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WO2016043260A1 - Composé d'amidine ou de guanidine cyclique - Google Patents

Composé d'amidine ou de guanidine cyclique Download PDF

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Publication number
WO2016043260A1
WO2016043260A1 PCT/JP2015/076443 JP2015076443W WO2016043260A1 WO 2016043260 A1 WO2016043260 A1 WO 2016043260A1 JP 2015076443 W JP2015076443 W JP 2015076443W WO 2016043260 A1 WO2016043260 A1 WO 2016043260A1
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substituted
unsubstituted
compound
group
alkyl
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PCT/JP2015/076443
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一生 加藤
徳文 中橋
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塩野義製薬株式会社
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Publication of WO2016043260A1 publication Critical patent/WO2016043260A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/12—Nitrogen atoms not forming part of a nitro radical
    • C07D239/14—Nitrogen atoms not forming part of a nitro radical with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel cyclic guanidine or amidine compound having an antifungal activity or a salt thereof, and an antifungal agent containing them.
  • Non-Patent Documents 1 and 2 It is expected that the number of severely immunocompromised patients in developed countries in Europe and the United States and Japan will increase in the future, and it is important to take measures against deep mycosis. Antifungal chemotherapy has been applied to the treatment of deep mycosis. Amphotericin B has a strong fungicidal effect against Candida and Aspergillus spp., But currently, liposome preparations are mainly used to reduce nephrotoxicity. There is no problem (Non-Patent Document 3).
  • Echinocandin drugs such as caspofungin and micafungin have a fungicidal activity against Candida spp. And are relatively safe, and thus are frequently used for candidiasis and have a good clinical effect.
  • Non-patent Document 4 Azolic drugs such as itraconazole and voriconazole have fungicidal activity against Aspergillus by inhibiting Sterol 14 ⁇ -demethylase in the ergosterol synthesis pathway and are more safe than amphotericin B. has been used a lot and contributed greatly to the improvement of mortality.
  • Non-patent Document 5 an inhibitor of Sterol 24-C-methyltransferase (hereinafter referred to as SMT) (Non-Patent Document 9), an enzyme that does not exist in humans in the ergosterol synthesis pathway, kills Aspergillus spp.
  • SMT Sterol 24-C-methyltransferase
  • Non-patent Document 1 A compound having an amidine structure and useful as a fungicide (Patent Document 1) is disclosed, and a compound useful as an antifungal agent against a specific fungus (Patent Documents 2 to 7) is disclosed.
  • Non-Patent Document 12 discloses that a compound having a guanidine structure, which is known as an antifungal agent, has an action of inhibiting methyl group transfer to sterol in Candida cells. The activity is not disclosed, and the compound having a cyclic guanidine or amidine structure of the present invention is not disclosed.
  • the object of the present invention is to have excellent enzyme inhibitory activity against SMT and / or excellent antifungal activity against pathogenic fungi including Candida and Aspergillus and various resistant bacteria. It is to provide a novel compound useful as a pharmaceutical.
  • the present invention solves the above problems by synthesizing a compound having an aromatic ring having at least a cyclic guanidyl group or a cyclic amidyl group, and provides the following inventions.
  • R 1 and R 2 each independently represents a hydrogen atom, a halogen atom, cyano, nitro, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted di (C 1- 6 alkyl) amino, a substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted aryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted aryl, substituted or unsubstituted monocyclic heterocyclic
  • R 4 is —NH— or —CR a R b —;
  • R a and R b are each independently a hydrogen atom, a halogen atom, hydroxy, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkyl;
  • Each R 5 is independently —CR i R j — or —C ( ⁇ O) —;
  • R i and R j are each independently a hydrogen atom
  • R 4 is —CR a R b — and X 1 is an oxygen atom is excluded.
  • a pharmaceutically acceptable salt thereof (Item 2 ') The compound according to item 1 ′ or a pharmaceutically acceptable salt thereof, wherein R 4 is —NH—.
  • R 1 and R 2 are each independently a hydrogen atom, halogen atom, cyano, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, optionally protected hydroxy or protected
  • X 1 is an oxygen atom, C 1-3 alkylene, C 1-3 alkyl substituted with one or more groups selected from substituent group E1a, or —NR c —. Any one of the compounds or pharmaceutically acceptable salts thereof,
  • the substituent group E1a is represented by a halogen atom, an optionally protected amino, a substituted or unsubstituted C 1-3 alkoxy, an optionally protected hydroxy, and an optionally protected carboxy. It consists of a group.
  • R 3 is Substituted or unsubstituted pyridyl, Substituted or unsubstituted monocyclic nitrogen-containing and oxygen heterocyclic groups, Substituted or unsubstituted monocyclic nitrogen-containing and sulfur heterocyclic groups, The compound according to any one of Items 1 ′ to 10 ′, which is a substituted or unsubstituted bicyclic nitrogen-containing heterocyclic group or a substituted or unsubstituted bicyclic nitrogen-containing and oxygen heterocyclic group, or Its pharmaceutically acceptable salt.
  • R 3 represents the formula (X ′): (Where Z 4 is a nitrogen atom or C (R e ); R e is a hydrogen atom, a halogen atom, cyano, nitro, hydroxy, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted Or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted di (C 1-6 alkyl) amino, substituted Or unsubstituted C 1-6 alkylthio, substituted or unsubstituted aryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted aryl, substituted or unsubstituted aryl,
  • A is Hydrogen atom, Halogen atoms, C 1-6 alkyl which is unsubstituted or substituted with one or more groups selected from substituent group F1, C 2-6 alkenyl substituted with one or more groups selected from unsubstituted or substituted group F1; C 2-6 alkynyl substituted with one or more groups selected from unsubstituted or substituted group F1; C 3-8 cycloalkyl, which is unsubstituted or substituted with one or more groups selected from substituent group F1, Aroyl substituted with one or more groups selected from unsubstituted or substituted group G1; Ar C 1-6 alkyl substituted with one or more groups selected from unsubstituted or substituted group G1; Aryl which is unsubstituted or substituted with one or more groups selected from substituent group G1, A bicyclic carbocyclic group which is unsubstituted or substituted with one or more groups selected from the substituent group G1, A bicyclic carbocyclic
  • the substituent group F1 is: A halogen atom, amino, optionally protected hydroxy, optionally protected carboxy, unsubstituted or substituted with one or more C 1-6 alkyl carbamoyl, substituted or unsubstituted arylsulfonyl, and C 1 A group represented by -6 alkoxy;
  • the substituent group F2 is C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, halo C 3-8 cycloalkyl, ar C 1-6 alkyl, and aryl unsubstituted or substituted with one or more halogen atoms
  • a group represented by The substituent group G1 is Halogen atom, cyano, oxo, adamantyl, carbamoyl, C 1-6 alkyl, unsubstituted or substituted with
  • A is Aryl which is unsubstituted or substituted with one or more groups selected from substituent group G1, A bicyclic carbocyclic group which is unsubstituted or substituted with one or more groups selected from the substituent group G1, Aroyl substituted with one or more groups selected from unsubstituted or substituted group G1; A carbamoyl substituted with one or more groups selected from unsubstituted or substituted group F2; A monocyclic heterocyclic group substituted with one or more groups selected from unsubstituted or substituted group G1; Optionally protected amino, unsubstituted or C 1-6 alkoxy substituted with one or more halogen atoms, or C 3- substituted with one or more groups selected from unsubstituted or substituted group F1
  • a pharmaceutical composition comprising the compound according to any one of items 1 ′
  • R 3 represents substituted or unsubstituted phenyl, substituted or unsubstituted polycyclic aromatic carbocyclic group, substituted or unsubstituted monocyclic nitrogen-containing aromatic heterocyclic group, substituted or unsubstituted monocyclic group.
  • Oxygen-containing aromatic heterocyclic group of a ring substituted or unsubstituted monocyclic sulfur-containing aromatic heterocyclic group, substituted or unsubstituted monocyclic nitrogen-containing and oxygen-aromatic heterocyclic group, substituted or non-substituted Substituted monocyclic nitrogen-containing and sulfur aromatic heterocyclic groups, substituted or unsubstituted bicyclic nitrogen-containing aromatic heterocyclic groups, substituted or unsubstituted bicyclic oxygen-containing aromatic heterocyclic groups Group, substituted or unsubstituted bicyclic sulfur-containing aromatic heterocyclic group, substituted or unsubstituted bicyclic nitrogen-containing and oxygen aromatic heterocyclic group or substituted or unsubstituted bicyclic Nitrogen and sulfur aromatic heterocyclic groups; R 4 is —NR m — or —CR a R b —; R a and R b are each independently a hydrogen atom, a halogen atom, hydroxy, substituted or unsub
  • R k and R l are each independently a hydrogen atom, a halogen atom, cyano, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-3 8 cycloalkyl or C 1-6 alkoxy, or R k and R 1 bonded to the same carbon atom may be taken together to form a substituted or unsubstituted C 2-6 alkylene;
  • R c is a substituted or unsubstituted C 1-6 alkyl, or imino protecting group;
  • Z 1 , Z 2 and Z 3 are each independently a nitrogen atom or C (R d );
  • Each R d independently represents a hydrogen atom, a halogen atom, cyano, nitro, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6
  • R 3 is not a substituted or unsubstituted phenyl and 2) excludes the following compounds: Or a pharmaceutically acceptable salt thereof.
  • (Item 2) 2. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is —NR m —.
  • R m is a hydrogen atom, a compound or a pharmaceutically acceptable salt of item 2, wherein.
  • (Item 4) 2. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is —CR a R b —.
  • (Item 5) 5. The compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 4, wherein n is 2 or 3.
  • (Item 6) 6.
  • (Item 7) 7.
  • (Item 8) Item 7.
  • (Item 9) 7.
  • each R d is independently a hydrogen atom or substituted or unsubstituted C 1-6 alkyl.
  • R 1 is a hydrogen atom, a halogen atom, cyano, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, optionally protected hydroxy or optionally protected carboxy.
  • R 1 is substituted or unsubstituted C 1-6 alkyl
  • Z 3 is C (R d ), wherein R d is substituted or unsubstituted C 1-6 alkyl. 12.
  • X 1 is, -O -, - CR k R l -, or the formula :-( R 6) m - is a group represented by, R 6 are each independently, -O- or -CR k R l -
  • R 3 is Substituted or unsubstituted monocyclic nitrogen-containing and oxygen heterocyclic groups, Substituted or unsubstituted monocyclic nitrogen-containing and sulfur heterocyclic groups, 14.
  • R 3 is represented by formula (X): (Where Z 4 is a nitrogen atom or C (R e ); Z 5 is an oxygen atom or a sulfur atom; R e is a hydrogen atom, a halogen atom, cyano, nitro, hydroxy, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted Or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted di (C 1-6 alkyl) amino, substituted Or unsubstituted C 1-6 alkylthio, substituted or unsubstituted aryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted
  • A is Substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted bicyclic carbocyclic group, substituted or unsubstituted single A heterocyclic group of a ring, a substituted or unsubstituted bicyclic heterocyclic group, a substituted or unsubstituted carbamoyl, a substituted or unsubstituted C 1-6 alkoxy, an optionally protected amino, a protected It may be hydroxy, or may be protected carboxy. ) 14.
  • X 1 is -CR k R l -, - O -, - O-CR k R l -, - CR k R l -CR k R l - or -CR k R l -CR k R l -CR k R l R k and R l are each independently a hydrogen atom, a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl or C 1-6 alkoxy; Or R k and R l bonded to the same carbon atom may be taken together to form a substituted or unsubstituted alkylene; R 3 is represented by formula (X): (Where Z 4 is a nitrogen atom or C (R e ); R e is a hydrogen atom, a halogen atom or a substituted or
  • the substituent group F3 is: Substituted or unsubstituted aryl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted bicyclic carbocyclic group, substituted or unsubstituted monocyclic heterocyclic group and substituted or unsubstituted And a group represented by a bicyclic heterocyclic group.
  • a pharmaceutical composition comprising the compound according to any one of items 1 to 17 or a pharmaceutically acceptable salt thereof. (Item 19) Item 19.
  • a method for treating or preventing a disease associated with a fungal infection which comprises administering the compound according to any one of items 1 to 17, or a pharmaceutically acceptable salt thereof.
  • (Item 101) A pharmaceutical composition for oral administration, comprising the compound according to any one of items 1 ′ to 17 ′ and items 1 to 21, or a pharmaceutically acceptable salt thereof.
  • Item 101 which is a tablet, powder, granule, capsule, pill, film, suspension, emulsion, elixir, syrup, limonade, spirit, aromatic water, extract, decoction or tincture
  • the pharmaceutical composition as described. (Item 103) Sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets, orally disintegrating tablets, dry syrups, soft capsules, microcapsules, or sustained-release capsules, 103.
  • a pharmaceutical composition according to item 102 A pharmaceutical composition according to item 102.
  • a pharmaceutical composition for parenteral administration comprising the compound according to any one of items 1 ′ to 17 ′ and items 1 to 21, or a pharmaceutically acceptable salt thereof.
  • (Item 105) 105.
  • the pharmaceutical composition according to item 104 for transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop or intravaginal administration.
  • the pharmaceutical composition according to item 104 or 105 which is a patch, poultice, powder for external use or suppository.
  • the compound represented by the formula (I) or (I ′), or a pharmaceutically acceptable salt thereof has excellent enzyme inhibitory activity against SMT and / or Candida, Aspergillus or It has excellent antifungal activity against ringworms and is useful as an antifungal agent.
  • it has an enzyme inhibitory activity against SMT of Aspergillus and / or an antifungal activity against Aspergillus.
  • it has an enzyme inhibitory activity against SMT of Candida and Aspergillus, and / or has renewal institutional properties against Candida and Aspergillus.
  • the compound represented by the formula (I) or (I ′) or a pharmaceutically acceptable salt thereof is excellent in safety, pharmacokinetics, solubility, stability, etc. Useful.
  • 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.
  • C 1-6 alkyl means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t -Butyl, pentyl, isopentyl, hexyl and the like.
  • C 2-6 alkenyl means, for example, linear or branched C 2-6 alkenyl such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl and hexenyl. Means.
  • C 2-6 alkynyl means a straight or branched C 2-6 alkynyl such as, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl.
  • “Cycloalkyl” means a cyclic saturated hydrocarbon group. Preferably, it has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 3 to 8 carbon atoms.
  • C 3-8 cycloalkyl for example, cyclopropyl, cyclobutyl, C 3-8 cycloalkyl such as cyclopentyl and cyclohexyl.
  • Aryl means, for example, phenyl, naphthyl, indanyl, indenyl or tetrahydronaphthyl.
  • C 1-6 alkoxy means, for example, linear or branched C, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy and hexyloxy Means 1-6 alkyloxy.
  • C 1-6 alkylamino means, for example, linear or branched, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, t-butylamino, pentylamino and hexylamino. Means branched C 1-6 alkylamino.
  • Di (C 1-6 alkyl) amino means, for example, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, di (t-butyl) amino, dipentylamino, dihexylamino, (ethyl) (methyl) ) Means linear or branched di (C 1-6 alkyl) amino such as amino and (methyl) (propyl) amino.
  • C 1-6 alkylthio means C 1-6 alkylthio such as, for example, methylthio, ethylthio and propylthio.
  • Aryloxy means a group in which an oxy group is bonded to the above “aryl”. Examples include phenoxy or naphthyloxy.
  • Arylthio means a group in which a thio group is bonded to the above “aryl”. Examples include phenylthio or naphthylthio.
  • aromatic carbocyclic group means a monocyclic or bicyclic or higher aromatic hydrocarbon group.
  • aromatic carbocyclic group For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned.
  • a preferred embodiment of the “aromatic carbocyclic group” includes phenyl.
  • Non-aromatic carbocyclic group means a monocyclic or bicyclic or more cycloalkyl or cyclic non-aromatic unsaturated hydrocarbon group.
  • the “non-aromatic carbocyclic group” having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more non-aromatic carbocyclic group.
  • the “non-aromatic carbocyclic group” includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
  • the non-aromatic carbocyclic group having two or more rings preferably has 8 to 20 carbon atoms, and more preferably has 8 to 16 carbon atoms.
  • indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like can be mentioned.
  • “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring To do.
  • the bicyclic or higher aromatic heterocyclic group includes a monocyclic or bicyclic or higher aromatic heterocyclic group condensed with the ring in the above “aromatic carbocyclic group”.
  • the monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members.
  • Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like.
  • the bicyclic aromatic heterocyclic group is preferably 8 to 10 members, more preferably 9 or 10 members.
  • indolyl isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazoazolyl, benzoxadiazolyl, benzoisodiazolyl Ril, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl, etc.
  • aromatic heterocyclic group having three or more rings examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl and the like.
  • Non-aromatic heterocyclic group means a monocyclic or bicyclic or more cyclic non-aromatic cyclic group having at least one hetero atom selected from O, S and N in the ring. Means group.
  • the non-aromatic heterocyclic group having two or more rings is a monocyclic or non-aromatic heterocyclic group having two or more rings, the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group”, and / Or each condensed ring in the “aromatic heterocyclic group” is condensed, and further, the ring in the above “aromatic heterocyclic group” is condensed with a monocyclic or bicyclic or more non-aromatic carbocyclic group.
  • non-aromatic heterocyclic group includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members.
  • the non-aromatic heterocyclic group having two or more rings is preferably 8 to 20 members, more preferably 8 to 10 members.
  • indolinyl, isoindolinyl, chromanyl, isochromanyl and the like can be mentioned.
  • the “monocyclic heterocyclic group” means a monocyclic “aromatic heterocyclic group” and a monocyclic “non-aromatic heterocyclic group”.
  • a monocyclic nitrogen-containing heterocyclic group a monocyclic oxygen-containing heterocyclic group, a monocyclic sulfur-containing heterocyclic group, a monocyclic nitrogen-containing and oxygen heterocyclic group, or a monocyclic nitrogen-containing group And sulfur heterocyclic groups.
  • it is a 5- to 6-membered monocyclic heterocyclic group.
  • Bicyclic heterocyclic group means an aromatic or non-aromatic bicyclic nitrogen-containing heterocyclic group, bicyclic oxygen-containing heterocyclic group, bicyclic sulfur-containing group It means a heterocyclic group, a bicyclic nitrogen-containing and oxygen heterocyclic group or a bicyclic nitrogen-containing and sulfur heterocyclic group. A 9 to 10-membered bicyclic heterocyclic group is preferable.
  • “Monocyclic oxygen-containing heterocyclic group” means “monocyclic oxygen-containing aromatic heterocyclic group” and “monocyclic oxygen-containing non-aromatic heterocyclic group”.
  • the “monocyclic oxygen-containing aromatic heterocyclic group” means a monocyclic aromatic heterocyclic group having only one or more oxygen atoms as heteroatoms in the ring. For example, furanyl and the like can be mentioned.
  • “Monocyclic oxygen-containing non-aromatic heterocyclic group” means a monocyclic non-aromatic heterocyclic group having only one or more oxygen atoms as heteroatoms in the ring. For example, tetrahydrofuranyl, tetrahydropyranyl, pyranyl and the like can be mentioned.
  • “Monocyclic sulfur-containing heterocyclic group” means “monocyclic sulfur-containing aromatic heterocyclic group” and “monocyclic sulfur-containing non-aromatic heterocyclic group”.
  • the “monocyclic sulfur-containing aromatic heterocyclic group” means a monocyclic aromatic heterocyclic group having only one or more sulfur atoms as heteroatoms in the ring.
  • thienyl and the like can be mentioned.
  • the “monocyclic sulfur-containing non-aromatic heterocyclic group” means a monocyclic non-aromatic heterocyclic group having only one or more sulfur atoms as hetero atoms in the ring. For example, tetrahydrothienyl and the like can be mentioned.
  • “Monocyclic nitrogen-containing and oxygen-heterocyclic group” means “monocyclic nitrogen-containing and oxygen-aromatic heterocyclic group” and “monocyclic nitrogen-containing and oxygen-nonaromatic heterocyclic group” To do.
  • “Monocyclic nitrogen-containing and oxygen aromatic heterocyclic group” means a monocyclic aromatic heterocyclic group having only one or more nitrogen atoms and one or more oxygen atoms as heteroatoms in the ring. To do. For example, oxazolyl, isoxazolyl, oxadiazolyl and the like can be mentioned.
  • “Monocyclic nitrogen-containing and oxygen non-aromatic heterocyclic group” means a monocyclic non-aromatic heterocyclic group having only one or more nitrogen atoms and one or more oxygen atoms as heteroatoms in the ring. Means. For example, morpholinyl etc. are mentioned.
  • “Monocyclic nitrogen-containing and sulfur heterocyclic group” means “monocyclic nitrogen-containing and sulfur aromatic heterocyclic group” and “monocyclic nitrogen-containing and sulfur non-aromatic heterocyclic group” To do.
  • “Monocyclic nitrogen-containing and sulfur aromatic heterocyclic group” means a monocyclic aromatic heterocyclic group having only one or more nitrogen atoms and one or more sulfur atoms as heteroatoms in the ring. To do. For example, thiazolyl, isothiazolyl, thiadiazolyl and the like can be mentioned.
  • “Monocyclic nitrogen-containing and sulfur non-aromatic heterocyclic group” means a monocyclic non-aromatic heterocyclic group having only one or more nitrogen atoms and one or more sulfur atoms as heteroatoms in the ring. Means. Examples thereof include thiomorpholinyl, 1-oxidethiomorpholinyl, 1,1-dioxidethiomorpholinyl and the like.
  • “Monocyclic nitrogen-containing heterocyclic group” means “monocyclic nitrogen-containing aromatic heterocyclic group” and “monocyclic nitrogen-containing non-aromatic heterocyclic group”.
  • “Monocyclic nitrogen-containing aromatic heterocyclic group” means a monocyclic aromatic heterocyclic group having only one or more nitrogen atoms as heteroatoms in the ring. Examples thereof include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl and the like.
  • the “monocyclic nitrogen-containing non-aromatic heterocyclic group” means a monocyclic non-aromatic heterocyclic group having only one or more nitrogen atoms in the ring as a hetero atom.
  • the “bicyclic nitrogen-containing heterocyclic group” means “bicyclic nitrogen-containing aromatic heterocyclic group” and “bicyclic nitrogen-containing non-aromatic heterocyclic group”.
  • the “bicyclic nitrogen-containing aromatic heterocyclic group” means a bicyclic aromatic heterocyclic group having only one or more nitrogen atoms in the ring as a hetero atom. Examples include indolyl, isoindolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, quinolyl, isoquinolinyl, quinolidinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, plinyl, pteridinyl and the like.
  • the “bicyclic nitrogen-containing non-aromatic heterocyclic group” means a bicyclic non-aromatic heterocyclic group having only one or more nitrogen atoms in the ring as a hetero atom. Examples include tetrahydroquinoline, tetrahydroisoquinolinyl, indolinyl, isoindolinyl, cinnolinyl, dihydroquinoxalinyl, quinuclidine and the like.
  • Nonrogen-containing aromatic heterocyclic group means an aromatic heterocyclic group which is a monocyclic or bicyclic or more aromatic ring and has only one or more nitrogen atoms as heteroatoms in the ring. To do. A 5- to 14-membered ring is preferable, and a 5- to 6-membered ring or a 9 to 10-membered ring is more preferable. The number of nitrogen atoms is preferably 1 to 4, more preferably 1 to 3, and still more preferably 1 or 2.
  • Examples of the monocyclic “nitrogen-containing aromatic heterocyclic group” include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl and the like.
  • nitrogen-containing aromatic heterocyclic group examples include, for example, indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzotriayl Examples include zolyl, imidazopyridyl, triazolopyridyl, pyrazinopyridazinyl, carbazolyl, acridinyl and the like.
  • a preferred embodiment is a monocyclic or bicyclic group, a more preferred embodiment is a 5- to 6-membered monocycle or a 9- to 10-membered bicyclic group, and a more preferred embodiment is a 5- to 6-membered monocyclic group. It is a cyclic group.
  • nitrogen-containing heterocyclic group is a monocyclic or bicyclic or more aromatic or non-aromatic ring having only one or more nitrogen atoms as heteroatoms in the ring. Means. "Monocyclic nitrogen-containing heterocyclic group” and “bicyclic nitrogen-containing heterocyclic group” are included.
  • nitrogen-containing heterocyclic ring means a ring derived from the above “nitrogen-containing heterocyclic group”.
  • bicyclic oxygen-containing heterocyclic group means “bicyclic oxygen-containing aromatic heterocyclic group” and “bicyclic oxygen-containing non-aromatic heterocyclic group”.
  • bicyclic oxygen-containing aromatic heterocyclic group means a bicyclic aromatic heterocyclic group having only one or more oxygen atoms as heteroatoms in the ring. Examples include benzofuranyl, isobenzofuranyl, and the like.
  • bicyclic oxygen-containing non-aromatic heterocyclic group means a bicyclic non-aromatic heterocyclic group having only one or more oxygen atoms as hetero atoms in the ring. Examples include 2,3-dihydrobenzofuranyl, chromanyl, chromenyl, isochromanyl, 1,3-benzodioxolyl, 1,3-benzodioxanyl, 1,4-benzodioxanyl and the like.
  • bicyclic sulfur-containing heterocyclic group means “bicyclic sulfur-containing aromatic heterocyclic group” and “bicyclic sulfur-containing non-aromatic heterocyclic group”.
  • bicyclic sulfur-containing aromatic heterocyclic group means a bicyclic aromatic heterocyclic group having only one or more sulfur atoms as hetero atoms in the ring.
  • benzothienyl and the like can be mentioned.
  • bicyclic sulfur-containing non-aromatic heterocyclic group means a bicyclic non-aromatic heterocyclic group having only one or more sulfur atoms as hetero atoms in the ring.
  • 2,3-dihydrobenzothienyl and the like can be mentioned.
  • Bicyclic nitrogen-containing and oxygen heterocyclic group means “bicyclic nitrogen-containing and oxygen aromatic heterocyclic group” and “bicyclic nitrogen-containing and oxygen non-aromatic heterocyclic group”. "Means.
  • Bicyclic nitrogen-containing and oxygen aromatic heterocyclic group means a bicyclic aromatic heterocyclic group having only one or more nitrogen atoms and one or more oxygen atoms as heteroatoms in the ring. Means. For example, benzoxazolyl, benzoisoxazolyl, benzooxadiazolyl and the like can be mentioned.
  • “Bicyclic nitrogen-containing and oxygen non-aromatic heterocyclic group” means a bicyclic non-aromatic heterocyclic ring having only one or more nitrogen atoms and one or more oxygen atoms as heteroatoms in the ring. Means a formula group. Examples include benzomorpholinyl, dihydropyranopyridyl, dihydrodioxynopyridyl, dihydropyridoxazinyl and the like.
  • Bicyclic nitrogen-containing and sulfur heterocyclic group means "bicyclic nitrogen-containing and sulfur aromatic heterocyclic group” and "bicyclic nitrogen-containing and sulfur non-aromatic heterocyclic group" "Means.
  • Bicyclic nitrogen-containing and sulfur aromatic heterocyclic group means a bicyclic aromatic heterocyclic group having only one or more nitrogen atoms and one or more sulfur atoms as heteroatoms in the ring. Means. Examples include benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl and the like.
  • “Bicyclic nitrogen-containing and sulfur non-aromatic heterocyclic group” means a bicyclic non-aromatic heterocyclic ring having only one or more nitrogen atoms and one or more sulfur atoms as heteroatoms in the ring. Means a formula group. For example, tetrahydrobenzothiazolyl, tetrahydrobenzoisothiazolyl, tetrahydrobenzothiadiazolyl and the like can be mentioned.
  • C 1-6 alkylene means a linear or branched C 1-6 alkylene such as methylene, ethylene, propylene, butylene and hexylene.
  • C 2-6 alkylene means linear or branched C 2-6 alkylene such as ethylene, propylene, butylene and hexylene.
  • “Aroyl” is carbonyl having aryl, and the aryl moiety is as defined above for “aryl”. For example, it means benzoyl or naphthoyl.
  • aralkyl C 1-6 alkyl means, for example, benzyl, diphenylmethyl, trityl, Al C 1-6 alkyl, such as phenethyl and naphthylmethyl groups.
  • “Bicyclic carbocyclic group” means, for example, pentalenyl, indenyl, indanyl, naphthyl, tetrahydronaphthyl or dihydronaphthyl.
  • arylsulfonyl examples include benzenesulfonyl, p-toluenesulfonyl, naphthalenesulfonyl and the like.
  • Halo C 1-6 alkyl is a group substituted with one or more of the above “halogen atoms” at any position of the above “C 1-6 alkyl”, and examples thereof include monofluoromethyl, difluoromethyl, Examples include trifluoromethyl, monochloromethyl, chlorodifluoromethyl, and the like.
  • Arylsulfonyloxy means a group in which an oxy group is bonded to the above “arylsulfonyl”.
  • arylsulfonyl For example, benzenesulfonyloxy, p-toluenesulfonyloxy, naphthalenesulfonyloxy and the like can be mentioned.
  • Halo C 3-8 cycloalkyl is a group substituted with one or more of the above “halogen atoms” at any position of the above “C 3-8 cycloalkyl”, such as monofluorocyclopropyl, Examples include dichlorocyclopropyl and difluorocyclopentyl.
  • “Substituted or unsubstituted sulfamoyl” means sulfamoyl optionally substituted with one or more groups selected from substituent group H1.
  • substituent group H1 For example, sulfamoyl, N-methylsulfamoyl, N, N-dimethylsulfamoyl, N-ethyl-N-methylsulfamoyl, N, N-diethylsulfamoyl, Nn-propylaminosulfamoyl, N-isopropylsulfamoyl, N-morpholinosulfamoyl, N-tetrahydrofuranylsulfamoyl, N-piperidylsulfamoyl, N-tetrahydropyranylsulfamoyl, N-benzylsulfamoyl, N-acetylsulfamoyl, N-methylsulfony
  • nitrogen-containing heterocyclic sulfonyl means a group in which a sulfonyl group is bonded to a nitrogen atom or a carbon atom in the ring of the “nitrogen-containing heterocyclic ring”.
  • Carbocycle means a ring derived from the above “carbocyclic group”.
  • the “carbocycle carbonyl” means a group in which a carbonyl group is bonded to any ring constituent atom of the “carbocycle”.
  • heterocyclic carbonyl means a group in which a carbonyl group is bonded to any ring constituent atom of the above “heterocycle”.
  • the “carbocycle sulfonyl” means a group in which a sulfonyl group is bonded to any ring constituent atom of the “carbocycle”.
  • heterocyclic sulfonyl means a group in which a sulfonyl group is bonded to any ring constituent atom of the above “heterocycle”.
  • Substituents for “optionally protected amino” include all groups that can be used as protecting groups for conventional amino groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 696-926, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, ar C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, acyl, C 1-6 alkoxycarbonyl, al C 1-6 alkoxycarbonyl, aryloxycarbonyl, C 1-6 alkylsulfonyl , Arylsulfonyl or silyl.
  • the “imino protecting group” includes all groups that can be used as protecting groups for ordinary imino groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 696-868, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, ar C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, acyl, C 1-6 alkoxycarbonyl, al C 1-6 alkoxycarbonyl, aryloxycarbonyl, C 1-6 alkylsulfonyl , Arylsulfonyl or silyl.
  • Substituents for “optionally protected hydroxy” include all groups that can be used as protecting groups for conventional hydroxyl groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 16-299, 2007, John Wiley & Sons (John Wiley & Sons, INC.).
  • a C 2-6 alkenyl group C 2-6 alkynyl, alk 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, alk 1-6 alkoxy C 1-6 alkyl
  • Examples include acyl, C 1-6 alkoxycarbonyl, al C 1-6 alkoxycarbonyl, C 1-6 alkylsulfonyl, arylsulfonyl, silyl, tetrahydrofuranyl or tetrahydropyranyl.
  • Substituents for “optionally protected carboxy” include all groups that can be used as protecting groups for ordinary carboxyl groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 533-643, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, al C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, al C 1-6 alkoxy C Examples include 1-6 alkyl, acyl C 1-6 alkyl, acyloxy C 1-6 alkyl or silyl.
  • “Silyl” means, for example, trimethylsilyl, triethylsilyl or tributylsilyl.
  • Al C 1-6 alkoxy refers to al C 1-6 alkyloxy such as, for example, benzyloxy, phenethyloxy and naphthylmethyloxy.
  • C 1-6 alkoxy C 1-6 alkyl means, for example, a C 1-6 alkyloxy C 1-6 alkyl such as methoxymethyl and 1-ethoxyethyl.
  • Acyl means, for example, formyl, succinyl, glutaryl, maleoyl, C 2-12 alkanoyl, aroyl, heterocyclic carbonyl or ( ⁇ -substituted) aminoacetyl.
  • C 1-6 alkoxycarbonyl means, for example, linear or branched C 1-6 such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and 1,1-dimethylpropoxycarbonyl. Means an alkyloxycarbonyl group;
  • AlC 1-6 alkoxycarbonyl means alC 1-6 alkyloxycarbonyl such as benzyloxycarbonyl and phenethyloxycarbonyl.
  • Aryloxycarbonyl means, for example, phenyloxycarbonyl or naphthyloxycarbonyl.
  • C 1-6 alkylsulfonyl means C 1-6 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl and propylsulfonyl.
  • AlC 1-6 alkoxyC 1-6 alkyl means an ar C 1-6 alkyloxy C 1-6 alkyl such as, for example, benzyloxymethyl and phenethyloxymethyl.
  • Examples of the “leaving group” include a halogen atom, a C 1-6 alkylsulfonyloxy group, or an arylsulfonyloxy group.
  • Substituent group A1 Halogen atoms, Cyano, Nitro, A carbamoyl unsubstituted or substituted with one or more C 1-6 alkyl groups, C 1-6 alkoxy which is unsubstituted or substituted with one or more groups selected from substituent group A2; C 1-6 alkylamino which is unsubstituted or substituted with one or more groups selected from substituent group A2; Di (C 1-6 alkyl) amino which is unsubstituted or substituted with one or more groups selected from substituent group A2; Aryl which is unsubstituted or substituted with one or more groups selected from substituent group B1; A monocyclic heterocyclic group substituted with one or more groups selected from unsubstituted or substituted group B1; A bicyclic heterocyclic group which is unsubstituted or substituted with one or more groups selected from the substituent group B1; Optionally protected amino, Imino, which may be protected, Optionally protected hydroxyl, An
  • Substituent group A1a Halogen atoms, amino, Imino, Hydroxyl.
  • Substituent group A2 Halogen atoms, Cyano, A carbamoyl substituted with one or more groups selected from unsubstituted or substituted group E1; Sulfamoyl substituted with one or more groups selected from unsubstituted or substituted group E1; C 1-6 alkyl which is unsubstituted or substituted with one or more groups selected from substituent group E1; C 1-6 alkoxy which is unsubstituted or substituted with one or more groups selected from substituent group E1; C 3-8 cycloalkyl, which is unsubstituted or substituted with one or more groups selected from substituent group E1; Aryloxy substituted or unsubstituted with one or more groups selected from substituent group B1; Aryl which is unsubstituted or substituted with one or more groups selected from substituent group B1; A monocyclic or bicyclic or more non-aromatic carbocyclic group substituted with one or more groups selected from unsubstitute
  • Substituent group A2a Halogen atoms, Cyano, Oxo, Carbamoyl, Sulfamoyl, C 1-6 alkyl which is unsubstituted or substituted by one or more halogen atoms, C 1-6 alkoxy, unsubstituted or substituted with one or more halogen atoms, Optionally protected amino, Optionally protected hydroxyl, An optionally protected carboxyl.
  • Substituent group B1 Halogen atoms, Cyano, Nitro, Oxo, A carbamoyl substituted with one or more groups selected from unsubstituted or substituted group F2; C 1-6 alkyl substituted with one or more groups selected from unsubstituted or substituted group A2a, C 1-6 alkoxy substituted with one or more groups selected from unsubstituted or substituted group A2a, C 3-8 cycloalkyl which is unsubstituted or substituted with one or more groups selected from substituent group A2a, C 1-6 alkylamino which is unsubstituted or substituted with one or more groups selected from Substituent Group A2a, Di (C 1-6 alkyl) amino unsubstituted or substituted with one or more groups selected from substituent group A2a, Aryloxy substituted with one or more groups selected from unsubstituted or substituent group A2a, Aryl which is unsubstituted or substituted with one or
  • Substituent group C1 Halogen atoms, Cyano, Nitro, Oxo, A carbamoyl substituted with one or more groups selected from unsubstituted or substituted group H1; A nitrogen-containing heterocyclic carbonyl which is unsubstituted or substituted with one or more groups selected from substituent group B1; C 1-6 alkyl substituted with one or more groups selected from unsubstituted or substituted group A2; C 2-6 alkenyl which is unsubstituted or substituted by one or more groups selected from substituent group A2; C 2-6 alkynyl which is unsubstituted or substituted with one or more groups selected from substituent group A2; C 3-8 cycloalkyl substituted with one or more groups selected from unsubstituted or substituent group A2; C 1-6 alkoxy which is unsubstituted or substituted with one or more groups selected from substituent group A2; C 1-6 alkylamino which is unsubstituted or
  • Substituent group C2 Halogen atoms, Cyano, Nitro, Oxo, A carbamoyl substituted with one or more groups selected from unsubstituted or substituted group H1; A C 1-6 alkylsulfonyl which is unsubstituted or substituted with one or more groups selected from substituent group A2; C 2-12 alkanoyl which is unsubstituted or substituted with one or more groups selected from substituent group A2; C 1-12 alkyl which is unsubstituted or substituted with one or more groups selected from substituent group A2; C 2-6 alkenyl which is unsubstituted or substituted by one or more groups selected from substituent group A2; C 2-6 alkynyl which is unsubstituted or substituted with one or more groups selected from substituent group A2; C 3-8 cycloalkyl substituted with one or more groups selected from unsubstituted or substituent group A2; C 1-6 alkoxy which is unsub
  • Substituent group D1 Halogen atoms, Cyano, Nitro, Oxo, Carbamoyl unsubstituted or substituted with one or more C1-6 alkyl groups, C 1-6 alkyl substituted with one or more groups selected from unsubstituted or substituted group A2; C 2-6 alkenyl which is unsubstituted or substituted by one or more groups selected from substituent group A2; C 2-6 alkynyl which is unsubstituted or substituted with one or more groups selected from substituent group A2; C 3-8 cycloalkyl, which is unsubstituted or substituted with one or more groups selected from substituent group C2; C 1-6 alkoxy which is unsubstituted or substituted with one or more groups selected from substituent group A2; C 1-6 alkylamino which is unsubstituted or substituted with one or more groups selected from substituent group A2; Di (C 1-6 alkyl) amino which is unsubstituted
  • Substituent group D1a Halogen atoms, Oxo, C 1-6 alkyl, amino, Imino, Hydroxyl.
  • Substituent group E1 Halogen atoms, Cyano, Nitro, C 1-6 alkyl substituted with one or more groups selected from unsubstituted or substituted group E2; C 3-8 cycloalkyl, unsubstituted or substituted with one or more groups selected from E2; C 1-6 alkoxy unsubstituted or substituted with one or more groups selected from E2; C 1-6 alkylamino which is unsubstituted or substituted by one or more groups selected from substituent group E2; Di (C 1-6 alkyl) amino unsubstituted or substituted with one or more groups selected from substituent group E2; Optionally protected amino, optionally protected hydroxyl, An optionally protected carboxyl.
  • Substituent group E1a Halogen atoms, C 1-6 alkyl which is unsubstituted or substituted by one or more halogen atoms, C 1-6 alkoxy, unsubstituted or substituted with one or more halogen atoms, Optionally protected amino, Optionally protected hydroxyl, An optionally protected carboxyl.
  • Substituent group E1b C 1-6 alkyl which is unsubstituted or substituted by one or more halogen atoms, An optionally protected hydroxyl.
  • Substituent group E2 Halogen atoms, Carbamoyl, C 1-6 alkyl, C 1-6 alkoxy, Optionally protected amino, Optionally protected hydroxyl, An optionally protected carboxyl.
  • Substituent group F1 Halogen atoms, amino, Hydroxyl, Carboxyl, Carbamoyl, C 1-6 alkyl, C 1-6 alkoxy.
  • Substituent group F2 C 1-6 alkyl, Halo C 1-6 alkyl, C 3-8 cycloalkyl, Halo C 3-8 cycloalkyl, Al C 1-6 alkyl, Aryl which is unsubstituted or substituted with one or more halogen atoms.
  • a monocyclic heterocyclic group which is unsubstituted or substituted with one or more halogen atoms.
  • Substituent group G1 Halogen atoms, Cyano, Oxo, Adamantyl, A carbamoyl unsubstituted or substituted with one or more C 1-6 alkyl groups, C 1-6 alkylsulfonyl, C 1-6 alkyl which is unsubstituted or substituted with one or more groups selected from a halogen atom and a cyano group, C 3-8 cycloalkyl, unsubstituted or substituted with one or more C 1-6 alkyl groups, C 1-6 alkoxy unsubstituted or substituted with one or more groups selected from halogen atoms and cyano groups, C 1-6 alkylamino, Di (C 1-6 alkyl) amino, Aryl which is unsubstituted or substituted with one or more groups selected from halogen atoms and C 1-6 alkyl groups, Ar C 1-6 alkoxy unsubstituted or substituted with one or more groups selected from halogen atoms
  • Substituent group G2 Halogen atoms, C 1-6 alkyl which is unsubstituted or substituted by one or more halogen atoms.
  • Substituent group G3 Halogen atoms, C 1-6 alkyl which is unsubstituted or substituted by one or more halogen atoms, C 3-8 cycloalkyl, unsubstituted or substituted with one or more halogen atoms, Aryl which is unsubstituted or substituted with one or more groups selected from substituent group F1.
  • Substituent group H1 C 1-6 alkyl substituted with one or more groups selected from unsubstituted or substituted group A2a, C 2-6 alkenyl substituted with one or more groups selected from unsubstituted or substituted group A2a, C 2-6 alkynyl which is unsubstituted or substituted with one or more groups selected from substituent group A2a, C 1-6 alkylcarbonyl which is unsubstituted or substituted with one or more groups selected from substituent group A2a, C 2-6 alkenylcarbonyl which is unsubstituted or substituted with one or more groups selected from substituent group A2a, C 2-6 alkynylcarbonyl which is unsubstituted or substituted with one or more groups selected from substituent group A2a, Aryl which is unsubstituted or substituted with one or more groups selected from substituent group B1; A cycloalkyl that is unsubstituted or substituted with one or more groups
  • R 1 C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, di (C 1-6 alkyl) amino And C 1-6 alkylthio may be substituted with one or more groups selected from Substituent Group A1.
  • the aryloxy, arylthio, aryl, monocyclic heterocyclic group and bicyclic heterocyclic group represented by R 1 may be substituted with one or more groups selected from the substituent group B1.
  • R 1 C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, di (C 1-6 alkyl) amino And C 1-6 alkylthio may be substituted with one or more groups selected from Substituent Group A1.
  • the aryloxy, arylthio, aryl, monocyclic heterocyclic group and bicyclic heterocyclic group represented by R 2 may be substituted with one or more groups selected from the substituent group B1.
  • R 3 phenyl, polycyclic aromatic carbocyclic group, monocyclic nitrogen-containing aromatic heterocyclic group, monocyclic oxygen-containing aromatic heterocyclic group, monocyclic sulfur-containing aromatic heterocyclic group Groups, monocyclic nitrogen-containing and oxygen aromatic heterocyclic groups, monocyclic nitrogen-containing and sulfur aromatic heterocyclic groups, bicyclic nitrogen-containing aromatic heterocyclic groups, bicyclic oxygen-containing aromatics
  • Aromatic heterocyclic groups, bicyclic sulfur-containing aromatic heterocyclic groups, bicyclic nitrogen-containing and oxygen aromatic heterocyclic groups and bicyclic nitrogen-containing and sulfur aromatic heterocyclic groups are: It may be substituted with one or more groups selected from the substituent group C1.
  • C 1-6 alkoxy and C 1-6 alkyl of R a and R b may be substituted with one or more groups selected from substituent group A1.
  • C 1-6 alkyl of R m may be substituted with one or more groups selected from substituent group A1.
  • C 2-6 alkylene and C 1-6 alkylene in A) to D) may be substituted with one or more groups selected from substituent group A1.
  • substituents of “substituted or unsubstituted methylidene” include one or more groups selected from the substituent group C1. “Substituted or unsubstituted unsubstituted methylidene” specifically refers to the following formula: (Wherein, R n and R o are each independently a hydrogen atom or a group selected from substituent group C1) It is group shown by these.
  • the C 2-6 alkylene formed by R k and R 1 bonded to the same carbon atom may be substituted with one or more groups selected from the substituent group A1.
  • C 1-6 alkyl of R c may be substituted with one or more groups selected from substituent group A1.
  • Examples of the imino protecting group for R c include, for example, al C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, acyl, C 1-6 alkoxycarbonyl, al C 1-6 alkoxycarbonyl, aryloxycarbonyl, C 1-6 alkylsulfonyl, arylsulfonyl, silyl and the like.
  • C 1-6 alkylthio may be substituted with one or more groups selected from Substituent Group A1.
  • the aryloxy, arylthio, aryl, monocyclic heterocyclic group and bicyclic heterocyclic group of R d may be substituted with one or more groups selected from the substituent group B1.
  • Preferred compounds of the general formula (I ′) of the present invention include the following compounds.
  • R 1 and R 2 are each independently a hydrogen atom, a halogen atom, cyano, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkynyl, substituted or unsubstituted C 1-1
  • R 1 and R 2 are each independently a halogen atom, cyano, substituted or unsubstituted C 1-6 alkyl or substituted or unsubstituted C 1-6 alkoxy.
  • R 1 and R 2 are each a halogen atom, C is unsubstituted or substituted with one or more C 1-6 substituted by a halogen atom alkyl or unsubstituted or one or more halogen atoms 1-6 More preferred are compounds that are alkoxy.
  • R 1 and R 2 are each independently a fluorine atom, a chlorine atom, an unsubstituted or C 1-4 alkyl group substituted with one or more halogen atoms, or an unsubstituted or substituted with one or more halogen atoms Even more preferred are compounds that are C 1-4 alkoxy. Particularly preferred are compounds wherein R 1 and R 2 are the same and are methyl.
  • R 3 is an optionally substituted pyridyl group, substituted or unsubstituted monocyclic nitrogen-containing and oxygen heterocyclic group, substituted or unsubstituted monocyclic nitrogen-containing and sulfur heterocyclic group, substituted or unsubstituted Compounds that are substituted bicyclic nitrogen-containing heterocyclic groups or substituted or unsubstituted bicyclic nitrogen-containing and oxygen heterocyclic groups are preferred. More preferred are compounds wherein R 3 is a substituted or unsubstituted monocyclic nitrogen-containing and oxygen heterocyclic group or a substituted or unsubstituted monocyclic nitrogen-containing and sulfur heterocyclic group.
  • R 3 is substituted or unsubstituted thiazolyl or substituted or unsubstituted thiadiazolyl.
  • preferred substituents are a hydrogen atom and one or more groups selected from substituent group C1.
  • Further preferred substituents are a hydrogen atom, a halogen atom, C 1-6 alkyl substituted with one or more groups selected from unsubstituted or substituent group F1, and one selected from unsubstituted or substituent group F1.
  • R 3 represents the formula (X ′): Wherein Z 4 is a nitrogen atom or C (H); A is Hydrogen atom, Halogen atoms, C 1-6 alkyl which is unsubstituted or substituted with one or more groups selected from substituent group F1, C 2-6 alkenyl substituted with one or more groups selected from unsubstituted or substituted group F1; C 2-6 alkynyl substituted with one or more groups selected from unsubstituted or substituted group F1; C 3-8 cycloalkyl, which is unsubstituted or substituted with one or more groups selected from substituent group F1, C 1-6 alkoxy, unsubstituted or substituted with one or more halogen atoms, Aryl which is unsubstituted or substituted with one or more groups selected from substituent group G1, A bicyclic carbocyclic group which is unsubstituted or substituted with one or more groups selected from the substituent group G1, A monocyclic heterocyclic group substitute
  • A is aroyl substituted with one or more groups selected from unsubstituted or substituted group G1, and substituted with one or more groups selected from unsubstituted or substituted group G1.
  • More preferred are compounds that are monocyclic heterocyclic groups or bicyclic heterocyclic groups substituted with one or more groups selected from unsubstituted or substituted group G1.
  • A is substituted with one or more groups selected from unsubstituted or substituted group G32, benzoyl group substituted with one or more groups selected from unsubstituted or substituted group G3 A substituted phenyl group, an unsubstituted or substituted naphthyl group with one or more groups selected from substituent group G2, an unsubstituted or substituted tetrahydronaphthyl group with one or more groups selected from substituent group G2.
  • a bicyclic oxygen-containing heterocyclic group substituted with one or more groups selected from substituent group G2 a monocyclic group substituted with one or more groups selected from unsubstituted or substituent group G2
  • a compound that is an oxygen-containing heterocyclic group or a monocyclic nitrogen-containing heterocyclic group substituted with one or more groups selected from unsubstituted or substituted group G2 is more preferable.
  • R 4 is —CR a R b —
  • R a and R b are each independently hydrogen atom, halogen atom, hydroxy, unsubstituted or C 1-4 alkyl substituted with one or more halogen atoms, or Preferred are compounds that are C 1-4 alkoxy unsubstituted or substituted with one or more halogen atoms. More preferably, they are each independently a hydrogen atom or a halogen atom.
  • R 5 is independently —CR i R j — or —C ( ⁇ O) —.
  • R i and R j are each independently a hydrogen atom, a halogen atom, C 1-3 alkyl, halo C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or C 1-3 alkoxy is preferred. More preferably, they are a hydrogen atom, a halogen atom, C 1-3 alkyl or halo C 1-3 alkyl.
  • the general formula (I ′) is represented by the following formula (I′-5): (Wherein R 5a , R 5b , R 5c , R 5d and R 5e are each independently —CR i R j — or —C ( ⁇ O) —, and the other symbols are as defined above. is there.) Can be expressed as The preferred embodiments of R 5a , R 5b , R 5c , R 5d and R 5e are the same as the preferred embodiments of R 5 .
  • n is an integer of 2 to 5, preferably 2 or 3.
  • X 1 is an oxygen atom, an unsubstituted or C 1-6 alkylene substituted with one or more halogen atoms, or —NH—.
  • X 1 is an oxygen atom, methylene which is unsubstituted or substituted with one or more halogen atoms, 1,2-ethylene which is unsubstituted or substituted with one or more halogen atoms, or unsubstituted or one or more halogens
  • More preferred are compounds that are 1,3-propylene substituted with atoms, or 1,4-butylene unsubstituted or substituted with one or more halogen atoms. More preferred are compounds wherein X 1 is an oxygen atom, methylene, 1,2-ethylene, or 1,3-propylene.
  • Z 1 and Z 2 are each independently a nitrogen atom or C (H) is preferred.
  • Preferred compounds of the general formula (I) of the present invention include the following compounds.
  • R 1 is hydrogen atom, halogen atom, cyano, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkynyl, substituted or unsubstituted C 1-6 alkoxy, protected Compounds that are good hydroxy or optionally protected carboxy are preferred. More preferred is a compound wherein R 1 is a halogen atom, cyano, substituted or unsubstituted C 1-6 alkyl or substituted or unsubstituted C 1-6 alkoxy.
  • R 1 is a halogen atom, unsubstituted or C 1-6 alkyl substituted with one or more halogen atoms, or unsubstituted or C 1-6 alkoxy substituted with one or more halogen atoms.
  • a compound which is R 1 , a fluorine atom, a chlorine atom, a C 1-4 alkyl group which is unsubstituted or substituted with one or more halogen atoms, or a C 1-4 alkoxy which is unsubstituted or substituted with one or more halogen atoms Is even more preferable.
  • R 3 is substituted or unsubstituted phenyl, substituted or unsubstituted bicyclic aromatic carbocyclic group, substituted or unsubstituted monocyclic nitrogen-containing aromatic heterocyclic group, substituted or unsubstituted monocyclic Ring nitrogen and oxygen aromatic heterocyclic groups, substituted or unsubstituted monocyclic nitrogen and sulfur aromatic heterocyclic groups, substituted or unsubstituted bicyclic nitrogen containing heterocyclic groups or substituted or unsubstituted Compounds that are unsubstituted bicyclic nitrogen-containing and oxygen heterocyclic groups are preferred.
  • R 3 is substituted or unsubstituted phenyl, substituted or unsubstituted bicyclic aromatic carbocyclic group, substituted or unsubstituted monocyclic nitrogen-containing aromatic heterocyclic group, substituted or unsubstituted monocyclic
  • a compound that is a nitrogen-containing and oxygen-aromatic heterocyclic group of a ring or a substituted or unsubstituted monocyclic nitrogen-containing and sulfur-aromatic heterocyclic group is more preferable.
  • R 3 represents substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted monocyclic nitrogen-containing and oxygen heterocyclic groups, or substituted or unsubstituted monocyclic nitrogen-containing and sulfur heterocyclic groups.
  • the compound which is group is more preferable. More preferred are compounds wherein R 3 is substituted or unsubstituted phenyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted thiadiazolyl or substituted or unsubstituted oxadiazolyl.
  • R 3 is substituted or unsubstituted phenyl, substituted or unsubstituted polycyclic aromatic carbocyclic group, substituted or unsubstituted monocyclic nitrogen-containing aromatic heterocyclic group, substituted or unsubstituted monocyclic Oxygen-containing aromatic heterocyclic groups, substituted or unsubstituted monocyclic sulfur-containing aromatic heterocyclic groups, substituted or unsubstituted monocyclic nitrogen-containing and oxygen-aromatic heterocyclic groups, substituted or unsubstituted Monocyclic nitrogen-containing and sulfur aromatic heterocyclic groups, substituted or unsubstituted bicyclic nitrogen-containing aromatic heterocyclic groups, substituted or unsubstituted bicyclic oxygen-containing aromatic heterocyclic groups Substituted, unsubstituted bicyclic sulfur-containing aromatic heterocyclic groups, substituted or unsubstituted bicyclic nitrogen-containing and oxygen aromatic heterocyclic groups, or substituted or unsubstituted bicyclic nitrogen-containing
  • substituents include a hydrogen atom, a halogen atom, cyano, oxo, unsubstituted or C 1-6 alkyl substituted with one or more groups selected from Substituent Group A2, from unsubstituted or substituent group A2 C 3-8 cycloalkyl substituted with one or more selected groups, aryl substituted with one or more groups selected from unsubstituted or substituted group C2, 1 selected from unsubstituted or substituted group C2 Monocyclic heterocyclic group substituted by one or more groups, unsubstituted or substituted bicyclic or more carbocyclic group substituted by one or more groups selected from substituent group C2, unsubstituted or substituted groups One or more groups selected from two or more heterocyclic groups substituted with one or more groups selected from C2 and aryloxy substituted with one or more groups selected from unsubstituted or substituent group C2 It is.
  • substituents include a hydrogen atom, a halogen atom, cyano, oxo, unsubstituted or C 1-6 alkyl substituted with one or more groups selected from substituent group B1, from unsubstituted or substituent group B1 C 3-8 cycloalkyl substituted with one or more selected groups, aryl substituted with one or more groups selected from unsubstituted or substituent group B1, 1 selected from unsubstituted or substituted group B1 Monocyclic heterocyclic group substituted with one or more groups, unsubstituted or substituted bicyclic or more carbocyclic group substituted with one or more groups selected from substituent group B1, unsubstituted or substituted group One or more groups selected from bicyclic or more heterocyclic groups substituted with one or more groups selected from B1 and aryloxy substituted with one or more groups selected from unsubstituted or substituent group B1 It is.
  • preferred substituents include hydrogen atom, halogen atom, oxo, cyano, unsubstituted or C 3-8 cycloalkyl substituted with one or more groups selected from substituent group A2.
  • R 3 is represented by formula (X): Wherein Z 4 is a nitrogen atom or C (H); Z 5 is an oxygen atom or a sulfur atom; A is Hydrogen atom, Halogen atoms, Cyano, Nitro, A carbamoyl substituted with one or more groups selected from unsubstituted or substituted group H1; A nitrogen-containing heterocyclic carbonyl which is unsubstituted or substituted with one or more groups selected from substituent group B1; C 1-6 alkyl substituted with one or more groups selected from unsubstituted or substituted group A2; C 2-6 alkenyl which is unsubstituted or substituted by one or more groups selected from substituent group A2; C 2-6 alkynyl which is unsubstituted or substituted with one or more groups selected from substituent group A2; C 3-8 cycloalkyl substituted with one or more groups selected from unsubstituted or substituent group A2; C 1-6 alkoxy which is unsubstit
  • A represents a hydrogen atom, a halogen atom, cyano, oxo, unsubstituted or substituted C 1-6 alkyl substituted with one or more groups selected from substituent group A2, unsubstituted or substituted group C 3-8 cycloalkyl substituted with one or more groups selected from A2, unsubstituted or substituted with one or more groups selected from substituent group C2, selected from unsubstituted or substituted group C2
  • a monocyclic heterocyclic group substituted by one or more groups selected from the above, an unsubstituted or bicyclic or more carbocyclic group substituted by one or more groups selected from the substituent group C2, unsubstituted or substituted Bicyclic or more heterocyclic groups substituted with one or more groups selected from group C2 or aryloxy substituted with one or more groups selected from unsubstituted or substituent group C2 are preferred.
  • A represents a hydrogen atom, a halogen atom, cyano, oxo, unsubstituted or substituted C 1-6 alkyl substituted with one or more groups selected from substituent group A2, unsubstituted or substituted group C 3-8 cycloalkyl substituted with one or more groups selected from A2, unsubstituted or substituted with one or more groups selected from substituent group C2, selected from unsubstituted or substituted group C2
  • a monocyclic heterocyclic group substituted by one or more groups selected from the above, an unsubstituted or bicyclic or more carbocyclic group substituted by one or more groups selected from the substituent group C2, unsubstituted or substituted Bicyclic or more heterocyclic groups substituted with one or more groups selected from group C2 or aryloxy substituted with one or more groups selected from unsubstituted or substituent group C2 are preferred.
  • a more preferred embodiment of formula (X2) is formula (X2a) or (X2b)
  • R 4 is —CR a R b —
  • R a is a hydrogen atom, a halogen atom, substituted or unsubstituted C 1-6 alkyl or substituted or unsubstituted C 1-6 alkoxy
  • R b is The case where it is a hydrogen atom is preferable. More preferably, R a and R b are hydrogen atoms.
  • R 4 is preferably —NR m —.
  • R 5 is preferably each independently —CR i R j —.
  • R i and R j are preferably each independently a hydrogen atom, C 1-6 alkyl C 2-6 alkenyl, C 2-6 alkynyl or C 3-8 cycloalkyl. More preferably, they are each independently a hydrogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl or C 3-8 cycloalkyl.
  • n is an integer of 2 to 5, preferably 2 or 3.
  • R 5a , R 5b , R 5c , R 5d and R 5e are each independently —CR i R j — or —C ( ⁇ O) —, and the other symbols are as defined above. is there.)
  • R 5a , R 5b , R 5c , R 5d and R 5e are the same as the preferred embodiments of R 5 .
  • R 4 and / or R 5 includes a case selected from the following A) to D).
  • A) R i and R j bonded to the same carbon atom may be taken together to form a substituted or unsubstituted methylidene, or a substituted or unsubstituted C 2-6 alkylene. That is, A) includes a group in which —R 5 — is represented by the following formula.
  • R p and R q are each independently a hydrogen atom or a group selected from substituent group C1, and R ia -R ja is one or more selected from unsubstituted or substituent group D1a) C 2-6 alkylene substituted with a group.
  • R p and R q are preferably each independently a hydrogen atom, C 1-6 alkyl or haloC 1-6 alkyl.
  • R ia -R ja is preferably ethylene, unsubstituted or substituted with halogen.
  • R i and R i bonded to different carbon atoms may be combined to form a substituted or unsubstituted C 1-6 alkylene. That is, B) includes the case where a crosslinked structure is formed between any different R 5 and R 5 . “When a crosslinked structure is formed between any different R 5 and R 5 ” means, for example, when n is 3, But the following formula: (Wherein R ib is substituted or unsubstituted C 1-6 alkylene, and R jb1 and R jb2 each independently represent a hydrogen atom, a halogen atom, cyano, hydroxy, C 1-6 alkyl, halo C 1.
  • R 5a is —CR i R j — or —C ( ⁇ O) — And other symbols are as defined above.) The case where it is group shown by these is mentioned.
  • R ib is preferably C 1-3 alkylene which is unsubstituted or substituted with one or more groups selected from substituent group D1a.
  • R jb1 and R jb2 are preferably each independently a hydrogen atom, a halogen atom, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl or C 1-6 alkoxy, more preferably a hydrogen atom Or C 1-6 alkyl.
  • a preferred embodiment of R 5a is the same as the preferred embodiment of R 5 described above.
  • R i and R m may be taken together to form a substituted or unsubstituted C 1-6 alkylene. That is, C) includes a case where a crosslinked structure is formed between R 4 which is —NR m — and any R 5 .
  • R ic is a substituted or unsubstituted C 1-6 alkylene
  • R jc1 is a hydrogen atom, a halogen atom, cyano, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or C 1-6 alkoxy
  • R 5a and R 5b are each independently —CR i R j — or —C ( ⁇ O) —.
  • R ic is preferably C 1-3 alkylene which is unsubstituted or substituted with one or more groups selected from substituent group D1a.
  • R jc1 is preferably a hydrogen atom, a halogen atom, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl or C 1-6 alkoxy, more preferably a hydrogen atom or C 1-6 alkyl.
  • Preferred embodiments of R 5a and R 5b are the same as the preferred embodiments of R 5 described above.
  • R i and R a may be taken together to form a substituted or unsubstituted C 1-6 alkylene, and R b is a hydrogen atom. That is, D) includes a case where a crosslinked structure is formed between R 4 which is —CR a R b — and an arbitrary R 5 .
  • R 4 which is —CR a R b — and an arbitrary R 5
  • R id is a substituted or unsubstituted C 1-6 alkylene
  • R jd1 is a hydrogen atom, a halogen atom, cyano, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or C 1-6 alkoxy
  • R 5a and R 5b are each independently —CR i R j — or —C ( ⁇ O) —.
  • R id is preferably C 1-3 alkylene which is unsubstituted or substituted with one or more groups selected from substituent group D1a.
  • R jd1 is preferably a hydrogen atom, a halogen atom, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl or C 1-6 alkoxy, more preferably a hydrogen atom or C 1-6 alkyl.
  • Preferred embodiments of R 5a and R 5b are the same as the preferred embodiments of R 5 described above.
  • R 6 is preferably a compound independently of —O— or —CR k R 1 —.
  • m is preferably 2 or 3. More preferably 2.
  • R c is preferably C 1-6 alkyl which is unsubstituted or substituted with one or more groups selected from Substituent Group A1a.
  • R k and R l are preferably each independently a hydrogen atom, a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl or C 1-6 alkoxy, or, taken together are R k and R l are attached to the same carbon atom, a C 2-6 alkylene substituted with 1 or more groups selected from unsubstituted or substituent group D1a.
  • R k and R l are preferably each independently a hydrogen atom, a halogen atom, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, or the same carbon R k and R l bonded to an atom are C 2-4 alkylene, taken together or unsubstituted or substituted with one or more halogen atoms.
  • a compound in which X 1 is a group represented by —O—, —C ( ⁇ O) —, —CR k R 1 — or the formula: — (R 6 ) m — is preferable.
  • R 6a , R 6b and R 6c in the formula are each independently —O— or —CR k R l —.
  • X 1 is an oxygen atom, methylene which is unsubstituted or substituted with one or more halogen atoms, 1,2-ethylene which is unsubstituted or substituted with one or more halogen atoms, or unsubstituted or one or more halogens More preferred are compounds that are 1,3-propylene substituted with atoms, or 1,4-butylene unsubstituted or substituted with one or more halogen atoms. More preferred are compounds wherein X 1 is an oxygen atom, methylene, 1,2-ethylene, or 1,3-propylene.
  • R d is the same as the preferred embodiment of R 1 .
  • Z 1 , Z 2 and Z 3 are simultaneously C (R d ), or any one of Z 1 , Z 2 and Z 3 is a nitrogen atom, and the other symbols are C (R d ) Is preferred. More preferably, it is C (R d ) at the same time, or Z 1 or Z 2 is a nitrogen atom, and the other symbol is C (R d ).
  • Z 3 is preferably C (R d ), more preferably C (R d3 ).
  • R d3 is hydrogen atom, halogen atom, cyano, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkynyl, substituted or unsubstituted C 1-6 alkoxy, protected Optionally hydroxy or optionally protected carboxy.
  • Preferred R d3 is a hydrogen atom, a fluorine atom, a chlorine atom, a C 1-4 alkyl group which is unsubstituted or substituted with one or more halogen atoms, or a C 1 -1 which is unsubstituted or substituted with one or more halogen atoms. 4 alkoxy.
  • R d1 , R 2d and R d3 are each independently a hydrogen atom, a halogen atom, cyano, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkynyl, substituted Or unsubstituted C 1-6 alkoxy, optionally protected hydroxy or optionally protected carboxy.
  • R d1 and R d2 are the same as the preferred embodiments of R d3 above.
  • An antifungal agent means a substance that acts on a pathogenic fungus and has the ability to suppress or sterilize its growth. It may be something that suppresses fungal growth or kills some fungi to reduce their number.
  • pathogenic fungi examples include yeast-like fungi, filamentous fungi, zygomycetes, and the like.
  • yeast-like fungi examples include Candida genus (Candida albicans, Candida glabrata, Candida giermondii, Candida crusei, Candida parapsilosis, Candida tropicalis, etc.), Cryptococcus genus (such as Cryptococcus neoformans), Examples include the genus Malassezia (such as Malassezia fullfur) and the genus Trichosporon (such as Trichosporon and Asahi).
  • Aspergillus genus (Aspergillus fumigatus, Aspergillus tereus, Aspergillus niguel, Aspergillus flavus, etc.), Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonlances, etc.
  • Genus Fusarium such as Fusarium solani
  • genus Sedsporium such as Sedosporum / Apiospermum
  • microspores such as Microsporum canis.
  • the zygomycete examples include a genus Mucor (mucor, plumbeus, etc.), a genus Rhizopus (eg, Rhizopus oryzae), and a genus Absidia (eg, Absidia cholinebifera).
  • the antifungal agent of the present invention exhibits an excellent antifungal action against bacterial species such as Candida, Aspergillus, and Cryptococcus, and more excellent antifungal action against Aspergillus.
  • the antifungal agent of the present invention exhibits excellent antifungal activity against bacterial species such as Candida albicans, Aspergillus fumigatus, Aspergillus flavus and Cryptococcus neoformans.
  • the antifungal agent of the present invention exhibits excellent antifungal activity against various resistant bacteria.
  • the compound represented by the formula (I) or (I ′) or a pharmaceutically acceptable salt thereof exhibits excellent safety.
  • Safety is evaluated by various tests. For example, cytotoxicity test, HCA (High Content Assay) test, hERG test, repeated dose toxicity test, cytochrome P450 (CYP) activity inhibition test, metabolism-dependent inhibition test, Various safety tests selected from an in vivo mouse micronucleus test and an in vivo rat liver UDS test can be used.
  • Examples of the pharmaceutically acceptable salt of the compound represented by the formula (I) or (I ′) include a salt of a commonly known basic group such as an amino group or an acidic group such as hydroxyl or carboxyl. it can.
  • salts in basic groups include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Can be mentioned.
  • mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid
  • formic acid acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid
  • Salts with organic carboxylic acids
  • Salts in acidic groups include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And a salt thereof.
  • Preferred salts include pharmacologically acceptable salts.
  • the compound represented by the formula (I) or (I ′) of the present invention or a pharmaceutically acceptable salt thereof forms a solvate (for example, hydrate etc.), a co-crystal and / or a crystal polymorph.
  • the present invention also encompasses such various solvates, co-crystals and crystal polymorphs.
  • the “solvate” may be coordinated with any number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I) or (I ′).
  • solvent molecules for example, water molecules
  • a crystal polymorph may be formed by recrystallizing the compound represented by the formula (I) or (I ') or a pharmaceutically acceptable salt thereof.
  • “Co-crystal” means that the compound or salt represented by the formula (I) or (I ′) and the counter molecule are present in the same crystal lattice, and may be formed with any number of counter molecules. .
  • formulation adjuvants may be mixed as appropriate. These are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops, patches in accordance with conventional methods. It can be administered orally or parenterally in the form of an agent, ointment or injection. In addition, the administration method, the dose, and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. Usually, for adults, 0.01 to 1000 mg / kg is administered in 1 to several divided doses a day by oral or parenteral administration (eg, injection, infusion, and administration to the rectal site) do it.
  • the compound of the present invention is produced by combining methods known per se, and can be produced, for example, according to the production method shown below.
  • Step 1 Compounds represented by the formula [2] which can be synthesized by a known method (WO2013018735A1, WO2014119617A1) and a known method (Bioorganic & Medicinal Chemistry), 2000, Vol. 8, 1567-1577 and Tetra
  • the activator is not particularly limited as long as the above process can be efficiently advanced. Examples thereof include mercury (II) chloride and copper (II) chloride.
  • the activator may be used in an amount of 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, relative to the compound of the general formula [2].
  • the base is not particularly limited as long as it allows the above process to proceed efficiently.
  • triethylamine, pyridine, dimethylaminopyridine, diazabicycloundecene, 1,8-bis (dimethylamino) naphthalene, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned.
  • triethylamine is particularly preferred.
  • the amount of the base used may be 1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, relative to the compound of the general formula [2].
  • the amount of the compound of the general formula [3] used may be 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents relative to the compound of the general formula [2].
  • the reaction temperature is 0 to 200 ° C, preferably 20 to 100 ° C.
  • the reaction time is 10 minutes to 48 hours.
  • the reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently.
  • amide solvents eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, etc.
  • acetate solvents eg, ethyl acetate, Propyl acetate, etc.
  • hydrocarbon solvents eg, toluene, benzene, hexane, etc.
  • ether solvents eg, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, anisole, etc.
  • nitriles One or more selected from a solvent (eg, acetonitrile, propionitrile, etc.), a halogen solvent (eg, dichloromethane, chloroform, etc.), a ketone solvent (eg, acetone, methyl ethyl ketone, etc.), di
  • Step 2 Compound [1] can be obtained by subjecting compound [3] to a known general deprotection reaction of an amino protecting group.
  • Manufacturing method B (In the formula, each symbol is as defined above.)
  • Step 1 In this method, the compound represented by the formula [2] and the compound represented by the formula [6] are reacted in the presence of an activator to produce a compound represented by the formula [5].
  • the activator is not particularly limited as long as the above process can be efficiently advanced. For example, phosphorus trichloride, phosphorus pentachloride, phosphoryl chloride, diphosphorus pentoxide and the like can be mentioned. Particularly preferred is phosphoryl chloride.
  • the activator may be used in an amount of 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, relative to the compound of the general formula [2].
  • the amount of the compound of the general formula [6] used may be 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents relative to the compound of the general formula [2].
  • the reaction temperature is 0 to 200 ° C, preferably 20 to 150 ° C.
  • the reaction time is 10 minutes to 48 hours.
  • the reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently.
  • hydrocarbon solvents eg, toluene, benzene, hexane, etc.
  • ether solvents eg, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, anisole, etc.
  • halogen solvents eg, , Dichloromethane, chloroform, etc.
  • Step 2 Compound [1 ′] can be obtained by subjecting compound [5] to a known general deprotection reaction of an amino protecting group.
  • a compound that can take the form of a salt can also be used as a salt.
  • salts include the same salts as the pharmaceutically acceptable salts of the compounds represented by formula (I) or (I ′).
  • isomers for example, optical isomers, geometric isomers, tautomers and the like
  • these isomers can also be used.
  • solvates, hydrates and crystals of various shapes when solvates, hydrates and crystals of various shapes are present, these solvates, hydrates and crystals of various shapes can also be used.
  • a compound having a substituent that can be protected for example, amino, hydroxy, carboxy or the like, is protected in advance with a normal protecting group.
  • these protecting groups can be removed by a method known per se.
  • Manufacturing method C (Wherein, P 1 is an amino protecting group, and other symbols have the same meaning as defined above, P 1 is Protective Groups IN Organic Synthesis, protected by Theodora W Green (John Wiley & Sons ) The method according to such and / Or any group that can be deprotected, for example, P 1 is lower alkyloxycarbonyl or the like.)
  • This reaction may be carried out by the method described in Tetrahedron Letters, 1993, Vol. 34, 7777-7680, or the like, or a method analogous thereto.
  • Step 1 A compound represented by the formula [2] that can be synthesized by a known method (WO2013018735A1, WO2014119617A1, WO2014025962A1, etc.) and a known method (Bioorganic & Medicinal Chemistry), 2000, Vol. 8, 1567- 1577 and Tetrahedron Letters (2012, 53, 4532-4535, etc.) can be prepared by reacting a compound represented by the formula [4] with an activator in the presence of a base.
  • the activator is not particularly limited as long as the above process can be efficiently advanced. Examples include mercury (II) chloride and copper (II) chloride. Particularly preferred is mercury (II) chloride.
  • the activator may be used in an amount of 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, relative to the compound of the general formula [2].
  • the base is not particularly limited as long as it allows the above process to proceed efficiently.
  • triethylamine, pyridine, dimethylaminopyridine, diazabicycloundecene, 1,8-bis (dimethylamino) naphthalene, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned.
  • triethylamine is particularly preferred.
  • the amount of the base used may be 1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, relative to the compound of the general formula [2].
  • the amount of the compound of the general formula [3] used may be 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents relative to the compound of the general formula [2].
  • the reaction temperature is 0 to 200 ° C, preferably 20 to 100 ° C.
  • the reaction time is 10 minutes to 48 hours.
  • the reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently.
  • amide solvents eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, etc.
  • acetate solvents eg, ethyl acetate, Propyl acetate, etc.
  • hydrocarbon solvents eg, toluene, benzene, hexane, etc.
  • ether solvents eg, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, anisole, etc.
  • nitriles One or more selected from a solvent (eg, acetonitrile, propionitrile, etc.), a halogen solvent (eg, dichloromethane, chloroform, etc.), a ketone solvent (eg, acetone, methyl ethyl ketone, etc.), di
  • Step 2 Compound [1] can be obtained by subjecting compound [3] to a known general deprotection reaction of an amino protecting group.
  • the compound represented by the formula [2] and the compound represented by the formula [6] are reacted in the presence of an activator to produce a compound represented by the formula [5].
  • the activator is not particularly limited as long as the above process can be efficiently advanced.
  • phosphorus trichloride, phosphorus pentachloride, phosphoryl chloride, diphosphorus pentoxide and the like can be mentioned.
  • Particularly preferred is phosphoryl chloride.
  • the amount of the activator used may be 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, relative to the compound of the general formula [2].
  • the amount of the compound of the general formula [6] used may be 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents relative to the compound of the general formula [2].
  • the reaction temperature is 0 to 200 ° C., preferably 20 to 150 ° C.
  • the reaction time is 10 minutes to 48 hours.
  • the reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently.
  • hydrocarbon solvents eg, toluene, benzene, hexane, etc.
  • ether solvents eg, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, anisole, etc.
  • halogen solvents eg, , Dichloromethane, chloroform, etc.
  • Step 1 In this method, the compound represented by the formula [2] and the compound represented by the formula [8] are reacted in the presence of a base to produce a compound represented by the formula [7].
  • the base is not particularly limited as long as it allows the above process to proceed efficiently.
  • An inorganic base such as an organic base or an inorganic carbonate can be used.
  • triethylamine, pyridine, diazabicycloundecene, 1,8-bis (dimethylamino) naphthalene, diisopropylethylamine, N-methylmorpholine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, calcium carbonate and the like can be mentioned.
  • triethylamine and calcium carbonate are particularly preferred.
  • the amount of the base used may be 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, relative to the compound of the general formula [2].
  • the amount of the compound of the general formula [6] used may be 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents relative to the compound of the general formula [2].
  • the reaction temperature is 0 to 200 ° C, preferably 20 to 100 ° C.
  • the reaction time is 10 minutes to 48 hours.
  • the reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently.
  • hydrocarbon solvents eg, toluene, benzene, hexane, etc.
  • ether solvents eg, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, anisole, etc.
  • halogen solvents eg, , Dichloromethane, chloroform, etc.
  • water or the like can be used.
  • the solvent can be used as a two-layer solvent with water or a water-containing solvent as necessary.
  • Preferred is a two-layer solvent of an ether solvent, a halogen solvent and water.
  • Step 2 This is a method for producing a compound represented by the formula [9] by reacting a compound represented by the formula [7] with a compound represented by the formula [10].
  • the amount of the compound of general formula [10] used may be 1 to 20 molar equivalents, preferably 2 to 5 molar equivalents, relative to the compound of general formula [7].
  • the reaction temperature is 0 to 200 ° C, preferably 20 to 100 ° C.
  • the reaction time is 10 minutes to 48 hours.
  • the reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently.
  • amide solvents eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone
  • hydrocarbon solvents eg, toluene, benzene
  • ether solvents eg, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, anisole, etc.
  • nitrile solvents eg, acetonitrile, propionitrile, etc.
  • halogen solvents One or more selected from (eg, dichloromethane, chloroform, etc.), dimethyl sulfoxide and the like can be used.
  • An ether solvent is preferred.
  • Step 3 the compound represented by the formula [9] is produced by the activator of the compound represented by the formula [9] in the presence of a base.
  • the base is not particularly limited as long as it allows the above process to proceed efficiently.
  • triethylamine, pyridine, dimethylaminopyridine, diazabicycloundecene, 1,8-bis (dimethylamino) naphthalene, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned.
  • triethylamine is particularly preferred.
  • the amount of the base used may be 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, relative to the compound of the general formula [9].
  • the activator is not particularly limited as long as the above process can be efficiently advanced. Examples thereof include N, N′-dicyclohexylcarbodiimide, N, N′-diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and the like. Particularly preferred is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.
  • the amount of the activator used may be 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, relative to the compound of the general formula [9].
  • the reaction temperature is 0 to 200 ° C, preferably 20 to 100 ° C.
  • the reaction time is 10 minutes to 48 hours.
  • the reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently.
  • amide solvents eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone
  • hydrocarbon solvents eg, toluene, benzene) Hexane, etc.
  • ether solvents eg, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, anisole, etc.
  • nitrile solvents eg, acetonitrile, propionitrile, etc.
  • halogen solvents One or more selected from (eg, dichloromethane, chloroform, etc.), dimethyl sulfoxide and the like can be used.
  • An ether solvent is preferred.
  • Step 1 This is a method for producing a compound represented by the formula [11] by reacting a compound represented by the formula [7] with a compound represented by the formula [12] in the presence of a base.
  • the base is not particularly limited as long as it allows the above process to proceed efficiently.
  • triethylamine, pyridine, dimethylaminopyridine, diazabicycloundecene, 1,8-bis (dimethylamino) naphthalene, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned.
  • the amount of the base used may be 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, relative to the compound of the general formula [2].
  • the amount of the compound of the general formula [12] used may be 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents relative to the compound of the general formula [7].
  • the reaction temperature is 0 to 200 ° C, preferably 20 to 100 ° C.
  • the reaction time is 10 minutes to 48 hours.
  • the reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently.
  • hydrocarbon solvents eg, toluene, benzene, hexane, etc.
  • ether solvents eg, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, anisole, etc.
  • halogen solvents eg, , Dichloromethane, chloroform, etc.
  • An ether solvent is preferred.
  • Step 2 This is a method for producing a compound represented by the formula [13] from a compound represented by the formula [11] using an activator.
  • an activator mercury oxide or the like may be used.
  • the amount of the activator used may be 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, relative to the compound of the general formula [11].
  • the reaction temperature is 0 to 200 ° C, preferably 20 to 100 ° C.
  • the reaction time is 10 minutes to 48 hours.
  • the reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently.
  • hydrocarbon solvents eg, toluene, benzene, hexane, etc.
  • ether solvents eg, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, anisole, etc.
  • halogen solvents eg, , Dichloromethane, chloroform, etc.
  • An ether solvent is preferred.
  • the NMR analysis obtained in the examples was performed at 300 MHz or 400 MHz and measured using DMSO-d 6 , CDCl 3 or the like.
  • Measurement condition B Column: ACQUITY UPLC® BEH C18 (1.7 ⁇ m id 2.1 ⁇ 50 mm) (Waters) Flow rate: 0.8 mL / min PDA detection wavelength: 254 nm
  • Step 2 Synthesis of Compound I-001 4 mol / L hydrochloric acid in ethyl acetate (10 mL) was added to Compound 1b (212 mg) obtained in Step 1 and stirred at room temperature overnight.
  • the reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound I-001 (70 mg).
  • Step 2 Synthesis of Compound I-002 2-Pyrrolidone (0.049 mL, 0.648 mmol) was dissolved in toluene (2 mL), phosphorus oxychloride (0.039 mL, 0.421 mmol) was added, and the mixture was stirred at room temperature for 3 hours. .
  • Compound 2b 100 mg, 0.324 mmol was added to the reaction solution, and the mixture was stirred at 120 ° C. for 3 hours.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 2 Synthesis of Compound I-003
  • Compound 3b (84.0 mg, 0.205 mmol) was dissolved in tetrahydrofuran (4.2 mL) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (78.0 mg) was dissolved.
  • 0.409 mmol and triethylamine (0.057 mL, 0.409 mmol) were added and stirred at 70 ° C. for 3 hours.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 2 Synthesis of Compound 4c
  • Compound 4c was obtained in the same manner as in Step 1 of Example 3 using Compound 4b.
  • LCMS measurement condition A
  • MS MS (ESI) m / z: 277 (M + H + )
  • Step 3 Synthesis of Compound 4d
  • Compound 4d was obtained in the same manner as in Step 2 of Example 3 using Compound 4c.
  • Step 4 Synthesis of Compound 4e
  • Compound 4d (310 mg, 1.28 mmol) was charged with 4 mol / L ethyl acetate solution (4.97 mL, 19.9 mmol) and O, O-diethyl dithiophosphate (0.300 mL, 1.91 mmol). The mixture was further stirred for 18 hours. The resulting solid was collected by filtration to give compound 4e (393 mg, yield 98%) as a white solid.
  • Step 5 Synthesis of Compound I-004
  • Compound 4e (20.0 mg, 0.064 mmol) was dissolved in ethanol (0.4 mL), and 2-bromo-1- (5,6,7,8-tetrahydronaphthalene-2- Yl) ethanone (16.2 mg, 0.064 mmol) was added and stirred at room temperature for 16 hours.
  • Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform.
  • the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 2 Synthesis of Compound 5c
  • Compound 5c was obtained in the same manner as in Step 1 of Example 3 using Compound 5b.
  • Triphenylphosphine (24.1 mg, 0.092 mmol) and carbon tetrabromide (28.1 mg, 0.085 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (chloroform-methanol) to give compound I-005 (3.4 mg, yield 12%) as a white solid.
  • Step 2 Synthesis of Compound 8c
  • Compound 8c was obtained in the same manner as in Step 4 of Example 4 using Compound 8b.
  • 1 H-NMR (CDCl 3 ) ⁇ : 4.23 (s, 2H), 6.88 (s, 1H), 7.44 (s, 1H), 8.15 (s, 1H), 8.22 (s, 1H).
  • Step 3 Synthesis of Compound 8d
  • Compound 8d was obtained in the same manner as in Step 5 of Example 4 using Compound 8c.
  • Step 4 Synthesis of Compound 8e
  • Compound 8e was obtained in the same manner as in Step 1 of Example 2 using Compound 8d.
  • Step 5 Synthesis of Compound I-008
  • Compound I-008 was obtained in the same manner as in Step 2 of Example 2 using Compound 8e.
  • Step 2 Synthesis of Compound 9c
  • Compound 9c was obtained in the same manner as in Step 4 of Example 4 using Compound 9b.
  • Step 4 Synthesis of Compound 9e
  • Compound 9e was obtained in the same manner as in Step 1 of Example 2 using Compound 9d.
  • Step 5 Synthesis of Compound I-009
  • Compound I-009 was obtained in the same manner as in Step 2 of Example 2 using Compound 9e.
  • Step 2 Synthesis of Compound 10c
  • Compound 10c was obtained in the same manner as in Step 1 of Example 2 using Compound 10b.
  • Step 3 Synthesis of Compound 10d
  • Compound 10d was obtained in the same manner as in Step 1 of Example 1 using Compound 10c.
  • LCMS measurement condition A
  • MS MS (ESI) m / z: 592 (M + H + )
  • Step 4 Synthesis of Compound I-010
  • Compound I-010 was obtained in the same manner as in Step 2 of Example 1 using Compound 10d.
  • Step 2 Synthesis of Compound 11c
  • Compound 11b (3.83 g, 9.54 mmol) was dissolved in 1,2-dichloroethane (20 mL) and tert-butyldimethyl [(tributylstannyl) methoxy] silane (4.79 g, 11. 0 mmol) and dichlorobistriphenylphosphine palladium (670 mg, 0.954 mmol) were added, and the mixture was stirred for 6 hours with heating under reflux. After allowing to cool to room temperature, diethyl ether (60 mL) was added, and after ice cooling, saturated aqueous potassium fluoride (60 mL) was added, and the mixture was stirred for 10 min.
  • diethyl ether 60 mL
  • saturated aqueous potassium fluoride 60 mL
  • Step 3 Synthesis of Compound 11d
  • Compound 11c (1.48 g, 3.17 mmol) was dissolved in tetrahydrofuran (10 mL), 1 mol / L tetrabutylammonium fluoride tetrahydrofuran solution (6.34 mL, 6.34 mmol) was added at room temperature. Stir for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 4 Synthesis of Compound 11e
  • Compound 11d (972 mg, 2.76 mmol) was dissolved in methylene chloride (10 mL), and triethylamine (0.765 mL, 5.52 mmol) and methanesulfonyl chloride (0.322 mL, 4.76 mmol) were cooled with ice. 14 mmol) was added and stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 5 Synthesis of Compound 11f
  • Compound 11f was obtained in the same manner as in Step 4 of Example 4 using Compound 11e.
  • 1 H-NMR (DMSO-D 6 ) ⁇ : 1.98 (s, 3H), 2.22 (s, 3H), 3.63 (s, 2H), 5.43 (s, 2H), 7.05 (s, 1H), 9.04 (s , 1H), 9.42 (s, 1H).
  • Step 6 Synthesis of Compound I-011
  • Compound I-011 was obtained in the same manner as in Step 5 of Example 4, Step 1 and Step 2 of Example 1, using Compound 11f.
  • LCMS measurement condition A
  • MS MS (ESI) m / z: 392 (M + H + )
  • Step 2 Synthesis of Compound 12c
  • Compound 12b (1.59 g, 4.10 mmol) was dissolved in tetrahydrofuran (20 mL), and lithium aluminum hydride (93.0 mg, 2.46 mmol) was added under ice-cooling. Stir for hours. Sodium sulfate decahydrate and ethyl acetate were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. After removing insolubles, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain Compound 12c (989 mg, 67% yield).
  • Step 3 Synthesis of Compound 12d
  • Compound 12d was obtained in the same manner as in Step 4 of Example 11 using Compound 12c.
  • 1 H-NMR (CDCl 3 ) ⁇ : 1.42 (s, 18H), 3.82 (s, 2H), 7.84 (s, 1H), 8.38 (s, 1H).
  • Step 4 Synthesis of Compound 12e
  • Compound 12e was obtained in the same manner as in Step 4 of Example 4 using Compound 12d.
  • 1 H-NMR (DMSO-D 6 ) ⁇ : 3.62 (s, 2H), 6.16 (s, 2H), 7.54 (s, 1H), 7.83 (s, 1H), 9.31 (s, 1H), 9.46 (s , 1H).
  • Step 5 Synthesis of Compound 12f
  • Compound 12f was obtained in the same manner as in Step 5 of Example 4 using Compound 12e.
  • Step 6 Compound 12g Synthetic Compound 12f (69.0 mg, 0.218 mmol) was dissolved in methylene chloride (2 mL) and water (2 mL), and thiophosgene (0.033 mL, 0.437 mmol) and calcium carbonate (87.0 mg, 0.874 mmol) was added and stirred at room temperature for 1 day. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 7 Synthesis of Compound 12h
  • Compound 12h was obtained in the same manner as in Step 1 of Example 3 using 12 g of Compound 12h.
  • LCMS measurement condition A
  • MS MS (ESI) m / z: 432 (M + H + )
  • Step 8 Synthesis of Compound I-012
  • Compound I-012 was obtained in the same manner as in Step 2 of Example 3 using Compound 12h.
  • Step 5 Synthesis of Compound I-013
  • Compound I-013 was obtained in the same manner as in Step 3 of Example 4 using Compound 13e.
  • LCMS measurement condition A
  • MS MS (ESI) m / z: 376 (M + H + )
  • Step 2 Synthesis of Compound 14c
  • Compound 14c was obtained in the same manner as in Step 2 of Example 13 using Compound 14b.
  • Step 3 Synthesis of Compound 14d
  • Compound 14d was obtained in the same manner as in Step 1 of Example 1 using Compound 14c.
  • LCMS measurement condition A
  • MS MS (ESI) m / z: 594 (M + H + )
  • Step 4 Synthesis of Compound I-014
  • Compound I-014 was obtained in the same manner as in Step 2 of Example 1 using Compound 14d.
  • Step 2 Synthesis of Compound 15c
  • Compound 15b (1.28 g, 2.77 mmol) was dissolved in tetrahydrofuran (6.4 mL) and methanol (6.4 mL), and a 2 mol / L aqueous sodium hydroxide solution (2.77 mL, 5.55 mmol) was dissolved.
  • aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 3 Synthesis of Compound I-015
  • Compound 15c (50.0 mg, 0.119 mmol), naphthalen-2-ylmethanol (26.4 mg, 0.167 mmol) and triphenylphosphine (40.6 mg, 0.155 mmol) were mixed with tetrahydrofuran. (0.5 mL) was dissolved, diisopropyl azodicarboxylate (0.028 mL, 0.143 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 19 hours.
  • Triphenylphosphine (37.5 mg, 0.143 mmol) and diisopropyl azodicarboxylate (0.023 mL, 0.119 mmol) were added, and the mixture was stirred at room temperature for 2.5 hours.
  • Step 2 Synthesis of Compound 16c
  • Compound 16c was obtained in the same manner as in Step 1 of Example 2 using Compound 16b.
  • Step 3 Synthesis of Compound 16d
  • Compound 16d was obtained in the same manner as in Step 1 of Example 1 using Compound 16c.
  • LCMS measurement condition A
  • MS MS (ESI) m / z: 546 (M + H + )
  • Step 3 Synthesis of Compound 17d
  • Compound 17c (138 mg, 0.327 mmol) was dissolved in ethanol (1.38 mL) and tetrahydrofuran (0.69 mL), hydrazine monohydrate (0.018 mL, 0.360 mmol) was added, Stir at 80 ° C. for 4 hours. After removing insolubles, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate-chloroform) to obtain Compound 17d (51.7 mg, 54% yield) as a colorless oily substance.
  • Step 4 Synthesis of Compound 17e
  • Compound 17e was obtained in the same manner as in Step 1 of Example 4 using Compound 17d.
  • LCMS measurement condition A
  • MS MS (ESI) m / z: 334 (M + H + )
  • Step 5 Synthesis of Compound 17f
  • Compound 17f was obtained in the same manner as in Step 2 of Example 4 using Compound 17e.
  • LCMS measurement condition A
  • MS MS (ESI) m / z: 408 (M + H + )
  • Step 6 Synthesis of Compound I-017
  • Compound I-017 was obtained in the same manner as in Step 3 of Example 4 using Compound 17f.
  • Step 2 Synthesis of Compound 18c
  • Compound 18c was obtained in the same manner as in Step 1 of Example 2 using Compound 18b.
  • Step 3 Synthesis of Compound 18d
  • Compound 18d was obtained in the same manner as in Step 6 of Example 17 using Compound 18c.
  • Step 4 Synthesis of Compound 18e
  • Compound 18e was obtained in the same manner as in Step 1 of Example 3 using Compound 18d.
  • LCMS measurement condition A
  • MS MS (ESI) m / z: 407 (M + H + )
  • Step 5 Synthesis of Compound I-018
  • Compound I-018 was obtained in the same manner as in Step 2 of Example 3 using Compound 18e.
  • Step 3 Synthesis of Compound 1dd
  • Compound 1dd was obtained in the same manner as in Step 1 of Example 1 using 1 cc of compound.
  • LCMS measurement condition A
  • MS MS (ESI) m / z: 586 (M + H + )
  • Step 4 Synthesis of Compound II-003
  • Compound II-003 was obtained in the same manner as in Step 2 of Example 1 using Compound 1dd.
  • Step 4 Synthesis of Compound 2ee
  • Compound 2dd 50 mg, 0.13 mmol was dissolved in 1,4-dioxane (0.4 mL), and 4-methylphenylboronic acid (23 mg, 0.17 mmol), tetrakistriphenylphosphine (7 0.4 mg, 0.06 mmol) and a 2 mol / L aqueous sodium carbonate solution (0.19 mL, 0.39 mmol) were added, and the mixture was stirred at 95 ° C. for 10 hours. Water and chloroform were added to the reaction solution and stirred, followed by extraction with chloroform.
  • Step 5 Synthesis of Compound 2ff
  • Compound 2ff was obtained in the same manner as in Step 1 of Example 15 using Compound 2ee.
  • LCMS measurement condition A
  • MS MS (ESI) m / z: 302 (M + H + )
  • Step 6 Synthesis of Compound 2gg
  • Compound 2gg was obtained in the same manner as in Step 1 of Example 1 using Compound 2ff.
  • LCMS measurement condition A
  • MS MS (ESI) m / z: 584 (M + H + )
  • Step 7 Synthesis of Compound II-002
  • Compound II-002 (35 mg, 87%) was obtained in the same manner as in Step 2 of Example 1 using 2 gg of compound II.
  • Test Example 1 MIC Test Method The antifungal activity of the test substance was measured using a micro liquid dilution method recommended by the Clinical and Laboratory Standards Institute (CLSI).
  • Medium for measurement is minimal synthetic medium for yeast culture (2% glucose, 0.67% yeast nitrogen base w / o amino acid (YNB) and 0.2% amino acid / nucleotide mix) and morpholine propane sulfonic acid (MOPS, final concentration 50 mM) was added to make a buffer solution, and 1M sodium hydroxide was added to adjust the pH to 7.0 (YNB / MOPS).
  • test drug was serially diluted 2-fold with DMSO, and 2 ⁇ L was dispensed into each well of a 96-well microplate.
  • Candida albicans ATCC90028 cultured overnight at 35 ° C on Sabro-Agar medium was suspended in sterile physiological saline, turbidity was measured with a spectrophotometer, and the bacterial suspension was diluted with YNB / MOPS and inoculated A liquid (about 2.5 ⁇ 10 3 CFU / mL) was prepared.
  • Aspergillus flavus ATCC204304, IFM50915 and IFM52628, and Aspergillus fumigatus ATCC204305 and IFM47064 stored at ⁇ 80 ° C.
  • Candida albicans was cultured at 35 ° C for 1 day, and Aspergillus fumigatus and Aspergillus flavus were cultured at 35 ° C for 2 days, followed by MIC determination.
  • the MIC of Candida albicans was set to the minimum concentration that inhibits growth by 50% or more in turbidity compared to the control without addition of the test substance.
  • the MIC of Aspergillus fumigatus and Aspergillus flavus was set to the minimum concentration that visually inhibited growth by 100%.
  • the used strains are shown in Table 42.
  • Table 43 shows the MIC measurement results. In the table, all units of MIC are ⁇ g / mL.
  • Test Example 2 A homogeneous time-resolved fluorescence (HTRF) assay for measuring the inhibitory effect of the compound of the present invention on SMT Recombinant SMT of Aspergirus genus fungi was prepared according to a conventional method using Escherichia coli as a host (Arch Biochem Biophys. 1998 May 15; 353 (2): 297-311.). The enzyme activity of SMT was measured using an EPIgeneous TM Methyltransferase Assay kit (CisBio).
  • HTRF time-resolved fluorescence
  • Test Example 3 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively.
  • the degree to which the amount of metabolite produced was inhibited by the compound of the present invention was evaluated.
  • reaction conditions are as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points) .
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the centrifugation supernatant was quantified with a fluorescent multi-label counter
  • tolbutamide hydroxide CYP2C9 metabolite
  • mephenytoin 4 ′ hydroxide CYP2C19 metabolite
  • Dextrorphan CYP2D6 metabolite
  • terfenadine alcohol CYP3A4 metabolite
  • the residual activity (%) at each concentration of the compound of the present invention added to the solvent was calculated by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the concentration and inhibition rate were calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model.
  • Intravenous administration was carried out from the tail vein using a syringe with an injection needle.
  • the bioavailability (BA) of the compound of the present invention was calculated from the AUC of the group.
  • the compound of the present invention in the centrifugal supernatant was quantified by LC / MS / MS, and the residual amount of the compound of the present invention after the reaction was calculated with the compound amount at 0 minute reaction as 100%.
  • the hydrolysis reaction can be carried out in the absence of NADPH, the glucuronic acid conjugation reaction can be carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same operation can be carried out thereafter.
  • CYP3A4 (MDZ) MBI Test This test evaluates the mechanism based inhibition (MBI) ability from the enhancement by metabolic reaction regarding CYP3A4 inhibition of the compounds of the present invention. Pooled human liver microsomes were used to evaluate CYP3A4 inhibition using midazolam (MDZ) 1-hydroxylation as an indicator.
  • the reaction conditions are as follows: substrate, 10 ⁇ mol / L MDZ; pre-reaction time, 0 or 30 minutes; reaction time, 2 minutes; reaction temperature, 37 ° C .; pooled human liver microsomes, pre-reaction 0.5 mg / mL, reaction time 0.05 mg / mL (when diluted 10-fold); concentration during pre-reaction of the compound of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points) Pooled human liver microsomes and the compound solution of the present invention were added to a 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition, and the substrate and K-Pi buffer were added to another 96-well plate.
  • K-Pi buffer pH 7.4
  • a part of the solution was transferred so that the solution was diluted to 1/10, and a reaction using NADPH as a coenzyme was started as an index (no pre-reaction).
  • methanol / acetonitrile 1
  • the reaction was stopped by adding a 1/1 (V / V) solution.
  • NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer. The reaction was started by shifting the part.
  • IC value at start of pre-reaction / IC value 30 minutes after start of pre-reaction is referred to as a Shifted IC value, when Shifted IC is 1.5 or more (+), and when Shifted IC is 1.0 or less. (-).
  • Test Example 7 Fluctuation Ames Test The mutagenicity of the compound of the present invention is evaluated. 20 ⁇ L of Salmonella typhimurium TA98 strain, TA100 strain, which has been cryopreserved, is inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For TA98 strain, 9 mL of the bacterial solution is centrifuged (2000 ⁇ g, 10 minutes) to remove the culture solution.
  • Micro F buffer K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0.
  • MicroF containing 110 mL Exposure medium Biotin: 8 ⁇ g / mL, Histidine: 0.2 ⁇ g / mL, Glucose: 8 mg / mL) suspended in 25 g / L, MgSO 4 ⁇ 7H 2 0: 0.1 g / L) Buffer).
  • the TA100 strain is added to 120 mL of Exposure medium with respect to the 3.16 mL bacterial solution to prepare a test bacterial solution.
  • Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 ⁇ g / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 ⁇ g / mL 2-aminoanthracene DMSO solution for the strain and 20 ⁇ g / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 ⁇ L of the test bacterial solution (498 ⁇ L of the test bacterial solution and S9 under metabolic activation conditions).
  • Test Example 8 For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, it is important for ventricular repolarization process using CHO cells expressing human ether-a-go-go related gene (hERG) channel The action of the compounds of the present invention on the delayed rectifier K + current (I Kr ), which plays an important role, was investigated.
  • the cell was held at a membrane potential of ⁇ 80 mV by a whole cell patch clamp method, and after applying a leak potential of ⁇ 50 mV, a depolarization stimulus of +20 mV for 2 seconds, and further records the I Kr induced repolarization stimulation of -50mV when given 2 seconds.
  • an extracellular solution NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl 2 : 2 mmol / L, MgCl 2 : 1 mmol
  • an extracellular solution NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl 2 : 2 mmol / L, MgCl 2 : 1 mmol
  • the absolute value of the maximum tail current was measured from the obtained I Kr based on the current value at the holding membrane potential.
  • the inhibition rate with respect to the maximum tail current before application of the compound of the present invention was calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I Kr was evaluated.
  • Test Example 9 Solubility test The solubility of the compound of the present invention was determined under the condition of addition of 1% DMSO. Prepare a 10 mmol / L compound solution in DMSO, and add 2 ⁇ L of the compound solution of the present invention to JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid to make 1000 mL), JP-2 solution (hereinafter referred to as “1”). Any of A, B, and C. A: About 200 mL of 0.2N sodium hydroxide reagent solution is added to 200 mL of 0.2 mol / L potassium dihydrogen phosphate reagent solution to adjust pH to 6.8, and then 600 mL of water is added.
  • SPE solid phase extraction
  • Test Example 10 Powder solubility test An appropriate amount of the compound of the present invention is placed in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid is added to 1000 mL) and JP-2 solution are added to each container. (Add 500 mL of water to 500 mL of phosphate buffer solution at pH 6.8), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution is added to 1.08 g of TCA to make 100 mL) 200 ⁇ L each Added. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C.
  • the compound of the present invention is quantified using HPLC by the absolute calibration curve method.
  • Test Example 11 About 5 mg of visual solubility test compound is weighed into three microscopic test tubes, and each medium (water for injection, saline feed, 0.5% glucose solution) is added to a compound concentration of 20%. After stirring by vortex, visually check for dissolution. If so, the solubility in the medium is> 20%. Each medium (water for injection, raw food injection, glucose solution) is further added to these test solutions to prepare a test solution with a compound concentration of 10%. After stirring by vortexing, the presence or absence of dissolution is visually confirmed. If dissolved, the solubility in the medium should be 20% to 10%. Similarly, test to 5% concentration, 2.5% concentration, 1% concentration, and if not soluble at 1% concentration, the solubility in the medium should be ⁇ 1%. Measure and record the pH with 1% test solution.
  • Test Example 12 pKa measurement (capillary electrophoresis method (capillary electrophoresis method, CE method) measurement method) This is a separation method using capillary zone electrophoresis technology and free migration of each sample component in a buffer solution containing an electrolyte. After injecting a compound solution into a fused silica capillary filled with a buffer solution adjusted to pH 2.5 to 11.5 and then applying a high voltage (Inlet side +, Outlet side-) to the capillary, the compound is at the buffer pH. It moves at a speed that reflects the ionization state (+ charged compounds are fast, -charged compounds are slow).
  • Test Example 12 Ames test The mutagenicity of the compound of the present invention is evaluated by the Ames test using Salmonella typhimurium TA98 strain, TA100 strain, TA1535 strain, TA1537 strain and Escherichia coli WP2uvrA strain as test strains.
  • Salmonella typhimurium TA98 strain, TA100 strain, TA1535 strain, TA1537 strain and Escherichia coli WP2uvrA strain as test strains.
  • a DMSO solution of the compound of the present invention 0.5 mL of S9mix is mixed under metabolic activation conditions, and 0.5 mL of a phosphate buffer solution and 0.1 mL of a test bacterial solution are mixed under non-metabolic activation conditions, and histidine and biotin are mixed.
  • Formulation Examples are merely illustrative and are not intended to limit the scope of the invention.
  • Formulation Example 1 Tablet A compound of the present invention, lactose and calcium stearate are mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
  • Formulation Example 2 Capsule The compound of the present invention, lactose and calcium stearate are uniformly mixed to form a powder as a powder or fine granules. It is filled into a capsule container to form a capsule.
  • Formulation Example 3 Granules The compound of the present invention, lactose and calcium stearate are uniformly mixed, compression-molded, pulverized, sized and sieved to give granules of an appropriate size.
  • Formulation Example 4 Orally disintegrating tablet The compound of the present invention and crystalline cellulose are mixed and tableted after granulation to obtain an orally disintegrating tablet.
  • Formulation Example 5 Dry syrup The compound of the present invention and lactose are mixed, pulverized, sized and sieved to obtain a dry syrup of an appropriate size.
  • Formulation Example 6 Injection The compound of the present invention and a phosphate buffer are mixed to form an injection.
  • Formulation Example 7 Instillation A compound of the present invention and a phosphate buffer are mixed to form an instillation.
  • Formulation Example 8 Inhalant The compound of the present invention and lactose are mixed and finely pulverized to make an inhalant.
  • Formulation Example 9 Ointment The compound of the present invention and petrolatum are mixed to form an ointment.
  • Formulation Example 10 Patch A compound of the present invention and a base such as an adhesive plaster are mixed to obtain a patch.
  • the compound represented by the formula (I) or (I ′), or a pharmaceutically acceptable salt thereof is useful as an antifungal agent because it has excellent SMT inhibitory activity and further has excellent antifungal activity. is there.
  • the compound represented by the formula (I) or (I ′), or a pharmaceutically acceptable salt thereof is excellent in safety and is used as an antifungal agent against Candida and Alpergillus. Useful.

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Abstract

L'invention concerne un composé représenté par la formule générale (I), dans laquelle n représente un nombre entier de 2 à 5 ; R1 représente un atome d'hydrogène, un atome d'halogène, un groupe cyano, un groupe nitro, un groupe alkyle en C1 à 6 substitué ou non substitué, ou similaire ; R3 représente un groupe phényle substitué ou non substitué, un groupe hétérocyclique aromatique azoté monocyclique substitué ou non substitué, ou similaire ; R4 représente -NRm- ou -CRaRb- ; R5 représentent indépendamment -CRiRj- ou -C (=O)- ; X1 représente -O-, -S-, -C(= O)-, -NRc-, -CRkRl- ou similaire ; et Z1, Z2 et Z3 représentent indépendamment un atome d'azote ou C(Rd) ; ou un sel pharmaceutiquement acceptable de celui-ci, utile en tant qu'agent anti-fongique.
PCT/JP2015/076443 2014-09-19 2015-09-17 Composé d'amidine ou de guanidine cyclique WO2016043260A1 (fr)

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CN108440414A (zh) * 2018-05-16 2018-08-24 中国人民解放军第二军医大学 吡唑酮酰胺类抗真菌药物及其制备方法和应用

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