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  • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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  • C07—ORGANIC CHEMISTRY
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  • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
  • C07F5/02—Boron compounds

Definitions

• the present invention relates to an oxo-substituted compound useful as a medicine, or a pharmaceutically acceptable salt thereof. More particularly, the present invention relates to a pharmaceutical composition containing a novel oxo-substituted compound or a pharmaceutically acceptable salt thereof. The present invention relates to a therapeutic agent containing the oxo-substituted compound or a pharmaceutically acceptable salt thereof.
• ⁇ -lactam drugs for example, penicillin antibacterial agents, cephalosporin antibacterial agents, carbapenem antibacterial agents
• penicillin antibacterial agents for example, penicillin antibacterial agents, cephalosporin antibacterial agents, carbapenem antibacterial agents
• carbapenem antibacterial agents are the most widely used drugs for the treatment of bacterial infections due to their strong bactericidal activity and high safety .
• ⁇ -lactam drugs the emergence and spread of pathogenic bacteria that have acquired resistance to ⁇ -lactam drugs has become a global problem.
• the resistance mechanisms of these pathogens include ⁇ -lactamase production, structural changes in the target molecules of ⁇ -lactam drugs, decreased drug permeability into the bacterial body, and increased drug excretion.
• ⁇ -lactamase that degrades and inactivates system drugs is one of the most important factors in maintaining the effectiveness of ⁇ -lactam drugs.
• Various bacteria have evolved ⁇ -lactamases that counteract the efficacy of various ⁇ -lactams. Based on their amino acid sequences, ⁇ -lactamases can be classified into four classes, namely Ambler classes A, B, C and D. Class A, C and D type enzymes have serine residues at the center of enzyme activity, so they are called serine- ⁇ -lactamases, and class B enzymes do not have serine residues at the center of enzyme activity. Since it has a metal ion zinc (Zn 2+ ), it is called a metallo- ⁇ -lactamase (zinc- ⁇ -lactamase).
• Non-patent Document 1 a combination of a ⁇ -lactamase inhibitor and a ⁇ -lactam agent is effective in solving the problem of resistance development due to the production of ⁇ -lactamase, and a commercially available ⁇ -lactamase inhibitor clavulanic acid , Sulbactam, and tazobactam mainly inhibit class A ⁇ -lactamases except KPC (Klebsiella pneumoniae Carbapeenase), and abibactam is class A including KPC, class C, and some class D including OXA-48 It is known to inhibit ⁇ -lactamase (Non-patent Document 1).
• Patent Documents 1 to 9 Recently, boronic acid derivatives having an inhibitory effect on ⁇ -lactamase have been reported in Patent Documents 1 to 9 and the like. These patent documents include oxo-substituted compounds contained in the present invention, that is, oxo-substituents bonded to a non-aryl heterocycle (preferably nitrogen-containing non-aryl heterocycle) structure in the side chain at a specific position. There is no disclosure of structures related to boronic acid compounds having (—C ( ⁇ O) —, —S ( ⁇ O) —, —S ( ⁇ O) 2 —, etc.).
• the present invention provides a novel compound having an excellent ⁇ -lactamase inhibitory action, and provides a useful preventive or therapeutic agent for bacterial infection in combination with or in combination with a ⁇ -lactam drug.
• sepsis febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary respiratory infections, Pharyngeal / laryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraabdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic vessel / lymphadenitis, trauma / burn, surgical wound, etc.
• a prophylactic or therapeutic agent useful for the treatment of secondary diseases, urinary tract infections, genital infections, eye infections or odontogenic infections, etc., in combination with ⁇ -lactam drugs.
• the inventors of the present invention describe a compound represented by the following formula (1a), (1b) or (11), or a pharmaceutically acceptable salt thereof (hereinafter referred to as “the compound of the present invention”).
• the compound of the present invention has been found to have excellent ⁇ -lactamase inhibitory action, and the present invention has been completed. That is, the present invention is as follows.
• R a3 , R a4 , R a5 , R a6 , R b2 , R b3 And R b4 are independently the same or different and the R a1 , R a2 And R b1 Where R is the same as R a3 And R b2 , R a4 And R b3 Or R a5 And R b4 Are bonded to the same nitrogen atom, they may be taken together to form a 4- to 10-membered nitrogen-containing non-aryl heterocycle, R m1 Is 1) a hydrogen atom, 2) C 1-6 An alkyl group, 3) C 3-10 An alicyclic group, 4) C 6-10 Aryl, 5) 5 or 6 membered heteroaryl, or 6) 4-10 membered non-aryl heterocycle (Provided that each substituent in the above 2) to 6) may be substituted) However, R m1 When R is bonded to a boron atom through an oxygen atom, two R m1
• ZL 2 -L 1 Is a hydrogen atom, optionally substituted C 1-6 An alkyl group, or optionally substituted C 1-6 The compound or a pharmaceutically acceptable salt thereof according to Item A1 or Item A2, which is an alkylthio group.
• G is a compound according to any one of Items A1 to A4 or a pharmaceutically acceptable salt thereof, wherein G is an oxygen atom.
• X is a hydroxyl group or an optionally substituted C 1-6 The compound or a pharmaceutically acceptable salt thereof according to any one of Items A1 to A5, which is an alkoxy group.
• X is a compound according to any one of Items A1 to A6 or a pharmaceutically acceptable salt thereof, wherein X is a hydroxyl group.
• Y is a compound according to any one of Items A1 to A13 or a pharmaceutically acceptable salt thereof, wherein Y is an oxygen atom.
• Compounds of formula (1a) and (1b), compounds of formula (3a) and (3b) or compounds of formula (4a) and (4b) are respectively represented by the following formulas (5a) and (5b): [In Formulas (5a) and (5b), Ring A is an optionally substituted 4- to 6-membered nitrogen-containing non-aryl heterocycle.
• the compound or a pharmaceutically acceptable salt thereof according to any one of Items A1 to A18, which is an alkyl group or an optionally substituted 4- to 10-membered non-aryl heterocyclic carbonyl group.
• R 5 Is optionally substituted 5 or 6 membered heteroaryl or optionally substituted C 6-10 The compound or a pharmaceutically acceptable salt thereof according to any one of Items A1 to A21, which is aryl.
• L 4 Is a single bond and R 5 Is -NR e1 OH, where R e1 Is a hydrogen atom or optionally substituted C 1-6 The compound or a pharmaceutically acceptable salt thereof according to any one of Items A1 to A21, which is an alkyl group.
• R e2 And R f2 are each independently the same or different, a hydrogen atom, or an optionally substituted C 1-6 The compound or a pharmaceutically acceptable salt thereof according to any one of Items A1 to A32, which is an alkyl group.
• R e2 And R f2 The compound or a pharmaceutically acceptable salt thereof according to any one of Items A1 to A33, wherein is a hydrogen atom.
• R 6a Is -NR e2 R f2 And R e2 And R f2 Has one hydrogen atom and the other is C 1-4
• the compound or a pharmaceutically acceptable salt thereof according to any one of Items A24 to A33, which is an alkyl group (provided that the alkyl group may be substituted with an amino group or a hydroxyl group).
• the compound of formula (11) is represented by the following formula (12): [In formula (12), X, R 1 , R 2 , R 3 And R 4 Is synonymous with the definition of term A8]
• the compound of formula (12) is represented by the following formula (13): [In formula (13), X, Y, ring A, L 3 , L 4 , R 1 , R 2 , R 4 And R 5 Is synonymous with the definition of any of term A10 to term A14 or term A16 to term A27]
• X and R G Is a hydroxyl group and R 4
• X is hydroxyl or C 1-6
• [Section A46] The compound according to any one of Items A38 to A45 or a pharmaceutically acceptable salt thereof, wherein X is a hydroxyl group.
• [Section A47] The compound or a pharmaceutically acceptable salt thereof according to any one of Items A42 to A46, wherein m is 1 or 2, n is 1 or 2, and m + n is 2 or 3.
• [Section A48] The compound according to any one of Items A42 to A47 or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1.
• [Section A52] A pharmaceutical comprising the compound according to any one of Items A1 to A51 or a pharmaceutically acceptable salt thereof.
• the pharmaceutical according to Item A52 which is a therapeutic or prophylactic agent for bacterial infection.
• a ⁇ -lactamase inhibitor comprising the compound according to any one of Items A1 to A51 or a pharmaceutically acceptable salt thereof as an active ingredient.
• a pharmaceutical composition comprising the compound according to any one of Items A1 to A51 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
• the pharmaceutical composition according to Item A55 further comprising an additional drug.
• Additional ⁇ -lactam drugs are amoxicillin, ampicillin (pibampicillin, hetacillin, bacampicillin, tampicillin, tarampicillin), epicillin, carbenicillin (calindacillin), ticarcillin, temocillin, azurocillin, piperacillin, mezirocimline, mezolicimline, mezirocimbu Sulbenicillin, benzylpenicillin (G), crometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethylpenicillin (V), propicillin, benzathine phenoxymethylpenicillin, pheneticillin, cloxacillin, cloxacillin, dicloxacillin, Oxacillin, methicillin, nafcillin, faropenem, biapenem, doripene , Eltapenem, imipenem,
• Additional ⁇ -lactam drugs are amoxicillin, ampicillin (pibampicillin, hetacillin, bacampicillin, tampicillin, tarampicillin), epicillin, carbenicillin (calindacillin), ticarcillin, temocillin, azurocillin, piperacillin, mezirocimline, mezolicimline, mezirocimbu Sulbenicillin, benzylpenicillin (G), crometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethylpenicillin (V), propicillin, benzathine phenoxymethylpenicillin, pheneticillin, cloxacillin, cloxacillin, dicloxacillin, Oxacillin, methicillin, nafcillin, faropenem, biapenem, doripene , Eltapenem, imipenem,
• Bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of chronic respiratory lesions, Pharyngeal / laryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraabdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic vessel / lymphadenitis, trauma / burn, surgical wound, etc.
• the compound or a pharmaceutically acceptable salt thereof according to Item A68 or Item A69 which is a secondary infection, urinary tract infection, genital infection, eye infection or dental infection.
• a pharmaceutical comprising a combination of at least
• a pharmaceutical composition comprising a ⁇ -lactam agent, wherein the pharmaceutical composition is administered together with the compound according to any one of Items A1 to A51 or a pharmaceutically acceptable salt thereof.
• a pharmaceutical composition characterized.
• a bacterial infection characterized by administering a therapeutically effective amount of a compound according to any one of Items A1 to A51 or a pharmaceutically acceptable salt thereof to a patient in need of treatment. How to treat.
• the bacterial infection is a bacterial infection involving bacteria that may have ⁇ -lactamase.
• Bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of chronic respiratory lesions, Pharyngeal / laryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraabdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic vessel / lymphadenitis, trauma / burn, surgical wound, etc.
• Item A73 or Item A74 which is a secondary infection, a urinary tract infection, a genital infection, an eye infection, or a dental infection.
• Stection A76 The method according to any one of Items A73 to A75, wherein the method is administered with an additional drug.
• R a3 , R a4 , R a5 , R a6 , R b2 , R b3 And R b4 are independently the same or different and the R a1 , R a2 And R b1 Where R is the same as R a3 And R b2 , R a4 And R b3 Or R a5 And R b4 Are bonded to the same nitrogen atom, they may be taken together to form a 4- to 10-membered nitrogen-containing non-aryl heterocycle, R m1 Is 1) a hydrogen atom, 2) C 1-6 An alkyl group, 3) C 3-10 An alicyclic group, 4) C 6-10 Aryl, 5) 5 or 6 membered heteroaryl, or 6) 4-10 membered non-aryl heterocycle (Provided that each substituent in the above 2) to 6) may be substituted) However, R m1 When R is bonded to a boron atom through an oxygen atom, two R m1
• ZL 2 -L 1 Is a hydrogen atom, optionally substituted C 1-6 An alkyl group, or optionally substituted C 1-6 Item 3.
• ZL 2 -L 1 The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein is a hydrogen atom.
• G is an oxygen atom, The compound or its pharmaceutically acceptable salt as described in any one of the said clauses.
• X is a hydroxyl group or an optionally substituted C 1-6 The compound or a pharmaceutically acceptable salt thereof according to any one of the above items, which is an alkoxy group.
• X is a hydroxyl group, or a pharmaceutically acceptable salt thereof according to any one of the preceding items.
• Y is a compound according to any one of the preceding items or a pharmaceutically acceptable salt thereof, wherein Y is an oxygen atom.
• Compounds of formula (1a) and (1b), compounds of formula (3a) and (3b) or compounds of formula (4a) and (4b) are respectively represented by the following formulas (5a) and (5b): [In Formulas (5a) and (5b), Ring A is an optionally substituted 4- to 6-membered nitrogen-containing non-aryl heterocycle.
• R 1 And R 2 are independently the same or different, 1) a hydrogen atom, 2) a halogen atom, 3) C 1-6 An alkyl group, 4) C 1-6 An alkoxy group, and 5) C 1-6 Alkylthio group (However, each substituent in the above 3) to 5) may be substituted)
• R 1 And R 2 Are independently the same or different, 1) a hydrogen atom, 2) a halogen atom, 3) C which may be substituted 1-6 An alkyl group,
• the compound or pharmaceutically acceptable salt thereof according to any one of the above items, wherein the compound is selected from the group consisting of: [Claim 21] R 1 And R 2
• L 4 Is a single bond, —CH 2 -, -CH (NH 2 )-Or -CH (NH 2 ) -CH 2 -, Where L 4 When an amino group is present therein, the carbon to which the amino group is bonded is L 3 Or a pharmaceutically acceptable salt thereof.
• L 4 Is a single bond, —CH 2 -, -CMe (NH 2 )-, -CH (NHMe)-, -CD (NH 2 )-(Where D represents a deuterium atom), -CH (NH 2 )-Or -CH 2 CH 2
• the compound or a pharmaceutically acceptable salt thereof according to any one of the above items, which is-.
• L 4 Is a single bond, —CH 2 -Or -CH (NH 2 ) — Or the pharmaceutically acceptable salt thereof.
• R 5 Is a hydrogen atom, optionally substituted C 1-6 An alkyl group, an optionally substituted 4- to 10-membered non-aryl heterocycle, an optionally substituted C 6-10 Aryl, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C 1-6 An alkylthio group, or -NR e1 OH, where R e1 Is a hydrogen atom or optionally substituted C 1-6 The compound or a pharmaceutically acceptable salt thereof according to any one of the above items, which is an alkyl group.
• R 5 Is optionally substituted 5 or 6 membered heteroaryl or optionally substituted C 6-10 The compound or pharmaceutically acceptable salt thereof according to any one of the preceding clauses, which is aryl.
• R 5 The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein is an optionally substituted 5- or 6-membered heteroaryl.
• R 5 The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein is a substituted 4- to 10-membered non-aryl heterocycle.
• R 5 Is a hydrogen atom or optionally substituted C 1-4 An alkyl group, The compound according to any one of the above items or a pharmaceutically acceptable salt thereof.
• R 5 Is the following Selected from the group consisting of Subscript d is R 5 The number of substitutable positions on the ring of Each R 6a Is independent 1) a hydrogen atom, 2) a hydroxyl group, 3) a cyano group, 4) Nitro group, 5) halogen, 6) C 1-4 An alkyl group, 7) C 3-10 An alicyclic group, 8) C 1-4 An alkoxy group, 9) C 3-10 An alicyclic oxy group, 10) C 6-10 An aryloxy group, 11) a 5- or 6-membered heteroaryloxy group, 12) 4 to 10 membered non-aryl heterocyclic oxy group, (However, each substituent of the above 6) to 12) may be substituted) 13) -SO 2 -NR e2
• R e2 And R f2 Are each independently the same or different, a hydrogen atom, or an optionally substituted C 1-6 39.
• R e2 And R f2 40 The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 31 and 36 to 39, wherein is a hydrogen atom.
• R 6a Is -NR e2 R f2 And R e2 And R f2 Has one hydrogen atom and the other is C 1-4 40.
• L 4 Is —CH (NH 2 )-(CH 2 ) q -CHR 13 -, Q is 0 or 1, and the NH 2
• L 4 Is -CHR 13 -Or-CH 2 -CHR 13 -And R 5 Is hydrogen, R 13 Is —C ( ⁇ O) NH 2 Or —C ( ⁇ O) NHOH, The compound according to any one of the above items or a pharmaceutically acceptable salt thereof.
• the compound of formula (12) is represented by the following formula (13): [In formula (13), X, Y, ring A, L 3 , L 4 , R 1 , R 2 , R 4 And R 5 Is synonymous with the definition according to any one of the preceding items], or a pharmaceutically acceptable salt thereof.
• X and R G Is a hydroxyl group and R 4 58 is a carboxyl group, and ring A is an optionally substituted 4- to 6-membered nitrogen-containing non-aryl heterocyclic ring, or a pharmaceutically acceptable compound thereof, Salt.
• the compound of formula (13) is represented by the following formula (14): [In formula (14), X, L 3 , L 4 , M, n, and R 5 Is synonymous with the definition according to any one of the preceding paragraphs] 59.
• the compound or a pharmaceutically acceptable salt thereof according to any one of Items 55 to 58 which is represented by: [Section 60] R G 60.
• [Section 61] R G Item 61.
• X is hydroxyl or C 1-6 62.
• [Section 63] The compound according to any one of Items 55 to 62 or a pharmaceutically acceptable salt thereof, wherein X is a hydroxyl group.
• [Section 64] Item 64. The compound according to any one of Items 55 to 63, or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2, n is 1 or 2, and m + n is 2 or 3.
• [Section 65] The compound according to any one of Items 55 to 64 or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1.
• [Section 70] A pharmaceutical comprising the compound according to any one of Items 1 to 69 or a pharmaceutically acceptable salt thereof.
• [Claim 71] Item 70. The pharmaceutical according to Item 70, which is a therapeutic or preventive for bacterial infections.
• [Section 72] A ⁇ -lactamase inhibitor comprising the compound according to any one of Items 1 to 69 or a pharmaceutically acceptable salt thereof as an active ingredient.
• a pharmaceutical composition comprising the compound according to any one of items 1 to 69 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
• [Section 74] Item 74. The pharmaceutical composition according to Item 73, further comprising an additional drug.
• [Section 75] Item 75.
• the pharmaceutical composition according to Item 74 wherein the additional agent is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent and an antiallergic agent.
• the additional agent is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent and an antiallergic agent.
• Additional ⁇ -lactam drugs are amoxicillin, ampicillin (pibampicillin, hetacillin, bacampicillin, tampicillin, tarampicillin), epicillin, carbenicillin (calindacillin), ticarcillin, temocillin, azurocillin, piperacillin, mezirocimline, mezolicimline, mezirocimbu Sulbenicillin, benzylpenicillin (G), crometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethylpenicillin (V), propicillin, benzathine phenoxymethylpenicillin, pheneticillin, cloxacillin, cloxacillin, dicloxacillin, Oxacillin, methicillin, nafcillin, faropenem, biapenem, doripene , Eltapenem, imipenem,
• the pharmaceutical composition according to Item 75 or Item 76 selected from the group consisting of BAL30072, SYN2416, ceftiofur, cefquinome, cefovecin, aztreonam, tigenonam, carmonam, RWJ-442831, RWJ-333441, and RWJ-333442.
• Item 76 The pharmaceutical composition according to Item 76 or Item 77, wherein the ⁇ -lactam drug is selected from ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, or panipenem.
• Item 76 selected from ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, or panipenem.
• Item 74 The pharmaceutical composition according to Item 73, which is administered together with an additional drug.
• the additional agent is selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent or an antiallergic agent.
• the additional drug is a ⁇ -lactam drug.
• Additional ⁇ -lactam drugs are amoxicillin, ampicillin (pibampicillin, hetacillin, bacampicillin, tampicillin, tarampicillin), epicillin, carbenicillin (calindacillin), ticarcillin, temocillin, azurocillin, piperacillin, mezirocimline, mezolicimline, mezirocimbu Sulbenicillin, benzylpenicillin (G), crometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethylpenicillin (V), propicillin, benzathine phenoxymethylpenicillin, pheneticillin, cloxacillin, cloxacillin, dicloxacillin, Oxacillin, methicillin, nafcillin, faropenem, biapenem, doripene , Eltapenem, imipenem,
• the pharmaceutical composition according to Item 81 or Item 82 selected from the group consisting of BAL30072, SYN2416, ceftiofur, cefquinome, cefovecin, aztreonam, tigenonam, carmonam, RWJ-442831, RWJ-333441, and RWJ-333442.
• the pharmaceutical composition according to Item 82 or 83, wherein the ⁇ -lactam drug is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem.
• the ⁇ -lactam drug is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem.
• the ⁇ -lactam drug is selected from the group consisting of aztreonam, tigenonam, BAL30072, SYN2416, and carmonam.
• the bacterial infection is a bacterial infection involving bacteria that may have ⁇ -lactamase.
• Bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of chronic respiratory lesions, Pharyngeal / laryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraabdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic vessel / lymphadenitis, trauma / burn, surgical wound, etc.
• the compound or a pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the compound is a secondary infection, urinary tract infection, genital infection, eye infection or dental infection.
• [Section 90] A pharmaceutical composition comprising a ⁇ -lactam drug, wherein the pharmaceutical composition is administered together with the compound according to any one of the above items or a pharmaceutically acceptable salt thereof.
• Pharmaceutical composition. To treat a bacterial infection, characterized by administering to a patient in need of treatment a therapeutically effective amount of a compound according to any one of the preceding clauses or a pharmaceutically acceptable salt thereof. the method of.
• the bacterial infection is a bacterial infection involving bacteria that may have ⁇ -lactamase.
• Bacterial infection is sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of chronic respiratory lesions, Pharyngeal / laryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraabdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic vessel / lymphadenitis, trauma / burn, surgical wound, etc.
• the compound of the present invention has an excellent inhibitory action on serine- ⁇ -lactamase having a serine residue at the enzyme active center.
• a more excellent embodiment of the compound of the present invention is expected to have a broad ⁇ -lactamase inhibitory action against multiple types of ⁇ -lactamases and a metallo- ⁇ -lactamase inhibitory action having zinc (Zn 2+ ) at the enzyme active center. .
• the compounds of the present invention are used as a single agent or in combination with a ⁇ -lactam agent to cause bacterial infections involving bacteria that may have ⁇ -lactamase, specifically sepsis, febrile neutrophils Reduction, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, secondary infection of chronic respiratory lesions, sore throat / laryngitis, tonsillitis, osteomyelitis, arthritis , Peritonitis, intraabdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic / lympathitis, secondary infection such as trauma / burn and surgical wound, urinary tract infection, genital infection It is useful as a therapeutic and / or prophylactic agent for eye infections or dental infections.
• group means a monovalent group unless otherwise specified. Examples of non-monovalent groups include alkylene groups (divalent). Further, in the following description of substituents, the term “group” may be omitted.
• the number of substituents in the case of being defined as “optionally substituted” or “substituted” is not particularly limited, and is not particularly limited as long as substitution is possible. There are multiple. Further, unless otherwise specified, the description of each substituent also applies when the substituent is a part of another substituent or a substituent.
• the substituent in “optionally substituted” is selected from the substituent group ⁇ consisting of the following, and may be substituted with 1 to 5 substituents which are the same or different. Although it does not restrict
• Substituent group ⁇ is 1) halogen atom 2) hydroxyl group 3) carboxyl group 4) cyano group 5) sulfanyl group, 6) Nitro group, 7) C 1-6 alkyl group 8) C 2-6 alkenyl group 9) C 2-6 alkynyl group 10) C 1-6 alkoxy group 11) C 1-6 alkylthio group 12) C 1-6 alkylcarbonyl group 13 )
• Each substituent of the C 1-6 alkylsulfonyl group (7 to 13) may be substituted with the same or different 1 to 5 substituents selected from the substituent group ⁇ ) 14) C 3-10 alicyclic group 15) C 3-10 alicyclic oxy group 16) C 6-10 aryloxy group 17) 5 or 6 membered heteroaryloxy group 18) 4 to 10 membered non- Aryl heterocyclic oxy group 19) C 3-10 alicyclic thio group 20) C 6-10 aryl thio group 21) 5 or 6 member
• substituents in “optionally substituted” include the following substituents.
• Substituent group ⁇ is preferably 1) halogen atom 2) hydroxyl group 3) carboxyl group 4) cyano group 5) C 1-6 alkyl group 6) C 1-6 alkoxy group 7) C 1-6 alkylthio group 8) C 1-6 alkylcarbonyl group
• Each of the substituents 5) to 8) may be substituted with the same or different 1 to 5 substituents selected from the substituent group ⁇ ) 9) C 3-10 alicyclic group 10) C 3-10 alicyclic oxy group 11) C 6-10 aryloxy group 12) 5 or 6 membered heteroaryloxy group 13) 4-10 membered non-
• substituent in “optionally substituted” include the following substituents.
• Substituent group ⁇ is more preferably 1) halogen atom 2) hydroxyl group 3) cyano group 4) C 1-6 alkyl group 5) C 1-6 alkoxy group 6) C 1-6 alkylthio group 7) C 1-6 alkylcarbonyl group (provided from 4) 7)
• Each substituent in 7) may be substituted with the same or different 1 to 5 substituents selected from substituent group ⁇ ) 8) 5 or 6 membered heteroaryloxy group 9) 4 to 10 membered nonaryl heterocyclic oxy group 10) 5 or 6 membered heteroarylthio group 11) 4 to 10 membered nonaryl heterocyclic thio group 12) C 6-10 aryl 13) 5-membered or 6-membered heteroaryl 14) 4-10 membered non-aryl heterocycles (provided 4) to 14) each has 1-5 substituent groups ⁇ Or 1) optionally substituted by a C cyan
• C 1-6 means having 1 to 6 carbon atoms. The same applies to other numbers. For example, “C 1-4 ” means 1 to 4 carbon atoms.
• Hetero atom means oxygen atom, nitrogen atom, sulfur atom and the like.
• Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferably they are a fluorine atom or a chlorine atom. More preferably, it is a fluorine atom.
• the “halogen atom” may be referred to as “halogen”.
• 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 “C 1-4 alkyl group”, more preferably “C 1-3 alkyl group”, and still more preferably “C 1-2 alkyl group”. is there.
• Specific examples of the “C 1-6 alkyl group” include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, sec-butyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl and the like.
• C 2-6 alkenyl group means a linear or branched unsaturated hydrocarbon group of 2 to 6 carbon atoms containing one or more carbon-carbon double bonds To do.
• the “C 2-6 alkenyl group” is preferably a “C 2-4 alkenyl group”.
• Specific examples of “C 2-6 alkenyl group” include, but are not limited to, vinyl group, 1-propylenyl group, 2-propylenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, Examples include 2-methyl-1-propylenyl group and 2-methyl-2-propylenyl group.
• C 2-6 alkynyl group means a straight or branched unsaturated aliphatic hydrocarbon group having one or more triple bonds.
• the “C 2-6 alkynyl group” is preferably “C 2-4 alkynyl group”. Specific examples include, but are not limited to, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 1-methyl-2-propynyl group, 3-butynyl group, 1-pentynyl group, Examples include 1-hexynyl group.
• C 3-20 alicyclic group means a monocyclic or bicyclic non-aromatic hydrocarbon ring having 3 to 20 carbon atoms, partially having an unsaturated bond, partially Those having a crosslinked structure, those partially spirolated and those having one or two carbonyl structures are also included.
• An “alicyclic group” includes a cycloalkyl group, a cycloalkenyl group, and a cycloalkynyl group.
• the “C 3-20 alicyclic group” is preferably a “C 3-10 alicyclic group”, and more preferably a “C 3-6 alicyclic group”.
• C 3-20 alicyclic group include, but are not limited to, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclohexazinyl group, A cycloheptazinyl group, a cyclooctazinyl group, adamantyl, norbornyl, etc. are mentioned.
• Specific examples of the “C 3-20 alicyclic group” having a partially crosslinked structure include, but are not limited to, those having the structures shown below.
• the “C 3-20 alicyclic group” also includes a compound condensed with an aromatic ring. Specific examples include groups represented by the following.
• C 3-10 alicyclic group means a substituent in which “C 3-10 alicyclic group” is a monovalent group among the above “C 3-20 alicyclic group”.
• C 6-10 aryl means a monocyclic or bicyclic aromatic hydrocarbon ring having 6 to 10 carbon atoms, and specifically includes a phenyl group, 1-naphthyl group, 2-naphthyl group. Groups and the like.
• the C 6-10 aryl is preferably C 6 or C 10 aryl.
• “5- or 6-membered heteroaryl” is a monocyclic ring composed of 5 to 6 atoms, including the same or different 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms. Of the aromatic heterocycle.
• 5- to 10-membered heteroaryl means a monocyclic ring of 5 to 10 atoms, including 1 to 4 heteroatoms that are the same or different selected from the group consisting of oxygen, nitrogen and sulfur A bicyclic aromatic heterocycle is meant.
• “9- or 10-membered heteroaryl” is a bicyclic ring of 9 to 10 atoms containing the same or different 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms Of the aromatic heterocycle.
• “5- or 6-membered nitrogen-containing heteroaryl” includes, in addition to one nitrogen atom, the same or different 0 to 3 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. It means a monocyclic aromatic heterocycle consisting of 5 to 6 atoms.
• 6-membered heteroaryl include, but are not limited to, pyridine, pyridazine, pyrimidine, pyrazine, and the like.
• 5-membered heteroaryl include, but are not limited to, for example, thiophene, pyrrole, thiazole, isothiazole, pyrazole, imidazole, furan, oxazole, isoxazole, oxadiazole, thiadiazole, triazole, tetrazole Etc., preferably triazole, tetrazole or thiadiazole, more preferably thiadiazole.
• 5-membered or 6-membered heteroaryl include the above-mentioned specific examples of “5-membered heteroaryl” and “6-membered heteroaryl”.
• a “4- to 20-membered non-aryl heterocycle” is composed of 4 to 20 atoms, including the same or different 1 or 2 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms.
• Monocyclic or bicyclic non-aromatic heterocycles including partially unsaturated bonds, partially bridged structures, and partially spirolated.
• Non-aryl heterocycles may form fused rings with aryl or heteroaryl.
• a heterocycle includes a case where it is condensed with C 6-10 aryl or 5-membered or 6-membered heteroaryl.
• the non-aryl heterocycle may contain 1 or 2 carbonyl, thiocarbonyl, sulfinyl or sulfonyl, such as lactam, thiolactam, lactone, thiolactone, cyclic imide, cyclic carbamate.
• a cyclic group such as a cyclic thiocarbamate is also included in the non-aryl heterocycle.
• the oxygen atom of carbonyl, sulfinyl and sulfonyl and the sulfur atom of thiocarbonyl are not included in the number of 4 to 20 members (ring size) and the number of heteroatoms constituting the ring.
• the “4- to 20-membered non-aryl heterocycle” include, but are not limited to, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, oxetane, tetrahydrofuran, tetrahydropyran, etc. The thing of the structure shown below etc. are mentioned.
• the “4- to 20-membered nitrogen-containing non-aryl heterocycle” includes, in addition to one nitrogen atom, the same or different 0 or 1 heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom Means a monocyclic or bicyclic non-aromatic heterocycle composed of 4 to 20 atoms, partially having an unsaturated bond, partially having a bridged structure and partially Including spirated ones.
• “4- to 10-membered non-aryl heterocycle” refers to a substituent in which “4- to 10-membered non-aryl heterocycle” in the “4- to 20-membered non-aryl heterocycle” is a monovalent group. means.
• “4- to 10-membered nitrogen-containing non-aryl heterocycle” means that “4- to 10-membered nitrogen-containing non-aryl heterocycle” in the above “4- to 20-membered nitrogen-containing non-aryl heterocycle” is a monovalent group Is a substituent.
• “5- to 7-membered non-aryl heterocycle” is a substituent in which “5- to 7-membered non-aryl heterocycle” in the above “4 to 20-membered non-aryl heterocycle” is a monovalent group. means.
• the “4- to 7-membered non-aryl heterocycle” is a substituent in which “the 4- to 7-membered non-aryl heterocycle” in the “4- to 20-membered non-aryl heterocycle” is a monovalent group. means.
• 4-membered non-aryl heterocycle include, but are not limited to, azetidine, oxetane, thietan, and the like.
• 5-membered non-aryl heterocycle examples include, but are not limited to, pyrrolidine, pyrrolidone, oxazolidinone, tetrahydrofuran, tetrahydrothiophene, and the like.
• 6-membered non-aryl heterocycle include, but are not limited to, piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrothiopyran and the like.
• 6-membered non-aryl heterocycle having a partially unsaturated bond
• examples of the “6-membered non-aryl heterocycle” having a partially unsaturated bond include, but are not limited to, those having the structures shown below.
• 6-membered non-aryl heterocycle having a partially crosslinked structure
• examples of the “6-membered non-aryl heterocycle” having a partially crosslinked structure include, but are not limited to, those having the structures shown below.
• C 1-6 alkoxy group means “C 1-6 alkyloxy group”, and the C 1-6 alkyl moiety has the same meaning as the above C 1-6 alkyl group.
• the “C 1-6 alkoxy group” is preferably a “C 1-4 alkoxy group”, more preferably a “C 1-3 alkoxy group”, and still more preferably a “C 1-2 alkoxy group”. .
• C 1-6 alkoxy group examples include, but are not limited to, for example, methoxy group, ethoxy group, propoxy group, butoxy group, isopropoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group Isopentyloxy group, neopentyloxy group, tert-pentyloxy group, 1,2-dimethylpropoxy group and the like.
• C 3-10 alicyclic oxy group means a (C 3-10 alicyclic group) -O— group, wherein the C 3-10 alicyclic moiety is a C 3-10 alicyclic group. Is synonymous with.
• C 3-6 alicyclic oxy group means a (C 3-6 alicyclic group) -O— group, wherein the C 3-6 alicyclic moiety is a C 3-6 alicyclic group. Is synonymous with.
• the “C 3-6 alicyclic oxy group” is preferably “C 3-5 alicyclic oxy group”.
• C 3-6 alicyclic oxy group examples include, but are not limited to, a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, and the like.
• the C 6-10 aryl part of the “C 6-10 aryloxy group” has the same meaning as the above C 6-10 aryl.
• the “C 6-10 aryloxy group” is preferably “C 6 or C 10 aryloxy group”. Specific examples of “C 6-10 aryloxy group” include, but are not limited to, phenoxy group, 1-naphthyloxy group, 2-naphthyloxy group and the like.
• the 5-membered or 6-membered heteroaryl moiety of the “5-membered or 6-membered heteroaryloxy group” has the same meaning as the above-mentioned “5-membered heteroaryl” or “6-membered heteroaryl”.
• Specific examples of “5-membered or 6-membered heteroaryloxy group” include, but are not limited to, for example, pyrazoyloxy group, triazoyloxy group, thiazoyloxy group, thiadiazoyloxy group, pyridyloxy group And pyridazoyloxy group.
• the 4- to 10-membered non-aryl heterocycle portion of the “4- to 10-membered non-aryl heterocycle oxy group” has the same meaning as the “4- to 10-membered non-aryl heterocycle”.
• the “4- to 10-membered non-aryl heterocyclic oxy group” is preferably a “4- to 6-membered non-aryl heterocyclic oxy group”.
• Specific examples of the “4- to 10-membered non-aryl heterocyclic oxy group” include, but are not limited to, for example, tetrahydrofuranyloxy group, tetrahydropyranyloxy group, azetidinyloxy group, pyrrolidinyloxy group, Peridinyloxy group etc. are mentioned.
• the C 1-6 alkyl part of the “C 1-6 alkylthio group” has the same meaning as the above C 1-6 alkyl.
• the “C 1-6 alkylthio group” is preferably a “C 1-4 alkylthio group”, and more preferably a “C 1-3 alkylthio group”.
• C 1-6 alkylthio group include, but are not limited to, for example, methylthio group, ethylthio group, propylthio group, butylthio group, isopropylthio group, isobutylthio group, tert-butylthio group, sec-butylthio group Group, isopentylthio group, neopentylthio group, tert-pentylthio group, 1,2-dimethylpropylthio group and the like.
• C 3-10 alicyclic thio group means (C 3-10 alicyclic group) -S— group, and the C 3-10 alicyclic moiety is the above C 3-10 alicyclic group. Synonymous with group.
• the “C 3-10 alicyclic thio group” is preferably “C 3-6 alicyclic thio group”. Specific examples of the “C 3-6 alicyclic thio group” include, but are not limited to, a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group, a cyclohexylthio group, and the like.
• the C 6-10 aryl part of the “C 6-10 arylthio group” has the same meaning as the above C 6-10 aryl.
• Preferred examples of the “C 6-10 arylthio group” include “C 6 or C 10 arylthio groups”.
• Specific examples of “C 6-10 aryloxy group” include, but are not limited to, phenylthio group, 1-naphthylthio group, 2-naphthylthio group and the like.
• the 5-membered or 6-membered heteroaryl moiety of the “5-membered or 6-membered heteroarylthio group” has the same meaning as the above-mentioned “5-membered heteroaryl” or “6-membered heteroaryl”.
• Specific examples of the “5-membered or 6-membered heteroarylthio group” include, but are not limited to, for example, pyrazoylthio group, triazoylthio group, thiazoylthio group, thiadiazoylthio group, pyridylthio group, pyridazoylthio group, and the like. Can be mentioned.
• the 4- to 10-membered non-aryl heterocycle portion of the “4- to 10-membered non-aryl heterocycle thio group” has the same meaning as the “4- to 10-membered non-aryl heterocycle”.
• the “4- to 10-membered non-aryl heterocyclic thio group” is preferably “a 4- to 6-membered non-aryl heterocyclic thio group”.
• Specific examples of the “4- to 10-membered non-aryl heterocyclic thio group” include, but are not limited to, a tetrahydropyranylthio group, a piperidinylthio group, and the like.
• the “C 1-6 alkylcarbonyl group” means a carbonyl group substituted with 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” include, but are not limited to, an acetyl group, a propionyl group, a butyryl group, and the like.
• the “C 3-10 alicyclic carbonyl group” means a carbonyl group substituted with the above “C 3-10 alicyclic group”.
• the “C 3-10 alicyclic carbonyl group” is preferably “C 3-6 alicyclic carbonyl group”. Specific examples of the “C 3-10 alicyclic carbonyl group” include, but are not limited to, a cyclopropylcarbonyl group, a cyclopentylcarbonyl group, and the like.
• the “C 6-10 arylcarbonyl group” means a carbonyl group substituted with the above “C 6-10 aryl”.
• the “C 6-10 arylcarbonyl group” is preferably “C 6 or C 10 arylcarbonyl group”. Specific examples of “C 6-10 arylcarbonyl group” include, but are not limited to, benzoyl group, 1-naphthylcarbonyl group, 2-naphthylcarbonyl group and the like.
• the “5-membered or 6-membered heteroarylcarbonyl group” means a carbonyl group substituted with the above “5-membered or 6-membered heteroaryl”.
• Specific examples of the “5-membered or 6-membered heteroarylcarbonyl group” include, but are not limited to, for example, pyrazoylcarbonyl group, triazoylcarbonyl group, thiazoylcarbonyl group, thiadiazoylcarbonyl group, pyridylcarbonyl group, A pyridazoyl carbonyl group etc. are mentioned.
• the “4- to 10-membered non-aryl heterocycle carbonyl group” means a carbonyl group substituted with the above “4- to 10-membered non-aryl heterocycle”.
• the “4- to 10-membered non-aryl heterocyclic carbonyl group” is preferably “a 4- to 6-membered non-aryl heterocyclic carbonyl group”.
• Specific examples of “4- to 10-membered non-aryl heterocyclic carbonyl group” include, but are not limited to, azetidinylcarbonyl group, pyrrolidinylcarbonyl group, piperidinylcarbonyl group, morpholinylcarbonyl group and the like. Can be mentioned.
• the “C 1-6 alkylsulfonyl group” means a sulfonyl group substituted with 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” include, but are not limited to, a methylsulfonyl group, a propionylsulfonyl group, a butyrylsulfonyl group, and the like.
• the “C 3-10 alicyclic sulfonyl group” means a sulfonyl group substituted with the above “C 3-10 alicyclic group”.
• the “C 3-10 alicyclic sulfonyl group” is preferably “C 3-6 alicyclic sulfonyl group”.
• Specific examples of the “C 3-10 alicyclic sulfonyl group” include, but are not limited to, a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group, a cyclohexylsulfonyl group, and the like.
• the “C 6-10 arylsulfonyl group” means a sulfonyl group substituted with the above “C 6-10 aryl”.
• the “C 6-10 arylsulfonyl group” is preferably “C 6 or C 10 arylsulfonyl group”.
• Specific examples of “C 6-10 arylsulfonyl group” include, but are not limited to, phenylsulfonyl group, 1-naphthylsulfonyl group, 2-naphthylsulfonyl group and the like.
• the “5-membered or 6-membered heteroarylsulfonyl group” means a sulfonyl group substituted with the above “5-membered or 6-membered heteroaryl”.
• Specific examples of the “5-membered or 6-membered heteroarylsulfonyl group” include pyrazoylsulfonyl group, triazoylsulfonyl group, thiazoylsulfonyl group, thiadiazoylsulfonyl group, pyridylsulfonyl group, pyridazoylsulfonyl group and the like. Etc.
• C 1-6 alkylene group means a substituent that is a divalent group by removing two hydrogen atoms from a saturated hydrocarbon having 1 to 6 carbon atoms.
• C 1-3 alkylene group” and “C 2-4 alkylene group” are divalent groups by removing two hydrogen atoms from a saturated hydrocarbon having 1 to 3 carbon atoms and 2 to 4 carbon atoms. Each means a substituent.
• the “C 3-10 cycloalkylene group” means a substituent which is a divalent group by removing two hydrogen atoms from a saturated cyclic hydrocarbon having 3 to 10 carbon atoms.
• the “C 3-6 cycloalkylene group” and the “C 4-6 cycloalkylene group” are obtained by removing two hydrogen atoms from a saturated cyclic hydrocarbon having 3 to 6 carbon atoms and 4 to 6 carbon atoms.
• Each substituent is a valent group.
• C 6-10 arylene group means a substituent which is divalent by removing two hydrogen atoms from an aromatic hydrocarbon having 6 to 10 carbon atoms.
• C 6 arylene group means a substituent which is divalent by removing two hydrogen atoms from an aromatic hydrocarbon having 6 carbon atoms.
• the “5-membered or 6-membered heteroarylene group” means a substituent that is a divalent group by removing two hydrogen atoms from a 5-membered or 6-membered heteroaryl ring.
• “5-membered heteroarylene group” and “6-membered heteroarylene group” mean a substituent that is divalent by removing two hydrogen atoms from a 5-membered and 6-membered heteroaryl ring, respectively. To do.
• the “4- to 10-membered non-aryl heterocyclylene group” means a substituent that is divalent by removing two hydrogen atoms from a 4- to 10-membered non-aryl heterocycle.
• “4-5 membered non-aryl heterocyclylene group” and “4-6 membered non-aryl heterocyclylene group” are two hydrogen atoms from a 4-5 membered and 4-6 membered nonaryl heterocycle. Each of the substituents which is a divalent group by removing is meant.
• a “bioisostere” refers to another partial structure (functional group) that plays the same biological role as a certain group (eg, carboxyl group) in a pharmaceutical molecule (in the present invention, a prosthetic group). Drug structure is also included as a concept of biological equivalent).
• Carboxylic acid equivalent means a biological equivalent of a carboxylic acid.
• Examples of the carboxylic acid equivalent include, but are not limited to, —SO 3 H, —SO 2 NHR 19a , —B (OR m1 ) 2 , —PO (OR m1 ) (OR m2 ), —CONHR 19a , — CONHSO 2 R 19a , —CONR 19a CN, —CONHNHSO 2 R 19a and the following formulas (8A), (8B), (8C), (8D), (8E), (8F), (8G), (8H), (8I), (8J), (8K), (8L), (8M), (8N), (8O), (8P), (8Q), (8R), (8S), (8T), (8U) ), (8V) and (8W) substituents (each of the substituents may be further substituted with 1 to 3 R 19b which are the same or different at the chemically substitutable position) Etc.
• R s represents a hydrogen atom, a C 1-6 alkyl group or a C 3-10 alicyclic group (the C 1-6 alkyl group or C 3-10 alicyclic group is substituted with 1 to 5 halogen atoms) That may have been)
• R t is a hydrogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group (the C 1-6 alkyl group or C 1-6 alkoxy group may be substituted with 1 to 5 halogen atoms) C 3-10 alicyclic group, C 3-10 alicyclic oxy group, phenyl group, phenoxy group, pyridyl group or pyridyloxy group (the C 3-10 alicyclic group, C 3-10 alicyclic group)
• the cyclic oxy group, phenyl group, phenoxy group, pyridyl group, and pyridyloxy group are substituents selected from the group consisting of 1
• R 19a and R 19b are each independently the same or different and are each a hydrogen atom, a hydroxyl group, a C 1-6 alkyl group, a C 6-10 aryl, a 5-membered or 6-membered heteroaryl, or a 4-10 membered
• R m1 is 1) hydrogen atom, 2) a C 1-6 alkyl group, 3) C 3-10 alicyclic group, 4) C 6-10 aryl, 5) 5-membered or 6-membered heteroaryl, or 6) 4- to 10-membered non-aryl heterocycle (wherein each substituent of 2) to 6) may be substituted)
• R m1 is bonded to a boron atom via an oxygen atom
• the two R m1 s are C 2-4 alkylene, together with the boron atom and the two oxygen atoms, May form a non-aryl heterocycle (the non-aryl heterocycle may be substitute
• R s is a hydrogen atom or a C 1-6 alkyl group
• R t is any one of a hydrogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 3-10 alicyclic group, or a C 3-10 alicyclic oxy group.
• R 19a and R 19b are each independently the same or different and each represents a hydrogen atom, a hydroxyl group, or a C 1-6 alkyl group.
• R m1 and R m2 are each independently the same or different and are a hydrogen atom, a C 1-6 alkyl group, or a C 3-10 alicyclic group.
• G is an oxygen atom, a sulfur atom, or —NR a1 —;
• X is a hydroxyl group, an optionally substituted C 1-6 alkoxy group, or —NR a2 R b1 ;
• R a1 , R a2 and R b1 are each independently the same or different, 1) hydrogen atom, 2) a C 1-6 alkyl group, 3) C 3-10 alicyclic group, 4) C 6-10 aryl 5) 5 or 6 membered heteroaryl, 6) 4-10 membered non-aryl heterocycle, 7) a C 1-6 alkylcarbonyl group, 8) C 3-10 alicyclic carbonyl group, 9) C 6-10 arylcarbonyl group, 10) a 5- or 6-membered heteroarylcarbonyl group, 11) a C 1-6 alkyl
• R 4 is 1) —C ( ⁇ O) R 8 , 2) —SO 2 —L 6 —R 8
• R 8 represents —NR a5 R b4 , —NR a5 —L 7 —B (OR m1 ) 2 , —OR m1 , or optionally substituted C 1-6
• L 6 is a single bond or —NR a6 —), 3) -NR a4 R b3 , 4) -B (OR m1 ) 2 , 5) -PO (OR m1 ) (OR m2 ), 6) optionally substituted 5-membered heteroaryl, 7) an optionally substituted 5-membered non-aryl heterocycle, or 8) any of the biological equivalents of 1) to 7) (provided above 2), 4), 5) and 6) are Carboxylic acid equivalents, 8) may contain duplicates thereof) Either R a3 , R a4 ,
• R m1 is 1) hydrogen atom, 2) a C 1-6 alkyl group, 3) C 3-10 alicyclic group, 4) C 6-10 aryl, 5) 5-membered or 6-membered heteroaryl, or 6) 4- to 10-membered non-aryl heterocycle (provided that each substituent of 2) to 6) above may be substituted)
• R m1 is bonded to a boron atom via an oxygen atom
• the two R m1 s are C 2-4 alkylene, together with the boron atom and the two oxygen atoms
• R m2 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 3-10 alicyclic group
• L 7 is an optionally substituted C 1-3 alkylene group.
• ZL 2 -L 1 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 1-6 alkylthio group.
• L 1 is a single bond.
• L 2 is a single bond or an optionally substituted C 1-6 alkylene group. In one embodiment, L 2 is a single bond.
• Z is 1) hydrogen atom, 2) a hydroxyl group, 3) a cyano group, 4) a carboxyl group, 5) C 3-10 alicyclic group, 6) C 6-10 aryl, 7) 5 or 6 membered heteroaryl, 8) 4-10 membered non-aryl heterocycle, 9) a C 1-6 alkoxy group, 10) C 3-10 alicyclic oxy group, 11) a C 6-10 aryloxy group, 12) a 5- or 6-membered heteroaryloxy group, 13) 4 to 10 membered non-aryl heterocyclic oxy group, 14) a C 1-6 alkylthio group, 15) C 3-10 alicyclic thio group, 16) a C 6-10 arylthio group, 17) a 5- or 6-membered heteroarylthio group, 18) 4 to 10 membered non-aryl heterocyclic thio group, (However, each substituent in the above 5) to 18) may be substituted
• R e1 , R f1 , R g1 and R h1 are as defined in this specification.
• Z is any of 1), 2), 5) -8), 39), or 42) above.
• Z is a hydrogen atom.
• Z is an optionally substituted C 1-6 alkylthio group.
• Z is an optionally substituted C 1-6 alkyl group.
• ZL 2 -L 1 is a hydrogen atom.
• ZL 2 -L 1 is an optionally substituted C 1-6 alkylthio group.
• ZL 2 -L 1 is an optionally substituted C 1-6 alkyl group.
• G is an oxygen atom, a sulfur atom, or —NR a1 —. In one embodiment, G is an oxygen atom or a sulfur atom. In a preferred embodiment, G is an oxygen atom. Said R a1 is as defined in this specification.
• X is a hydroxyl group, an optionally substituted C 1-6 alkoxy group, or —NR a2 R b1 . In one embodiment, X is a hydroxyl group or an optionally substituted C 1-6 alkoxy group. In a preferred embodiment, X is a hydroxyl group. Said R a2 and R b1 are as defined in this specification.
• any one of R 1 , R 2, and R 3 is represented by the following formula (2): [In Formula (2), Y is an oxygen atom, a sulfur atom, or —NR j —, Ring A is an optionally substituted 4-20 membered non-aryl heterocycle, L 3 is —C ( ⁇ O) —, —S ( ⁇ O) —, or —S ( ⁇ O) 2 —, L 4 is 1) single bond, 2) a C 1-6 alkylene group, 3) a C 3-10 cycloalkylene group, 4) C 6-10 arylene group 5) 5 or 6 membered heteroarylene group, 6) 4 to 10 membered non-aryl heterocyclylene group, or 7) —C ( ⁇ N—OR h1 ) — (However, each substituent of the above 2) to 6) may be substituted) Either R 5 is 1) hydrogen atom, 2) a C 1-6 alkyl group, 3) C 3-10 alicyclic group, 4) 4-10 member
• R 5 of formula (2) is 2) a C 1-6 alkyl group, 3) a C 3-10 alicyclic group, 4) a 4-10 membered non-aryl heterocycle, 5) C 6- When 10 aryl, 6) 5 or 6 membered heteroaryl, or 7) C 1-6 alkylthio group, the above 2), 3), 4), 5), 6) and 7) are carboxyl groups It may be substituted, or may be substituted with a C 1-6 alkyl group substituted with a carboxyl group. In one embodiment, 2), 3), 4), 5), 6) and 7) may be substituted with a carboxyl group. In one embodiment, 2), 3), 4), 5), 6) and 7) may be substituted with a C 1-6 alkyl group substituted with a carboxyl group.
• R 1 , R 2 and R 3 when one of R 1 , R 2 and R 3 is represented by formula (2), the remaining two of R 1 , R 2 and R 3 which do not take the structure of formula (2) Are each independently selected from the group consisting of a hydrogen atom, a halogen atom, methyl, trifluoromethyl, methoxy, and trifluoromethoxy.
• R 3 is represented by formula (2), and R 1 and R 2 are each independently selected from the group consisting of a hydrogen atom, a halogen atom, methyl, trifluoromethyl, methoxy, and trifluoromethoxy. Selected.
• Y is an oxygen atom, a sulfur atom, or —NR j —. In one embodiment, Y is an oxygen atom or a sulfur atom. In a preferred embodiment, Y is an oxygen atom. R j is as defined in this specification.
• Ring A is an optionally substituted 4-20 membered non-aryl heterocycle. In one embodiment, Ring A is an optionally substituted 4-10 membered non-aryl heterocycle. In one embodiment, Ring A is an optionally substituted 4-7 membered non-aryl heterocycle. In one embodiment, Ring A is an optionally substituted 4-7 membered nitrogen-containing non-aryl heterocycle. In one embodiment, Ring A is an optionally substituted 4-6 membered non-aryl heterocycle. In one embodiment, ring A is an optionally substituted 4-6 membered nitrogen-containing non-aryl heterocycle. In one embodiment, ring A is an optionally substituted azetidine ring.
• ring A is And a, wherein, R 6 represents a substituent on the azetidine ring, have the same definition as R 6a, coupled perpendicular to the wavy line represents a bond and Y, the bond marked with * and L 3 Indicates a bond.
• each R 6 is independently the same or different, 1) hydrogen atom, 2) a halogen atom, 3) a C 1-6 alkyl group, 4) selected from the group consisting of C 1-6 alkoxy groups (provided that each substituent of the above 3) and 4) may be substituted with a halogen atom;
• Ring A is Where m is 1, 2 or 3, n is 1, 2 or 3, m + n is 2, 3, 4 or 5, and a bond orthogonal to the wavy line indicates a bond with Y. the bond marked with * indicates a bond with L 3.
• m + n is 2, 3 or 4.
• m + n is 2 or 3.
• m + n is 2.
• L 3 is —C ( ⁇ O) —, —S ( ⁇ O) —, or —S ( ⁇ O) 2 —. In one embodiment, L 3 is —C ( ⁇ O) — or —S ( ⁇ O) 2 —. In preferred embodiments, L 3 is —C ( ⁇ O) —.
• L 4 is 1) single bond, 2) a C 1-6 alkylene group, 3) a C 3-10 cycloalkylene group, 4) C 6-10 arylene group 5) 5 or 6 membered heteroarylene group, 6) 4 to 10 membered non-aryl heterocyclylene group, or 7) —C ( ⁇ N—OR h1 ) — (However, each substituent of the above 2) to 6) may be substituted) One of them.
• L 4 is a single bond, —C ( ⁇ N—OR h1 ) —, or an optionally substituted C 1-6 alkylene group, wherein R h1 is optionally substituted. A good C 1-6 alkyl group.
• it is a C 1-6 alkylene group that is a single bond or optionally substituted with —NR 21 R 22 or ⁇ NOR 23 , wherein R 21 , R 22, and R 23 are each Independently, it is a hydrogen atom, an optionally substituted C 1-6 alkyl group, or an optionally substituted 4- to 10-membered non-aryl heterocyclic carbonyl group.
• L 4 is a bond, —CH 2 —, —CH (NH 2 ) —, or —CH (NH 2 ) —CH 2 —, wherein an amino group is present in L 4. In this case, the carbon to which the amino group is bonded is bonded to L 3 .
• L 4 is a single bond, —CH 2 —, —CMe (NH 2 ) —, —CH (NHMe) —, —CD (NH 2 ) — (where D represents a deuterium atom). ), —CH (NH 2 ) —, or —CH 2 CH 2 —. In one embodiment, L 4 is a single bond, —CH 2 —, or —CH (NH 2 ) —.
• L 4 is 1) — (CH 2 ) p —CR 10 (NHR 11 ) —, 2) — (CH 2 ) q —CR 12 R 13 —, or 3) — (CH 2 ) p —CR 10 (NHR 11 ) — (CH 2 ) q —CR 12 R 13 —, where p And q are independently 0 or 1, and R 10 is 1) hydrogen atom, 2) a carboxyl group or 3) —C ( ⁇ O) NR 10a R 10b R 11 is 1) hydrogen atom, 2) —C ( ⁇ O) R 11a , or 3) an optionally substituted 5- or 6-membered non-aryl heterocyclic carbonyl group, Provided that when R 10 is —C ( ⁇ O) NR 10a R 10b , R 10b and R 11 may together form —CH 2 CH 2 —, R 12 is 1) a hydrogen atom, or 2) an optionally substituted C 1-4 alkyl group, R 13 is 1) hydrogen atom,
• L 4 is —CH (NH 2 ) —CHR 13 —, and the carbon to which NH 2 is attached is attached to L 3 ;
• R 5 is a hydrogen atom, R 13 is 1) —NH—C ( ⁇ O) CH 3 , 2) —NH—C ( ⁇ O) NH 2 , 3) —NH—C ( ⁇ O) CH (NH 2 ) —CH 2 C ( ⁇ O) NH 2 , 4) —NH—C ( ⁇ O) CH 2 —NH 2 , 5) —NH—C ( ⁇ O) CH (NH 2 ) —CH 2 OH, or 6) pyrrolidin-2-ylcarbonylamino group.
• L 4 is —CH (NH 2 ) —CR 12 R 13 —, and the carbon to which NH 2 is bonded is bonded to L 3 ;
• R 5 is a hydrogen atom or methyl;
• R 12 is a hydrogen atom or methyl;
• R 13 is a benzylthio group or a sulfanyl group.
• L 4 is —CH (NH 2 ) — (CH 2 ) q —CHR 13 —, q is 0 or 1, and the carbon to which NH 2 is bonded is bonded to L 3 ;
• R 5 is a hydrogen atom, R 13 is 1) a carboxyl group, 2) —C ( ⁇ O) NH 2 , 3) —C ( ⁇ O) NH (CH 3 ), 4) —C ( ⁇ O) N (CH 3 ) 2 , 5) —C ( ⁇ O) NH— (CH 2 ) 2 —OH, 6) —C ( ⁇ O) NH— (CH 2 ) 2 —NH 2 , 7) —C ( ⁇ O) NH—S ( ⁇ O) 2 —CH 3 , 8) —C ( ⁇ O) NHOH, 9) —S ( ⁇ O) 2 —NH 2 , 10) —S ( ⁇ O) 2 —CH 3 , or 11) a hydroxyl group.
• L 4 is —CH (NHR 11 ) —CH 2 —, and the carbon to which NHR 11 is bonded is bonded to L 3 ;
• R 5 is hydrogen;
• R 11 is 1) —C ( ⁇ O) CH (NH 2 ) —CH 2 C ( ⁇ O) NH 2 , 2) —C ( ⁇ O) CH 2 —NH 2 , 3) —C ( ⁇ O) CH (CH 3 ) —NH 2 , 4) —C ( ⁇ O) CH (NH 2 ) —CH 2 OH, or 5) pyrrolidin-2-ylcarbonyl.
• L 4 is —CH (NHR 11 ) —CH (COOH) —, and the carbon to which NHR 11 is bonded is bonded to L 3 ;
• R 5 is hydrogen;
• R 11 is 1) —C ( ⁇ O) CH (NH 2 ) —CH 2 C ( ⁇ O) NH 2 , 2) —C ( ⁇ O) CH 2 —NH 2 , 3) —C ( ⁇ O) CH (CH 3 ) —NH 2 , 4) —C ( ⁇ O) CH (NH 2 ) —CH 2 OH, or 5) pyrrolidin-2-ylcarbonyl.
• L 4 is —CHR 13 — or —CH 2 —CHR 13 —
• R 5 is hydrogen
• R 13 is —C ( ⁇ O) NH 2 or —C ( ⁇ O) NHOH.
• L 4 is —CH 2 —CR 10 (NH 2 ) —, the CH 2 group is attached to L 3 , R 5 is hydrogen; R 10 is a carboxy group or —C ( ⁇ O) NH 2 .
• L 4 represents — (CH 2 ) p —CR 10 (NHR 11 ) — (CH 2 ) q —CHR 13 — or —CHR 13 — (CH 2 ) q —CR 10 (NHR 11 ) — ( CH 2 ) p —, where q is 0 or 1; R 5 is hydrogen; (1) When L 4 is —CHR 13 — (CH 2 ) q —CR 10 (NHR 11 ) — (CH 2 ) p —, The carbon of the —CHR 13 — group is bonded to L 3 ; p is 0; R 10 is a hydrogen atom, a carboxyl group, or —C ( ⁇ O) NHR 10b ; R 11 is a hydrogen atom, R 10b is a hydrogen atom, Provided that when R 10 is —C ( ⁇ O) NHR 10b , R 10b and R 11 together may form —CH 2 CH 2 —, R 13 is a hydrogen atom
• L 4 is —CR 12 (NH 2 ) —
• R 12 is a hydrogen atom or a methyl group
• R 5 is a C 1-4 alkyl group which may be substituted with one hydroxyl group.
• R 5 is 1) hydrogen atom, 2) a C 1-6 alkyl group, 3) C 3-10 alicyclic group, 4) 4-10 membered non-aryl heterocycle, 5) C 6-10 aryl, 6) 5 or 6 membered heteroaryl, 7) C 1-6 alkylthio group, or each substituent in 2) to 7) above may be substituted) 8) -NR e1 OH, One of them.
• R 5 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted 4-10 membered non-aryl heterocycle, an optionally substituted C 6- 10 aryl, optionally substituted 5 or 6 membered heteroaryl, optionally substituted C 1-6 alkylthio group, or —NR e1 OH, wherein R e1 is a hydrogen atom, or An optionally substituted C 1-6 alkyl group. In one embodiment, it is an optionally substituted 5- or 6-membered heteroaryl or optionally substituted C 6-10 aryl.
• R 5 is an optionally substituted 5 or 6 membered heteroaryl. In one embodiment, R 5 is an optionally substituted 4-10 membered non-aryl heterocycle. In one embodiment, R 5 is a hydrogen atom or an optionally substituted C 1-4 alkyl group.
• R 5 is Selected from the group consisting of The subscript d is the number of substitutable positions on the ring of R 5 ;
• R 5 is 5 or 6 membered aryl or heteroaryl selected from the group consisting of The subscript d is the number of substitutable positions on the ring of R 5 ;
• Each R 6a is independently 1) hydrogen atom, 2) a hydroxyl group, 3) halogen, 4) C 1-4 alkyl group, (However, the alkyl group may be substituted with NR e2 R f2 , 5-membered or 6-membered non-aryl heterocycle, —C ( ⁇ O) OR f2 , or hydroxyl group) 5) C 1-4 alkoxy group 6) —NR e2 R f2 , and 7) —C ( ⁇ O) OR e2 Selected from the group consisting of Each R 6b is independently 1) hydrogen atom, 2) a hydroxyl group, and 3) a C 1-4 alkyl group, (However, the alkyl group may be substituted with NR e2 R f2 , —C ( ⁇ O) NR —
• R e2 and R f2 are each independently the same or different and are each a hydrogen atom, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 3-10 fatty acid. It is a cyclic group. In one embodiment, R e2 and R f2 are each independently the same or different, a hydrogen atom, or an optionally substituted C 1-6 alkyl group. In one embodiment, R e2 and R f2 are hydrogen atoms.
• R 6a is —NR e2 R f2 , one of R e2 and R f2 is a hydrogen atom, and the other is a C 1-4 alkyl group (provided that the alkyl group is an amino group or It may be substituted with a hydroxyl group).
• each R 6a may independently be a halogen.
• each R 6a can independently be an alkylamino group substituted with an amino group.
• each R 6a may independently be NR e2 R f2 , where R e2 is a C 1-6 alkyl group, and the C 1-6 alkyl group is —NR 10a R 11a is substituted with, independently each R 10a and R 11a are defined as described in the specification.
• each R 6a can independently be —C ( ⁇ O) OH.
• each R 6a and / or each R 6b may independently be an alkyl group substituted with a carboxyl group. In one embodiment, each R 6a and / or each R 6b can independently be a C 1-4 alkyl group substituted with a —C ( ⁇ O) OH group.
• R 5 is A 4-6 membered non-aryl heterocycle selected from the group consisting of: The subscript d is the number of substitutable positions on the ring of R 5 ;
• R 5 is A 4-6 membered non-aryl heterocycle selected from the group consisting of: The subscript d is the number of substitutable positions on the ring of R 5 ;
• Each R 7a is independently 1) hydrogen atom, 2) a hydroxyl group, 3) halogen, 4) C 1-4 alkyl group, (However, the alkyl group may be substituted with NR e3 R f3 , 5-membered or 6-membered non-aryl heterocycle, —C ( ⁇ O) OR f3 or a hydroxyl group) 5) C 1-4 alkoxy group 6) —NR e3 R f3 , 7) —C ( ⁇ O) OR e3 , and 8) C 6-10 aryl 9) —C ( ⁇ O) NR e3 R f3 Selected from the group consisting of
• Each R 7b is independently 1) hydrogen atom, 2) a hydroxyl group, and 3) a C 1-4 alkyl group, (However, the al
• R 1 , R 2 and R 3 when any one of R 1 , R 2 and R 3 is represented by formula (2), the remaining two are each independently the same or different and are each independently a hydrogen atom, halogen atom, an optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkoxy group, an optionally substituted C 1-6 alkylthio group, 5-membered optionally substituted or 6-membered heteroaryl, or —NR a3 R b2 , wherein R a3 and R b2 are as described herein.
• R 3 is represented by formula (2).
• R 1 and R 2 are each independently the same or different, 1) hydrogen atom, 2) a halogen atom, 3) a C 1-6 alkyl group, 4) C 1-6 alkoxy group, and 5) C 1-6 alkylthio group (provided that each substituent of 3) to 5) above may be substituted) Selected from the group consisting of
• R 1 and R 2 are each independently the same or different, 1) hydrogen atom, 2) a halogen atom, and 3) an optionally substituted C 1-6 alkyl group, Selected from the group consisting of In the preferred embodiment, R 1 and R 2 are both hydrogen atoms.
• R 4 of formulas (1a) and (1b) is 1) —C ( ⁇ O) R 8 , 2) —SO 2 —L 6 —R 8
• R 8 represents —NR a5 R b4 , —NR a5 —L 7 —B (OR m1 ) 2 , —OR m1 , or optionally substituted C 1-6
• An alkyl group, and L 6 is a single bond or —NR a6 —), 3) -NR a4 R b3 , 4) -B (OR m1 ) 2 , 5) -PO (OR m1 ) (OR m2 ), 6) optionally substituted 5-membered heteroaryl, 7) an optionally substituted 5-membered non-aryl heterocycle, or 8) any of the biological equivalents of 1) to 7) (provided above 2), 4), 5) and 6) are Carboxylic acid equivalents, 8) may contain duplicates thereof)
• R 4 is —C ( ⁇ O) —OR m1 or a carboxylic acid equivalent thereof.
• R 4 is 1) —COOH (ie, a carboxyl group), or 2) a carboxylic acid equivalent.
• Said R a4 , R a5 , R a6 , R b3 , R b4 , L 7 , R m1 and R m2 are as defined in this specification.
• R 4 is 1) —COOR m1 (where R m1 represents a hydrogen atom, a C 1-6 alkyl group, a C 3-10 alicyclic group, a C 6-10 aryl, a 5-membered or 6-membered heteroaryl, or 4- Any of 10-membered non-aryl heterocycles, wherein the C 1-6 alkyl group, the C 3-10 alicyclic group, the C 6-10 aryl, the 5-membered or 6-membered heteroaryl And the 4- to 10-membered non-aryl heterocycle is each selected from the group consisting of optionally substituted) and 2) bioequivalents of 1).
• R 4 is 1) —COOH (ie, a carboxyl group), or 2) a carboxylic
• Preferred embodiments of the compound of the present invention are specifically the following formulas (4a) and (4b): Or a pharmaceutically acceptable salt thereof.
• X, R 4 , Y, ring A, L 3 , L 4 , and R 5 are as defined herein, and R 1 and R 2 are Each independently or independently, a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group (provided that the C 1-6 alkyl group and the C 1-6 alkoxy group are 1 to Optionally substituted with 5 halogen atoms).
• More preferred embodiments of the compound of the present invention are specifically the following formulas (5a) and (5b): Or a pharmaceutically acceptable salt thereof.
• R 1 , R 2 , Y, L 3 , L 4 , R 5 , and ring A are as defined herein, and ring A is substituted A 4- to 6-membered nitrogen-containing non-aryl heterocycle which may be substituted.
• an even more preferred embodiment of the compound of the present invention is specifically represented by the following formulas (6a) and (6b): Or a pharmaceutically acceptable salt thereof.
• L 3 , L 4 , and R 5 are as defined herein, m is an integer of 1, 2, or 3, and n is 1 Is an integer of 2, or 3, and m + n is 2, 3, or 4.
• m is 1 or 2
• n is 1 or 2
• m + n is 2 or 3.
• m is 1 and n is 1.
• R ZL is a substituent selected from the group consisting of the following Z1 to Z4, R 1 , R 2 , R 3 are any one of And in the remaining two are hydrogen atom, the linking group L a is a substituent selected from the group consisting of: L1 ⁇ L36, substituents Q a is selected from the group consisting of Q1 ⁇ Q103 Or a pharmaceutically acceptable salt thereof.
• R ZL Linking group L a : Substituent Q a :
• a more preferred embodiment of the compound of the present invention can be specifically exemplified as a compound of the following formula.
• the following formula Or a pharmaceutically acceptable salt thereof R ZL is a substituent selected from the group consisting of Z1 to Z4, R 1 and R 2 are hydrogen atoms, R 3 is The linking group L a is a substituent selected from the group consisting of L1 to L36, and the substituent Q a is a substituent selected from the group consisting of Q1 to Q103, A compound or a pharmaceutically acceptable salt thereof.
• a further preferred embodiment of the compound of the present invention can be exemplified as a compound of the following Table (1) or a pharmaceutically acceptable salt thereof.
• Another embodiment of the compound of the present invention is specifically represented by the following formula (11): Or a pharmaceutically acceptable salt thereof.
• formula (11) Z, L 1 , L 2 , X, R 1 , R 2 , R 3 , and R 4 are as defined herein, and R G is a hydroxyl group, a thiol group or —NHR a1 , where R a1 is as defined herein.
• Another embodiment of the compound of the present invention is specifically represented by the following formula (12): Or a pharmaceutically acceptable salt thereof.
• formula (12) X, R 1 , R 2 , R 3 , and R 4 are as defined herein, R G is a hydroxyl group, a thiol group, or —NHR a1 , and R a1 Is as defined herein.
• the compound of the formula (12) can be interconverted with the compound of the formula (1a) or (3a) in an aqueous solution or in vivo by an equilibrium reaction, and can be biologically equivalent.
• Another embodiment of the compound of the present invention specifically includes the following formula (13): Or a pharmaceutically acceptable salt thereof.
• formula (13) X, Y, ring A, L 3 , L 4 , R 1 , R 2 , R 4 , and R 5 are as defined in this specification, and R G is a hydroxyl group, A thiol group or —NHR a1 , where R a1 is as defined herein.
• a preferred embodiment of the compound of the present invention is specifically the following formula (14): Or a pharmaceutically acceptable salt thereof.
• formula (14) X, L 3 , L 4 , m, n, and R 5 are as defined herein, R G is a hydroxyl group, a thiol group, or —NHR a1 , and R a1 is as defined in this specification.
• stereoisomers such as tautomers and geometric isomers and optical isomers may exist depending on the type of substituent, and the present invention also includes them. That is, when one or more asymmetric carbon atoms are present in the compound of the present invention, diastereomers and optical isomers exist, but a mixture or an isolated product of these diastereomers or optical isomers. Are also included in the compounds of the present invention.
• the compound of the present invention may exist in a structure represented by the following formula (11) depending on an environmental condition such as temperature and humidity, or a physical factor such as a solid, liquid, or solution, depending on an equilibrium state or the like.
• the compounds of the present invention also include them.
• X represents a hydroxyl group, a thiol group, —NHR a1 , and Z, L 1 , L 2 , R G , R 1 , R 2 , R 3 , R 4 , and R a1 are defined in the present specification. It is synonymous with the definition as described in a book, and Formula (1a) is synonymous with the definition as described in this specification.
• the structure of the example compound of the present application is based on the estimation most appropriate for those skilled in the art using proton nuclear magnetic resonance spectrum ( 1 H-NMR), liquid chromatography mass spectrometry (LCMS), etc. It is merely a structure estimation under each specific measurement environment, and in particular, the structure of the above formula (1a), the structure of the formula (1b), and the structure of the formula (11) are characteristic of each compound, temperature, humidity. There is a possibility that they are converted into each other or partly converted into any one of them and mixed due to various environmental conditions such as, physical factors such as in a solid, liquid, or solution.
• 1 H-NMR proton nuclear magnetic resonance spectrum
• LCMS liquid chromatography mass spectrometry
• the compounds of the present invention also include various hydrates, solvates and crystal polymorphs.
• the compounds of the present invention may contain isotope elements (eg, 2 H (or D), 3 H (or T), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 35 S, 18 F, 125 I and the like), and these compounds are also included in the compounds of the present invention.
• isotope elements eg, 2 H (or D), 3 H (or T), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 35 S, 18 F, 125 I and the like
• the scope of the present invention includes prodrugs of the compounds of the present invention.
• the prodrug means a derivative that is obtained by acid hydrolysis or enzymatic degradation in vivo to give the compound of the formula (1a), (1b), or (11).
• the compound of the above formula (1a), (1b) or (11) has a hydroxyl group, an amino group or a carboxyl group, these groups can be modified according to a conventional method to produce a prodrug.
• a compound having a carboxy group a compound in which the carboxyl group has become an alkoxycarbonyl group, a compound in which the alkylthiocarbonyl group has been formed, or a compound in which an alkylaminocarbonyl group has been mentioned.
• a compound having an amino group a compound in which the amino group is substituted with an alkanoyl group to form an alkanoylamino group
• a compound having a hydroxyl group a compound in which the hydroxyl group is substituted with the alkanoyl group to form an alkanoyloxy group, a compound in which a phosphate ester is formed, or a compound in which an alkanoyloxymethyloxy group is formed.
• alkyl portion of the group used for the prodrug formation examples include the alkyl group, and the alkyl group may be substituted with, for example, an alkoxy group.
• Preferable examples include the following.
• alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl, methoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl or Examples include alkoxycarbonyl substituted with an alkoxy group such as valoyloxymethoxycarbonyl.
• “pharmaceutically acceptable salts” mean acid addition salts and base addition salts that are pharmaceutically acceptable.
• “Pharmaceutically acceptable salt” includes, but is not limited to, for example, acetate, propionate, butyrate, formate, trifluoroacetate, maleate, fumarate, tartrate, Citrate, stearate, succinate, ethyl succinate, malonate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, benzenesulfonic acid, paratoluenesulfonate (Tosylate), lauryl sulfate, malate, ascorbate, mandelate, saccharate, xinafoate, pamoate, cinnamate, adipate, cysteine salt, N-acetylcysteine salt , Hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide
• the compound of the present invention can be administered by oral administration or parenteral administration, directly or by using a suitable dosage form into a preparation, a pharmaceutical or a pharmaceutical composition.
• suitable dosage form include, but are not limited to, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, cataplasms, and the like.
• these preparations can be produced by known methods using additives that are used as usual pharmaceutical additives.
• additives include excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers depending on the purpose. , Sweeteners, flavors and the like can be used.
• additives include, but are not limited to, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxy
• examples include propylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.
• the dosage of the compound of the present invention is appropriately selected depending on the animal to be administered, administration route, disease, patient age, weight and symptoms.
• the lower limit is 0.01 mg (preferably 100 mg) and the upper limit is 10,000 mg (preferably 6000 mg) per day, and this amount can be once or several times a day. Can be administered separately.
• the compound of the present invention is a compound having inhibitory activity against ⁇ -lactamase. Therefore, it can be a useful preventive or therapeutic agent for bacterial infections when used in combination with an antibacterial agent.
• bacterial infections include sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung abscess, empyema, chronic respiratory tract Secondary infection of the lesion, pharynx / laryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraabdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic / lymph nodeitis, trauma Examples include secondary infections such as burns and surgical wounds, urinary tract infections, genital infections, eye infections, and dental infections.
• the compounds of the present invention are at least selected from antibacterial agents, antifungal agents, antiviral agents, anti-inflammatory agents or antiallergic agents to treat one or more bacterial infections described herein. It can be used in combination with one or more drugs.
• antibacterial agents more preferably ⁇ -lactams, specifically amoxicillin, ampicillin (pibampicillin, hetacillin, bacampicillin, methampicillin, tarampicillin), epicillin, carbenicillin (calindacillin), ticarcillin, temocillin , Azulocillin, Piperacillin, Mezulocillin, Mecillinam (Pibmesilinum), Sulbenicillin, Benzylpenicillin (G), Clomethosillin, Benzathine Benzylpenicillin, Procaine Benzylpenicillin, Azidocillin, Penamecillin, Phenoxymethylpenicillin (V), Propisinline, V Pheneticillin, cloxacillin (dicloxaci
• the administration timing of the compounds of the present invention and their therapeutic agents is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference. Moreover, it is good also as a combination of the compound of this invention and those therapeutic agents.
• the dosage of these therapeutic agents can be appropriately selected based on the clinically used dose.
• the compounding ratio of the compounds of the present invention and their therapeutic agents can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
• compositions comprising such ⁇ -lactams are also within the scope of the present invention and include sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, Pneumonia, lung abscess, empyema, secondary infection of chronic respiratory lesions, sore throat / laryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraabdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection , Used for the treatment or prevention of secondary infections such as lymphatic vessels / lymphadenitis, trauma / burns and surgical wounds, urinary tract infections, genital infections, eye infections or dental infections be able to.
• secondary infections such as lymphatic vessels / lymphadenitis, trauma / burns and surgical wounds, urinary tract infections, genital infections, eye infections or dental infections be able to.
• Such medicaments, formulations and pharmaceutical compositions may be combined with the compounds of the present invention and / or additional agents (eg, antibacterial agents such as ⁇ -lactams) using any technique known in the art. Or separately, as a combination or as a separate drug, by mixing with any appropriate component, using any technique known in the art, using appropriate formulations, such as tablets, It can be formulated into capsules, powders, granules, solutions, suspensions, injections, patches, and poultices.
• additional agents eg, antibacterial agents such as ⁇ -lactams
• a compound of the invention and / or an additional agent eg, an antibacterial agent such as a ⁇ -lactam agent
• an additional agent for example, an antibacterial agent such as a ⁇ -lactam agent, an additional agent (eg, an antibacterial agent such as a ⁇ -lactam agent)
• the compound of the present invention may be provided together with instructions (such as a package insert) indicating that the compounds are administered at the same time or different times.
• the compound of the present invention is used as a pharmaceutical active ingredient, it is not intended to be used only for humans, but is also used for other animals other than humans (cats, dogs, cows, chickens, fish, etc.). It is possible.
• the compound of the present invention is not limited to these, but can be produced, for example, by the production method described below. These production methods can be improved as appropriate based on the knowledge of a person skilled in organic synthetic chemistry.
• a salt thereof may be used as long as the reaction is not hindered.
• any functional group other than the reactive site changes depending on the reaction conditions, or is inappropriate for carrying out the treatment after the reaction.
• the compound other than the reaction point is protected as necessary, and the target compound can be obtained by deprotection after completion of the reaction or after a series of reactions.
• the protecting groups used in these processes the literature is described in (T. W. Greene and P. G. M. Wuts, "Protective Group in OrganicSynthesis", 3 rd Ed., John Wiley and Sons, inc., New York (1999)) , etc.
• the usual protecting groups can be used.
• the introduction and removal of the protecting group can be performed by a method commonly used in organic synthetic chemistry (for example, the method described in the above document) or a method analogous thereto.
• the starting materials and intermediates in the following production methods can be purchased as commercial products, or can be obtained by synthesizing from known methods or known compounds according to known methods. 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 be converted into other compounds included in the present invention by appropriately converting their functional groups. Conversion of functional groups in that case, a method (e.g., conventionally used in organic synthetic chemistry, R. C. Larock, "Comprehensive Organic Transformations", 2 nd Ed., John Wiley and Sons, inc., Is described in New York (1999) Etc.) or a method according to them.
• a method e.g., conventionally used in organic synthetic chemistry, R. C. Larock, "Comprehensive Organic Transformations", 2 nd Ed., John Wiley and Sons, inc., Is described in New York (1999) Etc.
• the inert solvent in the following production method refers to a solvent that does not react with raw materials, reagents, bases, acids, catalysts, ligands, etc. (hereinafter sometimes referred to as “raw materials used in the reaction”) used in the reaction. means. Further, even when the solvent used in each step reacts with the raw material used in the reaction, it can be used as an inert solvent as long as the target reaction proceeds and the target compound is obtained.
• a compound represented by the following formula (1-7) can be produced, for example, by the following production method.
• L 1 , L 2 , Y, Z, ring A, L 3 , L 4 , G, R 1 , R 2 , R 4 , R 5 are as defined in item 1 and
• X a Is a hydroxyl group or a C 1-6 alkoxy group
• H is a hydrogen atom
• LG is a leaving group (eg, a halogen atom such as chlorine, bromine or iodine, a lower alkylsulfonyloxy group such as methanesulfonyloxy, trifluoro Represents a trihalogenomethanesulfonyloxy group such as lomethanesulfonyloxy, benzenesulfonyloxy, an arylsulfonyloxy group such as p-toluenesulfonyloxy),
• arylsulfonyloxy group such as oxy
• PG 1 represents a hydroxyl protecting group (e.g., tert- butoxycarbonyl group, an acetyl group , Methoxymethyl group, p-methoxybenzyl group, tert-butyldimethylsilyl group, trimethylsilyl group and the like)
• PG 2 and PG 3 are boronic acid protecting groups (for example, optionally substituted C 1 A -6 alkyl group, or a structure represented by the following formula:
• PG 4 is a hydrogen atom, a hydroxyl protecting group (for example, tert-butoxycarbonyl group, acetyl group, methoxymethyl group, p-methoxybenzyl group, tert-butyldimethylsilyl group, trimethylsilyl group, etc.), thiol group Protecting group (for example, acetamidomethyl group or trityl group) or protecting group
• the starting material compound (1-1) a commercially available one can be used, or one produced by a known method (for example, WO2016 / 003929, WO2016 / 149393, etc.) can be used.
• Compound (1-5) may be a commercially available product, or may be a known document (for example, WO 2008/008895, WO 2011/118818, J. Med. Chem., 28 (11), 1721, 1985, Tetrahedron, 67 (52), 10208, 2011, Tetrahedron Letters, 26 (39), 4739, 1985, J. Antibiot. 59 (4), 241, 2006, etc.) or a known method from a known compound (for example, RCLarock, "Comprehensive Organic Transformations” , 2 nd Ed., JohnWileyand Sons, inc., New York (1999) can be used after synthesized according to the method, etc.) described in.
• a known document for example, WO 2008/008895, WO 2011/118818, J. Med. Chem., 28 (11), 1721, 1985, Tetrahedron, 67 (52), 10208, 2011, Tetrahedron Letters, 26 (39), 4739, 1985, J. Antibiot. 59
• salts thereof can be used as long as they do not hinder the reaction, and those having a functional group protected as necessary can be used.
• Step 1-1 Compound (1-3) is reacted with Compound (1-2) in the presence of a base in an inert solvent at normal pressure or under pressure.
• a base inert solvent
• the inert solvent include, for example, ether solvents such as THF or DME, halogenated hydrocarbon solvents such as dichloromethane or dichloroethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), Examples include aprotic solvents such as dimethyl sulfoxide (DMSO).
• the base include tert-butoxy potassium, sodium hydride, triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate and the like.
• 0.001 to 100 equivalents can be used, preferably 0.5 to 10 equivalents, relative to compound (1-1).
• the equivalent of compound (1-2) can be 0.001 to 100 equivalents, preferably 1 to 10 equivalents, relative to compound (1-1).
• the reaction temperature is selected from the range of about ⁇ 10 ° C. to about 100 ° C.
• Step 1-2 Compound (1-4) can be produced by deprotecting protecting group PG 1 of compound (1-3).
• This step is for example the literature (T. W. Greene and P. G. M. Wuts, "Protective Group in OrganicSynthesis", 3 rd Ed., John Wiley and Sons, inc., New York (1999)) be carried out according to a method such as that described in Can do.
• Step 1-3 The compound (1-6) can be produced using the production method (1-3-1) or the production method (1-3-2) shown below.
• Step 1-3-1 When Y is an oxygen atom and T is a hydroxyl group, the compound (1-6) is obtained by reacting the compound (1-4) with an azo compound analog and organic phosphorus in an inert solvent. It can be produced by reacting with compound (1-5) under the conditions of so-called Mitsunobu reaction in the presence of a compound / or in the presence of a phosphorane compound at normal pressure or under pressure.
• the inert solvent include ether solvents such as THF or DME, hydrocarbon solvents such as toluene or benzene, and the like.
• Examples of the azo compound analog include diethyl azodicarboxylate, diisopropyl azodicarboxylate, and the like.
• the molar equivalent of the azo compound analog can be 0.001 to 100 molar equivalents relative to compound (1-4), but preferably 1 to 10 molar equivalents.
• Examples of the organic phosphorus compound include triphenylphosphine and tributylphosphine.
• the molar equivalent of the organophosphorus compound can be 0.001 to 100 molar equivalents relative to compound (1-4), but preferably 1 to 10 molar equivalents.
• Examples of the phosphorane compound include (cyanomethylene) tributylphosphorane, (cyanomethylene) trimethylphosphorane, and the like.
• the molar equivalent of the phosphorane compound can be 0.001 to 100 molar equivalents relative to compound (1-4), but preferably 1 to 10 molar equivalents.
• the reaction temperature is selected from the range of about ⁇ 10 ° C. to about 100 ° C.
• Step 1-3-2 Y is an oxygen atom, a sulfur atom, or —NR j —, and T is a leaving group (for example, a halogen atom such as chlorine, bromine or iodine, a lower alkyl such as a methanesulfonyloxy group)
• a sulfonyloxy group, a trihalogenomethanesulfonyloxy group such as a trifluoromethanesulfonyloxy group, an arylsulfonyloxy group such as a benzenesulfonyloxy group, and a p-toluenesulfonyloxy group is an oxygen atom, a sulfur atom, or —NR j —
• T is a leaving group (for example, a halogen atom such as chlorine, bromine or iodine, a lower alkyl such as a methanesulfonyloxy group)
• 6) can be produced by reacting compound (1-4) with compound (1-5) in an inert solvent in the presence of a base at normal pressure or under pressure.
• a base at normal pressure or under pressure.
• the inert solvent include ether solvents such as THF or DME, halogenated hydrocarbon solvents such as dichloromethane or dichloroethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), Examples include aprotic solvents such as dimethyl sulfoxide (DMSO).
• the base include tert-butoxy potassium, sodium hydride, triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, cesium carbonate and the like.
• molar equivalent of the base 0.001 to 100 molar equivalents can be used with respect to compound (1-1), and preferably 0.5 to 10 molar equivalents.
• molar equivalent of compound (1-5) 0.001 to 100 molar equivalents can be used, preferably 1 to 10 molar equivalents, relative to compound (1-4).
• the reaction temperature is selected from the range of about ⁇ 10 ° C. to about 100 ° C.
• Step 1-4 This reaction can be produced from the corresponding compound (1-6) according to a known method (for example, WO2014 / 151958, WO2015 / 191907, WO2016 / 003929, etc.). Preferably, it can be produced using the production method (1-4-1) or the production method (1-4-2) shown below.
• the boronic acid include phenylboronic acid and 2-methylpropylboronic acid.
• the equivalent of boronic acid can be used in the range of 0.001 to 100 equivalents, preferably 1 to 3 equivalents, relative to compound (1-6).
• the acid examples include hydrochloric acid and trifluoroacetic acid.
• the equivalent amount of the acid can be used in the range of 0.001 to 100 equivalents relative to the compound (1-6), but preferably 1 to 10 equivalents.
• Specific examples of the inert solvent include halogenated hydrocarbon solvents such as dichloromethane or dichloroethane, hydrocarbon solvents such as hexane or heptane, ether solvents such as THF or CPME, acetonitrile or propionitrile, and the like.
• a nitrile solvent and water are mentioned, and can be used alone or as a mixed solvent.
• the acid shown above can also be used as a solvent as it is.
• a mixed solvent of hexane / acetonitrile is used as the solvent.
• the reaction temperature is selected from the range of about ⁇ 10 ° C. to about 100 ° C.
• Production method (1-4-2): Compound (1-7) can be produced by reacting compound (1-6) as a starting material with triethylsilane in a trifluoroacetic acid solvent.
• the equivalent amount of triethylsilane can be used in the range of 0.001 to 100 equivalents, preferably 1 to 50 equivalents, relative to compound (1-6).
• the reaction temperature is selected from the range of about ⁇ 10 ° C. to about 70 ° C.
• the compound of the formula (1a) can be produced from a corresponding raw material that can be purchased or prepared in the same manner as in the production method of the compound (1-7). Also, depending on the nature of the compound (1a), for example, nucleophilic X - resulting alkali metal salt to produce, a C 1-6 alkoxide anion - (X anion) reagent to produce (e.g., a hydroxide anion HO Reaction with an alkali metal salt of a C 1-6 alkoxide, an alkali metal salt of the amide that generates an amide anion R a2 R b1 N — , etc.) may be obtained as a compound of the formula (1b).
• a C 1-6 alkoxide anion - (X anion) reagent to produce e.g., a hydroxide anion HO Reaction with an alkali metal salt of a C 1-6 alkoxide, an alkali metal salt of the amide that generates an amide ani
• X, Z, L 1 , L 2 , G, R 1 , R 2 , R 3 , and R 4 are as defined in Item 1.
• a compound of the following formula (1a ′) in which X is a hydroxyl group is treated with a sodium hydroxide aqueous solution, and depending on the properties of the compound, the compound of the formula (1b ′) It may be obtained as a sodium salt compound.
• a compound represented by the following formula (2-7) can be produced, for example, by the following production method.
• the compound (2-7) represents a case where in the compound (1-7), L 1 is —NR d (C ⁇ O) — and R d is a hydrogen atom.
• L 2 , Y, Z, ring A, L 3 , L 4 , G, R 1 , R 2 , R 4 , R 5 are as defined in item 1 and X a is a hydroxyl group or C 1-6 alkoxy group, H is a hydrogen atom, T, LG, PG 1 , PG 2 , PG 3 , and PG 4 have the same definitions as described in Production Method 1, respectively, and TMS is a trimethylsilyl group Represents.
• compound (1-1) and compound (1-5) may be those purchased as commercially available products or those produced by the method described in Production Method 1.
• Compounds (2-2) and compound (2-3) used was purchased commercially known methods from known compounds (e.g., R. C. Larock, "Comprehensive Organic Transformations", 2 nd Ed., John (The method described in Wiley and Sons, inc., New York (1999)) Those synthesized according to the above can be used.
• compound (1-5), compound (2-2), and compound (2-3) do not interfere with the reaction, their salts can be used, and the functional group is protected as necessary. It is also possible to use what has been done.
• Step 2-1 The compound (2-1) can be produced by reacting the compound (1-1) with hexamethyldisilazane lithium in an inert solvent at normal pressure or under pressure.
• the inert solvent include ether solvents such as THF or diethyl ether.
• ether solvents such as THF or diethyl ether.
• the equivalent of hexamethyldisilazane lithium 0.001 to 100 equivalents can be used, preferably 1 to 10 equivalents, relative to compound (1-1).
• the reaction temperature is selected from the range of about ⁇ 78 ° C. to about 50 ° C.
• Step 2-2 The compound (2-4) is a compound with respect to the compound (2-1) in an inert solvent in the presence or absence of a condensing agent and / or a base under normal pressure or pressure. It can be produced by reacting with (2-2) or (2-3).
• the inert solvent include ether solvents such as THF or DME, halogenated hydrocarbon solvents such as dichloromethane or chloroform, and aprotic solvents such as DMF, NMP, and DMSO.
• the equivalent of (2-2) or (2-3) can be used in an amount of 0.001 to 100 equivalents, preferably 1 to 10 equivalents, relative to compound (2-1).
• the condensing agent various condensing agents used in a conventional method can be used.
• 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide including hydrochloride
• equivalent of the condensing agent 0.001 to 100 equivalents can be used, preferably 1 to 10 equivalents, relative to compound (2-1).
• Examples of the base include diisopropylethylamine and triethylamine. With respect to the equivalent of the base, 0.001 to 100 equivalents can be used, but preferably 1 to 10 equivalents, relative to compound (2-1).
• the reaction temperature is selected from the range of about ⁇ 78 ° C. to about 100 ° C.
• Step 2-3 The compound (2-5) can be produced using the compound (2-4) as a starting material and using the same conditions as in Step 1-2 of Production Method 1.
• Step 2-4 The compound (2-6) is reacted with the compound (1-5) using the compound (2-5) as a starting material under the same conditions as in Step 1-3 of Production Method 1. Can be manufactured.
• Step 2-5 Compound (2-7) can be produced using compound (2-6) as a starting material under the same conditions as in Step 1-4 of Production Method 1.
• L 1 , L 2 , Z, L 3 , L 4 , G, R 1 , R 2 , R 4 , R 5 are as defined in Item 1;
• X a is a hydroxyl group or a C 1-6 alkoxy group, H is a hydrogen atom, and
• T, LG, PG 2 , PG 3 , and PG 4 are as defined in Production Method 1, respectively.
• PG 5 is an amino group protecting group (for example, ethoxycarbonyl group, tert-butoxycarbonyl group, acetyl group, benzoyl group, trifluoroacetyl group, benzyloxycarbonyl group, 3- or 4-chlorobenzyloxy group) Carbonyl group, triphenylmethyl group, methanesulfonyl group, p-toluenesulfonyl group, trimethylsilyl group, benzyloxycarbonyl group, 3- or 4-chlorobenzyloxycarbo Group, benzylsulfonyl group, benzyl group, 4-nitrobenzyl group, 4-methoxybenzyl group, methyl group, ethyl group, etc.), J is a hydroxyl group or a leaving group (for example, chlorine, bromine, iodine) Halogen atoms such as, lower alkylsulfonyloxy groups such as methanesulfon
• compound (3-1) and compound (3-2) which are purchased as commercially available products or those produced by the method described in Production Method 1 and Production Method 2 can be used.
• the compound (3-2) and compound (3-5) is either used as purchased commercially known methods from known compounds (e.g., R. C. Larock, "Comprehensive Organic Transformations", 2 nd Ed., John And those synthesized according to the method described in Wiley and Sons, Inc., New York (1999).
• salts thereof can be used, and those having a functional group protected as necessary can also be used. I can do it.
• Step 3-1 The compound (3-3) is reacted with the compound (3-2) using the compound (3-1) as a starting material under the same conditions as in Step 1-3 of Production Method 1. Can be manufactured.
• Step 3-2 The compound (3-4) can be produced by deprotecting the protecting group PG 5 of the compound (3-3).
• This step is for example the literature (T. W. Greene and P. G. M. Wuts, "Protective Group in OrganicSynthesis", 3 rd Ed., John Wiley and Sons, inc., New York (1999)) be carried out according to a method such as that described in Can do.
• Step 3-3 Compound (3-6) can be produced using compound (3-4) as a starting material and using the same conditions as in Step 2-2 of Production Method 2.
• Step 3-4 The compound (3-7) can be produced using the compound (3-6) as a starting material and using conditions according to the above-mentioned production method 1, step 1-4.
• a compound represented by the following formula (4-4) can be produced, for example, by the following production method.
• Y, ring A, L 3 , L 4 , G, R 1 , R 2 , R 4 , R 5 are as defined in item 1
• X a is a hydroxyl group or a C 1-6 alkoxy
• H is a hydrogen atom
• T, PG 1 , PG 2 , PG 3 , and PG 4 have the same definitions as described in Production Method 1.
• compound (4-1) and compound (1-5) may be commercially available products or those produced by the method described in Production Method 1. As long as compound (1-5) does not interfere with the reaction, a salt thereof can be used, and if necessary, a functional group protected can be used.
• Step 4-1 Compound (4-2) can be produced using compound (4-1) as a starting material and using the same conditions as in Step 1-2 of Production Method 1.
• Step 4-2 Compound (4-3) is reacted with compound (1-5) using compound (4-2) as a starting material under the same conditions as in Production Method 1, Step 1-3. Can be manufactured.
• Step 4-3 The compound (4-4) can be produced by using the compound (4-3) as a starting material and using the conditions according to the above-mentioned production method 1, step 1-4.
• the compound represented by the following formula (5-4) can be produced, for example, by the following production method.
• L 3 , L 4 , G, R 1 , R 2 , R 4 , R 5 are as defined in Item 1
• m and n are as defined in Item 28, and
• X a is a hydroxyl group or a C 1-6 alkoxy group
• H is a hydrogen atom
• T, PG 2 , PG 3 , and PG 4 are as defined in Production Method 1
• PG 5 and J are production methods.
• Compound (4-1), compound (3-2), and compound (3-5), which are starting materials, are commercially available products, or are produced by the methods described in Production Method 1 and Production Method 3. Can be used. As long as compound (3-2) and compound (3-5) do not interfere with the reaction, salts thereof can be used, and those having a functional group protected as necessary can be used.
• Step 5-1 Compound (5-1) is reacted with Compound (3-2) using Compound (4-1) as a starting material under the same conditions as in Step 3-1 of Production Method 3. Can be manufactured.
• Step 5-2 The compound (5-2) can be produced by using the compound (5-1) as a starting material and using the conditions according to the above-mentioned production method 3, step 3-2.
• Step 5-3 The compound (5-3) is reacted with the compound (3-5) using the compound (5-2) as a starting material under the conditions according to the above-mentioned production method 3, step 3-3. Can be manufactured.
• Step 5-4 The compound (5-4) can be produced by using the compound (5-3) as a starting material and using the conditions according to the above-mentioned production method 3, step 3-4.
• the compound represented by the following formula (6-5) can be produced, for example, by the following production method.
• L 1 , L 2 , Y, Z, ring A, L 3 , L 4 , G, R 4 , R 5 are as defined in item 1, provided that one end of Y, R 1a and R 2a, R 1 each binds with bondable either three positions is a representation of unsubstituted on drawing in the benzene ring, R 1a and R 2a as defined herein to claim 1 , R 2 and R 3 represent the remaining two not taking the structure of formula (2), X a is a hydroxyl group or a C 1-6 alkoxy group, H is a hydrogen atom, T, LG, PG 1 , PG 2 , PG 3 , and PG 4 have the same definitions as in Production Method 1, respectively.
• compound (6-1), compound (1-2), and compound (1-5) are either commercially available products or those produced by the method described in Production Method 1. Can be used. As long as compound (3-2) and compound (3-5) do not interfere with the reaction, salts thereof can be used, and those having a functional group protected as necessary can be used.
• Step (6-1) The compound (6-2) reacts with the compound (1-2) using the compound (6-1) as a starting material under the same conditions as in Step 1-1 of Production Method 1. Can be manufactured.
• Step (6-2) The compound (6-3) can be produced by using the compound (6-2) as a starting material and using the same conditions as in Step 1-2 of Production Method 1.
• Step (6-3) The compound (6-4) is reacted with the compound (1-5) using the compound (6-3) as a starting material under the same conditions as in Step 1-3 of Production Method 1. Can be manufactured.
• the compound represented by the following formula (7-5) can be produced, for example, by the following production method.
• This compound represents the case where, in the above compound (6-5), L 1 is —NR d (C ⁇ O) — and R d is a hydrogen atom.
• L 2 , Y, Z, ring A, L 3 , L 4 , G, R 4 , R 5 are as defined in item 1, provided that one end of Y, R 1a and R 2a Are bonded at any of the three bondable positions, each of which is an unsubstituted notation on the benzene ring in the figure, and R 1a and R 2a are R 1 , R 2 as defined in item 1 of this specification.
• R 3 represent the remaining two not taking the structure of formula (2), X a is a hydroxyl group or a C 1-6 alkoxy group, H is a hydrogen atom, T, LG, PG 1 , PG 2 , PG 3 and PG 4 have the same definitions as those described in Production Method 1, and TMS represents trimethylsilyl.
• Compound (6-1), compound (1-2), and compound (1-5), which are starting materials, are either commercially available products or those produced by the method described in Production Method 1. Can be used. Further, Compounds (2-2) and compound (2-3) used was purchased commercially known methods from known compounds (e.g., R. C. Larock, "Comprehensive Organic Transformations", 2 nd Ed., John And those synthesized according to the method described in Wiley and Sons, Inc., New York (1999). As long as compound (2-2), compound (2-3), and compound (1-5) do not hinder the reaction, their salts can be used, and the functional group is protected as necessary. Things can also be used.
• Step 7-1 The compound (7-1) can be produced using the compound (6-1) as a starting material and using the conditions according to the above-mentioned production method 2, step 2-1.
• Step 7-2 Compound (7-2) is compound (2-2) or compound (2) using compound (7-3) as a starting material and using the same conditions as in Step 2-2 of Production Method 2. It can be produced by reacting with -3).
• Step 7-3 The compound (7-3) can be produced using the compound (7-2) as a starting material and using the same conditions as in Step 2-3 of Production Method 2.
• Step 7-4 The compound (7-4) is reacted with the compound (1-5) using the compound (7-3) as a starting material under the same conditions as in Step 2-4 of Production Method 2. Can be manufactured.
• Step 7-5 The compound (7-5) can be produced using the compound (7-4) as a starting material and using the same conditions as in Step 2-5 of Production Method 2.
• the compound represented by the following formula (8-4) can be produced, for example, by the following production method.
• L 1 , L 2 , Z, L 3 , L 4 , G, R 4 , and R 5 are as defined in Item 1 except that one end of the oxygen atom substituted on the benzene ring, R 1a and R 2a are bonded at any of the three bondable positions, each of which is an unsubstituted notation on the benzene ring in the figure, and R 1a and R 2a are defined in Item 1 of this specification.
• R 1 , R 2 and R 3 represent the remaining two not taking the structure of formula (2), m and n are as defined in Item 28, and X a is a hydroxyl group or a C 1-6 alkoxy H is a hydrogen atom, T, PG 2 , PG 3 , and PG 4 have the same definitions as in Production Method 1, and PG 5 and J have the same definitions as in Production Method 3, respectively. is there.)
• the starting material compound (6-3) a commercially available product or a product produced by the method described in Production Method 1 and Production Method 2 can be used.
• the compound (3-2) and the compound (3-5) commercially available products can be used, or those produced by the method described in Production Method 3 can be used.
• salts thereof can be used, and those having a functional group protected as necessary can also be used. I can do it.
• Step 8-1 The compound (8-1) is reacted with the compound (3-2) using the compound (6-3) as a starting material under the same conditions as in Step 1-3 of Production Method 1. Can be manufactured.
• Step 8-2 The compound (8-2) can be produced by using the compound (8-1) as a starting material and using conditions according to the above-mentioned production method 3, step 3-2.
• Step 8-3 The compound (8-3) is reacted with the compound (3-5) using the compound (8-3) as a starting material and using the same conditions as in Step 3-3 of Production Method 3. Can be manufactured.
• Step 8-4 The compound (8-4) can be produced using the compound (8-3) as a starting material and using conditions according to the above-mentioned production method 1, step 1-4.
• a compound represented by the following formula (9-4) can be produced, for example, by the following production method.
• Y, ring A, L 3 , L 4 , G, R 4 and R 5 are as defined in item 1, except that one end of Y, R 1a and R 2a are R 1a and R 2a are bonded at any of the three bondable positions on the middle benzene ring, which are unsubstituted, and R 1a and R 2a are defined as R 1 , R 2 and R 3 as defined in item 1 of this specification
• the compound (9-1) and the compound (1-5) which are purchased as commercially available products or those produced by the method described in Production Method 1 can be used.
• a salt thereof can be used, and if necessary, a functional group protected can be used.
• Step 9-1 The compound (9-2) can be produced using the compound (9-1) as a starting material and using the same conditions as in Step 1-2 of Production Method 1.
• Step 9-2 The compound (9-3) is reacted with the compound (1-5) using the compound (9-2) as a starting material and using the same conditions as in Step 1-3 of Production Method 1. Can be manufactured.
• Step 9-3 The compound (9-4) can be produced by using the compound (9-3) as a starting material and using the conditions according to the production method 1, step 1-4.
• a compound represented by the following formula (10-4) can be produced, for example, by the following production method.
• L 3 , L 4 , G, R 4 , and R 5 are as defined in Item 1, and T, PG 2 , PG 3 , and PG 4 are the same as defined in Production Method 1, respectively.
• R 1a and R 2a are bonded at any of the three possible bonding positions on the benzene ring, each of which is an unsubstituted notation.
• R 1a and R 2a represent the remaining two of R 1 , R 2 and R 3 defined in Item 1 that do not have the structure of Formula (2), and m and n are defined in Item 28.
• Xa is a hydroxyl group or a C 1-6 alkoxy group
• H is a hydrogen atom
• PG 5 and J are as defined in Production Method 3.
• Compound (9-2), compound (3-2), and compound (3-5) as starting materials are either commercially available products or are produced by the methods described in Production Method 1 and Production Method 3. Can be used. As long as compound (3-2) and compound (3-5) do not interfere with the reaction, salts thereof can be used, and those having a functional group protected as necessary can be used.
• Step 10-1 The compound (10-1) is reacted with the compound (3-2) using the compound (9-2) as a starting material under the same conditions as in Step 3-1 of Production Method 3. Can be manufactured.
• Step 10-2 The compound (10-2) can be produced using the compound (10-1) as a starting material and using conditions according to the above-mentioned production method 3, step 3-2.
• Step 10-3 The compound (10-3) is reacted with the compound (3-5) using the compound (10-2) as a starting material under the same conditions as in Step 3-3 of Production Method 3. Can be manufactured.
• Step 10-4 The compound (10-4) can be produced by using the compound (10-3) as a starting material and using the conditions according to the above-mentioned production method 3, step 3-4.
• a compound represented by the following formula (11-3) can be produced, for example, by the following production method.
• the compound (11-3) represents the case where L 3 is —S ( ⁇ O) 2 — in the compound (3-7).
• L 1 , L 2 , Z, L 4 , G, R 1 , R 2 , R 4 , R 5 are as defined in item 1 and m and n are defined in item 28.
• Xa is a hydroxyl group or a C 1-6 alkoxy group
• H is a hydrogen atom
• PG 2 , PG 3 , and PG 4 have the same definitions as in Production Method 1, respectively.
• the starting material compound (3-4) those produced by the method described in Production Method 3 can be used. Further, Compounds (11-1) is used which has been purchased as a commercially available product, known methods from known compounds (e.g., R. C. Larock, "Comprehensive Organic Transformations", 2 nd Ed., John Wiley and Sons, inc., Those synthesized according to the method described in New York (1999) can be used. As the compound (11-1), a salt thereof can be used as long as the reaction is not hindered, and a compound in which a functional group is protected can be used as necessary.
• Step 11-1 The compound (11-2) is obtained by reacting the compound (11-2) with respect to the compound (3-4) in an inert solvent in the presence or absence of a base under normal pressure or pressure. It can manufacture by making it react.
• the inert solvent include ether solvents such as THF or DME, halogenated hydrocarbon solvents such as dichloromethane or chloroform, and aprotic solvents such as DMF, NMP and DMSO.
• ether solvents such as THF or DME
• halogenated hydrocarbon solvents such as dichloromethane or chloroform
• aprotic solvents such as DMF, NMP and DMSO.
• the equivalent of compound (11-1) 0.001 to 100 equivalents can be used, preferably 1 to 10 equivalents, relative to compound (3-4).
• the base include diisopropylethylamine and triethylamine. With respect to the equivalent of the base, 0.001 to 100 equivalents can be used, but preferably 1 to 10 equivalents
• Step 11-2 The compound (11-3) can be produced by using the compound (11-2) as a starting material and using the conditions according to the production method 1, step 1-4.
• a compound represented by the following formula (12-2) can be produced, for example, by the following production method.
• the compound (12-2) represents a case where, in the compound (5-4), L 3 is —S ( ⁇ O) 2 —.
• L 4 , G, R 1 , R 2 , R 4 , R 5 are as defined in item 1, m and n are as defined in item 28, and X a is a hydroxyl group.
• H is a hydrogen atom
• PG 2 , PG 3 , and PG 4 have the same definitions as in Production Method 1, respectively.
• the starting material compound (5-2) one produced by the method described in Production Method 5 can be used. Further, Compounds (11-1) is used which has been purchased as a commercially available product, known methods from known compounds (e.g., R. C. Larock, "Comprehensive Organic Transformations", 2 nd Ed., John Wiley and Sons, inc., Those synthesized according to the method described in New York (1999) can be used. As the compound (11-1), a salt thereof can be used as long as the reaction is not hindered, and a compound in which a functional group is protected can be used as necessary.
• Step 12-1 The compound (12-1) can be produced by using the compound (5-4) as a starting material and using the conditions according to the step 11-1 of the production method 11.
• Step 12-2 The compound (12-2) can be produced by using the compound (12-1) as a starting material and using conditions according to the above-mentioned production method 1, step 1-4.
• the compound represented by the following formula (13-5) can be produced, for example, by the following production method.
• the compound (13-5) represents the case of 1H-1,2,3-triazole in which R 5 in the compound (5-4) may be substituted.
• R 5 in the compound (5-4) may be substituted.
• H is a hydrogen atom
• U is an amino group, a nitro group, a carboxylic acid, an alcohol or a leaving group (eg, a halogen atom such as chlorine, bromine, iodine, methanesulfonyloxy lower alkylsulfonyloxy groups such as, represents tri halogen methanesulfonyloxy group such as trifluoromethanesulfonyloxy, benzenesulfonyloxy, the p- arylsulfonyloxy group such as toluenesulfonyloxy and the like),
• R p is among the R a as defined in claim 36 is acceptable base or the R a convertible based on the compound of formula (13-4)
• PG 2, P 3, PG 4 are the same as defined according to each method 1 J have the same meanings as defined described in Preparation 3.
• the starting material compound (5-2) one produced by the method described in Production Method 5 can be used. Further, Compounds (13-1) is used which has been purchased as a commercially available product, known methods from known compounds (e.g., R. C. Larock, "Comprehensive Organic Transformations", 2 nd Ed., John Wiley and Sons, inc., Those synthesized according to the method described in New York (1999) can be used. As the compound (13-1), a salt thereof can be used as long as the reaction is not hindered, and a compound in which a functional group is protected can be used as necessary.
• Step 13-1 The compound (13-2) can be produced using the compound (5-4) as a starting material and using the same conditions as in Step 5-3 of Production Method 5.
• Step 13-2 Compound (13-3) is produced by reacting Compound (13-2) with an azidating agent in an inert solvent in the presence or absence of a base at normal pressure.
• an inert solvent include halogenated hydrocarbon solvents such as dichloromethane and chloroform, and aprotic solvents such as DMF, NMP, and DMSO.
• an azidating agent include sodium azide, trimethylsilyl azide, diphenyl phosphate azide and the like.
• the equivalent of the azidating agent can be 0.001 to 100 equivalents relative to compound (13-2), but preferably 1 to 10 equivalents.
• the base examples include diisopropylethylamine, triethylamine, 4-dimethylaminopyridine and the like.
• the base can be used in an amount of 0.001 to 100 equivalents, preferably 1 to 10 equivalents, relative to compound (13-2).
• the reaction temperature is selected from the range of about ⁇ 78 ° C. to about 100 ° C.
• Step 13-3 Compound (13-5) is reacted with Compound (13-3) in an inert solvent in the presence or absence of a base, in the presence or absence of a catalyst, at normal pressure or under pressure. It can be produced by reacting with compound (13-4) under pressure.
• the inert solvent include ether solvents such as THF or DME, halogenated hydrocarbon solvents such as dichloromethane or chloroform, and aprotic solvents such as acetonitrile, DMF, NMP, and DMSO.
• the equivalent of compound (13-4) can be used in the amount of 0.001 to 100 equivalents, preferably 1 to 10 equivalents, relative to compound (13-3).
• the base examples include diisopropylethylamine and triethylamine.
• 0.001 to 100 equivalents can be used, preferably 1 to 10 equivalents, relative to compound (13-3).
• Specific examples of the catalyst include, for example, copper sulfate, copper iodide, (chloro-[(1,2,3,4,5-h) -1,2,3,4,5-pentamethyl-2,4- Pentacyclodien-1-yl] bis (triphenylphosphine) ruthenium (II)
• the catalyst may be used in an amount of 0.001 to 100 equivalents relative to compound (13-3), Preferably it is 0.01 to 10 equivalents, and the reaction temperature is selected from the range of about ⁇ 78 ° C. to about 100 ° C.
• Step 13-4 The compound (12-6) can be produced by using the compound (12-5) as a starting material and using conditions according to the above-mentioned production method 1, step 1-4.
• the intermediates and target compounds in the above production method can be obtained by subjecting them to purification methods commonly used in organic synthetic chemistry (for example, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc.). It can be separated and purified. In addition, each intermediate can be subjected to the next reaction without any particular purification.
• purification methods commonly used in organic synthetic chemistry for example, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc.
• An optically active compound of the present invention can be produced by using an optically active starting material or intermediate, or by optically resolving the intermediate or final racemate.
• Examples of the optical resolution method include, but are not limited to, separation methods such as a separation method using an optically active column and a fractional crystallization method.
• separation methods such as a separation method using an optically active column and a fractional crystallization method.
• the diastereomer of the compound of this invention is not limited to these, For example, it can manufacture by separation methods, such as column chromatography and a fractional crystallization method.
• the pharmaceutically acceptable salt of the compound represented by the formula (1a) or the formula (1b) is not limited to these.
• the compound was identified using proton nuclear magnetic resonance spectrum ( 1 H-NMR), liquid chromatography mass spectrometry (LCMS) and the like. Tetramethylsilane was used as an internal standard for the nuclear magnetic resonance spectrum.
• the column chromatography in the reference examples and examples is a silica gel column manufactured by Yamazen Co., Ltd., an ODS-A column manufactured by YMC, and a YMC-Actus Triart manufactured by YMC. C18 was used. Further, Silica gel 60F254 (Merck) was used for TLC (silica gel plate) and TLC plate NH (Fuji Silysia) was used for TLC (NH silica gel plate) when purified using thin layer chromatography (TLC).
• NMR spectra [ 1 H-NMR] 400 MHz: JEOL JNM-AL series AL400, JEOL EX270, and 500 MHz: JEOL ECA-500. 600 Hz: Agilent DD2 600 MHz NMR Spectrometer.
• LC-MS spectrum Waters ACQUITY TM UltraPerformance LC, Waters AQUITY UPLC H-Class System, Shimadzu LCMS-2020.
• the measurement conditions (hereinafter also referred to as measurement method) of the high performance liquid chromatography mass spectrometer (LCMS) are as follows, and the observed mass spectrometry value [MS (m / z)] is represented by [M + 1] + The retention time at which the mass spectrometric value was observed is indicated by Rt (min, min).
• reaction solution was distilled off under reduced pressure, 1 mol / L hydrochloric acid (40 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration, washed with water, and dried to give the title compound (6.03 g).
• Reference Example 1-2 tert-butyl 3-bromo-2,6-bis [(tert-butoxycarbonyl) oxy] benzoate
• THF 120 mL
• tert-butanol 60 mL
• di-tert-butyl dicarbonate 65.2 g, 299 mmol
• DMAP 0. 608 g, 4.98 mmol
• Reference Example 1-3 tert-butyl 2,6-bis [(tert-butoxycarbonyl) oxy] -3-ethenylbenzoate
• tri-n-butylvinyltin (2.04 mL, 6.95 mmol) and bis (Triphenylphosphine) palladium (II) chloride 0.488 g, 0.695 mmol
• Reference Example 1-4 tert-butyl 2,6-bis [(tert-butoxycarbonyl) oxy] -3- [2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Yl) ethyl] benzoate
• dichloromethane 32 mL
• 1,4-bis (diphenylphosphino) butane 0.547 g, 1.28 mmol
• Reference Example 1-5 tert-butyl 2,6-bis [(tert-butoxycarbonyl) oxy] -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro- 4,6-methano-1,3,2-benzodioxaborol-2-yl] ethyl ⁇ benzoate (1S, 2S, 3R, 5S)-(+)-Pinanediol (0.736 g, 4.32 mmol) was added to a solution of the compound of Reference Example 1-4 (0.976 g, 1.73 mmol) in THF (5 mL). And stirred at room temperature for 62 hours.
• Reference Example 1-6 tert-butyl 2-[(tert-butoxycarbonyl) oxy] -6-hydroxy-3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro -4,6-methano-1,3,2-benzodioxaborol-2-yl] ethyl ⁇ benzoate Pyrrolidine (0.121 mL, 1.46 mmol) was added to a THF (5 mL) solution of the compound of Reference Example 1-5 (0.899 g, 1.46 mmol), and the mixture was stirred at room temperature for 3 hours.
• Reference Example 1-7 Benzyl 3- [2- (tert-butoxycarbonyl) -3-[(tert-butoxycarbonyl) oxy] -4- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5 , 5-Trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl] ethyl ⁇ phenoxy] azetidine-1-carboxylate Under a nitrogen atmosphere, cesium carbonate (4.01 g) was added to a DMF (20.5 mL) solution of the compound of Reference Example 1-6 (2.117 g) and benzyl 3-iodoazetidine-1-carboxylic acid (1.95 g).
• Reference Example 1-8 tert-butyl 6-[(azetidin-3-yl) oxy] -2-[(tert-butoxycarbonyl) oxy] -3- ⁇ 2-[(3aS, 4S, 6S, 7aR)- 3a, 5,5-Trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl] ethyl ⁇ benzoate monohydrochloride
• 1N hydrochloric acid 0.567 mL
• 50% water-containing 10% palladium carbon (0.149 g
• Reference Example 2 tert-butyl 6-[(1-methylsulfonylazetidin-3-yl) oxy] -2-[(tert-butoxycarbonyl) oxy] -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxabolol-2-yl] ethyl ⁇ benzoate Using the compound of Reference Example 1-8 as a starting material, the reaction, workup and purification were performed in the same manner as described in Reference Example 1 to give the title compound.
• reaction mixture was concentrated, DMF (2.5 mL), DIPEA (0.5 mL) and hydroxylamine hydrochloride (51 mg) were added to the residue, and the mixture was stirred at room temperature for 3 hr. A saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (56.5 mg) as a colorless solid.
• Reference Example 36-2 Amino (1H-imidazol-4-yl) acetic acid dihydrochloride Sodium cyanide (46.7 g, 953 mmol) was added to an ethanol solution (227 mL) of the compound of Reference Example 36-1 (161 g, 794 mmol) and 28% aqueous ammonia (371 mL) (internal temperature: 14 ° C.). . The reaction solution was stirred at room temperature for 4 hours and then extracted with chloroform (500 mL, 4 times). The organic phase was dried over sodium sulfate, filtered and concentrated. 6N aqueous hydrochloric acid (850 mL) was added to the obtained solid residue, and the mixture was heated to reflux for 4 hours.
• reaction solution was cooled to room temperature and then concentrated under reduced pressure.
• the obtained solid residue was stirred and washed with a THF-ethanol mixed solvent (1: 1, 750 mL) and collected by filtration to obtain the title compound (160 g) as a brownish yellow solid.
• Reference Example 36-3 [(tert-butoxycarbonyl) amino] (1H-imidazol-4-yl) acetic acid hydrochloride
• a 3N aqueous sodium hydroxide solution (374 mL) was added dropwise over 45 minutes under ice cooling.
• the reaction mixture was stirred for 15 minutes under ice-cooling, and di-tert-butyl dicarbonate was added over 15 minutes.
• the reaction solution was stirred for 45 minutes under ice cooling, and then warmed to room temperature.
• N, N-dimethyl-4-aminopyridine (2.28 g, 18.7 mmol) and 2,2,2-trifluoroethanol (53.4 mL, 747 mmol) were added to the reaction solution at room temperature, and the reaction solution was added for 2 hours. Heated to reflux. The reaction mixture was allowed to cool, and 6N aqueous hydrochloric acid (25 mL) was added under ice cooling to adjust the pH of the solution to 6.0. After stirring for 1 hour under ice cooling, the precipitated solid was collected by filtration, washed with an acetone-water mixed solvent (1: 1, 1 L), and dried under reduced pressure to give the title compound (40.0 g) as white. Obtained as a solid.
• Reference Example 37 6-[(1- ⁇ [(tert-butoxycarbonyl) amino] (1-methyl-1H-imidazol-4-yl) acetyl ⁇ azetidin-3-yl) oxy] -2-[(tert- Butoxycarbonyl) oxy] -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxabo Roll-2-yl] ethyl ⁇ tert-butyl benzoate Using the compound of Reference Example 1-8 (325 mg, 0.535 mmol) and the compound of Reference Example 37-1 (205 mg, 0.803 mmol) as starting materials, the reaction was carried out in the same manner as described in Reference Example 36-4. Workup and purification gave the title compound (130 mg).
• Reference Example 38-2 [(tert-Butoxycarbonyl) amino] (2-methyl-1H-imidazol-4-yl) potassium acetate
• a methanol solution 3.2 mL
• potassium carbonate 0.35 g, 2.40 mmol
• the aqueous layer was washed with ethyl acetate and concentrated to give the title compound (0.47 g).
• Reference Example 38 6-[(1- ⁇ [(tert-butoxycarbonyl) amino] (2-methyl-1H-imidazol-4-yl) acetyl ⁇ azetidin-3-yl) oxy] -2-[(tert- Butoxycarbonyl) oxy] -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxabo Roll-2-yl] ethyl ⁇ tert-butyl benzoate
• the same method as described in Reference Example 36-4 was performed using the compound of Reference Example 1-8 (0.328 g, 0.539 mmol) and the compound of Reference Example 38-2 (0.234 g, 0.799 mmol) as starting materials. According to the method, reaction, workup and purification were carried out to obtain the title compound (68.3 mg).
• Reference Example 39-1 Methyl amino (1H-imidazol-4-yl) acetate dihydrochloride To a methanol solution (265 mL) of the compound of Reference Example 36-2 (44 g, 206 mmol), thionyl chloride (75 mL, 1.21 mol) was added dropwise under ice cooling. The reaction mixture was warmed to room temperature and stirred at 50 ° C. for 8 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (46.9 g) as a pale yellow oil.
• Reference Example 39-2 tert-butyl 4- ⁇ 1-[(tert-butoxycarbonyl) amino] -2-methoxy-2-oxoethyl ⁇ -1H-imidazole-1-carboxylate
• N, N-dimethyl-4-aminopyridine (0.113 g, 0.928 mmol)
• triethylamine (0. 863 mL, 6.19 mmol
• di-tert-butyl dicarbonate (1.08 mL, 4.64 mmol) were added and stirred for 24 hours.
• the reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound (1.10 g) as a colorless oil.
• Reference Example 39-3 tert-butyl 4- ⁇ 2-[(tert-butoxycarbonyl) amino] -1-methoxy-1-oxopropan-2-yl ⁇ -1H-imidazole-1-carboxylate
• Methyl iodide (0.832 mL, 13.3 mmol) was added to the reaction solution at ⁇ 78 ° C., and the mixture was warmed to room temperature and stirred for 4 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound (2.15 g) as a pale yellow oil. Got as.
• Reference Example 39-4 2-[(tert-butoxycarbonyl) amino] -2- (1H-imidazol-4-yl) propanoic acid
• Lithium hydroxide monohydrate 0.513 g, 12.2 mmol
• 6N aqueous hydrochloric acid 2.1 mL
• Saturated saline was added to the reaction solution, and the solvent was distilled off under reduced pressure to obtain the title compound (1.49 g) as a crude product.
• Reference Example 39 6-[(1- ⁇ 2-[(tert-butoxycarbonyl) amino] -2- (1H-imidazol-4-yl) propanoyl ⁇ azetidin-3-yl) oxy] -2-[(tert -Butoxycarbonyl) oxy] -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxy Sabolol-2-yl] ethyl ⁇ tert-butyl benzoate
• the same method as described in Reference Example 36-4 was performed using the compound of Reference Example 1-8 (0.30 g, 0.493 mmol) and the compound of Reference Example 39-4 (0.176 g, 0.691 mmol) as starting materials. According to the method, reaction, workup and purification were carried out to obtain the title compound (153 mg).
• Reference Example 40 2-[(tert-butoxycarbonyl) oxy] -6- ⁇ [1- (1H-imidazol-4-carbonyl) azetidin-3-yl] oxy ⁇ -3- ⁇ 2-[(3aS, 4S , 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl] ethyl ⁇ tert-butyl benzoate To a methanol solution (3 mL) of the compound of Reference Example 1-7 (200 mg, 0.283 mmol) was added palladium carbon (20 mg, Pd content: 10%, approximately 55% water-wet product), and at room temperature under a hydrogen atmosphere.
• Reference Example 41 2-[(tert-butoxycarbonyl) oxy] -6- ⁇ [1- (4H-1,2,4-triazole e-3-sulfonyl) azetidin-3-yl] oxy ⁇ -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl] ethyl ⁇ benzoic acid Tert-Butyl acid To a methanol solution (3 mL) of the compound of Reference Example 1-7 (200 mg, 0.283 mmol) was added palladium carbon (20 mg, Pd content: 10%, approximately 55% water-wet product), and at room temperature under a hydrogen atmosphere.
• Reference Example 42 6-( ⁇ 1- [N 2- (tert-butoxycarbonyl) -L-asparaginyl] azetidin-3-yl ⁇ oxy) -2-[(tert-butoxycarbonyl) oxy] -3- ⁇ 2 -[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl] ethyl ⁇ benzoic acid tert-butyl To a methanol solution (3 mL) of the compound of Reference Example 1-7 (200 mg, 0.283 mmol) was added palladium carbon (20 mg, Pd content: 10%, approximately 55% water-wet product), and at room temperature under a hydrogen atmosphere.
• Reference Example 43-1 2-[(tert-butoxycarbonyl) oxy] -6- ⁇ [1- (chloroacetyl) azetidin-3-yl] oxy ⁇ -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxabolol-2-yl] ethyl ⁇ tert-butyl benzoate Under a nitrogen atmosphere, a solution of the compound of Reference Example 1-8 (160 mg, 0.263 mmol) in dichloromethane (5.3 mL) was ice-cooled to 0 ° C., chloroacetyl chloride (30 ⁇ L, 0.377 mmol), triethylamine (0.11 mL) , 0.789 mmol), and stirred at room temperature for 1 hour.
• reaction solution was ice-cooled, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate.
• organic phase was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure.
• Reference Example 43-2 6- ⁇ [1- (azidoacetyl) azetidin-3-yl] oxy ⁇ -2-[(tert-butoxycarbonyl) oxy] -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl] ethyl ⁇ tert-butyl benzoate Sodium azide (69.0 mg, 1.06 mmol) was added to a solution of the compound of Reference Example 43-1 (140 mg, 0.216 mmol) in DMSO (4.3 mL), and the mixture was stirred at room temperature for 1.5 hours.
• Reference Example 45 6-( ⁇ 1-[(5- ⁇ [(tert-butoxycarbonyl) (methyl) amino] methyl ⁇ -1H-1,2,3-triazol-1-yl) acetyl] azetidine-3- Yl ⁇ oxy) -2-[(tert-butoxycarbonyl) oxy] -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano -1,3,2-Benzodioxaborol-2-yl] ethyl ⁇ benzoate tert-butyl Using the compound of Reference Example 43-2 as a starting material, the title compound was obtained in the same manner as described in Reference Example 44 by carrying out reaction, post-treatment and production.
• Reference Example 46-1 [4- (2-hydroxyethyl) -1H-1,2,3-triazol-1-yl] benzyl acetate
• Water (12 mL) was added to a solution of benzyl 2-azidoacetate (2.50 g, 13.0 mmol) in tert-butyl alcohol (12 mL), and sodium L-ascorbate (527 mg, 2.66 mmol), 3-butyne-1 -Ol (1.5 mL, 19.8 mmol) and copper sulfate pentahydrate (347 mg, 1.39 mmol) were added and stirred at room temperature for 2 hours. Thereafter, water was added to the reaction solution, and the mixture was extracted with chloroform.
• Reference Example 46-2 ⁇ 1- [2- (benzyloxy) -2-oxoethyl] -1H-1,2,3-triazol-4-yl ⁇ acetic acid
• acetonitrile 28 mL
• 0.67 M sodium dihydrogen phosphate aqueous solution 28 mL
• 2,2,6,6-tetramethylpiperidine was added.
• Reference Example 46-4 [4- (2-tert-butoxy-2-oxoethyl) -1H-1,2,3-triazol-1-yl] acetic acid
• ethyl acetate (12 mL) ethyl acetate
• 10% palladium carbon 88.7 mg
• the reaction mixture was then filtered through celite, and the filtrate was evaporated under reduced pressure to give the title compound (288 mg).
• Reference Example 47-1 6- ⁇ [1-( ⁇ 1- [2- (benzyloxy) -2-oxoethyl] -1H-1,2,3-triazol-4-yl ⁇ acetyl) azetidin-3-yl ] Oxy ⁇ -2-[(tert-butoxycarbonyl) oxy] -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano- 1,3,2-Benzodioxaborol-2-yl] ethyl ⁇ benzoate tert-butyl Using the compound of Reference Example 1-8 as a starting material, the title compound was obtained by performing the reaction, post-treatment and purification in the same manner as described in Reference Example 36-4.
• Reference Example 48-1 [(tert-Butoxycarbonyl) amino] (1H-imidazol-4-yl) methyl acetate
• THF-water (3: 1) 18. mL
• sodium bicarbonate (1.03 g, 12.2 mmol) and di-tert-butyl dicarbonate ( 2.06 mL, 8.95 mmol) was added, and the mixture was stirred at room temperature for 20 hours, and then stirred at 70 ° C. for 2 days.
• the reaction mixture was allowed to cool, water (10 mL) was added, and the mixture was extracted with ethyl acetate.
• Reference Example 48-2 [(tert-Butoxycarbonyl) amino] [1- (2-tert-Butoxy-2-oxoethyl) -1H-imidazol-4-yl] methyl acetate
• sodium hydride (23.4 mg, 60% liquid paraffin dispersion, 0. 586 mmol
• Bromoacetic acid-tert-butyl (86.0 ⁇ L, 0.586 mmol) was added, and the mixture was stirred for 3 hours.
• Reference Example 48-3 [(tert-butoxycarbonyl) amino] [1- (2-tert-butoxy-2-oxoethyl) -1H-imidazol-4-yl] acetic acid Triethylamine (0.291 mL, 2.10 mmol) was added to an aqueous solution (4.2 mL) of the compound of Reference Example 48-2 (155 mg, 0.420 mmol) and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol) to give the title compound (84.9 mg) as a colorless solid.
• Reference Example 48 6-[(1- ⁇ [(tert-butoxycarbonyl) amino] [1- (2-tert-butoxy-2-oxoethyl) -1H-imidazol-4-yl] acetyl ⁇ azetidin-3-yl ) Oxy] -2-[(tert-butoxycarbonyl) oxy] -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano- 1,3,2-Benzodioxaborol-2-yl] ethyl ⁇ benzoate tert-butyl To a methanol solution (3 mL) of the compound of Reference Example 1-7 (200 mg, 0.283 mmol) was added palladium carbon (20 mg, Pd content: 10%, approximately 55% water-wet product), and at room temperature under a hydrogen atmosphere.
• Reference Example 49-1 Methyl [1- (2-amino-2-oxoethyl) -1H-imidazol-4-yl] [(tert-butoxycarbonyl) amino] acetate
• sodium hydroxide 70.5 mg, 60% liquid paraffin dispersion, 1. 76 mmol
• 2-bromoacetamide 243 mg, 1.76 mmol
• Reference Example 49-2 [1- (2-Amino-2-oxoethyl) -1H-imidazol-4-yl] [(tert-butoxycarbonyl) amino] acetic acid, 1/2 (triethylamine) salt Triethylamine (0.204 mL, 1.47 mmol) was added to an aqueous solution (3.0 mL) of the compound of Reference Example 49-1 (92.0 mg, 0.295 mmol), and the mixture was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain the title compound (123 mg) as a colorless amorphous.
• Reference Example 49 6-[(1- ⁇ [1- (2-amino-2-oxoethyl) -1H-imidazol-4-yl] [(tert-butoxycarbonyl) amino] acetyl ⁇ azetidin-3-yl) oxy ] -2-[(tert-butoxycarbonyl) oxy] -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1, 3,2-Benzodioxaborol-2-yl] ethyl ⁇ tert-butyl benzoate
• the compound of Reference Example 1-7 (200 mg, 0.283 mmol) and the compound of Reference Example 49-2 (109 mg, 0.312 mmol) were used as starting materials, and the reaction was carried out in the same manner as described in Reference Example 42.
• the title compound (130 mg) was obtained as a colorless solid by treatment and purification.
• Reference Example 50-2 (1-Benzyl-1H-1,2,3-triazol-4-yl) [(methanesulfonyl) oxy] ethyl acetate Under a nitrogen atmosphere, triethylamine (0.12 mL, 0.856 mmol) and methylsulfonyl chloride (36 ⁇ L, 0.476 mmol) were added to a solution of the compound of Reference Example 50-1 (102 mg, 0.389 mmol) in dichloromethane (1.9 mL). The mixture was further stirred at 0 ° C. for 4 hours. Thereafter, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to give the title compound (110 mg).
• Reference Example 50-4 [(tert-Butoxycarbonyl) amino] (1H-1,2,3-triazol-4-yl) ethyl acetate
• the compound of Reference Example 50-3 101 mg, 0.349 mmol
• di-tert-butyl dicarbonate 114 mg, 0.524 mmol
• the atmosphere was changed to a hydrogen atmosphere and stirred at room temperature for 2 hours.
• 1M hydrochloric acid (0.35 mL) was added to the reaction solution, and the mixture was further stirred at room temperature for 44 hours.
• the reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure to give the title compound (98.9 mg).
• Reference Example 50-5 [(tert-butoxycarbonyl) amino] (1H-1,2,3-triazol-4-yl) acetic acid
• a mixed solution (1.7 mL) of the compound of Reference Example 50-4 (45.4 mg, 0.168 mmol) in THF / water (3: 1)
• lithium hydroxide monohydrate (14.1 mg, 0.336 mmol
• 1M hydrochloric acid was added until the pH reached 4, followed by extraction with ethyl acetate, and then the aqueous layer was extracted again with chloroform.
• the organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure.
• the obtained residue was washed and purified with diethyl ether by decantation to give the title compound (12.7 mg).
• Reference Example 50 6-[(1- ⁇ [(tert-butoxycarbonyl) amino] (1H-1,2,3-triazol-4-yl) acetyl ⁇ azetidin-3-yl) oxy] -2-[( tert-butoxycarbonyl) oxy] -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodio Oxaborol-2-yl] ethyl ⁇ tert-butyl benzoate Using the compound of Reference Example 1-8 and the compound of Reference Example 50-5 as starting materials, the title compound was obtained by carrying out the reaction, post-treatment and purification in the same manner as described in Reference Example 36-4. It was.
• Reference Example 51-2 (4-Nitro-1H-1,2,3-triazol-1-yl) acetic acid To the compound of Reference Example 51-1 (329 mg, 1.44 mmol) was added 4N hydrogen chloride / 1,4-dioxane solution (14 mL), and the mixture was stirred at room temperature for 23 hours. Then, the title compound was obtained by depressurizingly distilling a reaction liquid.
• Reference Example 51 2-[(tert-butoxycarbonyl) oxy] -6-( ⁇ 1-[(4-nitro-1H-1,2,3-triazol-1-yl) acetyl] azetidin-3-yl ⁇ Oxy) -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborole-2 -Yl] ethyl ⁇ tert-butyl benzoate Using the compound of Reference Example 1-8 and the compound of Reference Example 51-2 as starting materials, the title compound was obtained by carrying out the reaction, post-treatment and purification in the same manner as described in Reference Example 36-4. It was.
• Reference Example 52-1 6-[(1- ⁇ N-[(benzyloxy) carbonyl] -D-seryl ⁇ azetidin-3-yl) oxy] -2-[(tert-butoxycarbonyl) oxy] -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl] ethyl ⁇ Tert-Butyl benzoate
• the same method as described in Reference Example 3 was carried out using the compound of Reference Example 1-8 (114.4 mg, 0.188 mmol) and N-carbobenzoxy-D-serine (91.8 mg, 0.384 mmol) as starting materials. According to the method, reaction, workup and purification were carried out to obtain the title compound (71.4 mg).
• Reference Example 52 2-[(tert-butoxycarbonyl) oxy] -6-[(1-D-serylazetidin-3-yl) oxy] -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a , 5,5-Trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl] ethyl ⁇ benzoate tert-butyl To a methanol solution (3.0 mL) of the compound of Reference Example 52-1 (200 mg, 0.252 mmol) was added palladium carbon (20 mg, Pd content: 10%, approximately 55% water-wet product), and a hydrogen atmosphere at room temperature was added. For 30 minutes. The reaction solution was filtered through cellulose, the filtrate was washed with methylene chloride, and the combined filtrate was concentrated to obtain the title compound (198 mg).
• Reference Example 53-1 6-[(1- ⁇ (2R) -4- (benzyloxy) -2-[(tert-butoxycarbonyl) amino] -4-oxobutanoyl ⁇ azetidin-3-yl) oxy]- 2-[(tert-Butoxycarbonyl) oxy] -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3, 2-benzodioxaborol-2-yl] ethyl ⁇ tert-butyl benzoate Using the compound of Reference Example 1-8 and benzyl (R) -3-[(tert-butoxycarbonyl) amino] -4-oxobutanoate as starting materials, the reaction was carried out according to the same method as described in Reference Example 3. Treatment and purification gave the title compound (1.84 g).
• Reference Example 53 6-( ⁇ 1- [N 2- (tert-butoxycarbonyl) -N-methyl-D-asparaginyl] azetidin-3-yl ⁇ oxy) -2-[(tert-butoxycarbonyl) oxy]- 3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl] Ethyl ⁇ tert-butyl benzoate Using the compound of Reference Example 53-2 and methylamine hydrochloride as starting materials, the reaction, workup and purification were carried out in the same manner as described in Reference Example 36-4 to give the title compound (270 mg).
• Reference Example 54 6-( ⁇ 1- [N 2- (tert-butoxycarbonyl) -N, N-dimethyl-D-asparaginyl] azetidin-3-yl ⁇ oxy) -2-[(tert-butoxycarbonyl) oxy ] -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2- Yl] ethyl ⁇ tert-butyl benzoate Using the compound of Reference Example 53-2 and dimethylamine hydrochloric acid as starting materials, the reaction, workup and purification were performed in the same manner as described in Reference Example 36-4 to give the title compound (251 mg).
• Reference Example 55-1 Benzyl (3R) -3- [2- (tert-butoxycarbonyl) -3-[(tert-butoxycarbonyl) oxy] -4- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl] ethyl ⁇ phenoxy] pyrrolidine-1-carboxylate To a toluene solution (5 mL) of the compound of Reference Example 1-6 (500 mg, 0.968 mmol) and (S) -1-Cbz-3-pyrrolidinol (321 mg) was added cyanomethylene tri-n-butylphosphorane (0.762 mL).
• Reference Example 55-2 2-[(tert-butoxycarbonyl) oxy] -6- ⁇ [(3R) -pyrrolidin-3-yl] oxy ⁇ -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl] ethyl ⁇ benzoate tert-butyl To a solution of the compound of Reference Example 55-1 (681 mg, 0.945 mmol) in methanol (5 mL) was added 10% palladium carbon (340 mg), and the mixture was stirred at room temperature for 5 hours in a hydrogen atmosphere.
• 10% palladium carbon 340 mg
• reaction solution was filtered through Celite, and the filtrate was distilled off under reduced pressure.
• Reference Example 55 6- ⁇ [(3R) -1- ⁇ [(tert-butoxycarbonyl) amino] (1H-imidazol-4-yl) acetyl ⁇ pyrrolidin-3-yl] oxy ⁇ -2-[(tert- Butoxycarbonyl) oxy] -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxabo Roll-2-yl] ethyl ⁇ tert-butyl benzoate Using the compound of Reference Example 55-2 (86 mg, 0.138 mmol) as a starting material, the title compound (90.90) was prepared by performing reaction, post-treatment, and purification in the same manner as described in Reference Example 36-4. 7 mg) was obtained.
• Reference Example 56-1 benzyl (3S) -3- [2- (tert-butoxycarbonyl) -3-[(tert-butoxycarbonyl) oxy] -4- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl] ethyl ⁇ phenoxy] pyrrolidine-1-carboxylate
• Reference Example 1-6 and (R) -1-Cbz-3-pyrrolidinol as raw materials and carrying out the reaction, post-treatment and purification according to the same method as described in Reference Example 55-1, The title compound was obtained.
• Reference Example 56-2 2-[(tert-butoxycarbonyl) oxy] -6- ⁇ [(3S) -pyrrolidin-3-yl] oxy ⁇ -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl] ethyl ⁇ benzoate tert-butyl Using the compound of Reference Example 56-1 as a starting material, the title compound was obtained by performing the reaction, post-treatment and purification in the same manner as described in Reference Example 55-2.
• Reference Example 120-1 tert-butyl (2S, 4S) -4-azido-2- ⁇ 3- [2- (tert-butoxycarbonyl) -3-[(tert-butoxycarbonyl) oxy] -4- ⁇ 2 — [(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl] ethyl ⁇ phenoxy]
• Azetidine-1-carbonyl ⁇ pyrrolidine-1-carboxylate To a methanol solution (6 mL) of the compound of Reference Example 1-7 (400 mg, 0.567 mmol) was added palladium carbon (40 mg, Pd content: 10%, approximately 55% water-wet product) under a hydrogen atmosphere at room temperature.
• Reference Example 120 tert-butyl (2S, 4S) -4-amino-2- ⁇ 3- [2- (tert-butoxycarbonyl) -3-[(tert-butoxycarbonyl) oxy] -4- ⁇ 2- [ (3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxabolol-2-yl] ethyl ⁇ phenoxy] azetidine- 1-Carbonyl ⁇ pyrrolidine-1-carboxylate To a methanol solution (5 mL) of the compound of Reference Example 120-1 (392 mg, 0.484 mmol) was added palladium carbon (40 mg, Pd content: 10%, approximately 55% water-wet product), and at room temperature under a hydrogen atmosphere.
• palladium carbon 40 mg, Pd content: 10%, approximately 55% water-wet product
• Reference Example 121 tert-butyl (2S, 4S) -4-acetamido-2- ⁇ 3- [2- (tert-butoxycarbonyl) -3-[(tert-butoxycarbonyl) oxy] -4- ⁇ 2- [ (3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxabolol-2-yl] ethyl ⁇ phenoxy] azetidine- 1-Carbonyl ⁇ pyrrolidine-1-carboxylate To a THF solution (2.4 mL) of the compound of Reference Example 120 (190 mg, 0.242 mmol), triethylamine (101 ⁇ L, 0.727 mmol) and acetyl chloride (19 ⁇ L, 0.267 mmol) were added and stirred for 30 minutes.
• Reference Example 122-1 tert-butyl (2S, 4R) -4-azido-2- ⁇ 3- [2- (tert-butoxycarbonyl) -3-[(tert-butoxycarbonyl) oxy] -4- ⁇ 2 — [(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl] ethyl ⁇ phenoxy] Azetidine-1-carbonyl ⁇ pyrrolidine-1-carboxylate To a methanol solution (6 mL) of the compound of Reference Example 1-7 (400 mg, 0.567 mmol) was added palladium carbon (40 mg, Pd content: 10%, approximately 55% water-wet product) under a hydrogen atmosphere at room temperature.
• palladium carbon 40 mg, Pd content: 10%, approximately 55% water-wet product
• Reference Example 122 tert-butyl (2S, 4R) -4-amino-2- ⁇ 3- [2- (tert-butoxycarbonyl) -3-[(tert-butoxycarbonyl) oxy] -4- ⁇ 2- [ (3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxabolol-2-yl] ethyl ⁇ phenoxy] azetidine- 1-Carbonyl ⁇ pyrrolidine-1-carboxylate Using the compound of Reference Example 122-1 (397 mg, 0.490 mmol) as a starting material, the title compound (368 mg) was purified by reaction, post-treatment, and purification according to the same method as described in Reference Example 120. Obtained as amorphous.
• Reference Example 123 tert-butyl (2S, 4R) -4-acetamido-2- ⁇ 3- [2- (tert-butoxycarbonyl) -3-[(tert-butoxycarbonyl) oxy] -4- ⁇ 2- [ (3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxabolol-2-yl] ethyl ⁇ phenoxy] azetidine- 1-Carbonyl ⁇ pyrrolidine-1-carboxylate Using the compound of Reference Example 122 (181 mg, 0.232 mmol) as a starting material, the title compound (162 mg) was converted to colorless amorphous by performing the reaction, post-treatment and purification according to the same method as described in Reference Example 121. Obtained.
• Reference Example 124-2 Benzyl (2S) -2- (dimethylcarbamoyl) -4- (2-ethoxy-2-oxoethylidene) pyrrolidine-1-carboxylate N-Butyllithium / hexane solution (1.57 mol / L, 1.38 mL, 2.16 mmol) in THF solution (4.9 mL) of ethyl dimethylphosphonoacetate (423 mg, 2.16 mmol) at ⁇ 78 ° C. was slowly added and stirred for 30 minutes.
• Reference Example 124-3 Ethyl [(3R, 5S) -5- (dimethylcarbamoyl) pyrrolidin-3-yl] acetate
• a methanol solution (3.8 mL) of the compound of Reference Example 124-2 (190 mg, 0.526 mmol) was added palladium carbon-ethylenediamine complex (180 mg, Pd content: 10%, approximately 55% water-wet product), and a hydrogen atmosphere The mixture was stirred for 7.5 hours.
• the reaction solution was filtered through celite, the filtrate was washed with methanol, and the combined filtrate was concentrated to give the titled compound (116.3 mg) as a colorless oil.
• Reference Example 124-4 tert-butyl (2S, 4R) -2- (dimethylcarbamoyl) -4- (2-ethoxy-2-oxoethyl) pyrrolidine-1-carboxylate
• THF-water (1: 1) a mixed solution (3 mL) of the compound of Reference Example 124-3 (116 mg, 0.509 mmol) in THF-water (1: 1), sodium hydrogen carbonate (128 mg, 1.53 mmol) and di-tert-butyl dicarbonate (0 .237 mL, 1.02 mmol) was added and stirred at room temperature for 14 hours.
• reaction solution was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated.
• the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (125 mg) as a colorless oil.
• Reference Example 124-5 [(3R, 5S) -1- (tert-butoxycarbonyl) -5- (dimethylcarbamoyl) pyrrolidin-3-yl] acetic acid
• 2N aqueous sodium hydroxide solution (0.38 mL, 0.76 mmol)
• 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with chloroform.
• the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated to give the titled compound (114 mg) as a white solid.
• Reference Example 125-1 tert-butyl (2R) -2- (dimethylcarbamoyl) -4- (2-ethoxy-2-oxoethylidene) pyrrolidine-1-carboxylate Using tert-butyl (R) -2- (dimethylcarbamoyl) -4-oxopyrrolidine-1-carboxylate (325 mg, 1.27 mmol) as a starting material, according to a method similar to that described in Reference Example 124-2, The title compound (167 mg) was obtained as a colorless oil by reaction, workup and purification.
• Reference Example 125-2 tert-butyl (2R, 4S) -2- (dimethylcarbamoyl) -4- (2-ethoxy-2-oxoethyl) pyrrolidine-1-carboxylate Using the compound of Reference Example 125-1 (167 mg, 0.511 mmol) as a starting material, the title compound (128 mg) was purified by carrying out the reaction and post-treatment according to the same method as described in Reference Example 124-3. Obtained as an oil.
• Reference Example 125-3 [(3S, 5R) -1- (tert-butoxycarbonyl) -5- (dimethylcarbamoyl) pyrrolidin-3-yl] acetic acid Using the compound of Reference Example 125-2 (128 mg, 0.388 mmol) as a starting material, the title compound (117 mg) was converted to white by reacting and working up according to the same method as described in Reference Example 124-4. Obtained as a solid.
• Reference Example 125 tert-butyl (2R, 4S) -4- (2- ⁇ 3- [2- (tert-butoxycarbonyl) oxy-3-[(tert-butoxycarbonyl) oxy] -4- ⁇ 2-[( 3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxabolol-2-yl] ethyl ⁇ phenoxy] azetidine-1 -Yl ⁇ -2-oxoethyl) -2- (dimethylcarbamoyl) pyrrolidine-1-carboxylate Using the compound of Reference Example 1-8 (149 mg, 0.260 mmol) and the compound of Reference Example 125-3 (116 mg, 0.386 mmol) as starting materials, the reaction was carried out in the same manner as described in Reference Example 36-4. Workup and purification yielded the title compound (153 mg) as a
• Reference Example 126-1 [4- (tert-butoxycarbonyl) -1,1-dioxo-1 ⁇ 6 -thiomorpholin-2-yl] acetic acid tert-Butyl 2- (2-ethoxy-2-oxoethyl) thiomorpholine-4-carboxylate 1,1-dioxide (247 mg, 0.769 mmol) in methanol solution (7 mL) under ice-cooling, 2N aqueous sodium hydroxide solution (1.15 mL, 2.31 mmol) was added, and the mixture was stirred at room temperature for 4.5 hours.
• Reference Example 127 2-[(tert-butoxycarbonyl) oxy] -6- ⁇ [1- (1H-imidazol-2-carbonyl) azetidin-3-yl] oxy ⁇ -3- ⁇ 2-[(3aS, 4S , 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxabolol-2-yl] ethyl ⁇ tert-butyl benzoate Using the compound of Reference Example 1-7 (200 mg, 0.283 mmol) as a starting material, the title compound (119 mg) was obtained by carrying out reaction, workup and purification according to the same methods as described in Reference Example 40. It was.
• Reference Example 128-2 N- (tert-butoxycarbonyl) -D-seryl-D-alanine To a solution of the compound of Reference Example 128-1 (955 mg, 2.61 mmol) in methanol (18 mL) was added 10% palladium carbon (48 mg), followed by hydrogen substitution and stirring at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to give the title compound (735 mg).
• Reference Example 128 N 2- (tert-butoxycarbonyl) -N-[(2R) -1- ⁇ 3- [2- (tert-butoxycarbonyl) -3-[(tert-butoxycarbonyl) oxy] -4- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl] ethyl ⁇ Phenoxy] azetidin-1-yl ⁇ -1-oxopropan-2-yl] -D-serinamide Using the compound of Reference Example 1-7 (200 mg, 0.283 mmol) and the compound of Reference Example 128-2 (86.1 mg, 0.312 mmol) as raw materials, the reaction was carried out according to the same method as described in Reference Example 117. The title compound (203 mg) was obtained by post-treatment and purification.
• N ⁇ - (tert-butoxycarbonyl) -D-asparagine and N ⁇ - (tert-butoxycarbonyl) -D-tert-butyl aspartate were used as raw materials and described in Reference Examples 128-1 and 128-2.
• the reaction, post-treatment, and purification were performed in the same manner as in the above methods to obtain Reference Example compounds 129 and 130 shown in Table 2-21.
• Reference Example 138 tert-butyl 4- [2- ⁇ 3- [2- (tert-butoxycarbonyl) -3-[(tert-butoxycarbonyl) oxy] -4- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxabolol-2-yl] ethyl ⁇ phenoxy] azetidin-1-yl ⁇ -1- (Methylamino) -2-oxoethyl] -1H-imidazole-1-carboxylate
• Reference Example 138-1 ⁇ [(Benzyloxy) carbonyl] amino ⁇ (1H-imidazol-4-yl) acetic acid
• a mixed solution (57 mL) of the compound of Reference Example 36-2 (3.68 g, 17.2 mmol) in ethanol / water (1: 1) sodium hydrogen carbonate (5.78 g, 68.8 mmol) and benzyl chloroformate (5. 87 g, 34.4 mmol) was added under ice cooling. After stirring for 15 minutes, the reaction solution was warmed to room temperature and further stirred for 12 hours.
• Reference Example 138-2 6-( ⁇ 1-[ ⁇ [(benzyloxy) carbonyl] amino ⁇ (1H-imidazol-4-yl) acetyl] azetidin-3-yl ⁇ oxy) -2-[(tert-butoxy Carbonyl) oxy] -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol -2-yl] ethyl ⁇ tert-butyl benzoate
• Reference Example 138-3 tert-butyl 4- (1- ⁇ [(benzyloxy) carbonyl] amino ⁇ -2- ⁇ 3- [2- (tert-butoxycarbonyl) -3-[(tert-butoxycarbonyl) oxy ] -4- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborole-2- Yl] ethyl ⁇ phenoxy] azetidin-1-yl ⁇ -2-oxoethyl) -1H-imidazole-1-carboxylate To a solution of the compound of Reference Example 138-2 (956 mg, 1.15 mmol) in dichloromethane (5.75 mL), triethylamine (0.641 mL, 4.6 mmol), and di-tert-butyl dicarbonate (503 mg, 2.3 mmol) And
• Reference Example 138-4 tert-butyl 4- (1-amino-2- ⁇ 3- [2- (tert-butoxycarbonyl) oxy] -4-[(tert-butoxycarbonyl) oxy] -4- ⁇ 2-[( 3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxabolol-2-yl] ethyl ⁇ phenoxy] azetidine-1 -Il ⁇ -2-oxoethyl) -1H-imidazole-1-carboxylate To a methanol solution (4 mL) of the compound of Reference Example 138-3 (228 mg, 0.245 mmol), palladium hydroxide (22 mg) was added, and the mixture was stirred at room temperature in a hydrogen atmosphere. After 12 hours, the reaction solution was filtered through Celite, and the filtrate was concentrated. The obtained residue was purified by
• Reference Example 138 tert-butyl 4- [2- ⁇ 3- [2- (tert-butoxycarbonyl) -3-[(tert-butoxycarbonyl) oxy] -4- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxabolol-2-yl] ethyl ⁇ phenoxy] azetidin-1-yl ⁇ -1- (Methylamino) -2-oxoethyl] -1H-imidazole-1-carboxylate To a diethyl ether solution (3 mL) of the compound of Reference Example 138-4 (123 mg, 0.154 mmol), a formalin solution (30% methanol solution, 2.32 ⁇ L, 0.231 mmol) was added and stirred at room temperature for 1.5 hours.
• a formalin solution (30% methanol solution, 2.
• Reference Example 150 (4S) -4-[(tert-butoxycarbonyl) amino] -6- ⁇ 3- [2- (tert-butoxycarbonyl) -3-[(tert-butoxycarbonyl) oxy] -4- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborol-2-yl] ethyl ⁇ phenoxy Azetidin-1-yl ⁇ -6-oxohexanoic acid To a solution of the compound of Reference Example 142 (334 mg, 0.369 mmol) in methanol (7 mL) was added 10% palladium carbon (113 mg), followed by hydrogen substitution and stirring at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to give the title compound (329 mg).
• Reference Examples 144 and 145 were used as starting materials, and the reaction, post-treatment and purification were performed according to the same methods as described in Reference Example 151, and Reference Example compounds 151 and 152 shown in Table 2-27 were respectively Obtained.
• Reference Example 153 6-[(1- ⁇ (3S) -6-amino-3-[(tert-butoxycarbonyl) amino] -6-oxohexanoyl ⁇ azetidin-3-yl) oxy] -2-[( tert-butoxycarbonyl) oxy] -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodio Oxaborol-2-yl] ethyl ⁇ tert-butyl benzoate To a DMF (1 mL) solution of the compound of Reference Example 150 (153 mg, 0.188 mmol), N, N-diisopropylethylamine (0.131 mL, 0.750 mmol) and HATU (107 mg, 0.281 mmol) were added, and at room temperature.
• Reference Examples 151 and 152 were used as starting materials, and the reaction, post-treatment and purification were performed according to the same methods as described in Reference Example 153, and Reference Example compounds 154 and 155 shown in Table 2-28 were respectively Obtained.
• Example 1 7-[(1-acetylazetidin-3-yl) oxy] -2-hydroxy-3,4-dihydro-2H-1,2-benzooxaborin-8-carboxylic acid
• CPME 0.9 mL
• 3 mol / L hydrochloric acid 1.14 mL
• Example 2 2-hydroxy-7-( ⁇ 1-[(1H-imidazol-5-yl) acetyl] azetidin-3-yl ⁇ oxy) -3,4-dihydro-2H-1,2-benzoxabol Nin-8-carboxylic acid hydrochloride TFA (0.9 mL) was added to the compound of Reference Example 3 (96 mg) and phenylboronic acid (14 mg) in addition to triethylsilane (0.2 mL), and the mixture was stirred at room temperature for 3 hours.
• Example 3 2-hydroxy-7- ⁇ [1- (methanesulfonyl) azetidin-3-yl] oxy ⁇ -3,4-dihydro-2H-1,2-benzooxaborin-8-carboxylic acid TFA (0.9 mL) was added to the compound of Reference Example 2 (96 mg) and phenylboronic acid (14 mg) in addition to triethylsilane (0.2 mL), and the mixture was stirred at room temperature for 3 hours.
• Example 4 8-( ⁇ 1-[(2R) -2-amino-2- (4-hydroxyphenyl) acetyl] azetidin-3-yl ⁇ oxy) -4,4-dihydroxy-5-oxa-4- Boranidabicyclo [4.4.0] deca-1 (6), 7,9-triene-7-carboxylic acid disodium salt
• phenylboronic acid (16.2 mg)
• acetonitrile 2.0 mL
• hexane 2.0 mL
• 4N hydrochloric acid / dioxane solution 1.0 mL
• Example 4 The compounds of Reference Examples 4 to 16 and 18 to 33 shown in Table 2 were used as raw materials and reacted, worked up and purified in the same manner as described in Example 4 to obtain each of Example compounds 5 to 33. Got. However, when the free form is the final product (Examples 5 and 34), the free form is obtained without sodium hydroxide treatment, and when the hydrochloride is the final product (Example 6) by reverse phase chromatography. After purification, the hydrochloride was obtained by adding hydrochloric acid and concentrating. Using Reference Example Compound 34 as a starting material, the reaction, post-treatment and purification were performed according to the same methods as described in Example 3 to obtain Example Compound 34.
• Example 35 2-hydroxy-7- ⁇ [1- (hydroxycarbamoyl) azetidin-3-yl] oxy ⁇ -3,4-dihydro-2H-1,2-benzooxaborin-8-carboxylic acid
• Phenylboronic acid (10.3 mg) 4N hydrochloric acid / ethyl acetate solution and hexane (3.6 mL) were added to a solution of the compound of Reference Example 35 in acetonitrile (0.73 mL), and the mixture was stirred at room temperature for 7 hours and left overnight. The acetonitrile phase was washed with hexane and concentrated. The residue was washed with acetonitrile to obtain the title compound (0.4 mg).
• Example 36 7-( ⁇ 1-[(2R) -2-amino-2- (1H-imidazol-4-yl) acetyl] azetidin-3-yl ⁇ oxy) -2-hydroxy-3,4-dihydro -2H-1,2-Benzoxaborin-8-carboxylic acid
• Phenylboronic acid (0.146 g) and 1N hydrochloric acid / acetic acid solution (25.2 mL) were added to Reference Example (R) -36 (1.0 g), and the mixture was stirred at room temperature for 1 hour and concentrated.
• Example 37 8-( ⁇ 1-[(2S) -2-amino-2- (1H-imidazol-4-yl) acetyl] azetidin-3-yl ⁇ oxy) -4,4-dihydroxy-5-oxa -4-Boraneudabicyclo [4.4.0] deca-1 (6), 7,9-triene-7-carboxylic acid disodium salt
• acetonitrile 0.337 mL
• phenylboronic acid (2.46 mg)
• hexane 0.337 mL
• 4N hydrochloric acid / cyclopentyl methyl ether solution 0.
• Example 38 8-( ⁇ 1- [amino (1-methyl-1H-imidazol-4-yl) acetyl] azetidin-3-yl ⁇ oxy) -4,4-dihydroxy-5-oxa-4-boranui Dabicyclo [4.4.0] deca-1 (6), 7,9-triene-7-carboxylic acid disodium salt
• acetic acid (1.61 mL)
• phenylboronic acid (18.6 mg)
• 4N hydrochloric acid / cyclopentylmethyl ether solution (1.21 mL) were added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Stir.
• Example 39 2-hydroxy-7- ⁇ [1- (4H-1,2,4-triazol-3-sulfonyl) azetidin-3-yl] oxy ⁇ -3,4-dihydro-2H-1,2- Benzoxaborin-8-carboxylic acid trifluoroacetate
• Phenylboronic acid (35.6 mg), hexane (2.9 mL), and TFA (2.23 mL) were added to a solution of the compound of Reference Example 41 (205 mg) in acetonitrile (2.9 mL), and the mixture was stirred at room temperature for 5 hours.
• Example 40 7-( ⁇ 1- [2-amino-2- (1H-imidazol-4-yl) (2H) ethanoyl] azetidin-3-yl ⁇ oxy) -2-hydroxy-3,4-dihydro- 2H-1,2-Benzoxaborin-8-carboxylic acid dihydrochloride
• Acetic acid-d1 (3 mL) was added to the compound of Reference Example 36-4 (0.3 g, 0.377 mmol), and the mixture was stirred at room temperature for 4 days. Then, phenylboronic acid (46 mg, 0.377 mmol) and 4N cyclopentyl hydrochloride were used.
• Example 41 7-( ⁇ 1- [2-Amino-2- (1H-imidazol-4-yl) propanoyl] azetidin-3-yl ⁇ oxy) -2-hydroxy-3,4-dihydro-2H-1 , 2-Benzoxaborin-8-carboxylic acid Using the compound of Reference Example 39 (153 mg, 0.189 mmol) as a starting material, the title compound (42 mg) was obtained as a white solid by carrying out reaction, post-treatment and purification according to the same methods as described in Example 36. Obtained.
• Example Compound 42 and 43 were obtained by carrying out the reaction, post-treatment and purification in the same manner as described in Example 37, respectively.
• the hydrochloride was the final product (Example 43)
• it was purified by reverse phase chromatography without treatment with sodium hydroxide, and then concentrated by adding hydrochloric acid to obtain the hydrochloride. .
• Example compounds 44 to 51 were obtained.
• the hydrochloride is the final product (Examples 46 and 51)
• the product is purified by reverse phase chromatography without treatment with sodium hydroxide, and then concentrated by adding hydrochloric acid to obtain the hydrochloride. Obtained.
• Example compounds 52 to 54 were used as raw materials and reacted, worked up and purified in the same manner as described in Example 38, to give the following Example compounds 52 to 54.
• Example compounds 55 to 71 were obtained (however, the corresponding raw materials were in no particular order).
• the free form is the final product (Examples 57, 61, 64, 65, 67 and 71)
• the free form is obtained by purification without sodium hydroxide treatment
• the hydrochloride is the final product.
• Examples 58, 62 and 63 were purified by reverse phase chromatography without treatment with sodium hydroxide, and then concentrated by adding hydrochloric acid to obtain the hydrochloride.
• Examples 55 to 71 The names of the compounds of Examples 55 to 71 are shown below. 8-( ⁇ 1-[(2-amino-1,3-thiazol-4-yl) acetyl] azetidin-3-yl ⁇ oxy) -4,4-dihydroxy-5-oxa-4-boranidabicyclo [ 4.4.0] Deca-1 (6), 7,9-triene-7-carboxylic acid disodium salt (Example 55) 8- ⁇ [1- (2-Amino-1,3-thiazol-4-carbonyl) azetidin-3-yl] oxy ⁇ -4,4-dihydroxy-5-oxa-4-boranidabicyclo [4.4 .0] deca-1 (6), 7,9-triene-7-carboxylic acid disodium salt (Example 56) 2-hydroxy-7-( ⁇ 1-[(1H-1,2,3-triazol-1-yl) acetyl] azetidin-3-yl ⁇
• Example 72 7-( ⁇ 1- [amino (3,4-dihydroxyphenyl) acetyl] azetidin-3-yl ⁇ oxy) -2-hydroxy-3,4-dihydro-2H-1,2-benzoxabol Nin-8-carboxylic acid hydrochloride
• Example 72-1 6-[(1- ⁇ [(tert-butoxycarbonyl) amino] (3,4-dihydroxyphenyl) acetyl ⁇ azetidin-3-yl) oxy] -2-[(tert-butoxycarbonyl) Oxy] -3- ⁇ 2-[(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-2H-4,6-methano-1,3,2-benzodioxaborole-2 -Il] ethyl ⁇ tert-butyl benzoate
• a methanol solution (2 mL) of the compound of Reference Example 67 190 mg, 0.187 mmol
• palladium carbon (19 mg, Pd content: 10%, approximately 55% water-wet product)
• Example 72 7-( ⁇ 1- [amino (3,4-dihydroxyphenyl) acetyl] azetidin-3-yl ⁇ oxy) -2-hydroxy-3,4-dihydro-2H-1,2-benzoxabol Nin-8-carboxylic acid hydrochloride
• phenylboronic acid 18.7 mg, 0.153 mmol
• hexane 1.5 mL
• 4N hydrochloric acid / dioxane solution 0.76 mL was added, and the mixture was stirred at room temperature for 17 hours.
• reaction solution was allowed to stand, the supernatant solution (upper layer) was removed, hexane (5 mL) was added to the remaining lower layer, and the mixture was stirred and allowed to stand to remove the supernatant solution. This operation was performed 5 times. Diethyl ether (5 mL) was added to the remaining lower layer, and after stirring, the mixture was allowed to stand, and the supernatant solution (upper layer) was removed. This operation was performed three times. The obtained residue was dried under reduced pressure.
• Example 73 7-( ⁇ 1- [amino (2,4-dihydroxyphenyl) acetyl] azetidin-3-yl ⁇ oxy) -2-hydroxy-3,4-dihydro-2H-1,2-benzoxabol Nin-8-carboxylic acid hydrochloride
• Example 73-1 7-[(1- ⁇ amino [2,4-bis (benzyloxy) phenyl] acetyl ⁇ azetidin-3-yl) oxy] -2-hydroxy-3,4-dihydro-2H-1 , 2-Benzoxaborin-8-carboxylic acid
• the title compound 78 mg was obtained as a colorless solid by carrying out reaction, post-treatment and purification according to the same methods as described in Example 72. Obtained.
• Example 73 7-( ⁇ 1- [amino (2,4-dihydroxyphenyl) acetyl] azetidin-3-yl ⁇ oxy) -2-hydroxy-3,4-dihydro-2H-1,2-benzoxabol Nin-8-carboxylic acid hydrochloride
• a THF solution 25 mL
• palladium carbon 13 mg, Pd content: 10%, approximately 55% water-wet product
• methanol (0.25 mL) was added and stirred at room temperature for 4 days.
• Example 74 7- ⁇ [1- (S-benzyl-D-cysteinyl) azetidin-3-yl] oxy ⁇ -2-hydroxy-3,4-dihydro-2H-1,2-benzooxaborin 8- Carboxylic acid trifluoroacetate Trifluoroacetic acid (3.3 mL) was added to the compound of Reference Example 72 (106 mg), and the mixture was stirred at room temperature for 8 hours. The title compound (24.6 mg) was obtained as a white solid by drying under reduced pressure and purifying the resulting dry residue by reverse phase column chromatography. The resulting dry residue was washed with acetonitrile and dried under reduced pressure.
• Example compounds 75 and 76 were used as starting materials, and the reaction was carried out in the same manner as described in Example 74, followed by post-treatment and purification to give the following Example compounds 75 and 76, respectively.
• Example 75 The names of the compounds of Examples 75 and 76 are shown below. 7-[(1-D-Cysteinylazetidin-3-yl) oxy] -2-hydroxy-3,4-dihydro-2H-1,2-benzooxaborin-8-carboxylic acid trifluoroacetate (Example 75) 2-hydroxy-7- ⁇ [1- (3-sulfanyl-D-valyl) azetidin-3-yl] oxy ⁇ -3,4-dihydro-2H-1,2-benzooxaborin-8-carboxylic acid tri Fluoroacetate (Example 76)
• Example compounds 87 to 89 were in no particular order.
• Example 97 to 127 The compounds of Reference Examples 82 to 105 and 117 to 123 were used as starting materials, and the reaction was carried out in the same manner as described in Example 38, followed by reaction, workup, and purification to give the following Example compounds 97 to 127. (However, the corresponding raw materials are in random order.) However, when the hydrochloride is the final product (Examples 119, 120, and 123), it is purified by reverse phase chromatography without performing sodium hydroxide treatment, and then concentrated by adding hydrochloric acid. Salt was obtained.
• Example compounds 128 and 129 were obtained by purification by reverse phase chromatography, respectively.
• Example compounds 130 to 137 were used as raw materials.
• the reaction and post-treatment were performed in the same manner as described in Example 38, but purified by reverse phase chromatography without sodium hydroxide treatment. Then, hydrochloric acid was added and concentrated to obtain the following Example compounds 130 to 137 (however, the corresponding raw materials were in no particular order).
• Example 130 7-( ⁇ 1-[(2S) -4-Acetamido-2-aminobutanoyl] azetidin-3-yl ⁇ oxy) -2-hydroxy-3,4-dihydro-2H-1,2-benzooxaborinine -8-carboxylic acid hydrochloride (Example 130) 7- ⁇ [1- (L- ⁇ -Asparaginyl) azetidin-3-yl] oxy ⁇ -2-hydroxy-3,4-dihydro-2H-1,2-benzooxaborin-8-carboxylic acid hydrochloride ( Example 131) 7- ⁇ [1- (L-alanyl-L-alanyl) azetidin-3-yl] oxy ⁇ -2-hydroxy-3,4-dihydro-2H-1,2-benzooxaborin-8-carboxylic acid hydrochloric acid Salt (Example 132) 7- ⁇ [1- (L-alanyl-L-alany
• Example compounds 138 and 139 were obtained.
• Examples 138 and 139 The names of the compounds of Examples 138 and 139 are shown below. 2-hydroxy-7-( ⁇ 1-[(1H-imidazol-4-yl) (methylamino) acetyl] azetidin-3-yl ⁇ oxy) -3,4-dihydro-2H-1,2-benzoxabol Nin-8-carboxylic acid dihydrochloride (Example 138) 2-hydroxy-7-( ⁇ 1-[(1H-imidazol-4-yl) (methylamino) acetyl] azetidin-3-yl ⁇ oxy) -3,4-dihydro-2H-1,2-benzoxabol Nin-8-carboxylic acid dihydrochloride (Example 139)
• Example 140 2-hydroxy-7- ⁇ [1- (2-methyl-D-seryl) azetidin-3-yl] oxy ⁇ -3,4-dihydro-2H-1,2-benzooxaborin-8 -carboxylic acid Using the compound of Reference Example 140 (245 mg, 0.317 mmol) as a starting material, the title compound (21.8 mg) was obtained in white by reacting, working up and purifying according to the same method as described in Example 36. Obtained as a solid.
• Example 141 The compounds of Reference Examples 141, 143, and 150 to 155 were used as raw materials and reacted according to the same method as described in Example 36. Further, the reaction mixture was concentrated under reduced pressure as a post-treatment, and then subjected to reverse phase chromatography ( Columns: YMC-Actus pro C18, A solution: 0.05% TFA / water, B solution: 0.03% TFA / acetonitrile), thereby obtaining the following Example compounds 141 to 148. However, when the hydrochloride was the final product (Example 145), after purification by reverse phase chromatography, the hydrochloride was obtained by adding hydrochloric acid and concentrating.
• Example compounds 149 and 150 were obtained by adding hydrochloric acid and concentrating.
• Example compounds 151 and 152 were obtained, respectively.
• Examples 151 and 152 The names of the compounds of Examples 151 and 152 are shown below.
• Test Example 1 Evaluation of minimum inhibitory concentration (MIC) of MEPM against ⁇ -lactamase producing bacterium
• a test compound against a ⁇ -lactamase producing bacterium and a ⁇ -lactam agent The combined effect was evaluated.
• MEPM meropenem
• A is 1/32 to 1/16
• B is 1/8 to 1/4
• C is 1 /
• a value of 2 or more is shown as D below. “-” Indicates untested.
• Test Example 2 Evaluation of minimum inhibitory concentration (MIC) of MEPM against ⁇ -lactamase-producing bacterium
• E. coli ATCC BAA-2469 E. coli ATCC BAA-2469
• NDM-1 K.I. pneumoniae ATCC BAA-2470
• K. pneumoniae. pneumoniae NCTC 13439 VIM-1
• K. pneumoniae. pneumoniae NCTC 13440 VIM-1
• E. pneumoniae It is possible to evaluate the metallo- ⁇ -lactamase inhibitory activity of a test compound using E. coli NCTC 13476 (IMP) or the like.
• Test Example 3 Evaluation of minimum inhibitory concentration (MIC) of MEPM against ⁇ -lactamase producing bacteria
• a test compound against ⁇ -lactamase producing bacteria and a ⁇ -lactam The combined effect was evaluated.
• MEPM meropenem
• MIC minimum inhibitory concentration
• the compound of the present invention has a strong inhibitory action on ⁇ -lactamase, and is associated with sepsis, febrile neutropenia, bacterial meningitis, bacterial endocarditis, otitis media, sinusitis, pneumonia, lung Abscess, empyema, secondary infection of chronic respiratory lesions, sore throat / laryngitis, tonsillitis, osteomyelitis, arthritis, peritonitis, intraabdominal abscess, cholecystitis, cholangitis, liver abscess, deep skin infection, lymphatic vessel -It is useful as a therapeutic and / or prophylactic agent for secondary infections such as lymphadenitis, trauma / burn and surgical wounds, urinary tract infections, genital infections, eye infections or odontogenic infections.

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