R ^g2 , 6) -CR ^g3 (=NR ^h1 ), 7) -C(=NR ^h2 )NR ^g4 R ^g5 , 8) ^{-C (= O) NR g6 R} g7, 9) -C (= O) NR g26 OR g27, 10) -C (= O) NR g8 -SO 2 -R g9, 11) -SO 2 -NR g10 R ^G11 , 12) -NR ^g12 -CR ^g13 (=NR ^h3 ), 13) -NR ^g14 -C(=NR ^h4 )NR ^g15 R ^g16 , 14) -NR ^g17 -C(=O)NR ^g18 R ^g19 , 15 -NR ^g20 -C(=O)R ^g21 , 16) -NR ^g22 -C(=O)OR ^g23 , 17) -NR ^g24 -SO ₂ -R ^g25 , 18) C _1-6 alkyl, or 19 a C _1-6 alkoxy group (the C _1-6 alkyl group, a C _1-6 alkoxy group may be selected from 1) a halogen atom, 2) a hydroxyl group, 3) a carboxyl group, 4) a cyano group, 5) C _{1 -6} alkoxy, 6) -NR ⁱ¹ R ⁱ² , 7) -CR ⁱ³ (=NR ^j1 ), 8) -C(=NR ^j2 )NR ⁱ⁴ R ⁱ⁵ , 9) -C(=O)NR ⁱ⁶ R ^I7 , 10) -C(=O)NR ⁱ⁸ -SO ₂ -R ⁱ⁹ , 11) -SO ₂ -NR ⁱ¹⁰ R ⁱ¹¹ , 12) -NR ⁱ¹² -CR ⁱ¹³ (=NR ^j3 ), 13) -NR ⁱ¹⁴ -C(=NR ^j4 )NR ⁱ¹⁵ R ⁱ¹⁶ , 14 -NR ⁱ¹⁷ -C(=O)NR ⁱ¹⁸ R ⁱ¹⁹ , 15) -NR ⁱ²⁰ -C(=O)R ⁱ²¹ , 16) -NR ⁱ²² -C(=O)OR ⁱ²³ , or 17) -NR ⁱ²⁴ - 1 to 3 substituents in the substitution of 1 to 3 substituents in SO ₂ -R ⁱ²⁵ ), wherein R ^g1 , R ^g2 , R ^g3 , R ^g4 , R ^g5 , R ^g6 , R ^g7 , R ^g8 , R ^g9 , R ^g10 , R ^g11 , R ^g12 , R ^g13 , R ^g14 , R ^g15 , R ^g16 , R ^g17 , R ^g18 , R ^g19 , R ^g20 , R ^g21 , R ^g22 , R ^g23 , R ^{g24 , R g25, R g26, R} g27, R i1, R i2, R i3, R i4, R i5, R i6, R i7, R i8, R i9, R i10, R i11, R i12, R i13, R ^I14 , R ⁱ¹⁵ , R ⁱ¹⁶ , R ⁱ¹⁷ , R ⁱ¹⁸ , R ⁱ¹⁹ , R ⁱ²⁰ , R ⁱ²¹ , R ⁱ²² , R ⁱ²³ , R ⁱ²⁴ , R ^{i25 are the} same or different and each independently represent a hydrogen atom or may pass through -NR ⁱ²⁶ R ^I27 substituted C _1-6 alkyl, R ⁱ²⁶ , R ^{i27 are the} same or different, each independently represents a hydrogen atom or a C _1-6 alkyl group, and R ^g1 and R ^g2 , R ^g4 and R ^g5 , R ^g6 and R ^g7 , R ^g10 and R ^g11 , R ^g15 and R ^{g1 6.} R ^g18 and R ^g19 , R ⁱ¹ and R ⁱ² , R ⁱ⁴ and R ⁱ⁵ , R ⁱ⁶ and R ⁱ⁷ , R ⁱ¹⁰ and R ⁱ¹¹ , R ⁱ¹⁵ and R ⁱ¹⁶ or a combination of R ⁱ¹⁸ and R ⁱ¹⁹ are bonded to the same nitrogen. In the case of an atom, these may also form a nitrogen-containing non-aryl heterocyclic ring of 4 to 10 members which may be substituted, R ^h1 , R ^h2 , R ^h3 , R ^h4 , R ^j1 , R ^j2 , R ^j3 , R ^{J4 is the} same or different and each independently represents a hydrogen atom, a hydroxyl group, a _C1-6 alkyl group, or a _C1-6 alkoxy group. The compound according to any one of claims 1 to 5, wherein the Y is represented by any one of the following formulas (3A) or (3B): (Formula 2) Formula (3A) ); (3B): [In the formula (3A), m is an integer of 0, ¹ , 2 or 3, and L ¹ is a carbon atom, an oxygen atom, a carbonyl group (-C(=O)-) or -NR ^y5 -, and L ² and L ^{3 are the} same Or different, each independently a carbon atom, or a carbonyl group (-C(=O)-), R ^y1 , R ^y2 , R ^y3 on a carbon atom in the nitrogen-containing ring capable of chemically replacing the position to satisfy the formation of the ring All of the carbon atoms have a sufficient number of valences to bond (ie, R ^y1 , R ^y2 , and R ^y3 may exist in plural), and are the same or different, each independently being 1) a hydrogen atom 2) a hydroxyl group, 3 ) -NR ^g1 R ^g2 , 4) -CR ^g3 (=NR ^h1 ) 5) -C(=NR ^h2 )NR ^g4 R ^g5 , 6) -NR ^g12 -CR ^g13 (=NR ^h3 ), 7) -NR ^g14 -C(=NR ^h4 )NR ^g15 R ^g16 , 8) -NR ^g20 -C(=O)R ^g21 , 9) -NR ^g24 -SO ₂ -R ^g25 , 10) -C(=O)NR ^g6 R ^g7 , 11) C _1-3 alkyl, or 12) C _1-3 alkoxy (the C _1-3 alkyl, C _1-3 alkoxy group may be selected from a hydroxyl group, a C _1-3 alkoxy group, Any of the substituent substitutions in -NR ⁱ¹ R ⁱ² (wherein R ^g1 , R ^g2 , R ^g3 , R ^g4 , R ^g5 , R ^g6 , R ^g7 , R ^g12 , R ^g13 , R ^g14 , R ^g15 , R ^g16 , R ^g20 , R ^g21 , R ^g24 , R ^g25 , R ⁱ¹ , R ^{i 2 is the} same or different and each independently represents a hydrogen atom or a C _1-3 alkyl group which may be substituted by -NR ⁱ²⁶ R ⁱ²⁷ , and R ⁱ²⁶ and R ^{i27 are the} same or different, each independently represents a hydrogen atom or a C _1-6 alkyl group, R ^H1 , R ^h2 , R ^h3 and R ^{h4 are the} same or different, each independently being a hydrogen atom, a hydroxyl group, a C _1-3 alkyl group, a C _1-3 alkoxy group), and R ^y1 and R ^y2 may also be bonded carbon. The atom together with each of R ^y1 and R ^y2 forms a non-aryl heterocyclic ring containing a C _3-7 alicyclic group or a 4 to 7 member (the C _3-7 alicyclic group or a 4 to 7 member non-aryl group) The heterocyclic ring may be selected from a hydroxyl group, -NR ⁱ²⁸ R ⁱ²⁹ , C _1-3 alkyl, C _1-3 alkoxy group (the C _1-3 alkyl group, C _1-3 alkoxy group may be selected from a hydroxyl group) a spiro ring or a crosslinked structure of a C _1-3 alkoxy group, a substituent substituted by a substituent in -NR ⁱ³⁰ R ⁱ³¹ ), R ⁱ²⁸ , R ⁱ²⁹ , R ⁱ³⁰ , R ^{i31 are the} same or different, and each Independently represents a hydrogen atom or a C _1-3 alkyl group, R ^y5 is 1) a hydrogen atom 2) -CR ^g28 (=NR ^h5 ), 3) -C(=NR ^h6 )NR ^g29 R ^g30 , or 4) C _1- Any one of ₃ alkyl, (the C _1-3 alkyl group may be substituted with a substituent selected from a hydroxyl group, a C _1-3 alkoxy group, or -NR ⁱ³² R ⁱ³³ ) (here, R ^g28 , R ^G29 , R ^G30 , R ⁱ³² and R ^{i33 are the} same or different and each independently represents a hydrogen atom or a C _1-3 alkyl group, and R ^h5 and R ^{h6 are the} same or different and each independently represents a hydrogen atom, a hydroxyl group, a C _1-3 alkyl group, and C _{1 . -3} alkoxy), in the formula (3B), n is an integer of 1 or 2, and L ⁴ is an oxygen atom, a sulfur atom, -SO ₂ - or -NR ^y6 -, and R ^y4 is a carbon atom in the nitrogen-containing ring The position at which the chemical substitution can be performed is such that a sufficient number of valences of all the carbon atoms forming the ring are bonded (ie, R ^y4 may exist in plural), and the same or different, each independently being the above R Any of 1) to 12) in the definition of ^y1 , R ^y2 , and R ^y3 , R ^y6 is the same as defined in the above R ^y5 )]. The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein Y is represented by the following formula (3C), (3D), (3E), (3F), (3G) or Any of 3H) means: (Chemical Formula 3) Formula (3C); (3D); (3E); (3F); (3G); (3H): [In the formula (3C), R ^y5 is 1) a hydrogen atom 2) a hydroxyl group, 3) -NR ^g1 R ^g2 , 4) -C(=NR ^h2 )NR ^g4 R ^g5 , 5) -NR ^g12 -CR ^g13 (= NR ^h3 ), 6) -NR ^g14 -C(=NR ^h4 )NR ^g15 R ^g16 , 7) -NR ^g20 -C(=O)R ^g21 , 8) -NR ^g24 -SO ₂ -R ^g25 , 9) - C(=O)NR ^g6 R ^g7 , 10) C _1-3 alkyl, or 11) C _1-3 alkoxy (the C _1-3 alkyl, C _1-3 alkoxy group may be selected from a hydroxyl group Any one of a C _1-3 alkoxy group, a substituent in the -NR ⁱ¹ R ⁱ² ), and R ^y5 may be any chemically possible on a carbon atom in the nitrogen-containing ring of the formula (3C) Substitution at position (here, R ^g1 , R ^g2 , R ^g4 , R ^g5 , R ^g6 , R ^g7 , R ^g12 , R ^g13 , R ^g14 , R ^g15 , R ^g16 , R ^g20 , R ^g21 , R ^g24 , R ^G25 , R ⁱ¹ and R ^{i2 are the} same or different and each independently represents a hydrogen atom or a C _1-3 alkyl group which may be substituted by -NR ⁱ²⁶ R ⁱ²⁷ , and R ⁱ²⁶ and R ^{i27 are the} same or different and each independently represents a hydrogen atom or C _{1 . -6} alkyl, R ^h2 , R ^h3 and R ^h4 are each a hydrogen atom), p is an integer of 0, 1, or 2, q is an integer of 1 or 2, and in the formula (3D), L ⁵ is an oxygen atom or -NR ^y10 -, (here, R ^y10 is 1) hydrogen atom 2) -CR ^g3 (=NR ^h1 ) , 3) -C(=NR ^h2 )NR ^g4 R ^g5 , or 4) C _1-3 alkyl, (the C _1-3 alkyl group may be selected from a hydroxyl group, a C _1-3 alkoxy group, -NR ⁱ¹ Any one of the substituents in R ⁱ² (wherein R ^g3 , R ^g4 , R ^g5 , R ⁱ¹ , R ^{i2 are the} same or different, each independently represents a hydrogen atom or a C _1-3 alkyl group, R ^h1 And R ^h2 are each a hydrogen atom), R ^y6 is a hydrogen atom, or a C _1-3 alkyl group, (the C _1-3 alkyl group may be substituted by -NR ⁱ¹ R ⁱ² ), and R ^y6 may be in the formula (3D) The chemically arbitrary position on the carbon atom in the nitrogen-containing ring is substituted, r is an integer of 1 or 2. In the formula (3E), R ^y7 is 1) a hydrogen atom, 2) a hydroxyl group, 3) -NR ^g1 R ^g2 or 4) C _1-3 alkoxy (the C _1-3 alkoxy may be substituted by -NR ⁱ¹ R ⁱ² ), and R ^y7 may be a nitrogen ring of formula (3E) Substituting chemically at any position on the carbon atom (wherein, R ^g1 , R ^g2 , R ⁱ¹ , R ^{i2 are the} same or different, each independently represents a hydrogen atom or a C _1-3 alkyl group), and the formula (3F In the above, L ⁶ , L ⁷ , L ⁸ may all be methylene (-CH ₂ -), or either one may be -NR ^y11 -, and the other two are methylene (-CH ₂ -) (here) , R ^y11 is 1) hydrogen atom 2) -C ^{Any of} R ^g3 (=NR ^h1 ), or 3) C _1-3 alkyl (the C _1-3 alkyl group may be substituted by -NR ⁱ¹ R ⁱ² ) (here, R ^g3 , R ⁱ¹ , R ⁱ² represents a hydrogen atom or a C _1-3 alkyl group, R ^h1 is a hydrogen atom), R ^y8 is 1) -NR ^g1 R ^g2, or ^{2) -NR g14 -C (= NR} h4) according to any of the NR ^g15 R ^{g16 Alternatively} , R ^y8 may be substituted at any position chemically possible on a carbon atom in the nitrogen-containing ring of formula (3F) (here, R ^g1 , R ^g2 , R ^g14 , R ^g15 , R ^{g16 are the} same or Different, each independently represents a hydrogen atom or a C _1-3 alkyl group, R ^h4 is a hydrogen atom), s is an integer of 0 or 1, and in the formula (3G), L ⁹ is a methylene group (-CH ₂ -) or a carbonyl group. (-C(=O)-), L ¹⁰ is an oxygen atom or -NH-, or L ⁹ is an oxygen atom or -NH-, and L ¹⁰ is a methylene group (-CH ₂ -) or a carbonyl group (-C (= O)-), R ^y9 is a hydrogen atom, C _1-3 alkyl (the C _1-3 alkyl group may be substituted by -NR ^g1 R ^g2 ) or -NR ^g1 R ^g2 (here, R ^g1 , R ^{g2 are the} same Or different, each independently represents a hydrogen atom or a C _1-3 alkyl group, and in the formula (3H), L ¹¹ is a methylene group (-CH ₂ -), a carbonyl group (-C(=O)-), an oxygen atom or -NH-]. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein Y is represented by formula (3C), and p is 0 and q is 1. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R ^y5 is MeO-, NH ₂ -, a hydrogen atom, HO-, NH ₂ -CH ₂ -, or H ₂ NCH ₂ CH ₂ NHC (= O)-. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R ^y5 is MeO-. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R ^y5 is NH ₂ -. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R ^y5 is a hydrogen atom. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R ^y5 is HO-. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R ^y5 is NH ₂ -CH ₂ -. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R ^y5 is H ₂ NCH ₂ CH ₂ NHC(=O)-. The compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein X is an oxygen atom or -NR ^a1 -. The compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein X is an oxygen atom or a sulfur atom. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein X is an oxygen atom. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein Z is hydroxy, C _1-6 alkoxy or -NR ^a2 R ^b1 . A compound according to any one of claims 1 to 19, wherein Z is a hydroxy group or a C _1-6 alkoxy group, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein Z is a hydroxyl group. The compound of any one of claims 1 to 21, wherein R ¹ and R ^{2 are the} same or different and each independently represents a hydrogen atom, a halogen atom, and may be substituted by 1 to 5 halogen atoms, or a pharmaceutically acceptable salt thereof. C _1-6 alkyl. The compound of any one of claims 1 to 22, wherein R ¹ and R ² are each a hydrogen atom, or a pharmaceutically acceptable salt thereof. A compound according to any one of claims 1 to 23, wherein R ³ is a hydrogen atom, a halogen atom, a triazolyl group, a methoxy group, an ethoxy group or a methylthio group, or a pharmaceutically acceptable salt thereof. A compound according to any one of claims 1 to 24, wherein R ³ is a hydrogen atom, a triazolyl group, a methoxy group or a methylthio group, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R ^{4 is} represented by the following formulas (4A), (4B), (4C), (4D), (4E), (4F) ), (4G), (4H), (4I), (4J), (4K), (4L), (4M), (4N), (4O), (4P), (4Q) or (4R) Either one of them: (4A); (4B); (4C); (4D); (4E); (4F); (4G); (4H); (4I); (4J) ;(4K);(4L);(4M);(4N);(4O);(4P);(4Q);(4R): [In the formulae (4Q) and (4R), R ^j is a hydrogen atom, a C _1-6 alkyl group, or a C _3-10 alicyclic group (the C _1-6 alkyl group or the C _3-10 alicyclic group may be used. Substituted by 1 to 5 halogen atoms), R ^k is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group (the C _1-6 alkyl group, the C _1-6 alkoxy group may be 1 to 1) 5 halogen atoms substituted), C _3-10 alicyclic group, phenyl group, phenoxy group, pyridyl group, pyridyloxy group (the C _3-10 alicyclic group, phenyl group, phenoxy group, pyridyl group, The pyridyloxy group may be substituted by 1 to 5 substituents selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and a C _1-6 alkoxy group. A compound according to claim 26, or a pharmaceutically acceptable salt thereof, wherein R ⁴ of the claim 26 is a formula (4A) (i.e., a carboxyl group). The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: (3R)-3-{[2-(3-aminopyrrolidin-1-yl)-2 -Side oxyethyl]thio}-2-hydroxy-7-methoxy-3,4-dihydro-2H-1,2-benzoxoxaborox-8-carboxylic acid [Chemical 5] (3R)-4,4-Dihydroxy-3-{[2-(3-Aminopyrrolidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5- Oxa-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chemical 6] , (3R)-2-hydroxy-7-methoxy-3-{[2-o-oxy-2-(pyrrolidin-1-yl)ethyl]thio}-3,4-dihydro-2H -1,2-benzoxoxaborox-8-carboxylic acid [Chemical 7] (3R)-4,4-Dihydroxy-3-{[2-Sideoxy-2-(pyrrolidin-1-yl)ethyl]thio}-8-methoxy-5-oxa- 4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chemical 8] , (3R)-2-hydroxy-3-{[2-o-oxy-2-(pyrrolidin-1-yl)ethyl]thio}-3,4-dihydro-2H-1,2-benzene Oxa-heteroborocyclo-8-carboxylic acid [Chemical 9] , (3R)-4,4-dihydroxy-3-{[2-trioxy-2-(pyrrolidin-1-yl)ethyl]thio}-5-oxa-4-boran anion heterobicyclic [4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chemical 10] , (3R)-2-hydroxy-7-methoxy-3-{[1-o-oxy-1-(pyrrolidin-1-yl)propan-2-yl]thio}-3,4-di Hydrogen-2H-1,2-benzoxoxaborylcyclo-8-carboxylic acid [Chemical 11] (3R)-4,4-Dihydroxy-3-{[1-o-oxy-1-(pyrrolidin-1-yl)propan-2-yl]thio}-8-methoxy-5- Oxa-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chemical 12] , (3R)-2-hydroxy-7-methoxy-3-{[2-(4-methylpiperazin-1-yl)-2-yloxyethyl]thio}-3,4-di Hydrogen-2H-1,2-benzoxaazepinehex-8-carboxylic acid [Chemical 13] (3R)-4,4-Dihydroxy-3-{[2-(4-methylpiperazin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5- Oxa-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chemical 14] , (3R)-2-hydroxy-7-methoxy-3-{[2-(3-methoxyazetidin-1-yl)-2-yloxyethyl]thio}-3,4 -Dihydro-2H-1,2-benzoxaazepinehex-8-carboxylic acid [Chemical 15] (3R)-4,4-Dihydroxy-3-{[2-(3-methoxyazetidin-1-yl)-2-yloxyethyl]thio}-8-methoxy- 5-oxa-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chemical 16] (3R)-3-{[2-(3-Aminoazetidin-1-yl)-2-oxoethyl]thio}-2-hydroxy-7-methoxy-3,4- Dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid [Chem. 17] (3R)-4,4-Dihydroxy-3-{[2-(3-Aminoazetidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5 -oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chemical 18] , (3R)-2-hydroxy-7-methoxy-3-{[2-o-oxy-2-(piperazin-1-yl)ethyl]thio}-3,4-dihydro-2H -1,2-benzoxoxaborox-8-carboxylic acid [Chemical 19] , (3R)-4,4-dihydroxy-3-{[2-o-oxy-2-(piperazin-1-yl)ethyl]thio}-8-methoxy-5-oxa- 4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chemical 20] (3R)-3-{[2-(4-Aminopiperidin-1-yl)-2-oxoethyl]thio}-2-hydroxy-7-methoxy-3,4-di Hydrogen-2H-1,2-benzoxaazepinene-8-carboxylic acid [Chem. 21] (3R)-4,4-Dihydroxy-3-{[2-(4-Aminopiperidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5- Oxa-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [22] , (3R)-3-{[2-(azetidin-1-yl)-2-oxoethyl]thio}-2-hydroxy-7-methoxy-3,4-dihydro-2H -1,2-benzoxaazepinehex-8-carboxylic acid [Chemical 23] , (3R)-4,4-dihydroxy-3-{[2-(azetidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5-oxa- 4-boron anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid [Chemical 24] (3R)-2-Hydroxy-7-methoxy-3-{[2-(3-methoxypyrrolidin-1-yl)-2-oxoethyl]thio}-3,4- Dihydro-2H-1,2-benzoxaazepinehex-8-carboxylic acid [Chemical 25] (3R)-4,4-Dihydroxy-3-{[2-(3-methoxypyrrolidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5 -oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chem. 26] , (3R)-3-({2-[2-(dimethylaminocarbamimido)pyrrolidin-1-yl]-2-yloxyethyl}thio)-2-hydroxy-7-methoxy Base-3,4-dihydro-2H-1,2-benzoxaazepinehex-8-carboxylic acid [Chem. 27] , (3R)-4,4-dihydroxy-3-({2-[2-(dimethylaminecarbamimido)pyrrolidin-1-yl]-2-oxoethyl}thio)-8 -Methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [28] , (3R)-2-hydroxy-7-methoxy-3-({2-[2-(methoxymethyl)pyrrolidin-1-yl]-2-oxoethyl}thio)- 3,4-dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid [Chemical 29] , (3R)-4,4-dihydroxy-3-({2-[2-(methoxymethyl)pyrrolidin-1-yl]-2-oxoethyl}thio)-8-A Oxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid [Chem. 30] (3R)-2-Hydroxy-7-methoxy-3-{[2-(porphyrin-4-yl)-2-oxoethyl]thio}-3,4-dihydro-2H- 1,2-benzoxaaborylcyclo-8-carboxylic acid [31] (3R)-4,4-Dihydroxy-3-{[2-(porphyrin-4-yl)-2-oxoethyl]thio}-8-methoxy-5-oxa-4 Boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [32] , (3R)-2-hydroxy-3-{[2-(3-hydroxyazetidin-1-yl)-2-yloxyethyl]thio}-7-methoxy-3,4-di Hydrogen-2H-1,2-benzoxoxaborylcyclo-8-carboxylic acid [Chem. 33] (3R)-4,4-Dihydroxy-3-{[2-(3-hydroxyazetidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5- Oxa-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chem. 34] (3R)-2-Hydroxy-3-({2-[2-(hydroxymethyl)pyrrolidin-1-yl]-2-yloxyethyl}thio)-7-methoxy-3, 4-dihydro-2H-1,2-benzoxoxaborylcyclo-8-carboxylic acid [Chem. 35] (3R)-4,4-Dihydroxy-3-({2-[2-(hydroxymethyl)pyrrolidin-1-yl]-2-oxoethyl}thio)-8-methoxy -5-oxa-4-boron anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid [Chem. 36] (3R)-2-Hydroxy-3-{[2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]thio}-7-methoxy-3,4-dihydro -2H-1,2-benzoxoxaboryl-8-carboxylic acid [Chem. 37] (3R)-4,4-Dihydroxy-3-{[2-(4-hydroxypiperidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5-oxygen Hetero-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chem. 38] (3R)-3-{[2-(3-Aminopyrrolidin-1-yl)-2-oxoethyl]thio}-2-hydroxy-7-(methylthio)-3, 4-Dihydro-2H-1,2-benzoxoxaborylcyclo-8-carboxylic acid [Chem. 39] (3R)-4,4-Dihydroxy-3-{[2-(3-Aminopyrrolidin-1-yl)-2-yloxyethyl]thio}-8-methoxy-5- Oxa-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [40] , (3R)-2-hydroxy-3-((2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)thio)-7-methoxy-3,4-dihydro -2H-1,2-benzoxoxaborox-8-carboxylic acid [Chemical 41] (3R)-4,4-Dihydroxy-3-[2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl]thio-8-methoxy-5-oxa- 4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [42] ,((3R)-((2-((3S)-Aminopyrrolidin-1-yl)-2-yloxyethyl)thio)-2-hydroxy-7-methoxy-3,4- Dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid [Chemical 43] (4R)-4-[2-[(3S)-3-Aminopyrrolidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy- 2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [44] ,((3R)-((2-((3R)-Aminopyrrolidin-1-yl)-2-yloxyethyl)thio)-2-hydroxy-7-methoxy-3,4- Dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid [45] (4R)-4-[2-[(3R)-3-Aminopyrrolidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy- 2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 46] (3R)-2-Hydroxy-7-methoxy-3-((2-(3-(methylamino)pyrrolidin-1-yl)-2-yloxyethyl)thio)-3 ,4-dihydro-2H-1,2-benzoxoxaborox-8-carboxylic acid [Chem. 47] , (4R)-3,3-dihydroxy-9-methoxy-4-[2-[3-(methylamino)pyrrolidin-1-yl]-2-oxoethyl]thio- 2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 48] (3R)-3-({2-[2-(Aminomethyl)pyrrolidin-1-yl]-2-oxoethyl}thio)-2-hydroxy-7-methoxy-3 ,4-dihydro-2H-1,2-benzoxoxaborox-8-carboxylic acid [Chem. 49] (4R)-4-[2-[2-(Aminomethyl)pyrrolidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy- 2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 50] ,(3R)-3-((2-(3-(Aminomethyl))pyrrolidin-1-yl)-2-yloxyethyl)thio)-2-hydroxy-7-methoxy-3 , 4-dihydro-2H-1,2-benzoxaazepinehex-8-carboxylic acid (higher polar non-image isomer (1)) [Chem. 51] , (4R)-4-[2-[3-(Aminomethyl)pyrrolidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy- 2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid (higher polar non-image isomer (1)) 52] ,(3R)-3-((2-(3-(Aminomethyl))pyrrolidin-1-yl)-2-yloxyethyl)thio)-2-hydroxy-7-methoxy-3 , 4-dihydro-2H-1,2-benzoxaazepinehex-8-carboxylic acid (lower polar non-image isomer (2)) [Chem. 53] , (4R)-4-[2-[3-(Aminomethyl)pyrrolidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy- 2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid (lower polar non-image isomer (2)) 54] (3R)-((2-(3-(Aminomethyl)azetidin-1-yl)-2-yloxyethyl)thio)-2-hydroxy-7-methoxy-3, 4-Dihydro-2H-1,2-benzoxoxaborylcyclo-8-carboxylic acid [Chem. 55] , (4R)-4-[2-[3-(Aminomethyl)azetidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy -2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 56] (3R)-3-[2-(4-Ethylimidopiperazin-1-yl)-2-oxoethyl]thio-2-hydroxy-7-methoxy-3,4- Dihydro-1,2-benzoxaazepinene-8-carboxylic acid [57] (4R)-4-[2-(4-Ethylimidopiperazin-1-yl)-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2 -oxa-3-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 58] (3R)-3-{[2-(3-Amino-4-methylpyrrolidin-1-yl)-2-yloxyethyl]thio}-2-hydroxy-7-methoxy- 3,4-dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid [Chem. 59] (4R)-4-[2-(3-Amino-4-methylpyrrolidin-1-yl)-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy -2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [60] (3R)-3-((2-(3-Aminopiperidin-1-yl)-2-oxoethyl)thio)-2-hydroxy-7-methoxy-3,4-di Hydrogen-2H-1,2-benzoxaazepinene-8-carboxylic acid (higher polar non-image isomer (1)) [Chem. 61] (4R)-4-[2-(3-Aminopiperidin-1-yl)-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2-oxo -3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid (higher polar non-image isomer (1)) [Chem. 62] (3R)-3-((2-(3-Aminopiperidin-1-yl)-2-oxoethyl)thio)-2-hydroxy-7-methoxy-3,4-di Hydrogen-2H-1,2-benzoxaazepinehex-8-carboxylic acid (lower polar non-image isomer (2)) [Chem. 63] (4R)-4-[2-(3-Aminopiperidin-1-yl)-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2-oxo -3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid (lower polar non-image isomer (2)) [Chem. 64] (3R)-3-((2-(2-(Aminomethyl)piperidin-1-yl)-2-yloxyethyl)thio)-2-hydroxy-7-methoxy-3 ,4-dihydro-2H-1,2-benzoxoxaboranyl-8-carboxylic acid [Chem. 65] (4R)-4-[2-[2-(Aminomethyl)piperidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy- 2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 66] (3R)-3-((2-(3-(2-Aminoethyl)amino)pyrrolidin-1-yl)-2-oxoethyl)thio)-2-hydroxy-7 -Methoxy-3,4-dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid (higher polar non-image isomer (1)) [Chem. 67] (4R)-4-[2-[3-(2-Aminoethylamino)pyrrolidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9- Methoxy-2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid (higher polar non-image isomer (1 )) [Chem. 68] (3R)-3-((2-(3-(2-Aminoethyl)amino)pyrrolidin-1-yl)-2-oxoethyl)thio)-2-hydroxy-7 -Methoxy-3,4-dihydro-2H-1,2-benzoxaazepinehex-8-carboxylic acid (lower polar non-image isomer (2)) [Chem. 69] (4R)-4-[2-[3-(2-Aminoethylamino)pyrrolidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9- Methoxy-2-oxa-3-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid (lower polar non-image isomer (2 )) [化70] (3R)-3-{[2-(3-Aminopyrrolidin-1-yl)-2-oxoethyl]thio}-6-chloro-2-hydroxy-7-methoxy-3 ,4-dihydro-2H-1,2-benzoxoxaborox-8-carboxylic acid [71] (4R)-4-[2-(3-Aminopyrrolidin-1-yl)-2-oxoethyl]thio-8-chloro-3,3-dihydroxy-9-methoxy- 2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 72] (3R)-((2-(4-(Aminomethyl)piperidin-1-yl)-2-yloxyethyl)thio)-2-hydroxy-7-methoxy-3,4 -dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid [Chem. 73] (4R)-4-[2-[4-(Aminomethyl)piperidin-1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy- 2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [74] , (3R)-3-[(2-1,7-diazaspiro[4.4]decane-7-yl-2-yloxyethyl)thio]-2-hydroxy-7-methoxy- 3,4-Dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid (higher polar non-image isomer (1)) [Chem. 75] , (4R)-4-[2-(1,7-diazaspiro[4.4]decane-7-yl)-2-oxoethyl]thio-3,3-dihydroxy-9- Oxy-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid (higher polar non-image isomer (1) ) [Chem. 76] , (3R)-3-[(2-1,7-diazaspiro[4.4]decane-7-yl-2-yloxyethyl)thio]-2-hydroxy-7-methoxy- 3,4-Dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid (lower polar non-image isomer (2)) [Chem. 77] , (4R)-4-[2-(1,7-diazaspiro[4.4]decane-7-yl)-2-oxoethyl]thio-3,3-dihydroxy-9- Oxy-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid (lower polar non-image isomer (2) ) [化78] , (3R)-3-[(2-2,8-diazaspiro[4.5]decane-2-yl-2-yloxyethyl)thio]-2-hydroxy-7-methoxy- 3,4-Dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid [Chem. 79] , (4R)-4-[2-(2,8-diazaspiro[4.5]decane-2-yl)-2-oxoethyl]thio-3,3-dihydroxy-9- Oxy-2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [80] , (3R)-3-[2-(3-acetamimidyryryl-1-yl)-2-oxoethyl]thio-2-hydroxy-7-methoxy-3,4-dihydro -2H-1,2-benzoxaazepinehex-8-carboxylic acid [81] (4R)-4-[2-(3-Acetylpyrrolidin-1-yl)-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2-oxo Hetero-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 82] , (3R)-3-[(2-2,6-diazaspiro[3.4]octane-6-yl-2-yloxyethyl)thio]-2-hydroxy-7-methoxy- 3,4-dihydro-2H-1,2-benzoxaazepinehexa-8-carboxylic acid [Chem. 83] , (4R)-4-[2-(2,6-diazaspiro[3.4]octane-6-yl)-2-oxoethyl]thio-3,3-dihydroxy-9- Oxy-2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 84] , (3R)-2-hydroxy-7-methoxy-3-[(2-octahydropyrrolo[3,4-c]pyrrol-2-yl-2-yloxyethyl)thio]-3 ,4-dihydro-2H-1,2-benzoxoxaborox-8-carboxylic acid [Chem. 85] , (4R)-4-[(2-octahydropyrrolo[3,4-c]pyrrol-2-yl-2-oxoethyl)thio]-3,3-dihydroxy-9-methoxy Alkyl-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 86] (3R)-3-[2-(3-Aminopyrrolidin-1-yl)-2-oxoethyl]thio-2-hydroxy-7-(triazol-1-yl)-3, 4-Dihydro-1,2-benzoxaazepinene-8-carboxylic acid [Chem. 87] (4R)-4-[2-(3-Aminopyrrolidin-1-yl)-2-oxoethyl]thio-3,3-dihydroxy-9-(triazol-1-yl) -2-oxa-3-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 88] , (3R)-2-hydroxy-7-methoxy-3-[2-o-oxy-2-(2-o-oxy-1,3-1,3-oxazolidin-3-yl)ethyl]thio -3,4-dihydro-2H-1,2-benzoxoxaborox-8-carboxylic acid [Chemical 89] , (4R)-3,3-dihydroxy-9-methoxy-4-[2-o-oxy-2-(2-o-oxy-1,3-oxazolidin-3-yl)ethyl Thio-2-oxo-3-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [90] , (3R)-3-[(2-2,7-diazaspiro[4.4]decane-2-yl-2-yloxyethyl)thio]-2-hydroxy-7-methoxy- 3,4-Dihydro-2H-1,2-benzoxaazepinene-8-carboxylic acid [Chem. 91] , (4R)-4-[2-(2,7-diazaspiro[4.4]decane-2-yl)-2-oxoethyl]thio-3,3-dihydroxy-9- Oxy-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1(6),7,9-triene-10-carboxylic acid [Chem. 92] , (3R)-3-[2-(2,9-diazaspiro[4.5]decane-2-yl)-2-yloxyethyl]thio-2-hydroxy-7-methoxy- 3,4-Dihydro-1,2-benzoxaazepinehex-8-carboxylic acid [Chem. 93] , (3R)-3-[2-(2,9-diazaspiro[4.5]decane-2-yl)-2-yloxyethyl]thio-4,4-dihydroxy-8- Oxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chem. 94] , (3R)-3-[2-(1,7-diazaspiro[3.4]octane-7-yl)-2-oxoethylethyl]thio-2-hydroxy-7-methoxy- 3,4-Dihydro-1,2-benzoxaazepinehex-8-carboxylic acid [Chem. 95] , (3R)-3-[2-(1,7-diazaspiro[3.4]octane-7-yl)-2-oxoethyl]thio-4,4-dihydroxy-8- Oxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chem. 96] , (3R)-2-hydroxy-7-methoxy-3-[2-o-oxy-2-(2-oxo-imidazolidine-1-yl)ethyl]thio-3,4-di Hydrogen-1,2-benzoxaazepinene-8-carboxylic acid [Chemical 97] (3R)-4,4-Dihydroxy-8-methoxy-3-[2-o-oxy-2-(2-oxoisidazolidine-1-yl)ethyl]thio-5- Oxa-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chem. 98] (3R)-2-Hydroxy-7-methoxy-3-[2-o-oxy-2-(3-o-oxypyrazolidin-1-yl)ethyl]thio-3,4- Dihydro-1,2-benzoxaazepinene-8-carboxylic acid [Chem. 99] (3R)-4,4-Dihydroxy-8-methoxy-3-[2-o-oxy-2-(3-o-oxypyrazolidin-1-yl)ethyl]thio-5 -oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid [100] , (3R)-3-[2-[3-(2-Aminoethylaminemethylmercapto)azetidin-1-yl]-2-oxoethyl]thio-2-hydroxy-7- Methoxy-3,4-dihydro-1,2-benzoxaaborylcyclo-8-carboxylic acid [Chem. 101] , (3R)-3-[2-[3-(2-Aminoethylamine-carbamoyl)azetidin-1-yl]-2-oxoethyl]thio-4,4-dihydroxy -8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chem. 102] (3R)-3-[2-[5-(Aminomethyl)-2-oxo-1,3-1,3-oxazolidin-3-yl]-2-oxoethyl]thio-2 -hydroxy-7-methoxy-3,4-dihydro-1,2-benzoxaazepinehex-8-carboxylic acid [Chem. 103] (3R)-3-[2-[5-(Aminomethyl)-2-oxo-1,3-1,3-oxazolidin-3-yl]-2-oxoethyl]thio-4 ,4-dihydroxy-8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chem. 104] (3R)-3-[2-(4-Amino-3-oxooxypyrazin-1-yl)-2-oxoethylethyl]thio-2-hydroxy-7-methoxy- 3,4-dihydro-1,2-benzoxaazepinehex-8-carboxylic acid [Chem. 105] , (3R)-3-[2-(4-Amino-3-epoxypyrazolidin-1-yl)-2-oxoethyl]thio-4,4-dihydroxy-8- Oxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [Chem. 106] (3R)-3-[3-(3-Aminopyrrolidin-1-yl)-3-oxopropyl propyl]thio-2-hydroxy-7-methoxy-3,4-dihydro -1,2-benzoxaazepinene-8-carboxylic acid [107] (3R)-3-[3-(3-Aminopyrrolidin-1-yl)-3-oxopropyl propyl]thio-4,4-dihydroxy-8-methoxy-5-oxygen Hetero-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [化108] (3R)-3-[4-(3-Aminopyrrolidin-1-yl)-4-oxobutyl]thio-2-hydroxy-7-methoxy-3,4-dihydro- 1,2-benzoxoxaboryl-8-carboxylic acid [Chem. 109] Or (3R)-3-[4-(3-Aminopyrrolidin-1-yl)-4-oxobutylbutyl]thio-4,4-dihydroxy-8-methoxy-5-oxygen Hetero-4-boron anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylic acid [110] . The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following compound name or structure: (3R)-4,4-dihydroxy-3-{[2-(3-amine) Pyryryryl-1-yl)-2-yloxyethyl]thio}-8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7 , 9-triene-7-carboxylic acid [111] . A compound according to claim 28 or 29 which is represented by the following compound name or structure: (3R)-4,4-dihydroxy-3-{[2-(3-aminopyrrolidin-1-yl)- 2-sided oxyethyl]thio}-8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9-triene-7-carboxylate Acid disodium salt [化112] . The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following compound name or structure: (3R)-4,4-dihydroxy-3-{[2-(3-A) Oxybutyridin-1-yl)-2-oxoethylethyl]thio}-8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6) , 7,9-triene-7-carboxylic acid [Chemical 16] . The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following compound name or structure: (3R)-4,4-dihydroxy-3-{[2-(3-amine) Ketopyridin-1-yl)-2-oxoethylethyl]thio}-8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6), 7,9-triene-7-carboxylic acid [Chemical 18] . The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following compound name or structure: (3R)-4,4-dihydroxy-3-{[2-(azetidine) -1-yl)-2-yloxyethyl]thio}-8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7,9- Triene-7-carboxylic acid [Chemical 24] . The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following compound name or structure: (3R)-4,4-dihydroxy-3-{[2-(3-hydroxyl) Azetidin-1-yl)-2-oxoethyl]thio}-8-methoxy-5-oxa-4-boran anion heterobicyclo[4.4.0]癸-1(6),7 , 9-triene-7-carboxylic acid [Chem. 34] . The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following compound name or structure: (4R)-4-[2-[3-(aminomethyl)azetidine -1-yl]-2-oxoethyl]thio-3,3-dihydroxy-9-methoxy-2-oxa-3-boroanion heterobicyclo[4.4.0]癸-1 (6 ), 7,9-triene-10-carboxylic acid disodium salt [Chemical 112A] . The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following compound name or structure: (3R)-3-[2-[3-(2-Aminoethylamine A) Mercapto)azetidin-1-yl]-2-oxoethyl]thio-2-hydroxy-7-methoxy-3,4-dihydro-1,2-benzoxazepine Cyclo-8-carboxylic acid [Chem. 101] . A medicine comprising a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof. The medicine of claim 37, which is a therapeutic or prophylactic agent for bacterial infection. A β-endoprostanase inhibitor comprising the compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 40, which further comprises an additional pharmaceutical agent. The composition of claim 41, wherein the additional agent is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent. The composition of claim 41 or 42, wherein the additional agent is a β-endoxime-based agent. The composition according to any one of claims 41 to 43, wherein the β-endoxime-based agent as an additional agent is preferably selected from the group consisting of amoxicillin and ampicillin (Bian Bixilin, Schindlerin, Baker) Xilin, Meidacillin, Ta'an Bixilin), Ipicillin, Caberinicil (Carbacycillin), Ticarcillin, Temocillin, Anoxicillin, Piperacillin, Mezlocillin, Mexilin Xilin), sulfacillin, benzylpenicillin (G), chloromethacetin, benzathine penicillin, procaine benzylpenicillin, adesicillin, phenacetin, phenoxymethylpenicillin (V), isoprocillin, benzathine Phenoxymethyl penicillin, fenacetin, cloxacillin (diclocillin, flucloxacillin), oxcillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertape South, imipenem, meropenem, panipenem, tomopenem, azupirin, cefazolin, cefacitrile, cefadroxil, cephalexin, ceftriax, cefprozin, cefotaxime , cefotaxime, cefpirin, ceftriaxone, cefotaxime, cefmenoxime, cephalosporin Ding, cefafloxadine, ceftezole, cefaclor, cefmenudene, cefminox, cefonicid, cefretide, cefotiam, cefprozil, cefradine, cefuroxime, cephalosporin Methane, cefoxitin, cefotetan, cefmetazole, cefotaxime, cefaclor, ceftazidime, ceftriaxone, cefaclor, cefdicarb, cefdinir, cefetacrot, cefetamet, cefeta Earthworm, cefmenoxime, cefoperazone, cefotaxime, cefotaxime, cefpiramide, cefpodoxime, cefsudene, ceftriaxone, ceftibuten, cefotaxime, ceftizoxime, oxyfluoride Cephalosporin, Latamoxef, cefepime, cefazolin, cefpirome, cefquinome, cefepip, ceftaroline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, ceftiofur, cefquinome, cefovecin, aztreonam, timumomon, carumonam, RWJ-442831, RWJ-333441, or RWJ-333442. The composition of claim 43 or 44, wherein the β-endoxime-based agent is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, or panipene south. The composition of claim 43 or 44, wherein the β-endoxime-based agent is selected from the group consisting of aztreonam, timumomon, BAL30072, SYN2416 or carumon. The pharmaceutical composition of claim 40, which is administered together with an additional pharmaceutical agent. The composition of claim 47, wherein the additional agent is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent. The composition of claim 47 or 48, wherein the additional agent is a β-endoxime-based agent. The composition according to any one of claims 47 to 49, wherein the β-endoxime-based agent as an additional agent is preferably selected from the group consisting of amoxicillin and ampicillin (Bian Bixilin, Schindlerin, Baker) Xilin, Meidacillin, Ta'an Bixilin), Ipicillin, Caberinicil (Carbacycillin), Ticarcillin, Temocillin, Anoxicillin, Piperacillin, Mezlocillin, Mexilin Xilin), sulfacillin, benzylpenicillin (G), chloromethacetin, benzathine penicillin, procaine benzylpenicillin, adesicillin, phenacetin, phenoxymethylpenicillin (V), isoprocillin, benzathine Phenoxymethyl penicillin, fenacetin, cloxacillin (diclocillin, flucloxacillin), oxcillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertape South, imipenem, meropenem, panipenem, tomopenem, azupirin, cefazolin, cefacitrile, cefadroxil, cephalexin, ceftriax, cefprozin, cefotaxime , cefotaxime, cefpirin, ceftriaxone, cefotaxime, cefmenoxime, cephalosporin Ding, cefafloxacin, ceftezole, cefaclor, cefmenudene, cefminox, cefonicid, cefreet, cefotiam, cefprozil, cefradine, cefuroxime, ceftizoxime, cephalosporin Sidding, cefotetan, cefmetazole, chlorocarbon cephalosporin, cefixime, ceftazidime, ceftriaxone, ceftriaxone, cefdaroxime, cefdinir, cefetacrot, cefetamet, cefmenoxime, cephalosporin Diqin, cefoperazone, cefotaxime, cefotaxime, cefpiramide, cefpodoxime, cefsulodin, ceftriaxone, ceftibuten, cefotaxime, cephalosporin, fluoxetine, oxycephalosporin, Cefepime, cefazolin, cefpirome, cefquinome, cefpiride, ceftaroline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, ceftiofur, cefquinome, Cefavidin, aztreonam, tigemonan, carumonam, RWJ-442831, RWJ-333441, or RWJ-333442. The composition of claim 49 or 50, wherein the β-endoxime-based agent is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, or panipene south. The composition of claim 49 or 50, wherein the β-endoxime-based agent is selected from the group consisting of aztreonam, timumomon, BAL30072, SYN2416 or carumon. a compound of the following formula (2) or a pharmaceutically acceptable salt thereof, [Chem. 113] (In the formula (2), Q represents a hydroxyl group, a thiol group, or -NHR ^a1 , and Z, L, Y, R ¹ , R ² , R ³ , R ⁴ and R ^a1 are the same as those defined in the claim 1 , Equation (1a) has the same meaning as Request Item 1). The compound of claim 53 or a pharmaceutically acceptable salt thereof, wherein the L system is the same as defined in any one of claims 2 to 4. The compound of any one of claims 5 to 54 or a pharmaceutically acceptable salt thereof, wherein Y is the same as defined in any one of claims 5 to 7. The compound of any one of claims 53 to 55, wherein the Q is a hydroxyl group or a thiol group, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 53 to 56, or a pharmaceutically acceptable salt thereof, wherein Q is a hydroxyl group. A compound according to any one of claims 53 to 57, wherein the Z system is the same as defined in any one of claims 19 to 21, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 53 to 58, or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are as defined in claim 22 or 23. The compound of any one of claims 53 to 59, or a pharmaceutically acceptable salt thereof, wherein R ³ is the same as defined in claim 24 or 25. The compound of any one of claims 53 to 60, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is the same as defined in claim 26 or 27. The compound of claim 53 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 3-[(2R)-{[2-(3-aminopyrrolidin-1-yl)- 2-sided oxyethyl]thio}-2-(dihydroxyboryl)ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 114] , 2-hydroxy-3-[(2R)-2-(hydroxyboranyl)-2-{[2-o-oxy-2-(pyrrolidin-1-yl)ethyl]thio}ethyl] -6-methoxybenzoic acid [化115] , 3-[(2R)-2-(Dihydroxyboryl)-2-{[2-o-oxy-2-(pyrrolidin-1-yl)ethyl]thio}ethyl]-2 -hydroxybenzoic acid [Chem. 116] , 3-[(2R)-2-(Dihydroxyboryl)-2-{[1-o-oxy-1-(pyrrolidin-1-yl)propan-2-yl]thio}ethyl ]-2-hydroxy-6-methoxybenzoic acid [Chemical 117] , 3-[(2R)-2-(Dihydroxyboryl)-2-{[2-(4-methylpiperazin-1-yl)-2-oxoethyl]thio}ethyl ]-2-hydroxy-6-methoxybenzoic acid [化118] , 3-[(2R)-2-(Dihydroxyboryl)-2-{[2-(3-methoxyazetidin-1-yl)-2-yloxyethyl]thio] Ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 119] , 3-[(2R)-2-{[2-(3-Aminoazetidin-1-yl)-2-yloxyethyl]thio}-2-(dihydroxyboryl)B 2-hydroxy-6-methoxybenzoic acid [120] , 3-[(2R)-2-(Dihydroxyboryl)-2-{[2-Sideoxy-2-(piperazin-1-yl)ethyl]thio}ethyl]-2 -hydroxy-6-methoxybenzoic acid [Chem. 121] , 3-[(2R)-2-{[2-(4-Aminopiperidin-1-yl)-2-yloxyethyl]thio}-2-(dihydroxyboryl)ethyl ]-2-hydroxy-6-methoxybenzoic acid [化122] , 3-[(2R)-2-{[2-(azetidin-1-yl)-2-yloxyethyl]thio}-2-(dihydroxyboryl)ethyl]-2 -hydroxy-6-methoxybenzoic acid [123] , 3-[(2R)-2-(Dihydroxyboryl)-2-{[2-(3-methoxypyrrolidin-1-yl)-2-yloxyethyl]thio}B 2-hydroxy-6-methoxybenzoic acid , 3-[(2R)-2-(Dihydroxyboryl)-2-({2-[2-(dimethylaminocarbamoyl)pyrrolidin-1-yl]-2-oxoxy B (yl)thio)ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 125] , 3-[(2R)-2-(Dihydroxyboryl)-2-({2-[2-(methoxymethyl)pyrrolidin-1-yl]-2-yloxyethyl} Thio)ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 126] , 3-[(2R)-2-(Dihydroxyboryl)-2-{[2-(porphyrin-4-yl)-2-yloxyethyl]thio}ethyl]-2- Hydroxy-6-methoxybenzoic acid [化127] , 3-[(2R)-2-(Dihydroxyboryl)-2-{[2-(3-hydroxyazetidin-1-yl)-2-yloxyethyl]thio}ethyl ]-2-hydroxy-6-methoxybenzoic acid [化128] , 3-[(2R)-2-(Dihydroxyboryl)-2-({2-[2-(hydroxymethyl)pyrrolidin-1-yl]-2-oxoethyl}thio) Ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 129] , 3-[(2R)-2-(Dihydroxyboryl)-2-{[2-(4-hydroxypiperidin-1-yl)-2-yloxyethyl]thio}ethyl] -2-hydroxy-6-methoxybenzoic acid [Chem. 130] , 3-[(2R)-2-{[2-(3-Aminopyrrolidin-1-yl)-2-oxoethyl]thio}-2-(dihydroxyboryl)ethyl ]-2-hydroxy-6-(methylthio)benzoic acid [Chem. 131] , 3-[(2R)-2-Dihydroxyboryl-2-{[2-(3-hydroxypyrrolidin-1-yl)-2-yloxyethyl]thio}ethyl]-2-hydroxyl -6-methoxybenzoic acid [化132] , 3-[(2R)-2-({2-[(3S)-3-Aminopyrrolidin-1-yl]-2-yloxyethyl}thio)-2-dihydroxyborylethyl ]-2-hydroxy-6-methoxybenzoic acid [化133] , 3-[(2R)-2-({2-[(3R)-3-Aminopyrrolidin-1-yl]-2-yloxyethyl}thio)-2-dihydroxyborylethyl ]-2-hydroxy-6-methoxybenzoic acid [Chem. 134] , 3-[(2R)-2-dihydroxyboryl-2-({2-[3-(methylamino)pyrrolidin-1-yl]-2-oxoethyl}thio)ethyl ]-2-hydroxy-6-methoxybenzoic acid [Chemical 135] , 3-[(2R)-2-({2-[2-(Aminomethyl)pyrrolidin-1-yl]-2-yloxyethyl}thio)-2-dihydroxyborylethyl ]-2-hydroxy-6-methoxybenzoic acid [Chemical 136] , 3-[(2R)-2-({2-[3-(Aminomethyl)pyrrolidin-1-yl]-2-yloxyethyl}thio)-2-dihydroxyborylethyl ]-2-hydroxy-6-methoxybenzoic acid (open ring corresponding to the more polar non-image isomer (1)) [Chem. 137] , 3-[(2R)-2-({2-[3-(Aminomethyl)pyrrolidin-1-yl]-2-yloxyethyl}thio)-2-dihydroxyborylethyl ]-2-hydroxy-6-methoxybenzoic acid (open ring corresponding to the less polar non-image isomer (2)) [Chem. 138] , 3-[(2R)-2-({2-[3-(Aminomethyl)azetidin-1-yl]-2-yloxyethyl}thio)-2-dihydroxyboryl 2-hydroxy-6-methoxybenzoic acid , 3-[(2R)-2-Dihydroxyboryl-2-{[2-(4-ethaneimidopiperazin-1-yl)-2-yloxyethyl]thio}ethyl] -2-hydroxy-6-methoxybenzoic acid [Chem. 140] , 3-[(2R)-2-{[2-(3-Amino-4-methylpyrrolidin-1-yl)-2-yloxyethyl]thio}-2-dihydroxyboryl 2-hydroxy-6-methoxybenzoic acid [Chemical 141] , 3-[(2R)-2-{[2-(3-Aminopiperidin-1-yl)-2-yloxyethyl]thio}-2-dihydroxyborylethyl]-2- Hydroxy-6-methoxybenzoic acid (open ring corresponding to the more polar non-image isomer (1)) [Chem. 142] , 3-[(2R)-2-{[2-(3-Aminopiperidin-1-yl)-2-yloxyethyl]thio}-2-dihydroxyborylethyl]-2- Hydroxy-6-methoxybenzoic acid (open ring corresponding to the less polar non-image isomer (2)) [Chem. 143] , 3-[(2R)-2-{[2-[2-(Aminomethyl)piperidin-1-yl]-2-yloxyethyl]thio}-2-dihydroxyborylethyl ]-2-hydroxy-6-methoxybenzoic acid [化144] , 3-{(2R)-2-[(2-{3-[(2-Aminoethyl)amino]pyrrolidin-1-yl}-2-yloxyethyl)thio]-2- Dihydroxyborylethyl}-2-hydroxy-6-methoxybenzoic acid (open ring corresponding to the more polar non-image isomer (1)) [Chem. 145] , 3-{(2R)-2-[(2-{3-[(2-Aminoethyl)amino]pyrrolidin-1-yl}-2-yloxyethyl)thio]-2- Dihydroxyborylethyl}-2-hydroxy-6-methoxybenzoic acid (open ring corresponding to the less polar non-image isomer (2)) [Chem. 146] , 3-[(2R)-2-{[2-(3-Aminopyrrolidin-1-yl)-2-yloxyethyl]thio}-2-dihydroxyborylethyl]-5- Chloro-2-hydroxy-6-methoxybenzoic acid [Chemical 147] , 3-[(2R)-2-({2-[4-(Aminomethyl)piperidin-1-yl]-2-yloxyethyl}thio)-2-dihydroxyborylethyl ]-2-hydroxy-6-methoxybenzoic acid [化148] , 3-[(2R)-2-Dihydroxyboryl-2-{[2-(1,7-diazaspiro[4.4]decane-7-yl)-2-oxoethyl]thio }Ethyl]-2-hydroxy-6-methoxybenzoic acid (open ring corresponding to the more polar non-image isomer (1)) [Chem. 149] , 3-[(2R)-2-Dihydroxyboryl-2-{[2-(1,7-diazaspiro[4.4]decane-7-yl)-2-oxoethyl]thio }Ethyl]-2-hydroxy-6-methoxybenzoic acid (open ring corresponding to the less polar non-image isomer (2)) [Chem. 150] , 3-[(2R)-2-Dihydroxyboryl-2-{[2-(2,8-diazaspiro[4.5]decan-2-yl)-2-yloxyethyl]thio }ethyl]-2-hydroxy-6-methoxybenzoic acid [化151] , 3-[(2R)-2-{[2-(3-acetamilidyrrolidin-1-yl)-2-yloxyethyl]thio}-2-dihydroxyborylethyl]-2 -hydroxy-6-methoxybenzoic acid [Chem. 152] , 3-[(2R)-2-dihydroxyboryl-2-{[2-(2,6-diazaspiro[3.4]octane-6-yl)-2-oxoethyl]thio }Ethyl]-2-hydroxy-6-methoxybenzoic acid [Chem. 153] , 3-[(2R)-2-dihydroxyboryl-2-{[2-(hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-2-yloxyethyl] Thioethyl}ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 154] , 3-[(2R)-2-{[2-(3-Aminopyrrolidin-1-yl)-2-yloxyethyl]thio}-2-dihydroxyborylethyl]-2- Hydroxy-6-(1H-1,2,3-triazol-1-yl)benzoic acid [Chem. 155] , 3-[(2R)-2-dihydroxyboryl-2-{[2-o-oxy-2-(2-o-oxy-1,3-1,3-oxazolidin-3-yl)ethyl]sulfide Ethyl}-2-hydroxy-6-methoxybenzoic acid [Chemical 156] , 3-[(2R)-2-Dihydroxyboryl-2-{[2-(2,7-diazaspiro[4.4]decan-2-yl)-2-yloxyethyl]thio }Ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 157] , 3-[(2R)-2-Dihydroxyboryl-2-{[2-(2,9-diazaspiro[4.5]decane-2-yl)-2-yloxyethyl]thio }Ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 158] , 3-[(2R)-2-dihydroxyboryl-2-{[2-(1,7-diazaspiro[3.4]octane-6-yl)-2-oxoethyl]thio }Ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 159] , 3-[(2R)-2-Dihydroxyboryl-2-{[2-Sideoxy-2-(2-Sideoxyimidazolidin-1-yl)ethyl]thio}ethyl]- 2-hydroxy-6-methoxybenzoic acid [化160] , 3-[(2R)-2-dihydroxyboryl-2-{[2-o-oxy-2-(3-o-oxypyrazolidin-1-yl)ethyl]thio}ethyl] -2-hydroxy-6-methoxybenzoic acid [Chem. 161] , 3-{(2R)-2-[(2-{3-[(2-Aminoethyl)aminemethanyl]azetidin-1-yl}-2-yloxyethyl)thio] -2-Dihydroxyborylethyl}-2-hydroxy-6-methoxybenzoic acid [Chem. 162] , 3-[(2R)-2-({2-[5-(Aminomethyl)-2-oxo-1,3-1,3-oxazolidine-3-yl]-2-yloxyethyl} Thio)-2-dihydroxyborylethyl]-2-hydroxy-6-methoxybenzoic acid [Chem. 163] , 3-[(2R)-2-{[2-(4-Amino-3-oxooxypyrazin-1-yl)-2-yloxyethyl]thio}-2-dihydroxyboron Ethylethyl]-2-hydroxy-6-methoxybenzoic acid , 3-[(2R)-2-{[3-(3-Aminopyrrolidin-1-yl)-3-yloxypropyl]thio}-2-dihydroxyborylethyl]-2 -hydroxy-6-methoxybenzoic acid [Chem. 165] Or 3-[(2R)-2-{[4-(3-Aminopyrrolidin-1-yl)-4-yloxybutyl]thio}-2-dihydroxyborylethyl]-2 -hydroxy-6-methoxybenzoic acid [Chemical 166] . The compound of claim 53 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 3-[(2R)-{[2-(3-aminopyrrolidin-1-yl)- 2-sided oxyethyl]thio}-2-(dihydroxyboryl)ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 167] . The compound of claim 53, wherein the compound is selected from the group consisting of 3-[(2R)-2-(dihydroxyboryl)-2-{[2- (3-methoxyazetidin-1-yl)-2-oxoethyl]thio}ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 119] . The compound of claim 53 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 3-[(2R)-2-{[2-(3-aminoazetidine-1- ))-2-oxoethyl]thio}-2-(dihydroxyboryl)ethyl]-2-hydroxy-6-methoxybenzoic acid [120] . The compound of claim 53 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 3-[(2R)-2-{[2-(azetidin-1-yl)-2 -Side oxyethyl]thio}-2-(dihydroxyboryl)ethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 123] . The compound of claim 53, wherein the compound is selected from the group consisting of 3-[(2R)-2-(dihydroxyboryl)-2-{[2- (3-hydroxyazetidin-1-yl)-2-oxoethyl]thio}ethyl]-2-hydroxy-6-methoxybenzoic acid [化128] . The compound of claim 53 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 3-[(2R)-2-({2-[3-(aminomethyl)) Pyridin-1-yl]-2-oxoethyl}thio)-2-dihydroxyborylethyl]-2-hydroxy-6-methoxybenzoic acid [Chemical 139] . The compound of claim 53 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 3-{(2R)-2-[(2-{3-[(2-aminoethyl) Aminomethyl hydrazinyl] azetidin-1-yl}-2-oxoethyl)thio]-2-dihydroxyborylethyl}-2-hydroxy-6-methoxybenzoic acid ] . A pharmaceutical composition comprising a compound of the formula (1a) or (1b) according to any one of claims 1 to 36, which may further comprise a compound of the formula (2) according to any one of claims 53 to 69. A pharmaceutical composition comprising a compound of the formula (2) according to any one of claims 53 to 69, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 70 or 71 for use with an additional pharmaceutical agent. The composition of claim 72, wherein the additional agent is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent. The composition of claim 72 or 73, wherein the additional agent is a β-endoxime-based agent. The composition according to any one of claims 72 to 74, wherein the β-endoxime-based agent as an additional agent is preferably selected from the group consisting of amoxicillin and ampicillin (Bian Bixilin, Schindlerin, Baker) Xilin, Meidacillin, Ta'an Bixilin), Ipicillin, Caberinicil (Carbacycillin), Ticarcillin, Temocillin, Anoxicillin, Piperacillin, Mezlocillin, Mexilin Xilin), sulfacillin, benzylpenicillin (G), chloromethacetin, benzathine penicillin, procaine benzylpenicillin, Azidocillin, phenacetin, phenoxymethylpenicillin (V), isoproterenol , benzathine phenoxymethylpenicillin, fenacetin, cloxacillin (diclocillin, flucloxacillin), oxcillin, methicillin, nafcillin, faropenem, biapenem, doripenem, Ertapenem, imipenem, meropenem, panipenem, tomopenem, azupirin, cefazolin, cefacitrim, cefadroxil, cephalexin, cefmenita, ceftaron, Ceftiodine, cefotaxime, cefpirin, ceftriaxone, cefotaxime, cephalosporin Fluoride, cefradine, cefafloxadine, ceftezole, cefaclor, cefmenudene, cefminox, cefonicoxif, cefreet, cefotiam, cefprozil, cefradine, cefuroxime, ceftizox , cefoxitin, cefotetan, cefmetazole, chlorocarbon cephalosporin, cefixime, ceftazidime, ceftriaxone, cefaclor, cefdicarb, cefdinir, cefetacrom, ceftazidime, cefmenoxime , cefodizime, cefoperazone, cefotaxime, cefotaxime, cefpiramide, cefpodoxime, cefsulodin, ceftriaxone, ceftibuten, cefotaxime, ceftizoxime, fluoxetine, pull oxygen Cephalosporin, cefepime, cefazolin, cefpirome, cefquinome, cefpiride, ceftaroline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, ceftiofur, cefquinome Conne, cefovirin, aztreonam, tigimonan, carumonam, RWJ-442831, RWJ-333441, or RWJ-333442. The composition of claim 74 or 75, wherein the β-endoxime-based agent is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, or panipene south. The composition of claim 74 or 75, wherein the beta-endoxime-based agent is selected from the group consisting of aztreonam, timumomon, BAL30072, SYN2416 or carumon. A therapeutic agent for a bacterial infection, which comprises a compound according to any one of claims 1 to 36, and a pharmaceutically acceptable salt thereof, as claimed in any one of claims 53 to 69. The therapeutic agent of claim 78, wherein the bacterial infection is a bacterial infection associated with a bacteria that may have beta-endoprostanase. The therapeutic agent according to claim 75 or 79, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, paranasal inflammation, pneumonia, lung abscess, empyema Secondary infection of chronic respiratory disease, pharyngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic/lymphitis, trauma Secondary infections such as burns and surgical wounds, urinary tract infections, genital infections, ocular infections or odontogenic infections. A use of a compound according to any one of claims 1 to 36 and a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for bacterial infection. The use of claim 81, wherein the bacterial infection is a bacterial infection associated with a bacteria that may have beta-endosaminolase. The use of claim 81 or 82, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, paranasalitis, pneumonia, lung abscess, empyema, Secondary infection of chronic respiratory disease, pharyngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic/lymphitis, trauma/ Secondary infections such as burns and surgical wounds, urinary tract infections, genital infections, ocular infections, or odontogenic infections. The use of any one of claims 81 to 83, wherein the therapeutic agent further comprises an additional agent. The application of claim 64, wherein the additional agent is the additional agent described in any one of claims 42 to 46. The use of any one of claims 81 to 83, wherein the therapeutic agent is administered together with an additional agent. The application of claim 86, wherein the additional agent is the additional agent described in any one of claims 48 to 52. A method for treating a bacterial infection, characterized in that a therapeutically effective amount of a compound according to any one of claims 1 to 36 and any one of claims 53 to 69 or a pharmaceutical thereof is administered to a patient in need of treatment The salt allowed. The method of claim 88, wherein the bacterial infection is a bacterial infection associated with a bacteria that may have beta-endosaminolase. The method of claim 88 or 89, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, paranasalitis, pneumonia, lung abscess, empyema, Secondary infection of chronic respiratory disease, pharyngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic/lymphitis, trauma/ Secondary infections such as burns and surgical wounds, urinary tract infections, genital infections, ocular infections, or odontogenic infections. The method of any one of claims 88 to 90, wherein the method is to administer additional medicament together. The method of claim 91, wherein the additional agent is the additional agent described in any one of claims 42 to 46. The compound of any one of claims 1 to 36, wherein the compound of any one of claims 53 to 69, or a pharmaceutically acceptable salt thereof, is for use in the treatment of a bacterial infection. A compound according to claim 93, or a pharmaceutically acceptable salt thereof, wherein the bacterial infection is a bacterial infection associated with a bacterium having beta-endosaminolase. The compound of claim 93 or 94 or a pharmaceutically acceptable salt thereof, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, paranasal nasal cavity Inflammation, pneumonia, lung abscess, empyema, secondary infection of chronic respiratory disease, pharyngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection Secondary infections such as lymphatic/lymphitis, trauma/scald, and surgical wounds, urinary tract infections, genital infections, ocular infections, or odontogenic infections. A medicinal preparation according to any one of claims 1 to 36 and a pharmaceutically acceptable salt thereof, and a septicemia, febrile neutropenia, bacterium Meningitis, bacterial endocarditis, otitis media, paranasal vaginitis, pneumonia, lung abscess, empyema, secondary infection of chronic respiratory disease, pharyngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraperitoneal Secondary infections such as abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic/lymphitis, trauma/scald, and surgical wounds, urinary tract infections, genital infections, ocular infections, or odontogenic At least one or more of the therapeutic agents for infection are combined. A pharmaceutical composition, which comprises a β-namidamide-based pharmaceutical agent, and the pharmaceutical composition is a compound according to any one of claims 1 to 36 and any one of claims 53 to 69 or a method thereof The pharmaceutically acceptable salt is administered together. The composition of claim 97, wherein the β-endamine compound is selected from the group consisting of amoxicillin, ampicillin (Bian Bixilin, sidacillin, Becksilin, Medacillin, Ta'an Bixilin), and Ipicillin , phenecillin (calicillin), ticarcillin, temocillin, anocillin, piperacillin, mezlocillin, mecillin (pimesicillin), benzylicillin, benzylpenicillin (G), chlorine Mexicillin, benzathine penicillin, procaine benzylpenicillin, adesicillin, phenacetin, phenoxymethylpenicillin (V), isoprocillin, benzathine phenoxymethylpenicillin, fenacetin, cloxacillin ( Diclocillin, flucloxacillin, ocillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem , tomopenem, azupiran, cefazolin, cefotaxime, cefadroxil, cephalexin, ceftriaxone, ceftronin, ceftazidime, cefotaxime, cefpirin, ceftriaxone, cefoxit Ketone, cefafluzin, cefradine, cefafloxacin, ceftezole, cefixime Lo, cefmenodone, cefminox, cefonicid, ceftrid, cefotiam, cefprozil, cefradine, cefuroxime, ceftizoxime, cefoxitin, cefotetan, cefmetazole, chlorine Carbon cephalosporin, cefixime, ceftazidime, ceftriaxone, ceftriaxone, cefdaroxime, cefdinir, cefetacrot, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cephalosporin Imidazole, cefpiramide, cefpodoxime, cefsulodin, ceftriaxone, ceftibuten, cefotaxime, cephalosporin, fluoxetine, cephalosporin, cefepime, cefazolin, cefpirome, Cefquinol, cefpiride, ceftaroline, CXA-101, RWJ-54428, MC-04546, ME1036, BAL30072, SYN2416, ceftiofur, cefquinome, cefavirin, aztreonam, tigemonan At least one of Carusmonan, RWJ-442831, RWJ-333441, or RWJ-333442. The composition of claim 97 or 98, wherein the beta-endoperamine-based agent is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, or panis Peinan. The composition of claim 97 or 98, wherein the beta-endoxime-based agent is selected from the group consisting of aztreonam, timumomon, BAL30072, SYN2416 or carumon. The composition of any one of claims 97 to 100 for use in the treatment of a bacterial infection. The composition of claim 101, wherein the bacterial infection is a bacterial infection associated with a bacterium having beta-endosaminolase. The composition of claim 101 or 102, wherein the bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, paranasalitis, pneumonia, lung abscess, empyema Secondary infection of chronic respiratory disease, pharyngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intra-abdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic/lymphitis, trauma Secondary infections such as burns and surgical wounds, urinary tract infections, genital infections, ocular infections or odontogenic infections. A method for producing a compound represented by the formula (1b) [Formula 168] Formula (1b): [In the formula (1b), X, Z, L, Y, R ¹ , R ² , R ³ , and R ⁴ are as defined in the claim 1], and include the following steps: in the formula (1a): ] In the formula (1a), a compound is added to the compound represented by X, Z, L, Y, R ¹ , R ² , R ³ and R ⁴ as defined by the formula (1b). The method of claim 104, wherein the base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate, potassium t-butoxide, sodium methoxide, sodium ethoxide. a group consisting of sodium amide, and lithium diisopropyl guanamine. The method of claim 104 or 105, wherein Z is a hydroxyl group, and the base is selected from the group consisting of lithium hydroxide, sodium hydroxide, and potassium hydroxide.